Tandem reaction for synthesizing 2-aminopyrazines and 2-aminoquinoxalines

A reaction of 1,2-diamines and aldehydes with silyl
cyanide as cyanide pronucleophile to access
2-aminopyrazines and 2-aminoquinoxalines†
Sankar K. Guchhait,* Garima Priyadarshani‡ and Nikhil M. Gulghane‡
A new condensation reaction of ethylene-1,2-diamines or o-phenylenediamines and aromatic aldehydes
with TMSCN as a cyanide-pronucleophile is documented. The reaction proceeds through a tandem
sequence of desilylation, Strecker reaction, amidine-forming cyclization and dehydrogenative
aromatization, and provides a straightforward synthetic route to access synthetically and biologically
important motifs, 3-aryl substituted 2-aminopyrazines and 2-aminoquinoxalines. DBU with its unique
function and rate-accelerating effect has made it possible to realize a reaction that involves several
C–C/N/Si bond forming/breaking events. Interestingly, the protocol has enabled the desired tandem
pathway, switching exclusively from usual transformations.
Introduction
Trialkylsilyl cyanide in Si-hypercoordination by a Lewis base
generates a silicate intermediate that the bears potential to
release active cyanide nucleophiles. This chemical property of
especially trimethylsilyl cyanide (TMSCN) as an effective
cyanide pronucleophile has been utilized extensively, since the
rst reports by Evans1
and Lidy2
in 1973, in the cyanosilylation
reaction of carbonyl compounds. The exploitation of such
a property of TMSCN is also known in the addition to imines
(Strecker3
and Reissert reactions4
), aziridines5
(average dissoci-
ation energy of N–Si is 420 kJ molÀ1
), oxiranes,6
and nitrones.7
The multicomponent reaction (MCR)8
is a powerful tool for
exploring the synthesis of a wide range of molecular skeletons,
including heterocyclic scaffolds.9
In the direction of use of
bifunctional substrates in the MCR, although keto-acids have
received signicant attention, 1,2-diamines are relatively
underexplored.10
The reactions provide 1,4-diazaheterocycles
possessing amidine with substitutions derived from iso-
cyanides. However, the full potential of reactivity of amidine
functionality that is used in versatile reactions can be realized
only aer possibility of removal of the substitutions (e.g., by
dealkylation) of 2-secondary amine in this class of compounds,
which would allow structural diversication. Herein, we report
a new tandem multicomponent reaction of ethylenediamine or
o-phenylenediamine (OPDA) and aldehyde with trialkylsilyl
cyanide as cyanide-pronucleophile and its nitrile functionality
as an effective electrophile, which affords an efficient and direct
route to access 2-amine and 3-aryl substituted pyrazine and
quinoxaline scaffolds.
The compounds containing pyrazine or quinoxaline,
including their 2-amino derivatives are known to display a wide
range of therapeutic activities. Furthermore, 2-aminopyrazines
and 2-aminoquinoxalines are excellent synthones for
construction of versatile N-heterocycles especially via reactions
of amidine functionality and pyrazine is a valuable nucleus for
arene C–H functionalization. These heterocyclic azines are also
used as ligands in metal-complex catalysts. Despite their enor-
mous importance, surprisingly, the synthesis of 2-amino-
pyrazine is limited to classical methods (Scheme 1a). It was rst
accomplished by a classical imine-formation based condensa-
tion reaction of glyoxal with 2-aminoacetamidine.11
The intra-
molecular amidine-forming reaction via nucleophilic addition
of amine with nitrile functionality of a Schiff base obtained
from diaminomaleonitrile (DAMN) and benzoyl cyanide
towards construction of 2-aminopyrazine was reported.12
Later,
the reaction was modied by oxidative conditions for Schiff
base derived from ethylenediamine and benzoyl cyanide.13
Other methods include Chichibabin amination of pyrazine
using sodamide,14
amination of 2-halopyrazine using
ammonia15
or sodium azide,16
Curtius rearrangement17
of
pyrazine-2-carbamate derived from corresponding carboxylic
acid and subsequent trapping of isocyanate with alcohol. These
methods are obviously feeble for preparation of versatile
functionalized/substituted 2-aminopyrazines that are required
in current drug discovery research and as synthones in the
organic synthesis.
Department of Medicinal Chemistry, National Institute of Pharmaceutical Education
and Research (NIPER), S. A. S. Nagar (Mohali)–160062, Punjab, India. E-mail:
skguchhait@niper.ac.in; Fax: +91 172 2214692; Tel: +91 172 2214683
† Electronic supplementary information (ESI) available: Scanned 1
H and 13
C
spectra for products 4a–p, 6a–l and 2D spectra (HMQC and HMBC) of 6h and
6i. See DOI: 10.1039/c6ra12028h
‡ The authors have contributed equally.
Cite this: RSC Adv., 2016, 6, 56056
Received 9th May 2016
Accepted 6th June 2016
DOI: 10.1039/c6ra12028h
www.rsc.org/advances
56056 | RSC Adv., 2016, 6, 56056–56063 This journal is © The Royal Society of Chemistry 2016
RSC Advances
PAPER

2-Aminoquinoxaline (Scheme 1b) has been prepared by
Chichibabin amination14
of quinoxaline, a three-steps process
involving condensation of OPDA, aldehyde and tetramethylbu-
tyl isocyanide, oxidation by DDQ and de-iso-octylation,18
and
a recent process of condensation of OPDA, aldehyde and
sodium cyanide/potassium cyanide.19
The preparation of
2-aminoquinoxalines via a reaction of 2-nitrosoanilines with
2-nitrobenzylcyanides has narrow substrate scope.20
Therefore,
literature-precedence is well-indicating the importance of
development of a strategy that can enable in a straightforward
and eﬃcient process to access 2-aminopyrazines and is also
applicable to preparation of 2-aminoquinoxalines.
Results and discussion
At the outset, we envisaged that chemistry aspects associated
with the present reaction of 1,2-diamine, aldehyde and TMSCN
could cause potential problems for its development (Scheme 2).
An acid as a reactant/catalyst in a MCR provides required elec-
trophilic activation; on the other hand, acid in the MCR reaction
using TMSCN causes the undesired Strecker reaction,21
and in
the reaction of phenylenediamine with aldehyde produces
benzimidazole (almost exclusively) and N-benzylimidazole.22
Secondly, in the present reaction, the dehydrogenative aroma-
tization is only the irreversible transformation, an important
requirement of MCR to proceed, and requires the oxidative
conditions. In addition, the aromatic aldehyde in the presence
of cyanide anion is known to undergo benzoin condensation.23
To minimize/circumvent these impediments, we judiciously
considered the conditions. Importance were given to nucleo-
philic desilylation of TMSCN by a non-protic base,24
generation
of silyl-based byproduct that can act as Lewis acid for required
chemoselective electrophilic activation of functionalities, and
presence of oxidant eﬀective for promoting in situ dehydro-
genative aromatization.
A model reaction of o-phenylenediamine and 4-chlor-
obenzaldehyde with TMSCN for construction of 2-amino-
quinoxaline was chosen. In preliminary screening of various
conditions, formation of benzimidazole as a major or exclusive
product was observed, indicating high preference of imine's
electrophilic attack by intramolecular amine nucleophile over
the desire attack by in situ generated cyanide anion (Strecker
reaction). We were glad to see that the usual reaction course
forming benzimidazole was switched to desired direction of
Strecker–Ugi pathway by DABCO-mediated nucleophilic activa-
tion of TMSCN in the reaction under oxygen (balloon pressure)
as oxidant. No benzimidazole product formed, although the
desired 2-aminoquinoxaline was obtained in low (30%) yield
(Table 1, entry 1). Furthermore, the product derived from
benzoin condensation did not form. Changing oxidizing agent
to DDQ or copper(II) acetate resulted in more side reactions. We
realized the importance of the nucleophilic activation of
TMSCN in promoting the present reaction and thus considered
screening of various amine bases (Table 1, entries 2–7). The
reaction with DBU was found to be dramatically faster
(completed at 1 h) compared to all other bases in which the
conversions were substantially incomplete aer 24 h.25
For
DBU-mediated reaction, great chemoselectivity as well as good
yield (70%) were obtained by lowering the reaction temperature
to an optimum (RT) and using an optimal quantity (1.2 equiv.)
of TMSCN and DBU. For reaction with L-proline or 2-hydrox-
ypyridine, which act as dual nucleo/electrophilic activators,
substrates remained nearly intact and a mixture of products
formed in traces. Use of anhydrous form of reaction solvent
(THF) provided similar yield, although little of product formed
in aqueous solvent, ruling out the possibility of HCN as active
cyanating species. The screening of solvents (used as received
commercially without prior distillation) indicated that 1,4-
Scheme 1 (a) Literature methods for the synthesis of 2-aminopyrazine;
(b) literature methods for the synthesis of 2-aminoquinoxaline.
Scheme 2 Possible transformations of the reaction.
This journal is © The Royal Society of Chemistry 2016 RSC Adv., 2016, 6, 56056–56063 | 56057
Paper RSC Advances

dioxane was best. Increasing the dilution from 1 (M) solution to
an optimal 0.33 (M) enhanced further the yield (92%). Pre-
formation of imine was found to be non-mandatory although
it was required for a faster reaction. It is interesting to note the
distinctive features of bases, which were found important for
promoting the present reaction involving TMSCN as cyanide-
pronucleophile as well as Strecker–Ugi-type pathway. The ob-
tained results were not in correlation with common parameters
of bases, Brønsted basicity (pKHB
+
), carbon basicity,26
H-bonding
basicity (pKHB)27
and carbon-nucleophilicity (see Table S1 in
ESI†). Non-involvement of HCN as cyanating species in the
reaction rules out also the inuence of pKHB. The silicon-philicity
of amine “N” of bases to react with TMSCN is certainly a signi-
cant inuencing factor. The results along with high rate-
acceleration clearly exemplify the unique function of DBU28
as
extremely efficient promoter and superior to other bases, which
suggests that the sterically hindered nucleophilic tertiary ami-
dine–amine motif of DBU is important to facilitate the reaction,
although the exact reason is currently unclear. This represents an
important nding in addition to the previous disclosures of DBU
as an effective catalyst/promoter, in contrast to its usual hindered
basic property, explored in (hetero)aromatic O/N–H methyl-
ation,25a
carboxylic acid esterication,25b
and the Baylis–Hillman
reaction involving stabilization of the intermediate b-ammonium
enolate.25c
Next, we were curious to immediate check the applicability of
the approach to the synthesis of 2-aminopyrazines, which is
relatively underexplored. Accordingly, a reaction of ethylene-1,2-
diamine and 4-chlorobenzaldehyde with TMSCN was per-
formed. Surprisingly, the desired 2-aminopyrazine was obtained
in 35% yield only and the conversion remained substantially
incomplete. The use of oxidizing agents, DDQ, CAN, CuCl2,
AgNO3 or MnO2 was ineffective to improve the yield. Gratifyingly,
MnO2 in alkaline methanolic solution29
provided 2-amino-
pyrazine in 75% yield. With this optimized protocol, we inves-
tigated its generality for varied starting materials (Table 2). We
were pleased to nd that aromatic aldehydes containing both
electron-withdrawing as well as electron-donating functional-
ities and heteroaromatic aldehydes underwent the reaction
smoothly. Unfortunately, aliphatic aldehydes (isobutyraldehyde,
octanal, phenylpropionaldehyde) produced multiple products
along with desired 2-aminopyrazines, according to mass spec-
trometry, which could not be isolated. The variation of ethyl-
enediamine component is also viable in the method. In case of
unsymmetric diamines, the regioselective formation of one
product (Table 2, 6g–6i) was observed. The structures of these
regioisomeric-products were conrmed by 2D NMRs (HMBC,
HMQC, see ESI†). Diaminomaleonitrile also was found to be
a feasible substrate in the reaction. It is noteworthy that the
present approach offers a convenient one-step synthesis of 3-
Table 1 Optimization of reaction conditions for the synthesis of 2-aminoquinoxaline
# Base (equiv.) Temp. (
C) TMSCN (equiv.) Solvent (mL) Time (h) Yieldb
(%)
1 DABCO (1) 70 1 THF (1) 24 30
2 DBU (1) 70 1 THF (1) 1 34
3 TMEDA (1) 70 1 THF (1) 24 16
4 DIPEA (1) 70 1 THF (1) 24 25
5 Triethylamine (1) 70 1 THF (1) 24 18
6 Piperazine (1) 70 1 THF (1) 24 8
7 Piperidine (1) 70 1 THF (1) 24 12
8 L-Proline (1) 70 1 THF (1) 24 NR
9 2-Hydroxypyridine (1) 70 1 THF (1) 24 NR
10 DBU (1) RTc
1 THF (1) 24 62
11 DBU (1.2) RT 1.2 THF (1) 24 70
12 DBU (1.2) RT 1.2 Anhyd. THF (1) 24 72
13 DBU (1.2) RT 1.2 DMF (1) 24 42
14 DBU (1.2) RT 1.2 1,4-Dioxane (1) 24 81
15 DBU (1.2) RT 1.2 2-Methyl–THF (1) 24 60
16 DBU (1.2) RT 1.2 PEG-400 (1) 24 43
17 DBU (1.2) RT 1.2 t-Butyl methyl ether (1) 24 38
18 DBU (1.2) RT 1.2 n-Butanol (1) 24 70
19 DBU (1.2) RT 1.2 t-Butanol (1) 24 62
20 DBU (1.2) RT 1.2 1,4-Dioxane (2) 24 87
21 DBU (1.2) RT 1.2 1,4-Dioxane (3) 36 92
22 DBU (1.2) RT 1.2 1,4-Dioxane (5) 48 77
a
Substrates, reagents and conditions: 1,2-phenylenediamine (1 mmol), ArCHO (1 equiv.), TMSCN (1.2 equiv.), base, solvent (3 mL), O2, Temp. (
C),
36–48 h. b
Yield for maximum conversion in optimum time. c
RT (25–27
C).
RSC Advances Paper

aryl-2-aminopyrazines from readily available and simpler start-
ing materials, while these compounds have been previously
prepared either by arylation of 2-aminopyrazines with aryl
lithium30
or by pre-functionalization of 2-aminopyrazines fol-
lowed by Suzuki-coupling using arylboronic acid.31
Next, we set out to explore the scope of the developed
methodology for preparation of 2-aminoquinoxalines (Table 3).
Various aldehydes and 1,2-phenylenediamines were investi-
gated. Pleasingly, the method was found to be exible in
accommodating a wide range of aldehydes, including aromatic
aldehydes possessing electron-withdrawing as well as electron-
donating groups, heteroaromatic, alkyl, arylalkenyl, and
metallocene-derived aldehydes and the products were obtained
in good-to-excellent yields. Indole-3-carboxaldehyde without
NH-protection underwent also the reaction smoothly. Remark-
ably, the methodology afforded also a high-yielding access to
pyridine-fused pyrazine-2-amine, another biologically impor-
tant heterocycle. Interestingly, the present approach eliminated
the formation of benzimidazoles32
and N-benzylated benz-
imidazoles,33
which are easily produced in the reported reac-
tions of 1,2-phenylenediamines with aldehydes, and benzoins19b
derived from condensation of aromatic aldehydes.
Conclusions
In conclusion, we have developed a new reaction of 1,2-
diamines and aldehydes with TMSCN, which affords an efficient
and diversity-feasible entry to 3-aryl substituted 2-amino-
pyrazines and 2-aminoquinoxalines. In the established
protocol, a complete switch from usual transformations of these
substrates producing benzimidazole, N-benzylbenzimidazole,
and benzoin to desired tandem pathway of a sequence of
desilylation, Strecker reaction, amidine-forming cyclization and
dehydrogenative aromatization has been accomplished. The
function of DBU as most efficient and rate-accelerating reagent
has been found to be crucial. This reaction opens a new path to
straightforward preparation of 2-aminopyrazines, which have
been previously obtained by multi-steps and non-convenient
synthetic approaches, and is also applicable to efficient prepa-
ration of 2-aminoquinoxalines. The practical features of the
Table 3 Synthesis of 3-aryl-2-aminoquinoxalinesa,b
3-Aryl-2-aminoquinoxalines
a
Substrates, reagents and conditions: 1,2-phenylenediamine (1 mmol),
ArCHO (1 equiv.), TMSCN (1.2 equiv.), DBU (1.2 equiv.), 1,4-dioxane
(3 mL), O2, RT (25–27
C), 36–48 h. b
Isolated yield.
Table 2 Synthesis of 3-aryl-2-aminopyrazinesa,b
3-Aryl-2-aminopyrazines
a
Substrates, reagents and conditions: 1,2-diamine (1 mmol), ArCHO
(1 equiv.), TMSCN (1.2 equiv.), DBU (1.2 equiv.), 1,4-dioxane (3 mL),
O2, RT (25–27
C), 3 h, then MnO2 in 0.4 M KOH in MeOH (10 mL),
16–18 h. b
Isolated yield for maximum conversion in optimum time.
c
Reaction was performed at 70
C. d
Diaminomaleonitrile was used as
diamine. e
MnO2 in 0.4 M KOH in MeOH was not added.
Paper RSC Advances

protocol are the use of readily available substrates, applicability
to versatile substrates and moderate-to-excellent yields. Given
the fact that 2-aminopyrazines and 2-aminoquinoxalines are
present in biologically active compounds and used as valuable
synthetic precursors, the present work is resourceful in broad
applications.
Experimental section
General information
Infrared (IR) spectra were recorded on a FTIR with ATR IR
Microscope spectrometer. 1
H NMR spectra were measured on
a 400 MHz spectrometer. Data were reported as follows:
chemical shis in ppm from tetramethylsilane as an internal
standard in CDCl3/CD3OD/DMSO-d6 integration, multiplicity (s
¼ singlet, d ¼ doublet, t ¼ triplet, q ¼ quartet, m ¼ multiplet,
ddd ¼ doublet of doublet of doublet, br ¼ broad), and coupling
constants (Hz). 13
C NMR spectra were measured on a 100 MHz
spectrometer with complete proton decoupling. Chemical shis
were reported in ppm from the residual solvent/TMS as an
internal standard. High-resolution mass spectra (HRMS) were
performed on a high resolution LCMS/MS instrument with
“Q-TOF” mass analyser. For thin layer chromatography (TLC)
analysis throughout this work, Merck precoated TLC plates
(silica gel 60 GF254, 0.25 mm) were used. The products were
puried by column chromatography on neutral alumina.
The starting materials and solvents were used as received
from commercial suppliers without further purication.
Representative experimental procedure for the synthesis of
3-(4-chlorophenyl)quinoxalin-2-amine (4a)
A mixture of 1,2-phenylenediamine (108 mg, 1 mmol) and
p-chlorobenzaldehyde (141 mg, 1 mmol, 1 equiv.) in 1,4-dioxane
(0.2 mL) taken in a round-bottomed ask was heated at 70
C for
30 min in a pre-heated silicon oil bath. The solution was then
cooled to room temperature. 1,4-Dioxane (3 mL), DBU (0.18 mL,
1.2 mmol, 1.2 equiv.) and TMSCN (0.15 mL, 1.2 mmol, 1.2
equiv.) were added and the resultant mixture was stirred for 5
minutes. The reaction mixture was then allowed to stir at RT
under oxygen atmosphere (using O2 balloon) until completion
of reaction (36 h) as indicated by TLC. The volatiles were
evaporated under rotary evaporator and the crude mixture was
puried by column chromatography on neutral alumina (60–
325 mesh) eluting with 20% ethyl acetate–hexane. It provided 3-
(4-chlorophenyl)quinoxalin-2-amine (235 mg, 92%).
Other compounds (4b–p) were synthesized following this
procedure and puried on neutral alumina using 20–30% ethyl
acetate–hexane as eluent.
Representative experimental procedure for synthesis of 3-(4-
chlorophenyl)pyrazin-2-amine (6a)
A mixture of ethylenediamine (0.08 mL, 1 mmol) and p-chlor-
obenzaldehyde (141 mg, 1 mmol, 1 equiv.) in 1,4-dioxane (0.2
mL) taken in a round-bottomed ask was heated at 70
C for 15
min in a pre-heated silicon oil bath. The solution was cooled to
room temperature. 1,4-Dioxane (0.5 mL), DBU (0.18 mL, 1.2
mmol, 1.2 equiv.) and TMSCN (0.15 mL, 1.2 mmol, 1.2 equiv.)
were added. The resultant mixture was then stirred at RT for 3 h
under oxygen atmosphere (using O2 balloon) and 10 mL solu-
tion of MnO2 (174 mg, 2 mmol, 2 equiv.) in 0.4 M KOH in
methanol was added to it. The mixture was stirred at RT until
completion of reaction as indicated by TLC (18 h). It was ltered
through celite bed and puried by column chromatography on
neutral alumina (60–325 mesh) eluting with 25% ethyl acetate–
hexane. It gave 3-(4-chlorophenyl)pyrazin-2-amine (167 mg,
81% yield).
Other compounds (6b–l) were synthesized following this
procedure and puried on neutral alumina using 25–40% ethyl
acetate–hexane as eluent.
3-(4-Chlorophenyl)pyrazin-2-amine13
(6a)
White crystalline solid, 154 mg, 75%, m.p. 170–172
C; 1
H NMR
(400 MHz, DMSO-d6): d 7.95 (d, J ¼ 2.6 Hz, 1H), 7.88 (d, J ¼ 2.6
Hz, 1H), 7.71 (d, J ¼ 8.6 Hz, 2H), 7.53 (d, J ¼ 8.6 Hz, 2H), 6.21 (s,
2H) ppm; 13
C{1
H}NMR (100 MHz, DMSO-d6): d 153.6, 141.8,
138.4, 136.8, 133.5, 133.0, 130.4, 129.1 ppm; IR: nmax 3305, 3163,
1638, 1527, 1430, 819 cmÀ1
; HRMS (ESI) m/z: calcd. for
C10H9ClN3 [M(35
Cl) + H]+
206.0485, found: 206.0484.
3-(4-Fluorophenyl)pyrazin-2-amine (6b)
Light yellow solid, 134 mg, 71%, m.p. 125–127
C; 1
H NMR (400
MHz, DMSO-d6): d 7.94 (d, J ¼ 2.6 Hz, 1H), 7.87 (d, J ¼ 2.6 Hz,
1H), 7.73 (dd, J ¼ 8.9 Hz, J ¼ 5.6 Hz, 2H), 7.30 (dd, J ¼ 8.9 Hz, J ¼
8.9 Hz, 2H), 6.16 (s, 2H) ppm; 13
C{1
H}NMR (100 MHz,
DMSO-d6): d 162.5 (d, JC–F ¼ 243 Hz), 153.6, 141.5, 138.8, 134.4
(d, JC–C–C–C–F ¼ 3 Hz), 132.9, 130.7 (d, JC–C–C–F ¼ 8 Hz), 115.9 (d,
JC–C–F ¼ 21 Hz) ppm; IR: nmax 3364, 3165, 1633, 1507, 1429, 1219
cmÀ1
; HRMS (ESI) m/z: calcd. for C10H9FN3 [M + H]+
190.0780,
found: 190.0778.
3-Phenylpyrazin-2-amine13
(6c)
C; 1
H NMR
Hz, 1H), 7.69 (d, J ¼ 7.24 Hz 2H), 7.51–7.41 (m, 3H), 6.12 (s, 2H)
ppm; 13
C{1
H}NMR (100 MHz, DMSO-d6): d 153.6, 141.4, 139.7,
138.0, 132.9, 129.1, 128.9, 128.5 ppm; IR: nmax 3306, 3187, 1637,
1527, 1427 cmÀ1
; HRMS (ESI) m/z: calcd. for C10H10N3 [M + H]+
172.0875, found: 172.0867.
3-(p-Tolyl)pyrazin-2-amine13
(6d)
C; 1
H NMR
Hz, 1H), 7.57 (d, J ¼ 8.1 Hz, 2H), 7.29 (d, J ¼ 7.9 Hz, 2H), 6.02 (s,
2H), 2.53 (s, 3H) ppm; 13
C{1
H}NMR (100 MHz, DMSO-d6):
d 153.5, 141.1, 139.9, 138.4, 135.1, 132.9, 129.7, 128.3, 21.3 ppm;
IR: nmax 3305, 3168, 1640, 1529, 1432, cmÀ1
; HRMS (ESI) m/z:
calcd. for C11H12N3 [M + H]+
186.1031, found: 186.1027.
3-(4-Methoxyphenyl)pyrazin-2-amine (6e)
Light yellow solid, 139 mg, 69%, m.p. 113–115
C; 1
H NMR (400
RSC Advances Paper

1H), 7.65 (d, J ¼ 8.5 Hz, 2H), 7.04 (d, J ¼ 8.5 Hz 2H), 6.05 (s, 2H),
3.81 (s, 3H) ppm; 13
C{1
H}NMR (100 MHz, DMSO-d6): d 159.9,
153.5, 140.8, 139.7, 132.9, 130.3, 129.8, 114.5, 55.7 ppm; IR: nmax
3436, 1613, 1512, 1432, 1250, 1175 cmÀ1
; HRMS (ESI) m/z: calcd.
for C11H12N3O [M + H]+
202.0980, found: 202.0979.
3-(Furan-2-yl)pyrazin-2-amine
C; 1
H NMR
(400 MHz, DMSO): d 7.95 (d, J ¼ 2.5 Hz, 1H), 7.86 (s, 1H), 7.85 (s,
1H), 7.09 (d, J ¼ 3.1 Hz, 1H), 6.69 (dd, J ¼ 3.4 Hz, J ¼ 1.8 Hz, 1H),
6.53 (s, 2H) ppm; 13
C{1
H}NMR (100 MHz, DMSO): d 152.0, 151.5,
143.9, 141.5, 132.6, 129.6, 112.4, 110.5 ppm; IR: nmax 3487, 1633,
1524, 1489, 1220, 1155 cmÀ1
C8H8N3O [M + H]+
162.0667, found: 162.0674.
3-(4-Chlorophenyl)-6-methylpyrazin-2-amine (6g)
Oﬀ-white solid, 101 mg, 46%, m.p. 190–192
C; 1
H NMR (400
MHz, CDCl3): d 7.90 (s, 1H), 7.65 (d, J ¼ 8.5 Hz, 2H), 7.45 (d, J ¼
8.5 Hz, 2H), 4.71 (s, 2H), 2.41 (s, 3H) ppm; 13
C{1
H}NMR (100
MHz, CDCl3): d 151.2, 150.6, 136.3, 135.8, 134.7, 134.1, 129.5,
129.2, 20.9 ppm; IR: nmax 3364, 3167, 1644, 1526, 1424, 825
cmÀ1
; HRMS (ESI) m/z: calcd. for C11H11ClN3 [M(35
Cl) + H]+
220.0642, found: 220.0634.
3-(4-Fluorophenyl)-6-methylpyrazin-2-amine (6h)
C; 1
H NMR (400
MHz, DMSO-d6): d 7.75 (s, 1H), 7.69 (dd, J ¼ 8.8 Hz, J ¼ 5.6 Hz,
2H), 7.27 (dd, J ¼ 8.9 Hz, J ¼ 8.9 Hz, 2H), 6.02 (s, 2H), 2.28 (s, 1H)
ppm; 13
C{1
H}NMR (100 MHz, DMSO-d6): d 162.3 (d, JC–F ¼ 244
Hz), 152.5, 150.2, 135.8, 134.5 (d, JC–C–C–C–F ¼ 3 Hz), 132.1, 130.6
(d, JC–C–C–F ¼ 9 Hz), 115.9 (d, JC–C–F ¼ 21 Hz), 20.9 ppm; IR: nmax
3418, 3055, 1619, 1510, 1400, 1200 cmÀ1
for C11H11FN3 [M + H]+
204.0937, found: 204.0941.
3-(4-Methoxyphenyl)-6-methylpyrazin-2-amine (6i)
C; 1
H NMR (400
MHz, CDCl3): d 7.88 (s, 1H), 7.63 (d, J ¼ 8.8 Hz, 2H), 6.99 (d, J ¼
8.8 Hz, 2H), 4.74 (s, 2H), 3.85 (s, 3H), 2.39 (s, 3H) ppm; 13
C{1
H}
NMR (100 MHz, CDCl3): d 159.9, 151.3, 149.5, 137.6, 133.8,
129.8, 129.4, 114.4, 55.4, 20.9 ppm; IR: nmax 3308, 3184, 1609,
1511, 1429, 1247, 1175 cmÀ1
C12H14N3O [M + H]+
216.1137, found: 216.1132.
3-(4-Chlorophenyl)-5,6,7,8-tetrahydroquinoxalin-2-amine (6j)
White crystalline solid, 142 mg, 55% yield, m.p. 160–162
C; 1
H
NMR (400 MHz, DMSO-d6): d 7.68 (d, J ¼ 8.5 Hz, 2H), 7.50 (d, J ¼
8.5 Hz, 2H), 5.83 (s, 2H), 2.69–2.67 (m, 4H), 1.80–1.78 (m, 4H)
ppm; 13
C{1
H}NMR (100 MHz, DMSO-d6): d 151.1, 148.7, 139.8,
137.0, 135.3, 133.0, 130.4, 128.9, 31.2, 30.6, 23.2, 22.8 ppm; IR:
nmax 3305, 3172, 2937, 1639, 1419, 832 cmÀ1
; HRMS (ESI) m/z:
calcd. for C14H15N3Cl [M + H]+
260.0955, found: 260.0946.
3-(Furan-2-yl)-5,6,7,8-tetrahydroquinoxalin-2-amine (6k)
A white crystalline solid, 127 mg, 59% yield, m.p. 161–163
C;
1
H NMR (400 MHz, DMSO-d6): d 7.79 (d, J ¼ 0.9 Hz, 1H), 6.97 (d,
J ¼ 3.3 Hz, 1H), 6.64 (dd, J ¼ 3.3 Hz, J ¼ 1.8 Hz, 1H), 6.18 (s, 2H),
2.69–2.67 (m, 4H), 1.80–1.78 (m, 4H), ppm; 13
C{1
H}NMR (100
MHz, DMSO-d6): d 152.3, 149.2, 148.7, 143.4, 139.4, 126.7, 112.3,
109.5, 31.4, 30.7, 23.2, 22.8 ppm; IR: nmax 3494, 1622, 1410, 1216,
1156 cmÀ1
; HRMS (ESI) m/z: calcd. for C12H14N3O [M + H]+
216.1137, found: 216.1132.
3-(4-Chlorophenyl)-6-cyanopyrazin-2-amine (6l)
Yellow solid, 85 mg, 37%, m.p. 200
C; 1
H NMR (400 MHz,
CDCl3): d 8.46 (s, 1H), 7.67 (d, J ¼ 8.4 Hz, 2H), 7.57 (d, J ¼ 8.4 Hz,
2H), 7.42 (s, 2H), ppm; 13
C{1
H}NMR (100 MHz, CDCl3): d 154.9,
147.8, 140.2, 134.9, 134.5, 130.6, 129.3, 118.2, 115.4 ppm; IR:
nmax 3455, 3144, 2924, 2226, 1627, 1526, 1469, 750 cmÀ1
; HRMS
(ESI) m/z: calcd. for C11H7ClN4 [M(35
Cl) + Na]+
253.0257, found:
253.0252.
3-(4-Chlorophenyl)quinoxalin-2-amine19b
(4a)
Light yellow solid, 235 mg, 92% yield, m.p. 170–172
C; 1
H NMR
(400 MHz, DMSO-d6): d 7.82–7.76 (m, 3H), 7.60–7.55 (m, 4H),
7.39–7.35 (m, 1H), 6.63 (s, 2H) ppm; 13
C{1
H}NMR (100 MHz,
DMSO-d6): d 151.9, 145.1, 141.9, 137.2, 136.3, 134.5, 130.8,
130.3, 129.2, 128.9, 125.5, 124.6 ppm; IR: nmax 3377, 3131, 1646,
1421, 751 cmÀ1
; HRMS (ESI) m/z: calcd. for C14H11N3Cl [M(35
Cl)
+ H]+
256.0642, found: 256.0636.
3-(2-Chlorophenyl)quinoxalin-2-amine19b
(4b)
Light yellow solid, 205 mg, 80% yield, m.p. 190–192
C; 1
H NMR
(400 MHz, DMSO-d6): d 7.79 (d, J ¼ 8.1 Hz, 1H), 7.63–7.57 (m,
3H), 7.56–7.50 (m, 3H), 7.40–7.36 (m, 1H), 6.49 (s, 2H) ppm; 13
C
{1
H}NMR (100 MHz, DMSO-d6): d 152.0, 145.3, 142.4, 136.5,
136.1, 132.6, 131.5, 131.2, 130.4, 130.2, 128.9, 128.1, 125.6, 124.3
ppm; IR: nmax 3464, 3105, 1637, 1434, 752 cmÀ1
; HRMS (ESI) m/
z: calcd. for C14H11N3Cl [M(35
Cl) + H]+
256.0642, found:
256.0634.
3-(4-Fluorophenyl)quinoxalin-2-amine (4c)
A light brown solid, 203 mg, 85%, m.p. 200
C; 1
H NMR (400
MHz, DMSO-d6): d 7.82–7.79 (m, 3H), 7.58–7.57 (m, 2H), 7.39–
7.34 (m, 3H), 6.59 (s, 2H) ppm; 13
C{1
H}NMR (100 MHz, DMSO-
d6): d 163.1 (d, JC–F ¼ 244 Hz), 152.9, 145.4, 141.8, 137.2, 133.9
(d, JC–C–C–C–F ¼ 3 Hz), 131.3 (d, JC–C–C–F ¼ 9 Hz), 130.1, 128.9,
125.5, 124.5, 116.1 (d, JC–C–F ¼ 21 Hz) ppm; IR: nmax 3429, 1639,
1427, 1233 cmÀ1
; HRMS (ESI) m/z: calcd. for C14H11N3F [M + H]+
240.0937, found: 240.0930.
3-(4-Bromophenyl)quinoxalin-2-amine34
(4d)
Light yellow solid, 242 mg, 81%, m.p. 200
C; 1
H NMR (400
MHz, DMSO-d6): d 7.81 (d, J ¼ 8.1 Hz, 1H), 7.75–7.70 (m, 4H),
7.58–7.57 (m, 2H), 7.39–7.35 (m, 1H), 6.64 (s, 2H) ppm; 13
C{1
H}
NMR (100 MHz, DMSO-d6): d 151.8, 145.1, 141.9, 137.2, 136.7,
132.1, 131.1, 130.3, 128.9, 125.5, 124.6, 123.2 ppm; IR: nmax
3432, 1637, 1429, 751 cmÀ1
C14H11N3Br [M(79
Cl) + H]+
300.0136, found: 300.0132.
Paper RSC Advances

3-(4-Nitrophenyl)quinoxalin-2-amine34
(4e)
Brown solid, 236 mg, 89%, m.p. 200
C; 1
H NMR (400 MHz,
DMSO-d6): d 8.38 (d, J ¼ 8.7 Hz, 2H), 8.04 (d, J ¼ 8.7 Hz, 2H), 7.84
(d, J ¼ 8.0 Hz, 1H), 7.64–7.59 (m, 2H), 7.42–7.38 (m, 1H), 6.76 (s,
2H) ppm; 13
C{1
H}NMR (100 MHz, DMSO-d6): d 151.8, 148.2,
144.2, 144.0, 142.2, 137.1, 130.8, 130.6, 129.1, 125.6, 124.8, 124.3
ppm; IR: nmax 3432, 1640, 1434, 1343 cmÀ1
; HRMS (ESI) m/z:
calcd. for C14H11N4O2 [M + H]+
267.0882, found: 267.0874.
3-Phenylquinoxalin-2-amine19b
(4f)
C; 1
H NMR (400 MHz,
DMSO-d6): d 7.81 (d, J ¼ 8.0 Hz, 1H), 7.78–7.75 (m, 2H), 7.58–
7.53 (m, 5H), 7.39–7.36 (m, 1H), 6.56 (s, 2H) ppm; 13
C{1
H}NMR
(100 MHz, DMSO-d6): d 151.9, 146.2, 141.8, 137.5, 137.3, 130.1,
129.8, 129.2, 128.9, 128.8, 125.5, 124.5 ppm; IR: nmax 3371, 3148,
1646, 1428 cmÀ1
222.1031, found: 222.1028.
3-(p-Tolyl)quinoxalin-2-amine19b
(4g)
Yellow solid, 190 mg, 81%, m.p. 174–176
C; 1
H NMR (400 MHz,
DMSO-d6): d 7.80 (d, J ¼ 8.1 Hz, 1H), 7.67 (d, J ¼ 8.0 Hz, 2H),
7.57–7.55 (m, 2H), 7.38–7.35 (m, 3H), 6.53 (s, 2H), 2.40 (s, 3H)
ppm; 13
C{1
H}NMR (100 MHz, DMSO-d6): d 151.9, 146.2, 141.7,
139.3, 137.3, 134.6, 129.9, 129.8, 128.84, 128.77, 125.5, 124.5,
21.4 ppm; IR: nmax 3433, 1645, 1428 cmÀ1
; HRMS (ESI) m/z:
calcd. for C15H14N3 [M + H]+
236.1188, found: 236.1180.
3-(4-Methoxyphenyl)quinoxalin-2-amine19b
(4h)
Light brown solid, 209 mg, 83%, m.p. 154–156
C; 1
H NMR (400
2H), 7.56–7.54 (m, 2H), 7.38–7.35 (m, 1H), 7.10 (d, J ¼ 8.7 Hz,
2H), 6.54 (s, 2H), 3.84 (s, 3H) ppm; 13
C{1
H}NMR (100 MHz,
DMSO-d6): d 160.8, 150.7, 145.6, 140.9, 138.2, 129.9, 129.7,
129.3, 128.9, 125.6, 125.2, 118.8, 116.2, 114.6, 55.5 ppm; IR: nmax
3425, 3148, 1607, 1429, 1252, 1176 cmÀ1
for C15H14N3O [M + H]+
252.1137, found: 252.1130.
3-(Naphthalen-2-yl)quinoxalin-2-amine19b
(4i)
Light green solid, 236 mg, 87%, m.p. 200
C; 1
H NMR (400
MHz, DMSO-d6): d 8.37 (s, 1H), 8.10–8.00 (m, 3H), 7.89–7.84 (m,
2H), 7.63–7.57 (m, 4H), 7.41–7.37 (m, 1H), 6.71 (s, 2H) ppm; 13
C
{1
H}NMR (100 MHz, DMSO-d6): d 152.1, 146.1, 141.8, 137.4,
134.9, 133.7, 133.2, 130.1, 129.1, 128.9, 128.8, 128.3, 128.1,
127.4, 126.9, 126.6, 125.5, 124.5 ppm; IR: nmax 3390, 3049, 1598,
1424 cmÀ1
272.1188, found: 272.1184.
3-(Furan-2-yl)quinoxalin-2-amine19b
(4j)
C; 1
H NMR (400
MHz, DMSO-d6): d 7.96 (dd, J ¼ 1.7 Hz, J ¼ 0.7 Hz, 1H), 7.80
(ddd, J ¼ 8.1 Hz, J ¼ 7.2 Hz, J ¼ 0.7 Hz, 1H), 7.56–7.55 (m, 2H),
7.41–7.36 (m, 2H), 6.93 (s, 2H), 6.76 (dd, J ¼ 3.5 Hz, J ¼ 1.7 Hz,
1H) ppm; 13
C{1
H}NMR (100 MHz, DMSO): d 151.3, 150.2, 145.4,
141.2, 136.6, 134.7, 130.2, 128.6, 125.5, 125.0, 113.4, 112.8 ppm;
IR: nmax 3483, 1637, 1494, 1422, 1275, 1037 cmÀ1
; HRMS (ESI) m/
z: calcd. for C12H10N3O [M + H]+
212.0824, found: 212.0816.
3-(Thiophen-2-yl)quinoxalin-2-amine19b
(4k)
Light green solid, 166 mg, 73%, m.p. 135–137
C; 1
H NMR (400
MHz, DMSO-d6): d 7.94 (dd, J ¼ 3.8, J ¼ 0.9 Hz, 1H), 7.81–7.78
(m, 2H), 7.59–7.54 (m, 2H), 7.42–7.37 (m, 1H), 7.25 (dd, J ¼ 5.1
Hz, J ¼ 3.8 Hz, 1H), 6.84 (s, 2H) ppm; 13
C{1
H}NMR (100 MHz,
DMSO-d6): d 150.8, 141.6, 141.2, 139.3, 136.8, 130.3, 130.0,
128.9, 128.42, 128.40, 125.5, 125.0 ppm; IR: nmax 3369, 3153,
1642, 1557, 1438, 1415 cmÀ1
C12H10N3S [M + H]+
228.0595, found: 228.0593.
3-(Pyridin-2-yl)quinoxalin-2-amine19b
(4l)
C; 1
H NMR (400
MHz, DMSO-d6): d 8.76 (dd, J ¼ 4.8 Hz, J ¼ 0.9 Hz, 1H), 8.66 (d, J
¼ 8.1 Hz, 1H), 8.09 (ddd, J ¼ 9.5 Hz, J ¼ 7.8 Hz, J ¼ 1.8 Hz, 1H),
7.90 (dd, J ¼ 8.2 Hz, J ¼ 0.9 Hz, 1H), 7.65–7.58 (m, 3H), 7.42
(ddd, J ¼ 8.2 Hz, J ¼ 6.6 Hz, J ¼ 1.6 Hz, 1H), ppm; 13
C{1
H}NMR
(100 MHz, DMSO-d6): d 156.0, 152.9, 148.1, 142.7, 138.4, 138.2,
136.4, 131.1, 129.4, 125.4, 124.9, 124.6, 123.8 ppm; IR: nmax
3319, 3130, 1629, 1605, 1423, 1022 cmÀ1
for C13H10N4 [M + H]+
223.0984, found: 223.0979.
3-(1H-Indol-3-yl)quinoxalin-2-amine (4m)
Light green solid, 185 mg, 71%, m.p. 200
C; 1
H NMR (400
MHz, DMSO-d6): d 11.71 (s, 1H), 8.40 (d, J ¼ 7.7 Hz, 1H), 8.18 (d,
J ¼ 2.8 Hz, 1H), 7.82 (dd, J ¼ 7.8 Hz, J ¼ 0.9 Hz, 1H), 7.56–7.47
(m, 3H), 7.36 (ddd, J ¼ 8.2 Hz, J ¼ 6.9 Hz, J ¼ 1.5 Hz, 1H), 7.25–
7.15 (m, 2H), 6.65 (s, 2H) ppm; 13
C{1
H}NMR (100 MHz, DMSO-
d6): d 152.0, 142.8, 140.0, 137.5, 136.9, 128.6, 128.2, 128.1, 126.9,
125.3, 124.4, 122.8, 122.3, 120.7, 112.2, 111.7 ppm; IR: nmax
3433, 1646, 1531, 1438 cmÀ1
C16H13N4 [M + H]+
261.1140, found: 261.1136.
3-(Ferrocenyl)quinoxalin-2-amine34
(4n)
Light brown solid, 263 mg, 80%, m.p. 200
C; 1
H NMR (400
MHz, DMSO-d6): d 12.37 (s, 1H), 7.54 (d, J ¼ 7.4 Hz, 1H), 7.44 (d,
J ¼ 7.4 Hz, 1H), 7.15–7.11 (m, 2H), 5.04 (s, 2H), 4.47 (s, 2H), 4.10
(s, 5H) ppm; 13
C{1
H}NMR (100 MHz, DMSO-d6): d 153.4, 144.4,
135.2, 121.9, 121.5, 118.4, 111.0, 74.8, 70.2, 69.8, 67.8 ppm; IR:
nmax 3431, 2923, 2857, 1622, 1420 cmÀ1
for C18H15FeN3 [M + Na]+
352.0524, found: 352.0535.
6,7-Dichloro-3-(4-chlorophenyl)quinoxalin-2-amine (4o)
Light brown solid, 265 mg, 82%, m.p. 200
C; 1
H NMR (400
MHz, DMSO-d6): d 8.04 (s, 1H), 7.78–7.76 (m, 3H), 7.60 (d, J ¼ 8.5
Hz, 2H), 7.01 (s, 2H) ppm; 13
C{1
H}NMR (100 MHz, DMSO-d6):
d 152.6, 146.9, 141.4, 136.1, 135.6, 134.9, 132.5, 130.9, 129.6,
129.3, 126.2, 126.1 ppm; IR: nmax 3472, 3362, 3137, 1641, 1443,
764, 750 cmÀ1
; HRMS (ESI) m/z: calcd. for C14H9Cl3N3 [M(35
Cl) +
H]+
323.9862, found: 323.9862.
RSC Advances Paper

3-(4-Chlorophenyl)pyrido[3,4-b]pyrazin-2-amine (4p)
C; 1
H NMR (400 MHz,
DMSO-d6): d 8.99 (s, 1H), 8.47 (d, J ¼ 5.7 Hz, 1H), 7.77 (d, J ¼ 8.4
Hz, 2H), 7.60 (d, J ¼ 8.4 Hz, 2H), 7.42 (d, J ¼ 5.7 Hz, 1H), 7.28 (s,
2H) ppm; 13
C{1
H}NMR (100 MHz, DMSO-d6): d 154.4, 152.1,
147.8, 147.5, 145.9, 135.5, 134.9, 133.4, 130.9, 129.3, 118.8 ppm;
IR: nmax 3296, 3107, 1643, 1544, 1426 cmÀ1
; HRMS (ESI) m/z:
calcd. for C13H10ClN4 [M(35
Cl) + H]+
257.0594, found: 257.0595.
Acknowledgements
We gratefully acknowledge nancial support from DST, New
Delhi for this investigation. GP and NG is thankful for the
fellowship provided by NIPER, Mohali.
Notes and references
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Paper RSC Advances

Tandem reaction for synthesizing 2-aminopyrazines and 2-aminoquinoxalines

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