ORGANIC CHEMISTRY

FRONTIERS

View Article Online

REVIEW View Journal
Published on 10 March 2021. Downloaded by University of Prince Edward Island on 5/16/2021 8:23:27 AM.

Recent advances in the synthesis and reactivity of

Cite this: DOI: 10.1039/d0qo01575j
quinoxaline
Gauravi Yashwantrao and Satyajit Saha *

Received 16th December 2020,
Accepted 10th March 2021
DOI: 10.1039/d0qo01575j
rsc.li/frontiers-organic
Quinoxaline has become a subject of extensive research due to its emergence as an important chemical
moiety, demonstrating a wide range of physicochemical and biological activities. The last few decades
have witnessed several publications utilizing quinoxaline scaffolds for the design and development of
numerous bioactive molecules, dyes, fluorescent materials, electroluminescent materials and organic
sensitizers for solar cell applications and polymeric optoelectronic materials. Therefore, to fulfill the need
of the scientific community, tremendous effort has been observed in the development of newer synthetic
strategies as well as novel methodologies to decorate the quinoxaline scaffold with proper functional
groups. Hence, to provide an updated comprehensive account of the diverse synthetic routes to access
quinoxaline as well as approaches for structural diversifications, we have attempted to document the syn-
thetic strategies and their functionalization with possible mechanistic rationalization. This will no doubt be
helpful for the readers who are anticipating a comprehensive overview on quinoxaline as well as benefi-
tting researchers for future development.

Quinoxaline belongs to a class of aromatic heterocycles
formed by the fusion of two six-membered aromatic rings, one
of which consists of two nitrogen atoms symmetrically placed
at the 1 and 4 positions. In general, the physical properties of
Department of Speciality Chemicals Technology, Institute of Chemical Technology,
Mumbai-400019, India. E-mail: ss.saha@ictmumbai.edu.in
quinoxaline are analogous to pyrazine. The positions 2, 4, 5, 7,
and 8a of quinoxaline are electron deficient, as can be
observed from the resonating structures depicted in Fig. 1, and
hence, are susceptible to nucleophilic attack.
Quinoxaline has received a great deal of attention over the
years. This molecule has become a subject of extensive
research because of the unique disposition of the two nitrogen

Ms Gauravi B. Yashwantrao Satyajit Saha earned his Ph.D.

completed her SSC from B.P.V.,
Ambernath, and HSC from
B. K. Birla College, Kalyan in
2010 and 2012, respectively.
Thereafter, she pursued a
Bachelor of Science with
Chemistry as a major in 2015
from B.K. Birla College and M.Sc
in Organic Chemistry in 2017
from Ruia College, Matunga. She
then worked as an ‘Assistant
Gauravi Yashwantrao Research Associate’ at Oriental
Aromatics Ltd for one year. In
October 2018, she joined the Institute of Chemical Technology,
Mumbai to pursue her Ph.D. under the guidance of Dr Satyajit
Saha. Her research interest is in the field of synthesis and process
intensification of N-heterocycles using greener approaches and
their applications thereafter as functional materials.
(organic chemistry) in the year
2011 from IIT Kanpur, India.
Thereafter, as a FWO Visiting
Postdoctoral Fellow, he visited
Belgium for his postdoctoral
research at the University of
Antwerpen, Belgium. In 2013 he
moved to Universitat Leipzig,
Germany for his second post-doc-
toral research. He returned to
India in 2015 to join the
Satyajit Saha Institute of Chemical
Technology, Mumbai, India as
an Assistant Professor at the Department of Dyestuff Technology
under the UGC-Faculty Recharge Programme. Currently, he is
associated with the Department of Speciality Chemicals
Technology of ICT Mumbai. His research interests are focused on
organic synthesis, catalysis, synthesis of functional materials,
stereoselective transformations, and green chemistry.

This journal is © the Partner Organisations 2021 Org. Chem. Front.


Review
Published on 10 March 2021. Downloaded by University of Prince Edward Island on 5/16/2021 8:23:27 AM.
Fig. 1 Resonating structures of quinoxaline.
atoms in one of the rings, which is abundant in many natural
and man-made compounds. The 1,4 disposition of the two
imine nitrogen atoms in one of the rings of the quinoxaline
bestows it with the electron-withdrawing property. In addition
to that, their easy synthetic accessibility has been the major
reason for the extensive applications of quinoxaline derivatives
as dyes, or as a building block in the synthesis of organic semi-
conductors, electroluminescent material, dye-sensitized solar
cells (DSSC), etc. Even quinoxaline derivatives possess a wide
range of physicochemical and biological activities such as anti-
bacterial, antiviral, anticancer activity, etc., Fig. 2.1,2
The last two decades have witnessed the appearance of
several publications demonstrating the utility of quinoxaline
scaffolds in the design and development of numerous bio-
active molecules, dyes, fluorescent materials, electrolumines-
cent materials, organic sensitizers for solar cell applications
and polymeric optoelectronic materials, Fig. 3. Therefore, to
fulfill the need of the scientific community, there has been a
persistent effort in the development of newer synthetic strat-
egies as well as novel methodologies to decorate the quinoxa-
line scaffold with proper functional groups. The necessity to
build the scaffold has resulted in a huge volume of publi-
cations that have appeared since the first synthesis of quinoxa-
line in 1950.3 Several synthetic protocols that are mild,
efficient, and sustainable have been developed over the last
two decades, so it will be a Herculean task to summarize the
developments in terms of synthesis and reactivity unless done
systematically (Fig. 4).
Two consecutive reviews by Zhukova et al. that appeared in
2012 and 2013 highlighted the synthesis and reactivities of
quinoxaline.4,5 Thereafter Vieira et al. in 20156 and Menezes
et al. in 20207 reported two reviews describing the applications
of 2,3-dichloroquinoxaline as a building block and the devel-
opment of bioactive quinoxaline derivatives, respectively.
Several publications have appeared since then on the synthesis
and functionalization of quinoxaline which need to be
addressed systematically. Therefore, the need for an update is
obvious considering the number of publications that have
appeared since the last review on quinoxaline scaffolds, high-
lighting their synthesis and reactivity.5
This review will provide an update on the synthetic strat-
egies of quinoxalines, their possible routes for functionali-
Org. Chem. Front.
View Article Online
Organic Chemistry Frontiers
zation and insights about their mechanistic pathways. The
review has been subdivided into two parts. The first part of
this review will focus on the several synthetic approaches to
access quinoxaline, while the second part will discuss the
functionalization routes of quinoxaline and its derivatives with
possible mechanistic interpretation. We believe that this
update will be beneficial for the advancement of quinoxaline
chemistry as well as equip the researchers for future
development.
Synthesis of quinoxalines
The significance of the quinoxaline scaffold in the areas of
medicinal chemistry, electroluminescent materials, DSSC,
molecular probes, and sensors has resulted in an upsurge of
the synthetic strategies to access quinoxaline sustainably
under milder conditions in higher yields. The recent develop-
ment in synthesizing quinoxaline derivatives has witnessed
several strategies that avoid hazardous chemicals, release fewer
chemical wastes and rely on sustainable technology.
The synthetic methodologies to access quinoxalines as
highlighted in Fig. 4 can be classified into four major cat-
egories and are listed below.
1. Condensation reaction
2. Oxidative condensation
3. Synthesis via Schmidt reaction
4. Oxidative dehydrogenation
Methods B, E, F, G, and H are categorized as condensation
reactions, while method C proceeds via the Schmidt reaction,
method D represents oxidative condensation pathways and A
represents oxidative dehydration reactions. Each method will
be discussed separately emphasizing the approaches under-
taken, as well as highlighting the different conditions, catalysts
used and strategies that will project the advancement in the
synthetic routes.
Condensation reaction
The condensation of ortho-phenylenediamines (o-PD)’s 2 with
aryl or alkyl-substituted 1,2-dicarbonyl compounds 3 in the
presence of either a Lewis acid or a Brønsted acid catalyst is
one the most widely employed protocols to access quinoxaline
4, Scheme 1.
The ease of synthesis along with the commercial availability
of the starting materials makes this cyclocondensation reac-
tion a widely explored route to access quinoxaline. Primarily,
the Lewis acids or Brønsted acids employed are associated
with the activation of the carbonyls which facilitate the nucleo-
philic addition followed by the cyclocondensation reaction, as
highlighted in Scheme 2.
Over the years, a variety of Lewis acids, as well as Brønsted
acids, have been employed by several research groups to syn-
thesize quinoxaline 4 from o-PDs 2 and 1,2-diketones 3.
Therefore, Table 1 provides a glimpse of the variety of Lewis
and Brønsted acid catalysts that were used to access quinoxa-
line via the condensation pathway.
This journal is © the Partner Organisations 2021

Organic Chemistry Frontiers
Published on 10 March 2021. Downloaded by University of Prince Edward Island on 5/16/2021 8:23:27 AM.
Fig. 2 Representative examples of molecules containing a quinoxaline scaffold.
The use of aqueous hydrofluoric acid acting both as a reac-
tion medium as well as a catalyst to access quinoxaline 4 in a
relatively milder condition in good yield was demonstrated
by Shekhar et al. The absence of coupling agents and easy
workup procedures highlights the advantages of this protocol
(entry 1, Table 1).8 Sulfamic acid in MeOH was employed as a
catalyst by the group of Darabi for the synthesis of quinoxaline
This journal is © the Partner Organisations 2021
View Article Online
Review
4 from 1,2-dicarbonyls 3. Apart from the recyclability of the
catalyst, mild reaction conditions to obtain the products in
nearly quantitative yields within a short reaction time offered
obvious advantages to access temperature or acid-sensitive
substrates (entry 2, Table 1).9 Later, More10 and Bhosale11 syn-
thesized quinoxaline 4 in excellent yields using a catalytic
amount of iodine in MeCN and DMSO solvent, respectively
Org. Chem. Front.
 View Article Online

Review Organic Chemistry Frontiers

Published on 10 March 2021. Downloaded by University of Prince Edward Island on 5/16/2021 8:23:27 AM.

Scheme 1 Condensation of 1,2-diamines 2 with 1,2-dicarbonyls 3 with

Brønsted and Lewis acid catalysts.

Fig. 3 Schematic representation of the areas of quinoxaline

applications.

(entries 3 and 4, Table 1). The high yield and short duration of
the reaction coupled with the use of non-toxic and inexpensive
iodine as a catalyst featured in the usefulness of the reaction.
In 2007, Heravi demonstrated the use of CuSO4·5H2O as an in-
expensive and mild Lewis acid catalyst to access quinoxaline 4
Scheme 2 Mechanistic pathway to access quinoxaline by the conden-
at room temperature in a solvent mixture of EtOH and water
sation of (o-PD)s 2 with 1,2-dicarbonyls 3 employing Brønsted and
(entry 5, Table 1).12 The group of Heravi further described a Lewis acid catalysts.
simple, one-pot efficient method for the synthesis of quinoxa-
lines via MnCl2-catalyzed condensation of a variety of o-PDs
and α-diketone derivatives (entry 6, Table 1).13 mechanochemical grinding of o-PDs 2 with 1,2-dicarbonyls 3.
However, many of these methods were not sustainable and The operational simplicity of running the reaction in solvent-
do not feature sufficient environmental benignancy in their free conditions which avoids the work-up and purification
reaction parameters. So, with the intention of avoiding volatile step was the key advantage of this process (entry 7, Table 1).14
organic solvents, Bhutia and the group established a solvent- Recently, Sajjadifar et al. explored silica-supported 1-(2-
free synthetic protocol to access quinoxaline by liquid-assisted (sulfoxy)ethyl)pyridine-1-ium chloride as an efficient recyclable

Fig. 4 Available methods for the synthesis of quinoxaline.

Org. Chem. Front. This journal is © the Partner Organisations 2021


Organic Chemistry Frontiers
Table 1 Reaction conditions and catalysts employed in the conden-
sation reaction of o-PD 2 with 1,2-diketones 3
Published on 10 March 2021. Downloaded by University of Prince Edward Island on 5/16/2021 8:23:27 AM.
Entry Reaction conditions
1 Aq. HF/rt (10 min–90 min)
GdCl3/EtOH, reflux (1–10 h)
2 Sulfamic acid/MeOH (5 mol%), rt., 5 min
3 I2 (10 mol%), MeCN, 25 °C, 3–30 min,
4 I2 (10 mol%), DMSO, rt.,
5 CuSO4·5H2O (10 mol%), EtOH, rt., 10–15 min
CuSO4·5H2O (10 mol%), water, rt., 15–30 min
6 MnCl2 (10 mol%), rt., 15–20 min
7 Mechanochemical grinding, EtOH, rt, 10–30 min
8 Silica supported 1-(2- (sulfoxy)ethyl)pyridin-1-ium
chloride (SiO2/[SEP]Cl), EtOH, 65 °C, 15–20 min
catalyst for the synthesis of quinoxaline in the presence of
ethanol as a green solvent at 65 °C (entry 8, Table 1).15
There were relentless efforts, which are still ongoing, to
look for alternative strategies to access quinoxaline sustain-
ably. One way to achieve environmental benignancy is by cata-
lyst immobilization, which has become one of the prominent
approaches to address the issue of sustainability. Moreover,
catalyst immobilization on a solid support seems to be crucial
in terms of stability, catalytic site availability, catalyst recover-
ability, and reusability. Based on this rationale, several
researchers have come up with different catalytic systems for
the efficient synthesis of quinoxaline as featured in Table 2.
Table 2 Solid supported catalysts used for the synthesis of quinoxaline
from o-PD 2 and 1,2-diketones 3
Entry Reaction conditions
1 Polyaniline sulfate salt catalyst (5 wt%), DCE, rt,
10 min–2 h
2 Nano-γ-Fe2O3-SO3H (0.1 g), solvent-free, 120 °C, 1 h
(1,2-diketone)
Nano-γ-Fe2O3-SO3H (0.1 g), solvent-free, 120 °C, 1 h
(α-bromoketone)
3 Sulfated polyborate (10 wt%), solvent-free, 100 °C,
3–10 min
4 Silica-supported polymeric Brønsted acidic ionic
liquid catalyst (0.5 mol%), EtOH, rt
5 Epoxidized novolac phenol-formaldehyde resin-
modified using sulphanilic acid (ENPFSA) (5 mol%),
EtOH, rt
6 PS/AlCl3 (10 mol%), EtOH, reflux
7 BiCl3/SiO2 (5 mol%), MeOH, rt
This journal is © the Partner Organisations 2021
View Article Online
Review
Polyaniline-sulfate salt 5, an easily synthesizable Brønsted
acid catalyst, is known for its excellent acidic properties along
with easy recoverability, reusability, and stability. In 2007
the research group of Srinivas demonstrated the synthesis of
quinoxaline in excellent yields by the condensation reaction
using a catalytic amount of polyaniline-sulfate salt (entry 1,
Table 2).16
Harsha et al. developed a magnetically retrievable hetero-
% yield geneous nano-γ-Fe2O3-SO3H catalytic system for the cyclocon-
densation of 1,2-diketones or α-bromoketones with o-PDs to
>958
>95 access quinoxaline under solvent-free conditions (entry 2,
up to 959 Table 2).17 Easy work-up and purification processes, along
>9010 with high product yield obtained in less time, are the obvious
>8511
>9512 advantages of this environmentally benign protocol. The cata-
lyst can be recovered magnetically and can be reused up to 5
>9013 times. The electron-rich o-PDs afforded excellent yields of the
85–9514
up to desired quinoxalines compared with the o-PDs attached with
9715 electron-withdrawing groups.17
Sulfated polyborate 6 belongs to a class of promising cata-
lytic systems displaying both Lewis and Brønsted acidic pro-
perties that were used to synthesize quinoxaline in high yields
within a short reaction time.23 The easy workup procedure
along with broad substrate scope provided both economical as
well as ecological rewards to this protocol (entry 3, Table 2).18
Brønsted acidic ionic liquids (BAILs) belong to a set of ILs dis-
playing dual properties of Brønsted acids and ionic liquids (IL)
simultaneously. In addition to that, one ionic center is co-
valently grafted to the polymeric backbone which features the
unique properties of ILs as well as the macromolecular poly-
meric architectures. Tamami prepared two silica-supported
polyvinyl imidazole based Brønsted acidic ionic liquids and
demonstrated their application in the sustainable synthesis of
quinoxaline derivatives in high yields (entry 4, Table 2).19
% yield
>9016
85–9017
>9518
85–9019
80–8520
Tarpada and co-workers designed a polymer-supported hetero-
84–9721 geneous catalyst based on sulphanilic acid for the one-pot syn-
85–9522 thesis of various quinoxaline derivatives 4. The developed
Org. Chem. Front.

Review
methodology features the advantages of operational simplicity,
easy workup, and recyclability to furnish the desired quinoxa-
lines with excellent purity and high yields. The reaction was
very much substrate-dependent. Diamines with electron-with-
drawing substituents afforded desired products in high yields
in comparison with the diamines with electron-donating
attachments (entry 5, Table 2).20
Published on 10 March 2021. Downloaded by University of Prince Edward Island on 5/16/2021 8:23:27 AM.
Like the polymer grafted Brønsted acids, heterogenizing
the homogeneous metal species by supporting it on in-
soluble supports is also an attractive strategy in terms of
catalyst recovery and recyclability. In 2012, Rahmatpour and
co-workers used aluminum chloride supported on cross-
linked polystyrene (PS/AlCl3) as a recyclable heterogeneous
Lewis acid catalyst for the synthesis of quinoxaline via a con-
densation reaction (entry 6, Table 2).21 Although AlCl3 is a
water-sensitive, corrosive, and environmentally harmful com-
pound, the PS–AlCl3 complex has sufficient stability and can
be easily recycled and reused without appreciable loss of its
activity.
The concept of heterogenization of the metal species was
further extended by the group of Aghapoor in the acid-cata-
lyzed condensation of various o-PDs 2 with 1,2-diketone 3. To
design catalysts with high selectivity and easy separability,
bismuth has been integrated into the framework of silica. The
catalyst (silica-supported bismuth(III) chloride (BiCl3/SiO2))
exhibited remarkable catalytic performance and can be reused,
unlike the homogeneous BiCl3 (entry 7, Table 2).22
Catalyst recoverability is an appealing strategy in terms of
achieving sustainability. Paul investigated the KF-alumina pro-
moted direct conversion of α-hydroxy ketones 10a as well as
α-halo ketones 10b into quinoxalines 4. It was observed that
functionalized quinoxalines as a condensation product of
o-PDs 2 and α-hydroxy ketones 10a or α-bromo ketones 10b
can be obtained at ambient temperature in good yield, as
shown in Scheme 3.24
Performing organic transformations in water is always a
challenging and demanding task. The reactions often take
place as an emulsion and exhibit unusual rate enhancement.
The advantages of replacing organic solvents with water rely
on the non-flammability and non-toxicity of the water exhibit-
ing strong polar character due to its intense hydrogen
bonding. Few efforts are evident in the literature where qui-
noxaline has been synthesized in an aqueous environment
(Table 3).
Delpivo reported a catalyst-free efficient synthesis of a series
of quinoxaline in water by reacting 1,2-dicarbonyl compounds
with o-PDs. The high yield and the absence of any condensing
Scheme 3 Tandem oxidation-condensation or condensation reactions
using KF-alumina catalyst.
Org. Chem. Front.
View Article Online
Organic Chemistry Frontiers
Table 3 Synthetic strategies for the preparation of quinoxaline 4 in
water from o-PD 2 and 1,2-diketones 3
Entry Conditions % yield
1 Water, rt, 30 min 70–9025
2 In powder (5 mol%), MWI (260 W, 60 °C, up to 9726
24–50 psi), water, <3 min
3 Itaconic acid (15 mol%), water, rt, 1 h up to 9627
Table 4 Solvent-free strategies for the synthesis of quinoxalines 4 from
o-PD 2 and 1,2-diketones 3
Entry Conditions % yield
1 Selectfluor (1 mol%), EtOH, rt., 5 min 85–9028
Selectfluor (1 mol%), solvent-free condition, 3 min 90–9528
2 Nano-TiO2 (0.12 mol), solvent-free, rt. <9629
agent made that protocol an appealing sustainable method-
ology compared with the conventional thermal processes invol-
ving acid–base catalysts (entry 1, Table 3).25
Microwave technology has emerged as a rapid synthetic tool
to access diverse molecules sustainably. To access quinoxaline
sustainably, Bandyopadhyay reported a microwave-assisted
convenient and expeditious synthesis of quinoxaline in water
using a trace amount of indium catalyst. The use of indium
circumvented the toxicity, cost, and air and moisture sensi-
tivity associated with the organometallic reagents used as cata-
lysts (entry 2, Table 3).26 The activation by indium followed by
cyclocondensation leads to the desired product. In the search
for an environmentally benign sustainable approach to synthe-
sizing the quinoxaline scaffold in water, Tamuli et al. devel-
oped a synthetic water route using o-PDs 2 and 1,2 diketone as
reactants and biodegradable itaconic acid as a mild acid pro-
motor. The proposed method is advantageous as it is energy
efficient, requires less reaction time, and the catalyst is reusa-
ble (entry 3, Table 3).27
The drive for the development of solvent-free reactions to
eliminate volatile organic solvents as well as to expedite the
product recovery process without involving tedious extraction
and evaporation steps has escalated tremendously to a new
horizon. Similar efforts were also noticed where quinoxaline
was synthesized under solvent-free conditions using catalysts
like selectfluor and nanoTiO2 in good to excellent yields
(Table 4).
Selectfluor, a commercially available, inexpensive, non-
toxic, non-volatile fluorinating agent, known to have efficient
Lewis acidic properties, was used as a catalyst for condensation
reactions by Hojati and co-workers (entry 1, Table 4).28
Mirjalili and co-workers further reported the synthesis of qui-
noxaline in the presence of nano-TiO2 under solvent-free con-
ditions with yields ranging from 88–90% in just 30–35 min
(entry 2, Table 4).29
A. Oxidative coupling. Another prominent strategy to access
quinoxaline relies on the redox condensation of 1,2-diols 12
with o-PDs 2 (Scheme 4). The use of renewable feedstocks in
This journal is © the Partner Organisations 2021

Organic Chemistry Frontiers
Published on 10 March 2021. Downloaded by University of Prince Edward Island on 5/16/2021 8:23:27 AM.
Scheme 4 General schematic representation of oxidative coupling
reaction to access quinoxaline.
chemical transformations is one of the many drives towards
sustainability. Carbohydrates, as biomass, were routinely used
as raw materials for the synthesis of a diverse set of chemicals.
Clement et al. have utilized carbohydrate feedstocks to develop
an efficient one-pot two-step methodology for the synthesis of
quinoxalines by oxidative coupling of glycols 14 derived from
biomass with o-PD derivatives 2. The reaction was catalyzed by
gold nanoparticles supported on nanoparticulated ceria (Au/
CeO2) or hydrotalcite (Au/HT). The reaction proceeds utilizing
air as the oxidant in the absence of any homogeneous base via
a cascade process with yields ranging between 75–80%. The
rate-limiting step for the reaction is the alcohol oxidation step
to generate the 1,2-diketones (Scheme 5).30
Nguyen et al. reported a method employing a sodium
sulfide (40 mol%) and iron(III) chloride hexahydrate (1 mol%)
combination for the redox condensation of o-nitro aniline 16
with alcohols to synthesize quinoxaline 4 with up to 85% yield.
Besides being a precursor for the iron-sulfur (Fe/S) catalyst,
hydrated sodium sulfide also behaved as an excellent non-
competitive, multi-electron reducing agent (Scheme 6).31
Scheme 5 Mechanistic pathway for the synthesis of quinoxaline from
ortho-dinitrobenzene 13 and vicinal diols 14.
This journal is © the Partner Organisations 2021
View Article Online
Review
Scheme 6 Synthesis of quinoxaline 4 using o-nitroaniline and the
probable mechanistic pathway.
Roy and co-workers developed a one-pot and metal-free
tandem synthesis of quinoxalines from ortho-nitroaniline 16 or
dinitrobenzene 13 using graphene oxide (GO) as the ‘carboca-
talyst’ in conjugation with hydrazine hydrate in 85–90% yield
(Scheme 6).32
Reduced graphene oxide (rGO) in combination with a large
excess of hydrazine hydrate were competent to reduce nitro-
benzene to aniline. In this reaction, the nitro group is in situ
being reduced by graphene oxide or reduced graphene oxide to
the corresponding amine group followed by cyclocondensation
as depicted in Scheme 6.32
DMSO-propyl phosphonic anhydride is a well-known oxidiz-
ing and cyclodehydrating agent. Harsha and co-workers
reported the use of propyl phosphonic anhydride–DMSO for
the first time as an oxidative condensing reagent for the syn-
thesis of quinoxalines 4 in excellent yields under simple and
mild reaction conditions in one step (Scheme 7).33 The
mechanistic details are highlighted in Scheme 7.
Bera and co-workers reported a (NiCl2/1,10-phenanthroline)
system for the synthesis of quinoxaline via dehydrogenative
condensation of primary alcohols and ethylene glycol 18 with
o-PDs 2 (Scheme 8). The catalytic system enabled the synthesis
of quinoxaline by releasing water and hydrogen gas as bypro-
ducts. The methodology has wide functional group tolerance
and tolerated challenging functional groups, like trifluoro-
methyl, as well as heterocyclic rings including unsaturated
alcohols (Scheme 8).34
An improvement in the yield of the above reaction was done
by Daw and co-workers in 2018. They have presented an acri-
dine-based pincer complex of earth-abundant manganese that
catalyzed the formation of quinoxalines 4 by dehydrogenative
coupling of o-PD 2 with 1,2-vicinal diols 14 in good to excellent
Org. Chem. Front.

Review
Published on 10 March 2021. Downloaded by University of Prince Edward Island on 5/16/2021 8:23:27 AM.
Scheme 7 Phosphorus acid-mediated tandem oxidative condensation
reaction to access quinoxaline and the probable mechanistic pathway
for the synthesis.
Scheme 8 Nickel catalyzed tandem oxidative condensation protocol
for the synthesis of quinoxaline.
35
yields (Scheme 9). The mechanistic pathway discloses that
the terminal alcoholic group of 1,2 diol system 14 gets oxidized
to the corresponding carbonyl 14a under the influence of a
manganese catalyst. Subsequently, diamine 2 condenses with
carbonyl moiety 14a followed by a proton shift and tautomeri-
zation furnishing the intermediate 14f. The second conden-
sation reaction of 14f with amine, and on subsequent aromati-
zation, delivered the final product in good yield 15 (Scheme 9).
In 2015, Tang and co-workers developed a diruthenium
complex with 2,7-bis(di-2-pyridinyl)-1,8-naphthyridine to act as
a catalyst for the oxidative coupling of 1,2-diols/1,2-amino
alcohol 17/20 with o-PDs 2 leading to quinoxalines 4 in yields
ranging up to 75% (Scheme 10).36
Dowlati et al. developed an electrochemical method for the
synthesis of quinoxaline 24 in an aqueous solution. The room
temperature synthesis of quinoxaline featured low energy con-
sumption electrochemical synthesis which avoided toxic
reagents making the entire process environmentally benign
(Scheme 11).37
An altogether different approach to accessing quinoxaline
employing a catalytic quantity of p-TSA was demonstrated by
Org. Chem. Front.
View Article Online
Organic Chemistry Frontiers
Scheme 9 Mechanistic pathway for the dehydrogenative coupling
reaction for the formation of quinoxaline.
Scheme 10 Oxidative cycloaddition of o-diamine 2 with various diols
17 or amino alcohols 20 using [Ru] catalyst.
Samsonov by heating benzofurazans 25 with ethanolamine 26,
which acts as a reducing agent (Scheme 12).38 The mechanistic
pathway highlights the formation of enamine 26a from
ethanolamine 26 on treatment with acid. Subsequent attack of
enamine on N atoms opened the furazan ring 25 and the ring
closure furnished quinoxaline-N-oxide 26d. Finally, the oxygen
atom of N-oxide gets eliminated upon treatment using ethanol-
amine 26 to furnish the substituted quinoxaline 27.
B. Schmidt reaction. Although o-PD is known to be the most
widely used precursor for the synthesis of quinoxaline, ortho-
halo carboxylic acid was also used as a starting precursor to
access quinoxaline. An altogether different approach has been
designed where the conversion of carboxylic acid to an amine
by the expulsion of nitrogen was the key step for this trans-
formation via Schmidt’s reaction.
Saha reported an unconventional but efficient strategy for
the synthesis of quinoxaline 4 employing 2-iodo benzoic acid
28a and sodium azide in the presence of organo-Cu(II) catalyst
This journal is © the Partner Organisations 2021

Organic Chemistry Frontiers
Published on 10 March 2021. Downloaded by University of Prince Edward Island on 5/16/2021 8:23:27 AM.
Scheme 11 Electrooxidation of 3,4-dihydroxybenzoic acid 22 with N1,
N2-dibenzylethane-1,2-diamine 23, and its mechanistic pathway.
Scheme 12 Formation of quinoxaline from benzofurazans 25 and
ethanolamine 26 and the probable mechanistic pathway.
via Schmidt reaction followed by the nucleophilic substitution
reaction and subsequent cyclocondensation reaction with
65–70% yield (Scheme 13).39 The mechanism of the formation
This journal is © the Partner Organisations 2021
View Article Online
Review
Scheme 13 Cu(II) mediated synthesis of quinoxaline.
of quinoxaline via the Schmidt reaction is highlighted in
Scheme 13.39 The conventional Schmidt reaction furnished
ortho-iodoaniline 32, which under the influence of Cu(II) cata-
lyst was transferred to o-PD 2 and subsequently reacted with
1,2-diketone 3 to furnish quinoxaline 4.
C. Oxidative dehydrogenation. The oxidative dehydrogena-
tion strategy is a one-step sustainable and atom-economical
route to access quinoxaline molecules from tetrahydroquinoxa-
line 33 (Scheme 14).
Treatment of 1,2-dichloroethane with o-PD in TBACl at
60 °C is one of the simplest ways to access tetrahydroquinoxa-
line in a moderate yield of 56% (Scheme 15).40
A B(C6F5)3 catalyzed one-pot metal-free tandem sequential
procedure involving cyclization and hydrosilylation of imines
and amides towards the formation of 1,2,3,4-tetrahydroquinox-
alines directly from o-PDs and α-keto esters was reported by
Scheme 14 General schematic representation of oxidative dehydro-
genation reaction.
Scheme 15 Synthesis of tetrahydro quinoxaline.
Org. Chem. Front.

Review
Published on 10 March 2021. Downloaded by University of Prince Edward Island on 5/16/2021 8:23:27 AM.
Scheme 16 B(C6F5)3 catalyzed synthesis of tetrahydroquinoxaline 36.
Pan (Scheme 16).41 The scalability and non-requirement of
anhydrous solvent or inert atmosphere are the advantages of
this method.
Depending on the involvement of a hydrogen atom accep-
tor, the oxidative dehydrogenation of aza-heterocycles can be
classified into two subclasses: acceptorless and acceptor-
assisted dehydrogenation. They can either be accessed by
hydrogen acceptorless metal-mediated processes involving
metals like Fe, V, Co, Rh, Pd, etc., or via oxidative dehydrogena-
tion involving oxidants leading to the complete aromatization
of the moiety.42–68
A representative mechanism depicting the oxidative dehy-
drogenation of tetrahydroquinoxaline to quinoxaline is rep-
resented in Scheme 17.55 The electron transfer from the
oxidant Cu(III)TPP to Cu(II)TPP resulted in the formation of an
amine radical species which then produced the imine inter-
mediate by α C–H abstraction, liberating water as the side
product. After tautomerization, the final dehydrogenation
product was then obtained by the second dehydrogenation
reaction (Scheme 17).55
Several groups have demonstrated an oxidative dehydro-
genation strategy to access quinoxaline from tetrahydroqui-
noxaline by employing diverse sets of catalysts. Therefore,
Table 5 highlights a list of several catalysts along with the
corresponding yields for the oxidative dehydrogenation reac-
tion to access quinoxaline 1.42–68
In 1990, Murahashi and colleagues employed sodium tung-
state in 30% methanolic hydrogen peroxide solution under
argon atm to synthesize quinoxaline in 37% yield by catalytic
oxidation of 1,2,3,4-tetrahydroquinoxaline at room tempera-
ture. The lower yield obtained was due to the formation of a
quinoline by-product. Na2WO4·2H2O was found to be the most
Scheme 17 Possible reaction pathway for oxidative dehydrogenation
reaction.
Org. Chem. Front.
View Article Online
Organic Chemistry Frontiers
effective catalyst among the other screened catalysts like
H2WO4, Na2MoO4, (Mo)2(acac)2, VO(acac)2 and CeO2 which
furnished poor yields of hydroxamic acids. The oxidation
process was strongly affected by the solvent used and superior
yields were obtained in water (entry 1, Table 5).42
Vanadium pentoxide, being the most stable and frequently
used mixed-oxide catalyst, was shown to be effective in oxi-
dative dehydrogenation (ODH) processes by Karki in 2013 for
the aromatization of tetrahydroquinoxaline in refluxing
toluene (entry 2, Table 5).43
Heterogeneous catalysts have mostly been used for the
dehydrogenation of N-heterocycles which require harsh con-
ditions and show poor functional-group tolerance. The urge
for the development of easily available and inexpensive cata-
lysts for the oxidative dehydrogenation of N-heterocycles has
led to the development of iron-based catalyst 37 in 2014 which
is inexpensive, abundant, and isoelectronic (d6 metal) with the
Ir(III) catalyst (entry 3, Table 5).44
Considering the disadvantages of nano-iron catalysts, like
poor stability and easy deactivation by aggregation and
leaching, led to the development of core–shell nanoparticles
by Cui and co-workers in 2015. They developed nitrogen-
doped graphene shells immobilized on carbon supports
surrounding the nanostructured iron oxides for the
catalytic dehydrogenation of tetrahydroquinoxalines (entry 4,
Table 5).45
In 2015, Iosub and co-workers initially employed a Pd-
based catalyst and got unsatisfactory results. Thereafter they
tested heterogeneous Co-oxide-based catalysts for the dehydro-
genative aromatization of N-heterocycles. Low yield was
obtained for other heterogeneous Mn, Fe, and Ni oxide cata-
lysts. However, the Co3O4-NGr/C catalyst exhibited superior
performance in terms of product yield at 60 °C, lower than the
temperatures typically required for dehydrogenation (entry 5,
Table 5).46
By considering the same strategy, in 2015 Xu and coworkers
employed the cobalt pincer catalyst 38 for dehydrogenation
and hydrogenation of N-heterocycles (entry 6, Table 5).47
Although several groups have already developed excellent
aerobic oxidative systems, reactions under external ligand-
free conditions was considered challenging for the practical
and cost-efficient synthesis of N-heterocycles. Hence, in
2016 Wang and the group reported a Pd-catalyzed aerobic
oxidation reaction for the preparation of quinoxaline and
other N-heterocycles using potassium tert-butoxide. Other
screened inorganic bases gave poor yield and only starting
materials were recovered in most of the cases (entry 7,
Table 5).48
This journal is © the Partner Organisations 2021
 View Article Online

Organic Chemistry Frontiers Review

Table 5 Reaction conditions for oxidative dehydrogenation of tetrahydroquinoxaline 33 to quinoxaline 1

Published on 10 March 2021. Downloaded by University of Prince Edward Island on 5/16/2021 8:23:27 AM.

Entry Reaction conditions % yield

1 H2O2/Na2WO4, MeOH 3742

2 V2O5 (2.0 equiv.), SiO2, toluene, reflux 24 h 8843
V2O5 (0.2 equiv.), DTBP, SiO2, toluene, reflux 84 h 79
3 Fe-Pincer catalyst (3 mol%), xylene reflux, 30 h 10044
4 FeOx@NGr-C (0.18 mol% Fe), heptane, 15 bar air, 100 °C, 12 h 9345
5 Co3O4-NGr/C, K2CO3, O2, MeOH, 16 h, 60 °C 9746
6 Co-Pincer catalyst (20 mol%), p-xylene, 150 °C, 2 day 9347
7 Pd(CH3CN)2Cl2, KOtBu, O2, DCE, 120 °C, sealed tube 9848
8 FeCl2, DMSO, O2, 100 °C, p-xylene, 26 h 4649
9 Rose Bengal catalyst (1.0 mol%), DMA, visible light, R.T., air 7950
10 PdNPs/SBA-15 (5 mol%), toluene-d8, 130 °C, 23 h 9951
RhNPs/SBA-15 (5 mol%), toluene-d8, 130 °C, 23 h 99
PtNPs/SBA-15 (5 mol%), toluene-d8, 130 °C, 23 h 72
11 Pd-NPs (4% of substrate), TBHP(8.0 equiv.), water, 80 °C, 18 h 7552
12 GO(30 mg), Na2CO3(40 mol%), EtOAc, 120 °C, 48 h, air 8553
13 Meso MnOx (25 mg), DMF, 130 °C, 20 h, air >9954
14 CoTPP (10 mg), DMF, 110 °C, O2, 15 h 6855
15 NaClO2, NaOCl, and catalytic amounts of TEMPO, CH3CN, 0 °C 4856
16 Ru(II)-NNC pincer catalyst (2 mol%), o-xylene, 140 °C, 48 h 8457
17 ISAS-Co/OPNC (25 mg), mesitylene, 120 °C, 8 h 9958
18 Laccase(200U)/DTBC(20 mol%), O2, NaPBS, MeCN, 45 °C, 24 h 9559
Laccase (200 U)/TEMPO(20 mol%), O2, NaPBS, MeCN, 45 °C, 24 h 93
19 PMI catalyst (50 mg), water: MeOH, O2, 120 °C, 300 rps, 24 h 7360
20 Ni2Mn-LDH (80 mg), mesitylene, O2, 120 °C, 9 h 6961
21 Ni(II)/TiO2, 4-amino TEMPO, i-PrOH, O2, blue LED 453 nm 8362
22 2[PW]-OMS-2 (20 mg), DMC, O2, 80 °C, 6 h 9863
23 99% KOtBu (1.5 mmol), o-xylene, 0.1 MPa N2, 140 °C, 36 h 9464
24 Ir catalyst (0.2 mol%), H2, H2O, 120 °C, 17 h 9565
25 Co NCs/N–C (50 mg), MeOH, 50 °C, 12 h 9966
26 PDI-SN (10 mg), ambient air, DMA, blue-LED 400 nm 8667
27 NiBr2/1,10-phenanthroline, TEMPO, t-BuOK, t-AmOH, O2, 95 °C, 24–48 h up to 99%68

The necessity to design and develop a suitable catalytic junction with tert-butyl hydroperoxide (TBHP) as an oxidant
system that will be inexpensive as well as efficient led Zhou for the hydrogenation of quinoxalines in water under mild
and co-workers to develop a simple FeCl2/DMSO system that conditions (entry 11, Table 5).52
can effectively catalyze the oxidative dehydrogenation of
N-heterocycles employing molecular oxygen as the oxidant
(entry 8, Table 5).49
In 2017 Sahoo et al. reported a room temperature visible
light-mediated organo-photoredox catalyst for the oxidative
dehydrogenation of tetrahydroquinoxalines to quinoxaline for
the first time under base- and additive-free conditions with
ambient air (entry 9, Table 5).50
Nanoparticles of Pd, Pt, Rh stabilized by G4OH PAMAM
dendrimers and supported on SBA-15 (MNPs/SBA-15 with M = In 2017, Zhang and co-workers reported an environmentally
Pd, Pt, Rh) were shown to be an effective catalytic system by friendly method for the synthesis of quinoxaline by the oxi-
Deraedt and co-workers for the acceptor less oxidative dehy- dative dehydrogenation of tetrahydroquinoxalines employing
drogenation of tetrahydroquinoxaline to quinoxaline at 130 °C graphene oxide (GO) (entry 12, Table 5).53
in toluene. These developed catalysts were robust, active, air- Nevertheless, the search for a simple and efficient catalytic
stable and recyclable, and afforded products in very good system for oxidative dehydrogenation under aerobic conditions
yields (entry 10, Table 5).51 was highly desirable as most of the existing techniques
Sun and co-workers employed a palladium nanocatalyst required harsh reaction conditions, difficult catalyst prepa-
stabilized by carbon-metal covalent bonds (PdvNPs) in con- ration, and the use of high oxygen pressure and additives.

This journal is © the Partner Organisations 2021 Org. Chem. Front.


Review
Hence, Mullick and group54 developed mesoporous manga-
nese oxide as an efficient catalytic system for environmentally
benign oxidative dehydrogenation under aerobic, additive-free
conditions (entry 13, Table 5).
Metalloporphyrins are typical biomimetic catalysts and
were studied as a new catalytic system for the aerobic oxidative
dehydrogenation of N-heterocycles without any additives.
Published on 10 March 2021. Downloaded by University of Prince Edward Island on 5/16/2021 8:23:27 AM.
Hence, Zhou and coworkers developed an additive-free
method for the synthesis of quinoxaline by aerobic oxidative
dehydrogenation of tetrahydroquinoxaline using cobalt por-
phyrin as a catalyst. The reaction mechanism suggested that
the oxidative dehydrogenation probably proceeded with the
imine formation and no high valent oxo-cobalt formation as
the active species (entry 14, Table 5).55
Chamorro-Arenas developed a protocol for the synthesis of
quinoxaline by using cheap and innocuous reagents, such as
NaClO2, NaOCl, and catalytic amounts of TEMPO (entry 15,
Table 5), Scheme 18.56 The subsequent oxidative deallylation
furnished the quinoxaline albeit in moderate yield.
Acceptor less dehydrogenation is favored over the tra-
ditional method because such processes are atom-economical
and environmentally benign and avoid the use of stoichio-
metric oxidants. Wang and coworkers in the year 2018 prepared
a highly active transition metal complex of ruthenium(II)
hydride bearing a pyrazolyl-(2-indol-1-yl)-pyridine ligand
(ruthenium(II)-NNC pincer complex) 41 which exhibited high
catalytic activity and broad substrate scope for the synthesis of
N-heterocycles and secondary alcohols via an acceptor less
dehydrogenation strategy (entry 16, Table 5).57
Single-atom catalysts (SACs) attracted extensive concern
because of their maximum atom utilization, superior reactivity
and selectivity and became potential substitutes for homo-
geneous catalysts. Porous N-doped carbon catalysts with Co
atomic sites (ISAS-Co/OPNC) were used by the group of Han
for the highly efficient dehydrogenation of tetrahydroquinoxa-
line. The dehydrogenation proceeds with the release of H2 and
the reverse transfer hydrogenation of tetrahydroquinoxaline to
Scheme 18 TEMPO-catalyzed selective dual C–H oxidation.
Org. Chem. Front.
View Article Online
Organic Chemistry Frontiers
store H2 employing either formic acid or external hydrogen as
the hydrogen source (entry 17, Table 5).58
The use of the transition metals due to their cost as well as
the requirement of high reaction temperatures is often con-
sidered unsuitable for the thermally unstable substrates. This
has led to the development of alternative non-metallic catalysts
that are sustainable for the aerobic oxidative synthesis of tetra-
hydroquinoxalines. Hence Saadati came up with a new biocata-
lytic approach employing Laccases ( p-benzenediol: oxygen
oxidoreductase) for the oxidation of electron-rich aromatic
substrates. The biocatalyst Laccases featured good thermal
stability, substrate selectivity, and the capability to catalyze the
reaction under mild reaction conditions (entry 18, Table 5).59
To bridge the gap between the homogeneous and hetero-
geneous catalysts, Zhang and coworkers have prepared a single-
active site heterogeneous catalyst via the oxidative polymeriz-
ation of maleimide derivatives and used it for selective oxi-
dation of heterocyclic compounds (entry 19, Table 5).60
During the development of efficient catalysts for aerobic
oxidation, Zhou demonstrated the use of NiMn-hydrotalcite as
an effective catalyst for the oxidative dehydrogenation of tetra-
hydroquinoxaline by molecular oxygen under mild conditions
(entry 20, Table 5).61
TiO2 has been known to be a widely used heterogeneous
photocatalyst due to its outstanding stability and nontoxicity
as well as its reusability. However, to improve the photo-
catalytic activity of TiO2, Balayeva and co-workers employed
transition-metal nanoparticles or ions grafted onto the TiO2
surface and demonstrated a visible-light-mediated dehydro-
genation of N-heterocycles (entry 21, Table 5).62
Bi and co-workers prepared recyclable OMS-2-based nano-
composites doped with Mn2O3 for the catalytic oxidative dehy-
drogenation of N-heterocycles in excellent yield (entry 22,
Table 5).63
Since many of the existing dehydrogenation protocols were
often affluent because of the involvement of expensive tran-
sition metals as well as additives for the reaction and were not
environmentally benign, Liu reported a transition metal-free,
acceptor less protocol for the dehydrogenation of
N-heterocycles to access quinoxalines and allied heterocycles
employing potassium tert-butoxide and molecular hydrogen
(entry 23, Table 5).64
Wang and co-workers developed an additive-free dehydro-
genation of N-heterocycles in water employing an iridium-
based catalyst bearing an electron-enriched dipyridylamine
ligand 42, under mild conditions (entry 24, Table 5).65
This journal is © the Partner Organisations 2021
 View Article Online

Organic Chemistry Frontiers Review

Since non-noble metals frequently get oxidated and leached

under harsh reaction conditions, the key concern to replace
the noble metals with non-noble metals to achieve the
superior catalytic activity, as well as sustainability, was towards
developing a robust catalytic system that will be sustainable as
well. Wu and co-workers developed a bifunctional catalyst,
namely Co NCs/N–C (cobalt nanocrystals stabilized by nitro-
Published on 10 March 2021. Downloaded by University of Prince Edward Island on 5/16/2021 8:23:27 AM.

gen-doped graphitized carbon), which can catalyze the oxi-

dative dehydrogenation with methanol as a solvent at 50 °C
within 4 h (entry 25, Table 5).66
Recently, Yu and coworkers developed a visible light-
mediated, additive-free, efficient reusable photocatalytic
system for the oxidative dehydration reaction utilizing
perylene diimide (PDI), Fig. 5.67 The formation of tiny
PDI semiconducting material because of the aggregation of
the PDI molecules on the SiO2 surface was responsible for the
high-efficiency photo-oxidative activity (entry 26, Table 5).67
Scheme 19 Selective C–H oxidative sulfonylation of tetrahydro-qui-
noxalines; and the mechanistic pathway.

dehydroaromatization furnished the final product 48,

Scheme 19.69

Using epoxides
Murata and coworkers demonstrated the use of epoxy
aldehydes or epoxy esters to access dihydroquinoxaline
derivatives.
They stated that o-PD 2 on reaction with 2,3-epoxy alde-
hyde 49 furnished 2-hydroxyalkyl-1,2-dihydro quinoxaline
50, whereas 2,3-epoxy esters 51 delivered either dihydro-
Fig. 5 PDIs in different phase states. quinoxaline derivatives 52 or uncyclized hydroxylamine
ester 51a. The reaction of epoxy aldehyde and o-PD initially
resulted in the formation of Schiff’s base which then
Bera et al. developed an efficient and selective nickel cata- underwent intramolecular nucleophilic ring-opening by
lyzed method for dehydrogenation of the six-membered epoxide resulting in the formation of dihydroquinoxaline
N-heterocycles via the application of molecular oxygen to derivatives 50. Whereas ring-opening reactions of epoxy
access quinoxaline and allied heterocycles (entry 27, Table 5).68 ester proceeded only in the presence of LiOH catalysts to
The selective introduction of the sulfonyl group into the activate epoxide oxygen to furnish the desired product,
organic molecules enhances the hydrophilicity and biologi- Scheme 20.70
cal affinity of the entire molecule. Therefore, there is a great
deal of interest in developing sulfonylated heterocycles.
Oxidative sulfonation of tetrahydroquinoxaline was demon-
strated by Xie and co-workers employing highly dispersed
cobalt catalysts using sodium sulfinate. This methodology
allowed access to a variety of sulfonyl quinoxalines with
high regio- and chemoselectivity with very good functional
group tolerance, Scheme 19.69 The mechanistic detail dis-
closes that the coupling between tetrahydroquinoxaline and
sodium sulfide occurs in the presence of iodine which
worked as a radical initiator to generate the N-radical via
single-electron oxidation (SEO). Subsequent deprotonation
followed by isomerization furnished the intermediate aryl
radical 33b. Simultaneously, an iodide radical initiated the
formation of the electrophilic sulfonyl radical 47b via the
SEO of sulfinate. Thereafter, radical coupling followed by Scheme 20 Synthesis of 1,2-dihydro quinoxaline using epoxides.

This journal is © the Partner Organisations 2021 Org. Chem. Front.


Review
In 2002, Antoniotti and co-workers employed a catalytic
amount of Bi(0) powder and triflic acid or copper triflate to
prepare substituted quinoxalines by reacting epoxides with
o-PD derivatives under molecular oxygen in DMSO at 100 °C.
For mono-substituted epoxides Cu(OTf )2 was used as an addi-
tive, whereas for di-substituted epoxide a strong Brønsted acid
such as triflic acid was used as an additive. This reaction pro-
Published on 10 March 2021. Downloaded by University of Prince Edward Island on 5/16/2021 8:23:27 AM.
ceeded via the oxidative ring opening of oxirane by DMSO in
the presence of an acid catalyst to generate α-hydroxy ketone.
Second oxidation of the alpha-hydroxy ketone in the presence
of Bi(0)/O2 system or a Bi(III)/Bi(0) redox process resulted in
the formation of α-diketone which then underwent a double
condensation reaction with the diamine to furnish the
required quinoxaline, Scheme 21.71
In 1980, Taylor and co-workers utilized α-substituted epox-
ides as bifunctional two-carbon synthons to synthesize qui-
noxaline by condensing with o-PDs 2 in DMF solvent.
The heterocyclization of α-cyano epoxide 54 with o-PD 2
resulted in achieving quinoxaline in up to 94% yield.
Mechanistic pathways suggested that nucleophilic attack on
α-cyano epoxides 54 occurred at the C-1 carbon atom rather
than C-2. Dehydration of the benzylic alcohol followed by
intramolecular conjugate addition resulted in the desired qui-
noxaline 55 in good yields, Scheme 22.72
Vinyl epoxides are known to furnish 1,4 addition products
through a nucleophilic opening of a π-allyl palladium complex.
However, altering the reagents can lead to the formation of
1,2-addition products intramolecularly. Capitalizing on this
concept, Srikanth and co-workers demonstrated the synthesis
of quinoxaline via a palladium-catalyzed stereoselective
opening of cis and trans-vinyl epoxides 56 with an amine
nucleophile in the presence of boron reagent 56a. The role of
the boron was to form a stable adduct with the o-PD and assist
the intramolecular Michael addition to access densely functio-
nalized chiral 1,2,3,4-tetrahydroquinoxaline derivatives in high
yield, Scheme 23.73
Tu and co-workers developed a domino strategy to syn-
thesize quinoxaline derivatives by [4 + 2] heterocyclization pro-
Scheme 21 Bi(0) catalyzed synthesis of substituted quinoxaline.
Scheme 22 Synthesis of 2-aryl-3-cyano-1,2,3,4-tetrahydroquinoxaline.
Org. Chem. Front.
View Article Online
Organic Chemistry Frontiers
Scheme 23 Palladium-catalyzed synthesis of 3,4-dihydro-1,4-benzox-
azine-1,2,3,4-tetrahydroquinoxaline derivatives from epoxides.
ceeding via ring-opening of oxirane. The use of Cs2CO3 with a
simple operational method and the use of inexpensive starting
materials, avoiding the use of oxidizing agents, are the advan-
tages of this procedure. The authors described the mechanistic
pathway where the reaction proceeded via the formation
of imine 59a. Subsequent nucleophilic addition, epoxide
ring-opening, and dehydration resulted in the formation of
a six-membered intermediate 59b. A 1,3-prototropic shift
finally afforded the desired quinoxaline 60 in good yield,
Scheme 24.74
Nitroepoxides were also used as precursors for the synthesis
of quinoxalines as they can be easily accessed by the one-step
epoxidation of nitroalkenes. Vidal-Albalat et al. employed such
a strategy to synthesize quinoxalines from nitroepoxides using
ethanol as an environmentally benign solvent, Scheme 25.75
A mechanistic pathway suggested the formation of
α-iminoamine intermediate 61a which then afforded the qui-
noxalines 62 on treatment with air, whereas the in situ
addition of reducing agents resulted in the formation of tetra-
hydroquinoxaline 62a.
In 2013, Ibrahim et al. developed a synthetic route to access
functionalized quinoxaline using α-nitroepoxides. The one-pot
approach involving an environmentally friendly metal-free
strategy employing easily accessible starting compounds made
Scheme 24 [4 + 2] heterocyclization towards the synthesis of quinoxa-
line derivatives and the probable mechanistic pathway.
This journal is © the Partner Organisations 2021

Organic Chemistry Frontiers
Published on 10 March 2021. Downloaded by University of Prince Edward Island on 5/16/2021 8:23:27 AM.
Scheme 25 Synthesis of quinoxaline from α-nitro epoxide and
mechanistic pathway for the formation of quinoxaline derivatives.
this protocol highly attractive and advantageous over the exist-
ing methods. Mechanistic studies revealed that the attack of
the diamine 58 on the α-nitroepoxide 63 on the less sterically
hindered side leads to the epoxide ring-opening followed by
intramolecular nucleophilic attack by the second amine group.
Subsequent ring closure accompanied by the release of nitrous
acid, along with dehydration and aromatization, furnished the
desired quinoxaline 64, Scheme 26.76
Perfluoroolefin oxides, being an important and versatile
synthon, were used for the synthesis of polyfunctional quinox-
alines containing fluorine atoms and perfluoroalkyl groups,
Scheme 27.77
In 2006, Saloutina and group employed epoxy derivatives of
internal perfluoro olefine 68 to synthesize quinoxaline 4 in
Scheme 26 Formation of quinoxaline from α-nitro epoxides and
mechanism for the formation of quinoxaline from α-nitroepoxide.
This journal is © the Partner Organisations 2021
View Article Online
Review
Scheme 27 Formation of fluorinated quinoxaline from
perfluoroepoxyoxolanes.
Scheme 28 The reaction of epoxide derivatives with o-PDs.
23–67% yield in the presence of aprotic solvent (dioxane),
Scheme 28.78
Reactivity and reactions
Electrophilic attack on quinoxaline is less likely to occur
because of the presence of N-atoms making it electron
deficient. However, the nucleophilic attack can occur at the 2,
4, 5, and 8a positions. Over the years, quinoxaline moiety has
gained tremendous importance due to its potential application
in dyes, pharmaceuticals, and advanced functional materials
and as a result, a rational design approach is very much essen-
tial. So here we will be documenting the different aspects of
the functionalization of quinoxaline moiety.
Halogenation and dehalogenation
Catalytic condensation of an aromatic o-PD with α-dialdehydes
(or α-diketones) in the presence of either a Lewis or a Brønsted
acid has been one of the most practiced methods for the syn-
thesis of quinoxalines because of the utilization of commer-
cially available reagents under ambient experimental con-
ditions. However, the synthetic route lacks diversity as the
existing methodologies do not leave us with many choices to
diversify the groups attached at the C2 and C3 positions.
Moreover, the challenges associated with bringing diketone
derivatives with structural complexity can be overcome by late-
stage functionalization of the quinoxaline scaffold.
Therefore, to overcome such limitations, halogenations to
access mono or di-halo substituted quinoxalines appear to be
a viable solution to access diverse quinoxaline derivatives. The
π electron-deficient character of the quinoxaline allowed facile
palladium-mediated oxidative addition reactions without invol-
ving any expensive ligands. Halo-substituted quinoxaline 70a/b
offered a perfect template for a wide range of cross-coupling
reactions, Scheme 29, and Fig. 6, and provided the
molecule with a perfect handle for structural and functional
diversification.6
Org. Chem. Front.

Review
Published on 10 March 2021. Downloaded by University of Prince Edward Island on 5/16/2021 8:23:27 AM.
Scheme 29 Schematic representation of several coupling reactions for
the functionalization of the quinoxaline scaffold.
Fig. 6 Scope of nucleophilic aromatic substitution of quinoxaline.
The importance of 2,3-dichloroquinoxaline (DCQX) 79 as a
synthetic precursor has been documented recently in 2020 by
Menezes and colleagues highlighting the application of this
scaffold towards the synthesis of diverse sets of functionally
and medicinally important molecules.7
The halo substituted quinoxaline 70a/b featuring C2 and C3
labile protons are exact matches for the metallation employing
lithium or magnesium. The corresponding organometallic inter-
mediate 71 can be easily converted into a functionalized deriva-
tive by reaction with an appropriate electrophile, Scheme 29.7
The bromination of quinoxalines often resulted in the for-
mation of N-bromo complexes. However, precise control over
the reaction parameters like solvent, temperature and light, as
well as the equivalents of brominating agents, will allow the
formation of several brominated derivatives as highlighted in
Fig. 7 and Table 6.79 The conditions under which different
bromo derivatives of quinoxaline are obtained are illustrated
in Table 6.79
The direct bromination of quinoxaline results in the bromi-
nation on the benzene ring of the quinoxaline, Fig. 7, and
Org. Chem. Front.
View Article Online
Organic Chemistry Frontiers
Fig. 7 Brominated products of quinoxaline under different conditions.
Table 6. However, C2 and C3 brominated quinoxalines can
only be accessed when the bromination of the quinoxaline
N-oxides is carried out. Quinoxaline N-oxides which can be
accessed from quinoxaline provided a unique platform for the
bromination at the electron-deficient ring of quinoxaline, as
evident from the different conditions highlighted in
Scheme 30.79 Bromination of N-oxides furnishes the bromi-
nated product 89 and 92 with bromination occurring at the
nitrogenous ring of the quinoxaline, Scheme 31.79
Directed lithiation of aromatics and heteroaromatics consti-
tuted an important strategy for ring functionalization.
However, the competitive nucleophilic addition reaction
makes the metalation of diazines even more challenging. A
highly active and soluble magnesium base (TMP)2Mg·2LiCl
(TMP = 2,2,6,6-tetramethylpiperamidyl) 93 smoothly allows the
metallations of quinoxaline with excellent functional group
compatibility. Dong demonstrated the use of (TMP)2Mg·2LiCl
93 for the synthesis of zincated quinoxaline 94b which was
further converted to iodo-substituted quinoxaline 94 in excel-
lent yields on treatment with nucleophilic iodine,
Scheme 32.80
In 2011, Blair and co-workers further synthesized 2-iodo
quinoxaline 94 demonstrating the chemoselective deprotona-
tive zincation reactions of a range of quinoxaline using lithium
zincate base [Li(TMP)Zn(tBu)2] 93 followed by treatment with
nucleophilic iodine in 50% yield, Scheme 32.81
The mechanistic details are highlighted in Scheme 33. In
pathway a, the formation of manganese-containing hetero-
cyclic species 94a from the reaction between quinoxaline 1 and
base (TMP)2Mg·2LiCl was proposed which then undergoes fast
transmetallation with zinc reagent to provide corresponding
zinc-containing heterocycle 94b. In pathway b, the base
(TMP)2Mg·2LiCl first reacts with zinc reagent and the formed
species further reacted with quinoxaline to yield the zinc-con-
taining heterocycle 94b. In pathway c, the heterocycle first
reacted with zinc reagent forming an intermediate zinc
complex 94c which then underwent fast transmetallation in
This journal is © the Partner Organisations 2021
 View Article Online

Organic Chemistry Frontiers Review

Table 6 Bromination of quinoxaline under different conditions with brominating agents

Entry Reaction conditions % yield

1 Br2 (6.6 equiv.), AcOH, 118 °C, 24 h B = 46%, E = 11%

2 Br2 (12 equiv.), H2SO4, 200 °C, 40 h B = 28%, E = 9%
3 Br2 (8 equiv.), MeCN, 82 °C, 25 h D = 75%
4 Br2 (8 equiv.)/BaCO3 (2 eq.), MeCN, 82 °C, 25 h B = 31%, C = 14%, D = 5%, E = 6%, F = 28%
5 Br2 (3 equiv.)/BaCO3 (2 eq.), MeCN, 82 °C, 72 h B = 65%
Published on 10 March 2021. Downloaded by University of Prince Edward Island on 5/16/2021 8:23:27 AM.

6 Br2 (8 equiv.), CCl4, hν (150 W projector lamp), 18 h D = 30%, F = 25%

7 Br2 (2 equiv.), CCl4, hν (150 W projector lamp), 45 h A = 70%, C = 3%, D = 10%
8 NBS (6 equiv.)/BPO (benzoyl peroxide), AcOH, 118 °C, 20 h B = 50%
9 NBS (6 equiv.)/BPO (benzoyl peroxide), DMF, 153 °C, 18 h B = 51%
10 NBS (7 equiv.)/BPO (benzoyl peroxide), chloroform, 62 °C, 45 h B = 29%, C = 29%, D = 3%, E = 10%
11 NBS (6 equiv.)/BPO (benzoyl peroxide), MeCN, 82 °C, 20 h B = 55%, C = 15%, E = 5%

Scheme 30 Synthesis of brominated quinoxaline from quinoxaline N-oxide.

the presence of a base to yield the corresponding zinc deriva-

tive, Scheme 33.
Fluorinated heterocycles are prevalent in pharmaceuticals,
agrochemicals, and materials.82 The selective introduction of
fluorine into small molecules often results in the alteration of
the acid dissociation constant and molecular conformation
due to the origin of non-covalent interactions resulting in
effects on the solubility, as well as the stability, compared with
the non-fluorinated counterpart.
In 1999, the research group of Chambers synthesized
2-fluoro- or 2,3-difluoro-quinoxaline 96 by treating quinoxaline
1 with a mixture of fluorine and iodine in the presence of tri-
ethylamine. The formation of poly-fluorinated products was
Scheme 31 Bromination of quinoxaline N-oxide under different dependent on the quantity of fluorine used in the reaction,
conditions. Scheme 34.83 Formation of iodonium and fluoride ion sources

This journal is © the Partner Organisations 2021 Org. Chem. Front.


Review
Published on 10 March 2021. Downloaded by University of Prince Edward Island on 5/16/2021 8:23:27 AM.
Scheme 32 Iodination of quinoxaline via the alkali–metal mediated
zincation.
Scheme 33 Postulated intermediates of the metalation of quinoxaline
with (TMP)2Mg·2LiCl in the presence of ZnCl2.
Scheme 34 Selective fluorination of quinoxaline.
was observed in situ when iodine was reacted with fluorine fol-
lowed by the fluorination of intermediate N-iodo-heterocycle
by fluoride ions.
Org. Chem. Front.
View Article Online
Organic Chemistry Frontiers
Table 7 Reaction conditions for dehalogenation of quinoxaline
Entry Reaction conditions % yield
1 Indium powder, water, reflux 4485,
5686
2 Pd(OAc)2 (5 mol%), PPh3 (20 mol%), NaBH4 (1.7 7287
equiv.), TMEDA (1.7 equiv.), THF, 25 °C, 1 h
PdCl2(dppf) (5 mol%), NaBH4 (1.7 equiv.), TMEDA 5287
(1.7 equiv.), THF, 25 °C, 1 h
3 Si-325 mesh, Co(OAc)2 (20 mol%), PPh3 (22 mol%), 8288
NaOH (130 mol%), TBAB (4 equiv.), H2O, 100 °C,
24 h
Similarly, Fier developed site-selective fluorination of a
single carbon–hydrogen bond in diazines using commercially
available silver(II) fluoride, Scheme 34.84
Dehalogenation
Several dehalogenative methods to access quinoxaline from
2-halo substituted quinoxalines 1 were reported by several
research groups and are highlighted in Table 7.85–88 The deha-
logenation step constitutes an important chemical transform-
ation in terms of accessing selective functionalization at either
C2 or C3 positions of quinoxaline.
Environmentally benign, facile, and safe protocols avoiding
standard dehalogenative reagents like Pd–C, RANEY® Ni, or
halogen–metal exchange were reported by Hirasawa85 and
Fukuda.86 They have employed indium for the dehalogenation
of aromatic halides in water (entry 1, Table 7).85,86 Indium
metal in water was reported to furnish quinoxaline from
2-haloquinoxaline in moderate yield.
Chelucci and co-workers employed a combination of
NaBH4-TMEDA together with a palladium catalyst for the dehy-
drohalogenation of halo substituted quinoxalines, as well as
other allied heterocycles. NaBH4-TMEDA was used as a hydride
source. Pd(OAc)2-PPh3 rapidly hydrodehalogenated the bromo-
heteroarenes whereas PdCl2(dppf ) and PdCl2(tbpf ) reduced
chlorinated heteroarenes. The reaction was compatible with a
wide variety of functional groups and offered high chemo-
selectivity in the presence of functional groups like ester,
alkyne, alkene, and nitrile (entry 2, Table 7).87
The Pd-based conditions were not effective for hydrodehalo-
genation of aryl halides because of the formation of biaryls
along with the dehydrohalogenation products making the sep-
aration tedious. A novel catalytic system comprising Co(OAc)2/
PPh3 was reported by Gevorgyan and coworkers which can
effectively catalyze the dehydrohalogenation with no formation
of side products and unreacted starting materials. The authors
reported that the utilization of 130% of the base to neutralize
the acid generated during the reaction was beneficial to
improve the yield of the reaction. The reaction was substrate-
dependent and found to work efficiently with electron-
This journal is © the Partner Organisations 2021
 View Article Online

Organic Chemistry Frontiers Review

deficient hetero-arenes or arenes attached with electron-with-
drawing groups rather than with electron-rich species (entry 3,
Table 7).88
C–C bond formation via Minisci reaction (acylation)
Other than the halogenations followed by coupling reactions,
direct functionalization of the C2 and C3 centers is a well-
Published on 10 March 2021. Downloaded by University of Prince Edward Island on 5/16/2021 8:23:27 AM.
quinoxaline was possible by precisely controlling the basicity
and lipophilicity balance between the quinoxaline and the
monoacylation products in a bi-phasic system. Decreasing the
basicity of heteroarenes was the key to improving the yield of
the monoacylated product 100. The mechanistic pathway is
highlighted in Scheme 36 and the reaction follows the redox
pathway forming the acyl radical as illustrated below.89

Chaubey developed a green protocol for the acylation of het-

explored strategy to get diversely substituted quinoxalines.
erocycles by using water as a green solvent for the reaction.
Acylation of electron-deficient heteroarenes is highly chal-
The protocol avoided the use of hazardous organic solvents as
lenging knowing the fact that conventional Friedel–Crafts acy-
well as performing under metal and additive-free conditions,
lation will be highly improbable with electron-deficient
Scheme 37.90 The reaction of N-heterocycles 102 and α-keto
species. Direct acylation of electron-deficient quinoxalines,
although challenging, has been widely explored because it pro-
vides a handle for further synthetic modifications.
The Minisci reaction is the insertion of C-centered radicals
to aromatic heterocycles followed by the rearomatization of the
ring with the loss of hydrogen atoms. The reaction has gained
extensive importance since its inception due to its ability to
directly functionalize the heteroaromatics rapidly.
The popularity of the Minisci reaction due to simple reac-
tion conditions has resulted in several applications in hetero-
cyclic chemistry including the acylation of quinoxalines. The
direct acylation of quinoxaline employing α-keto acids has
been carried out under different reaction conditions as illus-
trated in Scheme 35.89–92
Selective acylation of quinoxaline 1 by the silver catalyzed
decarboxylation of keto acids by persulfate was described by
Fontana in 1991, Scheme 35.89
Although multiple positions of high nucleophilic activity
are available in the quinoxaline, selective monoacylation of Scheme 36 Redox chain process of acylation reaction.

Scheme 35 Direct acylation of quinoxaline 1, with α-ketoacid.

This journal is © the Partner Organisations 2021 Org. Chem. Front.

 View Article Online

Review Organic Chemistry Frontiers

of radicals from the light absorption of the α–keto acid 99.

Second, by the formation of the electron donor–acceptor (EDA)
complex A, resulting from the photodecarboxylation process of
absorbing the visible light, and third, by the generation of the
EDA complex B resulting from the homolytic cleavage of
S2O82− to produce SO4•− which triggered the decarboxylation
of the α-keto acid. Formation of the acyl radical was followed
Published on 10 March 2021. Downloaded by University of Prince Edward Island on 5/16/2021 8:23:27 AM.

by the addition of the protonated heteroarene and subsequent

hydrogen atom transfer (HAT) and re-aromatization delivered
the acylated N-heterocycles, Scheme 39.92

Scheme 37 Metal-free acylation of quinoxaline. Cross-dehydrogenative coupling

A cross dehydrogenative coupling strategy has become one of
the most effective approaches for constructing C–C bonds
acids 99 was catalyzed by K2S2O8 and followed the radical directly from two unmodified C–H, C–C, or C–N bonds utiliz-
pathway as demonstrated in Scheme 37.90 ing oxidizing agents like TBHP, Scheme 40.93 The advantage of
Wang and co-workers used FeSO4 catalyst instead of expen- the CDC approach is that direct tandem oxidation of simple
sive Ag(I) salt as a catalyst for the Minisci type acylation reac-
tion, Scheme 37.91 A quinoxaline-bearing electron-donating
group furnishes a good yield of an acylated product compared
with the electron-withdrawing group, which resulted in a very
low yield along with unreacted starting material. The reaction
followed a pathway where persulfate oxidizes Fe(II) to Fe(III)
resulting in the decarboxylation of α-keto acid 99 to generate
acyl radicals. An alternative pathway stating the generation of
methyl radicals by Fe(II)/DMSO/S2O82− oxidation systems was
also proposed which subsequently afforded the acyl radical by
the abstraction of the hydrogen atom. The acyl radical 99a
then underwent radical addition with the protonated heteroar-
enes 102, and further oxidation by Fe(III) or persulphate
resulted in the desired acylated product 100, Scheme 38.91
Visible-light mediated reactions are known to occur under
extremely mild conditions and avoid the use of photosensiti-
zers. As a result, the photoinduced reaction pathway provided
a new direction towards sustainable development. Therefore, a
photo-induced pathway was explained by Guillemard as a sus-
tainable approach for the acylation of quinoxaline,
Scheme 35.92
Three different mechanistic pathways were suggested for
the generation of an acyl radical. First, by the direct generation

Scheme 38 Possible mechanistic pathways for the Minisci acylation Scheme 39 Mechanistic pathway for the acylation of quinoxaline by
reaction using Fe(II)/DMSO/S2O82− oxidation system. radical functionalization.

Org. Chem. Front. This journal is © the Partner Organisations 2021

 View Article Online

Organic Chemistry Frontiers Review

Scheme 40 General schematic representation for the cross dehydro-

genation coupling reaction.
Published on 10 March 2021. Downloaded by University of Prince Edward Island on 5/16/2021 8:23:27 AM.

C–H and N–H bonds allows the use of simple and readily avail-
able reagents and reduces the reaction steps.
The construction of carbon–carbon bonds between two
hydrocarbons via oxidative cross-coupling is considered one of Scheme 42 Proposed mechanisms for the oxidative CDC reaction.
the most cherished methodologies in organic chemistry.
However, some challenges like low reactivity of some C–H
bonds, overoxidation, selective C–H bond functionalization,
dimerization, etc. are still underexplored. A series of CDC strat-
egies for the construction of acylated quinoxaline has been
reported by the groups of Liu, Prabhu and Lei and are high-
lighted in Scheme 41.94–96
An efficient metal-free oxidative cross-dehydrogenative
coupling (CDC) of quinoxaline, as well as allied N-heterocycles
with a diverse series of aromatic aldehydes, was demonstrated
by Liu and co-workers in the presence of TBHP/TFA. Desired
mono substituted product 107 was obtained as the major com-
ponent with yields up to 70%, Scheme 41.94 The mechanistic
pathway illustrated in Scheme 42 shows that the benzaldehyde
gets converted to phenacyl radical 99d in the presence of
TBHP at 110 °C followed by the addition of the iminium ion to
generate the intermediate 109b. Subsequently, this generates Scheme 43 Visible-light mediated oxidative C–H acylation of
the desired product by a single electron transfer mechanism, quinoxaline.
Scheme 42.94
Prabhu and co-workers replaced the TFA used in the earlier
reported reaction by Liu with NCS (N-chlorosuccinamide) as
reactions between quinoxaline and an aldehyde avoiding the
an additive and received 53% overall yield comprising 42%
use of any photocatalyst and furnished mono acylated deriva-
mono substituted derivative 107 and 11% di substituted
tive 100 in 48% yield, Scheme 41.96 The probable mechanistic
derivative 108, Scheme 43.95
pathway is highlighted in Scheme 43 which indicates the
Visible light-mediated photoredox catalysis has evolved as a
initial formation of a complex of heteroarene and t-BuOOH
powerful tool for creating new chemical bonds under mild
102a. The resulting complex 102a promoted the light-mediated
reaction conditions. Zhang developed a direct cross-coupling
hemolytic cleavage pathway to produce the tert-butoxy radical
method for acylation of quinoxaline by visible-light mediated
and hydroxyl radical. The tert-butoxy radical or hydroxyl
radical then undergoes a hydrogen atom transfer with benz-
aldehyde to generate the phenacyl radical 99d. The resulting
phenacyl radical 99d undergoes nucleophilic addition on the
protonated heteroarene to generate the corresponding radical
cation 102d. Subsequent single electron transfer from the
intermediate afforded the desired product 107.96
The hunt for a sustainable CDC pathway has led several
research groups to try out innovative approaches for the acyla-
tion of electron-withdrawing heteroarenes. Such is the case for
the research groups of Sharma and Sultan who have used ionic
liquid and CFL light respectively to access acylated quinoxaline
113, Scheme 44.
Sharma and co-workers developed an ionic liquid-mediated
efficient strategy to access C-benzoylated quinoxalines in
Scheme 41 CDC strategy for the construction of acylated quinoxaline. 75–80% yield via cross-dehydrogenative coupling (CDC) of

This journal is © the Partner Organisations 2021 Org. Chem. Front.


Review
Published on 10 March 2021. Downloaded by University of Prince Edward Island on 5/16/2021 8:23:27 AM.
Scheme 44 Acylation of quinoxaline.
benzylamines 111 with quinoxalines 1. The benzoylation of
N-heterocycles occurred via (NH4)2S2O8 catalyzed benzoyl
radical formation, Scheme 44.97 The ionic liquid can be
recycled up to 5 times and the reaction has broad substrate
scope encompassing both electron-donating as well as elec-
tron-withdrawing groups. However, the yields reported for the
electron-donating groups were slightly lower than those of
electron-withdrawing groups.97
The mechanism highlighted in Scheme 45 describes that at
the initiation of the reaction, benzylamine 111 transforms to
benzaldehyde 109 via aerial oxidation. Subsequently,
ammonium persulfate generates the benzoyl radical 109a
which in turn attacks the C2 position of quinoxaline BF4−
complex 102 and finally, the aromatization results in the final
product 107. The [Bmim]BF4 helped in the radical formation,
Scheme 45.97
Sultan et al. utilized terminal alkynes 112 as an acyl source
for the photoredox-mediated acylation reaction of electron-
deficient quinoxaline and achieved 78% yield of the monoacy-
lated product 107, Scheme 46.98 The method relied on oxi-
dative cleavage of phenylacetylenes as the key step for the for-
Scheme 45 Probable mechanistic pathway for direct metal-free ben-
zoylation of the quinoxaline.
Org. Chem. Front.
View Article Online
Organic Chemistry Frontiers
Scheme 46 The mechanism for photoredox-catalyzed acylation of
heteroarenes.
mation of acyl radicals. Stoichiometric use of acyl precursors
and shorter reaction times are some of the advantages of this
protocol. The use of blue LEDs resulted in lower yields and
longer reaction times compared with the CFL, probably
because of the faster oxidative cleavage of the phenylacetylene
112 to acyl radicals and ultimately leading to benzaldehyde as
the by-product.
Therefore, the reaction was carried out in the presence of
CFL. The photoexcitation of Ru(bpy)3Cl2 leads to the single
electron transfer in the presence of persulfate salt leading to
the formation of the radical anion (SO4•−) and Ru(III).
Meanwhile, the decarboxylation of the phenylglyoxalic acid 99
formed in situ from phenylacetylene 112 followed by hydrogen
atom transfer (HAT) with sulfate radical anion (SO4•−) furn-
ished the acyl radical, which subsequently coupled with the
protonated heteroarene 102 to provide the intermediate 102a.
A SET reaction between the intermediate and Ru(III) completed
the photoredox catalytic cycle and resulted in the formation of
the acylated quinoxaline 107 as shown in the mechanistic
pathway, Scheme 46.98
A nickel catalyzed electrochemical method for the direct
acylation of quinoxaline employing α-keto acids 99 was
reported by Ding and co-workers in 2020. The reaction was per-
formed under constant current conditions and avoided the use
of excess oxidant as well as silver catalysts, Scheme 47.99
The mechanistic pathway illustrated the oxidation of Ni
(acac)2 at the anode in the presence of α-keto carboxylic acid
99 to generate a nickel(III) complex 114. Subsequent ligand-to-
metal electron transfer resulted in the generation of ArCOCOO
radicals along with the regeneration of Ni(acac)2 which, being
quite unstable, extruded CO2 to generate the acyl radical 109b.
The radical addition to the protonated quinoxaline afforded
This journal is © the Partner Organisations 2021
 View Article Online

Organic Chemistry Frontiers Review

Scheme 47 Nickel-catalyzed electrochemical Minisci acylation

reaction.
Published on 10 March 2021. Downloaded by University of Prince Edward Island on 5/16/2021 8:23:27 AM.

the adduct 114c. Subsequent oxidation and deprotonation

furnished the acylated product 100 followed by the cathodic
reduction of the proton to afford hydrogen, Scheme 48.

Alkylation Scheme 49 Direct alkylation of quinoxaline.

Alkylation of quinoxaline is yet another way of constructing C–
C bonds at the C2 or C3 positions. Alkyl groups normally get
substituted or added to the molecules as carbocations, carba-
nions, radicals, or carbenes. However, alkyl radicals have been
the prime source for the alkylation of quinoxaline.
Due to the electron-donating nature of the phenylalkynyl
attached at the 2-position of the quinoxaline moiety, a nucleo-
philic substitution reaction is unlikely to occur. The highly
delocalized pi-electrons from the phenyl ring and the acetyl
moiety make the –N=C–H site less electrophilic. Therefore,
very strong nucleophiles (n-BuLi has been used for the alkyl-
ation of quinoxaline) can be the solution, as depicted in
Scheme 49.100
The Minisci reaction, due to its high versatility, has become
a more and more attractive strategy for medicinal chemists
and appears as a frequent synthetic tool in the synthesis of
biologically active molecules, Scheme 50.92
The alkylation of quinoxaline via the cross dehydrogenative
coupling turned out to be one of the straightforward routes to
access alkyl-substituted quinoxalines. Although challenging,
diverse substrates like acid anhydrides 125, alpha-keto acids Scheme 50 General mechanism of Minisci reaction.
119 S-tert-butyl o-ethyl xanthates 126, aliphatic acids 119, and
aryldifluoro acetic acid 127 have efficiently reacted under
different reaction conditions to furnish alkylated quinoxalines internal oxidant is the main advantage of this methodology.
4, 128–129 in good to excellent yields as illustrated in The alkyl-substituted quinoxaline 4 was obtained in yields up
Scheme 51.101–103 to 75%, Scheme 51.101 Zeng et al. proposed a reaction mecha-
The direct C–H alkylation strategy of quinoxalines under nism portrayed in Scheme 52. Initial protonation of the qui-
Brønsted acid-catalyzed conditions (TfOH) employing alkyl noxaline followed by the attack of the alkyl radical on the pro-
peroxide 125 acting both as an alkylating reagent as well as an tonated quinoxaline 102 leads to the amino-radical cation
102a. Subsequent oxidation of the cation radical intermediate
102a generates the alkylated product 4 after workup.
Revil-Baudard and coworkers demonstrated the use of
S-tert-butyl o-ethyl xanthate 126 as a source of the tert-butyl
group for the easy functionalization of quinoxaline as well as
other allied N-heterocycles, Scheme 51.102 The presence of
dilauroyl peroxide (DLP) became instrumental in the gene-
ration of tertiary alkyl radicals involved in the alkylation
process. The detailed mechanistic pathway is highlighted in
Scheme 53.102
Yet another mild methodology for the direct alkylation of
Scheme 48 Plausible mechanistic pathway for the nickel catalyzed quinoxaline 1 employing carboxylic acid 119 as the alkylating
electrochemical acylation of quinoxaline. source was reported by Galloway and co-workers in 2017,

This journal is © the Partner Organisations 2021 Org. Chem. Front.

 View Article Online

Review Organic Chemistry Frontiers

Owing to the unique stability, isosteric properties, and lipo-

philic hydrogen-bond donor ability of the fluoride atoms, the
CF2 unit has gained importance in medicinal chemistry.
However, the installation of a difluoromethyl unit into a het-
eroaromatic scaffold is quite challenging. Therefore, to access
CF2 appended heteroarenes, Xie developed a mild silver-
promoted decarboxylative difluoro methyl arylation employing
Published on 10 March 2021. Downloaded by University of Prince Edward Island on 5/16/2021 8:23:27 AM.

aryldifluoro acetic acid 127 as difluoromethyl sources,

Scheme 51.104 An excellent yield of difluoromethylated qui-
noxaline 129 was obtained under the operational conditions.
Interestingly, another method for the difluoromethylation
of quinoxalines and other related heterocycles has been
reported by Lytkina and coworkers, employing cheap and
readily accessible sodium difluoromethane sulfinate,
Scheme 54.105 Sodium difluoromethane sulfinate is con-
sidered a cheap and promising alternative to zinc(II) difluoro-
methane sulfinate for the difluoromethylation of quinoxaline.
The authors proposed a mechanistic pathway quite analogous
to the Minisci reaction; however, quinoxaline turned out to be
a weakly reactive substrate toward sodium difluoromethane
sulfinate furnishing a moderate yield of the product even with
Scheme 51 C–H alkylation reaction of quinoxaline.
6–7 equivalents of catalyst loading.
Convenient access to 2 or 3-substituted quinoxaline by
C-nucleophiles via substitution reactions was reported by
Ndlovu and co-workers.100
The group has investigated the effect of the substituent at
the 2-position of mono-substituted quinoxalines in the syn-
thesis of di-substituted quinoxaline derivatives via Negishi
reaction, Scheme 55.100

Arylation using haloarenes

The direct arylation of electron-withdrawing heteroarenes,
although appealing, is challenging as it requires harsh reac-
Scheme 52 Metal-free approach for Brønsted acid promoted C–H- tion conditions. Nevertheless, several efficient strategies have
alkylation of quinoxaline. been reported for the direct arylation of electron-deficient het-
eroarenes involving halogenated aryls 135, aryl boronic acids
136, and aryls 137 to access C-arylated heterocycles, as illus-
trated in Scheme 56.106–118
The direct arylation strategies for synthesizing arylated qui-
noxaline by reacting quinoxaline with iodo arenes under
different reaction conditions are illustrated in Scheme 57.106–108
A rapid microwave-assisted direct arylation of quinoxaline 1
with ortho-iodoarene 135a in the presence of potassium t-but-
oxide was reported by Yanagisawa and co-workers,
Scheme 57.106 The transition metal-free protocol furnishing
products 133 and 140 in a very short time and with good yields
are some of the advantages of this methodology; however, the
Scheme 53 The mechanism for the xanthate-based heteroaromatic poor product regioselectivity is certainly the major setback in
alkylation. its wide-scale applicability.

Scheme 51.103 The silver catalyzed Minisci reaction using

selectfluor as a mild oxidant and carboxylic acid as the alkylat-
ing source furnished the 2-alkylated quinoxaline 4 in moderate
to good yield within 24 h. The role of TFA in the reaction is to
enhance the electrophilicity of heterocycles by protonation. Scheme 54 Difluoro methylation of quinoxaline.

Org. Chem. Front. This journal is © the Partner Organisations 2021

 View Article Online

Organic Chemistry Frontiers Review

and Li/Mg/Zn amides prepared easily from the secondary

amines.107
A similar kind of metalation of quinoxaline followed by a
cross-coupling strategy to access arylated quinoxaline was
reported by Wunderlich and co-workers. A directed ortho meta-
lation employing tmp2Zn·2MgCl2·2LiCl resulted in the corres-
ponding organometallic intermediate of quinoxaline which
Published on 10 March 2021. Downloaded by University of Prince Edward Island on 5/16/2021 8:23:27 AM.

was then subjected to a Pd-catalyzed cross-coupling reaction to

furnish the arylated quinoxaline 142. Other amide bases like
Scheme 55 The Negishi cross-coupling reaction. tmpMgCl·LiCl (tmp), 2,2,6,6-tetramethylpiperidyl, tmp2Mg·
2LiCl were also found to be equally competent. Highly reactive
tmp2Mg·2LiCl was found to be an effective agent for metala-
tion of less activated aromatic substrates, Scheme 57.108
Hyodo and co-workers developed a highly regioselective
nickel catalyzed oxidative nucleophilic arylation strategy for
the arylation of electron-deficient heteroarenes with good
yield. The regioselectivity, as well as substrate scope, comple-
mented the well-known direct arylations strategy as well as the
CMD pathway. The methodology avoided the use of any exter-
nal oxidants as the organozinc reagent functions both as an
Scheme 56 Schematic routes for the direct arylation of quinoxaline. aryl donor and an oxidant. Yields obtained from this reaction
at 80 °C were 66% with both mono and diaryl products,
whereas at 100 °C only diaryl product was obtained in 74%,
Scheme 58.109
Sakurai developed a method for decarbonylative direct ary-
lation using acyl fluorides 144 to furnish the arylated product
146 in 65% yield. An iridium(I) complex together with a
BrettPhos ligand served as an effective catalytic system for this
reaction. Therefore, the methodology only worked with acyl
fluorides 144, indicating the key role of fluorine in the acti-
vation of the C–H bond. However, the applicability of the pro-
tocol to acyl fluorides and not to other halo-fluorides is the
limitation of this methodology, Scheme 59.110
An electrochemical arylation protocol through reductive
activation of electro-deficient arenes and reacting with aryl dia-
zonium tetrafluoroborate 147 acting as an aryl source was
developed by Wang and co-workers. Cyclic voltammetry
studies revealed that both quinoxaline and aryl diazonium salt
had relatively low reduction potential, thereby proposing that
their activation could be via their reduction in the reaction,
Scheme 60.111
The mechanism for the electrochemical pathway is high-
lighted in Scheme 60. The reaction was initiated by the electro-

Scheme 57 Direct arylation of quinoxaline involving aryl halide as the

coupling component.

Later, a chemoselective direct arylation of quinoxaline was

reported by Rohbogner and co-workers, Scheme 57.107 The
one-pot chemoselective metalation (zincation or magnesiation)
of quinoxaline and subsequent cross-coupling with aryl iodide
in the presence of Pd-catalysts furnished quinoxaline 141 in
good yield and excellent selectivity, Scheme 57.107 The key for
the observed chemoselectivity was the directed magnesiation
or zincation of quinoxalines using a new kind of mixed Li/Mg Scheme 58 Sequential direct arylations of quinoxaline scaffold.

This journal is © the Partner Organisations 2021 Org. Chem. Front.


Review
Published on 10 March 2021. Downloaded by University of Prince Edward Island on 5/16/2021 8:23:27 AM.
Scheme 59 Iridium-catalyzed decarbonylative coupling of
fluorides with quinoxaline.
Scheme 60 Electrochemical method for the arylation of quinoxaline.
chemical reduction of the quinoxaline to generate the corres-
ponding radical cation species. Simultaneously, 4-methyl
phenyl radical 147a was also generated by the cathodic
reduction of 4-methylbenzenediazonium tetrafluoroborate 147.
Subsequent radical–radical coupling generated the 2-( p-tolyl)-
1,2-dihydro quinoxaline 147b which on oxidation at the anode
generated the aryl radical. A second single-electron-transfer
(SET) oxidation and deprotonation furnished the desired
product 148, Scheme 60.111
Arylation using boronic reagent
Direct arylation of electron-deficient quinoxaline with aryl
boronic acid allows rapid access to aryl functionalized quinoxa-
lines. Owing to the stability, nontoxicity, and compatibility with
various reaction conditions, boronic acids have been considered
as the most versatile coupling component. The age-old strategy
of using aryl boronic acid as the coupling partner has resulted
in the development of several novel protocols to gain access to
the arylated quinoxalines in good yields as highlighted in
Scheme 61.112 The substrate scope concerning the boronic acid
Org. Chem. Front.
View Article Online
Organic Chemistry Frontiers
acyl
Scheme 61 Arylation using a boronic acid reagent.
coupling partner together with the functional group compatibil-
ity are the additional features of this methodology.
The direct arylation of quinoxaline reported by Deb and co-
workers in 2013 with aryl boronic acid employing inexpensive
Fe(NO3)2 as a catalyst in presence of K2S2O8 as an oxidant furn-
ished the desired arylated product 148 in very good yield
Scheme 61.112 The one-pot operationally simple strategy
avoided the pre-functionalization of the heterocycles and toler-
ated a wide variety of functional groups.
A room temperature open flask arylation of quinoxaline 1
was reported by Singh and coworkers involving the cross-coup-
ling reaction of electron-deficient quinoxaline with aryl
boronic acid in the presence of iron(II) acetylacetonate, oxidant
K2S2O8, and phase-transfer catalyst (TBAB). The mono-arylated
quinoxaline was obtained in good yield within 12 h at room
temperature, Scheme 61.113
The enhanced stability of the potassium organotrifluorobo-
rates over their corresponding boronic acids is because of the
lack of empty p-orbitals, thereby making them robust, easy to
handle, and stable under harsh reaction conditions. Their
operational ease and enhanced stability have prompted a few
of the research groups to employ potassium organotrifluorobo-
rates as the coupling partners for the direct arylation of qui-
noxalines as highlighted in Scheme 61.
Molander et al. reported the direct alkylation of various het-
eroaryls using a stoichiometric amount of potassium alkyl-
and alkoxymethyl trifluoroborates as nucleophilic radical pre-
cursors, Scheme 62.114
Matsui and group employed mesityl acridinium perchlorate
as a photocatalyst for the synthesis of 2-heteroaryl-substituted
4-chromanones 154. The reaction involved a photoredox cata-
lyzed coupling between 2-trifluoroborato-4-chromanones and
various heteroarenes through a mechanistic pathway like the
Minisci reaction. The reaction offered a feasible route for
the radical-induced C–H functionalization of quinoxalines
leading to the arylation in good chemo- and regioselectivity,
Scheme 62.115
This journal is © the Partner Organisations 2021

Organic Chemistry Frontiers
Published on 10 March 2021. Downloaded by University of Prince Edward Island on 5/16/2021 8:23:27 AM.
Scheme 62 Direct arylation of quinoxalines
organotrifluoroborates.
Arylation via C–H activation strategy
Direct functionalization of heteroarenes through C–H bond
activation is a highly attractive strategy. Moreover, C–H acti-
vation has been a promising approach for functionalization of
the quinoxaline core, expanding the chemical space and pro-
ducing innovative compounds. The reported C–H activation
strategies to functionalize the C2 and C3 positions of quinoxa-
lines are highlighted in Scheme 63.116–118
Ren and co-workers have developed a Pd-catalyzed strategy
for the regioselective C2-arylation of unmodified quinoxaline 1
with 1,2-dichlorobenzene 155 using Ag2CO3 and O2 oxidants,
albeit in low yields of 24%, Scheme 63.116 The authors have
suggested a mechanistic pathway for the direct arylation of
unmodified quinoxaline with an arene, Scheme 64.116 It was
Scheme 63 Direct C–H activation methods for the synthesis of
quinoxaline.
This journal is © the Partner Organisations 2021
View Article Online
Review
Scheme 64 The mechanism for palladium-catalyzed C-2 selective
using arylation.
proposed that the formation of the palladium(II) complex with
the quinoxaline will lead to the palladium migration to the C2
center of the quinoxaline 158a. Subsequent palladation will
generate the intermediate 158b. Simultaneously, electrophilic
palladation of the dichlorobenzene through the C–H activation
will generate the intermediate 158c which will then undergo
reductive elimination to afford the desired product 158. The
subsequent oxidation of the Pd(0) to Pd(II) by the Ag(I)/PivOH/
O2 completes the catalytic cycle, Scheme 64.116
Chen demonstrated a novel method to access heteroarenes
by the direct coupling of quinoxaline with pyrrole and its
derivatives taking advantage of the cooperative actions of
iridium and NaOTf, Scheme 63.117 The high regioselectivity in
terms of achieving the mono-arylated product along with high
yield and atom economy were claimed as the beneficial fea-
tures of this methodology. The proposed mechanism high-
lighted in Scheme 65 117 discloses the course of the reaction
along with the origin of high selectivity. The proposed mecha-
nism suggested the formation of a complex between the het-
eroarene and iridium catalyst via the β-metalation pathway.
Simultaneously, the coordination of NaOTf to the quinoxaline
afforded the corresponding triflate salt of the quinoxaline 1a.
The insertion of the carbon-iridium bond into the imino bond
Scheme 65 The general mechanism for iridium catalyzed cross-coup-
ling reaction for the arylation of heteroarenes.
Org. Chem. Front.

Review
and subsequent β-hydride elimination generated the desired
product 159. Finally, the interaction of HX with [HIrIIIX2L3]
regenerated the catalyst with the release of the H2 gas.
In 2017, Quattrini and group developed facile sunlight-
induced derivatization of heteroaromatics via photocatalyzed
C–H functionalization of the alkylating agent using tetra-
butylammonium decatungstate (TBADT) photocatalyst.
Published on 10 March 2021. Downloaded by University of Prince Edward Island on 5/16/2021 8:23:27 AM.
Cyclohexane was used as a hydrogen donor as it has the stron-
gest C–H bond (95 kcal mol−1). The drawback of the proposed
method is that it gives a mixture of mono and disubstituted
products instead of giving monosubstituted products alone,
Scheme 63.118
Scheme 66 Mechanistic pathway for the photocatalytic cross-dehy-
drogenative coupling of quinoxalines.
Scheme 67 C–C, C–N, C–P bond formation strategies of quinoxaline N-oxide.
Org. Chem. Front.
View Article Online
Organic Chemistry Frontiers
The mechanistic pathway is detailed in Scheme 66,118
where the authors proposed a homolytic cleavage of the C–H
bond initiated by the excited TBADT and subsequent oxidation
of the photocatalyst by K2S2O8, liberating an equivalent of acid
along with a strong oxidant (SO4•−). The generated cyclohexyl
radical was trapped by the protonated quinoxaline 1a leading
to the formation of the desired derivative following the oxi-
dation by the strong oxidant (SO4•–), Scheme 66.
Reactions using N-oxide
Quinoxaline N-oxide belongs to a notable class of intermedi-
ates which provide regioselective access to several synthetic
intermediates that otherwise cannot be accessed by the direct
functionalization of quinoxaline. Several regioselective trans-
formations to selectively functionalize the C2-positions of qui-
noxaline have been achieved and are highlighted in
Scheme 67.119–123
Leclerc and co-workers reported a cross-coupling strategy
that involved the use of quinoxaline N-oxide 90 as an in-
expensive, bench stable reagent for the palladium-catalyzed
direct arylation with halo arenes involving Pd(OAc)2·tBu3PHBF4
in very good yields, Scheme 67.119
Transition metal-catalyzed Cross Dehydrogenative Coupling
(CDC) reactions of quinoxaline N-oxide and allied heterocycles
are known to construct C–C bonds. However, the construction
of a C–N bond via a CDC strategy was considered challenging
until the report by Li and co-workers in 2013. Li achieved C–H,
N–H dehydrogenative coupling of quinoxaline N-oxide with
lactams/cyclic amines in the presence of the Cu(OAc)2 catalyst
to afford the dehydrogenative amidation of quinoxaline
N-oxide in excellent yield, Scheme 67.120
This journal is © the Partner Organisations 2021

Organic Chemistry Frontiers
Published on 10 March 2021. Downloaded by University of Prince Edward Island on 5/16/2021 8:23:27 AM.
Scheme 68 Mechanistic pathway for the amidation of quinoxaline
N-oxide.
The mechanistic pathway is highlighted in Scheme 68.120
Metalation of heterocyclic N-oxide with Cu(OAc)2 generates an
intermediate 90a that reacts with amide followed by oxidation
using Ag2CO3 to form a metal complex 90c. The metal complex
then undergoes reductive elimination to release CuIOAc and
forms the final product 90d. Subsequently, CuIOAc gets oxi-
dized by Ag2CO3 to generate the active catalyst which then
initiates the catalytic cycle, Scheme 68.120
Realizing the fact that metal-free reactions have a great
impact on environmental remediation as well as cost
reduction, Bering and co-workers reported oxidant- and metal-
free regioselective cross-coupling of quinoxaline N-oxides with
aryl boronic acids to access 2-arylated quinoxaline 133 in a low
yield of 38%, Scheme 67.121 The authors suggested a plausible
mechanistic pathway where the coordination of the aryl
boronic acid with the quinoxaline nitrogen leads to the inter-
mediate 136a. Subsequent aryl migration from the intermedi-
ate 136a via a nucleophilic attack on C2 position of quin-
oxaline results in the formation of 2-arylated quinoxaline,
Scheme 69.121
Scheme 69 Mechanistic pathway for the C-2 arylation of quinoxaline
N-oxide with boronic acid.
This journal is © the Partner Organisations 2021
View Article Online
Review
Li and co-workers reported a copper acetate mediated direct
amination of quinoxaline N-oxide in the presence of Ag2CO3
and tBuOH via a C–H activation strategy employing O-benzoyl
hydroxylamine 166 as an electrophilic amination reagent,
Scheme 67.122 The electrophilic amidation initiates with the for-
mation of catalytically active species by reducing Cu(II) to Cu(I)
followed by complexation with the solvent. After that, metalliza-
tion leads to the generation of aryl copper complex 90e which is
then added to O-benzoyl hydroxylamine 166 to form an inter-
mediate 90f. Subsequently, this intermediate then undergoes
reductive elimination to release Cu(I)OBz and the final product
167. Finally, ligand exchanges the solvent and regenerates the
catalytic species to repeat the catalytic cycle, Scheme 70.120
A phosphonate group has been successfully introduced into
the C2 positions of quinoxaline in a very good yield of 85% by
the process described by Chen and co-workers employing
in situ activation of P(OR)3 with bromotrichloromethane under
mild conditions in the absence of solvent and metal catalysts,
Scheme 67.123 Excellent compatibility with a wide range of
functional groups, low operational cost, and scalability of the
process along with the easy availability of reagents made that
methodology a prominent complement to the well-known
Hirao coupling (synthesis of aryl phosphonates from haloar-
enes ArX (X = Br, I) by palladium catalyst).
trans-Styrylquinoxalines can be considered as isosteres of
stilbenes, which are widely present in natural compounds exhi-
biting a wide range of biological activities. Appropriate chemical
modification strategies for this core could be useful for medic-
inal chemistry applications. Franco achieved the efficient alke-
nylation of quinoxaline N-oxide via Pd-catalyzed C–H activation,
using the assistance of a mono-N-protected amino acid.
Quinoxaline N-oxide proved to be an ideal substrate for the
Fujiwara-Moritani coupling and offered enhanced reactivity at
the center ortho to the N-oxide functionality, Scheme 71.124
The mechanistic pathway highlights that the palladium(II)
acetate forms a complex with the N-protected amino acid at
Scheme 70 Mechanistic pathway for the electrophilic amination reac-
tion of quinoxaline N-oxide.
Org. Chem. Front.

Review
Published on 10 March 2021. Downloaded by University of Prince Edward Island on 5/16/2021 8:23:27 AM.
Scheme 71 Palladium-catalyzed C–H alkenylation of quinoxaline
N-oxide and proposed mechanism for quinoxaline N-oxide alkenylation
by the Fujiwara-Moritani reaction.
the beginning utilizing both the –NH and carboxylate groups
to coordinate with the Pd center in a bidentate fashion.
Subsequently, this Pd-complex coordinates with the oxygen at
the N-oxide, and reversible ligand exchange occurs by a con-
certed metalation/deprotonation (CMD) pathway. The complex
formation is relatively facile because of the hydrogen-bond
between the acetic acid ligand and the anionic oxygen. Finally,
coordination of Pd to the styrene, followed by carbopalladation
leads to the quinoxaline, Scheme 71.124
Accessing 2-substituted aminoquinoxaline 173 via a conven-
tional route will be a two-step process involving halogenation
followed by amination. However, a one-pot metal-free reductive
amination of quinoxaline N-oxides with acyl azides 172 to
access 2-substituted amino quinoxalines 173 was reported by
Kim and co-workers. The key step is the Curtius rearrangement
which leads to the formation of isocyanate intermediate 172a
from acyl azides thereafter undergoing a [3 + 2] dipolar cyclo-
addition reaction with quinoxaline N-oxides to afford the
2-substituted amino quinoxalines 173, Scheme 72.125
Apart from the direct C-2 arylation/alkylation of quinoxa-
line, nucleophilic substitution with C-centered nucleophiles is
also an interesting strategy to functionalize the quinoxaline at
the C-2 position. Substitution of quinoxalines with C-centered
nucleophiles was reported by Azev simply by treating quinoxa-
Org. Chem. Front.
View Article Online
Organic Chemistry Frontiers
Scheme 72 Deoxygenative C–H amination reaction and the mechanis-
tic pathway highlighting C–H amination via [3 + 2] cycloaddition.
line or its 6,7-difluoro derivative with С-nucleophiles in pres-
ence of conc. HCl under nitrogen atmosphere. Along with the
substituted product 174, the formation of bisquinoxaline 175
was also observed in a low yield of 11%, Scheme 73.126
An alternative route to access N,N’-diquaternised-3,3′-biqui-
noxalinium ions was reported by Leblanc and co-workers via
the oxidative radical coupling of dithionite reduced quinoxa-
line quaternary salts. Although the methodology furnished the
product in moderate yield as well as poor regioselectivity, the
scalability of the reaction and the involvement of inexpensive
reagents with no purification requirements were claimed to be
the advantages of this reported process, Scheme 74.127
The route to the electrophilic nitration of quinoxaline was
disclosed by Juarez-Ornelas and co-workers employing iodosyl-
benzene, which behaved as a nontoxic and iodine(III)-based
organocatalyst in conjunction with Al(NO3)3 acting as the
nitrate source, Scheme 75.128 The mechanistic pathway
depicted in Scheme 75 proposes the formation of Al-complex
obtained by the coordination of iodosylbenzene to aluminum
nitrate followed by [3,3] cycloaddition to yield an intermediate
having iodine(III)-nitrate bonds.
Thereafter, decomposition of the intermediate to release
the NO2+ was accompanied by the regeneration of the NO2+
which readily attacked the naphthol 179 or quinoxaline 1 and
Scheme 73 Direct nucleophilic substitution and dimerization of
quinoxaline.
This journal is © the Partner Organisations 2021

Organic Chemistry Frontiers
Published on 10 March 2021. Downloaded by University of Prince Edward Island on 5/16/2021 8:23:27 AM.
Scheme 74 Synthesis of N,N’-diquaternised biquinoxen dications and
the mechanism of oxidative radical homocoupling for the synthesis of
N,N‘-diquaternised biquinoxen dications.
Scheme 75 Nitration of quinoxaline and the mechanism for PhIO cata-
lyzed electrophilic nitration.
transferred a proton to the OAl(NO3)2 anion to afford nitrated
product 180 or 178, respectively.
Reduction
Tetrahydroquinoxaline 184 derivatives are abundant in natural
products as well as in medicinal chemistry. Therefore, the
direct reduction of quinoxalines represents one of the most
frequently adopted strategies for the preparation of tetrahydro-
quinoxalines in one step. Several methodologies for this one-
step transformation have been developed in the last two
decades employing several catalytic systems which are high-
lighted in Table 8.
A quick perusal of the several conditions listed in Table 8
confirms that most of the protocols relied on the transfer
hydrogenation strategy where the dihydrogen equivalent is
transferred from an alcoholic source to quinoxaline. Transfer
hydrogenation, therefore, is a useful industrial strategy that
This journal is © the Partner Organisations 2021
View Article Online
Review
offers the advantage of an easy setup and mild reaction con-
ditions contrary to the direct hydrogenation with hydrogen gas.
In 1981, quinoxaline was reduced to corresponding 1,2,3,4-
tetrahydro quinoxaline using bis(trifluoroacetoxy) borane-tetra-
hydrofuran in TFA/THF. The important feature of this catalyst
is its stability in TFA to allow its employment as a reducing
agent (entry 1, Table 8).129
Ranu and group used catalytic amounts of N,N-dimethyl
aniline, and zinc borohydride in DME under sonication for the
reduction of quinoxaline (entry 2, Table 8).130
McKinney used borane in THF solution for the reduction of
mono and di-substituted alkyl and aryl quinoxaline. It was
observed that the di-substituted compounds exclusively
yielded cis-isomer (entry 3, Table 8).131 Reduction of alkyl and
aryl quinoxalines was also achieved using sodium borohydride
in acetic acid; however, this resulted in diminished product
yields along with side products. Borane-THF complex was
found to be a superior reagent to render products in high
yields in a short duration.
Tan and co-workers developed a new catalytic system by
combining [Cp*IrCl2]2 with N-(2-aminoethyl)-4-(trifluoro-
methyl)benzenesulfonamide 185 in situ for regio- and chemo-
selective transfer hydrogenation of a variety of quinoxalines in
water employing HCOONa as the hydrogen source (entry 4,
Table 8). The catalyst was found to be air-stable and reduction
was performed without the protection of the nitrogen in an
acidic medium. The use of the HOAc/NaOAc buffer solution
was found to be essential for maintaining a stable pH during
the reaction, Scheme 76.132
Wu and coworkers developed iodine promoted transfer
hydrogenation in the presence of [(Cp*RhCl2)2] using KI as a
promotor and formic acid ( pKa 3.6) as the reductant by
heating in an azeotropic mixture of HCO2H/NEt3 at 40 °C. This
methodology could help to reduce the metal loading without
affecting the reaction conversion (entry 5, Table 8).133
A catalytic system comprising (pentamethylcyclopentadienyl)
rhodium dichloride dimer [Cp*RhCl2]2 in conjunction with 2,2′-
bipyridine (bpy) was reported by Zhang and co-workers for
transfer hydrogenation of quinoxalines under aqueous con-
ditions employing formate as the hydrogen source (entry 6,
Table 8). The choice of the ligand was found to be critical and
acidic pH is critical for optimal aqueous phase reduction,
Scheme 77.134
The mechanistic pathway highlighted in Scheme 77 indi-
cates the in situ formation of the formate complex with [Cp*Rh
(bpy)Cl]Cl 187, followed by the rhodium hydride generation
from the decarboxylation of formate complex and subsequent
transfer to the protonated substrate 15a to furnish the target
tetrahydroquinoxaline 186 in good yield.
The solvent has an important role to play in influencing the
reaction rate and selectivity of the catalytic hydrogenation reac-
tion. Sun used a new catalyst containing metallic ruthenium
nanoparticles intercalated in hectorite (nano-Ru′@hectorite) to
catalyze the reduction by NaBH4 in an aqueous solution under
self-generated pressure. The catalyst can be recycled by cen-
trifugation (entry 7, Table 8).135
Org. Chem. Front.
 View Article Online

Review Organic Chemistry Frontiers

Table 8 List of reaction conditions for the reduction of quinoxaline to access tetrahydroquinoxaline
Published on 10 March 2021. Downloaded by University of Prince Edward Island on 5/16/2021 8:23:27 AM.

Entry Reaction conditions % yield

1 BH[OC(O)CF3]2·THF, TFA/THF 86129

2 Zn(BH4)2/DME, N,N-dimethyl aniline, sonication, 10 h 90130
3 BH3·THF, N2 85–90131
4 [Cp*IrCl2]2 (2.5 µmol), N-(2-aminoethyl)-4-(trifluoromethyl)benzenesulfonamide (6.0 µmol), HCOONa, HOAc/NaOAc buffer, >91132
80 °C
5 [(Cp*RhCl2)2] (0.05–0.5 µmol), HCOOH/NEt3 azeotrope, KI (50 mol%), 40 °C, 12–24 h 99133
6 [(Cp*RhCl2)2] (0.025 µmol)/bpy (0.06 µmol), HCOOH/NaCOOH, H2O, 80 °C, pH 4.4, 3–12 h >90134
7 nanoRu’@hectorite, NaBH4, water, 60 °C, 4 h 99135
8 Pd(OAc)2 (10 mol%), B2pin2 (3.0 equiv.), water, N2, rt 75–80136
Pd(OAc)2 (10 mol%), B2pin2 (3.0 equiv.), Cs2CO3 (0.5 equiv.) water, N2, rt 90136
9 CoOx@CN (10 mg), MeOH, 3MPa H2, 120 °C, 10 h 77137
10 IrO2 NPs (0.04 mmol), H2 balloon, rt, 24 h 91–96138
11 B2(OH)4 (10 equiv.), 80 °C, 10 min 85139
12 PdNPs (1 mol%), water, H2 balloon, rt, 24 h 80–85140
13 Co(BF4)2·6H2O (5 mol%), tris(2-(diphenylphosphino) 88141
phenyl)phosphine (5 mol%), THF, H2 (10 bar), 60 °C, 15 h
14 Co(BF4)2·6H2O (5 mol%), tris(2-(diphenylphosphino) 90142
phenyl)phosphine (5 mol%), HCOOH (10 equiv.), dry i-PrOH, 100 °C, 20 h
15 B(C6H5)3 (5 mol%), NH3·BH3, toluene, 80 °C, 8 h 80143
16 B(C6H5)3 (5 mol%), Ph2SiH2 (5 equiv.), toluene, 110 °C, 24 h, N2 atm 78144
17 B(C6H5)3 (5 mol%), Et2SiH2 (3.5 equiv.), CHCl3, 25 °C–65 °C, 12 h, 0.25 M HCl/Et2O, Na2CO3, MeOH 80145
18 Co-NPs (5 mol%), 10 bar H2, 60 °C, 24 h 95146
19 Ru catalyst (1 mol%), t-BuOK (10 mol%), propanol, 80 °C, 24 h 70147
20 Mn catalyst (0.5 mol%), t-BuOK (5 mol%), propanol, 80 °C, 12 h 84148
21 HMPA (20 mol%), HSiCl3 (6.0 equiv.), DCM, 25 °C, 24 h 91–92149
22 Rh catalyst (1 mol%), 36 atm H2, neat, 100 °C, 48 h 92150
23 Co catalyst (0.1–3 mol%), KOH (10 mol%), i-PrOH, 30 atm H2, 100 °C, 48 h 92–95151
24 Ir catalyst (0.2 mol%), H2 (1 bar), water, 120 °C, 17 h 95152
25 Metallic Na, ammonia, t-BuOH 6579
Metallic Li, ammonia, t-BuOH 10079

Scheme 77 Possible mechanistic pathway for the transfer hydrogen-

ation of quinoxaline in water under acidic conditions.
Scheme 76 Transfer hydrogenation of 2-methylquinoxaline.

With this idea, Xuan and co-workers carried out Pd-catalyzed

Water being the most abundant, environmentally benign,
and inexpensive hydrogen-containing source in the world
could be an ideal source of hydrogen for the transfer hydro-
genation reaction. From the viewpoint of sustainable develop-
ment, water is considered the most interesting solvent because
it is not only a green solvent but also plays a promising role in
enhancing the catalyst activity.
transfer hydrogenation of various N-heteroaromatic compounds
employing air-stable and inexpensive borylating agent B2pin2 in
water which acts as a hydrogen donor (entry 8, Table 8).136
Often the presence of the N-heterocycle causes catalyst poi-
soning due to the coordination of nitrogen atoms with the
metal nanoparticles, thereby making the catalyst recyclability
difficult. Therefore, the need to design metal nanoparticles
encapsulated with a protective shield to minimize the catalyst

Org. Chem. Front. This journal is © the Partner Organisations 2021


Organic Chemistry Frontiers
leaching was highly desirable. The encapsulation of metal
nanoparticles within graphene layers opens an avenue for the
design of highly active and reusable heterogeneous catalysts
for more challenging molecules.
With that idea, Wei designed a nanomagnetic material featur-
ing nitrogen-doped carbon-coated cobalt NPs for the efficient
and selective catalytic hydrogenation of quinoxaline. The cata-
Published on 10 March 2021. Downloaded by University of Prince Edward Island on 5/16/2021 8:23:27 AM.
lytic performance was attributed to the enhanced recyclability of
the catalyst due to the protective layer between the quinoxaline
and the active metal NP along with the large surface area. The
mesoporous pores of the catalyst allow easy accessibility at the
catalytically active sites thereby allowing the catalyst to have
better contact with the reactants (entry 9, Table 8).137
Naked nanocatalysts usually exhibit higher catalytic
efficiency because of their large surface-to-volume ratio. But at
the same time, they suffer from aggregation and poor re-
usability, which impedes their applicability. However, in com-
parison with the stabilized transition metal nanocatalysts, the
naked/unsupported nanocatalysts offer a better opportunity to
comprehend the intrinsic catalytic activity more easily by the
elimination of the support effect.
Thereafter, Ji and co-workers prepared iridium(IV) oxide
nanoparticles by reacting iridium trichloride hydrate with
sodium hydroxide by ball-milling at room temperature and
employed them for the hydrogenation of a series of nitrogen
heterocycles in high yield (entry 10, Table 8). The reaction
demonstrated high efficiency and extraordinary recyclability
under mild reaction conditions.138
Boron atoms possess a strong affinity for O and N atoms
and have the propensity to activate H2O and N-heterocycles.
Encouraged by this information, in 2016 Xia and co-workers
reported diboronic acid-mediated hydrogenation of
N-heterocycles in water to access the tetrahydroquinoxaline
within 10 min in good yields, Scheme 78. Mechanistic studies
revealed the proposed reaction pathway followed an initial 1,2-
addition, where diboronic acid synergistically activated the
substrates and water via a six-membered ring transition state
188a followed by the transfer of hydrogen from H2O (entry 11,
Table 8).139
Zhang and co-workers demonstrated a mild protocol
employing carbon-metal covalent bond stabilized palladium
nanoparticles for the hydrogenation of quinoxaline in water.
The role of water is to accelerate substrate absorption and
synergistic activation of molecular hydrogen. The Pd catalyst
can be easily recovered and reused for 5 runs on the Pd nano-
particles surface (entry 12, Table 8).140
Although the homogeneous hydrogenation of arenes to
access tetrahydroarenes is difficult because of the superior
Scheme 78 Metal-free hydrogen atom transfer from water.
This journal is © the Partner Organisations 2021
View Article Online
Review
stability achieved from the aromaticity, Adam and Cabrero-
Antonino reported a general and efficient method for the
nonprecious metal homogeneous cobalt-catalyzed hydrogen-
ation of N-heterocycles to access quinoxaline in 88% yield,
under mild reaction conditions using the tetradentate ligand
tris(2-(diphenylphosphino) phenyl)phosphine and H2 balloon
(entry 13, Table 8).141 Even the authors have demonstrated that
formic acid can also be used as an inexpensive and convenient
source of hydrogen (entry 14, Table 8).142
A transition-metal-free method for the hydrogenation of
N-heterocycles to access tetrahydroquinoxaline was developed
by Ding and co-workers employing B(C6F5)3 along with
ammonia borane under mild reaction conditions. Contrary to
the frustrated Lewis pairs (FLP)-catalyzed hydrogenations
employing H2, the described method avoided the use of high-
pressure H2, thereby provided an alternative approach for the
hydrogenation of unsaturated nitrogen-containing compounds
(entry 15, Table 8).143
Liu and coworkers employed B(C6F5)3 as a reducing agent
for the efficient reduction of electron-deficient N-heteroarenes
with hydrosilanes (or hydroboranes) and amines in good
yields (entry 16, Table 8).144
Further, B(C6F5)3 was utilized by the group of Gandhamsetty
to develop a metal-free procedure for the reductive hydrogen-
ation of substituted N-heteroaromatics by using hydrosilanes as
reducing agents and heating quinoxaline in 0.25 M HCl/Et2O
mixture in MeOH at 65 °C (entry 17, Table 8).145
In 2018, Buschelberger and co-workers employed chemi-
cally stable Co(0) nanoparticles and developed a straight-
forward method for the catalytic hydrogenations of hetero-
cycles in a short time to access tetrahydroquinoxaline in good
yields. The easy catalyst recovery process together with recycl-
ability to perform multiple hydrogenations without any obser-
vable catalytic loss were the advantages of the reported proto-
col. The ease of preparing cobalt catalyst without the use of
any complex ligands, wide catalytic applicability, recyclability,
and long-term stability were claimed to be the other advan-
tages of this method (entry 18, Table 8).146
Alshakova reported the preparation of new ruthenium(II)
complexes supported by a pyrazole-phosphine ligand 189 and
its application in the synthesis via transfer hydrogenation of
various heterocycles (entry 19, Table 8).147
Dubey and coworkers developed a simple bipyridine ligated
MnI complex 190 as an efficient catalytic system for transfer
hydrogenation of quinoxalines to furnish tetrahydroquinoxa-
lines in good yield. Among the several substituted bipyridines
screened, the complex supported by dihydroxy-substituted
bipyridine was superior in catalytic activity, and the OH group
Org. Chem. Front.

Review
in bipyridine ligand 190 plays an important role in the transfer
hydrogenation step (entry 20, Table 8).148
Published on 10 March 2021. Downloaded by University of Prince Edward Island on 5/16/2021 8:23:27 AM.
Fu developed HMPA-mediated transfer hydrogenation for the
reduction of N-heteroarenes (entry 21, Table 8).149
Rhodium is known to be one of the most widely employed
metals in both homogeneous and heterogeneous transition
metals known to catalytically hydrogenate unsaturated organic
compounds.
Kim discovered additive-free hydrogenation of N-heteroarenes
using a homogeneous precatalyst [(η5-C5Me5)Rh(N–C)H] 191
(entry 22, Table 8).150
The need for the development of earth-abundant catalysts
to replace the noble metals led to the development of a highly
general and efficient method for homogeneous hydrogenation
of N-heteroarenes by Duan and co-workers in 2016. The group
has employed cobalt/tetraphosphine complex 192 to access the
Scheme 79 BTI catalyzed synthesis of quinoxaline core containing
molecules and the possible mechanistic pathway.
Table 9 Metal catalyzed alkylation of 2-methylquinoxaline
Entry Conditions
1 Fe(OAc)2 (5 mol%), 1,10-phenanthroline (6 mol%), t-BuOK, 1,4-dioxane, 140 °C, 24 h
2 Mn catalyst 201 (2 mol%), t-BuOK, t-AmOH, 140 °C, 24 h
Org. Chem. Front.
View Article Online
Organic Chemistry Frontiers
tetrahydroquinoxaline from quinoxaline in good yield display-
ing both high efficiency (up to 24 000 TON and 12 000 h−1
TOF) and excellent chemoselectivities (entry 23, Table 8).151
An iridium-based catalytic system bearing an electron-
enriched dipyridylamine ligand 193 was developed by
Wang and co-workers for the reversible hydrogenation of
N-heterocycle under mild conditions in water in the absence of
any co-catalyst or stoichiometric additives (entry 24, Table 8).152
Since one of the well-known and trivial methods for the controlled
reduction of aromatic rings is via Birch reduction, Uçar and co-
workers carried out the reduction of quinoxaline with metallic
sodium in liquid ammonia and with metallic Li and obtained
reasonably good yields of the product (entry 25, Table 8).79
Troian-Gautier reported efficient oxidation of various elec-
tron-poor quinoxaline-core-containing compounds using [bis
(trifluoroacetoxy)iodo]benzene and acetonitrile/water solvent
mixture. [Bis(trifluoroacetoxy)iodo]benzene (BTI) is an in-
expensive, hypervalent iodine system that is commercially avail-
able, easy to synthesize, and was used as an oxidant in the reac-
tion. Highly electron-poor heterocycles are normally resistant to
oxidation. However, the use of BTI made the oxidation process
facile, Scheme 79.153 The mechanistic pathway depicted in
Scheme 79 proposes a nucleophilic attack by the quinoxaline
nitrogen to the iodine atom followed by the addition of water,
leading to the intermediate 194b. The electron density on the
carbon atom is reduced compared with that of the pyridinic
core due to the presence of the second nitrogen atom, thereby
favoring the second nucleophilic attack by water, ultimately fur-
nishing the desired product 197 in good yield.153
Kabadwal et al. discovered the cost-efficient iron-catalyzed
system for the alkylation of 2-methyl quinoxalines 198 with
alcohols 199 with moderate to good yield (entry 1, Table 9).154
Recently, similar work has been reported by Jana et al.
where they explored manganese complex 201 as an efficient
% yield
up to 82%154
up to 81%155
This journal is © the Partner Organisations 2021

Organic Chemistry Frontiers
catalyst for the functionalization of 2-methylquinoxaline (entry
2, Table 9).155
Published on 10 March 2021. Downloaded by University of Prince Edward Island on 5/16/2021 8:23:27 AM.
Additionally, Zilla et al. reported a method for the functionali-
zation of quinoxaline where the authors have synthesized
2-phenoxyquinoxaline 204a and 1-phenylquinoxalin-2(1H)-one
204b in the ratio of 7 : 3 from quinoxaline-2(1H)-one. The reac-
tion proceeds via the formation of an aryne intermediate
which was generated in situ from 2-(trimethylsilyl)phenyl tri-
fluoromethane sulfonate and cesium fluoride, Scheme 80.156
The COVID pandemic situation has shaken the entire world
and the world has witnessed several publications highlighting
the design and development of molecules for the treatment of
COVID-19 disease. 2-Substituted pyrrolo[2,3-b] quinoxalines
206 was found to be a promising candidate against COVID-19.
Therefore, Chemboli et al. explored the synthesis of 2-substi-
tuted pyrrolo[2,3-b]quinoxalines 206 via the Cu-catalyzed
sequential coupling-cyclization-desulfinylation of 3-alkynyl-2-
chloroquinoxalines 205 with t-butyl sulfinamide under ultra-
sound irradiation, Scheme 81.157
Scheme 80 Reaction of different substituted (E)-3-styrylquinoxalin-2
(1H)-one derivatives with 2-(trimethylsilyl)phenyltrifluoro methane
sulfonate.
Scheme 81 Ultrasound-assisted synthesis of pyrrolo[2,3-b ]quinoxaline
derivatives.
This journal is © the Partner Organisations 2021
View Article Online
Review
Conclusions
The prominence of the quinoxaline scaffold in the areas of
medicinal chemistry, electroluminescent materials, DSSC,
molecular probes, and sensors has resulted in the upsurge of
the synthetic strategies to access quinoxaline, mildly and sus-
tainably in high yields. The necessity to decorate the scaffold
with proper functional groups to design quinoxaline-based
materials for diverse applications has reached a celestial
height. This account has presented an overview of the several
synthetic strategies to gain access to the quinoxaline scaffold
which having promising applications in the field of medicinal
chemistry, dyes, and optoelectronic materials. Routes to access
quinoxalines as well as functionalizing them have evolved
from the traditional routes to more sustainable routes invol-
ving greener catalytic systems, generating less wastes and less
energies. Despite this remarkable advancement, it is still
highly desirable to explore newer, greener, and cleaner routes
to access and decorate quinoxalines. We conclude this review
by hoping that it will benefit the readers in endowing a com-
prehensive overview about the quinoxaline chemistry and
stimulate interests in developing new catalytic methodologies
to gain access to the quinoxaline scaffold and employ those
scaffolds in designing functional molecules and materials for
diverse applications.
Conflicts of interest
The authors declare no conflicts of interest.
Acknowledgements
G.Y. is thankful to the Sarthi, Govt. of Maharashtra, India, for
her fellowship. S.S. acknowledges DST-SERB, CSIR ((02(0253)/
16/EMR-II)), UGC-Start-Up grant (FRP (F.4-5(128)/2014(BSR))),
ICT Golden Jubilee research grant (2018) and CoE-PI-TEQIP-III
for the financial assistance.
References
1 (a) Y. B. Kim, Y. H. Kim, J. Y. Park and S. K. Kim,
Synthesis and biological activity of new quinoxaline anti-
biotics of echinomycin analogues, Bioorg. Med. Chem.
Lett., 2004, 14, 541–544, DOI: 10.1016/j.bmcl.2003.09.086;
(b) A. Jaso, B. Zarranz, I. Aldana and A. Monge, Synthesis
of New Quinoxaline-2-carboxylate 1,4-Dioxide Derivatives
as Anti-Mycobacterium tuberculosis Agents, J. Med.
Chem., 2005, 48, 2019–2025, DOI: 10.1021/jm049952w;
(c) M. S. F. Franco, M. H. d. Paula, P. C. Glowacka,
F. Fumagalli, G. C. Clososki and F. d. S. Emery, Palladium-
catalyzed C–H alkenylation of quinoxaline N-oxide
enabled by a mono-N-protected amino acid, Tetrahedron
Lett., 2018, 59, 2562–2566, DOI: 10.1016/j.
tetlet.2018.05.054; (d) L. A. Raphoko, K. Lekgau,
Org. Chem. Front.

Review
C. M. Lebepe, T. C. Leboho, T. M. Matsebatlela and
W. Nxumalo, Synthesis of novel quinoxaline-alkynyl
derivatives and their anti-Mycobacterium tuberculosis,
activity, Bioorg. Med. Chem. Lett., 2021, 35, 127784, DOI:
10.1016/j.bmcl.2021.127784.
2 (a) D. W. Chang, H. J. Lee, J. H. Kim, S. Y. Park,
S.-M. Park, L. Dai and J.-B. Baek, Novel Quinoxaline-Based
Published on 10 March 2021. Downloaded by University of Prince Edward Island on 5/16/2021 8:23:27 AM.
Organic Sensitizers for DyeSensitized Solar Cells, Org.
Lett., 2011, 13(5), 3880–3883, DOI: 10.1021/ol2012378;
(b) K. Pei, Y. Wu, A. Islam, S. Zhu, L. Han, Z. Geng and
W. Zhu, Dye-Sensitized Solar Cells Based on Quinoxaline
Dyes: Effect of π–Linker on Absorption, Energy Levels, and
Photovoltaic Performances, J. Phys. Chem. C, 2014,
118(30), 16552–16561, DOI: 10.1021/jp412259t;
(c) D. N. Kanekar, S. Chacko and R. M. Kamble,
Quinoxaline based amines as Blue-orange emitters: Effect
of modulating donor system on Optoelectrochemical and
theoretical properties, Dyes Pigm., 2019, 167, 36–50, DOI:
10.1016/j.dyepig.2019.04.005; (d) S. K. Dey, M. A. Kobaisi
and S. V. Bhosale, Functionalized Quinoxaline for
Chromogenic and Fluorogenic Anion Sensing,
ChemistryOpen, 2018, 7, 934–952, DOI: 10.1002/
open.201800163; (e) A. A. Kalinin, L. N. Islamova,
A. G. Shmelev, G. M. Fazleeva, O. D. Fominykh,
Y. B. Dudkina, T. A. Vakhonina, A. I. Levitskaya,
A. V. Sharipova, A. S. Mukhtarov, A. R. Khamatgalimov,
I. R. Nizameev, Y. H. Budnikova and M. Y. Balakina, D–π-A
chromophores with a quinoxaline core in the π-bridge and
bulky aryl groups in the acceptor: Synthesis, properties,
and femtosecond nonlinear optical activity of the chromo-
phore/PMMA guest-host materials, Dyes Pigm., 2021, 184,
108801, DOI: 10.1016/j.dyepig.2020.108801; (f ) H. Yue,
X. Guo, Y. Du, Y. Zhang, H. Du, J. Zhao and J. Zhang,
Synthesis and characterization of donor–acceptor type
quinoxaline-based polymers and the corresponding elec-
trochromic devices with satisfactory open circuit memory,
Synth. Met., 2021, 271, 116619, DOI: 10.1016/j.synth-
met.2020.116619; (g) H. Wang, A. Q. Dayo, J. Wang,
J.-y. Wang and W.-b. Liu, Trifunctional quinoxaline-based
maleimide and its polymer alloys with benzoxazine:
Synthesis, characterization, and properties, J. Appl. Polym.
Sci., 2021, 138, 49694, DOI: 10.1002/app.49694.
3 G. W. H. Cheeseman and E. S. G. Werstiuk, Quinoxaline
Chemistry: Developments 1963-1975, Adv. Heterocycl.
Chem., 1978, 22, 367–431, DOI: 10.1016/S0065-2725(08)
60107-5.
4 V. A. Mamedov and N. A. Zhukova, Progress in
Quinoxaline Synthesis (Part 1), Prog. Heterocycl. Chem.,
2012, 24, 55–88, DOI: 10.1016/B978-0-08-096807-0.00002-
6.
5 V. A. Mamedov and N. A. Zhukova, Progress in
Quinoxaline Synthesis (Part 2), Prog. Heterocycl. Chem.,
2013, 25, 1–45, DOI: 10.1016/B978-0-08-099406-2.00001-7.
6 J. A. Pereira, A. M. Pessoa, M. N. D. S. Cordeiro,
R. Fernandes, C. Prudencio, J. P. Noronha and M. Vieira,
Quinoxaline, its derivatives and applications: A State of
Org. Chem. Front.
View Article Online
Organic Chemistry Frontiers
the Art review, Eur. J. Med. Chem., 2015, 97, 664–672, DOI:
10.1016/j.ejmech.2014.06.058.
7 J. M. Neri, L. N. Cavalcanti, R. M. Araujo and
F. G. Menezes, 2,3-Dichloroquinoxaline as a versatile
building block for heteroaromatic nucleophilic substi-
tution: a review of the last decade, Arabian J. Chem., 2020,
13, 721–739, DOI: 10.1016/j.arabjc.2017.07.012.
8 A. C. Shekhar, A. R. Kumar, G. Sathaiah, K. Raju,
P. V. S. S. Srinivas, P. S. Rao and B. Narsaiah, Aqueous
Hydrofluoric Acid Catalyzed Facile Synthesis of 2,3,6-
Substituted Quinoxalines, J. Heterocycl. Chem., 2014, 51(5),
1504–1508, DOI: 10.1002/jhet.1753.
9 H. R. Darabi, S. Mohandessi, K. Aghapoor and
F. Mohsenzadeh, A recyclable and highly effective sulfa-
mic acid/MeOH catalytic system for the synthesis of qui-
noxalines at room temperature, Catal. Commun., 2007, 8,
389–392, DOI: 10.1016/j.catcom.2006.06.033.
10 S. V. More, M. N. V. Sastry, C. C. Wang and C. F. Yao,
Molecular iodine: a powerful catalyst for the easy and
efficient synthesis of quinoxalines, Tetrahedron Lett., 2005,
46, 6345–6348, DOI: 10.1016/j.tetlet.2005.07.026.
11 R. S. Bhosale, S. R. Sarda, S. S. Ardhapure, W. N. Jadhav,
S. R. Bhusare and R. P. Pawar, An efficient protocol for the
synthesis of quinoxaline derivatives at room temperature
using molecular iodine as the catalyst, Tetrahedron Lett.,
2005, 46, 7183–7186, DOI: 10.1016/j.tetlet.2005.08.080.
12 M. M. Heravi, S. Taheri, K. Bakhtiari and H. A. Oskooie,
On Water: A practical and efficient synthesis of quinoxa-
line derivatives catalyzed by CuSO4.5H2O, Catal. Commun.,
2007, 8, 211–214, DOI: 10.1016/j.catcom.2006.06.013.
13 M. M. Heravi, K. Bakhtiari, H. A. Oskooie and S. Taheri,
MnCl2-Promoted Synthesis of Quinoxaline Derivatives at
Room Temperature, Heteroat. Chem., 2008, 19(2), 218–220,
DOI: 10.1002/hc.20401.
14 Z. T. Bhutia, G. Prasannakumar, A. Das, M. Biswas,
A. Chatterjee and M. Banerjee, A Facile, Catalyst-Free
Mechano-Synthesis of Quinoxalines and their In vitro
Antibacterial Activity Study, ChemistrySelect, 2017, 2,
1183–1187, DOI: 10.1002/slct.201601672.
15 S. Sajjadifar, G. Mansouri, I. Amini and M. Yari, Silica
Supported 1-(2-(Sulfooxy)ethyl)pyridin-1-ium Chloride
(SiO2/[SEP](Cl) as an Efficient and Solid Acid Catalyst for
the Synthesis of Quinoxaline Derivatives, J. Med. Chem.
Sci., 2021, 4, 8–16.
16 C. Srinivas, C. N. S. S. P. Kumar, V. J. Rao and
S. Palaniappan, Efficient, convenient and reusable polya-
niline-sulfate salt catalyst for the synthesis of quinoxaline
derivatives, J. Mol. Catal. A: Chem., 2007, 265, 227–230,
DOI: 10.1016/j.molcata.2006.10.018.
17 K. B. Harsha, S. Rangappa, H. D. Preetham,
T. R. Swaroop, M. Gilandoust, K. S. Rakesh and
K. S. Rangappa, An Easy and Efficient Method for the
Synthesis of Quinoxalines Using Recyclable and
Heterogeneous Nanomagnetic-Supported Acid Catalyst
under Solvent-Free Condition, ChemistrySelect, 2018, 3,
5228–5232, DOI: 10.1002/slct.201800053.
This journal is © the Partner Organisations 2021

Organic Chemistry Frontiers
18 K. S. Indalkar, C. K. Khatri and G. U. Chaturbhuj,
Rapid, efficient, and eco-friendly procedure for the syn-
thesis of quinoxalines under solvent-free conditions
using sulfated polyborate as a recyclable catalyst, J. Chem.
Sci., 2017, 129(2), 141–148, DOI: 10.1007/s12039-017-
1235-0.
19 B. Tamami, A. Sardarian and E. Ataollahi, Synthesis and
Published on 10 March 2021. Downloaded by University of Prince Edward Island on 5/16/2021 8:23:27 AM.
application of polyvinylimidazole-based Brønsted acidic
ionic liquid grafted silica as an efficient heterogeneous
catalyst in the preparation of quinoxaline derivatives,
Turk. J. Chem., 2016, 40, 422–433, DOI: 10.3906/kim-1504-
40.
20 U. P. Tarpada, B. B. Thummar and D. K. Raval, A green
protocol for the synthesis of quinoxaline derivatives cata-
lyzed by polymer supported sulphanilic acid, Arabian J.
Chem., 2017, 10, S2902–S2907, DOI: 10.1016/j.arabjc.
2013.11.021.
21 A. Rahmatpour, Polystyrene-Supported AlCl3 as a Highly
Active and Reusable Heterogeneous Lewis Acid Catalyst
for the One-Pot Synthesis of Quinoxalines, Heteroat.
Chem., 2012, 23(5), 472–477, DOI: 10.1002/hc.21039.
22 K. Aghapoor, F. Mohsenzadeh, A. Shakeri, H. R. Darabi,
M. Ghassemzadeh and B. Neumüller, Catalytic application
of recyclable silica-supported bismuth(III) chloride in the
benzo[N,N]-heterocyclic condensation, J. Organomet.
Chem., 2013, 743, 170–178, DOI: 10.1016/j.
jorganchem.2013.06.037.
23 V. P. Jejurkar, C. K. Khatri, G. U. Chaturbhuj and
S. Saha, Environmentally Benign, Highly Efficient and
Expeditious Solvent-Free Synthesis of Trisubstituted
Methanes Catalyzed by Sulfated Polyborate,
ChemistrySelect, 2017, 2, 11693–11696, DOI: 10.1002/slct.
201702610.
24 S. Paul and B. Basu, Synthesis of libraries of quinoxalines
through eco-friendly tandem oxidation–condensation or
condensation reactions, Tetrahedron Lett., 2011, 52, 6597–
6602, DOI: 10.1016/j.tetlet.2011.09.141.
25 C. Delpivo, G. Micheletti and C. Boga, paper A Green
Synthesis of Quinoxalines and 2,3-Dihydropyrazines,
Synthesis, 2013, 45, 1546–1552, DOI: 10.1055/s-0033-
1338441.
26 D. Bandyopadhyay, S. Mukherjee and B. K. Banik, A
Selective, Expeditious and Sustainable Entry en Route to
Benzopyrazines and bis-Benzopyrazines, Comb. Chem.
High Throughput Screening, 2015, 18, 53–62, DOI: 10.2174/
1386207318666150131125053.
27 K. J. Tamuli, S. Nath and M. Bordoloi, In Water Organic
Synthesis: Introducing Itaconic Acid as a Recyclable
Acidic Promoter for Efficient and Scalable Synthesis of
Quinoxaline Derivatives at Room Temperature,
J. Heterocycl. Chem., 2021, 58, 983–1002, DOI: 10.1002/
jhet.4231.
28 S. F. Hojati, Z. Nematdoust and T. Zeinali, The preparation
of quinoxaline and 2,3-dihydropyrazine derivatives using
selectfluor as an efficient and reusable catalyst, Iran.
Chem. Commun., 2015, 3, 6–15.
This journal is © the Partner Organisations 2021
View Article Online
Review
29 B. B. F. Mirjalili and A. Akbari, Nano-TiO2: An eco-friendly
alternative for the synthesis of quinoxalines, Chin. Chem.
Lett., 2011, 22, 753–756, DOI: 10.1016/j.cclet.2010.12.016.
30 M. J. Climent, A. Corma, J. C. Hernández, A. B. Hungría,
S. Iborra and S. Martínez-Silvestre, Biomass into chemi-
cals: One-pot two- and three-step synthesis of quinoxa-
lines from biomass-derived glycols and 1,2-dinitroben-
zene derivatives using supported gold nanoparticles as
catalysts, J. Catal., 2012, 292, 118–129, DOI: 10.1016/j.
jcat.2012.05.002.
31 T. B. Nguyen, L. Ermolenko and A. Al-Mourabit, Sodium
Sulfide: A Sustainable Solution for Unbalanced Redox
Condensation Reaction between o-Nitroanilines and
Alcohols Catalyzed by an Iron–Sulfur System, Synthesis,
2015, 47, 1741–1748, DOI: 10.1055/s-0034-1380134.
32 B. Roy, S. Ghosh, P. Ghosh and B. Basu, Graphene oxide
(GO) or reduced graphene oxide (rGO): Efficient catalysts
for onepot metal-free synthesis of quinoxalines from
2-nitroaniline, Tetrahedron Lett., 2015, 56, 6762–6767,
DOI: 10.1016/j.tetlet.2015.10.065.
33 K. B. Harsha and K. S. Rangappa, One-step Approach for
Synthesis of Functionalized Quinoxalines Mediated by
T3P® - DMSO or T3P® via Tandem Oxidation –
Condensation or Condensation Reaction, RSC Adv., 2016,
6, 57154–57162, DOI: 10.1039/C6RA03078E.
34 A. Bera, M. Sk, K. Singh and D. Banerjee, Nickel-Catalysed
Dehydrogenative Coupling of Aromatic Diamines with
Alcohols: Selective Synthesis of Substituted
Benzimidazoles and Quinoxalines, Chem. Commun., 2019,
55, 5958–5961, DOI: 10.1039/C9CC02319D.
35 P. Daw, A. Kumar, N. A. Espinosa-Jalapa, Y. Diskin-Posner,
Y. Ben-David and D. Milstein, Synthesis of Pyrazines and
Quinoxalines via Acceptorless Dehydrogenative Coupling
Routes Catalyzed by Manganese Pincer Complexes, ACS
Catal., 2018, 8, 7734–7741, DOI: 10.1021/acscatal.8b02208.
36 W. Tang, Y. Liu, S. Peng and S. Liu, Ruthenium(II) η6
-arene complexes containing a dinucleating ligand based
on 1,8-naphthyridine, J. Organomet. Chem., 2015, 775, 94–
100, DOI: 10.1016/j.jorganchem.2014.10.028.
37 B. Dowlati, D. Nematollahi and M. R. Othman, An
Efficient Electrochemical Method for the Synthesis of
Quinoxaline-dione Derivatives from Oxidation of
Catechols in the Presence of N1, N2-dibenzylethane-1,2-
diamine, J. Electrochem. Soc., 2013, 160(1), G32–G36, DOI:
10.1149/2.061301jes.
38 V. A. Samsonov, Furazan ring opening upon treatment of
benzofurazan with ethanolаmine to yield quinoxalines,
Russ. Chem. Bull., 2007, 56(12), 2510–2512.
39 B. Saha, B. Mitra, D. Brahmin, B. Sinha and P. Ghosh, 2-
Iodo benzoic acid: an unconventional precursor for the
one pot multi-component synthesis of Quinoxaline using
organo Cu(II) catalyst, Tetrahedron Lett., 2018, 59(41),
3657–3663, DOI: 10.1016/j.tetlet.2018.08.051.
40 A. Monopoli, P. Cotugno, M. Cortese, C. D. Calvano,
F. Ciminale and A. Nacci, Selective N-Alkylation of
Arylamines with Alkyl Chloride in Ionic Liquids: Scope
Org. Chem. Front.

Review
and Applications, Eur. J. Org. Chem., 2012, 3105–3111,
DOI: 10.1002/ejoc.201200202.
41 Y. Pan, C. Chen, X. Xu, H. Zhao, J. Han, H. Li, L. Xu,
Q. Fan and J. Xiao, Metal-free Tandem Cyclization/
Hydrosilylation to Construct Tetrahydroquinoxalines,
Green Chem., 2018, 20, 403–411, DOI: 10.1039/
C7GC03095A.
Published on 10 March 2021. Downloaded by University of Prince Edward Island on 5/16/2021 8:23:27 AM.
42 S. Murahashi, T. Oda, T. Sugahara and Y. Masui,
Tungstate-Catalyzed Oxidation of Tetrahydroquinolines
with Hydrogen Peroxide: A Novel Method for the
Synthesis of Cyclic Hydroxamic Acids, J. Org. Chem., 1990,
55(6), 1744–1749.
43 D. M. Karki, H. C. Araujo and J. Magolan,
Dehydroaromatization with V2O5, Synlett, 2013, 24, 1675–
1678, DOI: 10.1055/s-0033-1339277.
44 S. Chakraborty, W. W. Brennessel and W. D. Jones, A
Molecular Iron Catalyst for the Acceptorless
Dehydrogenation and Hydrogenation of N-Heterocycles,
J. Am. Chem. Soc., 2014, 136, 8564–8567, DOI: 10.1021/
ja504523b.
45 X. Cui, Y. Li, S. Bachmann, M. Scalone, A. Surkus,
K. Junge, C. Topf and M. Beller, Synthesis and
Characterization of Iron-Nitrogen-Doped Graphene/Core-
Shell Catalysts: Efficient Oxidative Dehydrogenation of
N-Heterocycles, J. Am. Chem. Soc., 2015, 137, 10652–
10658, DOI: 10.1021/jacs.5b05674.
46 A. V. Iosub and S. S. Stahl, Catalytic Aerobic
Dehydrogenation of Nitrogen Heterocycles Using
Heterogeneous Cobalt Oxide Supported on Nitrogen-
Doped Carbon, Org. Lett., 2015, 17, 4404–4407, DOI:
10.1021/acs.orglett.5b01790.
47 R. Xu, S. Chakraborty, H. Yuan and W. D. Jones,
Acceptorless, Reversible Dehydrogenation and
Hydrogenation of N-heterocycles with a Cobalt Pincer
Catalyst, ACS Catal., 2015, 5, 6350–6354, DOI: 10.1021/
acscatal.5b02002.
48 Y. Wang, C. Li and J. Huang, External ligand-free aerobic
oxidation of N, C-containing cyclic systems under Pd-cata-
lyzed conditions, Asian J. Org. Chem., 2016, 6(1), 44–46,
DOI: 10.1002/ajoc.201600465.
49 W. Zhou, P. Taboonpong, A. H. Aboo, L. Zhang, J. Jiang
and J. Xiao, A Convenient Procedure for the Oxidative
Dehydrogenation of N-Heterocycles Catalyzed by FeCl2/
DMSO, Synlett, 2016, 27, A–D, DOI: 10.1055/s-0035-
1561613.
50 M. K. Sahoo, G. Jaiswal, J. Rana and E. Balaraman,
Organo-Photoredox Catalyzed Oxidative Dehydrogenation
of N-Heterocycles, Chem. – Eur. J., 2017, 23, 14167–14172,
DOI: 10.1002/chem.201703642.
51 C. Deraedt, R. Ye, W. T. Ralston, F. D. Toste and
G. A. Somorjai, Dendrimer-Stabilized Metal Nanoparticles
as Efficient Catalysts for Reversible Dehydrogenation/
Hydrogenation of N-Heterocycles, J. Am. Chem. Soc., 2017,
139, 18084–18092, DOI: 10.1021/jacs.7b10768.
52 X. Sun, J. Zhu, Y. Xia and L. Wu, Metal-Carbon Covalent
Bonds Stabilized Palladium Nanoparticles as Expeditious
Org. Chem. Front.
View Article Online
Organic Chemistry Frontiers
Heterogeneous Catalyst for Oxidative Dehydrogenation of
N-Heterocycles, ChemCatChem, 2017, 9(13), 2463–2466,
DOI: 10.1002/cctc.201700370.
53 J. Zhang, S. Chen, F. Chen, W. Xu, G. Deng and H. Gong,
Dehydrogenation of N-Heterocycles Using Graphene
Oxide as a Versatile Metal-free Catalyst under Air, Adv.
Synth. Catal., 2017, 359, 2358–2363, DOI: 10.1002/
adsc.201700178.
54 K. Mullick, S. Biswas, A. M. Angeles-Boza and S. L. Suib,
Heterogeneous mesoporous manganese oxide catalyst for
aerobic and additive-free oxidative aromatization of
N-heterocycles, Chem. Commun., 2017, 53, 2256–2259,
DOI: 10.1039/c6cc09095h.
55 W. Zhou, D. Chen, F. Sun, J. Qian, M. He and
Q. Chen, Aerobic oxidative dehydrogenation of
N-heterocycles catalyzed by cobalt porphyrin, Tetrahedron
Lett., 2018, 59, 949–953, DOI: 10.1016/j.tetlet.2018.
01.094.
56 D. Chamorro-Arenas, U. Osorio-Nieto, L. Quintero,
L. Hernandez-García and F. Sartillo-Piscil, Selective,
Catalytic and Dual C(sp3)-H Oxidation of Piperazines and
Morpholines Under Transition Metal-Free Conditions,
J. Org. Chem., 2018, 83, 15333–15346, DOI: 10.1021/acs.
joc.8b02564.
57 Q. Wang, H. Chai and Z. Yu, Acceptorless
Dehydrogenation of N–Heterocycles and Secondary
Alcohols by Ru(II)-NNC Complexes Bearing a Pyrazoyl-
indolylpyridine Ligand, Organometallics, 2018, 37, 584–
591, DOI: 10.1021/acs.organomet.7b00902.
58 Y. Li, Y. Han, Z. Wang, R. Xu, W. Zhang, W. Chen,
L. Zheng, J. Zhang, J. Luo, K. Wu, Y. Zhu, C. Chen,
Q. Peng, Q. Liu, P. Hu, D. Wang and Y. Li, Ordered Porous
N-Doping Carbon Matrix with Atomically Dispersed Co
Sites as an Efficient Catalyst for Dehydrogenation/
Transfer Hydrogenation of N-Heterocycles, Angew. Chem.,
Int. Ed., 2018, 57(35), 11262–11266, DOI: 10.1002/anie.
201805467.
59 S. Saadati, N. Ghorashi, A. Rostami and F. Kobarfard,
Laccase-based oxidative catalytic systems for the aerobic
aromatization of tetrahydroquinazolines and related
Nheterocyclic compounds under mild conditions,
Eur. J. Org. Chem., 2018, (30), 4050–4057, DOI: 10.1002/
ejoc.201800466.
60 Y. Zhang, S. Pang, Z. Wei, H. Jiao, X. Dai, H. Wang and
F. Shi, Synthesis of a molecularly defined single-active site
heterogeneous catalyst for selective oxidation of
N-heterocycles, Nat. Commun., 2018, 9(1465), 1–10, DOI:
10.1038/s41467-018-03834-4.
61 W. Zhou, Q. Tao, F. Sun, X. Cao, J. Qian, J. Xu, M. He,
Q. Chen and J. Xiao, Additive-free aerobic oxidative dehy-
drogenation of N-heterocycles under catalysis by NiMn
layered hydroxide compounds, J. Catal., 2018, 361, 1–11,
DOI: 10.1016/j.jcat.2018.01.030.
62 N. O. Balayeva, N. Zheng, R. Dillert and
D. W. Bahnemann, Visible-Light Mediated Photocatalytic
Aerobic Dehydrogenation of N-Heterocycles by Surface
This journal is © the Partner Organisations 2021

Organic Chemistry Frontiers
Grafted TiO2 and 4-Amino-TEMPO, ACS Catal., 2019, 9,
10694–10704, DOI: 10.1021/acscatal.9b03322.
63 X. Bi, T. Tang, X. Meng, M. Gou, X. Liu and P. Zhao,
Aerobic oxidative dehydrogenation of N-heterocycles over
OMS-2-based nanocomposite catalysts: preparation,
characterization and kinetic study, Catal. Sci. Technol.,
2020, 10, 360–371, DOI: 10.1039/c9cy01968e.
Published on 10 March 2021. Downloaded by University of Prince Edward Island on 5/16/2021 8:23:27 AM.
64 T. Liu, K. Wu, L. Wang and Z. Yu, Potassium tert-
Butoxide-Promoted Acceptorless Dehydrogenation of
N-Heterocycles, Adv. Synth. Catal., 2019, 361, 1–8, DOI:
10.1002/adsc.201900499.
65 S. Wang, H. Huang, C. Bruneau and C. Fischmeister,
Iridium Catalyzed Hydrogenation and Dehydrogenation of
N–Heterocycles in Water under Mild Conditions,
ChemSusChem, 2019, 12(11), 2350–2354, DOI: 10.1002/
cssc.201900626.
66 Y. Wu, Z. Chen, W. Cheong, C. Zhang, L. Zheng, W. Yan,
R. Yu, C. Chen and Y. Lia, Nitrogen-Coordinated Cobalt
Nanocrystals for Oxidative Dehydrogenation and
Hydrogenation of N-Heterocycles, Chem. Sci., 2019, 10,
5345–5352, DOI: 10.1039/C9SC00475K.
67 K. Yu, H. Zhang, C. Su and Y. Zhu, Visible-Light-Promoted
Efficient Aerobic Dehydrogenation of NHeterocycles by
Tiny Organic Semiconductor under Ambient Conditions,
Eur. J. Org. Chem., 2020, (13), 1956–1960, DOI: 10.1002/
ejoc.202000170.
68 S. Bera, A. Bera and D. Banerjee, Nickel-Catalyzed
Dehydrogenation of N-Heterocycles Using Molecular
Oxygen, Org. Lett., 2020, 22, 6458–6463, DOI: 10.1021/acs.
orglett.0c02271.
69 F. Xie, G. Lu, R. Xie, Q. Chen, H. Jiang and M. Zhang,
MOF-Derived Subnanometer Cobalt Catalyst for Selective
C-H Oxidative Sulfonylation of Tetrahydroquinoxalines
with Sodium Sulfinates, ACS Catal., 2019, 9, 2718–2724,
DOI: 10.1021/acscatal.9b00037.
70 S. Murata, T. Sugimoto and S. Matsuura, A Novel Ring
Formation Of 1,2-Dihydroquinoxalines, Heterocycles, 1987,
26(4), 883–884.
71 S. Antoniottia and E. Dunach, Direct and catalytic
synthesis of quinoxaline derivatives from epoxides and
ene-1,2-diamines, Tetrahedron Lett., 2002, 43, 3971–
3973.
72 E. C. Taylor, C. A. Maryanoff and J. S. Skotnicki,
Heterocyclization with Cyano and Sulfonyl Epoxides.
Preparation of Quinoxalines and Tetrahydroquinoxalines,
J. Org. Chem., 1980, 45, 2512–2515.
73 G. Srikanth, K. V. S. Ramakrishna and G. V. M. Sharma,
A Double Activation Method for the Conversion of
Vinyl Epoxides into vic-Amino Alcohols and Chiral
Benzoxazine/Quinoxaline Derivatives, Org. Lett., 2015,
17(18), 4576–4579, DOI: 10.1021/acs.orglett.5b02304.
74 M. S. Tu, H.-W. Xu, W. Fan, B. Jiang and S. J. Tu, [4 + 2]
Heterocyclization for Efficient Formation of Substituted
Quinoxalines through Carbon–Oxygen Bonds Cleavage,
J. Heterocycl. Chem., 2015, 52(3), 719–725, DOI: 10.1002/
jhet.2128.
This journal is © the Partner Organisations 2021
View Article Online
Review
75 A. Vidal-Albalat, S. Rodríguez and F. V. González,
Nitroepoxides as Versatile Precursors to 1,4-Diamino
Heterocycles, Org. Lett., 2014, 16, 1752–1755, DOI:
10.1021/ol500444z.
76 M. M. Ibrahim, D. Grau, F. Hampel and S. B. Tsogoeva,
α-Nitro Epoxides in Organic Synthesis: Development of a
One-Pot Organocatalytic Strategy for the Synthesis of
Quinoxalines, Eur. J. Org. Chem., 2014, (7), 1401–1405,
DOI: 10.1002/ejoc.201301591.
77 T. I. Filyakova, A. Ya. Zapevalov, M. I. Kodess,
P. A. Slepukhin and V. I. Saloutin, Perfluoroepoxyoxolanes
in the Synthesis of Fluorine-Containing Heterocycles,
Russ. J. Org. Chem., 2009, 45(6), 884–889, DOI: 10.1134/
S1070428009060141.
78 L. V. Saloutina, A. Y. Zapevalov, V. I. Saloutin,
M. I. Kodess, V. E. Kirichenko, M. G. Pervova and
O. N. Chupakhin, Reactions of epoxide derived from
internal perfluoroolefins, with o-phenylene diamine and
2-aminophenol, Russ. J. Org. Chem., 2006, 42(4), 558–566,
DOI: 10.1134/S1070428006040130.
79 S. Uçar, S. Essiz and A. Dastan, Bromination of
Quinoxaline and Derivatives: Effective Synthesis of Some
New Brominated Quinoxalines, Tetrahedron, 2017, 73,
1618–1632, DOI: 10.1016/j.tet.2017.02.014.
80 Z. Dong, W. Zhu, Z. Zhang and M. Li, An efficient and
mild ortho-zincation of aromatics and heterocycles by
using TMP2Mg2LiCl in the presence of ZnCl2,
J. Organomet. Chem., 2010, 695, 775–780, DOI: 10.1016/j.
jorganchem.2009.12.016.
81 V. L. Blair, D. C. Blakemore, D. Hay, E. Hevia and
D. C. Pryde, Alkali-metal mediated zincation of
N-heterocyclic substrates using the lithium zincate
complex, (THF)Li(TMP)Zn(tBu)2 and applications in
in situ cross coupling reactions, Tetrahedron Lett.,
2011, 52, 4590–4594, DOI: 10.1016/j.tetlet.2011.
06.090.
82 (a) G. Liu, Transition Metal-Catalyzed Fluorination of
Multi Carbon-Carbon Bonds: New Strategies for
Fluorinated Heterocycles, Org. Biomol. Chem., 2012, 10,
6243–6248, DOI: 10.1039/C2OB25702E; (b) X.-G. Hu and
L. Hunter, Stereoselectively fluorinated N-heterocycles: a
brief survey, Beilstein J. Org. Chem., 2013, 9, 2696–2708,
DOI: 10.3762/bjoc.9.306; (c) D. DesMarteau, Fluorinated
Heterocyclic Compounds: Synthesis, Chemistry, and
Applications, J. Am. Chem. Soc., 2010, 132(9), 3229–3230,
DOI: 10.1021/ja100496w.
83 R. D. Chambers, M. Parsons, G. Sandford, C. J. Skinner,
M. J. Atherton and J. S. Moilliet, Elemental fluorine. Part
10.1 Selective fluorination of pyridine, quinoline and qui-
noxaline derivatives with fluorine–iodine mixtures,
J. Chem. Soc., Perkin Trans. 1, 1999, 1, 803–810, DOI:
10.1039/A809838G.
84 P. S. Fier and J. F. Hartwig, Selective C-H Fluorination of
Pyridines and Diazines Inspired by a Classic Amination
Reaction, Science, 2013, 342(6161), 956–960, DOI: 10.1126/
science.1243759.
Org. Chem. Front.

Review
85 N. Hirasawa, Y. Takahashi, E. Fukuda, O. Sugimoto and
K. Tanji, Indium-mediated dehalogenation of haloheter-
oaromatics in water, Tetrahedron Lett., 2008, 49, 1492–
1494, DOI: 10.1016/j.tetlet.2007.12.116.
86 E. Fukuda, Y. Takahashi, N. Hirasawa, O. Sugimoto and
K. Tanji, Dehalogenation And Barbier-Type
Hydroxyalkylation Of Π-Deficient Haloheterocycles Using
Published on 10 March 2021. Downloaded by University of Prince Edward Island on 5/16/2021 8:23:27 AM.
Indium, Heterocycles, 2009, 77(2), 1163–1170, DOI:
10.3987/COM-08-S(F)95.
87 G. Chelucci and S. Figus, NaBH4-TMEDA and a palladium
catalyst as efficient regio- and chemoselective system for
the hydrodehalogenation of halogenated heterocylces,
J. Mol. Catal. A: Chem., 2014, 393, 191–209, DOI: 10.1016/j.
molcata.2014.06.012.
88 A. Gevorgyan, S. Mkrtchyan, T. Grigoryan and
V. O. Iaroshenko, Application of Silicon-Initiated Water
Splitting for the Reduction of Organic Substrates,
ChemPlusChem, 2018, 83(5), 375–382, DOI: 10.1002/
cplu.201800131.
89 F. Fontana, F. Minisci, M. Claudia, N. Barbosa and
E. Vismara, Homolytic Acylation of Protonated Pyridines
and Pyrazines with a-Keto Acids: The Problem of
Monoacylation, J. Org. Chem., 1991, 56(8), 2866–2869,
DOI: 10.1021/jo00008a050.
90 N. R. Chaubey and K. N. Singh, Metal-Free
Decarboxylative Acylation of Isoquinolines using α-Keto
Acids in Water, Tetrahedron Lett., 2017, 58, 2347–2350,
DOI: 10.1016/j.tetlet.2017.04.098.
91 X. Wang and C. Zeng, Iron-catalyzed Minisci acylation of
N-heteroarenes with α-keto acids, Tetrahedron, 2019, 75,
1425–1430, DOI: 10.1016/j.tet.2019.01.060.
92 L. Guillemard, F. Colobert and J. Wencel-Delord, Visible-
light-triggered, metal- and photocatalyst-free acylation of
N-heterocycles, Adv. Synth. Catal., 2018, 360(21), 4184–
4190, DOI: 10.1002/adsc.201800692.
93 (a) L.-Y. Liu, J. X. Qiao, K.-S. Yeung, W. R. Ewing and J.,-
Q. Yu, meta C-H Arylation of Electron-Rich Arenes:
Reversing the Conventional Site-Selectivity, J. Am. Chem.
Soc., 2019, 141, 14870–14877, DOI: 10.1021/jacs.9b07887;
(b) S. A. Girard, T. Knauber and C.-J. Li, The Cross-
Dehydrogenative Coupling of Csp3H Bonds: A Versatile
Strategy for CC Bond Formations, Angew. Chem., Int. Ed.,
2013, 52, 2–29, DOI: 10.1002/anie.201304268;
(c) K. Matcha and A. P. Antonchick, Metal-Free Cross-
Dehydrogenative Coupling of Heterocycles with
Aldehydes, Angew. Chem., Int. Ed., 2013, 125(7), 2136–
2140, DOI: 10.1002/ange.201208851; (d) Z. Li and C.-J. Li,
CuBr-Catalyzed Direct Indolation of
Tetrahydroisoquinolines via Cross-Dehydrogenative
Coupling between sp3 C-H and sp2 C-H Bonds, J. Am.
Chem. Soc., 2005, 127(19), 6968–6969, DOI: 10.1021/
ja0516054; (e) F. A. H. Nasab, L. Z. Fekri, A. Monfared,
A. Hosseinian and E. Vessally, Recent advances in sulfur–
nitrogen bond formation via cross-dehydrogenative coup-
ling reactions, RSC Adv., 2018, 8, 18456–18469, DOI:
10.1039/C8RA00356D.
Org. Chem. Front.
View Article Online
Organic Chemistry Frontiers
94 J. Chen, M. Wan, J. Hua, Y. Sun, Z. Lv, W. Li and L. Liu,
TBHP/TFA Mediated Oxidative Cross-Dehydrogenative
Coupling of NHeterocycles with Aldehydes, Org. Biomol.
Chem., 2015, 13, 11561–11566, DOI: 10.1039/
C5OB01763G.
95 Y. Siddaraju and K. R. Prabhu, Transition Metal-Free
Minisci Reaction Promoted by NCS, and TBHP: Acylation
of Heteroarenes, Tetrahedron, 2016, 72, 959–967, DOI:
10.1016/j.tet.2015.12.065.
96 L. Zhang, G. Zhang, Y. Li, S. Wang and A. Lei, Synergistic
Effect of Self-assembling and Visible-light Induced the
Oxidative C-H Acylation of N-heterocyclic Aromatic
Compounds with Aldehydes, Chem. Commun., 2018, 54,
5744–5747, DOI: 10.1039/c8cc02342e.
97 R. Sharma, M. Abdullaha and S. B. Bharate, Oxidant-
Controlled C-sp2/sp3 – H Cross-dehydrogenative Coupling
of N-Heterocycles with Benzylamines, J. Org. Chem., 2017,
82, 9786–9793, DOI: 10.1021/acs.joc.7b00856.
98 S. Sultan, M. A. Rizvi, J. Kumar and B. A. Shah, Acyl rad-
icals from terminal alkynes: Photoredox-catalyzed acyla-
tion of heteroarenes, Chem. – Eur. J., 2018, 24, 10617–
10620, DOI: 10.1002/chem.201801628.
99 H. Ding, K. Xu and C. Zeng, Nickel-catalyzed electro-
chemical Minisci acylation of aromatic N-heterocycles
with a-keto acids via ligand-to-metal electron transfer
pathway, J. Catal., 2020, 381, 38–43, DOI: 10.1016/j.
jcat.2019.10.030.
100 N. T. Ndlovu and W. Nxumalo, Nucleophilic Substitution
on 2-Monosubstituted Quinoxalines Giving 2,3-
Disubstituted Quinoxalines: Investigating the Effect of the
2-Substituent, Molecules, 2016, 21(10), 1304, DOI: 10.3390/
molecules21101304.
101 Y. Zeng, B. Qian, Y. Li and H. Bao, A Metal-Free Approach
for Brønsted Acid Promoted C–H Alkylation of
Heteroarenes with Alkyl Peroxides, Synthesis, 2018, 50,
3250–3256, DOI: 10.1055/s-0037-1609965.
102 V. L. Revil-Baudard, J. Vors and S. Z. Zard, Xanthate-
Mediated Incorporation of Quaternary Centers into
Heteroarenes, Org. Lett., 2018, 20, 3531–3535, DOI:
10.1021/acs.orglett.8b01299.
103 J. D. Galloway, D. N. Mai and R. D. Baxter, Silver-Catalyzed
Minisci Reactions Using Selectfluor as a Mild Oxidant,
Org. Lett., 2017, 19, 5772–5775, DOI: 10.1021/acs.
orglett.7b02706.
104 X. Xie, Y. Zhang, J. Hao and W. Wan, Ag-catalyzed Minisci
C-H difluoromethylarylation of N-heteroarenes, Org.
Biomol. Chem., 2020, 18, 400–404, DOI: 10.1039/
C9OB02586C.
105 M. A. Lytkina, E. V. Eliseenkov, V. P. Boyarskii and
A. A. Petrov, Sodium Difluoromethanesulfinate—A
Difluoromethylating Agent toward Protonated
Heterocyclic Bases, Russ. J. Org. Chem., 2017, 53(4), 539–
546, DOI: 10.1134/S1070428017040066.
106 S. Yanagisawa, K. Ueda, T. Taniguchi and K. Itami,
Potassium t-Butoxide Alone Can Promote the Biaryl
Coupling of Electron-Deficient Nitrogen Heterocycles and
This journal is © the Partner Organisations 2021

Organic Chemistry Frontiers
Haloarenes, Org. Lett., 2008, 10(20), 4673–4676, DOI:
10.1021/ol8019764.
107 C. J. Rohbogner, S. H. Wunderlich, G. C. Clososki and
P. Knochel, New Mixed Li/Mg and Li/Mg/Zn Amides for
the Chemoselective Metallation of Arenes and
Heteroarenes, Eur. J. Org. Chem., 2009, 1781–1795, DOI:
10.1002/ejoc.200801277.
Published on 10 March 2021. Downloaded by University of Prince Edward Island on 5/16/2021 8:23:27 AM.
108 S. H. Wunderlich, C. J. Rohbogner, A. Unsinn and
P. Knochel, Scaleable Preparation of Functionalized
Organometallics via Directed Ortho Metalation Using Mg-
and Zn-Amide Bases, Org. Process Res. Dev., 2010, 14, 339–
345, DOI: 10.1021/op9002888.
109 I. Hyodo, M. Tobisu and N. Chatani, Catalytic Arylation of
a CH Bond in Pyridine and Related Six-Membered
N-Heteroarenes Using Organozinc Reagents, Chem. –
Asian J., 2012, 7(6), 1357–1365, DOI: 10.1002/
asia.201100971.
110 S. Sakurai, T. Yoshida and M. Tobisu, Iridium-Catalyzed
Decarbonylative Coupling of Acyl Fluorides with Arenes
and Heteroarenes via C-H Activation, Chem. Lett., 2019,
48(2), 94–97, DOI: 10.1246/cl.180857.
111 P. Wang, Z. Yang, Z. Wang, C. Xu, L. Huang, S. Wang,
H. Zhang and A. Lei, Electrochemical Arylation of
Electron-Deficient Arenes through Reductive Activation,
Angew. Chem., Int. Ed., 2019, 131(44), 15894–15898, DOI:
10.1002/anie.201909600.
112 A. Deb, S. Manna, A. Maji, U. Dutta and D. Maiti, Iron-
Catalyzed Direct C–H Arylation of Heterocycles and
Quinones with Arylboronic Acids, Eur. J. Org. Chem., 2013,
(24), 5251–5256, DOI: 10.1002/ejoc.201300743.
113 P. P. Singh, S. K. Aithagani, M. Yadav, V. P. Singh and
R. A. Vishwakarma, Iron catalyzed cross coupling of elec-
tron-deficient heterocycles and quinone with organoboron
species via innate C-H functionalization: Application in
total synthesis of pyrazine alkaloid Botryllazine A, J. Org.
Chem., 2013, 78, 2639–2648, DOI: 10.1021/jo302797r.
114 G. A. Molander, V. Colombel and V. A. Braz, Direct
Alkylation of Heteroaryls Using Potassium Alkyl- and
Alkoxymethyltrifluoroborates, Org. Lett., 2011, 13(7),
1852–1855, DOI: 10.1021/ol2003572.
115 J. K. Matsui and G. A. Molander, Organocatalyzed,
Photoredox Heteroarylation of 2–
Trifluoroboratochromanones via C–H Functionalization,
Org. Lett., 2017, 19, 950–953, DOI: 10.1021/acs.
orglett.7b00196.
116 X. Ren, P. Wen, X. Shi, Y. Wang, J. Li, S. Yang, H. Yan and
G. Huang, Palladium-Catalyzed C–2 Selective Arylation of
Quinolines, Org. Lett., 2013, 15(20), 5194–5197, DOI:
10.1021/ol402262c.
117 C. Chen, X. Chen, H. Zhao, H. Jiang and M. Zhang, Direct
Access to Nitrogen Bi-heteroarenes via Iridium-Catalyzed
Hydrogen-Evolution Cross-Coupling Reaction, Org. Lett.,
2017, 19, 3390–3393, DOI: 10.1021/acs.orglett.7b01349.
118 M. C. Quattrini, S. Fujii, K. Yamada, T. Fukuyama,
D. Ravelli, M. Fagnoni and I. Ryu, Versatile Cross-
Dehydrogenative Coupling of Heteroaromatics and
This journal is © the Partner Organisations 2021
View Article Online
Review
Hydrogen Donors via Decatungstate Photocatalysis, Chem.
Commun., 2017, 53, 2335–2338, DOI: 10.1039/
C6CC09725A.
119 J. Leclerc and K. Fagnou, Palladium-Catalyzed Cross-
Coupling Reactions of Diazine N-Oxides with Aryl
Chlorides, Bromides, and Iodides, Angew. Chem., Int. Ed.,
2006, 45, 7781–7786, DOI: 10.1002/anie.200602773.
120 G. Li, C. Jia and K. Sun, Copper-Catalyzed Intermolecular
Dehydrogenative Amidation/Amination of Quinoline N–
Oxides with Lactams/Cyclamines, Org. Lett., 2013, 15(20),
5198–5201, DOI: 10.1021/ol402324v.
121 L. Bering and A. P. Antonchick, Regioselective Metal-Free
Cross-Coupling of Quinoline N–Oxides with Boronic
Acids, Org. Lett., 2015, 17, 3134–3137, DOI: 10.1021/acs.
orglett.5b01456.
122 G. Li, C. Jia, K. Sun, Y. Lv, F. Zhao, K. Zhou and H. Wu,
Copper(II)-Catalyzed Electrophilic Amination of Quinoline
N–Oxides with O–Benzoyl hydroxylamines, Org. Biomol.
Chem., 2015, 13, 3207–3210, DOI: 10.1039/C5OB00135H.
123 M. Chen, X. You, L. Bai and Q. Luo, Metal-free phospho-
nation of heteroarene N-oxides with trialkyl phosphite at
room temperature, Org. Biomol. Chem., 2017, 15, 3165–
3169, DOI: 10.1039/c7ob00402h.
124 M. S. F. Franco, M. H. d. Paula, P. C. Glowacka,
F. Fumagalli, G. C. Clososki and F. d. S. Emery,
Palladium-catalyzed C–H alkenylation of quinoxaline
N-oxide enabled by a mono-N-protected amino acid,
Tetrahedron Lett., 2018, 59, 2562–2566, DOI: 10.1016/j.
tetlet.2018.05.054.
125 D. Kim, P. Ghosh, N. Y. Kwon, S. H. Han, S. Han,
N. K. Mishra, S. Kim and I. S. Kim, Deoxygenative
Amination of Azine-N-oxides with Acyl Azides via [3 + 2]
Cycloaddition, J. Org. Chem., 2020, 85, 2476–2485, DOI:
10.1021/acs.joc.9b03173.
126 Y. А. Azev, О. S. Ermakova, V. А. Bakulev, I. S. Kovalev,
А. N. Tsmokalyuk, А. N. Kozitsina, М. G. Pervova and
V. I. Filyakova, Features of Quinoxaline Reactions with
C-Nucleophiles: Examples of Dimerization of Heterocycle
in Course of Hydrogen Substitution, Russ. J. Gen. Chem.,
2015, 85(7), 1635–1638, DOI: 10.1134/S1070363215070105.
127 N. Leblanc, S. Sproules and A. K. Powell, An alternative
method to access diverse N,N′ -diquaternised-3,3′ -biqui-
noxalinium “biquinoxen” dications, New J. Chem., 2017,
41, 2949–2954, DOI: 10.1039/c7nj00531h.
128 K. A. Juarez-Ornelas, J. O. C. Jimenez-Halla, T. Kato,
C. R. Solorio-Alvarado and K. Maruoka, Iodine(III)-
Catalyzed Electrophilic Nitration of Phenols via
NonBrønsted Acidic NO2+ Generation, Org. Lett., 2019, 21,
1315–1319, DOI: 10.1021/acs.orglett.8b04141.
129 B. E. Maryanoff, D. F. McComsey and S. O. Nortey,
Properties of Bis(trifluoroacetoxy)borane as a Reducing
Agent of Organic Compounds, J. Org. Chem., 1981, 46,
355–360.
130 B. C. Ranu, U. Jana and A. Sarkar, Regioselective
Reduction of Quinolines and Related Systems to 1,2,3,4-
Tetrahydro Derivatives with Zinc Borohydride, Synth.
Org. Chem. Front.

Review
Commun., 1998, 28(3), 485–492, DOI: 10.1080/
00397919808005103.
131 A. M. McKinney, K. R. Jackson, R. N. Salvatore,
E.-M. Savrides, M. J. Edattel and T. Gavin, A Rapid and
Efficient Method for the Reduction of Quinoxalines,
J. Heterocycl. Chem., 2005, 42, 1031–1034.
132 J. Tan, W. Tang, Y. Sun, Z. Jiang, F. Chen, L. Xu, Q. Fan
Published on 10 March 2021. Downloaded by University of Prince Edward Island on 5/16/2021 8:23:27 AM.
and J. Xiao, pH-Regulated transfer hydrogenation of qui-
noxalines with a Cp*Irediamine catalyst in aqueous
media, Tetrahedron, 2011, 67, 6206–6213, DOI: 10.1016/j.
tet.2011.06.067.
133 J. Wu, C. Wang, W. Tang, A. Pettman and J. Xiao, The
Remarkable Effect of a Simple Ion: Iodide-Promoted
Transfer Hydrogenation of Heteroaromatics, Chem. – Eur.
J., 2012, 18(31), 9525–9529, DOI: 10.1002/
chem.201201517.
134 L. Zhang, R. Qiu, X. Xue, Y. Pan, C. Xu, H. Li and L. Xu,
Versatile (Pentamethylcyclopentadienyl)rhodium-2,2′-
Bipyridine (Cp*Rh-bpy) Catalyst for Transfer
Hydrogenation of N-Heterocycles in Water, Adv. Synth.
Catal., 2015, 357, 3529–3537, DOI: 10.1002/
adsc.201500491.
135 B. Sun, D. Carnevale and G. Süss-Fink, Selective N-cycle
hydrogenation of quinolines with sodium borohydride in
aqueous media catalyzed by hectorite-supported ruthe-
nium nanoparticles, J. Organomet. Chem., 2016, 821, 197–
205, DOI: 10.1016/j.jorganchem.2016.07.010.
136 Q. Xuan and Q. Song, Diboron-Assisted Palladium-
Catalyzed Transfer Hydrogenation of N–Heteroaromatics
with Water as Hydrogen Donor and Solvent, Org. Lett.,
2016, 18, 4250–4253, DOI: 10.1021/acs.orglett.6b01999.
137 Z. Wei, Y. Chen, J. Wang, D. Su, M. Tang, S. Mao and
Y. Wang, Cobalt encapsulated in N-doped graphene
layers: an efficient and stable catalyst for hydrogenation of
quinoline compounds, ACS Catal., 2016, 6, 5816–5822,
DOI: 10.1021/acscatal.6b01240.
138 Y. Ji, K. Wei, T. Liu, L. Wu and W. Zhang, “Naked”
Iridium(IV) Oxide Nanoparticles as Expedient and Robust
Catalysts for Hydrogenation of Nitrogen Heterocycles:
Remarkable Vicinal Substitution Effect and Recyclability,
Adv. Synth. Catal., 2016, 359(6), 933–940, DOI: 10.1002/
adsc.201601370.
139 Y. Xia, X. Sun, L. Zhang, K. Luo and L. Wu, Chem. – Eur.
J., 2016, 22, 17151–17155, DOI: 10.1002/chem.201604503.
140 Y. Zhang, J. Zhu, Y. Xia, X. Sun and L. Wu, Metal-Free
Hydrogen Atom Transfer from Water: Expeditious
Hydrogenation of N-Heterocycles Mediated by Diboronic
Acid, Adv. Synth. Catal., 2016, 358(19), 3039–3045, DOI:
10.1002/adsc.201600505.
141 R. Adam, J. R. Cabrero-Antonino, A. Spannenberg,
K. Junge, R. Jackstell and M. Beller, A General and Highly
Selective Cobalt-Catalyzed Hydrogenation of N-Heteroarenes
under Mild Reaction Conditions, Angew. Chem., Int. Ed.,
2017, 56, 1–6, DOI: 10.1002/anie.201612290.
142 J. R. Cabrero-Antonino, R. Adam, K. Junge, R. Jackstell
and M. Beller, Cobalt-catalysed Transfer Hydrogenation of
Org. Chem. Front.
View Article Online
Organic Chemistry Frontiers
Quinolines and Related Heterocycles Using Formic Acid
under mild Conditions, Catal. Sci. Technol., 2017, 7, 1981–
1985, DOI: 10.1039/C7CY00437K.
143 F. Ding, Y. Zhang, R. Zhao, Y. Jiang, R. L. Bao, K. Lin and
L. Shi, B(C6F5)3-promoted hydrogenations of N-heterocycles
with ammonia borane, Chem. Commun., 2017, 53, 9262–
9264, DOI: 10.1039/c7cc04709f.
144 Z. Liu, Z. Wen and X. Wang, B(C6F5)3-Catalyzed Cascade
Reduction of Pyridines, Angew. Chem., Int. Ed., 2017, 56,
5817–5820, DOI: 10.1002/anie.201702304.
145 N. Gandhamsetty, S. Park and S. Chang, Boron-Catalyzed
Hydrogenative Reduction of Substituted Quinolines to
Tetrahydroquinolines with Hydrosilanes, Synlett, 2017,
2396–2400, DOI: 10.1055/s-0036-1588442.
146 P. Buschelberger, E. Reyes-Rodriguez, C. Schottle,
J. Treptow, C. Feldmann, A. J. v. Wangelin and R. Wolf,
Recyclable Cobalt(0) Nanoparticle Catalysts for
Hydrogenations, Catal. Sci. Technol., 2018, 8, 2648–2653,
DOI: 10.1039/C8CY00595H.
147 I. D. Alshakova, B. Gabidullin and G. I. Nikonov, Ru-
Catalyzed Transfer Hydrogenation of Nitriles, Aromatics,
Olefins, Alkynes, and Esters, ChemCatChem, 2018, 10(21),
4860–4869, DOI: 10.1002/cctc.201801039.
148 A. Dubey, S. M. W. Rahaman, R. R. Fayzullin and
J. R. Khusnutdinova, Transfer hydrogenation of carbonyl
groups, imines and Nheterocycles catalyzed by simple,
bipyridine-based MnI complexes, ChemCatChem, 2019,
11(16), 3844–3852, DOI: 10.1002/cctc.201900358.
149 Y. Fu and J. Sun, HMPA-Catalyzed Transfer Hydrogenation
of 3-Carbonyl Pyridines and Other N-Heteroarenes with
Trichlorosilane, Molecules, 2019, 24, 401, DOI: 10.3390/
molecules24030401.
150 S. Kim, F. Loose, M. J. Bezdek, X. Wang and P. J. Chirik,
Hydrogenation of N-Heteroarenes Using Rhodium
Precatalysts: Reductive Elimination Leads to Formation of
Multimetallic Clusters, J. Am. Chem. Soc., 2019, 141,
17900–17908, DOI: 10.1021/jacs.9b09540.
151 Y. Duan, X. Du, Z. Cui, Y. Zeng, Y. Liu, T. Yang, J. Wen
and X. Zhang, Homogeneous hydrogenation with a
cobalt/tetraphosphine catalyst: a superior hydride donor
for polar double bonds and N-heteroarenes, J. Am. Chem.
Soc., 2019, 141, 20424–20433, DOI: 10.1021/jacs.9b11070.
152 S. Wang, H. Huang, C. Bruneau and C. Fischmeister,
Iridium Catalyzed Hydrogenation and Dehydrogenation of
N–Heterocycles in Water under Mild Conditions,
ChemSusChem, 2019, 12(11), 2350–2354, DOI: 10.1002/
cssc.201900626.
153 L. Troian-Gautier, J. D. Winter, P. Gerbaux and
C. Moucheron, A Direct Method for Oxidizing Quinoxaline,
Tetraazaphenanthrene, and Hexaazatriphenylene Moieties
Using Hypervalent λ3 –Iodinane Compounds, J. Org.
Chem., 2013, 78, 11096–11101, DOI: 10.1021/jo401872e.
154 L. M. Kabadwal, S. Bera and D. Banerjee, Iron-catalysed
alkylation of 2-methyl and 4-methyl azaarenes with alco-
hols via C–H bond activation, Chem. Commun., 2020, 56,
4777–4780, DOI: 10.1039/d0cc01593h.
This journal is © the Partner Organisations 2021

Organic Chemistry Frontiers
155 A. Jana, A. Kumar and B. Maji, Manganese catalyzed
C-alkylation of methyl N-heteroarenes with primary alco-
hols, Chem. Commun., 2021, 57, 3026–3029, DOI: 10.1039/
D1CC00181G.
156 M. K. Zilla, S. Mahajan, R. Khajuria, V. K. Gupta,
K. K. Kapoor and A. Ali, An efficient synthesis of
4-phenoxy-quinazoline, 2-phenoxy-quinoxaline, and
Published on 10 March 2021. Downloaded by University of Prince Edward Island on 5/16/2021 8:23:27 AM.
2-phenoxy-pyridine derivatives using aryne chemistry,
This journal is © the Partner Organisations 2021
View Article Online
Review
RSC Adv., 2021, 11, 3477–3483, DOI: 10.1039/
d0ra09994e.
157 R. Chemboli, R. Kapavarapu, K. Deepti, K. R. S. Prasad,
A. G. Reddy, A. V. D. N. Kumar, M. V. B. Rao and M. Pal,
Pyrrolo[2,3 -b, ]quinoxalines in attenuating cytokine storm
in COVID-19: their sonochemical synthesis and in silico
/in vitro assessment, J. Mol. Struct., 2021, 1230, 129868,
DOI: 10.1016/j.molstruc.2020.129868.
Org. Chem. Front.