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Green Chemistry in the Synthesis of Pharmaceuticals

Supratik Kar, Hans Sanderson, Kunal Roy, Emilio Benfenati, and Jerzy Leszczynski*

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ABSTRACT: The principles of green chemistry (GC) can be comprehensively

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implemented in green synthesis of pharmaceuticals by choosing no solvents or green

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solvents (preferably water), alternative reaction media, and consideration of one-pot

synthesis, multicomponent reactions (MCRs), continuous processing, and process
intensification approaches for atom economy and final waste reduction. The GC’s execution
in green synthesis can be performed using a holistic design of the active pharmaceutical
ingredient’s (API) life cycle, minimizing hazards and pollution, and capitalizing the resource
efficiency in the synthesis technique. Thus, the presented review accounts for the
comprehensive exploration of GC’s principles and metrics, an appropriate implication of
those ideas in each step of the reaction schemes, from raw material to an intermediate to the final product’s synthesis, and the final
execution of the synthesis into scalable industry-based production. For real-life examples, we have discussed the synthesis of a series
of established generic pharmaceuticals, starting with the raw materials, and the intermediates of the corresponding pharmaceuticals.
Researchers and industries have thoughtfully instigated a green synthesis process to control the atom economy and waste reduction
to protect the environment. We have extensively discussed significant reactions relevant for green synthesis, one-pot cascade
synthesis, MCRs, continuous processing, and process intensification, which may contribute to the future of green and sustainable
synthesis of APIs.

CONTENTS 5. Frequently Used Chemical Reactions Relevant to

the Green Synthesis and GC 3647
1. Introduction 3638 5.1. C−H Activation 3647
2. Green Chemistry (GC) 3639 5.2. Asymmetric Hydrogenation 3649
2.1. Definition 3639 5.3. Oxidations 3650
2.2. The Principles of GC 3641 5.4. Reductions 3652
2.3. The Metrics of GC 3641 5.5. Amide Bond 3653
2.3.1. Standardization of the E Factor Concept 3641 5.6. Alcohol Activation for Nucleophilic Displace-
2.3.2. Baran’s Process Ideality Metric 3641 ment 3655
2.3.3. Identification of Process Complexity 3641 5.7. Metal-Catalyzed Cross-Coupling 3657
2.3.4. The Green Aspiration Level Concept 3642 5.8. Organocatalysis 3658
2.3.5. Innovation Green Aspiration Level 5.9. Biocatalysis 3660
(iGAL) 3642 6. One-Pot Cascade Synthesis 3662
3. The Choice of Solvents in the Green Synthesis of 7. Multicomponent Reactions for Green and Sus-
APIs 3642 tainable Synthesis 3666
4. The Reaction with Green Solvents 3643 7.1. The Biginelli Reaction 3667
4.1. The No-Solvent Process 3644 7.2. The Strecker Reaction 3668
4.2. Water 3644 7.3. The Mannich Reaction 3668
4.2.1. Water in the Phase-Transfer Catalysis 7.4. The Passerini Reaction 3668
(PTC) 3645 7.5. The Ugi Reaction 3669
4.2.2. Water as a Solvent and under Microwave 7.6. The Hantzsch Reaction 3670
Irradiation (MWI) Conditions 3645
4.2.3. Water as a Solvent under Ultrasound-
Accelerated Conditions 3646 Received: July 15, 2021
4.3. Aqueous Biphasic Catalysis 3647 Published: December 15, 2021
4.3.1. Aqueous Biphasic Oxidation 3647
4.3.2. Aqueous Biphasic Carbonylation 3647
4.3.3. Aqueous Biphasic Hydroformylation 3647

© 2021 American Chemical Society https://doi.org/10.1021/acs.chemrev.1c00631

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7.7. The Petasis Reaction 3670 10.7. (1S,2R)-2-(Methoxycarbonyl)cyclohex-ene-

7.8. The Kabachnik−Fields Reaction 3671 1-carboxylic Acid for Chemokine Receptor
7.9. The Bucherer−Bergs Reaction 3671 Modulators 3697
7.10. The Gewald Reaction 3672 10.8. Chiral Monoacetate Esters for Baraclude 3698
8. The Green Synthesis of APIs 3672 11. The Role of Continuous Processing and Process
8.1. Ibuprofen 3672 Intensification in GC 3698
8.2. Sertraline 3674 12. Overview, Conclusions, and Future Aspects 3700
8.3. Artemisinin 3675 Author Information 3701
8.4. Sildenafil Citrate 3676 Corresponding Author 3701
8.5. Atorvastatin 3678 Authors 3701
8.6. Paroxetine 3678 Notes 3701
8.7. Sitagliptin 3678 Biographies 3701
8.8. Levetiracetam 3679 Acknowledgments 3701
8.9. Pregabalin 3681 References 3702
8.10. β-Lactam Antibiotics 3681
8.11. Aprepitant 3683
8.12. Imatinib 3684 1. INTRODUCTION
8.13. Paclitaxel 3684 The revolutionary idea of alternative synthetic reaction schemes
8.14. Simvastatin 3685 to control environmental hazards and pollution, which were the
8.15. Celecoxib 3686 result of the traditional synthesis route, was first conceptualized
8.16. Clopidogrel Bisulfate 3688 by Paul Anastas and Roger Garrett in 1991 and later termed
8.17. Quinapril 3689 “green chemistry (GC)” by Joe Breen.1 This idea was
8.18. Valsartan 3690 popularized with the 1995 Presidential Green Chemistry
8.19. LY300164 3690 Challenge (PGCC) to endorse hazard-free and economically
8.20. ABT-546 3690 competitive chemical synthesis and is primarily followed by
9. The Green Synthesis of Starting Raw Materials of major pharmaceutical industries in the United States. The idea
APIs 3691 of GC became more effective with the introduction of the 12
9.1. Ketal Ester for Oseltamivir Phosphate 3691 principles of GC by Anastas and Warner.2 In the last two
9.2. (S)-N-BOC-3-Hydroxyadamantylglycine for decades, many pharmaceutical industries have tried to practice
Saxagliptin 3692 GC by employing green drug design followed by green synthesis
9.3. (S)-tert-Leucine for Atazanavir, Boceprevir, for selective pharmaceuticals wherever possible logistically, as
and Telaprevir 3692 strongly suggested by the United States Environmental
9.4. Allysine Ethylene Acetal for Vanlev 3692 Protection Agency (US EPA) ‘The Presidential Green
9.5. Dihydrodiols for Indinavir (Crixivan) 3692 Chemistry Challenge Awards Program’.3 A recent report
9.6. (R)-3-(4-Fluorophenyl)-2-hydroxy Propionic predicted that the global market of GC is increasing
Acid for Rhinovirus Protease Inhibitor Rupin- exponentially. As per a recent report, it hit $98.5 billion by the
trivir (AG7088) 3693 end of 2020.4 The execution of GC is one of the reasons for the
9.7. (R)-Phenylacetyl Carbinol for Ephedrine 3694 reduced amount of chemical waste released into the environ-
9.8. (S)-3-(3,4-Dichlorophenyl)-5-ethoxy-5-oxo- ment. However, the synthesis of chemicals has increased over
pentanoic Acid for NK1/NK2 Dual Antago- the years.5 Since the inception of GC, the US EPA policies and
nists 3694 the Registration, Evaluation, Authorization and Restriction of
9.9. Nitroalkanes for Tamsulosin and Selegiline 3695 Chemicals (REACH) legislations under European Union’s
10. The Green Synthesis of Key Intermediates of regulation have been advocating for GC principles as well as
APIs 3695 playing an integral role in the implementation of those ideas.6 In
10.1. (1S,2R)-[3-Chloro-2-hydroxy-1- October 2020, the European Union, as the second largest
(phenylmethyl)propyl]carbamic acid, 1,1- chemical producer in the world with 17% of global production,
Dimethylethyl Ester for Atazanavir 3695 proposed a bold new strategy for sustainable chemicals,
10.2. N-Acetylneuraminic Acid for Zanamivir including active pharmaceutical ingredients (APIs), toward a
(Relenza) 3696 zero-pollution and toxic-free environment as part of the Green
10.3. (3S,5R)-Dihydroxy-6-(benzyloxy) Hexanoic Deal in Europe.7 The strategy implies a public−private
Acid, Ethyl Ester for Statins (Anticholesterol partnership and includes boosting the investment and
Drugs) 3696 innovative capacity for production and use of safe and
10.4. (S)-2-[3,2[7-Chloro-2-quinolinyl]ethenyl]- sustainable chemicals by design and throughout their life cycle.8
phenyl-3-hydroxypropyl]benzoic Acid, The synthesis of raw materials, intermediates, and APIs
Methyl Ester for Montelukast 3696 generates substantial waste byproducts and hazardous con-
10.5. The Enzymatic Preparation of (R)-Allylic taminants in the form of adulterated and toxic solvents, reagents,
Alcohol for an Integrin Receptor Antagonist 3696 and contaminated gas.9 Pharmaceutical industries generate
10.6. (1R,4S)-2-Azabicyclo[2.2.1]hept-5-en-3-one more waste per unit product and byproducts compared to any
and (1R,4S)-tert-Butyl 3-Oxo-2- oil refining, bulk, and fine chemical industries. However, each
azabicyclo[2.2.1]hept-5-ene-2-carboxylate pharmaceutical product is orders of magnitude more compli-
for Synthesis of Abacavir 3697 cated than output from the chemical or petroleum industry.9
GlaxoSmithKline (GSK) reported that a complete life cycle
analysis of APIs assessed that 80% of their waste is solvent-
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related.10 If this is the trend for all other pharmaceutical
industries, then addressing the issue of selection, recovery, and
recycling of solvents followed by legalized disposal of solvents
may control the environmental hazards and directly and
indirectly reduce the toxicity to the animal kingdom.11
Therefore, GC has an immense role to play in the green
synthesis of pharmaceuticals. As per the report from the US
EPA’s Toxics Release Inventory (TRI), there was a sharp
decrease of chemical waste release into the environment by 7%
between 2004 and 2013.5 The reported data showed a 60%
decrease in the release of chemicals like trichloroethylene,
hydrochloric acid, and methyl isobutyl ketone due to the
implementation of the GC principles in the synthesis of
pharmaceuticals.
With the increasing emphasis on GC, there are multiple
emerging areas of research, including the development of green
solvents,12−14 water15−17 and solventless or no-media-involved
reactions,18−20 as well as reaction media in the form of aqueous
biphasic catalysis.21 Therefore, a series of orthodox and old-age
synthesis routes of traditional drugs are changing due to
incorporating the idea of green solvents.22 Biobased building
blocks generated from renewable resources can be a sustainable
substitute to traditional petrochemical-derived solvents.23,24
Additionally, to be of value to GC, scientists designing the
reaction routes may consider reaction mechanisms like C−H
activation, metal-catalyzed cross-coupling, alcohol activation for
nucleophilic displacement, biocatalysis, organocatalysis,
etc.25−29 The principles of GC in green synthesis can be used
in the following manner:
(a) The efficient utilization of raw materials (preferably 100%
recycled solvents) in the synthesis process, which can
nullify or stop unnecessary waste formation.30,31
(b) The use of biobased building blocks most of which are
self-degrading in nature.32
(c) The designing of synthetic methods where all of the input
materials can be used in the process to prepare the final
material, which means creating a theoretical 100% atom
economy process.33,34
(d) If possible and practicable, the use of green or safer raw
materials as solvents (water as a solvent, green
solvents)11−21 and enzymes as biocatalysts,22,23 which
will generate nontoxic and/or low-toxicity materials
having minimal impact on humans as well as the
environment.35,36
(e) The consideration of multicomponent reactions
(MCRs)37−39 and one-pot cascade synthesis40−42 to
minimize the reaction steps, followed by purification of
the APIs and ultimately reducing waste and gaining atom
economy.
(f) The implication of continuous processing/engineer-
ing43−45 for fast reaction screening and optimization is
critical in green synthesis. Additionally, in-line reaction
analysis with improved automation and modernization of
new hybrid equipment by scrapping traditional reactions
and operation units for high reactor yield productivity and
highly pure products can be achieved through the process
intensification.46 To support the green synthesis of
pharmaceuticals, continuous processing techniques are
progressively being applied to decrease the amount of raw
material and energy utilized in a process while
maintaining the real-time analysis, control, and aug-
mented safety process. Along with the continuous
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process, flow chemistry and techniques can be used to
swiftly search a multidimensional reaction space to
upgrade the reaction process design, implementation,
and efficiency.45 The flow-screening platform is another
important aspect for time and material efficiency to scale
up the whole process. Therefore, flow chemistry is
another area necessary to explore for the green synthesis
of pharmaceuticals in upcoming days.45
(g) If waste is generated, proper treatment and disposal of
those wastes after eliminating the major toxic response of
those wastes.47,48
The US EPA announced a decision to reduce around 30% of
mammal study by 2025 and a complete eradication of all
mammal study requests and funding by 2035.49 Consideration
of the idea of the 3R’s approach of reduction, replacement, and
refinement of animal study as per Directive 2010/63/EU of the
European Parliament and of the Council50 followed by the
present decision of the US EPA take us to the upcoming years of
computerized molecular modeling. Campos et al.51 reported
that multiple approaches, such as reaction pathway prediction,
catalyst preparation to control cycloisomerization reaction,
optimization of ligands with enhanced selectivity and rate over
the existing ligand, forward reaction prediction, and prediction
of the performance of Buchwald−Hartwig amination reaction,
can be solved by machine-learning techniques. Therefore, the
implication of in silico approaches through biobased trans-
formations and materials, the next-generation green catalyst
design, molecular editing, and molecular design for reduced
hazard is the future of green synthesis through GC.52
Considering the utmost importance of the green synthesis
process, the present review will cover the areas where GC can be
used to decrease the environmental hazards, followed by
intelligent risk management. The primary goal of the
pharmaceutical industry is to reduce the E factor (mass ratio
of waste to final product), which is an essential indicator of the
environmental acceptability of a synthesis process. Over the
years, several reviews have been published on the specific topic
of GC and green synthesis. Still, there is a lack of a
comprehensive review considering the aspects of GC and its
implication and execution in the green and sustainable synthesis
of pharmaceuticals. This review starts with understanding GC
and its metrics to choose green solvents, alternative reaction
media, a major reaction mechanism of interest to GC, a one-pot
cascade synthesis, and MCRs for green and sustainable
synthesis. It also covers continuous processing and process
intensification engineering, followed by the implication of those
ideas for the green synthesis of multiple popular generic drugs,
from raw materials to major intermediates and APIs. The
discussed areas are thoroughly explained in detail to achieve a
better atom economy (% ratio of mass of wanted product(s) and
total mass of products) for sustainable product development.
2. GREEN CHEMISTRY (GC)
2.1. Definition
The US EPA has defined GC as the following: “Green chemistry is
the design of chemical products and processes that reduce or
eliminate the use or generation of hazardous substances. Green
chemistry applies across the life cycle of a chemical product, including
its design, manufacture, use, and ultimate disposal. Green chemistry
is also known as sustainable chemistry.”2 The idea of GC deals
with the management of toxicity from an enormous number of
chemicals used in day-to-day life as well as with waste reduction,
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Figure 1. Fundamental idea of sustainable and green chemistry.

Table 1. Commonly Employed Efficiency Metrics under GC

metric formula measure unit optimum value
Total mass of waste
environmental factor (E factor) E= kg kg−1 0
Mass of final product
Molecular weight of final product
atom economy (AE) AE (%) = × 100 % 100%
Sum of molecular weight of all reactants
Mass of product × Molecular weight of raw materials × 100
chemical yield (CY) CY (%) = % 100%
Mass of raw materials × Molecular weight of product
Total mass in process
mass intensity (MI) MI = kg kg−1 1
Mass of product
Total mass in process (including water)
process mass intensity (PMI) PMI = kg kg−1 1
Mass of product
Mass of product × 100
process mass efficiency (PME) PME = % 100%
Total mass of input materials including process water
Mass of process water
waste water intensity (WWI) WWI = kg kg−1 0
Mass of product
Mass of solvents
solvent intensity (SI) SI = kg kg−1 0
Mass of product
Total mass of raw materials + Total mass of reagents
reaction mass intensity (RMI) RMI = kg kg−1 1
Mass of product
Mass of product × 100
reaction mass efficiency (RME) RME (%) = % 100%
Total mass of reactants
Mass of product × 100
mass productivity (MP) MP (%) = % 100%
Total mass (including solvents)
Mass of product
effective mass yield (EMY) EMY (%) = % 100%
Mass of hazardus reactants
Carbon in product × 100
carbon economy (CE) CE (%) = % 100%
Total carbon in reactants

energy conservation, use of more renewable or sustainable including APIs.2 The noteworthy objectives of GC are the
feedstocks, and creation of chemicals benign by design, following:
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• The use of renewable, biodegradable materials that do not
persist in the environment.
• In synthesis, the implication of catalysis and biocatalysis
to enhance the efficiency and performance of the
reactions at ambient temperatures.
• The design of biodegradable chemical products, such as
pharmaceuticals, and processes to reduce their inherent
toxicity.
• A proven systematic and strategic approach to build a
sustainable future by generating reduced hazardous
substances to the environment directly from the source.
• Applicability of GC not only to chemistry but to all fields
of science.
2.2. The Principles of GC
Over the last two decades, GC has emerged as one of the most
prominent options for pharmaceutical synthesis, followed by
environmental risk management. From design to synthesis and
from recycling to disposal, GC can be employed to better the
living system and the environment. Regulatory agencies, federal
and state governments, and scientific societies do not doubt its
considerable advantage. Anastas and Warner summarized GC
into 12 principles that are pillars for a sustainable environment.2
Figure 1 reports the schematic idea of how GC is effective in
capitalizing on resource efficiency, reducing pollution and
hazardous substances at the molecular level, and designing
benign chemicals effectively.2,53
2.3. The Metrics of GC
A series of metrics were invented to measure the greenness and
compare diverse synthetic routes of a specific product.31,33,54
Two oldest but simple and most effective metrics are the E factor
(E) and the atom economy (AE). The E factor can be defined as
the ratio of the total mass of waste and the mass of the final
product, while AE describes the conversion efficiency of a
chemical process in terms of all atoms involved and the desired
products (here, the final API). The E factor can be applied in a
multistep reaction, thus offering an all-inclusive assessment of
the complete process. On the other hand, AE is generally
employed in individual steps. However, the most crucial feature
of AE is that it can be implemented without experimentation.
Thus, the AE metric can be used to predict and assess the
amounts of waste generated in diverse alternative routes to a
specific compound. Ideally, the value of AE should be 100%. On
the other hand, if the E factor is high, then the reaction generates
a large amount of waste; if it is low, then, the reaction generates
limited waste and hazards. The ideal value of E should be zero.
With the advancement and broad application of GC in the green
synthesis process, a series of mass-based metrics55 have been
proposed to measure the greenness of operations, and these can
be found in Table 1. In a broader perspective, these mass metrics
can be classified into two groups. The kg/kg analogous ones
[mass intensity (MI), waste water intensity (WWI), process
mass intensity (PMI), and solvent intensity (SI)] are related to
the E factor. In contrast, metrics associated with the percentage
of the ideal analogous ones [mass productivity (MP), reaction
mass efficiency (RME), effective mass yield (EMY), carbon
economy (CE)] can be categorized under AE. 33 The
mathematical formulas of classical and mass-based metrics are
illustrated in Table 1.55
Interestingly, many of the mentioned GC efficiency metrics in
Table 1 define similar ideas without universal and/or stand-
ardized acceptance among industries. Roschangar et al.56
proposed to standardize the definition, nomenclature, and
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algorithm of these existing metrics and introduced a set of novel
concepts of a quantitative GC aspiration level supported by
series of new metrics to define the GC process.
2.3.1. Standardization of the E Factor Concept.
Roschangar et al.56 proposed two new E factor metrics, namely,
complete E factor (cEF) and simple E factor (sEF). The cEF
metric considers all process materials involved in a chemical
reaction, including raw materials, solvents, reagents, water, and
final product suitable for the complete process waste stream
analysis. On the contrary, the sEF metric does not consider
water and solvents, which is why it is applicable to the early
development phase of the synthesis route activities. The cEF
does not reflect the degree at which the process water and
solvents will be recycled in due course across the entire process.
Thus, the “true” commercial E factor can be a value between sEF
and cEF. The authors also suggested calculating a recycling-
adjusted E factor when solvent loss data are available. They also
recommended switching from utilizing the sEF metric to the
cEF metric during post finalization of the API process.
ÄÅ
= ÅÅÅÅ ∑ mass(Raw materials) +
complete E factor (cEF)
Ç
∑ mass(Reagents)
ÉÑ
∑ mass(Solvents) + ∑ mass(Water)
− ∑ mass(Product)ÑÑÑÑ/mass(Product)
+
Ö
(1)
ÄÅ
= ÅÅÅÅ ∑ mass(Raw materials) + ∑ mass(Reagents)
simple E factor (sEF)
Ç
ÑÉ
− ∑ mass(Product)ÑÑÑÑ/mass(Product)
Ö
(2)
2.3.2. Baran’s Process Ideality Metric. Baran’s process %
ideality metric is ideal for assessing the relative process
greenness which simply unites the major definitions of an
ideal synthesis57 and can be mathematically explained as per eq
3.56 The idea of Baran’s process % ideality metric is based on
“reactions = transformations”.
% Ideality
No. of construction reactions + No. of strategic redox reactions
=
Total no. of reactions
(3)
Construction reactions (CRs) can be explained through
chemical transformations that form C−heteroatom or skeletal
C−C bonds. The strategic redox reactions (SRRs) are a form of
construction reaction that directly verifies the appropriate
functionality in the final product and incorporates asymmetric
oxidations or reductions, while all other types of “nonstrategic”
reactions are counted as concession steps (CSs) and involve
nonstrategic redox reactions, functional group interconversion,
and protecting group manipulations.
2.3.3. Identification of Process Complexity. To properly
prepare a green synthesis process, understanding the process
complexity is a must. Roschangar et al.56 implemented an
expansion of Baran’s methodology and included combining the
total number of reactions, multiplied by % ideality, which
measures the number of productive transformations. The higher
the complexity number, the greater the complexity of the
reaction process.
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Complexity = % Ideality × Total no. of reactions
= No. of construction reactions + No. of
strategic redox reactions (4)
2.3.4. The Green Aspiration Level Concept. To measure
the GC process performance in precise and absolute terms, the
process green aspiration level (GAL) measure has been
introduced.56 This offers to obtain objective levels for the
average chemical transformation or transformation-GAL
(tGAL) and process (GAL) according to the following
equations
xEF
tGAL =
Average complexity (5)
GAL = tGAL × Complexity (6)
where xEF = sEF or cEF.
Thus, one can now evaluate the development of phase-
dependent tGALs for sEF and cEF as the basis for harmonized
development of phase-dependent pharmaceutical GC synthesis
process goals. The GALs allow quantifying the green status of a
synthetic process relative to its aspiration level, employing a
metric called relative process greenness (RPG). An RPG greater
than 100% surpasses the process greenness goal (GAL). In
comparison, values less than 100% indicate that the green
chemistry performance is low as per average GC process
performance in the industry, which needs process optimization.
GAL(xEF)
RPG =
xEF(Actual) (7)
Here, xEF = sEF or cEF.
The overall process improvements can be quantified using a
metric called relative (green) process improvement (RPI), while
accounting for relative (process) complexity improvement
(RCI).
RPI = RPG(Current process) − RPG(Earlier process)
(8)
Complexity(Current process)
RCI = 1 −
Complexity(Earlier process) (9)
For simplification of calculation, one can assume that RPI and
RCI contribute equally to the overall green process improve-
ment (PI), which can be denoted as the following equation:
RPI + RCI
PI =
2 (10)
2.3.5. Innovation Green Aspiration Level (iGAL). One of
the significant drawbacks of this GAL metric is when chemists
develop a shorter synthesis scheme to lessen the process
complexity of the earlier route; the obtained RPG score gets
inferior, although the new scheme generates less overall waste.
Thus, the GAL metric does not effectively imitate the influence
of synthetic route and process design innovations. Therefore,
based on combined effects from the International Consortium
for Innovation and Quality in Pharmaceutical Development
(IQ), the American Chemical Society Green Chemistry
Institute Pharmaceutical Roundtable (ACS GCI PR), and
academia, a green manufacturing metric has been proposed
named iGAL.58 The proposed improved metric has supported
the statistical analysis of 64 drug manufacturing processes
encompassing 703 steps within 12 companies. Thus, the iGAL
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offers an exceptional proxy for molecular complexity and
presents a valuable molecular-weight-based “fixed” goal. The
iGAL can be represented employing eqs 11 and 12, where
mGAL defines the average coproduced waste per unit of average
commercial drug FMW. The FMW describes the salt-free MW
of API excluding salt, cocrystal, or solvate components.
mGAL = (average cEF × 100)/(average FMW) (11)
iGAL = (mGAL × FMW)/1000 (12)
Based on iGAL, the calculation of RPG will be as per the
following equation:
RPG = (iGAL/cEF) × 100%, where cEF = PMI − 1
(13)
59
Roschangar et al. proposed an improved model for the metric
named iGAL 2.0 to overcome current obstacles related to iGAL.
It can serve the purpose of the United Nations Sustainable
Development Goal 12, which aims at significantly reducing
production waste by 2030 with a vision to catalyze greener API
manufacturing around the world. The authors proposed the
yield (YD), which supports productivity, and convergence
(CV), which defines design efficiency, as new key sustainability
indicators and included a new formula for convergence with
potential applicability in computer-assisted synthesis planning
(CASP) algorithms. The improved metric represents a valuable
extension to the standard API process waste metrics, PMI and
cEF, by putting those measures into perspective: iGAL 2.0
enables the determination of RPG to identify possibly
underachieving and environmentally concerning processes
early.
ln(cEF) = 6.913 − (3.130 × CViGAL) − (1.987 × YD)
(14)
Here, CViGAL can be defined as follows
1 SM
CViGAL = × 100% = × 100
SSavg SSS (15)
where SSS is the sum of subprocess steps and SM represents the
starting materials.
Frank Roschangar led a joint effort by the IQ Consortium,
ACS GCIPR, and academic leaders to develop the iGAL 2.0
Scorecard Calculator to account for PMI by focusing on waste.
The calculator analyzes 64 bulk API manufacturing processes
covering 703 steps across 12 companies to offer a relative
process greenness score. The iGAL 2.0 Scorecard Calculator can
be accessed at https://www.acsgcipr.org/tools-for-innovation-
in-chemistry/green-chemistry-innovation-scorecard-calculator-
igal/.
3. THE CHOICE OF SOLVENTS IN THE GREEN
SYNTHESIS OF APIS
Sustainable and environmentally friendly synthesis of APIs
requires the concept of GC. In the synthesis process, a great
number of environmental hazards (solvents, depleted reagents,
and air contaminants) could be generated in the form of
pollutants. Another critical point is that the purity of
pharmaceuticals will naturally lead to more waste per kilogram
of product than other industries’ products. Thus, pharmaceutical
industries are enhancing their efforts to reduce the environ-
mental impact and protect people from the exposure to the
pharmaceutical synthesis-generated waste.60
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Considering the health hazards and environmental impact, Table 2. ICH Q3 Class, Concentration Limit in
solvents employed in pharmaceutical industries are classified Pharmaceuticals, and Ranking of Major Organic Solvents in
into four classes by the Center for Drug Evaluation and Research the Form of Hazardous Impact
(CDER) of the USA Food and Drug Administration (FDA) and
Center for Biologics Evaluation and Research (CBER).61 This
classification is documented for the International Council for
Harmonisation of Technical Requirements for Pharmaceuticals
for Human Use (ICH) guidance for the industry as “Q3C
Impurities: Residual Solvents” which suggests the safe thresholds
of residual solvents in pharmaceuticals (Table 2).34,62
In the synthesis process of any drug, half of the reagents used
are solvents, and they have the largest contribution to API waste,
carbon footprint, and energy use. Thus, restricting their use and
selecting suitable solvents or the “greenest” ones allows one to
achieve a substantial savings of the environmental impact of any
pharmaceutical synthesis. Additionally, using as few solvents as
possible in the process is a green design criterion, as it facilitates
solvent recycling. The choice of the “greenest” solvent is
occasionally contradictory, as multiple criteria lead to its green
status. Still, the major factors should be safety, environment,
occupational health, quality (risk and amount of impurities),
utilization of complete reagent, recyclability issues, and
industrial constraints (e.g., atom economy, freezing temper-
ature, boiling point, recyclability, density). Therefore, solvents
can be selected wisely and used in a limited amount with the
implication of a limited number of synthesis steps by applying
the green synthesis process. That means that solvents with
known hazardous characteristics need to be omitted as much as
possible either by altering the synthesis process or by
substituting the solvents with nonhazardous or less hazardous
solvents. Multiple tools are available for designing the green
synthesis process under the US EPA and Green Chemistry
Expert System (GCES),63 which offers the GC process
guidelines and support information as well as the green
solvents/reaction conditions module.
Again, it is challenging to select a green solvent, as the term
may be contradictory from person to person. Thus, some
essential criteria must be followed for the selection of a green
solvent.64 The conditions to be measured are occupational
health, safety, environmental impact, risk of residual solvents in
the API, industrial constraints (e.g., atom economy, freezing
temperature, boiling point, density, recyclability), and final cost.
Regulatory agencies such as US EPA and such regulations as
REACH suggest that chemical and pharmaceutical industries
stay away from the use of identified hazardous solvents, such as
traditional aprotic solvents like dimethylformamide (DMF).62
The overall ranking is generated based on the individual scores
and recommendations concerning health, safety, and environ-
ment issues by the following organizations and industries: ACS
Green Chemistry Institute Pharmaceutical Roundtable (GCI-
PR), AstraZeneca (AZ), GSK, Pfizer, and Sanofi are reported in
Table 3. Table 3 can be a good source of solvent selection for
green pharmaceutical synthesis for manufacturers considering *,#
Values are provided only for class 1 and class 2 solvents, as they
the overall ranking, permitted and concentration limit in need to be monitored carefully. PDE, permitted daily exposure; CL,
pharmaceuticals, and ICH Q3 solvent class.34,62 concentration limit in pharmaceuticals; TBC, to be confirmed; Perox.,
ability to form peroxides; Explo., explosion effects; Repro.,
4. THE REACTION WITH GREEN SOLVENTS reproductive damage; H224, low flash point and boiling point;
H350, mutagenic; H351, suspected carcinogenic; H360, classified as
The E factor, which is defined as the mass ratio of waste to the reprotoxic; H420, dangerous for the ozone layer. Class 1 solvents:
final product, is one of the critical measures to identify an categorized under toxic and environmental hazards, which are better
environment friendly chemical process. The E factor considers to avoid in the API synthesis. Class 2 solvents: should be restricted in
all wastes (reagents, solvent losses, aids, and fuel) included in the pharmaceutical synthesis due to their intrinsic toxicity with PDE at
process, excluding the final product and water, which are around 0.1 mg/day and acceptable concentration limit at 10 ppm.
generally not considered under waste technically.55 The fifth Class 3 solvents: include less hazardous and lower toxicity solvents

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Table 2. continued
commonly employed in pharmaceuticals with no evidence of long-
term toxicity or carcinogenicity as well as less toxicity in acute or
short-term studies with the threshold limit of these residual solvents at
50 mg/day or less than 5 000 ppm. Class 4 solvents: do not have
sufficient toxicological data, and one needs to employ these solvents
carefully with mentioning residual levels in pharmaceutical synthesis.
principle of GC deals with the implication of safer and greener
solvents with the consideration that they “should be made
unnecessary wherever possible and innocuous when used”.65
Solvents are key components for the green synthesis process.
They are volatile organic compounds (VOCs) employed in large
volumes and leading to high waste, pollution, and health
hazards. Thus, choosing safer and efficient solvents or, if
possible, eliminating solvents entirely for a specific process is one
of the challenging options.
On the other hand, alternative reaction media is gaining a lot
of attention, which can nullify the major drawbacks of
conventional VOCs and offer prospects for enabling the
complete recycling and recovery of the catalyst. Without any
doubt, the best solvent is no solvent, but still, if a solvent is
required, then the first option is water and/or catalysis in
aqueous biphasic systems. Scientists from all over the world
believe that water is the best possible reaction medium in
organic synthesis.66 It is noteworthy to mention that, to
overcome the solubility issues of water, newly engineered
“designer” surfactants offer an opportunity to productively
enable many of the frequently used transition-metal-catalyzed
and related reactions at ambient temperatures.66,67 It is followed
by such alternatives as fluorous biphasic,68,69 supercritical
carbon dioxide and/or biphasic systems,70,71 ionic liquids
(ILs),72−74 etc., as reaction media to have potential future
opportunities. Mechanochemistry is another futuristic solution
for effective and environmentally friendly synthesis (mechano-
synthesis) of various metal−organic frameworks (MOFs).75
Mechanosynthesis through solvent-free or solvent-less protocols
appears to be a fast and versatile method for green synthesis of
APIs in the future. Key updates of mechanochemistry and
mechanosynthesis can be found in the recent literature.76−78
These alternative solvents are often costly and do not have a
favorable environmental profile due to their complex nature, a
complicated synthesis method, and limited experimental use in
the major pharmaceutical industry. Thus, we have limited our
discussion strictly to the no-solvent process and water as a green
solvent in the green synthesis of pharmaceuticals.
4.1. The No-Solvent Process
Theoretically, solvent-free processes can remove the waste. Still,
considering the industrial scale, it is not hazard-free, as proper
knowledge of thermal characteristics of solvent-less reactions is
required; otherwise, serious accidents may occur.
Ranu et al.79 demonstrated the synthesis of dihydropyr-
imidinone and its derivatives by a catalyst-free and solvent-free
Biginellis condensation of a 1,3-dicarbonyl derivative (1.1),
aldehyde (1.2), and urea derivative (1.3) mixture of neat
reactants at 100−105 °C for 1 h, generating high yields (Scheme
1).
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Tokunaga et al.80 reported a revolution in the isolation of
terminal epoxides with high enantioselectivity through hydro-
lytic kinetic resolution of epoxides in water as the only reagent
that assists as a nucleophile in the presence of recyclable catalyst
(salen)Co(OAc) to open epoxides. The authors demonstrated a
reaction between 1 mol of 2-methyloxirane (2.1) and 0.55 equiv
of water in the presence of 0.2 equiv of catalyst to obtain (S)-2-
methyloxirane (2.2) and (R)-propane-1,2-diol (2.3) at ambient
temperature (Scheme 2). The reaction can be achieved on a
large scale, and the catalyst can be recycled at least three times
without losing enantioselectivity.
An enantioselective and organocatalytic conjugate addition of
nitroalkanes to nitroolefins has been done under neat conditions
without using an organic solvent (Scheme 3).81 Modified
Cinchona alkaloid catalyzed the reaction between 2-nitro-
propane (3.1) and (E)-1-chloro-2-(2-nitrovinyl)benzene (3.2)
at 0 °C without any solvent, preparing synthetically useful (R)-1-
chloro-2-(3-methyl-1,3-dinitrobutan-2-yl)benzene (3.3) in 81%
enantiomeric excess (ee) and 83% yields.
4.2. Water
Water as a solvent and/or cosolvent is the best possible green
solvent to have in any reaction.66,67 Over the years, water has
mostly been used in biocatalytic reactions, during reaction
workup, and in product isolation, but in recent times, water has
been used as a solvent and cosolvent, which resulted in low waste
and high atom economy in the commercial green synthesis
process due to a relatively easier removal process. A series of
reagents and reaction intermediates have limited or no solubility
in water. To overcome the problem, water is used as a process
solvent in the phase-transfer catalysis (PTC), which can improve
the yield and atom economy through the green process. Overall,
the use of water as a direct solvent or in the PTC technology is
simple, economical, and trustworthy and has discovered many
functions in the chemical and pharmaceutical industries.82−84 A
series of chemical reactions such as oxidation; reduction;
cycloaddition; Diels−Alder reaction; rearrangement reaction,
condensation, and addition; and Suzuki coupling reaction are
possible in water, making it one of the prominent solvents for
synthetic chemistry.
Alkylation of 6-chloro-5-(2-chloroethyl)indolin-2-one (4.1)
with 3-(piperazin-1-yl)benzo[d]isothiazole (4.2) in the pres-
ence of water and Na2CO3 produces a yield of 90−94% (Scheme
4) of ziprasidone (4.3) where water was used as the solvent to
improve the solubility of the reagents.85
Danofloxacin, a quinolone antibacterial drug whose amina-
tion step (reaction occurring between 1-cyclopropyl-6,7-
difluoro-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (5.1)
and hydrobromide salt of (1R,4R)-2-methyl-2,5-diazabicyclo-
[2.2.1]heptane (5.2)) was amended by directing it in
pressurized water at a higher temperature, ultimately helps in
increasing the reaction rate followed by achieving a 91% yield of
danofloxacin (5.3) (Scheme 5).86 The use of water as a solvent
allows removing major solvents like 1,8-diazabicyclo[5.4.0]-
undec-7-ene (DBU), alcohols, pyridine, and toluene from the
earlier approved process.
An important intermediate of ABT-963, a COX-2 inhibitor
NSAID, is dibromopyridazinone, which can be synthesized in a
one-pot synthesis incorporating water as a solvent over three
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Table 3. Solvents for Green Synthesis

hazardous and undesirable
solvents
comparatively less hazardous
solvents and use with caution
green and preferred solvents
benzene, diethyl ether, chloroform, dichloromethane, dichloroethane, ethylene glycol, isopropyl ether, pentane, HMPA, dioxane,
hexanes, carbon tetrachloride, dimethoxyethane, dimethylacetamide (DMAc), pyridine, N-methyl-2-pyrrolidone (NMP), DMF
toluene, MTBE, acetonitrile, acetic acid, n-butanol, toluene, trifluorotoluene, 1,2-propanediol, MTBE, TBME, heptane, N-
methylpyrrolidine, tetrahydrofuran (THF), 2-Me-THF, DMSO, isooctane, cyclohexane, methyl cyclohexane, ethylene glycol
water, ethanol, methanol, 2-propanol, 1-propanol, acetone, heptane, butyl acetate, propyl acetate, isopropyl acetate, isobutyl acetate,
methyl acetate, ethyl acetate, 1-butanol, 2-butanol, t-butanol, methyl ethyl ketone (MEK)

Scheme 1. Solvent-Free Synthesis of Dihydropyrimidinone and Its Derivatives

Scheme 2. Solvent-Free Reaction of Terminal Epoxides with Scheme 5. Amination Step of Danofloxacin in the Presence of
High Enantioselectivity Water as a Solvent

Scheme 3. Solvent-Free Conjugate Addition of Nitroalkenes

and Nitroolefins

Scheme 6. Synthesis of Dibromopyridazinone Incorporating

Water as a Solvent

consecutive steps.87 The reaction started with 3,4-difluoroani-

line (6.1) to prepare an intermediate product (6.2) in the first
two steps followed by reaction with 2,3-dibromo-4-hydrox-
ycyclopent-2-enone (6.3) to generate dibromopyridazinone
(6.4) (Scheme 6). All three-step processes with water can offer
an 82% overall yield of dibromopyridazinone with 96% purity
without additional purification.
4.2.1. Water in the Phase-Transfer Catalysis (PTC). A
pragmatic pilot-scale synthesis of 4-vinyl-2,3-dihydrobenzofuran
(7.2) was done employing phase-transfer catalysis (PTC) for
dehydrohalogenation of 4-(2-chloroethyl)-2,3-dihydrobenzo-
furan (7.1) in the presence of water (Scheme 7).88
To prepare enantio-enriched chiral compounds from Scheme 7. Synthesis of 4-Vinyl-2,3-dihydrobenzofuran with
prochiral materials, chiral PTC became quite popular among Water in PTC
chemists. The alkylation of a 6,7-dichloro-5-methoxy-2-phenyl-
2,3-dihydro-1H-inden-1-one (8.1) using chiral PTC (8.2) can
offer (S)-6,7-dichloro-5-methoxy-2-methyl-2-phenyl-2,3-dihy-
dro-1H-inden-1-one (8.3) with a 98% yield and 92% ee
(Scheme 8).89 The chiral induction step included an ion pair
where the enolate anion fit on top of the catalyst, positioned by
hydrogen-bonding effects and electrostatic and π−π stacking
interactions between the aromatic rings in the catalyst and the 4.2.2. Water as a Solvent and under Microwave
enolate. Irradiation (MWI) Conditions. Dehbi et al.82 depicted an

Scheme 4. Synthesis of Ziprasidone in the Presence of Water as a Solvent

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Scheme 8. Synthesis of Enantio-Enriched Chiral Compounds
from a Prochiral Compound with Water in PTC
eco-friendly and efficient approach to the synthesis of
disubstituted 5-aminopyrimidines (9.3) from vinyl azides
(9.1) and urea or thiourea (9.2) (Scheme 9). The reaction
Scheme 9. Synthesis of Disubstituted 5-Aminopyrimidines in
Water as a Solvent under MWI
was carried out in water as a solvent under microwave irradiation
(MWI) conditions. The one-step process has a shorter reaction
time, and the use of water as a solvent makes it a green synthesis.
To optimize the best possible reaction conditions, the authors
coupled 2-azido-3-(4-bromophenyl)-1-phenylprop-2-en-1-one
with urea in the presence of various solvents such as acetonitrile,
methanol, DMF, THF, dioxane, toluene, and water under MWI
for 10 min and found % yields of 36, 12, 79, 82, 46, 5, and 97,
respectively. The experiment proved that water is the most
efficient solvent to achieve an excellent yield over the other
hazardous or less safe solvents.
Gutierrez et al.83 discovered microwave-assisted or sono-
chemical one-pot synthesis of carbonylpyrazolo[3,4-b]pyridine
derivatives (10.4) through the condensation of 3-methyl-1-
phenyl-1H-pyrazolo-5-amine (10.1) with formaldehyde (10.2)
and β-diketones (10.3) catalyzed by InCl3 in the presence of
water (Scheme 10).
Scheme 10. MWI-Assisted One-Pot Synthesis of
Carbonylpyrazolo[3,4-b]pyridine Derivatives in Water as a
Solvent
Scheme 11. Synthesis of Guanidine Derivatives Incorporating Water as a Solvent under MWI
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Substituted guanidine derivatives (11.3) were prepared by
reacting thiourea (11.1) with amine (11.2) under alkaline
conditions utilizing water as a solvent under MWI (100 W)
(Scheme 11) by Sanghvi et al.90 Water replaced many organic
solvents to prepare the guanidine derivatives (11.3) as per the
earlier process. At the same time, sodium hydroxide was
employed to catalyze the reaction, followed by trapping the
evolved H2S gas. The whole process was controlled by a
microwave synthesizer, which makes it an eco-friendly process
and reduces the reaction time.
4.2.3. Water as a Solvent under Ultrasound-Accel-
erated Conditions. An ultrasound-accelerated one-pot
reaction of quinoline-1-oxide (12.1) and sulfonyl chloride
(12.2) obtained functionalized 2-sulfonylquinolines (12.3) in
water (Scheme 12).84 The ultrasound technique improves the
Scheme 12. Synthesis of 2-Sulfonylquinoline Derivatives in
Water as a Solvent under Ultrasound-Accelerated Conditions
efficiency and the rate of chemical reaction, simplifies scale-up,
and reduces other side reactions or formation of byproducts,
compared to the traditional heating approach. This one-pot
synthesis followed by a green protocol offered good product
yields (61−91%), high energy efficiency, chemo- and
regioselectivity, an atom economy of 70.7%, an eco-scale score
of 71, and an E factor of 1.17.
Sapkal et al.91 established a green protocol for the synthesis of
structurally diverse 2,2′-arylmethylene bis(3-hydroxy-5,5-di-
methyl-2-cyclohexene-1-one) (13.3) and 2-substituted 1H-
benzimidazole derivatives (13.5) from aldehydes (13.1)
depending on the starting materials 5,5-dimethylcyclohexane-
1,3-dione (13.2) and benzene-1,2-diamine (13.4), respectively
(Scheme 13). For both final products, the reaction was
Scheme 13. Synthesis of 2,2′-Arylmethylene Bis(3-hydroxy-
5,5-dimethyl-2-cyclohexene-1-one) and 2-Substituted 1H-
Benzimidazole Derivatives in Water as a Solvent under
Ultrasound-Accelerated Conditions
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Scheme 14. Synthesis of 2-Substituted Quinoline Derivatives in Water as a Solvent under Ultrasound-Accelerated Conditions
performed using BiOCl nanoparticles as a catalyst in the
presence of water under ultrasound irradiation with a temper-
ature of 35 °C. The nanocatalyst can be recycled and reused for
seven successive reactions without losing its catalytic activity.
This approach offered mild reaction conditions with faster
reactions compared to the previous ones.
An ultrasound-assisted rapid synthesis of 2-substituted
quinoline derivatives in the presence of SnCl2·2H2O as a
catalyst in water was reported by Pal et al.92 The one-pot
reaction occurred with three-component aniline derivatives
(14.1), aldehyde (14.2), and ethyl 3,3-diethoxypropionate
derivative (14.3) to produce the 2-substituted quinoline
derivatives (14.4) in good yields (Scheme 14).
4.3. Aqueous Biphasic Catalysis
This reaction is performed in an aqueous biphasic system in
which the catalyst stays in the water phase and the product is
dissolved in the organic phase. The system permits recycling and
recovery of the catalyst by simple phase separation.93
4.3.1. Aqueous Biphasic Oxidation. Hydrogen peroxide
has been utilized in aqueous biphasic systems for the oxidation
of primary and secondary alcohols to aldehydes and ketones,
respectively, the epoxidation of olefins, and the oxidative
cleavage of olefins/ketones to carboxylic acids. One of the
prominent examples of implication of this alternative media is
the synthesis of cyclohexene (15.1) to adipic acid (15.2)
(Scheme 15).94−96
Scheme 15. Synthesis of Adipic Acid from Cyclohexene
through Aqueous Biphasic Oxidation
4.3.2. Aqueous Biphasic Carbonylation. The Pd(tppts)3
complex catalyzes the carbonylation of 5-(hydroxymethyl)-
furan-2-carbaldehyde (16.1) to synthesize 2-(5-formylfuran-2-
yl)cetic acid (16.2), where a Brønsted acid acts as a cocatalyst
(Scheme 16) in the aqueous biphasic system.97 Ibuprofen
Scheme 16. Aqueous Biphasic Carbonylation to Synthesize 2-
(5-Formylfuran-2-yl)cetic Acid
(17.2) can be synthesized by aqueous biphasic carbonylation of
1-(4-isobutylphenyl)ethanol (17.1) in the presence of Pd-
(tppts)3 complex and acid cocatalyst (Scheme 17).98
4.3.3. Aqueous Biphasic Hydroformylation. The
Ruhrchemie/Rhône−Poulenc process is the best example of
the hydroformylation of propylene (18.1) to n-butanal (18.2)
and isobutanal (18.3) (Scheme 18), which employs a water-
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Scheme 17. Aqueous Biphasic Carbonylation to Synthesize
Ibuprofen
soluble rhodium(I) complex of trisulfonated triphenylphos-
phine (tppts) as the catalyst.99
5. FREQUENTLY USED CHEMICAL REACTIONS
RELEVANT TO THE GREEN SYNTHESIS AND GC
The knowledge of diverse reactions and transformations
relevant to green synthesis maintaining the protocol of GC is
the first requirement to design the complete synthesis routes/
schemes for starting materials, key intermediates, and the
ultimate APIs. Therefore, before focusing on the green synthesis
of pharmaceuticals, the most common reaction types under GC
and green synthesis need to be discussed. We had two choices:
to divide the green reaction schemes either based on reaction
types or based on catalytic approaches. As the review deals with
green synthesis and green products, we have decided to divide
this section based on reaction transformation instead of catalysts
and catalytic approaches.
The catalytic process and catalytic reagents (catalysts) play an
impactful role in the green synthesis process. The catalyst
participates in a chemical reaction yet remains unchanged after
the reaction is complete. The stoichiometric reactions can often
be prolonged, requiring significant energy input in heat or
producing unwanted byproducts hazardous to the environ-
ment.100 In contrast, a catalytic reaction works by lowering the
energy barrier of a given chemical transformation by interacting
with the specific reactants, facilitating high selectivity and
lessening the number of reaction steps. Solid acidic and basic
catalysts avoid ubiquitous salt formation linked with the use of
molecular acids and bases. Another significant aspect is the use
of a green catalyst itself along with designing a green process.
Thus, the choice of a catalyst depends on the greenness and
lifetime of its effectiveness. Although this specific section was
prepared based on reaction/transformation related to green
synthesis, in a broader perspective, sections 5.1−5.7 majorly deal
with homogeneous and heterogeneous catalytic-approach-based
transformations wherever a catalyst is involved. Again, section
5.8 deals with organocatalysis, and section 5.9 discusses
biocatalysis. Thus, green reaction transformations and utiliza-
tion of catalysis and catalytic methods for green synthesis are
connected in a single thread in this section.
5.1. C−H Activation
The direct activation and functionalization of C−H bonds help
avoid intermediate functional group insertion, resulting in
shorter synthesis steps and atom economy followed by reduced
waste. The C−H activation eliminates the requisites for
prefunctionalization and offers to reduce the step-count and
mass intensity of the chemical processes. Metal catalysis,
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Scheme 18. Aqueous Biphasic Hydroformylation of Propylene to Synthesize n-Butanal and Isobutanal
heterogeneous catalysts, avoiding and replacing static directing
groups, molecular oxygen, metal electrocatalysis, and greener
solvents can help immensely to nullify the hindrance factors of
C−H activation toward sustainability and implications in large-
scale industries.101−103
Evans et al.104 reported Cu-catalyzed direct α-amination of α-
carbonyls (ketones, esters, and aldehydes) (19.1) and secondary
aliphatic amines (19.2). The reaction occurs in the presence of
10 mol % CuBr2 as a catalyst, which helps develop an α-bromo
carbonyl intermediate (Scheme 19). The intermediate under-
goes a C−N bond formation (19.3) employing 2−3 equiv of
amine. Here, the air is utilized as the stoichiometric oxidant.
Scheme 19. One-Step Synthesis of Amide through Direct
Coupling of α-Carbonyls with Functionalized Amines
Li et al.105 developed an efficient C−H lactonization method
to construct biaryl lactones via carboxylic acid-directed C−H
functionalization/C−O bond reductive elimination. The
reaction utilizes a catalyst−ligand system, 5 mol % Pd(OAc)2
and 15 mol % N-acetylated glycine, for C−H functionalization
of 2-aryl carboxylic acids (20.1) from biaryl lactone (20.2). The
terminal oxidant (diacetoxyiodo)benzene is believed to produce
a palladium(IV) intermediate, which can more freely undergo
C−O reductive elimination (Scheme 20). Using two key steps,
the authors employed the reaction scheme to synthesize the
natural product cannabinol from commercially accessible
starting materials.
Ruiz Espelt et al.106 reported a Brønsted-acid-cocatalyzed
radical photocatalytic C−H activation at the α-amino site of 2-
Scheme 20. Pd-Catalyzed C−H Lactonization for the
Synthesis of Biaryl Lactones
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phenyl-1,2,3,4-tetrahydroisoquinoline (21.1) and But-3-en-2-
one (21.2) using a 23 W compact fluorescent lamp and
Ru(bpy)3Cl2 as a catalyst to synthesize 4-(2-phenyl-1,2,3,4-
tetrahydroisoquinolin-1-yl)butan-2-one (21.3). To find the
optimal % yield, the authors increased the ionic strength of
the reaction with the inclusion of 1 equiv of TFA in the
photocatylzed C−H activation (Scheme 21).
Scheme 21. Photocatalytic Radical Addition of α-Amino C−
H Bonds Across Michael Acceptors Using Brønsted Acid as
Cocatalysts
Huang et al.107 proposed an environmentally friendly aerobic
dehydrogenative cyclization of a pyridine derivative (22.1) and
an oxime ester derivative (22.2) to produce imidazo[1,2-
a]pyridine derivative (22.3) employing copper catalyzed with
ketone oxime esters. The reaction utilizes 20 mol % Li2CO3 and
20 mol % CuI with air as the stoichiometric oxidant (Scheme
22). Oximes derived from aryl methyl ketones react, leading to a
good yield of 31−89%, involving substituted heteroaryl, phenyl,
and naphthyl groups.
Scheme 22. Copper-Catalyzed Aerobic Dehydrogenative
Cyclization with Oxime Esters and Pyridines to Synthesize
Imidazo[1,2-a]pyridines
Pirnot et al.108 proposed direct activation at the β-position to a
carbonyl derivative through photoredox activation. The authors
took advantage of a compact fluorescent bulb of 26 W and a
commercially available catalyst (Ir(ppy)3) with only 1 mol %
loading. 1,4-Diazobicyclo[2.2.2]nonane (DABCO) and 1,3-
dimethyltetrahydropyrimidin-2(1H)-one (DMPU) are used as
the base of the reaction. An amine cocatalyst expedites enamine
formation with the aldehyde, chased by enamine oxidation and
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the consequent nucleophilic radical coupling with the arene at
the β-position. The authors reported 44−86% yields for diverse
aldehydes and ketones in a cyclic 6-membered ring system,
where X = C and EWG = CN. A series of electron-withdrawing
groups involving pyridine derivatives, where X = N, produces
excellent yields, while the best yields are delivered by esters and
sulfones at the ortho and para positions. In Scheme 23, the arene
Scheme 23. Direct β-Arylation of Aldehydes and Ketones
through Photoredox Activation
derivative (23.1) reacts with a carbonyl derivative (23.2) under
the reaction conditions as mentioned above to obtain β-aryl
aldehyde (23.3). The most significant feature of this approach is
the capability to use a cinchona-based amine catalyst to deliver
chiral products. Along with many advantages, the authors
highlighted the unfortunate formation of an equivalent of
cyanide during the reaction, generating an aqueous waste stream
that must be treated appropriately.
Fennewald and Lipshutz109 developed a trifluoromethylation
process that addresses solvent selection, recycling, and waste
minimization. An aqueous system of NaSO2CF3 as the
trifluoromethyl source along with the surfactant TPGS-750-M
and t-butylhydroperoxide (TBHP) was utilized as a reaction
vehicle. Later, the reaction conditions were optimized on 4-t-
butylpyridine (24.1) to utilize 2 wt % of the surfactant, 3 equiv of
NaSO2CF3, and 5 equiv of the TBHP as an oxidizing agent in
water as the solvent to synthesize 4-(tert-butyl)-2-
(trifluoromethyl)pyridine (24.2) (Scheme 24). The reaction
Scheme 24. Trifluoromethylation of Heterocycles in Water as
a Solvent at Room Temperature
can be run in water to address the greener solvent choice. After
the addition of ethyl acetate to remove the product, the authors
were able to reuse the aqueous layer in subsequent reactions,
which supports both recycling and waste minimization.
Huang et al.110 reported an iron-catalyzed oxidative radical
cross-coupling/cyclization of electron-rich phenols/naphthols
(25.1) with styrene derivatives/olefins (25.2) to synthesize
dihydrobenzofurans (25.3). The reaction is optimized for a
better yield with a combination of 10 mol % FeCl3, 1.2 equiv of
2,3-dichloro-5,6-dicyanobenzoquinone (DDQ), and toluene.
The reaction is initiated through DDQ-promoted one-electron
phenol oxidation. Iron coordination of the oxidized phenol
stabilizes the carbon-centered radical, which undergoes addition
with styrene followed by a C−O bond formation (Scheme 25).
The whole reaction can be completed at room temperature. The
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authors also reported one drawback that 2 equiv of olefin is
needed to achieve high yields.
Scheme 25. Iron-Catalyzed Oxidative Radical Cross-
Coupling/Cyclization between Phenols/Napthols and
Olefins to Synthesize Dihydrobenzofurans
A copper acetate-catalyzed benzylic oxidation has been
proposed by Jiang et al.111 Chemicals with a p-hydroxy group
directed the oxidation. A wide range of 2,6-disubstituted 4-
cresols were explored under the proposed scheme. Alkyl
substitution at R1 and alkoxy and/or alkyl substitution at R2
and R3 resulted in ketones, while aldehydes could be obtained
when R1 was a proton. The authors reported around 30
examples with resulting yields ranging from 62 to 87%. However,
substituting one or both R2, R3 groups with nitriles or halogens
caused poor conversion with recovery of significant amounts of
the starting material. Lastly, when R1 is hydroxyl or alkoxy, the
resultant aldehyde is produced under the same reaction
conditions in yields ranging from 84 to 96%. In Scheme 26,
aryl aldehyde or ketone derivatives (26.2) are synthesized from
aryl alcohol (26.1) depending on the types of substitutions.
Scheme 26. Cu(OAc)2-Catalyzed Remote Benzylic C(sp3)−
H Oxyfunctionalization for CO Formation
5.2. Asymmetric Hydrogenation
The asymmetric hydrogenation112−115 is one of the most
extensively utilized transformations in the asymmetric synthesis
of pharmaceuticals. This simple, atom economical, direct, and
sustainable approach stimulates chirality in a wide range of
substrates and is implemented in green synthesis schemes of
pharmaceuticals for large-scale purposes. The asymmetric
hydrogenation of enamides is applied for the synthesis of chiral
amines and their derivatives.
Zhou et al.116 reported a highly enantioselective and efficient
catalytic asymmetric hydrogenation of β-acylamino nitroolefins
to synthesize β-amino nitroalkane using Rh-TangPhos as a
catalyst. The solvent trifluoroethanol (TFE) plays a crucial role
in achieving the anticipated transformation from (Z)-N-(1-(3-
bromophenyl)-2-nitrovinyl)acetamide (27.1) to (R)-N-(1-(3-
bromophenyl)-2-nitroethyl)acetamide (27.2) in enantioselec-
tivity (∼93% ee) and high yields (98%) with 1 mol % catalyst
and 5 atm of H2 at 25 °C temperature (Scheme 27). This specific
scheme offers green synthesis routes for the pharmaceuticals like
oseltamivir, clopidogrel, asimadoline, GR-205171A, and
(+)-CP-99,994.
The asymmetric hydrogenation of aromatic olefins (28.1) to
synthesize a substituted alkane derivative (28.2) in the presence
of phosphinoimidazole (BIPI) ligands in combination with
Ir(cod)BARF catalyst was reported by Busacca et al.117
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Scheme 27. Synthesis of Chiral β-Amino Nitroalkanes
through Enantioselective Hydrogenation of β-Acylamino
Nitroolefins
Optimum yield was obtained under dichloromethane as a
solvent using 2 mol % catalyst at 0 °C temperature (Scheme 28).
Scheme 28. Asymmetric Hydrogenation of Unfunctionalized
Olefins with the BIPI Ligands
Bachmann et al.118 reported asymmetric hydrogenation of an
α-aryl, β-alkyl-substituted acrylic acid (29.1) under the
influence of a ruthenium catalyst to prepare dicyclohexylamine-
(R)-2-(3-chloro-4-(methylsulfonyl)phenyl)-3-cyclopentylpro-
panoate (29.2), a key intermediate in the synthesis of a
glucokinase activator (Scheme 29). The identified optimum
reaction conditions were found to be in methanol as a solvent, 50
bar of H2, and 50 °C with a substrate-to-catalyst molar ratio (S/
C) of 75000:1.
Liu et al.119 have developed enantioselective metal-free
hydrogenation of biaryl-substituted imines (30.1) to synthesize
a biaryl-substituted amine (30.2) using simple chiral boranes as
a catalyst. The authors identified optimized conditions of 2.5
mol % ligand and 5 mol % HB(C6F5)2 in mesitylene at 25 °C; a
variety of biaryl-substituted imines were screened to prepare
biaryl-substituted amines (Scheme 30). The asymmetric
reduction occurred under mild reaction conditions and achieved
up to 99% yield and 89% ee.
An extremely effective asymmetric synthesis of chiral
isochromenes (31.3) has been reported using the copper(II)/
Scheme 29. Practical Asymmetric Hydrogenation and a Scalable Synthesis of Glucokinase Activator
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Scheme 30. Metal-Free Asymmetric Hydrogenation of
Imines to Synthesize an Amine by Borane Catalysis
phosphate-catalyzed intramolecular cyclization/asymmetric
transfer hydrogenation sequence of o-alkynylacetophenone
derivatives (31.1) in the presence of dimethyl 2,6-dimethyl-
1,4-dihydropyridine-3,5-dicarboxylate (31.2) (Scheme 31).120
The authors used Hantzsch esters as the hydrogen source and
reported multisubstituted isochromenes in high yields (79%)
with high enantioselectivities (80−97%).
The asymmetric reduction of a series of heterocycle imines
(benzoxazines, benzoxazinones, benzothiazinones, quinaxali-
nones) (32.1) can generate a diverse set of heterocycle amines
(32.2) in the presence of the Ir(I)phosphine−phosphite
complex (Scheme 32).121 The authors identified an optimal
catalyst of 0.5−2 mol %. This catalytic process works perfectly at
room temperature and offers the product excellent yields in a
range of 94−99% with high enantioselectivities (94−99% ee).
5.3. Oxidations
The green oxidative process in organic synthesis has a significant
impact on the industry and environmental risk management.
The green oxidative procedures can be performed with O2,
H2O2, electrochemical oxidation, photocatalytic oxidation,
enzymatic oxidation, etc. A detailed explanation of oxidation
of diverse functional groups through the green process can be
found in the literature.122 The C−H functionalization through
oxidation is a critical aspect for GC, as it proposes prospects for
shorter synthesis routes generating reduced waste. Roduner et
al.123 demonstrated major advancements in C−H oxidations
employing molecular O2, encompassing biocatalytic/enzymatic
and organometallic approaches including water and supercritical
CO2 as solvents and flow chemistry in microreactors.
McAllister and Parsons124 proposed environmentally friendly
modifications to the asymmetric oxidation of pyrmetazole
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Scheme 31. Synthesis of Isochromene Derivatives by Intramolecular Cyclization and Asymmetric Transfer Hydrogenation of o-
Alkynylacetophenones
Scheme 32. Asymmetric Hydrogenation of Substituted C
N-Containing Heterocycle Imines Using [Ir(Cl)(cod)(P-
OP)] Catalysis to Synthesize Heterocycle Amine
(33.3) to synthesize the antiulcer medicine esomeprazole
(33.4). In the presence of thionyl chloride, 5-methoxy-1H-
benzo[d]imidazole-2(3H)-thione (33.2) reacted with pyrmeth-
yl alcohol (33.1) to obtain pyrmetazole (33.3) (Scheme 33).
The asymmetric oxidation of pyrmetazole is performed using
cumene hydroperoxide in the presence of (S,S)-diethyl tartrate
((S,S)-DET) to selectively form the S-enantiomer of the
sulfoxide, i.e., esomeprazole.
Engineered monoamine oxidase (MAO-N) from Aspergillus
niger can generate enantiomerically pure chiral amines. Ghislieri
and Turner125 explain the advancement of several variants of
MAOs from A. niger having a broad substrate scope and
applications in de-racemization reactions of substrates of
pharmaceutical interest. The reported de-racemization process
offers MAO selective oxidization of one enantiomer of a racemic
amine (34.1) to an imine (34.2). The undesired product (34.3)
can be converted back to the racemic amine with the help of
BH3−NH3 (Scheme 34).
Wang et al.126 proposed a metal-free oxidative spirocycliza-
tion of 1,3-cyclohexadione (35.1) with the hydroxymethylacry-
lamide (35.2) to synthesize spirooxindoles (35.3) under mild
Scheme 33. Asymmetric Oxidation of Pyrmetazole to Synthesize Esomeprazole
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Scheme 34. Biocatalytic Approach to the Synthesis of
Enantiomerically Pure Chiral Amines
conditions, an essential scaffold of many bioactive molecules.
The reported scheme occurs via tandem dual C−H function-
alization and intramolecular dehydration, resulting in the
cascade formation of two new C−C bonds and a C−O bond
(Scheme 35).
Scheme 35. Metal-Free Oxidative Spirocyclization of 1,3-
Dicarbonyls with Hydroxymethylacrylamide to Synthesize
Spirooxindoles
Lenze and Bauer127 reported a mild iron(II) complex catalyst
system to prepare hydroxy ketones through oxidation of
secondary alcohols utilizing H2O2 as the oxidant and bis-pyridyl
amine as the ligand and in the presence of primary alcohols at
room temperature. In Scheme 36, the mentioned ligand helps
convert 1,2-diols (36.1) into 1-hydroxybutan-2-one (36.2)
under the specified reaction conditions. The reaction is
important, as the 1,2-diol substrates do not suffer from the
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Scheme 36. Chemoselective Fe(II)-Catalyzed Oxidation of
Secondary Alcohols to Generate Hydroxy Ketones Utilizing
H2O2 as the Oxidant
oxidation/reduction sequence using borane−ammonia generat-
ing (R)-harmicine (83% yield and >99% ee) (Scheme 39).
Scheme 39. Enantioselective Amine Oxidase-Based
Oxidation for the Synthesis of Pharmaceutical Building
Blocks

C−C bond cleavage, which is typical of most strong oxidizing

agents.
Dandia et al.128 illustrated the stereoselective epoxidation of
3-aroylmethylene indole-2-one (37.1) under biphasic condi-
tions using ultrasonic irradiation to synthesize spiro[indole-3,2′-
oxirane]-3′-benzoyl-2(1H)-one derivatives (37.2) with high
yields (91−96%) (Scheme 37). The reaction occurred employ-

Scheme 37. Stereoselective Epoxidation of 3-Aroylmethylene

Indole-2-one for the Green Synthesis of Spiro[indole-3,2′-
oxirane]-3′-benzoyl-2(1H)-one Derivatives
ing hydrogen peroxide in a basic medium and with
cetyltrimethylammonium bromide as a phase-transfer catalyst
(PTC) and can be finished within 1 h. The authors reported the
best yields could be obtained with a 1:1.5:1 ratio of the
substrate:H2O2:NaOH in the presence of 5 mol % of a phase-
transfer catalyst. The reported derivatives and yields are the
following: X = H, R = 4-F, yield = 96%; X = H, R = 4-F, 3-Cl,
yield = 92%; X = H, R = 2,5-di-F, yield = 92%; X = 5-F, R = 4-F,
2-CH2, yield = 92%; X = 5-Cl, R = 4-F, yield = 90%; X = 5-CH3,
R = 4-F, yield = 91%; X = 5-Br, R = 4-F, 3-Cl, yield = 95%.
Singh et al.129 reported the ultrasound-assisted synthesis of
several β-cyanoepoxide derivatives (38.2) through epoxidation
of the corresponding β-cyanostyrenes (38.1) (see Scheme 38).
5.4. Reductions
Reducing amides to amines, esters to alcohols, and nitriles to
primary amines is an attractive target route for the
pharmaceutical industry. Several catalytic systems such as base
metals or metalloids, acids, enzymatic systems, etc., act as
effective catalysts for sustainable reduction reactions.131
Thomson et al.132 explored the use of scavengers with
frustrated Lewis pair (FLP) systems, and small amounts of an
alkylaluminum triisobutylaluminum (TIBAL) can avert poison-
ing and restore activity in a stalled reaction. The authors
proposed hydrogenations of imine substrates (40.1) employing
metal-free hydrogenation catalysts to synthesize amine deriva-
tives (40.2) with high yields, avoiding poisonous catalysts as per
earlier processes (Scheme 40).
Scheme 40. Metal-Free Hydrogenation of Imine Derivatives
to Synthesize Amines

Scheme 38. Ultrasound-Assisted Epoxidation of β-

Cyanoalkenes

Li et al. 133 proposed (10 mol %) that 5-bromo-2-

The reaction occurs in a 1:1 mixture of water and acetonitrile, benzothiopheneboronic acid (41.2) catalyzes the reduction of
employing the hypervalent iodide phenyliodo diacetate (PIDA) amides (41.1) to corresponding amines (41.3) in the presence
as an oxidant. The authors employed an ultrasonic bath with f = of a hydrosilane PhSiH3 (Scheme 41). The authors identified
40 kHz and P input of 50 W. The ultrasound favored the ring-
opening and the accompanying nucleophilic attack to yield the Scheme 41. Reduction of Amides to Amines by Boronic Acid-
β-cyanoepoxide derivatives. It also helps decrease the reaction Catalyzed Hydrosilylation
time from several hours to a few minutes, and the reaction could
be carried out at ambient room temperature.
Ghislieri et al.130 have developed a scheme to synthesize (R)-
harmicine (39.4) using the oxidase enzyme by two-step
transformations. In the first step, the indole derivative (39.1)
is oxidized to an iminium ion (39.2) trapped by the nucleophilic
indole to provide racemic harmicine (39.3). In the second step,
de-racemization in the same reaction vessel occurred via the
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Scheme 42. KOH-Catalyzed Reduction of Esters and Tertiary Amides to Alcohol and Amines, Respectively
the order of amide reactivity as tertiary > secondary > primary.
Additionally, the reducing reactivity can be explained by
increasing temperature and catalyst loading.
Fernández-Salas et al.134 reported a green synthesis scheme to
prepare alcohols (42.2) and amines (42.4) in high yields from
their corresponding esters (42.1) and tertiary amides (42.3)
under mild and environmentally friendly conditions. The system
catalyzed by KOH involves a simple hydrosilylation procedure
using 1.1 equiv of phenylsilane under solvent-free conditions
(Scheme 42).
Nicasio et al.135 demonstrated that Lewis acidity of boranes in
a FLP can effectively reduce electron-deficient olefins. Control
experiments showed that both components were necessary for
the reaction to occur. Applying the isolated borohydride reagent
followed by a 1,4-diazabicyclo[2.2.2]octane (DABCO)·H+
quench was not successful. The authors reported that the
optimal conditions were reached employing (2,4,6-F3Ph)3B as a
Lewis acid. A diverse set of substrates could be reduced using
this scheme where the olefin was activated by ester, sulfonyl, and
nitro groups. In the presented example, a nitroalkene derivative
(43.1) can be reduced to achieve a nitroalkane derivative (43.2)
in a one-step reaction (Scheme 43).
Scheme 43. Hydrogenation of Electron-Poor Alkenes to
Alkanes Employing Boranes as a Lewis Acid
Volkov et al.136 proposed a reduction of aryl or heteroaryl
tertiary amides (44.1), using 1.1 mol % [Ph-HEMIM][OTf], 1
mol % iron(II) acetate, 1 mol % LiCl, 2.2 mol % n-BuLi, and 3
equiv of polymethylhydrosiloxane (PMHS) in THF at 65 °C,
synthesizing the tertiary amine (44.2) in high yields with a
reaction time relatively shorter than previous approaches
(Scheme 44).
Scheme 44. Hydrosilylation of Tertiary Amides to Amines by
Iron/N-Heterocyclic Carbene Catalyst
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Junge et al.137 proposed an iron-catalyzed reduction of
carboxylic ester (45.1) to alcohols (45.2), using 5 mol %
Fe(stearate)2 with 10 mol % 1,2-diaminoethane as an ideal
iron−ligand combination (Scheme 45). The reductant poly-
Scheme 45. Fe-Catalyzed Reduction of Carboxylic Esters to
Alcohols
methylhydrosiloxane (PMHS) was used in 3.0 equiv in toluene
at 100 °C. Under these optimized conditions, the authors
reported that nitro, keto, and amide groups were fully reduced,
while the ester stayed mostly intact.
Hounjet et al.138 demonstrated the hydrogenation of 1,1-
diphenylethylene (46.1) to ethane-1,1-diyldibenzene (46.2)
with >95% conversion, using ether (C2H5O) as promoters
(Scheme 46). The crucial characteristics of this methodology are
Scheme 46. Conversion of Alkene to Alkane by Ethers and
B(C6F5)3 as Hydrogenation Catalysts
the Lewis basicity of the ether and the capability of the substrate
to produce a relatively stable tertiary cation. However, in the
absence of ether, dimerization of the substrate occurs.
Kumar et al.139 reported D-glucose as the only reducing agent
in a catalyst-free process to reduce nitroarenes (47.1) into
amines (47.2) (Scheme 47). The authors explored notable
chemoselectivity with halide, carbonyl, vinyl, and even addi-
tional nitro substituents staying unaltered by the conditions.
5.5. Amide Bond
The amide functionality is observed in a wide selection of
bioactive molecules like amino acids, proteins, and pharmaceut-
icals. The first choice to make amides is via acid chlorides, which
can be quite efficient and can be carried out in biphasic systems,
while one of the old-age synthesis routes of amides is through the
aid of coupling reagents with poor atom economy. Therefore,
the catalytic amide formation from nonactivated carboxylic acids
and amines is an emerging route considering GC and
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Scheme 47. Catalyst-Free Water-Mediated Reduction of
Nitroarenes to Amine Derivatives Using D-Glucose
sustainability principles.140,141 Microwave-assisted and biocata-
lytic/enzymatic pathways also come under the limelight for the
amide bond formation from diverse functional groups, which
replace many orthodox poor-atom-economy routes for the
synthesis of pharmaceuticals and their intermediates.142−144
Calcio Gaudino et al.145 proposed direct amidation of
carboxylic acids and amines at 100 °C in the presence of a
TiO2 powder catalyst (Aeroxide), under a monomodal micro-
wave reactor for 20 min. In Scheme 48, benzoic acid (48.1)
Scheme 48. Direct Amidation of Carboxylic Acids by TiO2
Catalysis under Mild Dielectric Heating
reacted with phenylmethanamine (48.2) to obtain N-
benzylbenzamide (48.3). The heterogeneous catalyst can be
recovered and regenerated by heating at 450 °C and reused for
over five cycles without losing % of yield, which strongly
supports the process’ sustainability.
A single-step, atom-economical, and redox-neutral ruthe-
nium-catalyzed amide synthesis from the reaction of alcohol and
nitrile was proposed by Kang et al.146 The optimal reaction can
occurred with the catalyst. The amide bond is effectively
constructed between the N atom of nitrile and the α-C of alcohol
with the help of an N-heterocyclic carbene-based ruthenium
catalyst RuH2(CO)(PPh3)3 with an 1,3-diisopropylimidazolium
bromide precursor (NHC) as a ligand with toluene at reflux as
the solvent and sodium hydride (NaH) added as base without
generating a single byproduct. In Scheme 49, 2-phenylethanol
(49.1) and cyclopropanecarbonitrile (49.2) reacted under the
mentioned reaction conditions to obtain N-(cyclopropylmeth-
yl)-2-phenylacetamide (49.3).
Scheme 49. A Single-Step Ruthenium-Catalyzed Amide
Synthesis from Nitrile and Alcohol
Wang et al.147 developed a hydroxyapatite-supported gold-
catalyst-mediated (Au/HAP) amide synthesis (N-benzylbenza-
mide (50.3)) by the reactions of primary alcohols including
aliphatic and benzylic ones (phenylmethanol (50.1)) and
amines (phenylmethanamine (50.2)) in water with up to 99%
yield (Scheme 50). The identified optimum conditions applied
NaOH as the base with 0.77 mol % of the Au/HAP catalyst with
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the reaction occurring under an oxygen atmosphere in H2O at
40 °C.
Scheme 50. Aerobic Oxidation of Primary Alcohols and
Amines to Synthesize Amides by a Hydroxyapatite-
Supported Gold Catalyst in Water
Das et al.148 proposed a clean synthesis of amide derivatives
(here, N-phenylbenzamide (51.3)) through the reaction of an
aryl carboxylic acid (here, benzoic acid (51.1)) and an aryl
amine (here, aniline (51.2)) employing nano magnesium oxide
(MgO) as a catalyst under solvent-free reaction conditions
(Scheme 51). The optimum catalyst load is 5 mol %, and it can
Scheme 51. Solvent-Free and Nano-MgO-Catalyzed Amide
Synthesis from an Aryl Carboxylic Acid and Amines
be recycled and reused five times without affecting its activity.
Regarding a carboxylic acid, the authors identified that aryl ones
are preferred over aliphatic carboxylic acids and long-chain
monocarboxylic acids.
Ayub Ali et al.149 showed solvent-free transamidation of
various amides and amines using heterogeneous Fe3+-exchanged
montmorillonite (Fe-mont) as a catalyst. The catalyst is
economical and recyclable for future usage. The reported
optimum reaction temperature is 140 °C over a reaction time of
30 h with 1 mol % of catalyst being utilized to synthesize N-
phenylacetamide (52.3) from the reaction between aniline
(52.1) and acetamide (52.2) (Scheme 52). The infrared
Scheme 52. Transamidation of Amides with Amines under
Solvent-Free Conditions and a Fe3+-Exchanged Clay Catalyst
analysis reveals that the initial interaction of the amide carbonyl
with Fe3+ sites on the catalyst’s surface causes an escalation in the
electrophilicity of the amide.
Sun et al.150 proposed H2O2-mediated amide formation from
aromatic amines, employing 1,3-diketones as the acylating
agent. The reaction occurred through a novel C−C bond
cleavage under oxidative metal-free conditions with water as the
solvent. The authors identified 30% aqueous and 3 equiv of
H2O2 to be the optimal oxidant for excellent yields. Interestingly,
aliphatic amines failed to react under the reaction conditions. In
Scheme 53, 4-bromoaniline (53.1) reacted with 1,3-diketone
(53.2) to obtain N-(4-bromophenyl)isobutyramide (53.3) at
room temperature under the above-mentioned reaction
conditions.
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Scheme 53. H2O2-Mediated Oxidative Formation of Amide
Derivative from 1,3-Diketone and Aromatic Amine
Gaspa et al.151 proposed a radical-type mechanism to
synthesize an amide (54.3) by reacting a benzylic alcohol
derivative (54.1) and an amine derivative (54.2) utilizing FeCl3·
6H2O with 70% aqueous tert-butyl hydroperoxide (TBHP) as
the oxidant. In the beginning, the amine is reacted with N-
chlorosuccinimide (NCS) to create the N-chloroamine in situ,
which is further treated with the alcohol, catalyst, and oxidant
(Scheme 54). Depending on the types of amines, both primary
and secondary amides can be synthesized.
Scheme 54. Iron-Catalyzed Oxidative Amidation of Alcohol
with Amine
Ghosh et al.152 reported another radical-type mechanism
utilizing Fe(NO3)3·9H2O as the catalyst for a tandem-fashion
reaction between aromatic alcohol and amine derivatives.
Primarily, the alcohol is oxidized in the presence of (2,2,6,6-
tetramethylpiperidin-1-yl)oxyl (TEMPO) and catalytic
amounts of the iron salt with air as the stoichiometric oxidant.
After 2 h, calcium carbonate, the amine HCl salt, and 70%
aqueous TBHP are added, and the reaction is heated to 60 °C for
16 h to form the amide. In Scheme 55, morpholino(phenyl)-
methanone (55.3) is synthesized via the reaction between
phenylmethanol (55.1) and morpholine (55.2) under the
mentioned conditions.
Scheme 55. Tandem Oxidative Amidation of Benzyl Alcohols
with Amine Hydrochloride Salts
Soulé et al.153 demonstrated the direct amidation of alcohols
and amines using heterogeneous-polymer-incarcerated gold
nanoparticles (PICB-Au) as the catalyst. Primary amines reacted
to alcohols under 1 mol % of a bimetallic PICB-Au/Co system
using NaOH as the base for activated alcohols. To obtain the
optimum yield, the solvent system should be mixed in the 19:1
(THF/H2O) ratio, and the concentration will be 0.75 M. The
whole reaction proceeds at ambient temperature under an
oxygen atmosphere. In Scheme 56, pyridin-2-ylmethanol (56.1)
and phenylmethanamine (56.2) reacted under the above-
mentioned conditions to obtain N-benzylpicolinamide (56.3).
Lebleu et al.154 proposed a simple transamidation method for
the formylation of amines using formamide. Water played a
crucial role in promoting the reaction as a solvent, and the whole
reaction occurred neat at 80 °C for 24 h to obtain optimal yield.
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Scheme 56. Amidation from Aromatic Alcohol and Aromatic
Amine through Tandem Oxidation by Gold Nanoparticles
under Aerobic Conditions
The reaction worked well for a range of aliphatic, aromatic, and
heteroaromatic amines with only a stoichiometric amount of
formamide. In Scheme 57, N-methyl-1-phenylmethanamine
(57.1) reacted with formamide to obtain N-benzyl-N-
methylformamide (57.2).
Scheme 57. Formylation of Amines through a Solvent- and
Catalyst-Free Transamidation Reaction
A few more amide formation reaction schemes employing GC
and engineering are displayed in Schemes 58,155 59,156 60,157
61,158 and 62.159
5.6. Alcohol Activation for Nucleophilic Displacement
Alcohols are crucial building blocks in the synthesis of APIs and
their intermediates. Activation of alcohol to facilitate nucleo-
philic substitution reactions to construct new C−C or C−N
bonds is an important reaction scheme in pharmaceutical
synthesis. The activation of alcohols by the short-term removal
of hydrogen has drawn good attention over the years, but the
substrates that work as good ligands for the catalyst need higher
catalyst loadings and temperatures in most cases. Thus,
uncovering simple, economic catalysts capable of accomplishing
alcohol activation for nucleophilic displacement under milder
conditions is another step toward green synthesis and GC.160,161
Pei Shan et al.162 reported N-alkylation of primary and
secondary amines by primary alcohols to generate the alkylated
products in a 62−99% yield. The reaction is catalyzed by
recyclable ruthenium catalysts synthesized from polystyrene- or
silica-supported phosphine ligands at 120−140 °C temperature
for 24 h (Scheme 63). The strategy has been implemented in the
synthesis of the anti-Parkinson agent piribedil with a yield of
98%.
Donthiri et al.163 proposed a metal-free N-alkylation of 2-
amino-substituted benzothiazoles (64.1) (pyridine, thiazoles,
pyrazine, and pyrimidine can be used too) with benzyl alcohols
(64.2) to produce N-benzyl 2-aminothiazole (64.3). The
reaction is performed in toluene at 120 °C with 20 mol %
NaOH as a catalyst (Scheme 64).
Chan et al.164 described the rhodium-catalyzed methylation of
aromatic and cyclopropylketones using methanol as the
methylating agent and the hydrogen-borrowing method.
Especially alkylated ketones can be synthesized from methyl
ketones and two distinct alcohols through a sequential one-pot
rhodium- and iridium-catalyzed process. In Scheme 65, 2-
methyl-1,3-diphenylpropan-1-one (65.2) is synthesized from
acetophenone (65.1) under the mentioned reaction conditions.
Bala et al.165 demonstrated the effectiveness of Fe(II)-
phthalocyanine (FePc) as a catalyst in N-alkylation between
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Scheme 58. A Direct Amide Derivative Synthesis (58.3) from a Carboxylic Acid Derivative (58.1) and an Amine Derivative (58.2)
Using B(OCH2CF3)3
Scheme 59. Hydration of a Nitrile Derivative (Picolinonitrile
(59.1)) to Synthesize an Amide Derivative (Picolinamide
(59.2)) by Acetaldoxime and Oxometallate
Scheme 60. Amidation of Aldehydes or Alcohols (60.1) with
Ammonium Salts (Ammonium Bicarbonate (60.2))
Catalyzed by Et4NI
Scheme 61. Metal-Free Amidation of Alkyl/Aryl Aldehydes
(Benzaldehyde (61.1)) Using N-Chloroamines (N-Chloro-1-
phenylmethanamine (61.2)) to Synthesize a Secondary
Amide (N-Benzylbenzamide (61.3)) Using
Azobisisobutylonitrile (AIBN) as the Initiator
Scheme 62. Desulfurization of Thioamides (1-(Piperidin-1-
yl)-2-(pyridin-3-yl)ethanethione (62.1)) into Amides (1-
(Piperidin-1-yl)-2-(pyridin-3-yl)ethenone (62.2)) under the
Visible-Light and Aerobic Condition Catalyzed by Eosin Y
Organophotoredox
Scheme 63. Alkylation of Piperidine (63.1) by
Cyclohexylmethanol (63.2) under Ruthenium as a Catalyst to
Obtain 1-(Cyclohexylmethyl)piperidine (63.3)
heterocyclic amines and alcohol in toluene with sodium tert-
butoxide at 120 °C. In Scheme 66, o-phenylenediamine (66.1)
reacted with primary alcohol (66.2) to obtain the 2-substituted
benzimidazole derivative (66.3) with a good yield of 92%
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Scheme 64. N-Alkylation of Hetero Aromatic Primary
Amines via Reaction with Benzyl Alcohols under NaOH as a
Catalyst
Scheme 65. Synthesis of α-Branched Derivatives through the
Rhodium-Catalyzed Ketone Methylation
Scheme 66. One-Pot Synthesis of N-Alkylation of
Heterocyclic Amines with Alcohols to Synthesize 2-
Substituted Benzothiazoles, Benzimidazoles, and
Benzoxazoles
(Scheme 66). Starting with diverse substituted heterocycles, one
can synthesize various benzazoles like benzothiazoles, benzox-
azoles via ring closures of ortho-substituted anilines reacting
with alcohols. The authors reported that the hydrogen transfer
mechanism of alcohol oxidation, imine coupling, and reduction
was verified by intermediate trapping with improved reaction
conditions.
Reddy et al.166 proposed the N-alkylation of heterocyclic
amines/anilines with benzyl alcohols via an SN1 reaction under a
heterogeneous catalyst named nanosized zeolite beta. The
reactions are run neat with 3 equiv of alcohol at 135 °C for 18−
24 h achieving the benzylation of a range of anilines and some
heterocyclic amines in moderate to good yields. The catalyst can
be recovered by filtration, recalcinated, and reused three times
for the benzylation of aniline without losing its activity and the
obtained yield. In Scheme 67, 1,2,3,4-tetrahydroisoquinoline
(67.1) reacted with benzyl alcohol (67.2) to obtain 2-benzyl-
1,2,3,4-tetrahydroisoquinoline (67.3).
Reactions related to alcohol activation for nucleophilic
displacement for GC are illustrated in Schemes 68,167 69,168
and 70.169
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Scheme 67. N-Alkylation of Amines with Alcohols Using
Nanosized Zeolite Beta
Scheme 68. N-Alkylation of Amines (Dipropylamine (68.1))
with Alcohols (68.2) Using Heterogeneous Ni Catalysts to
Synthesize the N,N-Dipropoyl-1-amine Derivative (68.3)
Scheme 69. Methylation of Amines, Nitrobenzenes, and
Aromatic Nitriles Employing CO2 and H2 and CuAlOx as a
Catalysta
a
N,N-Dimethyl-1-phenylmethanamine (69.1) synthesized from ben-
zonitrile (69.2).
Scheme 70. One-Pot Palladium-Catalyzed Synthesis of
Thioethers (Benzyl(phenyl)sulfane (70.3)) from Alcohol
(Benzyl Alcohol (70.1)) and Thiols (Benzenethiol (70.2))
5.7. Metal-Catalyzed Cross-Coupling
The metal-catalyzed cross-coupling reactions have been playing
critical roles over the decades. The introduction of new catalytic
methods employing metals is appealing due to the low cost,
ready accessibility, and very low toxicity in most cases.170−172
Over the past few years, iron-catalyzed cross-coupling reactions
have been profoundly used in the pharmaceutical industry due
to their sustainable nature and have been identified as green
catalyst alternatives to precious metals.191,192 The iron-catalyzed
system offers such perspectives as robustness and operational
simplicity, scalability, and sustainability in medicinal chemistry
applied to the pharmaceutical industry. In the present review, we
have confined our discussion only to the sustainable method-
ology of iron-catalyzed cross-coupling reactions implemented in
the synthesis of pharmaceuticals.
Bartoccini et al.173 reported a one-step cross-coupling of
halopurines in the presence of iron as a catalyst. The authors
reported that 1 mmol of 2-chloropurine (71.1) reacted with 1.2
equiv of n-butyl Grignard reagent (71.2) in THF. The reaction
proceeded under mild reaction conditions (room temperature in
1 h) in the presence of 10 mol % of iron(III) tris-
(acetylacetonate) [Fe(acac)3] as the precatalyst in THF/N-
methylpyrrolidone (NMP) (6:1 v/v, 15 mL) to obtain an
important intermediate of ST1535 (Scheme 71). The iron-
catalyzed Kumada cross-coupling reaction employing the
Fe(acac)3/NMP catalytic system offered the high-yield syn-
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Scheme 71. Synthesis of ST1535 through C(sp2)−C(sp3)
HetAryl−Alkyl Cross-Coupling
thesis of the ST1535, a selective adenosine A2A antagonist,
which is used for Parkinson’s disease.
Shakhmaev et al.174 proposed the effect of substoichiometric
amounts of NMP on C(sp2)−C(sp2) allyl−aryl cross-coupling
using 1 mol % of Fe(acac)3. The suggested approach can provide
a short synthesis route of allylamine pharmaceuticals such as
cinnarizine, naftifine, flunarizine, etc. The cross-coupling of
(2E)-3-chloro-N-methyl-N-(naphthalen-1-ylmethyl)-prop-2-
en-1-amine (72.1) with phenylmagnesium bromide (72.2) gave
naftifine (72.3) (an 89% yield with 98% stereoselectivity), an
antifungal drug used to treat skin infections, in the presence of 1
mol % of Fe(acac)3 in a mixture of THF with NMP (Scheme
72). It is interesting to mention that NMP, a reprotoxic, is
Scheme 72. Synthesis of Naftifine via the C(sp2)−C(sp2)
Allyl−Aryl Cross-Coupling
strategically used in substoichiometric amounts, which can
drastically decrease the reaction steps and time and obtain
higher yields compared to earlier methods.
Bisz and Szostak175 reported that cyclic ureas (1,3-dimethyl-
2-imidazolidinone (DMI), N,N-dimethylpropyleneurea
(DMPU)) can be efficient and sustainable alternatives to
NMP in iron-catalyzed alkylations of aryl chlorides or tosylates
(73.1) with alkyl Grignard reagents (73.2) to prepare a alkyl-
substituted aryl derivative (73.3) (Scheme 73). The authors
Scheme 73. Iron-Catalyzed Cross-Coupling of Aryl
Chlorides/Tosylates with Alkyl Grignard Reagent
confidently demonstrated that the proposed environmentally
benign approach achieves the C(sp2)−C(sp3) cross-coupling
with organometallics possessing β-hydrogens with efficiency
matching or better than NMP. To prove the point, the authors
applied their proposed method in the key coupling in the
synthesis of a dual NK1/serotonin receptor antagonist.
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Another important Fe-catalyzed cross-coupling reaction of
tert-alkyl electrophiles is reported by Tindall et al.176 The
authors reported the reaction of 1-alkynylcyclopropyl tosylates
(74.1) with alkylmagnesium halides (74.2) in the presence of
catalytic [Fe(acac)3] to prepare allene derivatives (74.3)
(Scheme 74).
Scheme 74. Cross-Coupling of 1-Alkynylcyclopropyl
Tosylates
Parmar et al.177 illustrated the iron-catalyzed cross-coupling of
3-iodoazetidines with various methyl, aryl, and vinyl Grignard
reagents to prepare functionalized azetidines. The azetidine
scaffold is vital for the synthesis of drugs for CNS disorders and a
calcium channel blocker (e.g., azelnipidine). The cross-coupling
reaction of 3-iodoazetidine (75.1) with (4-fluorophenyl)-
magnesium bromide (75.2) in the presence of [Fe(acac)3],
THF, and tetramethylethylenediamine (TMEDA) generates the
precursor (75.3) of the drug molecule used for CNS disorders
(Scheme 75).
Scheme 75. Cross-Coupling Reaction in the Synthesis of
Drugs for CNS Disorders
Sova et al.178 invented a sustainable ligand D-glucosamine for
Fe-catalyzed C−C cross-coupling reactions. The presented
scheme suggested a reaction between aryl and benzyl Grignard
reagents with alkenyl and allyl bromides in the presence of the
Fe(acac)2/D-glucosamine·HCl/Et3N catalytic system. The
introduction of biocompatible ligands in iron catalysis makes
the synthetic route promising. It was successfully implemented
in the synthesis of sitagliptin, a DPP-4 inhibitor used to treat
type II diabetes mellitus. In Scheme 76, (E)-3-bromoprop-1-en-
1-yl acetate (76.1) reacted with (2,4,5-trifluorophenyl)-
Scheme 76. Synthesis of Sitagliptin Precursor through Fe(acac)2/D-Glucosamine-Catalyzed C−C Cross-Coupling Reactions
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magnesium bromide (76.2) to prepare one of the important
precursors (76.3) of sitagliptin.
Jin et al.179 reported the first Fe-catalyzed enantioselective
cross-coupling reaction between an organometallic and an
organic electrophile compound in the presence of Fe(acac)3 as a
catalyst and a chiral highly electron-rich bisphosphine ligand
[(R,R)-BenzP*]. The reaction scheme illustrates the cross-
couplings of alkyl electrophiles for the sustainable synthesis of
enantio-enriched products (enantioselectivities up to 91:9).
Later, this system was successfully implemented in the synthesis
of dexibuprofen, the active enantiomer of ibuprofen. In Scheme
77, α-haloalkanoates (77.1) reacted with an aryl Grignard
reagent (77.2) to obtain α-arylalkanoic acids (77.3), an
important precursor of dexibuprofen under the above-
mentioned reaction conditions.
5.8. Organocatalysis
The term “organocatalysis” illustrates the acceleration of
chemical reactions by adding a substoichiometric quantity of
an organic compound without influencing the position of the
reaction equilibrium. In chemistry, a series of catalysts evolved
from metals/organometallic catalysts to biocatalysts to organo-
catalysts.180,181 The implication of metals and organometallic
compounds as catalysts in the synthesis scheme possesses
serious environmental concerns, mostly related to their
ecotoxicity and generating huge amounts of metal waste. In
this concept, enzymes/biocatalysts and small organic molecules
or organocatalysts came to the rescue to make the synthetic
chemistry greener and environmentally friendly. The green
reactions related to biocatalysis have been discussed in the above
section. Therefore, the present section is confined to organo-
catalysis.182 Along with the greener aspect, organocatalysis offers
multiple advantages:182,183
• Organocatalysts are robust, inexpensive, and readily
available.
• The reaction can occur under mild conditions (most of
the time), saving energy.
• Organocatalysts are less toxic to nontoxic in nature and
safer than organometallics.
• Organocatalysts are inert toward oxygen and moisture.
Thus, they are oxygen-stable reagents and do not require
anhydrous conditions.
• They are compatible with several functional groups that
are sensitive to organometallics and/or biocatalysis. Thus,
in most cases, there is no need to protect specific
functional groups, which reduces the number of reaction
steps.
• Using organocatalysts prevents generation of metallic
waste.
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Scheme 77. Cross-Couplings of an Organometallic and an Organic Electrophile to Synthesize an Enantio-Enriched Compound

Scheme 78. Green Synthesis through Heterogeneous Organocatalyst Polystyrene-Supported cis-4-Hydroxydiphenylprolinol TBS
Ether

Scheme 79. Green Synthesis through Organocatalysis Employing Amino Aromatic Tf-Amide

Scheme 80. Green Synthesis through C2-Symmetric Tertiary Amine-Squaramide as Organocatalyst

• The use of organocatalysts in the syntheses of most
pharmaceutical products prevents metal contamination.
Therefore, organocatalysis is the first choice in most of the
synthesis schemes.
The most frequently employed organocatalysts are L-proline,
nobin, 4-dimethylaminopyridine (DMAP), quinine, thiourea
derivative, TMS-protected (S)-diphenylprolinol, (S)-proline,
squaramide, dipeptide, cinchonidine, MacMillan’s catalyst,
etc.181−184
Among the organocatalysis reactions, asymmetric organo-
catalysis184−186 is becoming a significant tool for synthesizing
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chiral compounds related to pharmaceuticals and bioactive
molecules. Asymmetric organocatalysis can be combined with
diverse intensification techniques such as ball milling, high
pressure, flow, ultrasound, and microwave as well as introducing
sustainable reaction media such as supercritical CO2, ILs, water,
and deep eutectic solvent. Even in no-solvent conditions, it is
possible to achieve the perfect green synthesis.
Ö tvös et al.187 proposed a solvent-free enantioselective
conjugate addition of malonate to unsaturated (E)-3-(4-
fluorophenyl)acrylaldehyde in the presence of acetic acid and
catalyzed by a heterogeneous organocatalyst polystyrene-
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supported cis-4-hydroxydiphenylprolinol TBS ether (OC1) to
synthesize an important chiral diester intermediate of the
antidepressant drug (−)-paroxetine. The reaction proceeded
with high chemo- and stereoselectivity just in the presence of the
catalyst OC1 with f = 0.464 mmol g−1, achieving an 84% yield
and 97% ee in 7 h of the continuous flow experiment (Scheme
78).
Lee et al.188 reported that the optically pure primary amino
aromatic Tf-amide organocatalyst (OC2) offers an environ-
mentally benign approach to carry out the asymmetric aldol
(79.3/79.4) reaction of cycloalkanones (79.1) with diverse aryl
aldehydes (79.2) under an aqueous environment (here, brine).
Around 5 mol % of the catalyst offers good yields followed by
diastereo- and enantioselectivities (99:1 of 79.3 and 79.4 with
72−96% yield and 99% ee) (Scheme 79).
Kucherenko et al.189 detailed asymmetric Michael reactions of
kojic acid derivatives (80.1) with nitroolefins (80.2) catalyzed
by a highly efficient 1 mol % C2-symmetric tertiary amine−
squaramide organocatalyst (OC3) (Scheme 80) to prepare kojic
acid-derived adducts (80.3). The whole one-pot reaction is
performed under green conditions of either 96% ethanol or pure
water with enantioselectivity up to 99% without the requirement
of chromatographic purification.
Murphy et al.190 developed a catalytic strategy for the
enantioselective C−C bond formation, generating quaternary
stereogenic centers important for drug synthesis of many
biological interests. The authors employed a chiral organic
catalyst (OC4) with a redox-active carbazole moiety in
conjugate additions of benzodioxole derivative (81.1) with β-
substituted cyclic enones (81.2) to obtain compounds with
quaternary carbon stereocenters (81.3) (Scheme 81). The
Scheme 81. Green Synthesis through Organocatalysis
Employing a Chiral Organic Compound
authors used 5 mol % tetrabutylammonium decatungstate
(TBADT) and Ir[dF(CF3)ppy]2(dtbbpy)PF6 as the photo-
catalyst, which can simply generate a nucleophilic carbon-
centered radical by homolytically cleaving the methylene C−H
bond in the benzodioxole derivative via a hydrogen atom
transfer (HAT) mechanism.
Modrocká et al.191 investigated the Michael addition of 4-
hydroxycoumarin (82.1) with benzylideneacetone (82.2),
which directly produces the chiral anticoagulant drug (S)-
warfarin (82.3) in the presence of a squaramide catalyst (OC5)
(Scheme 82). The authors obtained (S)-warfarin in 90% ee
using either cyclopentyl(methyl)ether (CPME) or 2-methylte-
trahydrofuran (2-MeTHF) as a green solvent. Considering the
(S)-warfarin yield % and ee, it was identified that 2-MeTHF is
superior to CPME.
A chiral amino acid amide-based ionic liquid (OC6) acts as an
organocatalyst for replacing chiral transition-metal catalysts in
the asymmetric transfer hydrogenation of acetophenone (83.1)
using 2-propanol (83.2) as the hydrogen source to prepare the
enantio-enriched (S)-alcohol (83.3).192 Javle and Kinage192
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Scheme 82. Green Synthesis Employing a Squaramide
Derivative as an Organocatalyst
synthesized the ionic liquid by completing the amidation of
alanine with 4-chloroaniline, followed by the protonation of the
intermediate product with perchloric acid in dichloromethane.
The ionic liquid organocatalyst can be recycled and reused at
least three times without losing its stereoselectivity and the %
yield of the desired (S)-alcohol (ee 96−97%) (Scheme 83).
5.9. Biocatalysis
Biocatalysis is a chemical process through which biological
catalysts or enzymes generated from living systems (microbial
enzymes) carry out reactions between organic components. To
support the principles of GC, biocatalysis has been employed
extensively in the chemical and pharmaceutical industries.25,26
Over the years, especially, the pharmaceutical industry has
observed tremendous use of biocatalytic processes in small drug
molecule discovery.193−198 Biocatalysis has been integrated into
the mainstream organic synthesis particularly for the enantio-
selective synthesis of APIs, as many of the formulations exist as
enantiomers. Thus, the use of enantiomer-specific enzymes
offers the generation of definite enantiomers. The asymmetric
synthesis of enantiomeric chiral compounds can be prepared
with the help of a series of enzymes with outstanding selectivity
and specificity profiles. Considering the GC aspects, biocatalysis
offers the following characteristics over the traditional routes:
significantly reduced waste; more atom and step economy; low
environmental hazards; safer solvents and auxiliaries, as the
process is usually performed in water; energy-efficient, renew-
able enzymes for a certain period of time; evading the need for
functional group activation and circumventing the protection
and deprotection steps; environmentally compatible catalyst
enzymes; and finally mild and safe conditions (physiological pH
and temperature). Among the enzymes, oxidoreductase,
ketoreductase, diketoreducatase, amino acid dehydrogenases,
transminases, α-transminase, lipase, protease, adolase, and
nitrile hydratasephenylalanine-ammonia-lyase have shown
widespread use in the pharmaceutical industry.25,26 Enzymatic
processes have a great capacity for one-pot cascades, as reaction
conditions tend to be more comparable than chemical reactions.
6-Aminopenicillanic acid (6-APA) is a major raw material for
preparing semisynthetic penicillin and cephalosporin, by
hydrolysis of penicillin G. Previously, a chemical procedure for
the hydrolysis involved an environmentally hazardous reagent,
chlorinated hydrocarbon solvent (CH2Cl2), and a reaction
temperature of −40 °C. To produce 1 kg of 6-APA, 1.2 kg of
PCl5, 0.6 kg of Me3SiCl, 0.2 kg of NH3, 1.6 kg of PhNMe2, 8.4 L
of CH2Cl2, and 8.4 L of n-BuOH were required. On the contrary,
the enzymatic cleavage of penicillin G is performed in water at
37 °C with only NH3 (0.09 kg/kg of 6-APA) as a reagent, used to
adjust the pH (Scheme 84).199 In Scheme 84, penicillin G
(84.1) goes through chemical diacylation and enzymatic
diacylation to generate an intermediate (84.2) and 6-APA
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Scheme 83. Ionic Liquid as an Organocatalyst for Green Synthesis
Scheme 84. Biocatalytic Reaction in the Synthesis of 6-APA
(84.3). Later, the 6-APA can be prepared from the intermediate
in the presence of n-BuOH and water at a specified temperature.
Ked̨ ziora et al.200 evaluated the ability of R-specific alcohol
dehydrogenases (ADHs) for the bioreduction of several α,α-
dichloroacetophenone (85.1) derivatives from Lactobacillus
brevis LB19 (LBADH) (Scheme 85). The chiral secondary
Scheme 85. Biocatalytic Reaction in the Synthesis of Primary
and Secondary Alcohol
alcohols (85.2) can be produced from α,α-dichloroacetophe-
none derivatives (85.1) with this biocatalytic reaction with good
conversion and ee. Similarly, aldehydes can also be converted to
primary alcohols with the help of LBADH. In Scheme 85,
propionaldehyde (85.3) is converted to propan-1-ol (85.4)
under similar conditions.
Rajagopalan et al.201 have discovered an enzyme capable of
transforming styrene-type substrate (86.1) to aldehydes (86.2).
The enzyme was obtained from the fungus Trametes hirsuta and
expressed in E. coli. The enzyme has a proteinase backbone and
is dependent on manganese (Mn(III)) in oxidation state 3 for
catalytic activity with oxygen as the terminal oxidant. The
reaction occurred under mild conditions in the presence of
NaH2PO4 buffer (Scheme 86).
The asymmetric hydrogenation of unfunctionalized imines is
́
reported by Rodriguez-Mata et al.202 employing an (R)-selective
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Scheme 86. Biocatalytic Reaction in the Synthesis of
Aldehyde
imine reductase (IRED), Q1E1E0 from Streptomyces kanamy-
ceticus. In the presence of (R)-IRED, the 2-methyl-1-pyrroline
(87.1) can be reduced to (R)-2-methylpyrrolidine (87.2)
(Scheme 87).
Scheme 87. Biocatalytic Reaction in the Synthesis of (R)-2-
Methylpyrrolidine in the Presence of IRED
The synthesis of chiral amines is highly desirable in the
pharmaceutical industry. O’Reilly et al.203 have demonstrated
the synthesis of trans-2,5-disubstituted pyrrolidines (88.2) from
asymmetric diketone (88.1) using both the ω-transaminase
(TA) family and variants of monoamine oxidase from Aspergillus
niger (MAO-N) enzymes together in a cascade reaction
(Scheme 88). The TAs can facilitate the selective reductive
amination of prochiral ketones, thus generating the subsequent
chiral amines. On the other hand, MAO-N catalyzes the oxygen-
dependent conversion of amines into imines, and it is selective
for the (S)-enantiomer. In this route, (S)-selective transaminase
sets the first stereocenter at the methyl ketone, and the amine
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Scheme 88. Biocatalytic Reaction in the Synthesis of trans-
2,5-Disubstituted Pyrrolidine Derivative
cyclizes into the second ketone to form the pyrroline. Later, it is
reduced nonselectively with borane, while the MAO-N oxidizes
one enantiomer back to the pyrroline. Using this approach, a
single diastereoisomer of the pyrrolidine (88.2) is formed in a
one-pot synthesis with an excellent yield of 82%.
Liu and Li204 established a one-pot cascade synthesis
including enantioselective reduction of a CC double bond
followed by Baeyer−Villiger oxidation and lactone hydrolysis for
synthesizing enantiopure δ-lactones. An enoate reductase from
Acinetobacter sp. RS1 catalyzes the enantioselective reduction of
the CC double bond of 2-alkylidenecyclopentanones (89.1)
to produce (R)-2-hexylcyclopentanone (89.2). This is followed
by a Baeyer−Villiger oxidation performed by cyclohexanone
monooxygenase (CHMO) expressed in E. coli and glucose
dehydrogenase (GDH) from Bacillus subtilis with S enantiose-
lectivity to produce (R)-2-alkyl-δ-lactones (89.3) with an 83%
yield and 98% ee along with the S-form (89.4). Later, an
enantioselective lactone hydrolase from Acinetobacter sp. RS1
produces a carboxylic acid derivative (89.5) (Scheme 89).
Wu et al.205 discovered a cascade biocatalysis via intracellular
epoxidation and hydrolysis for enantioselective dihydroxylation
of aryl olefins (90.1) to prepare chiral vicinal diols. The E. coli
(SSP1) coexpressing styrene monooxygenase (SMO) and
epoxide hydrolase SpEH were used as a biocatalyst for S-
enantioselective dihydroxylation of terminal aryl olefins to
prepare (S)-vicinal diols (90.2). Again, E. coli (SST1)
coexpressing SMO and epoxide hydrolase StEH offered
complementary regioselectivity to SpEH as a biocatalyst to
prepare (R)-vicinal diols (90.3) through R-enantioselective
dihydroxylation of aryl olefins. With the change of E. coli SSP1 to
SST1 and SpEH to StEH, one can reverse the overall
enantioselectivity to produce S and R vicinal diols from olefins.
The authors showed the synthesis of multiple S vicinal diols with
an obtained range of 92.2−98.6% ee, while the % ee for R-vicinal
diols is 84.2−98.2%. This biocatalysis route (Scheme 90) has an
immense role to play in the pharmaceutical industry for green
synthesis.
Coelho et al.206 have designed a cytochrome “P411” with
distinctive serine−heme ligation, which catalyzes selectively and
efficiently olefin cyclopropanation in intact E. coli cells. The
mutation C400S in cytochrome P450BM3 from Bacillus
Scheme 89. Biocatalytic Synthesis of Enantiopure (R)-2-Alkyl-δ-lactones
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megaterium offers a signature ferrous CO Soret peak at 411
nm, raises the resting-state FeIII-to-FeII reduction potential by
substituting a cysteine thiolate ligand with a weakly donating
serine, abolishes monooxygenation activity, and substantially
improves NAD(P)H-driven activity. This engineered enzyme is
capable of performing the cyclopropanation of styrene (91.1)
under anaerobic conditions in the presence of ethyldiazoacetate
(91.2) and potassium phosphate (KPi). The formed 9:1 cis and
trans products (91.3 and 91.4) reported good yields with high
diastereo- and enantioselectivity (Scheme 91).
McIntosh et al.207 reported an intramolecular C−H
amination in azide substrate (in Scheme 92, 2,4,6-triethylbenze-
nesulfonyl azide (92.1)) employing the engineered P450BM3
enzyme expressed in E. coli cells in vivo under anaerobic and
reducing conditions (enzyme loading of 0.5 mol % in aqueous
media, 0.1 M KPi buffer, 2.5% v/v DMSO) with high yields and
total turnover numbers (TTNs) of sulfonamide (92.2) and
2,4,6-triethylbenzenesulfonamide (92.3) (Scheme 92).
Terpenoid products obtained from the cyclization of a
polyisoprene backbone have important applications from chiral
building blocks in synthesis to therapeutic compounds such as
taxol and artemisinin. Seitz et al.208 discovered that di- and
triheterocycles can be prepared from functionalized and
shortened polyisoprene units (93.1/93.3) using triterpene
cyclases. The squalene−hopene cyclase (SHC) from Zymomo-
nas mobiliz (Zmo(SHC1)) can produce enol ethers, cyclic
ethers, and lactones from a range of terminal nucleophiles. This
cyclase enzyme is highly flexible, efficient, and versatile to act as a
general Brønsted acid catalyst. This reaction step is beneficial for
preparing terpenoid products from polyisoprene units. In
Scheme 93, di- and triheterocycles (93.2 and 93.4, respectively)
were prepared from polyisoprene units (93.1 and 93.3) in the
presence of Zmo(SHC1) and citrate buffer.
6. ONE-POT CASCADE SYNTHESIS
The idea of a one-pot synthesis has a considerably broader
meaning than a simple one-pot cascade, a tandem reaction, or
domino reaction types, which are comparatively interchange-
able. Process chemists often execute multistep reactions in a
single reactor without the requirement to isolate intermediates,
which is generally termed as a telescoped reaction. The idea of a
one-pot synthesis comprises all of these reaction types as well as
the multistage approaches that are implemented in a single
vessel or reactor.209 Biocatalytic reactions and multicomponent
reactions (MCRs) are also performed under the concept of a
one-pot synthesis in many instances. Therefore, in this section,
we have focused only on a one-pot cascade synthesis, as
biocatalytic reactions were discussed under section 4, and MCRs
are discussed in section 7. The idea behind the one-pot synthesis
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Scheme 90. Biocatalytic Synthesis of S and R Vicinal Diols from Aryl Olefins
Scheme 91. Biocatalytic Reaction in Cyclopropanation of Styrene
Scheme 92. Biocatalytic Synthesis of Sulfonamide and the C−
H Aminated Product
Scheme 93. Biocatalytic Synthesis of Di- and Triheterocycles
from Polyisoprene Units
irrespective of types is the same. A one-pot synthesis offers
continuous chemical reactions in just one reactor, reducing the
reaction time and efforts along with the final waste, and prevents
a lengthy separation and purification process of the inter-
mediates, ultimately increasing the chemical yield.210−213
Nitro-azabicycles (94.3) are one of the important scaffolds for
drug design and discovery. Modification of the stereocenters and
functional groups around the core of nitro-azabicycles can lead
to diverse bioactive compounds such as epiquinamide
derivatives, polyhydroxylated azabicycles, decahydro-[1,7]-
naphthyridine, crispine A oxime, etc. Disadee and Ruchirawat214
illustrated a one-pot cascade metal-free synthesis of nitro-
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azabicycles (94.3) involving double intramolecular cyclizations
via the nitro-Mannich reaction and N-alkylation via an imine or a
cyclic iminium ion reliant on the mode of ring-size annulation
(Scheme 94). The authors reported 15 azabicycle derivatives,
Scheme 94. Examples of a One-Pot Metal-Free Simple
Cascade Synthesis
employing the reported scheme offering diverse ring systems of
azabicycles with yields up to 81% and an isomeric ratio of 62:1.
The reported approach provides atom and step economy along
with the flexibility to introduce a functionalized side chain to
prepare a series of azabicycles.
Fang et al.215 proposed a multicomponent, catalytic, one-pot
double asymmetric cascade reaction for synthesizing chlorinated
oxindoles (95.4) and geminal diamines (C−N aminals) (95.5).
The asymmetric cascade reaction occurred among 3-arylox-
indoles (95.1), NBoc imines (95.2), and N-chlorophthalimide
(95.3), where a calcium VAPOL phosphate complex acted as a
catalyst (Scheme 95). The synthesis scheme offers two
structurally complex and diverse chiral end-products with high
levels of stereocontrol in one pot. The reported conversion is
facile in nature and provides a high degree of both step and atom
economy.
Mertens et al.216 discovered a two-step one-pot chemo-
enzymatic cascade reaction to successfully synthesize a
methylene-bridged bis(2-substituted benzofuran) (96.4). The
one-pot synthesis is catalyzed by mutual deactivation of metal
and biocatalysts. In the first stage, a palladium-free Sonogashira
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Scheme 95. Examples of a One-Pot Asymmetric Cascade Synthesis
reaction was employed to synthesize a benzofuran derivative
(96.3) from the reaction of 2-iodophenol (96.1) and 3-
dimethylamino-1-propyne (96.2). The reaction occurred in the
presence of the Cu scorpionate catalyst (the complex
[CuCl2{HC(Pz)2MeIm}] ({bis(pyrazolyl)(methyl imidazol-
yl}-methane copper(II) chloride)) and DMSO as a solvent. In
the second step, the 2-substituted benzofuran (96.3) was
hydroxylated with the help of the monooxygenase P450 BM3
variant (A74S-F87V-L188Q) and underwent additional elimi-
nation reactions (Scheme 96). The authors obtained the desired
product in up to an 84% yield.
Scheme 96. Examples of a One-Pot Chemoenzymatic
Cascade Synthesis
Ma et al.217 developed a four-component and one-pot
synthesis involving N,S-acetylation and sequential decarbox-
ylative [3 + 2] cycloaddition, using two aldehydes (97.1 and
97.4), cysteine (97.2), and maleimides (97.5) as substrates for
the stereoselective synthesis of tetrahydropyrrolothiazoles
(97.6) through an intermediate 97.3 (Scheme 97). The reaction
scheme considers ethanol as a green solvent and acetic acid as a
catalyst for its high synthetic efficacy. As byproducts, the
reaction scheme generates only CO2 and H2O, which is highly
favorable in the green metrics analysis.
Oxazoles and their derivatives are a crucial component of
drugs such as aristoxazole, primprinine, AD-5061, PC-046,
pyrronazol, ulapualides, diazonamides A, hennoxazole A, etc.
Sun et al.218 reported an efficient diethyl azodicarboxylate
(DEAD)-promoted oxidative Ugi/Wittig reaction for the
synthesis of 2-(1,2,3,4-tetrahydroisoquinolin-1-yl)oxazoles
(98.4). The one-pot reactions of isocyano-
Scheme 97. Synthesis of Tetrahydropyrrolothiazoles through a One-Pot Cascade Synthesis
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(triphenylphosphoranylidene)acetates (98.1), carboxylic acids
(98.2), and N-aryl-1,2,3,4-tetrahydroisoquinolines (98.3) pro-
duced polysubstituted 2-(1,2,3,4-tetrahydroisoquinolin-1-yl)-
oxazoles in good yields in the presence of CH2Cl2 as a solvent
and DEAD as an oxidant under room temperature (Scheme 98).
Hayashi et al.219 established a 1,8-diazabicyclo (5.4.0) undec-
7-ene (DBU)-catalyzed aldol condensation between p-chlor-
obenzaldehyde (99.1) and acetaldehyde (99.2) to synthesize
the required α,β-unsaturated aldehyde (99.3) with acetal (99.4)
as a byproduct. Acetal 99.4 can be converted into the desired
aldehyde 99.3 via retro-acetalization and dehydration at 50 °C.
Subsequently, the aldehyde 99.3 went through an asymmetric
Michael reaction with nitromethane catalyzed by diphenylpro-
linol silyl ether (99.5) in the presence of DBU. To exert the
strong base effect of DBU without negotiating enantioselectivity,
the authors used formic acid, which led to the stereospecific
product 99.6. Successively, the oxidation and reduction
reactions prepared 99.7 and 99.8, respectively, in the same
pot (Scheme 99). The whole reaction scheme consists of six
major reactions (aldol addition reaction → dehydration →
retro-acetal reaction followed by dehydration → asymmetric
Michael reaction → oxidation → reduction) in a single reactor.
Ishikawa et al.220 created a four-component coupling reaction
between two distinct aldehydes, a nitroalkene, and a silylated
nucleophile to offer substituted chiral tetrahydropyrans in a
three-step one-pot reaction (Scheme 100). In the first step, a
diphenylprolinol silyl ether (100.3) facilitated an asymmetric
Michael reaction that occurred between a nitroalkene (100.1)
and an aldehyde (100.2), followed by a domino Henry reaction/
intramolecular acetalization (100.4 → 100.7) using another
aldehyde (100.5), where 100.6 is an intermediate state. In the
final step, a Lewis acid-catalyzed nucleophilic addition reaction
occurred to synthesize 100.8 from 100.7. One can easily prepare
diverse substituted chiral tetrahydropyrans just by employing
various nitroalkenes, aldehydes, and nucleophiles with excellent
diastereoselectivity and enantioselectivity.
Lorillière et al.221 investigated an effective concurrent cascade
of two enzymatic steps catalyzed by thermostable transaminase
(TA) and transketolase (TK) to synthesize L-erythro (3S,4S)-
ketoses (101.5) (prominent biological building blocks) in a
single reactor at 60 °C. At high temperature, thermostable
transketolase from Geobacillus stearothermophilus (TKgst)
catalyzed the stereospecific synthesis of L-erythro (3S,4S)-
configured ketoses (101.5) from β-hydroxypyruvate (101.3)
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Scheme 98. One-Pot Synthesis of 2-(1,2,3,4-Tetrahydroisoquinolin-1-yl)oxazole Derivatives via a DEAD-Promoted Oxidative

Reaction

Scheme 99. Six Reaction Steps in the One-Pot Synthesis of (S)-Baclofen

Scheme 100. One-Pot Synthesis of Multi-Substituted Chiral Tetrahydropyrans

Scheme 101. One-Pot, Two-Step Cascade Synthesis of Naturally Rare L-Erythro (3S,4S) Ketoses

and (2S)-hydroxylated aldehydes (101.4), in which the prior
one is generated from natural L-serine (101.1) and pyruvic acid
(101.2), using another thermostable L-α-transaminase from the
thermophilic bacterium Thermosinus carboxydivorans (TAtca)
(Scheme 101). The novel cascade synthesis precludes the
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thermal decomposition of the labile β-hydroxypyruvate (101.3)
and proposes an environmentally friendly green process.
Urushima et al.222 developed and improvised an asymmetric,
four-component one-pot synthesis of highly substituted chiral
piperidines with excellent diastereoselectivity and enantioselec-
tivity. The three-step reaction started with the diphenylprolinol
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Scheme 102. One-Pot Synthesis of Multi-Substituted Chiral Piperidines

silyl ether (102.3)-mediated Michael reaction between nitro- represented in Schemes 103−116. For a better understanding,
alkene (102.1) and aldehyde (102.2), followed by a domino the most popular and frequently used MCRs are discussed with a
aza-Henry/hemiaminalization reaction sequence to prepare
102.7 from 102.4 in the presence of 102.5, where 102.6 is an Scheme 103. Biginelli Reaction [Aldehydes (103.1), Urea
intermediate state before obtaining 102.7. In the final step, a (103.2), β-Ketoesters (103.3), Dihydropyrimidones (103.4)]
Lewis acid-mediated allylation or cyanation reaction occurred to
obtain 102.8 from 102.7 (Scheme 102). The reaction is quite
important, as all six carbons of the piperidine ring can be
substituted with diverse substitution along with the five
contiguous stereocenters.

7. MULTICOMPONENT REACTIONS FOR GREEN AND Scheme 104. Strecker Reaction [Aldehydes (104.1),
SUSTAINABLE SYNTHESIS Ammonia (104.2), Hydrogen Cyanide (104.3), α-
Multicomponent reactions (MCRs) can be defined as one-pot Aminonitrile (104.4)]
chemical reactions among three or more substrates in a highly
regio- and stereoselective manner to deliver a structurally
complex single organic molecule that retains all or most of the
atoms of the starting materials.223 Thus, considering atom
economy and waste reduction, the involvement of MCRs in the
synthesis of pharmaceuticals can help in the green and Scheme 105. Mannich Reaction [Non-Enolizable Aldehyde
sustainable process. Under MCRs, the final product is (105.1), Enolizable Carbonyl Compound (105.2), Amine
constructed as per the cascade of elementary chemical reactions (105.3), Aminomethylated Derivative (105.4)]
that maintain a network of reaction equilibria. Therefore, the
flow of the reaction is irreversible, and the amount of yield is
close to 100% most of the time.224−227 Interestingly, most
MCRs can be performed in a one-pot version and the major
byproduct from an MCR is water.
MCRs have multiple advantages over the stepwise linear
synthetic process, such as atom economy, time and energy Scheme 106. Passerini Reaction [Ketone (106.1) (Also
economies, less waste generation, a one-pot synthesis, less Aldehyde Can Be Considered), Isocyanide (106.2),
human effort and resources requirement, easy purification Carboxylic Acid (106.3), α-Hydroxy Carboxamides (106.4)]
issues, mild conditions, high convergence, and high yield of the
final product.228−233 Although MCRs are quite popular among
combinatorial and medicinal chemists, agrochemists, and
polymer scientists, the awareness to use them in sustainability
and GC is questionable. Such benefits as diversity-oriented
synthesis, combinatorial library generation, and convergence/ Scheme 107. Ugi Reaction [Aldehyde (107.1), Isocyanide
divergence acknowledge many aspects of GC and the (107.2), Carboxylic Acid (107.3), Amine (107.4), α-
sustainable synthesis process. For the purpose of green Aminoacyl Amide Derivatives (107.5)]
synthesis, well-known classical MCRs are Biginelli,234−237
Strecker,238−240 Mannich,241−243 Passerini,244−247 Ugi,248−250
Orru,251 Hantzsch,252−255 Petasis,256−260 Groebke−Black-
burn−Bienayme,261,262 Kabachnik−Fields,263−265 Willgerodt−
Kindler,266 Bucherer−Bergs,267−269 Gewald reactions,270−272
etc. The mentioned MCRs are used directly to synthesize many
pharmaceuticals and key intermediates following the major few examples to show how chemists can use them rationally for
principles of GC. The fundamental schemes of each reaction are the green and sustainable synthesis.
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Scheme 108. Orru Reaction [Aldehyde (108.1), Amine Scheme 111. Petasis Reaction [Aldehyde (111.1), Secondary
(108.2), α-Acidic Isocyanide (108.3), Imidazoline Derivative Amine (111.2), Boronic Acid (111.3), Amine Derivatives
(108.4)] (111.4)]

Scheme 112. Groebke−Blackburn−Bienayme Reaction

Scheme 109. Hantzsch Dihydropyridine Synthesis [Aldehyde [Aldehyde (112.1), Isocyanide (112.2), Pyridin-2-amine
(109.1), β-Ketoester (109.2), Ammonia (109.9), (112.3), Imidazopyridine Derivative (112.4)]
Dihydropyridine (109.4)]

Scheme 113. Willgerodt−Kindler Reaction [Aryl Ketone

(113.1), Sulfur (113.2), Morpholine (113.3), 1-Morpholino-
7.1. The Biginelli Reaction 2-phenylethanethione (113.4)]
The Biginelli MCR is an acid-catalyzed, three-component
reaction (3-CR) among an aldehyde, a β-ketoester, and urea,
reported in 1891 by Pietro Biginelli234 to prepare 3,4-
dihydropyrimidin-2(1H)-ones (or -thiones if thiourea is used
instead of urea) (DHPMs) (Scheme 103). The DHPMs have
multiple biological activities and applications in medical science
as small-molecule drugs such as mitotic Kinesin inhibitors, Scheme 114. Bucherer−Bergs Reaction [Ketone (114.1),
calcium channel modulators, antibacterials, adrenergic receptor Potassium Cyanide (114.2), Ammonium Carbonate (114.3),
antagonists, antivirals, etc. An introspection of the mechanism of Hydantoins (114.4)]
the reaction suggests the condensation between the aldehyde
and urea as the first step. The generated iminium intermediate
acts as an electrophile for the nucleophilic addition of the
ketoester enol. In the last step, the resulting adduct ketone
undergoes condensation with the urea to give the cyclized
product. Two examples have been demonstrated for a better Scheme 115. Gewald Reaction [α-Cyanoester (115.1), α-
understanding of a series of applications of the Biginelli MCR Methylene Carbonyl Derivative (115.2), Sulfur (115.3), 2-
over the years in synthetic chemistry. Aminothiophenes (115.4)]
Roy et al.236 applied the Biginelli MCR for the synthesis of
dihydropyrimidinones/-thiones (117.4) involving a β-keto ester
or β-diketone (117.1), an aldehyde (117.2), and urea/thiourea
(117.3) in a one-pot synthesis with excellent yields in a short
time, using organocatalyst 1-butyl-3-methylimidazolium-based
room-temperature ILs ([bmim][MeSO4]) (Scheme 117). This
is another important use of ILs as alternative reaction media, Scheme 116. Kabachnik−Fields Reaction [Carbonyl
considering the green synthesis along with the advantage of Derivative (Here, Ketone) (116.1), Amine (116.2),
MCRs over the linear synthesis. The IL can be recycled and used Hydrophosphoryl Derivative (116.3), α-
again for five consecutive reactions without losing its catalytic Aminophosphonates (116.4)]
efficiency. The proposed methodology can be easily imple-
mented for a large-scale reaction and bulk synthesis.
The Biginelli cyclocondensation of guanidine with β-
dicarbonyl and aldehydes synthesizes 2-amino-3,4-dihydropyr-
imidines, as proposed by Felluga et al.237 (Scheme 118). The
reaction protocol requires the MWI with a 2-fold excess of

Scheme 110. Hantzsch Pyrrole Synthesis [Ethyl 3-Oxopropanoate (110.1), Aniline (110.2), Ethyl 2-Bromo-3-oxobutanoate
(110.3), Diethyl 2,5-Dimethyl-1-phenyl-1H-pyrrole-3,4-dicarboxylate (110.4)]

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Scheme 117. Implementation of the Biginelli Reaction in the
Synthesis of Dihydropyrimidinones and -thiones
Scheme 118. Application of the Biginelli Reaction in the
Synthesis of 2-Aminodihydropyrimidines
guanidine hydrochloride partners in alcohol at 120 °C. The
reaction is simple and carried out under conventional heating
with good end yields.
7.2. The Strecker Reaction
The Strecker reaction involves the preparation of α-amino-
nitriles, using three components: an aldehyde, ammonia, and
hydrogen cyanide (Scheme 104).238 The α-aminonitriles are
major intermediates for the synthesis of amino acids through the
hydrolysis of the nitrile. Therefore, this MCR is very important
in the biomedical industry. The reaction is promoted by 1 equiv
of acid.
Takahashi et al.239 reported an iridium-catalyzed reductive
nucleophilic addition to a secondary amide (119.1) to produce a
secondary amine (119.2). Once the iridium-catalyzed reduction
is complete, the resulting imines can go through the Strecker
reaction, the Mannich reaction, and allylation followed by [3 +
2]-cycloaddition (Scheme 119). The reaction scheme shows
high-level chemoselectivity in the presence of functional groups
like methyl ester.
Scheme 119. Implementation of the Strecker Reaction in the
Synthesis of Amines
Gualtierotti et al.240 reported a one-pot oxidative three-
component reaction of aldehydes (120.1), amines (120.2), and
trimethylsilyl cyanide (TMSCN) (120.3) in a biphasic solvent
system (toluene/H2O: 10/1) containing oxone, sodium
bicarbonate, and tetra-n-butylammonium bromide (TBAB),
giving α-iminonitriles (120.4) with excellent yields (Scheme
120). This oxidative Strecker reaction can apply to a diverse set
of aldehydes and amines with aliphatic or aromatic systems. One
Scheme 120. Execution of the Strecker Reaction in the
Synthesis of Iminonitrile
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can prepare substituted 1-aza-2-cyano-1,3-dienes employing
α,β-unsaturated aldehydes as the starting material.
7.3. The Mannich Reaction
The Mannich MCR is an important scheme to afford an
aminomethylated derivative or β-amino carbonyl compounds
(BACs) through the multicomponent condensation of a primary
or secondary amine, a non-enolizable aldehyde, and an
enolizable carbonyl compound (Scheme 105).241 The Mannich
MCR is sometimes called the “direct Mannich” reaction. There
are series of asymmetric catalyzed versions of the Mannich
reaction. The Mannich reaction with enolates (or modified
enolates) is referred to as the indirect Mannich reaction, which is
the most widely used one. One of the significant involvements of
the Mannich reaction is in biosynthetic pathways for alkaloids.
A highly stereoselective one-pot intramolecular Mannich
reaction was developed to obtain 4-aminoisochromanones
(121.4), employing 2-oxopropyl-2-formylbenzoates (121.1)
and anilines (121.2) as substrates, catalyzed by a secondary
amine (121.3).242 The reaction scheme helps the desired
product to have two adjacent stereocenters with good yields up
to 85%, followed by excellent cis-stereoselectivities and ee values
of 92−99% (Scheme 121). The isochroman-1-one is a notable
Scheme 121. Execution of the Mannich Reaction in the
Synthesis of Isochroman-1-one Derivatives
and common scaffold for chemicals and drugs like ochtratoxin A,
(−)-hydrangenol (II), fusarentin, and aldosterone synthase
inhibitors. Thus, for the synthesis purpose of the mentioned
bioactive compounds, the Mannich reaction is very much handy.
Lu et al.243 implemented a one-pot Mannich reaction of
aldehydes with aromatic ketones and amines under solvent-free
conditions at room temperature. The MCR is catalyzed by
(C4H12N2)2[BiCl6]Cl·H2O, and it can be recycled and reused
several times by straightforward isolation procedures without
losing the catalytic efficiency. In Scheme 122, benzaldehyde
(122.1), aniline (122.2), and acetophenone (122.3) reacted in
the presence of 3 mol % of the catalyst to obtain 1,3-diphenyl-3-
(phenylamino)propan-1-one (122.4), an amide derivative. As
the whole reaction is performed without a solvent, there is no
question of solvent waste. In addition, recycling of catalysis helps
in maintaining high efficiency with minimum hazard waste and
full utilization of atom economy.
7.4. The Passerini Reaction
The Passerini reaction is another 3-CR among a carbonyl
compound such as a ketone or aldehyde, a carboxylic acid, and
an isocyanide, which synthesize α-hydroxy carboxamides
(Scheme 106).244 Passerini is one of the major isocyanide-
based MCRs (IMCRs). The Passerini reaction is usually
accelerated in aprotic solvents, indicating a non-ionic pathway
mechanism. The Passerini MCR is based on the isocyanide
insertion in the loosely hydrogen-bonded adduct afforded from
the acid and aldehyde interaction, where H-bonding is supposed
to play a critical role in the development of the presumed cyclic
transition state for this reaction. The intermediate has not been
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Scheme 122. Application of the Mannich Reaction in the Synthesis of Amide Derivatives
isolated, and it instantaneously goes through a rearrangement,
offering the Passerini adduct. High yields are expected with high
concentrations of the starting materials.
Brioche et al.245 proposed a modified Passerini reaction under
catalytic aerobic conditions, which permits the conversion of
alcohols instead of carbonyl compounds. The reaction of
alcohols (123.1), carboxylic acids (123.2), and isocyanides
(123.3) occurred in the presence of a catalytic amount of cupric
chloride, TEMPO (oxyl or oxidanyl), and NaNO2, under an
oxygen atmosphere to prepare 1-amino-1-oxopropan-2-yl
acetate derivative (123.4) (Scheme 123). The modified
Passerini reaction produces much better yields in this specific
scheme.
Scheme 123. Execution of the Passerini Reaction in the
Synthesis of 1-Amino-1-oxopropan-2-yl Acetate Derivative
Soeta et al.246 reported that the addition of isocyanides
(124.2) to aldehydes (124.1) proceeded efficiently in the
presence of silanol (124.3) to prepare α-siloxyamides (124.4) in
high yields (Scheme 124). Silanol plays a crucial role where
Scheme 124. Application of the Passerini Reaction in the
Synthesis of α-Siloxyamides
Ph3Si acts as an electrophile and the hydroxyl group plays the
role of a nucleophile. A series of α-siloxyamides were prepared
just by changing the types of aldehydes and isocyanides.
The role of arylboronic acids (125.1) to prepare α-
hydroxyketones (125.4) through the Passerini reaction is
illustrated by Yang et al.247 The reaction involves arylboronic
acids (125.1), aldehydes (125.2), and tertbutyl isocyanide
(125.3) in the presence of either chloroform or dichloro-
methane as a solvent under basic conditions with pH 8.0 under
an argon atmosphere for 24 h (Scheme 125). A series of drugs,
for example, ibuprofen, ketoprofen, naproxen, indomethacin,
gemfibrozil, and clofibrate, can be prepared using the
demonstrated reaction scheme following the green synthesis
protocols.
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Scheme 125. Implementation of the Passerini Reaction in the
Synthesis of α-Hydroxyketones
7.5. The Ugi Reaction
The Ugi is a four-component reaction (4-CR) to access peptide-
like structures. Like the Passerini reaction, the Ugi reaction is a
type of IMCRs. These two IMCRs are closely bonded, and their
mechanisms have many shared features. The Ugi reaction is
likely favored in polar protic solvents to afford an α-acetoamido
carboxamide or an α-aminoacyl amide derivative, using an
aldehyde, a carboxylic acid, an amine, and an isocyanide
(Scheme 107).248 Like the Passerini, the Ugi reaction also leads
to potentially bioactive peptidomimetic compounds. The Ugi
reaction can generate an enormous number of compound
libraries with potential bioactivity. The mechanism of the
reaction suggests an initial formation of an imine through the
condensation of the amine with the aldehyde, followed by the
addition of carboxylic acid oxygen and the imino carbon across
the isocyanide carbon. The obtained acylated isoamide
rearranges via acyl transfer to generate the final desired product.
van der Heijden et al.249 proposed 2-isocyanopyridines as an
easily convertible isocyanide for multicomponent chemistry,
where 2-bromo-6-isocyanopyridine (126.3) is identified as the
optimal one due to its stability and efficiency. It blends adequate
nucleophilicity with a good leaving group capacity of the
resulting amide moiety under both basic and acidic conditions.
In Scheme 126, aldehydes (126.1) and amines (126.2) reacted
Scheme 126. Implementation of the Ugi Reaction in the
Synthesis of 2-Isocyanopyridines
in the presence of 126.3 to obtain 2-bromo-6-isocyanopyridine
(126.4). Later, the Ugi products (126.4) are converted to
corresponding carboxylic acid derivatives (126.5) under mildly
basic conditions. One of the practical utilities of this reagent and
scheme is the two-step synthesis of the potent opioid carfentanil.
Xu et al.250 developed a two-step Ugi/cyclization reaction
scheme to synthesize hydantoins. The microwave-assisted one-
pot cyclization strategy involves aryl amine (127.1), protonated
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acid (127.2), aryl/alkyl isocyanide (127.3), and propiolic acid
(127.4) to produce the desired hydantoin derivatives (127.5)
efficiently (Scheme 127). Here, the alkyne group acts as a
Scheme 127. Execution of the Ugi Reaction in the Synthesis
of Hydantoins
leaving group under basic conditions. Considering the bioactive
nature of hydantoins, this Ugi reaction is a step forward to the
green synthesis of pharmaceuticals.
7.6. The Hantzsch Reaction
The Hantzsch MCR involves the cyclocondensation of two β-
keto esters, an aldehyde, and an ammonia donor, such as
ammonium acetate, to synthesize dihydropyridines (DHPs)
(Scheme 109).252 Interestingly, successive oxidation (or
dehydrogenation) of the product offers pyridine-3,5-dicarbox-
ylates. Again, decarboxylation helps to yield the corresponding
pyridines. A wide range of anti-hypertensives, multidrug-
resistant proteins, anti-inflammatory, and calcium channel
blockers can be prepared using the reaction scheme, which, in
addition, is effective as a tool for reducing imines to amines.
A wide range of N-tosylhydrazones (128.1) reacting with 3-
oxobutanoate derivative (128.2) offer a series of 1,4-
dihydropyridines (1,4-DHPs) (128.3) employing the Hantzsch
reaction in good yields in the presence of aluminum chloride
(Scheme 128).253 The 1,4-DHP building block is present in
Scheme 128. Synthesis of 1,4-DHPs Utilizing Aluminum
Chloride as a Catalyst
drugs like felodipine, nifedipine, etc. Debache et al.254 reported a
one-pot, inexpensive, and efficient utilization of the Hantzsch
reaction to produce 1,4-DHPs (129.4) in good yields via the 3-
CR of aromatic aldehydes (129.1), ethyl acetoacetate (129.2),
and ammonium acetate (129.3), using phenylboronic acid as
catalyst (Scheme 129).
Evans and Gestwicki255 reported a highly enantioselective
Hantzsch 4-CR among one equivalent dimedone (0.4 mmol), a
benzaldehyde, ethylacetoacetate, and ammonium acetate to get
DHPs catalyzed by BINOL−phosphoric acid (Scheme 130).
Scheme 129. Synthesis of 1,4-DHPs Employing
Phenylboronic Acid as a Catalyst
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The desired DHPs were obtained in good yields (80−94%) with
excellent ee (87 to >99%).
Scheme 130. Synthesis of DHPs by Means of the Catalyst
BINOL−Phosphoric Acid
7.7. The Petasis Reaction
The Petasis reaction is a powerful MCR of boronic acid, an
amine, and a carbonyl derivative. Highly functionalized amines
with multiple stereogenic centers can be efficiently accessed via
the Petasis reaction with high levels of both diastereoselectivity
and enantioselectivity. From a broader perspective of the Petasis
reaction, it can be a reaction between carbonyl derivatives,
amines, and aryl- or vinyl boronic acids, and it is sometimes
referred to as the Petasis boron−Mannich reaction (Scheme
111).256 The Petasis reaction is a compelling synthetic tool for
the high availability of the reagents and mild reaction conditions.
One of the most prominent applications of the asymmetric
Petasis reaction is chiral α-amino acids’ preparation by using
glyoxylic acid as the aldehyde component. The reaction is
catalyst-free in nature and needs minimal protecting groups;
water and alcohols can be used as reaction media. An overall
analysis of the Petasis reaction with a series of examples can be
found elsewhere.257
Zhang et al.258 proposed the use of trifluoroacetic acid (TFA)
as a polar solvent to fast-track the Petasis reaction. Previously,
the most used solvents for this reaction were CH2Cl2, MeCN,
and MeOH. The reaction of 5-nitroindoline, glyoxylic acid, and
boronic acid was accelerated by TFA to give a series of 2-(5-
nitroindolin-1-yl)-2-arylacetic acids in a much shorter time with
a moderate to good yield. The reaction offered boronic acids as a
good substrate apart from the more electron-deficient 4-
nitrophenylboronic acid. The obtained aryl acetic acids were
one of the important precursors of the synthesis of potential
HDAC inhibitors (Scheme 131).
Murafuji et al.259 reported the synthesis of azulenylglycine
derivatives in good yields through the reaction among glyoxylic
acid monohydrate (132.1), amines (132.2), and the boronic
component of azulene (132.3). They found that direct
borylation of azulene gave azulen-1-ylboronic acid pinacol
ester (132.4), which is the best possible boronic compound to
perform the reaction under mild conditions with excellent end
yield (Scheme 132). This Petasis reaction can be performed at
ambient room temperature with methanol as a solvent. Murafuji
et al.259 prepared a total of nine azulenylglycine derivatives by
simply changing the type of amine in the reaction scheme.
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Scheme 131. Petasis Reaction in the Synthesis of 2-(5-Nitroindolin-1-yl)-2-arylacetic Acids
Scheme 132. Petasis Reaction in the Synthesis of
Azulenylglycine Derivatives
Diehl et al.260 discovered the implications of sulfonamides as
the amine component in both Pd-catalyzed and catalyst-free
Petasis reactions. The proposed reaction can synthesize
substituted α-aryl- or α-alkenylglycines (133.4) from the
reaction of glyoxylic acid monohydrate (133.1), sulfonamides
(133.2), and aryl- or alkenylboronic acids (133.3). The major
advantages of this scheme are (a) a catalyst-free reaction, (b) air
and moisture tolerance, and (c) the scope for a wide substrate
selection in terms of both the sulfonamides and boronic acids
(Scheme 133). A total of 28 α-aryl- or α-alkenylglycines were
prepared using this synthetic scheme by Diehl et al.,260 where
many of them possess biological activity.
Scheme 133. Petasis Reaction in the Synthesis of Substituted
α-Aryl- or α-Alkenylglycines
7.8. The Kabachnik−Fields Reaction
The Kabachnik−Fields reaction is a 3-CR among an amine, a
carbonyl, and a hydrophosphoryl compound to obtain α-
aminophosphonates, which is an important scaffold to generate
peptidomimetic compounds (Scheme 116).263 The pathway of
the Kabachnik−Fields reaction strictly varies on the nature of
the substrates. The amine and hydrophosphoryl compounds
form a complex first, and then, the carbonyl compound reacts
with the intermediate. The basicity of the amine derives the
reaction pathway, where weak basic amines like anilines favor
the formation of an imine due to its proton donor nature, while
cyclohexylamines do not form imines. Additional catalysts can
have a positive influence on the reaction rate irrespective of the
use of an acid or a base. The diastereoselectivity of the formation
of α-aminophosphonates, as well as the final yield, is higher in
two-component systems using preformed imines. α-Amino-
phosphonates are an important class of organophosphorus
chemicals with diverse biological and veterinary applications.
Fiore et al.264 investigated the Kabachnik−Fields domino
reaction by mechanochemistry for the first time to prepare α-
aminophosphonate derivatives. For optimization of the reaction
conditions and the mechanochemical parameters, the yardstick
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reaction was performed parallel in a planetary ball-mill
employing amine derivatives (134.1) that were reacted with
diethyl phosphite (134.2) and benzaldehyde (134.3) to
generate α-aminophosphonate (Scheme 134). Interestingly,
Scheme 134. Zirconium-Oxide-Mediated Kabachnik−Fields
Reaction in the Synthesis of α-Aminophosphonate
Derivatives
the reaction had been performed via a metal-mediated process,
occurring on the surface of the jar without employing any
external catalyst. Here, zirconium oxide was used as the milling
media. The presented scheme offered high yields of α-
aminophosphonate with full selectivity compared to the
previous procedures.
Yu and Xu265 developed a highly efficient and rational one-pot
reaction scheme of aldehydes or ketones (135.1) reacting with
amines (135.2) and diethyl or triethyl phosphite (135.3) to
prepare analogous α-aminophosphonates (135.4) (Scheme
135). The reaction is performed in the presence of an IL
Scheme 135. Kabachnik−Fields Reaction in the Synthesis of
α-Aminophosphonate Derivatives Facilitated by an IL
Catalyst Based on Quaternary Ammonium Salts
catalyst based on quaternary ammonium salts (DABCO·HCl),
which is economical, eco-friendly, recyclable, and reusable to
follow the principles of GC. The reaction can be performed at
room temperature with an excellent final yield of α-amino-
phosphonates.
7.9. The Bucherer−Bergs Reaction
Another important MCR reaction among ketone, ammonium
carbonate, and potassium cyanide leading to the formation of
hydantoins is known as the Bucherer−Bergs reaction. A
preformed cyanohydrin can also react with ammonium
carbonate to obtain hydantoins (Scheme 114).267 This MCR
is equivalent to the Strecker synthesis with additional CO2. The
hydantoin scaffold plays an important role in drug discovery.
Important antiepileptic drugs such as phenytoin, fosphenytoin,
mephenytoin, and the anticancer drug nilutamide have the
hydantoin scaffold in them.
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Scheme 136. Bucherer−Bergs Reaction in the Synthesis of 5,5′-Disubstituted Hydantoins with an Organometallic Reagent

Montagne and Shipman reported a one-pot convenient
process including the treatment of aliphatic, aromatic, or
heteroaromatic nitriles (136.1) with an organometallic reagent
(RLi or RMgX), followed by KCN/(NH4)2CO3 to offer 5,5′-
disubstituted hydantoins (136.3) (Scheme 136). The synthesis
scheme generates moderate to good yields of hydantoins (40−
92%).268 The intermediate is metalated imine (136.2), which
directly leads to the NH imine.
Monteiro et al.269 discovered a two-feed continuous approach
to prepare hydantoins (137.2) by reacting carbonyl compounds
(137.1) with potassium cyanide and ammonium carbonate
within 32 min at 120 °C and maintaining an atmospheric
pressure of 20 bar (Scheme 137). Mechanistically, the carbonyl
Scheme 137. Bucherer−Bergs Reaction via a Cyclization-
Rearrangement Sequence to Obtain 5,5′-Disubstituted
Hydantoins
Scheme 138. L-Proline-Catalyzed Gewald Reactions in the
Synthesis of 2-Aminothiophenes
and 138.2) or a single nitrile compound (either 138.1 or 138.2)
and a carbonyl compound (138.3) reacted with elemental sulfur
in DMF at 60 °C in the presence of 10 mol % of L-proline to offer
2-aminothiophene (138.4) with excellent yield.
Ma et al.272 found that N-methylpiperazine-functionalized
polyacrylonitrile fiber acts as a catalyst in the Gewald reaction
between 2,5-dihydroxy-1,4-dithiane (139.1) and activated
nitriles (139.2) to synthesize 3-substituted 2-aminothiophenes
(139.3). A significantly low catalyst loading of 8 mol %, a
straightforward approach, and an excellent recyclability for up to
10 times without losing its catalytic activity are appealing
characteristics of this fiber catalyst. In the 1st and 10th run of the
fiber catalyst, the obtained yields of the 3-substituted 2-
aminothiophenes are 89 and 85%, respectively. Atom economy
and almost no waste make Scheme 139 a green procedure.

Scheme 139. N-Methylpiperazine-Functionalized

compound reacts with ammonia and the cyanide anion, resulting Polyacrylonitrile Fiber-Catalyzed Gewald Reactions in the
in an α-aminonitrile. Thereafter, nucleophilic addition of the Synthesis of 2-Aminothiophenes
intermediate to CO2 helps to generate cyano-carbamic acid.
Finally, the cyano-carbamic acid undergoes a cyclization−
rearrangement sequence to obtain hydantoins. The authors
reported 72−99% yields depending on the carbonyl derivatives.
The authors also reported that selective N(3)-monoalkylation of
the resulting heterocycles can be used to prepare potential
acetylcholinesterase inhibitors under batch microwave con-
ditions.
7.10. The Gewald Reaction
8. THE GREEN SYNTHESIS OF APIS
The Gewald reaction is a synthesis of 2-aminothiophenes via 3-
There are multiple examples where pharmaceutical companies
CR of sulfur, cyanoacetic acid derivatives, and an oxo-
and researchers employed the majority of GC principles through
component (Scheme 115).270 2-Aminothiophene derivatives
redesigning the entire reaction scheme of many established
show diverse bioactive profiles with anticonvulsant, antimicro-
APIs. We have thoroughly searched major search engines based
bial, and anti-inflammatory activity, adenosine agonist, and
on “green synthesis of starting materials, key intermediates as
JNK2 and JNK3 kinase inhibitors. As per the introspection of
well as final APIs applicable to industry application and scalable
the mechanism of the Gewald reaction, in the first step, the
to pilot synthesis”. The obtained synthesis schemes are further
Knoevenagel condensation occurred between an activated
scrutinized based on the green principles, cost-effectiveness,
nitrile and a carbonyl compound to generate acrylonitrile,
percentage of yield, and amount of waste generated.
which is then thiolated at the γ-methylene group with elemental
Considering all aspects, we have demonstrated the green
sulfur as per the SNX mechanism. The sulfurated intermediate
synthesis of 20 popular APIs, many of which received the
undergoes ring closure via a nucleophilic mercaptide attack at
American Chemical Society (ACS) Green Chemistry Awards
the cyano carbon to provide the penultimate intermediate.
and the US EPA’s Presidential Green Chemistry Challenge
Ultimately, a prototrophic rearrangement affords the desired 2-
Awards.
aminothiophene.
Wang et al.271 proposed a 3-CR Gewald reaction catalyzed by 8.1. Ibuprofen
L-proline. L-Proline is a nontoxic, native, and low-cost polyfunc- Ibuprofen, an NSAID, commonly used as a pain killer, was first
tional molecule and is one of the vital green catalysts in green patented by the Boots company in the 1960s.273 The Boots
synthesis. In Scheme 138, a mixture of nitrile compounds (138.1 synthesis comprises six steps (Scheme 140). According to their
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Scheme 140. Traditional Boot’s Synthesis of Ibuprofen

Scheme 141. Green Synthesis of Ibuprofen

Table 4. Comparison of Atom Economy and Atom Waste between the Boots Synthesis and the Green Synthesis of Ibuprofen
Boots Synthesis
reagent used in ibuprofen unused in ibuprofen
atom economy formula MW formula MW formula MW
C10H14 134 C10H13 133 H 1
C4H6O3 102 C2H3 27 C2H3O3 75
C4H7ClO2 122.5 CH 13 C3H6ClO2 109.5
C2H5ONa 68 N/A 0 C2H5ONa 68
H3O 19 N/A 0 H3O 19
NH3O 33 N/A 0 NH3O 33
H4O2 36 N/A 33 H3 3
total ibuprofen waste product
C20H42NO10ClNa 514.5 C13H18O2 206 C7H24NO8ClNa 308.5
waste box steps atom waste waste product
step 1 4 H, 2 C, 2 O CH3COOH
step 2 2 C, 6 H, 1 O, 1 Cl, 1 Na C2H5OH, NaCl
step 3 3 C, 6 H, 3 O C2H5OCOOH
step 4 1 O, 2 H H2O
step 5 1 O, 2 H H2O
step 6 1 N, 3 H NH3
BHC Green Synthesis
reagent used in ibuprofen unused in ibuprofen
atom economy formula MW formula MW formula MW
C10H14 134 C10H13 133 H 1
C4H6O3 102 C2H3O 43 C2H3O2 59
H2 2 H2 2 N/A N/A
CO 28 CO 28 N/A N/A
total ibuprofen waste product
C15H22O4 266 C13H18O2 206 C2H4O2 60
waste box steps atom waste waste product
step 1 4 H, 2 C, 2 O CH3COOH
step 2 no waste
step 3 no waste

patent, the starting material 2-methylpropylbenzene (140.1) AlCl3 and acetic anhydride to produce 1-(4-isobutylphenyl)-
went through the Friedel−Crafts acetylation in the presence of ethenone (140.2), which reacted with ethyl chloroacetate to
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Scheme 142. Pfizer’s Old Synthesis Route of Sertraline

give the α,β-epoxy ester (140.3) following the Darzens reaction. intermediate (142.2), which gave a mixture of cis and trans
In the next step, the α,β-epoxy ester was decarboxylated and amines (6:1) (142.3) through a catalytic reduction. The cis form
hydrolyzed to the 2-(4-isobutylphenyl)propanal (140.4). was purified as its HCl salt by fractional crystallization and was
Subsequently, the reaction with hydroxylamine gave the 2-(4- subsequently resolved with D-(−)mandelic acid to produce the
isobutylphenyl)propanal oxime (140.5), followed by a two-step desired (−)-(1S,4S)-sertraline. To recover these solvents,
hydrolysis to produce the penultimate product 2-(4- energy-intensive procedures such as distillation were required,
isobutylphenyl)propanenitrile (140.6) and the final product and even after that, 100% recovery was not possible. Moreover,
ibuprofen, respectively. the workers may have been exposed to solvents like toluene and
After the patent ran out, the Boots−Hoechst−Celanese
THF. Again, titanium tetrachloride employed in the imination
(BHC) company developed a new green synthesis method of
producing ibuprofen from the same starting material (Scheme reaction (Step 1, Scheme 142) is an air-sensitive corrosive liquid
141),274,275 using only three steps instead of six. As BHC that produces dense HCl fumes when exposed to moist air.
recycles and recovers the waste byproduct from the synthesis Later in 1998, Pfizer designed and implemented a combined
process, a bulky amount of aqueous salt wastes is eliminated. For process (Scheme 143) for the synthesis of sertraline, employing
this green synthesis, BHC received the Presidential Green only two solvents, ethyl acetate and ethanol, requiring over
Chemistry Challenge Award in 1997 and was recognized by the 24,000 L of both to produce 1000 kg of sertraline that directly
US EPA as a model for green synthesis. Like the Boots synthesis, saved around 76,000 L of solvents, and interestingly, both
the Friedel−Crafts acetylation of 2-methylpropylbenzene solvents are relatively safer for both the environment and the
(141.1) produced 1-(4-isobutylphenyl)ethenone (141.2) in
the presence of anhydrous hydrogen fluoride as a catalysis Scheme 143. Pfizer’s Green Synthesis of Sertraline
instead of AlCl3. In the following steps, hydrogenation with
Raney nickel gave the alcohol 1-(4-isobutylphenyl)ethanol
(141.3), followed by carbonylation to generate ibuprofen,
using cobalt and palladium for catalysis. A glance at Table 4
shows a calculation of the atom economy of the overall reaction,
which demonstrates that many of the reactant atoms do not
appear in the final product. In the case of the Boots synthesis, the
overall used atoms were around 40%, which suggested that 60%
of the materials were waste products. On the contrary, the new
three-catalytic-step green synthesis results in 77% atom
utilization (if we consider recovered acetic acid as byproducts,
then it is 99%).274,275
8.2. Sertraline
Sertraline is the active ingredient in the drug Zoloft, prescribed
as an antidepressant. Since its introduction, from 1992 to 1997,
the commercial synthesis (Scheme 142) of sertraline by Pfizer
involved five volatile solvents such as hexane, toluene, THF,
ethyl acetate, and ethanol, and in total around 100,000 L of
solvents to get a yield of 1000 kg of sertraline.276,277
Condensation of tetralone (142.1) with methylamine in the
presence of titanium tetrachloride prepared an imine
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workers. The condensation reaction between tetralone (143.1) Scheme 144. Semi-Synthetic Synthesis Scheme of
and monomethylamine was carried out in ethanol without the Artemisinin
need for a classical dehydrating agent, such as titanium
tetrachloride (TiCl4), which produces hazardous byproducts
and solid wastes. The obtained imine (143.2) was catalytically
reduced with Pd/CaCO3 as a catalyst in ethanol as the reaction
solvent to generate racemic mixtures of cis and trans isomers
(20:1) (143.3), followed by the resolution of the racemic cis
isomer with D-(−)-mandelic acid, resulting in a more efficient
sertraline mandelate (143.4). Finally, 143.4 was purified as a
HCl salt of sertraline. The green synthesis abolishes the
requirement for TiCl4, and the main hydrogenation step has
been redesigned through the implication of selective catalysis,
resulting in much smaller quantities of wastes and a higher
amount of yield. Until today, Pfizer has produced around 1500
tons of sertraline, employing GC with estimated prevention of
80 million gallons of waste.276,277
8.3. Artemisinin
Artemisinin, an important antimalarial drug for Plasmodium
falciparum, is generally employed as a combination therapy of
artemisinin derivatives. The commonly employed semisynthetic
production of artemisinin involves high economic and environ-
mental costs. Most of the production costs lie in the final
chemical steps, which follow a complex acid-catalyzed and Scheme 145. One-Pot Semi-Synthesis of Artemisinin
photocatalyzed route with oxygenation by both singlet and
triplet oxygen. This semisynthetic process278,279 consists of two
major subprocesses: (i) the bioprocess, where artemisinic acid
(144.1) is extracted either from Artemisia annua or from
Saccharomyces cerevisiae by a fed-batch fermentation process,
and (ii) the photochemical conversion of artemisinic acid
(144.1) to dihydroartemisinic acid (144.2) by hydrogenation
followed by acid catalysis and photocatalysis to obtain
artemisinin. The reaction of dihydroartemisinic acid with 1O2
results in two regioisomeric hydroperoxide derivatives, where
one is the required hydroperoxide (144.3) and the other one is
unwanted hydroperoxide (144.4). Thereafter, 144.3 is con-
verted into an intermediate enol (144.5) through a ring-opening
reaction under acid catalysis, and the intermediate enol is finally
oxidized to produce artemisinin with a longer reaction time
(Scheme 144). The use of the comparatively toxic solvent
dichloromethane (DCM) and toxic trifluoroacetic acid (TFA) temperature. Most importantly, the process yield is pure
for the 1O2 reaction, followed by manifold washing to remove artemisinin crystals (Scheme 146). In both processes, almost
the acid from the final product, makes the process different from all solvents, aqueous acid, and photocatalyst can be recycled.
the classical green synthesis. Not only that but performing The use of H2O as a reaction solvent helps in the spontaneous
photo-oxidation at lower temperature and the loss of the crystallization of artemisinin. Additionally, the H2O-soluble acid
photosensitizer followed by a solvent exchange to permit
crystallization are other serious problems to consider. Scheme 146. Photocatalytic Oxygenation of Aqueous
Amara et al.280 demonstrated two pioneering strategies based Mixtures of Organic Solvents for the Green Synthesis of
on the GC principles, which can eradicate many disadvantages Artemisinin
of the current photochemical method. The first strategy is a one-
pot synthesis of artemisinin, where liquid CO2 is used as a
solvent with a dual-functioning recyclable heterogeneous acid
and a photocatalyst system (Scheme 145). The major solvent
liquid CO2 is a green solvent due to its nontoxic and renewable
nature. For photocatalysis, the meso-tetraphenylporphyrin
(TPP) or meso-tetrakis(pentafluorophenyl)porphyrin
(TPFPP) bound to Amberlyst-15, the fixed-bed photoreactor,
gives a dual-catalyst effect with a more robust bifunctional
system and negligible leaching. Finally, with the help of a back
pressure regulator (BPR), artemisinin can be obtained. The
second strategy is photocatalytic oxygenation of 144.2 in
aqueous mixtures of organic solvents (ethanol) under ambient
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and the photosensitizer persist in the solution, which is available
for continuous application. Thus, this technique supports the
recycling of the aqueous solution of an acid catalyst and a
photosensitizer along with the evaporated EtOH for all cycles
without any waste, and the final yield is only artemisinin.
8.4. Sildenafil Citrate
Sildenafil citrate, a selective cyclic guanosine monophosphate
(cGMP)-specific phosphodiesterase 5 (PDE5) inhibitor, was
the first approved drug employed for the treatment of erectile
dysfunction. The first synthesis route developed at Pfizer in 1990
was an 11-step synthesis (Scheme 147), with a 4.2% overall
Scheme 147. Pfizer’s Old Commercial Synthesis Scheme of
Sildenafil
Scheme 148. Pfizer’s New Commercial Green Synthesis Scheme of Sildenafil
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yield, which is not suitable for large-scale industrial manufactur-
ing. Thereafter, in the year 1994, an optimized medicinal
chemistry route was developed, improving the environmental
perspective.281 The following changes were implemented:
a. The catalytic hydrogenation step was performed employ-
ing H2 and Pd/C, replacing SnCl2, which is a major
environmental hazard.
b. Stoichiometric quantities of thionyl chloride (SOCl2) in a
solvent, rather than thionyl chloride as a solvent in the
synthesis of 1-methyl-4-nitro-3-propyl-1H-pyrazole-5-
carboxamide (147.3), were used, which is a much safer
and environmentally friendly option.
c. H2O2 was replaced with KOBut in tBuOH to cyclize the
compounds 4-(2-ethoxybenzamido)-1-methyl-3-propyl-
1H-pyrazole-5-carboxamide (147.4) to 5-(2-ethoxyphen-
yl)-1-methyl-3-propyl-6,7-dihydro-1H-pyrazolo[4,3-d]-
pyrimidine (147.5) with zero impurities and a 100% yield.
The replacement of hazardous H2O2 was a significant
idea, as it causes burn during contact with skin and
represents a fire and transportation hazard.
d. For the preparation of 2-ethoxybenzoyl chloride, SOCl2
was employed, replacing oxalyl chloride, which provides
an upgrade in the worker safety by circumventing CO
emissions.
In 1997, Pfizer established the commercial route (Scheme
148) with clean cyclization followed by convergency and an
around 75% overall yield with a much lesser amount of waste
than the previous methods. Further, Pfizer worked out to
optimize the route for better solvent recovery with an overall
yield target of 82%.282,283 If we just compare the organic waste
between the first synthesis process in 1990 and the present
commercial route with the solvent recovery option, the organic
waste amount changed from 1300 to 7 L/kg.287 How each step is
optimized for green synthesis is discussed below:
• In the first step of Scheme 148, 1-methyl-4-nitro-3-
propyl-1H-pyrazole-5-carboxamide (147.3) was obtained
from 1-methyl-4-nitro-3-propyl-1H-pyrazole-5-carbox-
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Scheme 149. Conventional Synthesis Route of Atorvastatin
Scheme 150. Previous Synthesis Routes of Hydroxynitrile
ylic acid (147.2) in the presence of SOCl2, where the use
of toluene helped in the heat sink, which supports the
safety process as well as the reduction of the level of SOCl2
to 1.2−1.6 equiv. Most importantly, almost 100% toluene
could be recovered and recycled for the next batch use.
• In the next step, hydrogenation was performed using ethyl
acetate and H2, Pd/C to convert 1-methyl-4-nitro-3-
propyl-1H-pyrazole-5-carboxamide (147.3) to 4-amino-
1-methyl-3-propyl-1H-pyrazole-5-carboxamide (148.1).
Simultaneously, 2-ethoxy-5-((4-methylpiperazin-1-yl)-
sulfonyl)benzoic acid (148.3) was prepared from 2-
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ethoxybenzoic acid (148.2), employing chlorosulfonic
acid with 1 equiv of SOCl2 to ensure the conversion of
intermediate sulfonic acid to the sulfonyl chloride.
Further, the sulfonyl chloride was suspended in water to
provide 148.3 through reacting with N-methylpiperazine.
Hence, no organic solvent was used for the preparation of
the sulfonamide.
• Then, a reaction between 148.3 and 148.1 was performed
with N,N-carbonyldiimidazole (CDI) to synthesize
148.4. Although CDI is expensive, it has multiple
advantages with respect to green synthesis. It provided a
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clean and high-quality yield (90−96%), allowing hydro-
genation, activation, and acylation to be combined. Due
to the use of a single solvent, i.e., ethyl acetate, the solvent
recovery process was an efficient and low-energy one.
Significantly, the emission of volatile organic compounds
could be avoided from the interaction of either oxalyl
chloride or thionyl chloride with ethyl acetate.
• The obtained compound 148.4 was then cyclized with t-
BuOK and t-BuOH to produce sildenafil at a high
concentration (2.5−3.75 L/kg) to curtail environmental
waste.
8.5. Atorvastatin
Atorvastatin calcium, a cholesterol-lowering drug, acts as a
competitive HMG-CoA-reductase inhibitor that blocks the
synthesis of cholesterol in the liver. Atorvastatin contains a chiral
3,5-dihydroxy carboxylate side chain at position 7 in a cyclic
nucleus. Ethyl (R)-4-cyano-3-hydroxybutyrate or hydroxynitrile
(149.1) is the key starting material for the majority of
commercialized synthesis of atorvastatin (Scheme 149). The
initial industrial production route of hydroxynitrile required
kinetic resolutions employing whole-cell microbes and the use of
(S)-hydroxy butyrolactone (150.5) (routes A and B).284,285
Next, the asymmetric reduction of diketene (150.7) produced
ethyl 4-chloroacetoacetate (150.8) (route C). The final step
involved the reaction of an ethyl 3-hydroxy-4-halobutyrate
(150.6/150.9) with a cyanide ion at high temperature in an
alkaline solution, which is essential to forming the nucleophilic
cyanide anion (Scheme 150). The substitution of cyanide for
halide under extreme conditions resulted in extensive by-
products and required an exhaustive high-vacuum distillation to
purify the ultimate product 149.1. Most importantly, in the end,
the obtained yield was also low. Along with that, the whole
process required high loadings of enzymes, which added
significant cost to the whole process.284,285
To address these issues for a practical and economical process,
in 2010, Ma et al.286 developed a superior three-enzyme process
maintaining green synthesis and economical two steps for the
synthesis of hydroxynitrile (Scheme 151) under mild conditions
Scheme 151. Green Synthesis Route of Hydroxynitrile
at neutral pH with minimized byproduct. The first step is an
enantioselective reduction of ethyl 4-chloroacetoacetate
(150.8), employing a ketoreductase (KRED) and glucose
dehydrogenase (GDH) in combination with glucose and
NADP-dependent glucose dehydrogenase (GDH) for cofactor
regeneration to synthesize (S)-ethyl-4-chloro-3-hydroxybuty-
rate (150.9) (a 96% isolated yield) (Scheme 151). Here, glucose
is oxidized to gluconic acid that is neutralized by NaOH. In the
next step, halohydrin dehalogenases (HHDHs) catalyze the
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enantioselective ring closing and elimination of halohydrins to
the corresponding epoxide (151.1) in a reversible reaction.
These enzymes take cyanide as a nucleophile, leading to the
irreversible enantioselective generation of β-hydroxynitriles
(149.1) in an ambient environment.
8.6. Paroxetine
Paroxetine, a drug used for anxiety disorders, is sold under the
brand name Seroxat and Paxil by GlaxoSmithKline. The early
development route considered p-fluorobenzaldehyde with ethyl
acetoacetate, followed by esterification to get a diester. The
hydrolytic resolution of the diester in the presence of pig liver
esterase generated an acid ester. A series of deprotonation,
reduction, homologation, and further reduction offered
((3S,4R)-1-benzyl-4-(4-fluorophenyl)piperidin-3-yl)methanol.
Further etherification of the product with sesamol offered the
penultimate precursor that was subjected to hydrogenolysis to
yield paroxetine. The route was gained from a biocatalytic
desymmetrization to avert chemical resolution but did generate
significant amounts of aqueous waste during the workup.287
Later, GlaxoSmithKline287,288 developed an efficient green
reaction route employing biocatalysis. A shorter, cost-efficient,
and enzymatic desymmetrization strategy with double overall
transformation compared to the earlier route is shown in
Scheme 152. The critical step involves the desymmetrization of
the meso diester (152.2), utilizing a protease subtilisin
Carlsberg as a biocatalyst (a member of the family of serine
endopeptidases isolated from Bacillus subtilis). This leads to the
intermediate product (3R,4R,5S)-4-(4-fluorophenyl)-5-(me-
thoxycarbonyl)-1-methyl-2,6-dioxopiperidine-3-carboxylic acid
(152.3), which generates (3S,4R)-methyl 4-(4-fluorophenyl)-1-
methyl-2,6-dioxopiperidine-3-carboxylate (152.4) through de-
carboxylation. Demethylation and global reduction followed by
etherification with sesamol produces the desired paroxetine.
8.7. Sitagliptin
Sitagliptin, a US FDA approved drug for the treatment of type 2
diabetes, is a potent and selective dipeptidyl peptidase-IV (DPP-
IV) inhibitor. The first generation synthesis of sitagliptin was
developed by Hansen et al.289 and was incompetent due to a
large number of steps followed by poor atom economy and a
higher amount of organic waste. Later, Hansen et al.290 reported
an efficient synthesis of sitagliptin that included asymmetric
hydrogenation of an enamine at high pressure, employing a
rhodium-based chiral catalyst (second generation chemo-
catalytic route, Scheme 153). Later, Merck researchers reported
a ruthenium-catalyzed asymmetric direct reductive amination
for synthesizing unprotected β-amino amides (153.5) from β-
keto amides (153.3) (improved second generation, Scheme
154).291 Although in the case of the second generation route the
conversion of 153.3 to 153.4 occurred in one pot, it was still a
unit operation for the process. Thus, this step was removed in
the direct reductive amination of 153.3 to 153.5 for the
improved second generation route (Scheme 154). The
improved method supported an atom- and step-economical
methodology to obtain a 91% yield of sitagliptin with
unparalleled levels of asymmetric induction due to almost
perfect enantioselectivity and high chemoselectivity of the Ru
catalyst and its tolerance to high concentrations of ammonium
ion.
Savile et al.292 developed the third, or current, generation
synthesis (Scheme 155), employing a transaminase biocatalyst
instead of a metal catalyst. Thus, this route was termed as a
biocatalytic one. The reaction started with the β-keto amide
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Scheme 152. Green Synthesis Route for Paroxetine
Scheme 153. Chemocatalytic Second Generation Synthesis of Sitagliptin
(153.3), which was treated with the transaminase catalyst and
then crystallized with H3PO4 acid to produce the sitagliptin
phosphate. The synthesis of sitagliptin became greener and
more effective with each successive generation. The third
generation synthesis fulfills 8 of the 12 principles of GC. The
major characteristics are as follows:
• It comprises waste prevention and lessens the amount of
redundant waste by 19%, compared to the second
generation, and entirely eradicates the need for aqueous
waste.
• It restrains the waste-per-product weight to make the
synthesis economical and with minimum impact on the
environment.
• It is performed under ambient temperature and pressure.
• It permits optical purity through employing an engineered
transaminase biocatalyst to substitute for the rhodium
catalyst.
• It eliminates the need for high-pressure hydrogenation
devices.
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• It is a three-step synthesis with a significantly high overall
yield of 92%.
8.8. Levetiracetam
Levetiracetam [(S)-α-ethyl-2-oxo-1-pyrrolidinacetamide] is
used for the treatment of epilepsy, an API for Keppra. Most
existing synthesis processes of levetiracetam involve the use of
diastereomeric resolution using stoichiometric amounts of chiral
acids or bases. Huge amounts of chemicals and solvents were
used in the whole process, resulting in high process mass
intensity (PMI). One of the most common routes293 considered
the resolution of a racemic 2-amino amide (156.2) by L-tartaric
acid to generate the (S)-2-aminobutanamide (156.3) that was
later fused with a 4-chlorobutanoate (156.4) to prepare
levetiracetam (Scheme 156). In this specific route, the
resolution has a yield of only 35%, and most importantly, the
undesired (R)-enantiomer is difficult to recycle, which resulted
in high PMI. Additionally, a hazardous alkylating agent was used
in the concluding step. (Z)-2-Acetamidobut-2-enamide (156.5)
and (Z)-2-(2-oxopyrrolidin-1-yl)but-2-enamide (156.6) were
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Scheme 154. Improved Second Generation Synthesis of Sitagliptin

Scheme 155. Environmentally Friendly Biocatalytic Synthesis of Sitagliptin

Scheme 156. Commercial Synthesis Route of Levetiracetam through Chemical Resolution or Asymmetric Hydrogenation

converted to 156.3 and levetiracetam, respectively, through
asymmetric hydrogenation.
Later, a biocatalytic process was discovered, where the key
step involves a kinetic resolution of a racemic 2-pyrrolidinonyl
nitrile (157a.3) catalyzed by nitrile hydratases (Scheme 157,
route A), which has been prepared from 2-pyrrolidinone
(157a.1) by N-alkylation with racemic 2-chloro n-butylnitrile
(157a.2).294 The mutant engineered biocatalyst nitrile
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hydratase semirationally controls the resolution proceedings
with a good resolution yield (43%), high productivity, and high
stereoselectivity (94% ee) of 157a.4. Most importantly, the
undesired (R)-enantiomer (157a.5) can be recycled into 2-
pyrrolidinonyl nitrile to continue the process with minimum
waste and maximum atom efficiency. In addition, the hazardous
alkylation is avoided with a friendly SN2 reaction, using an
inexpensive pyrrolidinone.
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Scheme 157. Green Synthesis Biocatalytic Routes of
Levetiracetam
Arndt et al.295 proposed one of the most recent green
syntheses of levetiracetam via a dynamic kinetic resolution and a
ruthenium-catalyzed ex-cell anodic oxidation. The authors
identified Comamonas testosteroni nitrile hydratase variants
with high (S)-selectivity and activity for the enzymatic
resolution. The Strecker reaction was performed by the
enzymatic dynamic kinetic resolution of 2-(pyrrolidine-1-
yl)butanenitrile (157b.1) to the corresponding amide 157b.2.
Finally, the electrochemical stereoconservative and regiospecific
oxidation of 157b.2 in position α to the amine generated
levetiracetam (Scheme 157, route B). The oxidant was
electrochemically generated in an 86% yield.
8.9. Pregabalin
Pregabalin ((S)-(+)-3-aminomethyl-5-methylhexanoic acid), a
major component of Lyrica, is a lipophilic GABA (γ-amino-
butyric acid) analogue used to treat numerous central nervous
system ailments including neuropathic pain, epilepsy, anxiety,
fibromyalgia, and social phobia. The first generation synthesis
process (Scheme 158) of pregabalin started with the
Knoevenagel condensation of diethyl malonate (158.1) and
isovaleraldehyde (158.2); subsequently, cyanation provides the
key intermediate (158.4) that was considered as the regulatory
starting compound.296 The intermediate (158.4) then went
through hydrolysis, reduction, and decarboxylation in one pot
with a single isolation step to get converted into racemic 3-
aminomethyl-5-methylhexanoic acid (158.5). The racemic
pregabalin was then resolved to employ (S)-(+)-mandelic acid
in multistep crystallization, and the total yield of pregabalin was
only around 20%. This synthesis route failed the atom economy,
generated huge organic waste, and was expensive since the
unwanted γ-amino acid enantiomer could not be recycled.296
Scheme 158. First Generation Synthesis of Pregabalin
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To address the problem, a biocatalytic method, which
involves a lipolase-catalyzed resolution of rac-2-carboxyethyl-
3-cyano-5-methylhexanoic acid ethyl ester (CNDE) (159.1) to
produce the 2-carboxyethyl-3-cyano-5-methylhexanoic acid (R-
2) enantiomer (159.2) in enantioselectivity (98% ee) and high-
resolution yields (45%), was developed. A heat-promoted
decarboxylation of R-2 efficiently produces (S)-3-cyano-5-
methylhexanoic acid ethyl ester, a known precursor of
pregabalin. Followed by hydrolysis and hydrogenation, the
precursor provides pregabalin (Scheme 159).297 As the
unwanted (R-1)-enantiomer (159.3) was racemized to
CNDE, the overall yield was improved to 40%, almost doubling
the yield of the present route. Then, the reflux of 159.2 prepared
159.4 that went through hydrolysis to generate pregabalin. All
three steps after CNDE were performed in the aqueous
environment. Thus, the biocatalytic route is meaningfully
greener than the previous chemical route with the E factor
being reduced from 86 to 17, and the performed enzymatic
process has a brilliant volumetric activity of >500 g/L-d. It is
important to mention that nearly 2000 t of raw materials like
CNDE, mandelic acid, and Ni and around 10 million gallons of
alcoholic organic solvent were eradicated annually by
implementing this biocatalytic route. The obtained pregabalin
reported 99.5% purity with 99.75% ee.
8.10. β-Lactam Antibiotics
Commonly employed β-lactam antibiotics are amoxicillin,
ampicillin, cephalexin, cefaclor, and cefadroxil. Initially, these
antibiotics were prepared from penicillin G, which is a
fermentation product derived from non-ribosomal peptide
synthase (NRPS) through selective chemical deacylation,
where the carboxy group of penicillin G was protected first by
silylation, followed by selective deacylation through the imidoyl
chloride and the removal of the protecting group. The
protection step used stoichiometric amounts of the silylating
agent and an ample number of solvents such as dichloromethane
and phosphorus pentachloride, which are hazardous. Bruggink
et al.298 established a biocatalytic route for the kinetically
controlled synthesis of semisynthetic antibiotics at an industrial-
scale level through immobilized penicillin acylase, a biocatalyst.
Penicillin-derived antibiotics (160.3) like ampicillin and
amoxicillin are obtained by condensing 6-aminopenicillanic
acid (6-APA) (160.1) with the amide or ester of D-(−)-phenyl-
glycine and D-(−)-4-hydroxyphenylglycine (160.2), respec-
tively. If 160.2 is D-(−)-phenylglycine, then ampicillin will be
prepared. In the case of D-(−)-4-hydroxyphenylglycine,
amoxicillin will be synthesized. In the same way, cephalospor-
in-derived antibiotics (161.3) like cefaclor, cephalexin, and
cefadroxil can be synthesized from 7-aminodesacetoxycephalo-
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Scheme 159. Green Synthesis of Pregabalin

Scheme 160. Biocatalytic Synthesis Routes for Penicillin-Derived Antibiotics

Scheme 161. Biocatalytic Synthesis Routes for Cephalosporin-Derived Antibiotics

Scheme 162. Traditional Medicinal Chemistry Synthesis Route for Aprepitant

sporanic acid (7-ADCA) or 7-amino-3-chloro cephalosporanic kinetic control, the penicillin acylase was capable to catalyze the
acid (7-ACCA) (161.1) by reacting with 161.2. Under the acylation of 6-APA and 7-ADCA (Schemes 160 and 161) in
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aqueous environments and at room temperature without the
protection and deprotection of the mentioned functional
groups, which follows the eighth principle of GC. The key
feature of this technique is the development of a biocatalyst that
can be recycled manyfold and reused without losing its
bioactivity. The authors reported yields as high as or better
than those obtained in traditional chemical condensations.
8.11. Aprepitant
Aprepitant is a neurokinin-1 (NK-1) receptor antagonist
developed and marketed by Merck under the brand name
Emend.299 The early medicinal synthesis route involved
reduction of morpholinone derivative (162.1) with L-selectride,
followed by quenching of the prepared intermediate (2S,3S)-4-
benzyl-3-(4-fluorophenyl)morpholin-2-ol (162.2) with 3,5-
bis(trifluoromethyl) benzoyl chloride (162.3) to afford a 79%
yield of (2R,3S)-4-benzyl-3-(4-fluorophenyl)morpholin-2-yl
3,5-bis(trifluoromethyl)benzoate (162.4). This intermediate
was subsequently converted to aprepitant, employing a series of
reactions (Scheme 162).300 The route was considered environ-
mentally hostile due to the stoichiometric titanium-metal-
mediated olefination and the protecting group strategy.
Later, Merck scientists strategically offered green approaches
in different stages of the aprepitant synthesis. First, 2-
(benzylamino)ethanol (163.1) was condensed with 2,2-
dihydroxyacetic acid (163.2) at ambient temperature to afford
the intermediate 3-benzyloxazolidine-2-carboxylic acid (163.3)
in high yield.301 The resultant intermediate 163.3 rearranged to
4-benzyl-2-hydroxymorpholin-3-one (163.4) in a mixture of
water and THF, accompanied by decarboxylated byproduct 3-
benzyloxazolidine (163.5). The decarboxylated byproduct
could be converted to the starting material 163.1 at the expense
of formaldehyde, and ultimately, the scheme was able to achieve
a better yield of the final product 163.4, as shown in Scheme
163.299
Scheme 163. Green Synthesis Route of the Intermediate 4-
Benzyl-2-ydroxymorpholin-3-one for the Synthesis of
Aprepitant
The lactol derivative 4-benzyl-2-hydroxymorpholin-3-one
(163.4) was then activated as a trifluoroacetate ester without a
base to generate 4-benzyl-3-oxomorpholin-2-yl 2,2,2-trifluor-
Scheme 164. Green Synthesis Route of the Intermediate 2,2′-Oxybis(4-benzylmorpholin-3-one) for the Synthesis of Aprepitant
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oacetate (164.1). The reaction of freshly prepared 164.1 with
(S)-1-(3,5-bis(trifluoromethyl)phenyl)ethanol (164.2) cata-
lyzed by BF3·Et2O consequently yielded a 55:45 mixture of
164.3a and 164.3b (Scheme 164). The whole process is highly
scalable and efficient. Along with the dimeric impurity, the major
intermediate 2,2′-oxybis(4-benzylmorpholin-3-one) (164.4)
was synthesized with good yield.299
A robust one-pot process was also developed for the HCl salt
of the intermediate (165.1) that is one of the important
penultimate products of the green synthesis of aprepitant
(Scheme 165). This was followed by the completion of the
Scheme 165. Green Synthesis Route of the Intermediate
Morpholine Derivative for the Synthesis of Aprepitant
Grignard reaction with 164.3a; the mixture was quenched and
consequently hydrogenated by a Pd/C catalyst. The hydro-
genation selectivity in support of the preferred cis isomer 165.1
was boosted when the quenched Grignard reaction mixture was
acidified with p-toluenesulfonic acid (TSA) before hydro-
genation. The final product came out as morpholine derivative
in the form of hydrochloride salt (165.1).299
In the final step, aprepitant was achieved from a morpholine
derivative of the HCl salt by the reaction with 3-(chloromethyl)-
1H-1,2,4-triazol-5(4H)-one (166.1) (Scheme 166).302 The
Scheme 166. Final Step of the Green Synthesis of Aprepitant
Merck route involved a convergent approach to achieve the
synthesis in a fewer number steps than the previous route.
Additionally, these steps are significantly better from an
environmental standpoint due to the removal of certain
hazardous reagents. As per the atom economical green
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Scheme 167. First Synthesis Routes of Imatinib
Scheme 168. Green Synthesis Route of Imatinib
approach, approximately 41,000 kg of waste per 1000 kg of
aprepitant was eliminated.
8.12. Imatinib
Imatinib, a 2-phenyl amino pyrimidine derivative, is a potent and
selective inhibitor of BCR-ABL and c-kit oncogenic tyrosine
kinase, approved under the brand name of Gleevec for the
treatment of gastrointestinal stromal tumor and chronic myeloid
leukemia by the US FDA since 2001. One of the first synthesis
pathways was developed by Zimmermann et al. in 1993.303 This
route started with the reaction of 2-amino-4-nitrotoluene
(167.1) with 65% HNO3 to form its nitrate salt that was further
condensed under an aqueous solution of cyanamide to obtain
the guanidine nitrate intermediate (167.2). The intermediate
was then condensed with the 3-dimethylamino-l-(3-pyridyl)-2-
propen-l-one (167.3) in the presence of NaOH in isopropanol
to form a nitro pyrimidine derivative (167.4). Nitro pyrimidine
was then reduced employing ethyl acetate as a solvent and Pd on
carbon as a catalyst to yield N-(5-amino-2-methylphenyl)-4-(3-
pyridinyl)-2-pyrimidineamine (167.5). Finally, the amine
intermediate was condensed with 4-(4-methyl-piperazinometh-
yl)-benzoyl chloride (167.6) in pyridine to give crude imatinib
(Scheme 167). According to the patent document, the obtained
overall yield is only 50% due to the presence of inorganic
impurities with the nitro intermediate. Again, the use of pyridine
as a solvent and employing column chromatography in the final
purification step are the additional drawbacks.
Kompella et al.304 prepared a scalable, cost-effective, and
production friendly process considering the Zimmermann et
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al.303 route as a basis for the preparation of a highly pure (99.9%
purity) imatinib base with a 75% yield. The starting material 2-
methyl-5-nitroaniline (168.1) reacted with cyanamide in the
presence of HCl followed by neutralization to obtain 1-(2-
methyl-5-nitrophenyl)guanidine (168.2), which further reacted
with 3-(dimethylamino)-1-(3-pyridinyl)-prop-2-en-1-one
(168.3) to obtain N-(5-nitro-2-methylphenyl)-4-(3-pyridinyl)-
2-pyridineamine (168.4). Then, the intermediate went through
the reduction using Raney nickel to give N-(5-amino-2-
methylphenyl)-4-(3-pyridinyl)-2-pyrimidine-amine (168.5)
followed by condensation with 4-(4-methylpiperazino)-
methylbenzoyl chloride dihydrochloride (168.6) under the
inorganic base to obtain imatinib (Scheme 168). Most genotoxic
impurities can be removed from the imatinib base by integrating
additional purification steps.
8.13. Paclitaxel
Paclitaxel, a complex diterpenoid alkaloid isolated from the bark
of the Pacific yew tree Taxus brevifolia, is one of the major drugs
for the treatment for various tumors and hostile forms of lung,
ovarian, and breast cancer along with AIDS-related Kaposis
sarcoma. One of the first semisynthetic routes of paclitaxel was
based on Holton’s work, where 10-desacetyl baccatin III (10-
DAB) (169.1) is acetylated and silylated to obtain 7-OTES-10-
desacetyl baccatin III (169.2). This intermediate then reacted
with the protected β-lactam (169.3) to produce 2′-OMOP-7-
OTES-paclitaxel (169.4). Finally, the removal of C-2′
methoxypropyl (MOP) and C-7 TES (triethylsilyl) groups to
obtain paclitaxel (Scheme 169) was done by employing the
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Scheme 169. First Semi-Synthetic Synthesis Route of Paclitaxel
Scheme 170. Green Synthesis Route of Paclitaxel, Employing the Tissue Culture Technique
deprotection reaction.305 Although the MOP protecting group
can be removed easily under mildly acidic conditions, more
rigorous reaction conditions are needed to eliminate the TES
group from C-7. Additionally, the cleaving of silyl ethers
generated a substantial number of impurities.
A new plant tissue culture process was developed by Bristol
Myers Squibb (BMS) Pharmaceutical Research Institute for the
synthesis of paclitaxel using Taxus cell fermentation and
extraction from the culture medium, and subsequently
recrystallization.306 The two isoprenoid precursors farnesyl
diphosphate (170.1) and isoprenyl diphosphate (170.2) react
in the presence of geranylgeranyl pyrophosphate synthetase to
give geranylgeranyl pyrophosphate (170.3) that is further
cyclized (170.4) and converted to baccatin III (170.5) through
a set of enzymatic transformations such as hydroxylation,
acylation, oxidation, and generation of the oxetane ring. Next,
the side chain is installed in baccatin III (170.5) by enzymatic
transfer of phenylisoserine (170.6) to obtain 170.7 (Scheme
170).306 The plant tissue culture followed by the cell
fermentation process helped in eliminating the 11 chemical
transformations and a huge number of hazardous solvents and
wastes compared to the previous process.
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8.14. Simvastatin
Simvastatin, a 3-hydroxy-3-methylglutaryl (HMG) coenzyme A
reductase inhibitor, is used as a cholesterol-lowering agent for
the treatment of dyslipidemia and cardiovascular diseases
connected with hypercholesterolemia. Simvastatin is a semi-
synthetic product derived from lovastatin, a natural secondary
metabolite obtained from the filamentous fungus Aspergillus
terreus.307 Two semisynthetic processes were broadly recog-
nized, starting with lovastatin (Scheme 171).308,309 Route A308
started with the generation of the intermediate monacolin J acid
(171.2) through the hydrolysis of lovastatin acid (171.1),
followed by the lactonization of the acid to protect the C11
hydroxyl group and trimethylsilylation protection of the C13
hydroxyl. The protected monacolin J acid was further reacted
with α-dimethylbutyryl chloride for acylation to yield the
simvastatin in protected form, which was afterward deprotected
to yield simvastatin. Route B (Scheme 171) starts by the
deactivation of the δ-lactone carbonyl toward enolization via
conversion to the bis[(tert-butyldimethylsilyl)oxy]butylamide
followed by ester enolate alkylation.309 The succeeding
desilylation and basic amide hydrolysis in the presence of the
dimethylbutyrate ester moiety yielded the intermediate that
further lactonized to simvastatin with an overall yield of 86%.
Both methods were time-effective and expensive and generated a
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Scheme 171. Two Old-Generation Synthesis Routes for Simvastatin

Scheme 172. New-Generation Whole-Cell Biocatalytic Green Synthesis Schemes of Simvastatin

considerable amount of organic waste. Much later, a whole-cell 8.15. Celecoxib

biocatalytic process was reported307 that was capable of
converting monacolin J acid (171.2) to simvastatin efficiently
(>99% conversion) in a one-step synthesis (Scheme 172). A
novel thioester (172.1) as the acyl donor (LovD) was able to
catalyze the direct acylation of monacolin J by α-dimethylbu-
tyryl-S-N-acetylcysteamine (DMB-S-NAC) to produce simvas-
tatin. The purification and recovery processes were enhanced
due to the implication of a straightforward downstream
purification scheme and the use of a highly efficient enzyme
(1000-fold improved).
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Celecoxib, a nonsteroidal COX-2 anti-inflammatory drug, is
marketed under the brand name of Celebrex. The commercial
preparation of the pyrazole ring of Celecoxib needs recrystalliza-
tions through the water/IPA mixture to remove the unreacted
hydrazine (173.4) and the final regioisomer impurity (173.6),
which were produced during the cyclization (Scheme 173, route
A).310 This purification step added a significant amount of
solvent along with the requirement of heavy-waste disposal. In
search of green synthesis, chemists found that water would lead
to the hydration of the diketone, resulting in the formation of the
regioisomer impurity, as did the concentration of the hydrazine.
Therefore, the water concentration was kept low, and the
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Scheme 173. Commercially Launched Process (Route A) and the Improved Green Synthesis Route (Route B) for Celecoxib

Scheme 174. The Green Synthesis Route of Clopidogrel Bisulfate

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Scheme 175. The Green Synthesis Route for Quinapril
Scheme 176. Valsartan Synthesis Routes via Suzuki−Miyaura Coupling (Novartis Patented Synthesis Route)
effective concentration of hydrazine was reduced by adding it as
the HCl salt instead. Thus, the salt form of hydrazine had limited
solubility in the non-aqueous solution until the diketone sodium
salt (173.5) was added, which neutralized enough salt to lead to
a controlled reaction (Scheme 173, route B). These alterations
in the previous reaction steps helped to reduce the production of
the regioisomer to 0.5%, allowing the direct isolation of pure
Celecoxib from the reaction mixture through water dilution and
cooling only (Scheme 173, route B). In this green process, only
two safer solvents are used, namely, methanol and isopropanol,
eliminating the use of solvents like hexane and methylene
chloride. Furthermore, the process increased the yield from 63
to 84% while decreasing waste production by 35%, including
reduced use of hazardous hydrazine (173.4). This process
eliminated 5200 t of solvent annually.310
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8.16. Clopidogrel Bisulfate
Clopidogrel bisulfate (Plavix) or (+)-(S)-α-(2-chlorophenyl)-
6,7-dihydrothieno[3,2-c]pyridine-5(4H)-acetate sulfate (1:1) is
a thienopyridine class inhibitor of P2Y12 adenosine diphosphate
(ADP) platelet receptors employed as an orally active inhibitor
of platelet aggregation or an antithrombotic agent. In the
beginning days, two forms of synthesis routes of clopidogrel
were identified. The first one was from the derivatives of R-
halogenphenyl acetate through alkylation with 4,5,6,7-
tetrahydrothieno[3,2-c] pyridine.311 The second route was
demonstrated from the derivatives of R-aminophenylacetic
acid.312 Both methods experienced industrial inconveniences
with substandard yield, effectiveness, raw material cost, as well as
environmental impact due to heavy organic waste. Later, Wang
et al.313 discovered an improved synthesis of clopidogrel in four
steps in one pot with more than a 70% overall yield. The starting
material was 2-(2-chlorophenyl)-2-(6,7-dihydrothieno[3,2-c]-
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Scheme 177. Valsartan Synthesis Routes via Decarboxylated Biaryl Coupling
Scheme 178. Valsartan Synthesis via the Negishi Reaction
pyridine-5(4H)-yl)acetonitrile (174.4), which is a key inter-
mediate in the synthesis route and can be economically prepared
from 4,5,6,7-tetrahydrothieno[3,2-c]pyridine (174.3) and R-
bromo-2-chlorophenyl acetonitrile (174.2), which is previously
prepared from the bromination of 2-chlorophenyl acetonitrile
(174.1) (Scheme 174). The direct alkaline hydrolysis of nitrile
derivative (174.4) to acid (174.5) could be done quantitatively
in the presence of a highly concentrated mixed solvent of an
inorganic strong base with a phase-transfer catalyst. On the
contrary, the amide derivative (174.6) may also be obtained
selectively by controlling the concentration of the base (<20%).
L-Camphor sulfonic acid (L-CSA) (0.45−0.55 equiv) is then
used in toluene to prepare racemic clopidogrel (174.8) with an
around 88% total yield.
8.17. Quinapril
Quinapril hydrochloride, marketed as Accupril, is an angio-
tensin-converting enzyme (ACE) inhibitor, commonly used for
the treatment of congestive heart failure (CHF) and hyper-
tension. The initial medicinal synthesis route had a series of
undesirable characteristics, such as the use of the potentially
explosive hydroxybenzotriazole, methylene chloride, the sensi-
tizer dicyclohexylcarbodiimide (DCC), and an abundant
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volume of toluene used for removing acetic acid by solvent
exchange.
The green redesign process by Pfizer focused on the
elimination of the consumption of acetic acid, which helped to
minimize diketopiperazine formation. Thus, the starting ma-
terial was changed to the commercially available N-carbox-
yanhydride (175.1). The self-activated anhydride reacted with
the isoquinolinecarboxylic acid t-butyl ester salt (175.2) and led
to the direct amide coupling (175.3), allowing the elimination of
DCC, its waste product dicyclohexylurea (DCU), and the need
for a chlorinated solvent. Interestingly, the coupling progressed
well in the water and toluene mixture. Then, the ester was
cleaved, employing a minimum amount of acetic acid/HCl
whereby the salt (175.4) was formed. Later, isolation was
performed by simply adding the antisolvent acetone without a
lengthy drying operation or solvent exchange. Finally,
recrystallization in the presence of acetonitrile produced
quinapril (Scheme 175). With the introduction of greener
solvents,314 the overall yield astonishingly increased from 58 to
90% with a drastic reduction of waste.
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8.18. Valsartan
Valsartan, an angiotensin II (AT-II) receptor antagonist,
belongs to the sartans therapeutic class, employed to treat
congestive heart failure (CHF) and high blood pressure. The
biphenyl unit is a common structural scaffold, and its formation
is one of the important steps in the synthesis of the sartans group
of drugs through the use of Suzuki−Miyaura coupling patented
by Novartis, which is reported in Scheme 176. The scheme has
some basic drawbacks such as the use of expensive boronic acid
substrates in the cross-coupling step.315−317 Along with that, a
good amount of organic waste is generated throughout the
process. The reaction flow of route A is (176.1 + 176.2) →
(176.3 + 176.4) → 176.8 → valsartan, route B is (176.5 +
176.6) → (176.7 + 176.4) → 176.8 → valsartan, and route C is
(176.1 + 176.2) → (176.3) → (176.7 + 176.4) → 176.8 →
valsartan (Scheme 176). Later, Goossen and Melzer suggested a
four-step (Scheme 177) valsartan synthesis with a total yield of
39%, using decarboxylative coupling for the construction of the
biaryl moiety.318 Thus, a catalyst system including 1,10-
phenanthroline, copper(II) oxide, 2-cyanocarboxylic acid
(177.1), and palladium(II) bromide was coupled with 1-
bromo(4-dimethoxymethyl) benzene (177.2) for an 80% yield,
and with 4-bromotoluene, an around 71% yield can be obtained.
This route is quite economical and superior considering the
environmental aspect, compared to the literature process, as it is
short, and the stoichiometric amounts of costly organometallic
reagents are avoided.
Further, in 2010, Ghosh et al.319 reported a modified valsartan
synthesis (Scheme 178) employing the Negishi coupling of
oxazoline moieties instead of pricey coupling involving organo-
boronic acid. L-Valine methyl ester hydrochloride (178.1) was
coupled with valeryl chloride (178.2) in the presence of
triethylamine in dichloromethane at 0 °C to produce methyl N-
pentanoyl-L-valinate (178.3) (a 95% yield) that was N-
protected with 1-bromo-4-(bromomethyl)benzene (178.4) to
give methyl N-(4-bromobenzyl)-N-pentanoyl- L -valinate
(178.5) (a 70% yield) in the presence of sodium hydride in
THF. In the next step, the ortho-metalation of 5-phenyl-1-trityl-
1H-tetrazole (178.6) was done with n-butyllithium at 25 °C, and
thus, the obtained product subsequently reacted with zinc
chloride at −20 °C to obtain the required organozinc chloride.
Further, coupling with aryl bromide under the catalytic amount
of Q-phos and palladium acetate in THF at 75 °C generated
methyl N-pentanoyl-N-{[2-(1-trityl-1H-tetrazol-5-yl)biphenyl-
4-yl]methyl}-L-valinate (178.7) (an 80% yield) that is later
hydrolyzed to produce valsartan in the presence of 3N NaOH in
methanol.
In one of the latest approaches for the green synthesis of
valsartan, Pandarus et al.320 illustrated the heterogeneous
Suzuki−Miyaura coupling reaction under batch conditions
between 2-chlorobenzonitrile (176.1) and 4-tolylboronic acid
(176.2) to synthesize 4′-methyl-2-biphenylcarbonitrile (176.3)
in the presence of the catalyst organosilica matrix functionalized
with diphenylphosphine ligands bound to Pd(II) (SiliaCat DPP-
Pd) in the ethanol solvent (Scheme 179). This method can be
effectually useful for a high-yield (ranging from 70−100%)
synthesis of efficient and continuous coupling products, where
the optimal catalyst amount under scaled-up conditions is 0.7
mol % and 0.25 mmol/g of Pd loading.
8.19. LY300164
LY300164 is a potential drug employed majorly for the
treatment of neurodegenerative disorders like Alzheimer’s,
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Scheme 179. Scale-up of the Key Suzuki−Miyaura Coupling
over SiliaCat DPP-Pd
epilepsy, and Huntington’s diseases. The initial scalable
synthesis of LY300164 consisted of a linear eight-step approach
with a final overall yield of only 22%. Along with poor atom
economy, multiple reagents (chromium trioxide, borane,
perchloric acid, and hydrazine) made the whole process
disadvantageous and hazardous to the environment.
Later, Lilly Research Laboratories proposed environmentally
friendly protocols including air oxidation and a biocatalytic
reduction in the green route synthesis process of LY300164.321
The green route (Scheme 180) began with the preparation of
the chiral alcohol enzymatically from 1-(benzo[d][1,3]dioxol-5-
yl)propan-2-one (180.1) instead of previous late-stage borane
imine reduction for the required chirality in the synthesis
process. The biocatalytic reduction was performed in the
presence of resin-bound Zygosaccharomyces rouxii in water,
which has been used in the food industries for centuries. Then,
the chiral alcohol (180.2) generated chiral cyclic ether (180.3)
through the cyclization step. The oxidation at the benzylic center
was carried out by air via a base-mediated oxidation using
sodium hydroxide in DMSO to prepare the hemiketal
intermediate (180.4). The intermediate reacted with acetylhy-
drazine to form another intermediate (180.5) that was further
treated with mesyl chloride and triethylamine to generate
crystalline mesylate (180.6). Compared to the earlier scalable
process, in the green synthesis, chromium has been replaced
with air while hydrazine was replaced with the less dangerous
acetylhydrazine, and the environmental pollutant perchloric acid
is completely avoided. The subsequent cyclization of crystalline
mesylate cleanly forms the benzodiazepine (180.7) in a 93%
isolated yield. The catalytic hydrogenation in aqueous ethanol
using potassium formate as a hydrogen source reduces the nitro
group of the benzodiazepine derivative to form LY300164, and
the obtained yield is around 91%.
8.20. ABT-546
ABT-546 is a potent, highly selective, and active endothelin ETA
receptor antagonist. The early synthetic route to prepare the
racemic pyrrolidine core of ABT-546 needed consequent
resolution with D-tartaric acid. Further, this process required
several recrystallizations, and the resolved tartrate salt could be
obtained in only 40% yield theoretically. This encouraged a
search for the asymmetric synthesis of the pyrrolidine core to
provide enough material to generate ABT-546 in a greener way.
A catalytic and highly enantioselective conjugate-addition
procedure was developed, in which the β-ketoester anion (7,7-
dimethyldecane-3,5-dione) (181.1) was reacted with nitroolefin
((E)-4-methoxy-6-(2-nitrovinyl)benzo[d][1,3]dioxole)
(181.2) through catalysis with 4 mol % bis(oxazoline)−
Mg(OTf)2 amine complex (181.3) (Scheme 181). This resulted
in attaining 181.4 with 88% selectivity along with allowing less
dependence on the tartrate salt for upgrading the chiral
purity.322
Similarly, in the last three steps of the synthesis of ABT-546,
water was used as a cosolvent (Scheme 182). The tartrate salt
(182.1) was broken with K2CO3 in THF/water with the free
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Scheme 180. The Green Route to Synthesize LY300164

Scheme 181. New Approach to Synthesize the Skeleton of base (182.2) residing in the THF layer. In the following step,
ABT-546 bromoacetamide was added to the THF solution of the free
base, along with aqueous NaHCO3. The reaction was heated
until the alkylation was complete. Once the separation was
performed, the product (182.3) in the THF layer was diluted
with ethanol. For the final step, aqueous NaOH was used for
saponification. All three steps can be performed in a one-pot
sequence, offering a free base of ABT-546 in excellent yield
(96%) without the need for solvent removal and extraction.
In the last three steps of the synthesis, water was used as a
cosolvent (Scheme 182). The tartrate salt was broken with
K2CO3 in the presence of THF/water, with the free base
residing in the THF layer. In the penultimate step,
bromoacetamide was added to the THF solution of the free
base with aqueous NaHCO3, and the alkylation process was
completed under heat. After separation, the product in the THF
layer was diluted with ethanol, followed by saponification with
aqueous NaOH. The three-step process can be completed in a
one-pot sequence and can generate ABT-546 with an excellent
Scheme 182. Final Three Steps in the Green Synthesis Route yield of around 96% without the requirement for solvent
of ABT-546 removal and extraction.322

9. THE GREEN SYNTHESIS OF STARTING RAW

MATERIALS OF APIS
Any key starting raw materials used to prepare a specific API are
considered under this specific section. The green synthesis of
starting raw materials can ultimately lead to the greenness of
final APIs by maintaining the green chemistry principles from
start to end of the synthesis journey of an API.
9.1. Ketal Ester for Oseltamivir Phosphate
Oseltamivir phosphate (TamifluTM), a neuraminidase inhib-
itor, is one of the most employed drugs for the treatment and
prevention of influenza. Shikimic acid ((3R,4S,5R)-3,4,5-
trihydroxycyclohex-1-ene-1-carboxylic acid) (183.1) is the key
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starting material to produce the oseltamivir phosphate (183.2)
(Scheme 183).323 Isolation of shikimic acid from Chinese star
Scheme 183. Oseltamivir Phosphate Synthesis Route
anise seeds (Illicium verum) was low (a yield of 3−7%). Thus,
alternate fermentation methods to synthesize shikimic acid were
developed. In one of the first processes, the esterification step in
the synthesis of Tamiflu was performed using stoichiometric
amounts of toxic and corrosive thionyl chloride as an in situ
means for generating anhydrous hydrochloric acid as a catalyst
(Scheme 183).323 However, the toxicity of thionyl chloride
along with the formation of the greenhouse gases after the
hydrolyzation were serious environmental threats. The direct
ketalization synthesis employing 3-pentanone was stopped
prematurely, as the intermediate purification via crystallization
of crystalline acetonide was essential to attaining the required
overall purity. It is interesting to point out that the overall yield
was diminished by around 20% with this current process. To
develop an enhanced process for the synthesis of oseltamivir
phosphate, Ressmann et al.324 reported an IL strategy for the
reactive dissolution of star anise seeds (source of shikimic acid
(184.1)) in the presence of Bronsted-acidic ILs (1:1 mixture of
IL 5 {[HSO3C4mim]HSO4} or IL 8 {[HC2im]HSO4}) as a
solvent and a catalyst (ethanol and 3-pentanone) to prepare
shikimic acid ethyl ester (184.2) as an intermediate and for the in
situ formation of ketal ester (184.3) after 24 h at 80 °C with a
final yield of 79%. This single-step environmentally benign
strategy generates a higher yield with almost no organic waste
(Scheme 184).
9.2. (S)-N-BOC-3-Hydroxyadamantylglycine for Saxagliptin
Saxagliptin, a dipeptidyl peptidase-IV (DPP-IV) inhibitor,
developed by BMS and marketed under the trade name
Onglyza, is used for the treatment of type 2 diabetes mellitus.
Saxagliptin (185.2) requires (S)-N-BOC-3-hydroxyadamantyl-
glycine (185.1) as the starting material for the synthesis
(Scheme 185), which was prepared utilizing an asymmetric
Strecker amino acid ((R)-(−)-2-phenylglycinol) (186.2) with
the help of highly toxic potassium cyanide (Scheme 186),
starting with the adamantane-1-carboxylic acid derivative
(186.1).325 A modified synthesis pathway326 was proposed by
the BMS enzyme technology group which reported the synthesis
of (S)-3-hydroxyadamantylglycine (187.2) from the keto acid
derivative (187.1), employing a modified form of a recombinant
phenylalanine dehydrogenase enzyme cloned from Thermoacti-
nomyces intermedius and expressed in E. coli or Pichia pastoris.
During the synthesis, the obtained NAD (nicotinamide adenine
dinucleotide) was recycled to NADH (reduced form of
Scheme 184. Green Synthesis of the Starting Material Ketal Ester for the Oseltamivir Phosphate Synthesis
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nicotinamide adenine dinucleotide) with the help of formate
dehydrogenase. Then, (S)-3-hydroxyadamantylglycine (187.2)
could be protected as its BOC derivative without isolation to
have intermediate (S)-N-BOC-3-hydroxyadamantylglycine
(185.1) (Scheme 187). The new route decreased the number
of steps from five to one by restructuring the process through
eliminating cyanide, the costly chiral reagent, (R)-(−)-2-
phenylglycinol, and poor oxidation, utilizing potassium
permanganate in the final step. Additionally, the reductive
amination process used water as a solvent.
9.3. (S)-tert-Leucine for Atazanavir, Boceprevir, and
Telaprevir
(S)-tert-Leucine (188.2) is one of the key chiral amino acids
found as a structural element and required for the synthesis of
drugs like atazanavir, boceprevir, and telaprevir.327 Hanson et
al.328 reported an enzymatic reductive amination of ketoacid
(188.1) by recombinant E. coli expressing leucine dehydrogen-
ase from Thermoactinimyces intermedius to prepare (S)-tert-
leucine (188.2). The reaction needed NADH and ammonia as a
cofactor, and NAD produced during the reaction could be
converted back to NADH by recombinant E. coli by expressing
formate dehydrogenase from Pichia pastoris (Scheme 188).
Therefore, the reaction can be performed in a loop. Considering
100 g/L substrate, >95% of yield can be expected with an ee of
>99.5%.
9.4. Allysine Ethylene Acetal for Vanlev
Omapatrilat (generic name Vanlev), an anti-hypertensive drug,
inhibits both angiotensins converting enzyme (ACE) and
neutral endopeptidase (NEP). One of the important building
blocks for the synthesis of omapatrilat is (S)-2-amino-5-(1,3-
dioxolan-2-yl)-pentanoic acid [(S)-allysine ethylene acetal]
(189.2), which can be achieved by reductive amination of
ketoacid acetal (189.1), using phenylalanine dehydrogenase
(PDH) from Thermoactinomyces intermedius.328 The reaction
required NADH and ammonia, and NAD was produced during
the reaction. The NAD can be recycled to NADH by the
oxidation of formate to CO2, using formate dehydrogenase
(FDH). T. intermedius PDH was cloned and expressed in E. coli,
and the recombinant culture was used as a source of PDH
(Scheme 189).
9.5. Dihydrodiols for Indinavir (Crixivan)
Indinavir (Crixivan) is an HIV protease inhibitor. cis-(1S,2R)-1-
Aminoindan-2-ol (190.6) is a key chiral synthon for indinavir.
Microbial strains Rhodococcus sp. B 264-1 (MB 5655) and I-24
(MA 7205) are capable of biotransforming indene (190.1) to
cis-(1S,2R)-indandiol (190.2) and trans-(1R,2R)- indandiol
(190.3), respectively, which are the important precursors of cis-
(1S,2R)-1-aminoindan-2-ol. Isolated strain MB 5655 was found
to have a toluene dioxygenase (TDO), while isolated MA 7205
was found to hold both TDO and naphthalene dioxygenase
(NDO), which are responsible for the above biotransformation.
Later, dehydrogenase helped to produce indenediol (190.4)
from cis-(1S,2R)-indandiol (190.2), which further produced 1-
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Scheme 185. Medicinal Synthesis Route of Saxagliptin

Scheme 186. Old Industrial Synthesis Route of (S)-N-BOC-3-Hydroxyadamantylglycine

Scheme 187. Environmentally Friendly Synthesis Route of (S)-N-BOC-3-Hydroxyadamantylglycine, a Major Intermediate for
the Saxagliptin Synthesis

Scheme 188. Green Synthesis of (S)-tert-Leucine
keto-2-hydroxyindan (190.5) through isomerization. Finally, a
transamination reaction helped to prepare the desired cis-
(1S,2R)-1-aminoindan-2-ol or cis-indanediol (190.6) (Scheme
190). The directed evolution and metabolic engineering
technique helped avoid side reactions, blocked degradative
pathways, and improved the key reaction to convert indene
(190.1) to cis-(1S,2R)-1-aminoindan-2-ol (190.6).329
9.6. (R)-3-(4-Fluorophenyl)-2-hydroxy Propionic Acid for
Rhinovirus Protease Inhibitor Rupintrivir (AG7088)
Human rhinoviruses (HRVs) are one of the reasons for the
common cold and are also associated with multiple serious

Scheme 189. Enzymatic Synthesis of Allysine Ethylene Acetal

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Scheme 190. Making of Dihydrodiols by a Biocatalytic Process
Scheme 191. Enzymatic Synthesis of (R)-3-(4-Fluorophenyl)-2-hydroxy Propionic Acid
illnesses, especially the aggravation of sickness in person with
underlying respiratory diseases. Rupintrivir, commonly known
as AG7088, is a novel irreversible inhibitor of 3C protease
(rhinovirus protease inhibitor) and is used as intranasal delivery
in human clinical trials.
(R)-3-(4-Fluorophenyl)-2-hydroxy propionic acid (191.2) is
a key building block for the synthesis of rupintrivir. A continuous
biocatalytic process was developed for the synthesis of (R)-3-(4-
fluorophenyl)-2-hydroxy propionic acid (191.2) through
stereoselective enzymatic reduction of the keto acid (191.1)
in the presence of the enzymes D-lactate dehydrogenase (D-
LDH) and formate dehydrogenase (FDH) (Scheme 191).330
Here, the keto acid (191.1) was reduced to the desired (R)-3-(4-
fluorophenyl)-2-hydroxy propionic acid (191.2) in the presence
of D-LDH by NADH (cofactor), which itself is oxidized to
NAD+ in the process. The NAD+ was reduced back in situ to
NADH in the presence of FDH by oxidation of ammonium
formate to NH3 and CO2. The process is commercially feasible
and stable, as both D-LDH and FDH can be recycled, and the
reaction happens in a continuous membrane reactor.
9.7. (R)-Phenylacetyl Carbinol for Ephedrine
Ephedrine is a central nervous system (CNS) stimulant used for
the treatment of low blood pressure problems (orthostatic
hypotension), myasthenia gravis, breathing problems (bron-
chodilator), narcolepsy, and nasal congestion (decongestant).
(R)-Phenylacetyl carbinol ((R)-PAC) (192.3) is a precursor to
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(−)ephedrine. The stereoselective C−C bond forming reactions
are useful in asymmetric synthesis, as this allows the
instantaneous formation of up to two adjacent stereocenters,
and acyloin condensation is one of those types of reaction. The
industrial process for the production of (R)-PAC (192.3) is
based on a continuous enzymatic reaction by pyruvate
decarboxylase from Saccharomyces cerevisiae, Zymomonas mobi-
liz, and a potent mutant of the latter, PDCW392M, using
benzaldehyde (192.1) and acetaldehyde (192.2) as sub-
strates.331 The mutant enzyme is the most active and stable
one among the three. The acyloin condensation reaction
conditions were optimized, and the carboligation was performed
maintaining a continuous reaction system, followed by the
addition of both aldehyde substrates in equimolar concen-
tration. This biocatalytic green strategy helps the synthesis of
(R)-PAC in an aqueous reaction system employing common
and cheap substrates (Scheme 192).
9.8. (S)-3-(3,4-Dichlorophenyl)-5-ethoxy-5-oxopentanoic
Acid for NK1/NK2 Dual Antagonists
Neurokinin (NK-receptor) antagonists, especially the non-
peptide ones, are useful in the treatment of arthritis,
bronchospasm, asthma, and migraine. The drug design and
discovery process have led to the discovery of NK1/NK2 dual
antagonists, whose biological response exists in the (R,R)-
diastereomers. To prepare the structural skeleton of the example
antagonist, the synthesis of (S)-monoester (193.2) is the key
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Scheme 192. Biocatalytic Synthesis of (R)-Phenylacetyl
Carbinol
step. Therefore, an enzymatic process was prepared for the
desymmetrization of the prochiral diethyl 3-[3′,4′-dichloro-
phenyl] glutarate (193.1) to get the desired (S)-monoester
(193.2), employing commercial Chiralzyme L-2 or lipase B
from Candida antarctica with or without immobilization
(Scheme 193). Among the multiple tested enzymes, the lipase
Scheme 193. Enzymatic Synthesis of (S)-Monoester
B from Candid antarctica was selected due to its excellent
selectivity, high thermostability, and moderate cost of the
enzyme.332 The use of immobilized lipase B of 20 and 100 g/L
substrates can produce a yield of 97% with an ee of >99% for the
desired (S)-monoester (193.2).
9.9. Nitroalkanes for Tamsulosin and Selegiline
Tamsulosin (trade name Flomax) is an α1a adrenergic receptor
antagonist used in the treatment of benign prostatic hyperplasia
(BPH). Selegiline (brand name Eldepryl and Emsam) is used for
Parkinson’s disease and major depressive disorder. The chiral
amines are an important backbone for the synthesis of
tamsulosin and selegiline. The reduction of α-methyl-
substituted nitroalkenes (194.1) happens in a highly enantio-
selective fashion with an ene-reductase enzyme from Glucono-
Scheme 194. Enzymatic Synthesis of Nitroalkanes from Nitroalkene Derivatives
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bacter oxidans to obtain the desired nitroalkanes (194.2)
(Scheme 194) with conversions up to >99% and ee values of
up to 95%.333 The ene-reductases are flavin-dependent enzymes
that catalyze the asymmetric reduction of electronically
activated C−C double bonds. The conversion of α- or β-
substituted nitroalkenes to highly enantiopure nitroalkenes by
enzymatic asymmetric reduction is very important, as nitro-
alkanes can easily be converted into the subsequent aldehydes,
amines, oximes, carboxylic acids, and hydroxylamines.
10. THE GREEN SYNTHESIS OF KEY INTERMEDIATES
OF APIS
The syntheses of APIs require multistep processes, and many of
them occurred in different stages and different reactor systems.
Along with the starting raw materials and APIs, there are many
important intermediate materials for which green synthesis can
be used for specific APIs. We have identified many of those
important intermediates and tried to explain them from the
perspective of the green synthesis scheme.
10.1.
(1S,2R)-[3-Chloro-2-hydroxy-1-(phenylmethyl)propyl]-
carbamic acid, 1,1-Dimethylethyl Ester for Atazanavir
Atazanavir is an acyclic aza-peptidomimetic, a potent HIV
protease inhibitor used for the treatment of acquired
immunodeficiency syndrome (AIDS). A key chiral intermediate
(1S,2R)-[3-chloro-2-hydroxy-1-(phenylmethyl)propyl]-
carbamic acid, 1,1-dimethylethyl ester (195.2) is essential for
the synthesis of atazanavir. For green synthesis purposes, a
biocatalytic single-stage enzymatic process was developed by the
diastereoselective reduction of (1S)-[3-chloro-2-oxo-1-
(phenylmethyl)propyl] carbamic acid, 1,1-dimethylethyl ester
(195.1) with the cells of Rhodococcus erythropolis SC 13845 to
produce the intermediate 195.2 (Scheme 195).334 The
Scheme 195. Green Synthesis of (1S,2R)-[3-Chloro-2-
hydroxy-1-(phenylmethyl)propyl]carbamic Acid and 1,1-
Dimethylethyl Ester
biotransformation produces a 95% yield with an ee of 99.4%
and a diasteromeric purity of 98.2% at a substrate input of 10 g/
L. In earlier days, the chemical reduction of chloroketone
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employing NaBH4 generated the undesired chlorohydrin
diastereomer, which is hazardous.
10.2. N-Acetylneuraminic Acid for Zanamivir (Relenza)
Zanamivir (Relenza) is a neuraminidase inhibitor used for the
treatment and prophylaxis of influenza triggered by influenza A
and B viruses. N-Acetyl-D-neuraminic acid (196.3) is one of the
key intermediates for the synthesis of Zanamivir, which can be
prepared by the biocatalytic route, using N-acetyl-D-neuraminic
acid aldolase. To synthesize N-acetyl-D-neuraminic (196.3) acid
in batch processes, N-acetyl-D-mannosamine (196.2) and
pyruvate are allowed to react in the presence of free or
immobilized N-acetylneuraminic acid aldolase from E. coli and
Clostridium perfringens (Scheme 196). To continue the process
Scheme 196. Enzymatic Synthesis (Biocatalysis) of N-
Acetylneuraminic Acid
in the direction of the synthesis of N-acetyl-D-neuraminic acid,
pyruvate is used in a large quantity, making the downstream
processing rather difficult.335 Later, the N-acetylneuraminic
acid-2-epimerase is introduced for the epimerization of N-acetyl
glucosamine (196.1) to produce and continue the supply of N-
acetyl-D-mannosamine (196.2). The whole synthesis can be
performed in an enzyme-membrane reactor. In the production
scale, the same batch of enzymes can be reused >2000 cycles in
batch column reactors without any significant loss of activity.
10.3. (3S,5R)-Dihydroxy-6-(benzyloxy) Hexanoic Acid, Ethyl
Ester for Statins (Anticholesterol Drugs)
Statins such as atorvastatin (Lipitor) and rosuvastatin (Crestor)
are primarily used as lipid-lowering agents. (3S,5R)-Dihydroxy-
6-(benzyloxy) hexanoic acid, ethyl ester (197.2) is one the key
chiral intermediates needed for the synthesis of the majority of
statins. Guo et al.336 developed an enzymatic process for the
synthesis of (3S,5R)-dihydroxy-6-(benzyloxy) hexanoic acid,
ethyl ester (197.2) through an enantioselective reduction of
diketone 3,5-dioxo-6-(benzyloxy)hexanoic acid, ethyl ester
(197.1) (Scheme 197). The biocatalytic process was initiated
by Acinetobacter calcoaceticus sp. SC13876, which reduced the
ethyl diketoester to the desired product with an ee of 99% and a
diastereomeric excess (de) of 63%.
10.4.
(S)-2-[3,2[7-Chloro-2-quinolinyl]ethenyl]-
phenyl-3-hydroxypropyl]benzoic Acid, Methyl Ester for
Montelukast
Montelukast is a leukotriene receptor antagonist (LTRA) used
for the maintenance and treatment of asthma as well as for
relieving the symptoms of seasonal allergies. To prepare
montelukast, (S)-2-[3,2[7-chloro-2-quinolinyl]ethenyl]phenyl-
3-hydroxypropyl]benzoic acid, methyl ester (198.2) plays a
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Scheme 197. Biocatalytic Synthesis of (3S,5R)-Dihydroxy-6-
(benzyloxy) Hexanoic Acid and Ethyl Ester
crucial role as an intermediate. The commercial synthetic route
of Merck involved a stereoselective reduction of 2-[3,2[7-
chloro-2-quinolinyl]ethenyl]phenyl]-3-oxopropyl]-1-methoxy-
carbonylbenzene (198.1) to produce the desired product of S-
configuration (198.2). The alcohol afterward underwent an SN2
displacement with a thiol to give the R-configured product. The
whole process generated a large volume of solvent waste. Later,
considering green synthesis, a biocatalytic enzymatic process
was developed for the transformation of ketone to alcohol by
Codexis.337 The whole process was directed by a ketoreductase
CDX-026 (9.2 kg), using a slurry of the 198.1 (230 kg) in the
presence of a high concentration of isopropanol (5 volumes)
and toluene (1 volume) as cosolvents; triethanolamine buffer of
pH 8.0 (3 volumes) and cofactor NADP-Na (0.23 kg) were also
added at 40−45 °C under stirring (Scheme 198). The organic
phase containing the product was separated. The aqueous layer
was extracted with ethyl acetate (2 volumes), and the organic
phase was combined with the product layer. Later, the combined
organic phase was dried and concentrated to obtain the crude
198.2. Finally, the crude product was purified by recrystalliza-
tion from 70% aqueous methanol (14 volumes) to obtain the
pure product as monohydrate (233 kg), 97.2% yield, >99.9% ee.
10.5. The Enzymatic Preparation of (R)-Allylic Alcohol for an
Integrin Receptor Antagonist
Integrin receptors are involved in several physiological
processes, such as angiogenesis, tissue remodeling, homeostasis,
and development of the immune response. Additionally, they
have a crucial role in pathological disorders such as osteoporosis,
inflammatory and autoimmune diseases, cancer, and cardiovas-
cular diseases. (R)-Allylic alcohol (199.2) is a significant
intermediate for the synthesis of a desired monanoic derivate
beneficial as an integrin receptor antagonist for the treatment of
osteoporosis and inhibition of bone desorption. A pilot-scale
whole-cell enzymatic enantioselective reduction of prochiral
α,β-unsaturated ketone (199.1) to (R)-allylic alcohol (199.2)
(Scheme 199) was developed by Merck using yeast Candida
chilensis.338 The preliminary process showed a high ee of >95%
but a low product yield of around 10%. Thus, a combination of
statistically designed screening and optimization of experiments
helped to improve the desired alcohol yield to 90%. Factors such
as reaction media composition, fermentation growth stage, and
growth pH had a significant influence on bioconversion. On the
contrary, the process characterization identified such challenges
as the substrate/product toxicity, the presence of multiple
enzymes, and biphasic cellular morphology. Overall, the whole-
cell enzymatic approach proved to be a green alternative to the
chemical reduction routes.
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Scheme 198. Enzymatic Green Synthesis of (S)-2-[3-2[7-Chloro-2-quinolinyl]ethenyl]phenyl-3-hydroxypropyl]benzoic Acid
and Methyl Ester
Scheme 199. Enzymatic Synthesis of (R)-Allylic Alcohol
Scheme 200. Biocatalytic Synthesis of (1R,4S)-2-Azabicyclo[2.2.1]hept-5-en-3-one and (1R,4S)-tert-Butyl 3-Oxo-2-
azabicyclo[2.2.1]hept-5-ene-2-carboxylate
10.6. (1R,4S)-2-Azabicyclo[2.2.1]hept-5-en-3-one and
(1R,4S)-tert-Butyl
3-Oxo-2-azabicyclo[2.2.1]hept-5-ene-2-carboxylate for
Synthesis of Abacavir
Abacavir (Ziagen) is a potent and selective reverse transcriptase
inhibitor used for the treatment of HIV and HBV infections. An
unsubstituted γ-lactam ((1R,4S)-2-azabicyclo[2.2.1]hept-5-en-
3-one) (200.2) is a key intermediate for the synthesis of
abacavir. The ChiroTech group has developed an enzymatic
process, using γ-lactamase containing microorganisms Pseudo-
monas solanacearum NCIMB 40249 and Rhodococcus sp.
NCIMB 40213 for the resolution of racemic 2-
azabicyclo[2.2.1]hept-5-en-3-one (200.1) to prepare the
required (1R,4S)-2-azabicyclo[2.2.1]hept-5-en-3-one (200.2)
and the byproduct (1R,4S)-4-aminocyclopent-2-enecarboxylic
acid (200.3) (Scheme 200). Later, Glaxo found that activating
the lactam ring with acyl protecting groups such as acetyl or
BOC allowed finding a conventional hydrolytic enzyme, instead
of a specialized γ-lactamase, which hydrolyzes the lactam bond
enantioselectively to produce the N-BOC-substituted γ-lactam
in an optically pure synthesis of abacavir.339 Savinase, a serine-
type protease, was found to be highly enantioselective and is
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produced by the fermentation of recombinant alkalophilic
Bacillus sp. The reactions were carried in a 50% (v/v) organic
solvent such as THF at 30 °C in phosphate buffer (pH 8.0)
containing up to 100 g/L of racemic [(±)-tert-butyl 3-oxo-2-
azabicyclo(2.2.1)hept-5-ene-2-carboxylate] (200.4). Upon
completion of the reactions, the enantiomeric excess of
(1R,4S)-tert-butyl 3-oxo-2-azabicyclo[2.2.1]hept-5-ene-2-car-
boxylate (200.5) was >99%, which was isolated in a good
chemical yield of 84% by extraction into cyclohexane, followed
by evaporation of the solvent. The reported byproduct is an N-
acyl amino acid derivative (200.6).
10.7.
(1S,2R)-2-(Methoxycarbonyl)cyclohex-ene-1-carboxylic
Acid for Chemokine Receptor Modulators
Chemokine is a family of small cytokines found on the surface of
certain cells. Modulators of chemokine receptor activity are
beneficial for the treatment of a variety of immunoregulatory
disorders and inflammatory diseases, including allergic diseases,
rheumatoid arthritis, atherosclerosis, and asthma.
The chiral monoester, (1S,2R)-2-(methoxycarbonyl)-
cyclohex-4-ene-1-carboxylic acid (201.2), is a key intermediate
for the synthesis of a prospective drug candidate as a chemokine
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receptor modulator. The immobilized lipase (Novozym 435)
from Candida antarctica helped in the desymmetrization of
dimethyl-cyclohex-4-ene-cis-1,2-dicarboxylate (201.1) to the
desired monoester (1S,2R)-2-(methoxycarbonyl)cyclohex-4-
ene-1-carboxylic acid (201.2) with a yield of 96% and >99.9%
ee after 24 h of reaction.340 The enantiomer of (1S,2R) is a
(1R,2S)-monoester that can be prepared by desymmetrization
of the mesoanhydride, cis-1,2,3,6-tetrahydro phthalic anhydride
(201.3), through alcoholysis using cinchona alkaloids (Scheme
201). The synthesis of the (1R,2S)-monoester (201.2) is also
Scheme 201. Biocatalytic Synthesis of (1S,2R)-2-
(Methoxycarbonyl)-cyclohexene-1-carboxylic Acid by
Enzymatic Desymmetrization
possible by porcine liver enzyme-catalyzed desymmetrization of
the dimethyl-cyclohex-4-ene-cis-1,2-dicarboxylate (201.1).
Again, desymmetrization of the mesoanhydride (201.3) to the
required (1S,2R)-2-(methoxycarbonyl)cyclohex-4-ene-1-car-
boxylic acid (201.2) is possible by alcoholysis using quinine
alkaloids. Thus, based on biocatalysis and through a continuous
process, one can prepare the required chiral monoester for the
synthesis of the mentioned modulator of a chemokine receptor.
10.8. Chiral Monoacetate Esters for Baraclude
Chiral monoacetate esters are crucial intermediates for the
synthesis of baraclude (Entecavir), a reverse transcriptase
inhibitor, used for the medication of hepatitis B virus (HBV)
infection. Bristol Myers Squibb developed an economically
feasible and scalable enzymatic process for the enantioselective
asymmetric hydrolysis of (1α,2β,3α)-2-[(benzyloxy)methyl]-4-
cyclopenten-1,3-diol diacetate (202.1) to the (+)-monoacetate
(202.2), using cheap and readily accessible lipase PS-30 from
Pseudomonas cepacia immobilized on Accurel polypropylene and
Pancreatin (Scheme 202).341 The enzymatic asymmetric
acetylation of (1α,2β,3α)-2-[(benzyloxy) methyl]-4-cyclopent-
en-1,3-diol (203.1) to the following (−)-monoacetate (203.2)
Scheme 202. Biocatalytic Synthesis of (+)-Monoacetate
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is also possible in the presence of lipase PS-30 with isopropenyl
acetate as the acylating agent (Scheme 203). Thus, both
Scheme 203. Biocatalytic Synthesis of (−)-Monoacetate
monoacetate esters can be prepared using similar enzymatic
conditions just changing the solvent system and temperature, as
illustrated in Schemes 202 and 203. The biocatalytic reactions
are capable of producing 202.2 in an 80% yield with 98% ee, and
203.2 was isolated in an 80% yield with 98% ee.
11. THE ROLE OF CONTINUOUS PROCESSING AND
PROCESS INTENSIFICATION IN GC
The idea of continuous processing43−46 and process intensifi-
cation (PI)47 has attracted the full attention of synthetic organic
chemists since the beginning of the 21st century. The reasons are
environmental awareness and constant pressure from the
legislators to curtail the emissions of synthetic waste and
promote energy efficiency by adopting greener technologies.
Continuous processing is well accepted due to its benefits such
as quick reaction times, rapid reaction screening and
optimization, operational safety, enhanced automation with
feasible inclusion of in-line reaction analysis, and effortless
scalability to the plant scale. Similarly, PI can offer such required
modernization and invention of new equipment design and
processing to enhance process efficiency342 and the develop-
ment of new-age reactors and hybrid units, as well as separation
technologies offering high reactor yield productivity and
eventually high-purity products. Thus, sometimes an old-age
process can also be upgraded through continuous processing
and PI, without changing the reaction scheme at all.
For example, Yoshida et al.343 used microreactors to enable
flash chemistry comprising tremendously fast reactions (<1 s)
and highly reactive and unstable intermediates. The authors
supported the continuous processing and PI, using multiple
successful applications of active in situ catalyst generation along
with multistep consecutive lithiation reactions for protecting-
group-free synthesis. Again, Mascia et al.344 registered an end-to-
end integrated manufacturing plant for the preparation of
aliskiren hemifumarate, an important API in the pharmaceutical
industry. The model plant brings together chemical reactions,
crystallization, separations, and drying, followed by formulation
to generate the final tablet in a single automated system. Thus,
the system offers the flexibility of production volumes with
monitored and controlled quality.
Hernandez-Perez and Collins345 depicted a continuous
photoredox synthesis of N-aryl- and N-alkyl-bearing carbazoles
(204.2) through the C−C bond formation in alkyl/aryl-
substituted diphenylamine (204.1) in the presence of oxidants,
using in situ formed 5 mol % Cu-based [Cu(xantphos)(dmp)]-
BF4 or Ru-based {[Ru(bpy)3](PF6)2} sensitizers (Scheme 204).
On the contrary, in the presence of visible light under similar
batch conditions, the reaction offers a very slow formation of the
product. Thus, continuous processing substantially helps to
increase the exposure of the reaction mixture to ambient light,
which directly enhances the reaction rates.
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Scheme 204. Synthesis of N-Aryl- and N-Alkyl-Bearing
Carbazoles Using Continuous Processing
Lehmann et al.346 developed a continuous flow inverse-
electron-demand Kondrat’eva reaction to prepare cycloalka[c]-
pyridines (205.3) from cycloalkenes (205.1) and unactivated
oxazoles (205.2). The reaction occurs in a continuous tubular
reactor under the required extreme operating conditions of 230
°C temperature and 750 psi pressure for 120 min in the presence
of toluene and TFA (Scheme 205). The reaction is a one-step
Scheme 205. Synthesis of Cycloalka[c]pyridines
process to prepare many vital drug scaffolds such as the dihydro-
5H-cyclopenta[b]pyridine (serotonin receptor 5HT2c), the 4-
aza analogue of ramelteon (melatonin receptor agonist),
alkaloid sinensine for medicinal chemistry.
To avert phosgene-based preparation of carbamates, Grego et
al.347 developed an environmentally benign and alternate green
pathway. They carried out a catalytic fixed-bed continuous
process of carbamoylation of aniline (206.1) by dimethyl
carbonate (206.2) in the presence of the zinc carbonate catalyst
to synthesize methyl phenylcarbamate (206.3) (Scheme 206).
Scheme 206. Synthesis of Methyl Phenylcarbamate
The phosgene-free process showed high conversions (∼98%) at
200 °C and selectivity (97%) devoid of any substantial catalyst
deactivation even after 180 h notwithstanding a reaction
stoppage and restart in between. All of the reactions were
completed in an autoclave with the employment of a
continuous-flow apparatus.
Sedelmeier et al.348 demonstrated scalable and efficient
transformation of N-(3,4-dichlorophenyl)pivalamide (207.1)
to the subsequent 2-(tert-butyl)-6-chlorobenzo[d]oxazole
(207.3) within a continuous-flow reactor, using a two-stage
sequential flow process. The continuous process helps to escape
the decomposition of unstable intermediates under controlled
temperature. In the first step, transformation occurred via base-
mediated deprotonation, ortho-lithiation, and intramolecular
cyclization to obtain the unstable lithiated benzoxazole
intermediate moieties (207.2). This was followed by sequential
quenching by distinct electrophiles, as required in the second
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stage. The successive in-line electrophilic quench outcomes
substituted benzoxazoles in high yield and quality (Scheme
207).
Scheme 207. Synthesis of Benzoxazoles through Continuous
Processing
Pedersen et al.349 set up a continuous stirred-tank reactor
(CSTR) and plug-flow reactor (PFR) to implement a full-scale,
heterogeneous Grignard alkylation. In the proposed reaction
Scheme 208, 2-chlorothioxanthen-9-one (208.1) reacted with
Scheme 208. Continuous Processing and Synthesis of 9-Allyl-
2-chloro-9H-thioxanthen-9-ol
allylmagnesium chloride in THF to produce the magnesium
alkoxide intermediate (208.2) that was successively hydrolyzed
with dilute acid to form 9-allyl-2-chloro-9H-thioxanthen-9-ol
(208.3). The reactors helped the 35% reduction in the solvent
volume, and the formation of a key impurity was suppressed.
Additionally, the minireactor attained multiple economic
advantages ascribed to the microreactor technology by avoiding
the difficulties connected with the processing of solids in
microreactors.
Kozak et al.350 carried out a continuous approach for the
synthesis of cyclic carbonates (209.2) from epoxides (209.1)
and carbon dioxide in the presence of bromine or N-
bromosuccinimide (NBS) as a catalyst (Scheme 209). The
Scheme 209. Continuous Processing and Synthesis of Cyclic
Carbonate
catalyst is easily available and economical, and it converts the
reagents in under 30 min. The authors also demonstrated that
the addition of catalytic benzoyl peroxide can enhance the
reaction rate up to manyfold. The desired cyclic carbonates are
obtained in a good to excellent yield of 51−92%. Based on a
series of kinetics experiments, epoxide activation occurred by
electrophilic bromine and nucleophilic activation of CO2 by an
amide.
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Eli Lilly illustrated an eight-step reaction in continuous unit
operations for the synthesis of prexasertib monolactate
monohydrate.351 The researchers produced around 3 kg of
prexasertib monolactate monohydrate per day, employing small
continuous reactors, extractors, evaporators, crystallizers, and
filters in the laboratory fume hoods. This continuous process
allowed superior performance and process safety relative to the
traditional batch processes. The success of the entire process is
credited to the continuous process technologies facilitated by
flow chemistry, analytical science and engineering, process
modeling, and equipment design.
Heidlindemann et al.352 reported a concept of the continuous-
flow cascade one-pot synthesis of 1,3-diols based on the
immobilization of organo- and biocatalysts. The study
emphasizes the prospective for highly efficient biocatalysts
with excellent reusability in continuous flow organic syntheses.
Sathe et al.353 performed a multistep organometallic carbox-
ylation of olefins to cyclic organic carboxylates in a packed-bed
microreactor, using CO2 gaseous feedstock. The research
represents the utilization of CO2 in the direct synthesis of cyclic
organics, applying comparatively mild conditions. Laudadio et
al.354 reported an electrochemical arene−phenol C−C cross-
coupling and electrochemical anodic oxidation of thioethers,
employing a modular, scalable microflow reactor. All three
above-mentioned studies strongly support the role of flow
chemistry in green synthesis through the advancement of
continuous processing and PI.
12. OVERVIEW, CONCLUSIONS, AND FUTURE
ASPECTS
The idea of green chemistry and its principles has been known
since 1990, but the real implementation of those rules in drug
designing and synthesis has still been limited. For example, the
emerging sustainable chemicals policies in the European Union
with the newly adopted Chemicals Strategy for Sustainability
(https://echa.europa.eu/hot-topics/chemicals-strategy-for-
sustainability) as a part of the European Green Deal aiming for a
zero pollution and toxic-free future will need to consider GC and
apply appropriate tools to realize the policies. This review
accounts for the true implication of GC through the green
synthesis in the form of green solvents, alternative reaction
media balancing minimizing waste, and retaining the efficacy.
We have discussed a series of examples of reaction schemes, one-
pot cascade synthesis, multicomponent reactions, biocatalysis/
enzymatic synthesis for existing generic pharmaceuticals, as well
as starting materials and intermediates of many pharmaceuticals
for which researchers and industries used the green synthesis
process tactfully to control the atom economy and reduce waste.
We are advocating the applications of GC in the drug
designing process, where sustainable biobased building blocks
may be considered as the starting point. The main focus of the
present manuscript is the green synthesis of pharmaceuticals,
not just the drug designing aspect with respect to GC. Thus,
biobased building blocks are not discussed as a major section,
but without any doubt, this is another important concept that is
directly related to GC and the green synthesis of API. The
biobased building blocks can be produced from biomass or
through a bioprocessing route, and they are less hazardous
compared to petroleum-based chemicals; in most cases, the
products are self-degrading in the environment.355 The United
States Department of Energy reported 12 top value-added
chemicals from biomass that could hypothetically substitute
regularly used petroleum-based molecular building blocks.
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These 12 biobased chemicals (1,4-diacids (succinic, fumaric,
and malic acids), 2,5-furandicarboxylic acid (FDCA), aspartic
acid, 3-hydroxy propionic acid (3-HPA), glutamic acid, glucaric
acid, levulinic acid, itaconic acid, 3-hydroxybutyrolactone,
sorbitol, glycerol, and xylitol/arabinitol) can offer plausible
routes for producing everything from biofuels to pharmaceut-
icals following the major principles of GC.356,357
Continuous processing is another acceptable approach for
swift reaction times, rapid reaction screening and optimization,
operational protection, improved automation with feasible
inclusion of in-line reaction analysis, and easy scalability to the
plant scale. The process intensification offers modernization and
innovation of new hybrid equipment by scrapping old-age
reactions and units for high reactor yield productivity and
eventually high-purity products.
From the perspective of future aspects, in silico or computa-
tional approaches can be thoughtfully used for principle 4 of GC,
which defines that “Chemical products should be designed to
affect their desired function while minimizing their toxic-
ity.”358,359 These will be further developed in the coming years
to integrate the wealth of data produced by new high-
throughput assessment methods (NAMs) in further developing
adverse outcome pathways (AOPs) in support of environmental
decision making.360 Computational approaches, as one can
already see in, e.g., the Comparative Toxicogenomic Database
(CTD) (http://ctdbase.org/) for human health, will be further
developed. They will be applied in the area of environmental
hazard determination in machine learning (ML) and artificial
intelligence (AI) settings, e.g., in the form of intelligent Web
servers/software that combine data as evidence in the CTD.
These can save us the development of thousands of unnecessary
drug syntheses and chemicals by predicting their early toxicity
profiles and metabolism, which is another important aspect of
chemical risk management both in the design phase with the
company and with the approving authorities. AI techniques such
as computer-assisted synthesis design (CASD) and critical
assessment of protein structure prediction (CASP) can be
applied strategically to modern drug design and discovery,
considering various aspects of GC. Such approaches will save
time and money, reduce waste, and most importantly save
animal testing, too. In silico tools will thus be a big part of the
future for GC. The multi-criteria decision analysis (MCDA)
algorithm is another support tool in complex decision-making
processes, and some applications of it relate to the integration of
green chemistry and its assessments in analytical chemistry.361
For instance, the analytical hierarchy process (AHP) under
MCDA can be strategically applied to select appropriate solvents
for the synthesis process according to their environment, health,
and safety properties.
Campos et al.51 proposed a concept of molecular editing
capable of insertion, removal, or modification of atoms in
extremely functionalized chemicals at will and in a precise
fashion with computational tools’ involvement. They have
shown how analogues of a complex lead scaffold might be edited
via heteroaromatic reduction, site-selective C−H functionaliza-
tion, ring contraction, or ring expansion, evading a hypotheti-
cally lengthy synthesis of analogues followed by synthetic
hurdles. Integrated chemical databases with these Web servers
followed by AI-directed green synthesis are the future of drug
discovery. Selection of appropriate solvents, reaction conditions,
substrates, and types of reactions can be checked for millions of
compounds by permutation and combination, utilizing in silico
approaches even before practical synthesis within a period of an
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hour. This will offer much greater and broader options to
synthetic chemists. Especially with the rapid globalization
followed by the necessity for fast drug discovery and synthesis
along with banned animal experimentation, one needs to apply
the GC principles, for which the route of in silico drug designing
followed by complete green synthesis from the selection of
solvents to the production of APIs has to be adopted.
AUTHOR INFORMATION
Corresponding Author
Jerzy Leszczynski − Interdisciplinary Center for Nanotoxicity,
Department of Chemistry, Physics and Atmospheric Sciences,
Jackson State University, Jackson, Mississippi 39217, United
States; orcid.org/0000-0001-5290-6136; Phone: +1 601
979 3723; Email: jerzy@icnanotox.org; Fax: +1 601 979
7823
Authors
Supratik Kar − Interdisciplinary Center for Nanotoxicity,
Department of Chemistry, Physics and Atmospheric Sciences,
Jackson State University, Jackson, Mississippi 39217, United
States; orcid.org/0000-0002-9411-2091
Hans Sanderson − Department of Environmental Science,
Section for Toxicology and Chemistry, Aarhus University, DK-
4000 Roskilde, Denmark
Kunal Roy − Drug Theoretics and Cheminformatics
Laboratory, Department of Pharmaceutical Technology,
Jadavpur University, Kolkata 700032, India; Department of
Environmental Health Sciences, Istituto di Ricerche
Farmacologiche Mario Negri IRCCS, 20156 Milano, Italy
Emilio Benfenati − Department of Environmental Health
Sciences, Istituto di Ricerche Farmacologiche Mario Negri
IRCCS, 20156 Milano, Italy; orcid.org/0000-0002-3976-
5989
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.chemrev.1c00631
Notes
The authors declare no competing financial interest.
Biographies
Supratik Kar has been working as a postdoctoral research associate at
Jackson State University, Mississippi, USA, since 2015. He has
completed his B. Pharm. (2008) and M. Pharm. (2010) from Jadavpur
University, India, securing the first position in both degrees and earned
his Ph.D. (2015) from Jadavpur University, India. He is a former
visiting researcher at the University of Gdańsk, Poland, under a Marie-
Curie research fellowship. He has experience in molecular modeling
and the field of medicinal chemistry for over 12 years. He has published
73 research and review articles in peer-reviewed journals, 18 book
chapters, and coauthored two QSAR related books. Dr. Kar’s work has
been cited 3907 times according to Google Scholar with an h-index of
30. He serves as an associate editor of the journals Frontiers in
Pharmacology and IJQSPR. He is serving as an editorial board member
of the Journal of Clinical Medicine (MDPI) and Current Drug Metabolism
(Bentham). Dr. Kar serves in different capacities in the editorial and
review boards of several international journals.
Hans Sanderson received his Ph.D. in Denmark in 2002 and then
worked as a postdoctoral fellow with Prof Keith Solomon at the
University of Guelph, Canada. After this, he worked as the Director for
Environmental Safety for the Soap and Detergent Association (SDA) in
Washington, DC, USA. He then went back to Denmark and worked for
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5 years as a senior scientist at the National Environmental Research
Institute of Denmark. In 2011, he became an associate professor at the
Department of Environmental Science at Aarhus University, Denmark.
He is an adjunct associate Professor at the University of North Carolina
Greensboro, USA, and external lecturer at the University of
Saskatchewan, Canada. During his time in the USA, he continued his
professional education by following courses at Harvard (leadership,
legislation, and management). He has coauthored more than 100 peer-
reviewed publications and served on seven editorial boards.
Kunal Roy is Professor & Ex-Head in the Department of
Pharmaceutical Technology, Jadavpur University, Kolkata, India. He
has been a recipient of the Commonwealth Academic Staff Fellowship
(University of Manchester, 2007) and the Marie Curie International
Incoming Fellowship (University of Manchester, 2013). The field of his
research interest is QSAR and Molecular Modeling with application in
Drug Design and Ecotoxicological Modeling. Dr Roy has published
more than 300 research articles in refereed journals (current SCOPUS
h-index 45). He has also coauthored 2 QSAR related books, edited 8
QSAR related books, and published more than 10 book chapters. Dr
Roy is the Co-Editor-in-Chief of Molecular Diversity (Springer Nature)
and Editor-in-Chief of International Journal of Quantitative Structure−
Property Relationships (IGI Global). Dr Roy serves in different
capacities on the editorial boards of several international journals.
Emilio Benfenati is the head of the Department of Evironmental Health
Sciences, at the Mario Negri Institute, Milan, Italy, where he has worked
since 1997. Previously, he was a researcher at Stanford University,
California, USA (in that period, he also did collaborative research at
Berkeley University, California, USA). He coordinates/coordinated 22
European projects and participates/participated in 28 others. Many of
them are on toxicity and environmental modeling. His research
activities include toxicity and environmental modeling, molecular
descriptors, QSARs, toxicity prediction, characterization and assess-
ment of contaminants, risk assessment, and analysis of environmental
and food samples for pollutants such as dioxins, PCB, PAH, pesticides,
endocrine disruptors, and industrial pollutants. He is the author or
coauthor of 370 papers in international journals and has edited a few
books. He has organized some conferences, including SETAC 2011 and
QSAR 2014 (200 participants).
Jerzy Leszczynski, Professor of Chemistry and President’s Distin-
guished Fellow at Jackson State University (JSU). Prof. Leszczynski
attended the Technical University of Wroclaw (TUW) in Wroclaw,
Poland, obtaining his M.S. (1972) and Ph.D. (1975) degrees. He
directs the NSF Interdisciplinary Nanotoxicity CREST Center. Dr
Leszczynski has served as a referee for over 50 journals and has
published over 1000 referred papers and over 70 book chapters and has
served as an editor of over 50 books. He has given about 1000
presentations, with over 250 of those being invited presentations. His
papers have been cited about 36,000 times, and his Hirsh index
amounts to 91. He is the recipient of the White House Millennium
Award for Science and Technology, USA Presidential Award for
Excellence in Science, Mathematics and Engineering Mentoring, two
Honorary Doctorate Degrees, apart from several other international
awards.
ACKNOWLEDGMENTS
S.K. and J.L. are thankful to the National Science Foundation
(NSF/CREST HRD-1547754 and NSF/RISE HRD-1547836)
for financial support. K.R. and E.B. thank the European
Commission for financial assistance under the project VER-
MEER [LIFE16 ENV/IT/000167].
https://doi.org/10.1021/acs.chemrev.1c00631
Chem. Rev. 2022, 122, 3637−3710
Chemical Reviews
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