Molecules: Recent Advances in The Synthesis of Ibuprofen and Naproxen

molecules
Review
Recent Advances in the Synthesis of Ibuprofen and Naproxen
Min-Woo Ha 1,2 and Seung-Mann Paek 3, *
1 Jeju Research Institute of Pharmaceutical Sciences, College of Pharmacy, Jeju National University,
102 Jejudaehak-ro, Jeju 63243, Jeju-do, Korea; minuha@jejunu.ac.kr
2 Interdisciplinary Graduate Program in Advanced Convergence Technology & Science,
Jeju National University, 102 Jejudaehak-ro, Jeju 63243, Jeju-do, Korea
3 College of Pharmacy and Research Institute of Pharmaceutical Sciences, Gyeongsang National University,
501 Jinju-daero, Jinju 52828, Gyeongnam-do, Korea
* Correspondence: million@gnu.ac.kr; Tel.: +82-55-772-2424
Abstract: Herein, we review the recent progress in the synthesis of representative nonsteroidal
anti-inflammatory drugs (NSAIDs), ibuprofen and naproxen. Although these drugs were discovered
over 50 years ago, novel practical and asymmetric approaches are still being developed for their
synthesis. In addition, this endeavor has enabled access to more potent and selective derivatives from
the key frameworks of ibuprofen and naproxen. The development of a synthetic route to ibuprofen
and naproxen over the last 10 years is summarized, including developing methodologies, finding
novel synthetic routes, and applying continuous-flow chemistry.
Keywords: NSAIDs; ibuprofen; naproxen; synthesis
1. Introduction

Inflammation is a natural defense response of the immune system to non-self-recognition
Citation: Ha, M.-W.; Paek, S.-M. or unusual self-abnormality [1]. Although this crucial process protects our body from
Recent Advances in the Synthesis of unusual disorders, it sometimes causes unwanted physical symptoms such as pain and
Ibuprofen and Naproxen. Molecules
heat. In this regard, a therapeutic method for blocking uncontrolled inflammation has
2021, 26, 4792. https://doi.org/
been studied [2]. Steroids are the most powerful anti-inflammatory medicines used for
10.3390/molecules26164792
this purpose [3]. However, steroidal therapy for anti-inflammation causes additional side
effects such as anabolism, sexual dysfunction, and problematic mineral absorption [4,5].
Academic Editor: Michael John Plater
Since steroids are sensitive to hormones in various organs, non-steroidal therapy has also
been pursued. Acetylsalicylic acid (ASA), known as aspirin, has been used for this purpose,
Received: 11 July 2021
Accepted: 4 August 2021
although its exact mechanism was only uncovered almost 70 years after its first discovery
Published: 7 August 2021
in 1897 [6].
ASA exerts its effects through the formation of a covalent bond between an acetyl
Publisher’s Note: MDPI stays neutral
group in ASA and a serine residue in the active site of the cyclooxygenase enzyme
with regard to jurisdictional claims in
(COX). This irreversible bond formation inhibits the activity of COX in the production of
published maps and institutional affil- prostaglandin, which is pivotal in inflammation processes [7]. However, this irreversible in-
iations. hibition of target proteins causes severe side effects such as gastrointestinal ulceration [8,9]
and bleeding [10]. Since COX2 was reported in 1991 [11], numerous studies have been
performed to realize more selective and potent medicines. Currently, many medicines are
available in this class. These are nonsteroidal anti-inflammatory drugs (NSAIDs) as shown
Copyright: © 2021 by the authors.
in Figure 1 [12,13].
Licensee MDPI, Basel, Switzerland.
As NSAIDs prevail as pain relievers, they have become highly popular drugs in the
This article is an open access article
pharmaceutical market. Their large market has forced the pharmaceutical community
distributed under the terms and to discover advanced synthesis routes for NSAID skeletons [14–16]. From a structural
conditions of the Creative Commons viewpoint, NSAIDs skeletons are usually classified as being an aromatic acetic acid or
Attribution (CC BY) license (https:// propionic acid skeleton that contains an additional chiral center. Among the aromatic
creativecommons.org/licenses/by/ propionic acid skeletons, ibuprofen and naproxen are the most widely used. Ibuprofen was
4.0/). developed in the 1960s [17] and was valued at around 300 million US dollars in 2020 [18].
Molecules 2021, 26, 4792. https://doi.org/10.3390/molecules26164792 https://www.mdpi.com/journal/molecules

Molecules 2021, 26, 4792 2 of 22
In addition, it was prescribed more than 2.4 million times in the USA in 2018 [19] and was
the most prescribed NSAID in that year. The second most prescribed NSAID was naproxen,
which was developed in the 1970s. Considering that both ibuprofen and naproxen can
Molecules 2021, 26, x FOR PEER REVIEW
be purchased without a prescription, it is believed that their medicinal benefits have
significantly improved patients’ lives.
Figure
Figure Structure
1. 1. of representative
Structure NSAIDs.
of representative NSAIDs.
Ibuprofen and naproxen have an aryl-propanoic acid skeleton, possessing stereogenic
center.As NSAIDs
(Figure prevail
1) Although as pain
it features relievers,
a relatively they
small have become
structure, highly
its synthesis popular d
has been
pharmaceutical market. Their large market has forced the pharmaceutical com
studied to reduce synthetic steps, improve reaction conditions, increase reaction scales, and
acquire facial selectivity. It is also interesting that they were sometimes prepared for the
discover advanced synthesis routes for NSAID skeletons [14–16]. From a struc
purpose of demonstration of synthetic methodologies, which were recently developed.
point, NSAIDs
In this skeletons
review, we are usually
present novel endeavorsclassified
to improveas thebeing
synthesisanofaromatic
ibuprofen acetic
or aci
onic acid
naproxen skeleton
over that
the last 10 contains
years. Although ansynthetic
additional chiral
procedures center.
have Among
been well the aromati
established,
more advanced synthesis routes are still required to find efficient
acid skeletons, ibuprofen and naproxen are the most widely used. Ibuprofenpreparation methods and
potent derivatives of ibuprofen and naproxen [20].
oped in the 1960s [17] and was valued at around 300 million US dollars in 2
addition,
2. it was prescribed
Classical Synthesis of Ibuprofenmore than 2.4 million times in the USA in 2018 [1
the The
most prescribed
classical synthesis ofNSAID
ibuprofenin that in
is shown year.
SchemeThe second
1. When mostPure
the Boots prescribed
Drug N
Company developed ibuprofen in 1961, it was prepared in six steps,
naproxen, which was developed in the 1970s. Considering that both ibu including the use of
toxic aluminum chloride in the early stage [21]. However, in 1992, the Hoechst Company
naproxen can be purchased without a prescription, it is believed that their me
protocol improved this procedure by using recyclable hydrogen fluoride as an alternative
efits
to have significantly
aluminum improved
chloride. Moreover, patients’
the synthesis lives.
was accomplished using a simple carbon
Ibuprofen and naproxen have an aryl-propanoic acid skeleton,
monoxide (CO) insertion method without additional hydrolysis or dehydration [22]. Withpossess
a three-step procedure, ibuprofen can be supplied worldwide. However, there is still an
genic center. (Figure 1) Although it features a relatively small structure, its sy
unmet need for a simpler, more efficient, and stereospecific route.
been studied to reduce synthetic steps, improve reaction conditions, increa
scales, and acquire facial selectivity. It is also interesting that they were som
pared for the purpose of demonstration of synthetic methodologies, which w
developed.
In this review, we present novel endeavors to improve the synthesis of ib
naproxen over the last 10 years. Although synthetic procedures have been
lished, more advanced synthesis routes are still required to find efficient p
methods and potent derivatives of ibuprofen and naproxen [20].
2. Classical Synthesis of Ibuprofen

The classical synthesis of ibuprofen is shown in Scheme 1. When the Boots
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FOR PEER REVIEW 3 of 22 3 of 2
Scheme 1. Classical synthesis of ibuprofen.
Scheme
Scheme 1.1.Classical
3. Recent Classical
Synthetic synthesis
synthesis of ibuprofen.
of ibuprofen.
Advances in Ibuprofen
The Synthetic
3. Recent application of continuous-flow
Advances in Ibuprofen synthesis for ibuprofen is shown in Scheme
3. Recent Synthetic Advances in Ibuprofen
[23].The
This synthetic
application route adapts synthesis
of continuous-flow the iodine-mediated 1,2-aryl
for ibuprofen is shown migration
in Scheme 2 [23].reaction
This The
McQuade application
synthetic group
routeused of
adapts continuous-flow
trifluorosulfonic
the iodine-mediated synthesis
acid as for
a reaction
1,2-aryl ibuprofen
catalyst
migration is shown
instead
reaction. ofin
McQuade theScheme
conven
[23].
group This
tionalused
reagent,synthetic
aluminum route
trifluorosulfonic acid adapts tothe
as a reaction
chloride, iodine-mediated
catalyst
achieve instead of the1,2-aryl
continuous-flow migration
conventional
synthesis. reagent,
Aluminumreaction
by
McQuade
aluminum group
chloride,used
to trifluorosulfonic
achieve continuous-flowacid as a reaction
synthesis. catalyst
Aluminum
products are incompatible in further steps. The next step was the 1,2-aryl migration reacinstead
byproducts of the
are conven
incompatible
tional reagent,
tion. After in further
the aluminum
model steps.
study The next
chloride,
and tostep
careful was the
achieve
survey of1,2-aryl
continuous-flow
reaction migration reaction.
synthesis.
conditions, Afterketone
Aluminum
substrate by
the model are
products study and careful survey
incompatible in of reaction
further steps. conditions,
The next substrate
step was theketone 9 could
1,2-aryl be
migration reac
could be quantitatively converted into methyl ester 10. Finally, saponification of the me
quantitatively
tion. theconverted
Afterfunctionality into methyl
model study ester 10.
and ibuprofen
careful Finally,
survey ofsaponification
reaction of the methyl
conditions, esterketone
substrate
thyl ester
functionality afforded
afforded ibuprofen as a light orangeas solid.
a lightItorange solid. It
is noteworthy is noteworthy
that the reaction that th
could
reactionbe could
quantitatively converted
be completed into using
in 10 amin methyl ester reactor
a flow 10. Finally,
withsaponification
a yield
68% overall of the(51%
yield me
could be completed in 10 min using flow reactor with a 68% overall (51% after
thyl
afterester functionality
recrystallization).
recrystallization). Moreover,
afforded
Moreover, ibuprofen
the simplicitythe and as a lightoforange
simplicity
efficiencyand
solid. It is
efficiency
this
noteworthy
syntheticofprocess
this synthetic that th
makes it proces
reaction
makes
likely could
toitsatisfy be
likelythe completed
to unmet
satisfyneed in
the unmet 10 min using
need for
for improved a flow
improved
ibuprofen reactor with
ibuprofen
synthesis a 68% overall
[24]. synthesis [24]. yield (51%
after recrystallization). Moreover, the simplicity and efficiency of this synthetic proces
makes it likely to satisfy the unmet need for improved ibuprofen synthesis [24].
Scheme2.2.Synthetic
Scheme Syntheticstrategy for for
strategy continuous-flow synthesis
continuous-flow of ibuprofen.
synthesis of ibuprofen.
Another
Scheme approach
2. Synthetic employing
strategy continuous-flow
for continuous-flow synthesis,
synthesis reported in 2019, is shown
of ibuprofen.
Another approach employing continuous-flow synthesis, reported in 2019, is shown
in Scheme 3 [25]. This synthesis involves direct alkylation of the benzylic anion via
in Scheme 3 [25]. This synthesis involves direct alkylation of the benzylic anion via ‘su
‘superbase’-mediated deprotonation. Starting from p-xylene, in situ generated ‘superbase’
Another approach
perbase’-mediated employing continuous-flow
deprotonation. synthesis,
Starting from p-xylene, reported
in situ in 2019,
generated is shown
‘superbase
in Scheme
from KOtBu 3 and
[25].tBuLi
This synthesis involves
afforded the direct
desired alkylation
benzylic ofmeet
anion to the benzylic anion via
with adequate ‘su
electro
perbase’-mediated deprotonation. Starting from p-xylene, in situ generated ‘superbase
philes sequentially. After 10 min, the process, which employed the use of MeOTf, iPrI
from KOtBu
and CO and tBuLi afforded the desired benzylic anion to meet with adequate electro
2, produced 2.3 g ibuprofen (50% in three steps). The readily available starting
philes sequentially. After 10 min, the process, which employed the use of MeOTf, iPrI
Molecules 2021, 26, 4792 4 of 22
Molecules 2021, 26, x FOR PEER REVIEWKOtBu and tBuLi afforded the desired benzylic anion to meet with adequate4 elec-
from of 22
trophiles sequentially. After 10 min, the process, which employed the use of MeOTf, iPrI,
and CO2 , produced 2.3 g ibuprofen (50% in three steps). The readily available starting
material
material and repeated
repeated usage
usageofofthe
themixed
mixedbase
base increases
increases thethe cost-effectiveness
cost-effectiveness of this
of this ap-
approach.
proach. However, the strong basicity of this procedure still requires improvement forfor
However, the strong basicity of this procedure still requires improvement in-
industrial purposes.
dustrial purposes.
Scheme 3.
Scheme 3. Continuous-flow
Continuous-flow synthesis
synthesisof
ofibuprofen
ibuprofenusing
usingC-H
C-Hmetalation.
metalation.THF;
THF;tetrahydrofuran.
tetrahydrofuran.Tf;
Tf; trifluoromethansulfonyl.
trifluoromethansulfonyl.
The construction
The construction of of aa 2-arylpropionic
2-arylpropionic acid acid skeleton
skeleton inspired
inspired hydrocarboxylation,
hydrocarboxylation,
which is
which is crucial
crucial for
for ibuprofen
ibuprofen or naproxen synthesis [26]. Iron-catalyzed hydrocarboxyla-
tion, as
tion, asreported
reportedby byThomas
Thomasetetal.,al.,
is is shown
shown in in Scheme
Scheme 4 [27].
4 [27]. Although
Although hydrocarboxyla-
hydrocarboxylation
tion
of of styrene
styrene waswas expected
expected to introduce
to introduce thethe ibuprofenskeleton,
ibuprofen skeleton,the
theregioselectivity
regioselectivity ham-
pered itit [28].
pered [28]. However,
However, thethe highly
highly selective
selective addition
addition of
ofCO
CO22 was
was possible
possible by
by employing
employing
an iron catalyst
an catalyst and
andpyridine
pyridineligand
ligand15. 15.TheThe following
followingmechanistic
mechanistic study showed
study thatthat
showed the
transmetallation
the transmetallation andand
hydrometallation
hydrometallation of iron andand
of iron styrene moieties
styrene areare
moieties important for for
important re-
regioselective addition.
gioselective addition.
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2021,26, FOR PEER REVIEW 5 of 22
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Scheme 4. Iron-catalyzed hydrocarboxylation for ibuprofen synthesis.

Scheme4.4.Iron-catalyzed
Scheme Iron-catalyzedhydrocarboxylation
hydrocarboxylationforfor
ibuprofen synthesis.
Hydrocarboxylation of styrene
Hydrocarboxylation using Cp 2TiCl2 catalyst, reported by the Xi group in
Hydrocarboxylationofofstyrene
styreneusing
usingCpCp
2 TiCl2 catalyst,
2TiCl
reported by the Xi group in
2 catalyst, reported by the Xi group in
2016, is shown in Scheme 5 [29]. For this approach, the
2016, is shown in Scheme 5 [29]. For this approach, theregioselectivity
regioselectivity of
of the
the styrene
styrene moi-
2016, is shown in Scheme 5 [29]. For this approach, the regioselectivity of the styrene moi-
ety waswas
moiety screened
screenedusing various
using variousGrignard
Grignardreagents
reagentsand andadditives.
additives.When
When this
this reaction
reaction was
ety was screened using various Grignard reagents and additives. When this reaction was
applied
was to alkyl-substituted
applied alkenes,
to alkyl-substituted alkenes,reversed
reversedregioselectivity
regioselectivity was observed
observedtotohavehave re-
applied to alkyl-substituted alkenes, reversed regioselectivity was observed to have re-
sulted ininaalinear
resulted linearproduct,
product, nonanoic acid18.
nonanoic acid 18.
sulted in a linear product, nonanoic acid 18.
Scheme5.5.Titanium-mediated
Scheme Titanium-mediated hydrocarboxylation
hydrocarboxylation for for ibuprofen
synthesis. Cp; cyclopentadienyl.
Cp; cyclopentadienyl.
Scheme 5. Titanium-mediated hydrocarboxylation for ibuprofen synthesis. Cp; cyclopentadienyl.
AAsimilar
similarapproach
approachreported
reported bybyWang
Wang andandLi’sLi’s
groups
groupsin 2018 is shown
in 2018 in Scheme
is shown 6. 6.
in Scheme
They A similar
attempted approach
to insert reported
carbon by Wang
monoxide and
(CO) Li’s
into groups
styrene in
14 2018
[30].
They attempted to insert carbon monoxide (CO) into styrene 14 [30]. For a high regiose- is
For shown
a high in Scheme
regiose- 6.
They attempted
lectivity of styrene, to many
insertcocatalysts,
carbon monoxide
including (CO) intoor
metals styrene 14 [30].
acids, were For aWhen
tested. highiron
regiose-
lectivity of styrene, many cocatalysts, including metals or acids, were tested. When iron
chloride
lectivity (FeCl ) was many
of styrene, used as the cocatalyst,
cocatalysts, a highly
including selective
metals addition
or acids, wereoftested.
CO was per- iron
When
chloride (FeCl3 3) was used as the cocatalyst, a highly selective addition of CO was per-
formed
chloridewith approximately
(FeCl 3) was used90% yield.
as the Arylethanol
cocatalyst, 19 wasselective
a highly also used addition
in the reaction
of CO system.
was per-
formed with approximately 90% yield. Arylethanol 19 was also used in the reaction sys-
Interestingly,
formed withthe regioselectivity
approximately 90%was fullyArylethanol
yield. reversed when 19the
was iron cocatalyst
also used in was changed sys-
the reaction
tem. iron
from Interestingly,
bromide to the
ironregioselectivity
triflate. Although was fully reversed
mechanistic studies when
are the
still iron cocatalyst
required, 5 of
versatile was
22
tem. Interestingly,
changed from iron the regioselectivity
bromide to iron was fully
triflate. reversed
Although when the iron
mechanistic cocatalyst
studies are was
still re-
application
changed from of this
ironstrategy could
bromide tobeiron
usedtriflate.
as a valuable
Althoughlead mechanistic
compound instudies drug discovery.
are still re-
quired, versatile application of this strategy could be used as a valuable lead compound
quired, versatile application of this strategy could be used as a valuable lead compound
in drug discovery.
in drug discovery.
Scheme6.4.Iron-catalyzed
Scheme Iron-catalyzed hydrocarboxylation
regioselective for ibuprofen
carboxylation synthesis.
for ibuprofen synthesis. Ts; p-toluenesulfonyl.
Regioselective
Hydrocarboxylationhydrocarboxylation was also
of styrene using performed
Cp2TiCl using a nickel catalyst in the
2 catalyst, reported by the Xi group in
presence of visible light, such as a blue LED [31], and is shown in Scheme 7. of
2016, is shown in Scheme 5 [29]. For this approach, the regioselectivity Hantzsch ester,moi-
the styrene
ety was screened using various Grignard reagents and additives. When this reaction was
applied to alkyl-substituted alkenes, reversed regioselectivity was observed to have re-
sulted in a linear product, nonanoic acid 18.
Scheme 6. Iron-catalyzed regioselective carboxylation for ibuprofen synthesis. Ts; p-toluenesul-
fonyl.
Molecules 2021, 26, 4792 6 of 22
Regioselective hydrocarboxylation was also performed using a nickel catalyst in the
presence of visible light, such as a blue LED [31], and is shown in Scheme 7. Hantzsch
ester, molecular sieves, and nickel catalyst were added with the aid of visible light. Con-
molecular sieves, and nickel catalyst were added with the aid of visible light. Conversely,
versely,
König König
group group
used used a neocuproine
a neocuproine ligand tothe
ligand to amplify amplify the regioselectivity
regioselectivity of this re-
of this reaction.
action. When other phosphine ligands such as 1,4-bis(diphenylphosphino)butane
When other phosphine ligands such as 1,4-bis(diphenylphosphino)butane (dppb) were (dppb)
wereinstead
used used instead of neocuproine,
of neocuproine, a linear product
a linear addition additionwasproduct wasexclusively.
obtained obtained exclusively.
Addi-
Additionally,
tionally, theyperformed
they also also performed mechanistic
mechanistic studiesstudies to elucidate
to elucidate the generation
the in situ in situ generation
of
nickel-hydride complexes that are responsible for irreversible addition to styrene. Although Alt-
of nickel-hydride complexes that are responsible for irreversible addition to styrene.
hough
this this reaction
reaction system
system uses uses ligands
various variousfor
ligands for ibuprofen
ibuprofen synthesis,synthesis, visible-light-as-
visible-light-assisted
room-temperature reactionsreactions
sisted room-temperature may be valuable
may befor environmentally
valuable friendly industrial
for environmentally friendlysyn-
indus-
thesis [32–34].
trial synthesis [32–34].
Scheme 6. Iron-catalyzed regioselective carboxylation for ibuprofen synthesis. Ts; p-toluenesul-

fonyl.
Regioselective hydrocarboxylation was also performed using a nickel catalyst in the

Scheme7.7.Visible
Scheme
presence Visible
of light
light
visible combining
combining
light, regioselective
such regioselective
as a blue LED carboxylation
carboxylation isfor
[31], and for ibuprofen
ibuprofen
shown synthesis.
insynthesis.
Scheme 4CzIPN;
4CzIPN;
7. Hantzsch
2,4,5,6-Tetrakis(9H-carbazol-9-yl)
2,4,5,6-Tetrakis(9H-carbazol-9-yl) isophthalonitrile,
isophthalonitrile, N,N-dimethylformamide.
N,N-dimethylformamide.
ester, molecular sieves, and nickel catalyst were added with the aid of visible light. Con-
versely, König groupwas
AAsimilar used a neocuproine ligand to amplify the regioselectivity of this re-
similarresult
result waspublished
publishedinin2018;
2018;however,
however,itsitsapproach
approachdiffered
differedininthat
thatnono ex-
action. When
external other
reductant, phosphine
such as ligands such as 1,4-bis(diphenylphosphino)butane (dppb)
ternal reductant, such as Hantzsch
Hantzschester, was
ester, wasnecessary
necessary [35]. TheThe
[35]. replacement of benzylic
replacement of benzylic
were used
quaternary instead of neocuproine, a linear addition product was obtained exclusively.
quaternaryammonium
ammonium salt byby
salt carboxylic
carboxylicacid functionality
acid functionalitythrough an iridium-catalyzed
through an iridium-catalyzed
Additionally, process
carbonylation they also performed
is shown mechanistic
in Scheme studies
8 [36–38]. Upon tousing
elucidate theLED,
a blue in situ generation
a smooth
carbonylation process is shown in Scheme 8 [36–38]. Upon using a blue LED, a smooth
of nickel-hydride
conversion complexes
to the desired that was
product are responsible for irreversible
observed. Notably, addition
the reaction to styrene. Alt-
was completed
conversion to the desired product was observed. Notably, the reaction was completed
hough this
without reaction
the need system
for an uses various
additional reducingligands for ibuprofen
agent, similar synthesis,
to the previous visible-light-as-
conversion. It
without the need for an additional reducing agent, similar to the previous conversion. It
was designed
sisted such that the reactions
room-temperature released amine-leaving
may be valuable group formight act as an electron
environmentally donor.
friendly indus-
was designed
Additionally, such that
naproxen the released amine-leaving group might act as an electron donor.
trial synthesis [32–34].2 was successfully obtained by employing this reaction condition.
Additionally, naproxen 2 was successfully obtained by employing this reaction condition.
Scheme 8. Reductant-free coupling for ibuprofen or naproxen synthesis.

Scheme8.7.Reductant-free
Scheme coupling for
Visible light combining ibuprofen or carboxylation
regioselective naproxen synthesis.
for ibuprofen synthesis. 4CzIPN;
2,4,5,6-Tetrakis(9H-carbazol-9-yl) isophthalonitrile,
The carboxylation of quaternary ammonium N,N-dimethylformamide.
salt, achieved by a direct electrochemi-
The carboxylation of quaternary ammonium salt, achieved by a direct electrochemical
cal reaction with CO2, is shown in Scheme 9 [39]. Although this conversion shows a similar
reaction with CO
A similar 2 , is shown
result in Schemein92018;
was published [39]. Although this conversion shows ina similar
reaction pathway, it features electrochemicalhowever,
coupling its approach
of quaternarydiffered
ammonium that no ex-
bromide
reaction pathway, it features electrochemical coupling of quaternary ammonium bromide
ternal
23from
fromreductant, such
benzylicbromide
bromideas Hantzsch
22[40] ester,CO
[40]with
with waswithout
necessary [35]. metal
further The replacement of benzylic
catalysts,complex
complex lig-
23 benzylic 22 CO2 2 without further metal catalysts,
quaternary ammonium
ands, ororexternal salt by carboxylic acid functionality through an iridium-catalyzed
ligands, externalreducing
reducing agents.
agents. As the voltage
As the voltageapparatus
apparatusisisrenewable
renewable [41],
[41], this
this type of
type
carbonylation
conversion process
could is
provide shown
a in
solutionScheme
for the 8 [36–38].
green Upon
synthesis using
of a blue
NSAIDs
of conversion could provide a solution for the green synthesis of NSAIDs [42].
LED,
[42]. a smooth
conversion to the desired product was observed. Notably, the reaction was completed
without the need for an additional reducing agent, similar to the previous conversion. It
was designed such that the released amine-leaving group might act as an electron donor.
Additionally, naproxen 2 was successfully obtained by employing this reaction condition.
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Scheme 9. Electrochemical carboxylation for ibuprofen synthesis.
Scheme9.9.Electrochemical
Scheme Electrochemical carboxylation
carboxylation for ibuprofen
for ibuprofen synthesis.
synthesis.
A more direct CO2 addition from benzylic C-H activation through photo-activation
was Aperformed inCO
2019. After from
König et al. reported blue LED-mediated photocarboxyla
Amore
moredirect
direct 2 addition
CO benzylic C-H activation through photo-activation
2 addition from benzylic C-H activation through photo-activation
tionperformed
was (as shown in in Scheme
2019. 7), they
After König also
et al. attempted
reported to add CO 2 photocarboxylation
blue LED-mediated to the alkyl benzene sub
was performed in 2019. After König et al. reported blue LED-mediated photocarboxyla
strate,
(as shownwhich is readily
in Scheme available
7), they from commercial
also attempted to add COsources
2 to the [43–45].
alkyl Scheme
benzene 10 shows the
substrate,
tion (as
which is shownavailable
readily in Scheme from7),commercial
they also sources
attempted to add
[43–45]. CO 210toshows
Scheme the alkyl
the benzene sub
results
results of this endeavor [46]. Triisopropylsilyl thiol was used to facilitate hydrogen atom
strate,
of which is[46].
this endeavor readily available from commercial sources hydrogen
[43–45]. Scheme 10 shows the
transfer for practicalTriisopropylsilyl
conversion of the thiolsp
was used to facilitate
3-hybridized C-H bond to the atom transfer
carbanion interme
results
for of this
practical endeavorof[46].
conversion the spTriisopropylsilyl
3 -hybridized C-Hthiol bondwas used
to the to facilitate
carbanion hydrogen atom
intermediate.
diate. The resulting benzylic radical was3 then reduced to a carbanion intermediate via
transfer
The for practical
resulting conversion
benzylic radical was thenof the sp -hybridized
reduced C-Hintermediate
to a carbanion bond to the viacarbanion
electroninterme
electron transfer from 4CzIPN. Finally, the resultant benzylic anion intermediate reacted
transfer
diate. The from 4CzIPN.benzylic
resulting Finally, the resultant
radical was benzylic anion intermediate
then reduced to a carbanion reacted with
intermediate via
withtoCO
CO 2 to produce the desired 2-arylpropionic acid skeleton. Visible light was necessary
produce the desired 2-arylpropionic acid skeleton. Visible light was necessary to
electron transfer from 4CzIPN. Finally, the resultant benzylic anion intermediate reacted
2
to complete reaction
complete the reaction [47].
with CO2the to produce[47].the desired 2-arylpropionic acid skeleton. Visible light was necessary
to complete the reaction [47].
Scheme10.
Scheme 10.Photo-chemical
Photo-chemical carboxylation
carboxylation of alkylof alkyl benzene
benzene substrate
substrate for ibuprofenfor
or ibuprofen or naproxen
naproxen synthesis.
synthesis.
Scheme 10. Photo-chemical
However, the relativelycarboxylation
low chemicalof alkylhampers
yield benzenefurther
substrate for ibuprofen
application, alongorwith
naproxen
synthesis.
unwanted isomers
However, thefrom ibuprofen
relatively lowsynthesis,
chemicalwhich
yield is a problem
hampers that has
further not yet been
application, along with
solved. Nevertheless, this conversion method still presents a major opportunity because
unwanted isomers from ibuprofen synthesis, which is a problem that has not yet been
it canHowever,
be achieved thewithout
relativelya metal
low catalyst
chemical or yield
bulkyhampers
ligand under convenient
further reaction
application, along with
solved. Nevertheless,
conditions. In addition, this
the conversion
naproxen methodcan
skeleton still
be presents
accessed aselectively
major opportunity
using this becaus
unwanted isomers from ibuprofen synthesis, which is a problem that has not yet been
it can
reaction be achieved without a metal catalyst or bulky ligand under convenient reaction con
solved. as it has only one
Nevertheless, thisbenzylic carbon.method still presents a major opportunity because
conversion
ditions. In addition,
Another the naproxen
synthetic protocol skeleton
for ibuprofen can beisaccessed
synthesis summarized selectively
in Schemeusing this
11 [48]. It reaction
it can be achieved without a metal catalyst or bulky ligand under convenient reaction con
as it has only one benzylic carbon.
was attempted to substitute allylic alcohol 28 by the allylic oxidation of terminal methylene
ditions. aInsimple
27 using
addition, the naproxen
Appel reaction [49].
skeleton can befound
accessed selectively using this reaction
Another synthetic protocol forHowever,
ibuprofen they
synthesis that, unexpectedly,inisomeric
is summarized Scheme 11 [48]
as it has only
aldehyde 29 was one benzylic
obtained carbon.
as the major product. After thethemechanistic study andofoptimiza-
It was attempted to substitute allylic alcohol 28 by allylic oxidation terminal meth
tion Another
of the synthetic
reaction protocol
conditions, for ibuprofen
aldehyde 29 was synthesis
produced withis92%
summarized
yield, in Scheme
suggesting that 11 [48]
ylene 27 using a simple Appel reaction [49]. However, they found that, unexpectedly, iso
It was attempted
uneventful oxidationto of
substitute
the aldehydeallylic alcoholibuprofen
afforded 28 by theinallylic
good oxidation of terminal
yield. Although this meth
meric aldehyde 29 was obtained as the major product. After the mechanistic study and
ylene 27 using a simple Appel reaction [49]. However, they found that, unexpectedly, iso
optimization of the reaction conditions, aldehyde 29 was produced with 92% yield, sug
meric aldehyde 29 was obtained as the major product. After the mechanistic study and
optimization of the reaction conditions, aldehyde 29 was produced with 92% yield, sug
Molecules 2021, 26, 4792 gesting that uneventful oxidation of the aldehyde afforded ibuprofen8in good yie
of 22
hough this reaction protocol requires more steps than the conventional BHC proto
gesting that
scientific uneventful
importance oxidation
of various of the aldehyde
synthetic afforded
routes still exists. ibuprofen in good yi
hough this
reaction reaction
protocol protocol
requires requires
more steps than the more steps than
conventional BHCthe conventional
protocol, BHC prot
the scientific
scientific importance
importance of various
of various synthetic routes synthetic
still exists. routes still exists.
Scheme 11. CBr4/PPh3-mediated isomeric oxidation protocol for ibuprofen synthesis.
Scheme
Scheme CBr
11.11. 4 /PPh
CBr 3 -mediated
4/PPh isomeric
3-mediated oxidation
isomeric protocol for
oxidation ibuprofen
protocol forsynthesis.
A chemoselective aromatic coupling approach has also been studied and is sh
Scheme 12 [50]. In aromatic
A chemoselective 2014, Zhang
couplinggroup published
approach has also sequential
been studiedcoupling
and is shownwith an a
halide with zinc enolate, followed by an alkyl zinc reagent. Although thisand
in A
Schemechemoselective
12 [50]. In 2014, aromatic
Zhang group coupling
published approach
sequential has also
coupling been
with anstudied
aromatic is s
proced
Scheme
halide
quires 12zinc
with
complex[50]. In 2014,
enolate,
ligands Zhang
followed
and group
by an
metals, alkyl published
zinc reagent.sequential
the required coupling
Although this
reaction sequence with anMo
procedure
is simple. a
requires
halide complex
with ligands
zinc and metals,
enolate, followedthe required
by an reaction
alkyl sequence
zinc is simple.
reagent. Moreover,
Although this proce
thesimplicity
the simplicity of starting
of the the starting material
material is also impressive.
is also impressive. However, its However,
iterative use its iterative use
of metals
quires
als may complex
hamper ligands and metals, the required reaction sequence is simple. M
may hamper furtherfurther development.
development.
the simplicity of the starting material is also impressive. However, its iterative use
als may hamper further development.
Scheme12.12.Reformatsky–Negishi
Scheme approach
Reformatsky–Negishi for ibuprofen
approach synthesis. synthesis.
for ibuprofen Dba; dibenzylideneacetone,
Dba; dibenzylideneac
TFA; trifluoroacetic acid.
TFA; trifluoroacetic acid.
Scheme 12. Reformatsky–Negishi approach for ibuprofen synthesis. Dba; dibenzylideneac
A Pd-catalyzed allylic oxidation procedure was also developed and is shown in
TFA; A
trifluoroacetic
Pd-catalyzed acid.
allylic oxidation procedure was also developed and is sh
Scheme 13 [51]. Although this conversion can be performed using SeO2 /t-BuOOH as
Scheme 13
described [51].Jiang
earlier, Although thisoxygen
group used conversion
gas andcan be performed
catalytic using SeO
PdCl2 . The resulting 2/t-BuOOH
allylic
A
alcohol Pd-catalyzed
28 could be allylic
transformed oxidation
into procedure
ibuprofen by was
employing aalso developed
reduction/oxidation
scribed earlier, Jiang group used oxygen gas and catalytic PdCl 2. The resulting and is sh
a
Scheme 13 [51]. Although this conversion can be performed using SeO2/t-BuOOH
sequence. A novel synthetic route for ibuprofen is thus possible.
cohol 28 could be transformed into ibuprofen by employing a reduction/oxida
scribed earlier,
quence. A novelJiang group
synthetic usedfor
route oxygen gas and
ibuprofen catalytic
is thus PdCl 2. The resulting a
possible.
cohol 28 could be transformed into ibuprofen by employing a reduction/oxida
quence. A novel synthetic route for ibuprofen is thus possible.
Molecules
Molecules 2021, 26, 4792 999 of 22
Molecules 2021,
2021, 26,
26, x
x FOR
FOR PEER
PEER REVIEW
REVIEW of
of 22
22
Scheme
Scheme13.
Scheme 13. Aerobic
13. Aerobic oxidation
Aerobic oxidation approach for
oxidation approach for ibuprofen
synthesis. DMSO;
DMSO; dimethylsulfoxide,
DMSO; dimethylsulfoxide,PDC;
dimethylsulfoxide, PDC;
PDC;
pyridinium dichlorochromate.
pyridiniumdichlorochromate.
pyridinium dichlorochromate.
Another
Another impressive
Anotherimpressive strategy
impressivestrategy was
strategywas
was developed
developed
developed byby adding
adding
by adding cyanide
cyanide to
to aromatic
to aromatic
cyanide aromatic alkynes
alkynes [52]
alkynes
[52]
as as
shown
[52] shown in
in Scheme
as shown Scheme
14. For
in Scheme 14. For Markovnikov’s
14.Markovnikov’s addition
For Markovnikov’s addition of
of cyanide,
addition cyanide, 4-cyanopyridine
4-cyanopyridine
of cyanide, 4-cyanopyridine N-oxide N-
N-
oxide
34
oxide 34adapted
was34 was adapted
was adapted for cyanide
for cyanide
for cyanide supply.
supply. After
After
supply. the
thethe
After addition
addition
addition of
of of cyanidetoto
cyanide
cyanide toafford
affordterminal
afford terminal
terminal
methylene,
methylene, it underwent
underwent one-pot
one-pot reduction
reduction with
with NaBH
NaBH
methylene, it underwent one-pot reduction with NaBH4. Therefore, 4 . Therefore,
4 . Therefore,it
it was possible to
was
it possible
was to pro-
possible to
pro-
duce
producesubstituted
substituted benzyl
benzyl cyanide
cyanide3535using
usingthis strategy,
this strategy, which
which could
could
duce substituted benzyl cyanide 35 using this strategy, which could be transformed into be transformed
transformed into
into
ibuprofen
ibuprofen
ibuprofenviavia simple
viasimple acidic
simpleacidic hydrolysis.
acidichydrolysis. However,
hydrolysis.However,
However, this
this protocol
protocol
this protocol employs
employs
employs excess
excess
excess reagents,
reagents, in-
reagents,
including
cluding
including zinc.
zinc.
zinc. In
In this this
In this regard,
regard, further
further
regard, research
research
further is
is still
research still required.
required.
is still required. However,
However, its
its unique
However, unique syn-
synthetic
its unique syn-
thetic
thetic approach
approach and
and moderate
and moderate
approach chemical
moderate chemical yield
yield are
chemical are
are highly
highly
yield valuable.
highly valuable.
valuable.
Scheme14.
Scheme
Scheme 14. Alkyne-cyanation
14. Alkyne-cyanation
Alkyne-cyanation approach for ibuprofen
approach for ibuprofen synthesis.
synthesis. TFAA;
synthesis. TFAA; trifluoroacetic
TFAA; trifluoroaceticanhydride,
trifluoroacetic anhydride,
anhydride,
DMA;N,N-dimethylacetamide.
DMA;
DMA; N,N-dimethylacetamide.
N,N-dimethylacetamide.
Although
Althoughibuprofen
Although ibuprofenhas
ibuprofen has been
has been commercialized
been commercializedas
commercialized as aa
as a racemic
racemic mixture,
racemic mixture, enantiomerically
mixture, enantiomerically
enantiomerically
pure
pure (S)-ibuprofen has better efficacy and potency. In line with this
pure (S)-ibuprofen has better efficacy and potency. In line with this merit, synthesis
(S)-ibuprofen has better efficacy and potency. In line with this merit,
merit, synthesis
synthesis of of
of (S)-
(S)-
(S)-ibuprofen
ibuprofen hashas been
been studied
studied extensively.
extensively. Scheme
Scheme 1515 isis
a a good
good example
example
ibuprofen has been studied extensively. Scheme 15 is a good example of this endeavor. of
of this
this endeavor.
Incorporation
Incorporation of
Incorporation of CO
of CO and
CO and aniline
and aniline into
aniline into the
into the styrene
the styrene 27was
styrene 27
27 wasaccomplished
was accomplishedenantiomerically
accomplished enantiomerically
enantiomerically
pure
pure manner
manner. [53].
[53] It
It features
features asymmetric
asymmetric Markovnikov-type
Markovnikov-type hydroaminocarbonylation
hydroaminocarbonylation
pure manner. [53] It features asymmetric Markovnikov-type hydroaminocarbonylation of of
of styrene
styrene with
styrene with catalysis
with catalysis
catalysis of of
of Pd Pd
Pd and and phosphoramidite
and phosphoramidite
phosphoramidite ligand ligand
ligand 36. 36. Although
36. Although
Although this this
this type type
type of of
of addi-
addi-
addition
tion reaction
reaction has has
been been reported,
reported, it is it is impressive
impressive that that
this this reaction
reaction can can
be be achieved
achieved
tion reaction has been reported, it is impressive that this reaction can be achieved at room at roomat
room temperature,
temperature,
temperature, with with regioselectivity
with high
high high regioselectivity
regioselectivity (branched:linear
(branched:linear
(branched:linear =
= 99:1)= 99:1)
99:1) and and stereoselectivity
and stereoselectivity
stereoselectivity (90%
(90%
(90%
ee). ee).
ee).
Scheme
Scheme 15. Asymmetric
15. Asymmetric
Scheme15. synthesis
Asymmetric synthesis of
synthesis of (S)-ibuprofen.
of (S)-ibuprofen.
(S)-ibuprofen.

Molecules 2021, 26, 4792 10 of 22
4. Classical Synthesis of Naproxen
The classical
4. Classical synthesis
Synthesis of naproxen is shown in Scheme 16. Whilst ibuprofen is uti
of Naproxen
lized as a
4. Classical racemic
Synthesismixture, the
of Naproxen utilization of naproxen is optically active. Therefore, chira
The classical synthesis of naproxen is shown in Scheme 16. Whilst ibuprofen is uti
resolution [54] or asymmetric synthesis is [55–58] is necessary 16.inWhilst
early development. is When
lizedThe
as aclassical
racemicsynthesis
mixture,ofthe naproxen
utilization shown in
of naproxenScheme
is optically ibuprofen
active. Therefore, chira
Syntex
utilized introduced
as a[54]
racemic naproxen in 1976,
mixture, thesynthesis a synthetic
utilization[55–58] procedure
of naproxen was
is optically adopted
active. Therefore, the
based on tra
resolution or asymmetric is necessary in early development. When
ditional
chiral Friedel–Crafts
resolution alkylationsynthesis
[54] or asymmetric [59] and[55–58]
Willgerodt–Kindler rearrangement
is necessary in early development. [60] to af
Syntex introduced naproxen in 1976, a synthetic procedure was adopted based on the tra
ford arylacetic
When acid 40.naproxen
Syntex introduced Esterification and
in 1976, simple methylation
a synthetic procedure was directly
adoptedproduced
based on racemi
ditional
the Friedel–Crafts
traditional Friedel–Craftsalkylation
alkylation [59]
[59]and Willgerodt–Kindler
and Willgerodt–Kindler rearrangement
rearrangement [60] to af
[60] to
arylpropionic ester 41. Finally, saponification and chiral resolution using cinchonidine re
ford arylacetic
afford acid40.40.Esterification
Esterification andand simple methylation directly produced
racemic racemi
sultedarylacetic acid
in (S)-naproxen in an enantiomerically simple methylation
pure form [61].directly produced
arylpropionicester
arylpropionic ester41.41.Finally,
Finally, saponification
saponification andand chiral
chiral resolution
resolution using using cinchonidine re
cinchonidine
sulted in
resulted in(S)-naproxen
(S)-naproxen in inan
anenantiomerically
enantiomerically pure
pure formform
[61].[61].
Scheme 16. Classical synthesis of (S)-naproxen.
Scheme16.
Scheme 16.Classical
Classical synthesis
synthesis of (S)-naproxen.
of (S)-naproxen.
5. Recent Synthetic Advances in Naproxen
5. Recent Synthetic
In studies Advances synthesis,
of naproxen in Naproxenthe asymmetric induction of chiral centers and con
5. Recent Synthetic Advances in Naproxen
struction of anofarylpropionic
In studies acid skeleton
naproxen synthesis, are important.
the asymmetric induction Zakarian
of chiraletcenters
al. reported
and direc
In studiesanofarylpropionic
construction naproxen synthesis, theare
asymmetric induction of
al.chiral centers and con
methylationofof (S)-naproxen acidusing skeleton
a chiral important.
enolate, as Zakarian
shown inetScheme reported
17. direct
In contrast to
struction ofofan(S)-naproxen
methylation arylpropionic acid
using skeleton
arequiring
chiral areasimportant.
enolate, shown Zakarian
in Scheme 17. et al. reported
In contrast to direc
conventional chiral alkylation chiral auxiliary attachment and detachmen
methylationchiral
conventional of (S)-naproxen using achiral
chiral enolate, as shown indetachment
Scheme 17.[62,63],
In contrast to
[62,63], this chiralalkylation requiring
enolate (reagent) gives auxiliary attachment
the desired productand directly in a highly stereose
conventional
this chiral
chiral enolate alkylation
(reagent) gives therequiring chiral directly
desired product auxiliary in aattachment and detachmen
highly stereoselective
lective manner. Although the author reported that the recovery of chiral amines was pos
manner.
[62,63], Although
this chiralthe author(reagent)
enolate reported that thethe
gives recovery
desiredof product
chiral amines was in
directly possible andstereose
a highly
sible and
readily readily
available available
[64], excess [64],
use of excess
base anduse of base and
electrophile needselectrophile
to be needs
improved forto be improved
further
lective manner. Although the author reported that the recovery of chiral amines was pos
for furtherand
application application and industrial-scale
industrial-scale synthesis. synthesis.
sible and readily available [64], excess use of base and electrophile needs to be improved
for further application and industrial-scale synthesis.
Scheme17.
Scheme 17.Chiral
Chiral enolate
enolate strategy
strategy for (S)-naproxen
for (S)-naproxen synthesis.
synthesis.
Scheme 17. Chiral enolate

Diaryliodonium
Diaryliodonium salt
saltstrategy
waswas for
alsoalso (S)-naproxen
used for the
used synthesis.
forsynthesis
the of (S)-naproxen,
synthesis as shown
of (S)-naproxen, asinshown in
Scheme 18 [65]. For enantioselective α-arylation of the carbonyl group [66–68], silyl ketene
Scheme 18 [65]. For enantioselective α-arylation of the carbonyl group [66–68], silyl keten
N,O-aminal 43 was chosen
Diaryliodonium saltas the
wasnucleophile,
also usedwhile reactive
for the aryliodonium
synthesis salt 44 was used
of (S)-naproxen, as shown in
N,O-aminal
as the 43 was
electrophile chosen
[69,70]. When asthethe nucleophile,
nucleophile and while reactive
electrophile were aryliodonium
mixed with a salt 44 wa
chiral
Scheme 18 [65]. For enantioselective α-arylation of the carbonyl group [66–68], silyl keten
used
copper as the electrophile
catalyst, [69,70]. When the nucleophile and electrophile were mixed with
N,O-aminal 43 the
wasdesired
chosen (S)-arylpropionic
as the nucleophile,acid skeleton was enantiomerically
while reactive aryliodoniumpure.salt 44 wa
a chiral
While thiscopper
reactioncatalyst, the desired
can be performed in a(S)-arylpropionic acid skeleton
one pot reaction efficiently, was enantiomerically
the resource require-
used as the electrophile [69,70]. When the nucleophile and electrophile were mixed with
pure. of
ments While this reaction
diaryliodonium can be performed
electrophile in anon-atom
44 [71,72] and one pot economical
reaction efficiently,
nucleophilethe
43 resourc
a chiral
still need copper
further catalyst, the desired (S)-arylpropionic acid skeleton was enantiomerically
improvement.
requirements of diaryliodonium electrophile 44 [71,72] and non-atom economical nucleo
pure. While this reaction can be performed in a one pot reaction efficiently, the resourc
phile 43 still need further improvement.
requirements of diaryliodonium electrophile 44 [71,72] and non-atom economical nucleo
phile 43 still need further improvement.
Molecules 2021,2021,
Molecules 26, 26,
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4792 PEER REVIEW 11 of 22
Scheme 18. Asymmetric alkylation strategy using iodonium salt for (S)-naproxen synthes
butyldimethylsilyl.
Scheme
Scheme18.18.Asymmetric alkylation
Asymmetric strategy
alkylation using iodonium
strategy salt for (S)-naproxen
using iodonium synthesis. TBS;synthesi
salt for (S)-naproxen
t-butyldimethylsilyl.
A similar
butyldimethylsilyl. approach was studied using Pd-mediated alkylation of silyl keten
as shown
A similarinapproach
Schemewas 19 studied
[73]. For
usingthis conversion,
Pd-mediated aryl triflate
alkylation was used
of silyl ketene acetal,as the c
as A similar
reagent
shown with a approach
in Schemesimple
19 [73]. wasthis
ketene
For studied
acetal 48using
in the
conversion, Pd-mediated
arylpresence aalkylation
ofused
triflate was of More
Pdascatalyst. silyl keten
the coupling impo
as shown
a chiral
reagent with in
ligand Scheme 19acetal
49ketene
a simple [73].48
dominantly For this
directs
in the conversion, aryl triflate
facialofselectivity
presence toMore
a Pd catalyst. was used
produce aas the c
the (S)-arylp
importantly,
chiral
reagentligand
acid framework 49 dominantly
with a simple directs
ketene
50 [74]. facial
acetal
This selectivity
48 in the
strategy to produce
alsopresence the
showedofthat (S)-arylpropionic
a Pdother
catalyst. acid
More impo
NSAIDs, such
framework 50 [74]. This strategy also showed that other NSAIDs, such as (S)-fenoprofen,
afenoprofen,
chiral ligand 49 dominantly
(S)-flurbiprofen, directs
and facial selectivity
(S)-ketoprofen, could be toobtained
produceinthe good(S)-arylpr
chemi
(S)-flurbiprofen, and (S)-ketoprofen, could be obtained in good chemical yield and stereos-
acid framework
and stereoselectivity
electivity 50
(>90% yield, >88%[74].
(>90% This strategy
ee). yield, >88% ee). also showed that other NSAIDs, such
fenoprofen, (S)-flurbiprofen, and (S)-ketoprofen, could be obtained in good chemi
and stereoselectivity (>90% yield, >88% ee).
Scheme19.19.Asymmetric
Scheme AsymmetricPd-coupling strategy
Pd-coupling for (S)-naproxen
strategy synthesis.synthesis.
for (S)-naproxen TMS; trimethylsilyl,
TMS; trimethyls
TMEDA;
TMEDA; tetramethylethylenediamine, Cy; cyclohexyl.
tetramethylethylenediamine, Cy; cyclohexyl.
Pd-catalyzed couplingPd-coupling strategywith
of aromatic halides for carboxylic
(S)-naproxen synthesis.
acids has played TMS; trimethyls
an im-
TMEDA;
portantPd-catalyzed
in organiccoupling
synthesis of
tetramethylethylenediamine,
role aromatic
[75–77].Cy; halidesPd-coupling
cyclohexyl.
Employing with carboxylic
technologyacidsin has
this played
portant
regard, role in
Hartwig organic
group showedsynthesis [75–77].51Employing
that aryl bromide Pd-coupling
could react with propionic acidtechnology
via a in
TMS-enolate
Hartwigintermediate
gard,Pd-catalyzed group [78] to obtain
coupling
showed of thatanaryl
arylpropionic
aromatic halides acid
bromide with skeleton with with
carboxylic
51 could react an excellent
acids has played
propionic ac
yield [79] (Scheme 20). This conversion does not require a highly complex ligand or reac-
portant
TMS-enolate role in organic synthesis
intermediate [78] to [75–77].
obtain anEmploying
arylpropionic Pd-coupling
acid skeletontechnology
with anine
tion system. It was possible to synthesize racemic naproxen in gram scale or ibuprofen in
gard,
yield95%
over Hartwig
[79] (Scheme
yield group
using a20).showed
This
simple that aryl
conversion
procedure. bromide
doesthis
Although 51 couldastill
notprocedure
require react
highly with propionic
complex
requires further ligandac
TMS-enolate
tion system.
advances Itintermediate
was possible
in asymmetric [78]
synthesis, toability
toits obtain
synthesize to an arylpropionic
racemic
construct anaproxen acid skeleton
in gram
carbon framework scale
with with
an an e
or ibup
yield [79] (Scheme
efficient
over 95% methodology
yield using 20).aThis
is conversion
noteworthy.
simple procedure.does not require
Although thisa procedure
highly complex ligand
still requires
tion system.
advances in Itasymmetric
was possible to synthesize
synthesis, racemic
its ability naproxen aincarbon
to construct gram scale or ibup
framework
over 95% yield using a simple procedure.
efficient methodology is noteworthy. Although this procedure still requires
advances in asymmetric synthesis, its ability to construct a carbon framework
efficient methodology is noteworthy.
Molecules 2021, 26, x FOR PEER REVIEW 12
Molecules 2021,
Molecules 26,26,
2021, x FOR
4792 PEER REVIEW 12 of 22
Scheme 20. Pd-coupling for racemic naproxen or ibuprofen synthesis. LHMDS; lithium bis(tri
thylsilyl)amide.
Scheme
Scheme α-Haloester
20.20. was
Pd-coupling also
forutilized
for racemic
Pd-coupling naproxenin
racemic orthe coupling
ibuprofen
naproxen reaction
orsynthesis.
ibuprofen to lithium
LHMDS; affordLHMDS;
synthesis. (S)-naproxen
lithium[80
bis(trimethy- b
Nakamura
lsilyl)amide. et al. reported that an arylmagnesium reagent could react with α-chloro
thylsilyl)amide.
54 with the assistance
α-Haloester was also of an iron
utilized catalyst
in the [82–84]
coupling and
reaction to chiral phosphine ligand
afford (S)-naproxen [80,81]. 55 to a
enantiomerically
Nakamuraα-Haloester enriched
alsoanester
wasthat
et al. reported utilized56. in
For
arylmagnesiumtheincreased
coupling selectivity,
reaction
reagent could toan
react with uncommon
afford ester
(S)-naproxen
α-chloroester
used,
54 withas
Nakamuratheitassistance
could
et al.bereported
converted
of an iron thatto (S)-naproxen
catalyst
an[82–84] underphosphine
and chiral
arylmagnesium acidic
reagent conditions
ligand to[85]
could55react (Scheme
afford
with α-ch2
enantiomerically
mechanistic enriched ester
investigation was For increased
56. also performed selectivity,
to an uncommon
elucidate the ester
radical was
intermediate
54 with the assistance of an iron catalyst [82–84] and chiral phosphine ligand 55
used, as it could
divalent be converted
iron species to (S)-naproxen
important for56. under
theFor acidic
catalytic conditions
cycle. [85] (Scheme
The paper 21). A
alsouncommon
includes that
enantiomerically
mechanistic enriched
investigation was also ester
performed increased
to elucidate theselectivity, an
radical intermediate and e
reaction can be applied to (S)-ibuprofen synthesis in 65% yield with over 99% enanti
used, asiron
divalent it could
speciesbe converted
important to (S)-naproxen
for the under
catalytic cycle. The acidic
paper conditions
also includes that [85]
this (Schem
rity. can be applied to (S)-ibuprofen synthesis in 65% yield with over 99% enantiopurity.
reaction
mechanistic investigation was also performed to elucidate the radical intermed
divalent iron species important for the catalytic cycle. The paper also includes
reaction can be applied to (S)-ibuprofen synthesis in 65% yield with over 99% en
rity.
Scheme21.21.
Scheme Iron-catalyzed
Iron-catalyzed chiral
chiral coupling
coupling to α-haloester
to α-haloester strategy
strategy for for (S)-naproxen
(S)-naproxen synthesis. A
synthesis. Acac;
acetylacetonate.
acetylacetonate.
Nakamura et al. further modified the iron-catalyzed coupling reaction to enantios-

Nakamura
elective et al. further
Suzuki–Miyaura coupling modified the iron-catalyzed
with α-bromoester 58, as showncoupling
in Schemereaction to enant
22 [86].
lective
SchemeSuzuki–Miyaura
Considering 21.the efficiency of
Iron-catalyzed coupling
aryl
chiral with
borates forα-bromoester
coupling to α-haloester58,
metal-catalyzed as shown
coupling,
strategy intype
this
for Scheme
of chi-22synthe
(S)-naproxen [86].
sidering
ral couplingthecan
efficiency
acetylacetonate. be utilizedof for
aryl boratessynthesis.
practical for metal-catalyzed
Chiral couplingcoupling,
followedthis type of chiral
by simple
acidic
plinghydrolysis assessedfor
can be utilized bothpractical
enantiomerically
synthesis.enriched (S)-naproxen
Chiral couplingand (S)-ibuprofen.
followed by simple a
However,
hydrolysis readily available
assessedal.bothchiral ligands and
enantiomerically high selectivity are still required.
enriched (S)-naproxen and (S)-ibupr
Nakamura
The asymmetricet further
addition modified
of thiophenol the attempted,
was also iron-catalyzed
as shown coupling
in Schemereaction
23 [87]. to en
However,
lective
The
readily
Suzuki–Miyaura
α,β-unsaturated
available chiral
terminal coupling
ligands
with
alkene 62 was
and high
α-bromoester
treated
selectivity
58, to
with thiophenol
are
asproduce still required.
shownainMichael
Scheme 22 [8
sidering the efficiency of aryl borates for metal-catalyzed coupling, this type of ch
adduct 64. This conversion proceeded asymmetrically with the influence of cinchona-
derived catalyst
pling can be 63. Raney-Ni
utilized forand NaPH2 O2synthesis.
practical were treatedChiral
to cleave the carbon-sulfur
coupling followed bondby simp
in the next step. Finally, hydrolysis and recrystallization afforded enantiomerically pure
hydrolysis assessed both enantiomerically enriched (S)-naproxen
(S)-naproxen in good yields. Employing this strategy, (S)-ibuprofen could also be obtained
and (S)-ib
However,
with a similarreadily
yield and available
enantiomericchiral ligands
purity. Thus,and high selectivity
the author proposed that arethiourea
still required.
as
a chiral catalyst could interact with the dicarbonyl groups in the substrate via hydrogen
bonding, serving as a chiral platform for the asymmetric Michael addition of thiophenol.
Molecules 2021, 26, 4792 13 of 22
Scheme
Scheme Iron-catalyzed
22.22. Suzuki–Miyaura
Iron-catalyzed coupling coupling
Suzuki–Miyaura for (S)-naproxen or (S)-ibuprofen
for (S)-naproxen orsynthesis.
(S)-ibuprofen sy
The asymmetric addition of thiophenol was also attempted, as shown in Sc

[87]. The α,β-unsaturated terminal alkene 62 was treated with thiophenol to pr
Michael adduct 64. This conversion proceeded asymmetrically with the influenc
chona-derived catalyst 63. Raney-Ni and NaPH2O2 were treated to cleave the car
fur bond in the next step. Finally, hydrolysis and recrystallization afforded enan
cally pure (S)-naproxen in good yields. Employing this strategy, (S)-ibuprofen co
be obtained with a similar yield and enantiomeric purity. Thus, the author propo
thiourea as a chiral catalyst could interact with the dicarbonyl groups in the subs
hydrogen bonding, serving as a chiral platform for the asymmetric Michael add
thiophenol.
Scheme23.
Asymmetricaddition
addition of
of thiol
thiolfor
for(S)-naproxen
(S)-naproxensynthesis.
synthesis.Ra-Ni;
Ra-Ni;Raney-nickel.
Raney-nickel.
The
Thesynthesis
synthesisofofalkenyl boron
alkenyl viavia
boron hydroboration of 1,1-disubstituted
hydroboration allenes
of 1,1-disubstituted was also
allenes was
pursued, as shown
also pursued, in Scheme
as shown 24 [88–90].
in Scheme Hoveyda
24 [88–90]. et al.etreported
Hoveyda that that
al. reported asymmetric hy-
asymmetric
droboration of allene 65 could be achieved by employing a copper catalyst, N-heterocyclic
hydroboration of allene 65 could be achieved by employing a copper catalyst, N-hetero-
cyclic carbene (NHC) ligand 66, and pinacolborane. When the reaction was performed at
room temperature for 2 d, the desired alkenyl pinacolatoboron 67 could be produced with
excellent enantio-and regioselectivity. Finally, the oxidation of alkenes using OsO4 fol-
lowed by NaIO4 afforded (S)-naproxen directly. Mechanistic investigations and further
Scheme 23. Asymmetric addition of thiol for (S)-naproxen synthesis. Ra-Ni; Raney-nickel.
Molecules 2021, 26, 4792 14 of 22
The synthesis of alkenyl boron via hydroboration of 1,1-disubstituted allenes was
also pursued, as shown in Scheme 24 [88–90]. Hoveyda et al. reported that asymmetric
hydroboration of allene 65 could be achieved by employing a copper catalyst, N-hetero-
carbene (NHC)(NHC)
cyclic carbene ligandligand
66, and66,
pinacolborane. When When
and pinacolborane. the reaction was performed
the reaction at room
was performed at
temperature for 2 d, the desired alkenyl pinacolatoboron 67 could be produced
room temperature for 2 d, the desired alkenyl pinacolatoboron 67 could be produced with with excel-
lent enantio-and
excellent regioselectivity.
enantio-and Finally,Finally,
regioselectivity. the oxidation of alkenes
the oxidation of using
alkenesOsO 4 followed
using by
OsO4 fol-
NaIO afforded (S)-naproxen directly. Mechanistic investigations and further
lowed4 by NaIO4 afforded (S)-naproxen directly. Mechanistic investigations and furtherapplications
are currently are
applications in progress
currently[91].
in progress [91].
Scheme 24. Hydroboration of allene

Scheme 24. allene strategy
strategy for
for (S)-naproxen
(S)-naproxen synthesis.
synthesis. Pin;
Pin; pinacol.
pinacol.
Another
Another asymmetric
asymmetrichydroboration
hydroborationroute routeto to
(S)-naproxen
(S)-naproxen waswas
developed
developedin 2014 [92].
in 2014
The
[92]. terminal
The terminalalkene 68 was
alkene chosen
68 was forfor
chosen pivotal
pivotalhydroboration
hydroboration totouse
useaamore
moreversatile
versatile
substrate.
substrate. Remarkably,
Remarkably,cobaltcobaltcatalyst
catalyst6969was
was prepared
prepared forfor
this conversion
this conversionafter an extensive
after an exten-
screening of the catalyst and reaction conditions. After the desired pinacolatoboron
sive screening of the catalyst and reaction conditions. After the desired pinacolatoboron 70 was
obtained exclusively, it was oxidized to (S)-naproxen via a three-step
70 was obtained exclusively, it was oxidized to (S)-naproxen via a three-step sequence sequence without
any epimerization.
without The overall
any epimerization. The yield
overallwas 66%was
yield from66%thefrom
starting alkene 68,
the starting as shown
alkene 68, as
in Scheme 25. Hence, considering the easy preparation of chiral catalysts
shown in Scheme 25. Hence, considering the easy preparation of chiral catalysts and their and their low
loading, this reaction could be considered for the large-scale synthesis of other 15 of if
NSAIDs 22
low loading, this reaction could be considered for the large-scale synthesis of other
cobalt
NSAIDs canif be treated
cobalt canin
bean environmentally
treated friendly manner.
in an environmentally friendly manner.
Scheme25.
Scheme 25. Hydroboration
Hydroboration of
of terminal
terminalalkene
alkenestrategy
strategyfor
for(S)-naproxen
(S)-naproxensynthesis.
synthesis.
Hydroformylation
Hydroformylation in inflow
flowreactions
reactionshas
has also
also been
been studied
studied for for industrial
industrial pur-
purposes
poses [93–95]. Researchers at the University of Wisconsin-Madison and Eli Lilly
[93–95]. Researchers at the University of Wisconsin-Madison and Eli Lilly Corporate Cen-Corporate
Center published
ter published a paper
a paper on asymmetric
on the the asymmetric synthesis
synthesis of (S)-naproxen
of (S)-naproxen usingusing rhodium-
rhodium-cata-
catalyzed hydroformylation,
lyzed hydroformylation, as shown
as shown in Scheme
in Scheme 26In[96].
26 [96]. In this gas
this paper, paper,
andgas andreagents
liquid liquid
were mixed in a flow reactor. After a systematic survey of the reactor design and chiral
ligands, (S)-naproxen was produced in two steps in over 80% yield and 92% enantiomeric
excess from the simple vinyl substrate 72. As this reaction is designed to work in a contin-
uous-flow reactor system, its use for the industrial synthesis of (S)-naproxen is also possi-
Scheme 25. Hydroboration of terminal alkene strategy for (S)-naproxen synthesis.
Hydroformylation in flow reactions has also been studied for industrial purpose
Molecules 2021, 26, 4792 [93–95]. Researchers at the University of Wisconsin-Madison and Eli Lilly Corporate 15 of 22 Cen
ter published a paper on the asymmetric synthesis of (S)-naproxen using rhodium-cata
lyzed hydroformylation, as shown in Scheme 26 [96]. In this paper, gas and liquid reagent
were mixed
reagents were in a flow
mixed in areactor. After After
flow reactor. a systematic survey
a systematic of the
survey reactor
of the design
reactor design and chira
ligands, (S)-naproxen was produced in two steps in over 80% yield
and chiral ligands, (S)-naproxen was produced in two steps in over 80% yield and 92% and 92% enantiomeri
excess fromexcess
enantiomeric the simple
from thevinyl substrate
simple 72. As this
vinyl substrate reaction
72. As is designed
this reaction to work
is designed in a contin
to work
uous-flow
in reactor system,
a continuous-flow its use for
reactor system, thefor
its use industrial synthesis
the industrial of (S)-naproxen
synthesis of (S)-naproxenis also
is possi
also possible
ble [97]. [97].
Scheme26.
Scheme 26.Asymmetric
Asymmetric hydroformylation
hydroformylation strategy
for (S)-naproxen synthesis.
synthesis. BDP; (R,R,R)-
BDP; (R,R,R)-Bis-
Bisdiazaphos-SPE.
diazaphos-SPE.
Asymmetric
Asymmetric hydrogenation
hydrogenationis aisvaluable methodology
a valuable for chiral
methodology medicine
for chiral synthe-synthesi
medicine
sis [98–100]. For NSAID synthesis, the chiral ferrocene-ruthenium complex was reported to
[98–100]. For NSAID synthesis, the chiral ferrocene-ruthenium complex was reported t
be promising, as shown in Scheme 27 in 2016 [101]. This reduction process was developed
be promising, as shown in Scheme 27 in 2016 [101]. This reduction process was developed
for NSAID synthesis and other chiral propionic acid skeletons, such as artemisinin. In some
for NSAID
examples, synthesis
catalyst and
loading other
could chiral propionic
be reduced acid
to 0.02 mol%; skeletons,
therefore, such
further as artemisinin. In
development
and wide applications are promising. Moreover, (S)-naproxen and (S)-ibuprofenfurther
some examples, catalyst loading could be reduced to 0.02 mol%; therefore, were devel
opment in
obtained and wide
over 97%applications are
chemical yield andpromising. Moreover, (S)-naproxen
over 97% enantiomeric purity. and (S)-ibuprofen
were obtained in over 97% chemical yield and over 97% enantiomeric purity.
Scheme27.
Scheme 27.Asymmetric
Asymmetric hydrogenation
hydrogenation strategy
for (S)-naproxen or (S)-ibuprofen
or (S)-ibuprofen synthesis.synthesis.
Other chiral ligands for asymmetric hydrogenation have been reported simultane-
Other chiral ligands for asymmetric hydrogenation have been reported simultane
ously [102]. Pursuing high enantioselectivity and low catalyst loading, a new class of
ously [102]. Pursuing high enantioselectivity and low catalyst loading, a new class o
biphosphorus ligand with a ferrocene moiety was developed and screened. Wudaphos
biphosphorus
was chosen afterligand with
a survey a ferrocene
of the moiety
chiral ligands withwas developed
a rhodium andfor
catalyst screened. Wudapho
asymmetric
was chosen after a survey of the chiral ligands with a rhodium catalyst for asymmetric
reduction (Scheme 28) [103]. Mechanistically, this ligand was designed to interact via hy
drogen bonding of the ammonium ion of the ligand and carboxylate ion of the substrate
It is noteworthy that the turnover number (TON) reaches 20,000. Moreover, its high effi
Scheme 27. Asymmetric hydrogenation strategy for (S)-naproxen or (S)-ibuprofen synthesis.
Other chiral ligands for asymmetric hydrogenation have been reported simul
ously [102]. Pursuing high enantioselectivity and low catalyst loading, a new cla
Molecules 2021, 26, 4792 16 of 22
biphosphorus ligand with a ferrocene moiety was developed and screened. Wuda
was chosen after a survey of the chiral ligands with a rhodium catalyst for asymm
reduction (Scheme 28) [103]. Mechanistically, this ligand was designed to interact vi
reduction (Scheme 28)
drogen bonding [103].
of the Mechanistically,
ammonium ion ofthis
theligand
ligandwas
and designed to interact
carboxylate ion ofviathe subs
hydrogen bonding of the ammonium ion of the ligand and carboxylate ion of the sub-
It is noteworthy that the turnover number (TON) reaches 20,000. Moreover, its high
strate. It is noteworthy that the turnover number (TON) reaches 20,000. Moreover, its high
ciency has
efficiency hasreceived increasedindustrial
received increased industrial attention
attention for chiral
for chiral NSAIDs
NSAIDs or active
or other other active
maceutical ingredients
pharmaceutical (APIs).
ingredients (APIs).
Scheme
Scheme 28.28. Rhodium-catalyzed
Rhodium-catalyzed asymmetric
asymmetric hydrogenation
hydrogenation for (S)-naproxen
for (S)-naproxen synthesis. synthesis.
Cobalt-catalyzed asymmetric hydrogenation was also studied, as shown in Scheme 29.

Cobalt-catalyzed asymmetric hydrogenation was also studied, as shown in Sc
During his continuous research on cobalt-catalyzed asymmetric reduction [104], Chirik
et29.
al. During
reported his
thatcontinuous
the addition ofresearch
hydrogenoncould
cobalt-catalyzed asymmetric
be enantioselective reduction [104]
via cobalt-mediated
rik et al. reported that the addition of hydrogen could be enantioselective
catalysis [105]. A mechanistic study was also conducted. Carboxylic acid was added to the via cobal
diated
cobalt catalysis
complex [105]. and
as a ligand, A mechanistic study was
the face was selectively alsoItconducted.
reduced. was validatedCarboxylic
by X-ray acid
17
crystallography to elucidate the intermediate structure of the catalyst. This highly
added to the cobalt complex as a ligand, and the face was selectively reduced. It wa effective
methodology is compatible
idated by X-ray with varioustosubstrate
crystallography functionalities.
elucidate the intermediate structure of the cat
This highly effective methodology is compatible with various substrate functionaliti
Scheme
Scheme Cobalt-catalyzed
29.29. asymmetric
Cobalt-catalyzed hydrogenation
asymmetric for (S)-naproxen
hydrogenation synthesis. synthesis.
for (S)-naproxen
For the asymmetric synthesis of NSAIDs, a different approach was realized by List
For the asymmetric synthesis of NSAIDs, a different approach was realized by
et al. in 2019. As shown in Scheme 30 [106], chiral protonation of bis-TMS ketene acetal 75
et al.
was in 2019.toAs
attempted shown
afford instereogenic
a new Scheme 30center
[106], chiral protonation
[107–110]. of bis-TMS
The face-selective ketene ace
protonation
was attempted
could to afford
be accomplished in a ahigh
newratio
stereogenic
by using center [107–110]. The
chiral disulfonimide 76 face-selective
proton donors. proton
Similarly,
could beisobutyl analog 77in
accomplished wasa successfully
high ratio bytransformed
using chiralinto (S)-ibuprofen.
disulfonimide However,
76 proton do
this deracemization route has the drawback that it still requires complete
Similarly, isobutyl analog 77 was successfully transformed into (S)-ibuprofen. How construction
of a final racemic compound. In addition, they must compete with traditional and well-
this deracemization route has the drawback that it still requires complete constructi
established chiral resolution routes. Nevertheless, the low catalyst loading and simple
a final racemic
procedure compound.protonation
of this asymmetric In addition, theystill
process must compete
indicates with traditional
its potential for furtherand we
tablished and
application chiral resolution routes. Nevertheless, the low catalyst loading and simple
development.
cedure of this asymmetric protonation process still indicates its potential for furthe
plication and development.
could be accomplished in a high ratio by using chiral disulfonimide 76 proton donors.
Similarly, isobutyl analog 77 was successfully transformed into (S)-ibuprofen. However,
this deracemization route has the drawback that it still requires complete construction of
a final racemic compound. In addition, they must compete with traditional and well-es-
Molecules 2021, 26, 4792 tablished chiral resolution routes. Nevertheless, the low catalyst loading and simple pro-
17 of 22
cedure of this asymmetric protonation process still indicates its potential for further ap-
plication and development.
Scheme 30. Asymmetric protonation

Scheme30. protonation strategy
strategyfor
forenantiomerically
enantiomericallyenriched
enriched(S)-naproxen
(S)-naproxen
oror (S)-
(S)-
ibuprofensynthesis.
ibuprofen synthesis.DSI;
DSI;disulfonimide.
disulfonimide.
Another
Anothersynthetic
syntheticprocedure
procedurefor forracemic
racemic naproxen
naproxen was
wasreported
reported in 2018, as shown
in 2018, as shownin
Scheme
in Scheme 31 [111]. This
31 [111]. procedure
This procedurefeatures nickel-catalyzed
features cyanation
nickel-catalyzed of benzyl
cyanation pivalate
of benzyl 79
pivalate
through
79 through methylation andand
methylation esterification of the
esterification resulting
of the secondary
resulting alcohol
secondary starting
alcohol fromfrom
starting an
aromatic
an aromatic aldehyde 78. Zinc
aldehyde cyanide
78. Zinc waswas
cyanide used as aas
used 0.55 equivalent
a 0.55 for for
equivalent lowlowcyanide loading.
cyanide load-
Iting.
is also interesting that the use of zinc ligands suppresses the competing
It is also interesting that the use of zinc ligands suppresses the competing elimination elimination
process.
process.Therefore,
Therefore,racemic
racemicnaproxen
naproxenwas wasefficiently produced
efficiently produced with
withthis
thisfour-step synthesis.
four-step synthe-
sis.
Scheme 31.
Scheme 31. Ni-catalyzed
Ni-catalyzedcyanation
cyanationstrategy
strategyfor
fornaproxen
naproxen synthesis.
synthesis. Piv;
Piv; pivaloyl,
pivaloyl, DMAP;
DMAP; 4-dime-
4-dimethyl-
thylaminopyridine, 0
dppf; 1,1′- bis(diphenylphosphino)ferrocene.
aminopyridine, dppf; 1,1 - bis(diphenylphosphino)ferrocene.
Based thesynthetic
Based on the syntheticadvance
advancedescribed
described above,
above, more
more promising
promising derivatives
derivatives of
of ibu-
ibuprofen and naproxen are still studied. Scheme 32 presents
profen and naproxen are still studied. Scheme 32 presents an interesting an interesting showcase.
Grabowsky Beckmann’s group
Grabowsky and Beckmann’s group reported
reportedsubstitution
substitutionofofsilicon
siliconinstead
insteadofof carbon
carbon at
at alkyl
alkyl sidechain
side chainininibuprofen
ibuprofenstructure.
structure. This
This simple
simple silicon-substituted
silicon-substituted ibuprofen 82 82
showed
showed improved
improved physical
physical property
property such
such as
as solubility
solubility in
in body
body [112].
[112]. Although
Although selectivity
selectivity
on
on COX1/COX2
COX1/COX2 isisstill
stilldemanding,
demanding,this this simple
simple andand direct
direct change
change of structure
of structure cancan be
be an-
another solution for further development.
other solution for further development.
Scheme 32.
Scheme 32. Introduction
Introduction of
of silicon
silicon in
in ibuprofen
ibuprofen structure.
structure.
6. Conclusions
Since the discovery of aspirin on 10 August 1897, anti-inflammatory medicines have
attracted tremendous attention from pharmacologists and medicinal chemists. After the
elucidation and differentiation of COX into COX1 and COX2, mechanistic studies were
Molecules 2021, 26, 4792 18 of 22
6. Conclusions
Since the discovery of aspirin on 10 August 1897, anti-inflammatory medicines have
attracted tremendous attention from pharmacologists and medicinal chemists. After the
elucidation and differentiation of COX into COX1 and COX2, mechanistic studies were
deeply investigated. However, a breakthrough in chemical synthesis was essential for
more selective and potent medicines, as the Kolbe–Schmidt reaction occurred in 1859. The
reaction suggested that salicylic acid is not supplied from salicin, a natural source, but from
a chemical compound, phenol, NaOH, and CO2 . It is more impressive that the structural
modification of salicylic acid was extensively pursued using the confirmed structure of
salicylic acid and its easy availability. Thus, this synthetic breakthrough paved the way for
the discovery of aspirin.
However, there is still a need for further innovation in NSAID drug development,
as the Kolbe–Schmidt reaction did. Gratifyingly, enormous chemical studies on asym-
metric synthesis, large-scale preparation, and new methodology development are still
ongoing. Based on the achievement, NSAIDs such as ibuprofen or naproxen could be
purchased without a price issue nowadays. However, novel demonstrations of a newly
developed methodology for ibuprofen or naproxen skeleton are still a good showcase of
organic/medicinal chemistry research.
In addition, medicinal chemists have tried to find advanced NSAIDs with regard
to safety and efficacy. To find selective COX2 inhibitor without undesired side effects,
tremendous research is underway. This endeavor includes a simple exchange of atom as
well as a modification of mother skeleton in NSAIDs. Thus, it is anticipated that there will
be a promising breakthrough in the near future.
Author Contributions: M.-W.H. and S.-M.P. planned the paper and wrote the manuscript together.
Both authors have read and agreed to the published version of the manuscript.
Funding: This research was supported by the Basic Science Research Program through the National
Research Foundation of Korea (NRF) funded by the Ministry of Education, Science, and Technology
(NRF-2020R1F1A1050481).
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: Not applicable.
Conflicts of Interest: The authors declare no conflict of interest.
Sample Availability: Samples of the compounds are available from the authors.
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Molecules: Recent Advances in The Synthesis of Ibuprofen and Naproxen

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Molecules: Recent Advances in The Synthesis of Ibuprofen and Naproxen

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Keywords: NSAIDs; ibuprofen; naproxen; synthesis

Molecules 2021, 26, 4792. https://doi.org/10.3390/molecules26164792 https://www.mdpi.com/journal/molecules

2. Classical Synthesis of Ibuprofen

Scheme 1. Classical synthesis of ibuprofen.

Scheme 4. Iron-catalyzed hydrocarboxylation for ibuprofen synthesis.

Molecules 2021, 26, x FOR PEER REVIEW 6 of 22

Scheme 6. Iron-catalyzed regioselective carboxylation for ibuprofen synthesis. Ts; p-toluenesul-

Regioselective hydrocarboxylation was also performed using a nickel catalyst in the

Scheme 8. Reductant-free coupling for ibuprofen or naproxen synthesis.

Scheme 9. Electrochemical carboxylation for ibuprofen synthesis.

Molecules 2021, 26, x FOR PEER REVIEW

Scheme 11. CBr4/PPh3-mediated isomeric oxidation protocol for ibuprofen synthesis.

Molecules 2021, 26, x FOR PEER REVIEW 10 of 2

Scheme 16. Classical synthesis of (S)-naproxen.

Scheme 17. Chiral enolate

Nakamura et al. further modified the iron-catalyzed coupling reaction to enantios-

Molecules 2021, 26, x FOR PEER REVIEW 14 of 22

The asymmetric addition of thiophenol was also attempted, as shown in Sc

Scheme 24. Hydroboration of allene

Cobalt-catalyzed asymmetric hydrogenation was also studied, as shown in Scheme 29.

Scheme 30. Asymmetric protonation

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