An "all-water" strategy for regiocontrolled synthesis of 2-aryl quinoxalines

Article abstract of DOI:10.1039/c4ra16568c

A new synthetic strategy of tandem N-aroylmethylation-nitro reduction-cyclocondensation has been developed for the first and generalized regioselective synthesis of 2-aryl quinoxalines adopting "all water chemistry." Water plays the critical role through

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An “allꢀwater” strategy for regiocontrolled synthesis of 2ꢀaryl
quinoxalines
Babita Tanwar, Priyank Purohit, Banothu Naga Raju, Dinesh Kumar, Damodara N. Kommi and Asit K.
Chakraborti *a
5
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
A new synthetic strategy of tandem Nꢀaroylmethylation–nitro reduction–cyclocondensation has been
developed for the first and generalized regioselective synthesis of 2ꢀaryl quinoxalines adopting “all water
chemistry.” Water plays the critical role through hydrogen bond driven ‘synergistic electrophileꢀ
10 nucleophile dual activation’ for chemoselective Nꢀaroylmethylation of oꢀnitroanilines, that underlines the
origin of the regioselectivity, as the use of organic solvents proved to be ineffective. Water also provides
beneficial effects during the nitro reduction and the penultimate cyclocondensation steps.
Introduction
Quinoxalines exhibit a wide range of biological activities,1
15 represent the essential pharmacophoric feature of various drugs
(Scheme 1)2 and find versatile applications in material sciences.3
40 This presses the necessity for a new synthetic design for
regioselective construction of the quinoxaline moiety. Herein we
present a new strategy of “allꢀwater” tandem Nꢀaroylmethylationꢀ
reductionꢀcyclocondensation process for oneꢀpot synthesis of 2ꢀ
aryl quinoxalines in regiodefined manner (Scheme 3).
45
Scheme 3. “Allꢀwater” Nꢀaroylmethylationꢀreductionꢀcyclocondensation
strategy for regiocontrolled synthesis of quinoxalines.
Scheme 1. A few quinoxalineꢀbased drugs.
Results and Discussion
These have triggered interest to develop synthetic methodologies
20 of quinoxalines that involve the Lewis/Brönsted acid or Lewis
base promoted reaction of oꢀphenylenediamines (commercially
available or prepared in situ by reduction of the corresponding oꢀ
nitroanilines or 1,2ꢀdinitrobenzenes) with various coupling
partners such as 1,2ꢀdiketones (preformed or prepared in situ
As the Nꢀaroylmethylation is the critical step, to test the
50 feasibility of the metal and baseꢀfree CꢀN bond formation, in a
model study oꢀnitroaniline (1a) was treated with αꢀ
bromoacetophenone (2a) (Scheme 3, R = H) in various solvents
to form 2ꢀ[(2ꢀnitrophenyl)amino]ꢀ1ꢀphenylethanone (3a) (Table
1). The 2ꢀ[(2ꢀnitrophenyl)amino]ꢀ1ꢀphenylethanone (3a) was
55 obtained in excellent yields (91ꢀ92%) in water. The comparable
results in tap, pure, and ultra pure water (entries 2ꢀ4, Table 1)
indicate that the Nꢀbenzoylmethylation is not influenced by any
dissolved metallic/organic impurities. The specific assistance of
water in promoting the metal/base free Nꢀbenzoylmethylation is
60 revealed by the fact that 3a was formed in poor yield under neat
condition (entry 1, Table 1) and in hydrocarbon, halogenated
hydrocarbon, ethereal, and aprotic polar solvents (entries 10–20,
Table 1). Alcohols (protic polar solvents) gave moderate yields
(entries 5–9, Table 1).
25 from
acetylene
derivatives),
1,2ꢀketomonoximes,
αꢀ
hydroxyketones/αꢀhaloketones,
1,2ꢀdiols, αꢀmethyleno
aldehydes/ketones, substituted epoxides, substituted nitroolefins.4
However, regiocontrolled construction of the quinoxaline
scaffold from unsymmetrical substrates (reacting/coupling
30 partners) remains elusive. Some of the reported procedures5 form
regioisomeric mixtures while in all others4 the regioselectivity
issue remained unaddressed/suppressed. It was realized that the
reported procedures4,5 involve simultaneous condensation of 1,2ꢀ
bisnucleophiles with 1,2ꢀbisꢀelectrophilic coupling partners
35 (Scheme 2) and hence are ought to be associated with the
regioselectivity problem.
65 Table 1. Influence of the reaction medium for a metal/catalyst
and baseꢀfree selective Nꢀmonobenzoylmethylation of 1a with 2a.
a
Scheme 2. Regioselectivity in the synthesis of quinoxalines.
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16
60 17
18
19
20
21
65 22
23
2
2
2
2
2
5
2
2
2
120
110
110
110
110
110
rt
5
1
2
3
4
2
12
8
2
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
92
28
75
92
92
84
nil
35
87
Entry Solvent
Temp
(°C)
αb
βb
Yield
(%)c
80
120
1
None
110
ꢀꢀ
ꢀꢀ
7
24
5
2
3
4
5
6
7
8
9
Tap water
Reflux
Reflux
1.17 0.18 92
1.17 0.18 91
1.17 0.18 92
0.93 0.62 59
0.83 0.77 65
0.76 0.95 68
0.68 1.01 74
1.51 0.00 50
0.00 0.11 31
0.00 0.00 trace
Pure waterd
a1a (1 mmol) was treated with 2a under different reaction condition in
the water as a reaction medium. bmolar equiv with respect to 1a. cIsolated
70 yield of 3a.
Ultra pure watere Reflux
MeOH
EtOH
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
Reflux
110
The synthetic potential of the waterꢀassisted Nꢀaroylmethylation
of oꢀnitroanilines is demonstrated by the reaction of a few
10
iPrOH
tBuOH
TFE
substituted
oꢀnitroanilines
1
with
substituted
αꢀ
bromoacetophenones 2 to form 3 (Table 3).
10
11
Toluene
Hexane
DCE
1,4ꢀDioxane
THF
Acetone
MeNO2
DMF
75 Table 3. The base/catalystꢀfree Nꢀaroylmethylation of different oꢀ
nitroanilines (1) with different αꢀbromoacetophenones (2) in water to
form 3.a
15 12
13
0.00
0.00
35
0.00 0.37 55
0.00 0.55 21
0.08 0.48 13
0.22 0.00 33
0.00 0.69 36
14
15
16
20 17
18
19
DMA
Formamide
110
110
0.00
0.71
0.76
0.00
nil
23
Entry R1
R2
R3
Time (h)
Yield (%)b
80
85
1
2
3
4
5
6
H
H
Cl
H
CH3
CH3
H
H
H
Cl
H
H
H
Cl
H
H
H
3
3
4
4
3
3
92
91
89
90
92
90
20
MeCN
Reflux
0.19 0.31 trace
a1a (1 mmol) was treated with 2a (1.5 mmol, 1.5 equiv) in the appropriate
25 solvent (5 mL), except for entry 1, under heating at 110°C (oil bath) for 5
h. bThe α and β values represent the hydrogen bond donor (HBD) and
hydrogen bond acceptor (HBA) property of the solvent as provided under
Ref 13. cIsolated yield. dPure water was obtained by purification of
normal/tap water through reverse osmosis and ionic/organic removal and
OMe
a1 (1 mmol) was treated with 2 (1 mmol, 1 equiv) in water (2 mL) at 110
°C (oil bath) for stipulated time period. bIsolated yield of 3.
e
30 has the resistivity of 15 Mꢁ at 25 °C. Ultrapure water was obtained by
further subjecting pure water to UV treatment (185/254 nm), deionization
and ultra membrane filtration (0.01 µm under pressure up to 145 psi (10
bar) and has the resistivity of 18.2 Mꢁ at 25 °C.
The reported method for the preparation of Nꢀphenacylꢀoꢀ
nitroanilines involve the use of base in DMF for 48 h.6 Anilines
90 are known to react with αꢀhalogenated ketones to form indoles.7
Thus, the results of table 2 exemplify an excellent metal and
baseꢀfree CꢀN bond formation protocol for chemoselective
synthesis Nꢀphenacylꢀoꢀnitroanilines. The role of water can be
visualized by its ability to form hydrogen bond (HB) with the
95 NH2 hydrogen of 1 (nucleophilic activation). The second
molecule of the water dimer8 in turn forms HB with the Br atom
of 2 (electrophilic activation) and brings the bromomethylene
carbon in close proximity to the NH2 nitrogen of 1 in the Hꢀ
bonded species (Scheme 4). Further, the carbonyl oxygen of 2
100 also participates in HB formation with another water dimer in
which the second water molecule forms HB with the other NH2
hydrogen in 1. The array/network of HBs gives stability9 to the
Hꢀbonded cluster (Scheme 4) and facilitates ‘ambiphiphilic
nucleophilicꢀelectrophilic dual activation.’10
Further studies on the variation of different reaction parameters,
35 such as the molar equivalents of 2a, amount of water,
temperature, and time revealed the use of 1.0 molar equivalent of
2a in water (2 mL/mmol of 1a) at 110 °C (oil bath) for 3 h to be
the optimal condition (entry 19, Table 2).
Table 2. NꢀBenzoylmethylation of oꢀnitroaniline (1a) under different
40 condition.a
Entry Water
(mL)
Temp
(°C)
Time Equiv of 2ab
(h)
Yield
(%)c
1
2
3
4
5
6
7
8
9
10
11
55 12
13
14
5
5
5
5
5
5
0.5
1
2
3
4
2
2
2
2
110
110
110
110
110
110
110
110
110
110
110
rt
5
5
5
5
5
5
5
5
5
5
5
5
5
5
5
1.0
1.1
1.2
1.3
1.4
1.5
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
92
92
92
93
92
92
68
79
92
92
92
0
45
50
105
Scheme 4. The envisaged role of water in promoting Nꢀaroylmethylation
of 1 with 2 to form 3.
60
80
110
traces
41
92
15
The hydrogenꢀbond assisted/mediated formation of nonꢀcovalent
2
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50 aTo the mixture of 3a (1 mmol) in water (2 mL, entries 1ꢀ6) or the
specified organic solvent (4.1 mL, entries 7ꢀ15) was added In metal (1.5ꢀ
2.5 equiv as indicated against each entry) and the indicated amount (in
ML) of aq HCl at 110 °C (oil bath) and the mixture was stirred
adduct of the reactants and the promoter has been invoked in
various organoꢀcatalytic chemical reactions/synthesis.11
The physicoꢀchemical parameters (acceptor/donor number etc.) of
the solvent often play key role in organic reactions,12 and the HB
involving the reactant and the solvent has significant influence.13
Therefore, the role of the reaction medium for Nꢀ
aroylmethylation can be visualised through the formation of the
HB adducts (Scheme 4) due to the hydrogen bond donor (HBD)
(α scale) and hydrogen bond acceptor (HBA) (β scale) properties
d
magnetically for 3 h. bMolar equiv of HCl. cIsolated yield of 5a. The
55 unreacted 3a remained unchanged and could be recovered wherever 5a
5
e
was formed in poor yields. Only trace amount of 5a was formed in
performing the reaction at room temperature (35ꢀ40 °C). f5a was obtained
in 63% yield in performing the reaction at 80 °C.
To find out whether indium metal can be replaced by other less
60 costly metals such as Fe, Zn, Mg, Sn, or SnCl2·2H2O, 3a was
treated with different metals/reducing agent (2.5 equiv) in aq HCl
(2N 2.5 mL, 5 equiv) (Table 5).
10 of the solvent.14 Although, the HBD property (α value) is
expected to play the predominant role in activating the
electrophile (2a) the HBA ability (β value) is also important as it
determines the ability of the solvent to activate the nucleophile
(amine nitrogen of 1a). Therefore, TFE gave inferior results due
15 to its poor β value (entry 9, Table 1).
Table 5. The effect of different metals/reducing agent on the
65 cascade reductionꢀcycloconden sation step.a
The reduction of nitro group of 3a would form the intermediate
4a which on cyclocondensation would form the 2ꢀphenyl
quinoxaline 5a (Scheme 3, R = H). However, treatment of 3a
with In (2.5 equiv) and 12N HCl (5 equiv)15 in water (2 mL)
20 afforded 5a in 24% yield at 110 °C (oil bath) after 3 h (Table 4).
Further studies on standardization of the reaction conditions
revealed that the best result (90% yield) is obtained in using 5
equiv of 2N HCl (entry 3, Table 4). Organic solvents gave
inferior results highlighting the beneficial effect of water on the
25 reduction due to enhanced solvation of the In3+ cation in water
making the electron transfer more efficient.16
Entry
Metal
In
Fe
Zn
Mg
Al
Sn
Isolated Yield of 5a (%)
90
1
2
3
4
5
6
7
61
70
traceb
traceb
25b
64
SnCl2·2H2O
65
Table 4. The effect of solvent and the amount of aq. HCl and In
75 aTo the mixture of 3a (1 mmol) in water (2 mL) was added metal or the
metal on the cascade reductionꢀcyclocondensation step.a
indicated reducing agent (2.5 equiv) and aq HCl (2N, 2.5 mL; 5 equiv) at
b
110 °C (oil bath) and the mixture was stirred magnetically for 3 h. The
unreacted 3a remained unchanged and could be recovered.
Thus, the use of indium metal provided the best results. The
80 product isolation was found to be tedious in case of aluminium
due to gel formation in the reaction mixture. The use of Sn metal
or its popularly used salt SnCl2·2H2O were also less effective.17
To determine whether indium metal would offer similar
beneficial effect compared to Fe, Zn, Mg, Sn, or SnCl2·2H2O for
85 the one pot tandem Nꢀaroylmethylationꢀreductionꢀcondensation,
1a was sequentially treated with 2a in water followed by different
metals/reducing agent (2.5 equiv) in aq HCl (2N 2.5 mL, 5 equiv)
to form 5a (Table 6). The best result was obtained in using
indium metal. Herein also poor yields were obtained with Sn
90 metal and SnCl2·2H2O.17
30 Entry Solvent
In metal
(mmol)
aq HCl
(mL)
12N (0.4 mL)
6N (0.8 mL)
2N (2.5 mL)
2N (2 mL)
Equivb Yield
(%)c,d
1
2
3
4
5
6
7
8
water
water
water
water
water
water
water
water
EtOH
Toluene
Toluene
Dioxane
DCE
2.5
2.5
2.5
2.5
2.5
2.5
2.0
1.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
2.5
5
5
5
4
3
2
5
5
5
5
5
5
5
5
5
5
5
5
24
59
90e,f
67
35
40
2N (1.5 mL)
2N (1 mL)
42
21
64
44
2N (2.5 mL)
2N (2.5 mL)
12N (0.4 mL)
12N (0.4 mL)
2N (2.5 mL)
12N (0.4 mL)
12N (0.4 mL)
12N (0.4 mL)
12N (0.4 mL)
12N (0.4 mL)
12N (0.4 mL)
2N (2.5 mL)
9
trace
42
27
nil
nil
nil
nil
nil
nil
14
10
11
12
13
Table 6. The effect of different metals/reducing agent on the
tandem Nꢀaroylmethylationꢀ reductionꢀcyclocondensation during
the reaction of1a with 2a to form 5a.a
45 14
15
MeCN
DCE
16
THF
17
18
DMF
none
95 Entry
Metal
Isolated Yield of 5a (%)
1
2
3
In
Fe
Zn
84
59
traceb
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4
5
6
7
Mg
Al
Sn
traceb
15b
63
water to form 8a (Scheme 7).
SnCl2·2H2O
57
5
a1a (1 mmol) was treated with 2a in water (2 mL) at 110 °C (oil bath) for
3 h followed by addition of the metal/reducing agent (2.5 equiv) and aq
HCl (2N, 2.5 mL; 5 equiv) at 110 °C (oil bath) and the mixture was
Scheme 7. Synthesis of 8a.
b
stirred magnetically for further 3 h. The unreacted 1a and 2a remained
The acid/metalꢀfree NꢀBoc deprotection is reported to take place
55 in water19 and trifluoroethanol (TFE)20 under heating. The
treatment of 8a in water 110 °C (oil bath) gave 5a in 82% yield
after 2 h (Scheme 8). This indicated that the cyclocondensation of
the in situ formed 4a to 5a is promoted by water. However, 5a
was formed in 15% yield by the treatment of 8a in TFE under
60 reflux for 24 h. No significant amount of 5a was obtained by the
treatment of 8a in TFE under reflux for 5 h. The treatment of 8a
in water (in place of TFE) under similar condition (80 °C for 5 h)
afforded 5a in 71% yield. Thus, water is the best solvent for the
cyclocondensation step due its favourable α and β values that
65 render a better ‘dual activation’ ability of water compared to
organic solvents.
unchanged.
10 The poor yields of 5a obtained in organic solvents (Table 4)
during the treatment of 3a with In/HCl raised the query as to
whether the use of aqueous medium exerts beneficial effect only
for the nitro reduction or its beneficial effect extends for the
subsequent cyclocondensation step as well. To distinguish any
15 role of water in the cyclocondensation of 4a to 5a, it was felt
necessary to treat the preformed 4a in water as well as in organic
solvents. However 4a could not be isolated by the In/HCl
reduction of 3a, although the MS spectra of the crude reaction
mixture exhibited ion peak corresponding to 4a. Attempts such as
20 (i) Pd/C mediated hydrogenation of 3a (Scheme 5), and (ii)
reaction of oꢀphenylenediamine (6) with 2a (Scheme 6) were
unsuccessful and resulted in the formation of 5a in 35 and 60%
yields, respectively.
Scheme 8. Acid/metalꢀfree cyclocondensation of 7a to form 5a.
The generality of the new strategy of ‘all water’ oneꢀpot tandem
70 Nꢀaryolmethylationꢀreductionꢀcondensation for synthesis of 2ꢀ
aryl quinoxalines is demonstrated by sequential treatment of
various oꢀnitroanilines with different αꢀbromoacetophenones in
water under heating followed by treatment with In/HCl (2N)
(Table 8).
25
Scheme 5. PdꢀCatalysed hyrogenation of 2ꢀ[(2ꢀnitrophenyl)amino]ꢀ1ꢀ
phenylethanone (3a).
75 Table 8. ‘All water’ cascade synthesis of 2ꢀaryl quinoxalines.a
Scheme 6. Reaction of oꢀphenylenediaimine (6) with αꢀ
bromoacetophenone (2a).
30 Thus, it was planned to prepare 8a [proꢀ4a] which would
generate 4a inꢀsitu through NꢀBoc deprotection under acid/metalꢀ
free condition (Scheme 7). Although a few methods18 were
reported for monoꢀNꢀBoc formation of 6, repetition of some of
these led to the mixture of the monoꢀ and diꢀNꢀBoc derivatives of
35 6 (Table 7).
Entry R1
R2
R3
R4
Time (h)b Yield (%)c
1
H
H
H
H
H
H
H
H
H
H
Cl
Cl
Cl
Cl
H
H
H
H
H
OMe
H
H
H
H
H
H
H
H
H
H
H
H
H
H
OMe
H
Cl
Br
H
OMe
Cl
Br
H
OMe
Cl
Br
OMe
Br
H
5
5
5
5
5
6
6
6
6
6
6
6
6
5
5
5
86
83
84
82
84
81
80
82
80
83
81
82
83
80
80
82
2
H
Table 7. Preparation of tertꢀbutyl (2ꢀaminophenyl)carbamate
80
85
3
H
(7a).a
4
H
5
H
6
7
8
9
10
11
12
Cl
Cl
Cl
Cl
H
Entry(Boc)2O Catalyst
(equiv) (mol%)
Solvent
(amt)
Temp Time Yield (%)b
(oC)
(h)
7a 7b
H
H
40
45
1
2
3
4
5
1.2
1
1
1
1
Gu·HClc (15)EtOH (1 mL)
LiClO4 (20) DCM (2 mL)
35ꢀ40
30ꢀ40
0
35ꢀ40
30
3
5
2
4
52 28
42 23
64 21
35 35
71 22
90 13
14
15
H
Me
Me
OMe
none
Iodine (10) neat
none EtOH (4 mL)
DCM (1 mL)
16
0.5
a1 (1 mmol) was treated with 2 (1 mmol, 1 equiv) in water (2 mL) at 110
95 °C (oil bath) for 3 h followed by addition of In (2.5 mmol, 2.5 equiv), 2N
HCl (2.5 mL, 5 mmol, 5 equiv) and allowed to proceed for remaining
time. bTotal time for the oneꢀpot reaction.c Isolated yield of 5.
aTreatment of 6 (1 mmol) under different reaction condition in different
solvents at specified temperature for specified time. bIsolated
yield.cGu·HCl stands for guanidinium hydrochloride.
The monoꢀNꢀBoc 7a was obtained in 71% yield following
Condensation of oꢀphenylenediamine with phenacyl bromide has
been reported in water as well as organic solvents in the presence
50 modification of literature report18e and was treated with 2a in
4
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of organic/inorganic catalysts to form 2ꢀphenylqunoxalines.4a,dꢀj,5c 50 bromide is expected to form regioisomeric quinoxalines as has
However, a catalystꢀfree protocol in water that would reflect the
distinct influence of water in the Nꢀaroylmethylation and
subsequent cycloꢀcondensation step is lacking. Thus, to evaluate
any distinct advantage of water over organic solvents 6 was
been observed in one of these reports.5c However, the
regioselectivity issue remained unaddressed/suppressed in the
other reported methodologies.4a,dꢀj To throw light on this
regioselectivity issue and establish the distinctiveness of the “all
5
treated with 2a in various solvents in the absence of any added 55 water” strategy of the Nꢀaroylmethylationꢀnitro reductionꢀ
base/acid catalyst at 110 °C (oil bath) (Table 9).
cyclocondensation cascade for regioselective synthesis of 2ꢀaryl
quinoxalines, the condensation of 4ꢀchloroꢀ1,2ꢀphenylenediamine
9 with phenacyl bromide was performed in water as well as in
organic solvents under the reported reaction conditions4a,dꢀj,5c
60 (Table 10). In all of these cases the isolated product on being
Table 9. Reaction of 6 with 2a in various solvents under catalystꢀfree
condition.a
1
subjected to H NMR analyses revealed to be a mixture of the
regioisomeric products. In each case, the pure regioisomers were
isolated through flash column chromatography and were
identified as A and B based on the spectral data of authentic
65 compounds (products of entries 6 and 10, respectively, of Table
8) and on comparison with literature reports.5i,l On the other hand,
the reaction of 4ꢀchloroꢀ2ꢀnitroaniline with phenacyl bromide
10
Entry Solvent
Temp (°C)
Yield (%)b
1
2
3
4
5
6
7
8
9
Water
Water
EtOH
Toluene
1,4ꢀDioxane
THF
DMF
MeCN
TFE
80
62
Reflux
Reflux
Reflux
Reflux
Reflux
110
79,71c,74d
following
the
tandem
Nꢀaroylmethylationꢀreductionꢀ
65
40
61
47
52
45
40
15
20
cyclocondensation strategy resulted in exclusive formation of one
70 of the regioisomeric quinoxalines without any concomitant
formation of the other regioisomer (entry 10, Table 8). This
clearly demonstrates the distinct advantage of this new synthetic
strategy. The unambiguous route of construction of the
quinoxaline scaffold under the present method forms the basis of
75 regioselectivity control.
Reflux
Reflux
a6 (1 mmol) was treated with 2a in the specific solvent (2 mL) at 80/110
°C (oil bath temperature) for 4 h (unless specified). bIsolated yield of 5a.
cThe yield of 5a in performing the reaction for 3 h. The yield of 5a in
d
Table 10. Reaction of I with 2a under the reported reaction conditions.a
performing the reaction for 3 h in the presence of K2CO3 (1 equiv).
25 The best yield obtained in water clearly reflect the distinct
advantage of water as the reaction medium for the tandem Nꢀ
aroylmethylationꢀcyclocondensation. Comparable yield (74%)
obtained in performing the reaction in water in the presence of
K2CO3 (1 equiv) (Table 9, entry 2, footnote d) rules out the
30 possibility of any essential role of the liberated HBr (during the
initial Nꢀaroylmethylation step) for the final cyclocondensation.
The significant role of the solvent (Table 9) in the final
cyclocondensation step can be demonstrated by the best results
are obtained in water that acts both as good hydrogen bond donor
35 and hydrogen bond acceptor with the second best results obtained
in EtOH. The lesser yield obtained in TFE compared to that in
water and EtOH is the clear reflection of the inferior hydrogen
bond acceptor ability of TFE. The use of 1,4ꢀdioxane afforded the
next best result due to its appreciable hydrogen bond acceptor
40 ability (to activate the amino group of the intermediately formed
4a). The better result in 1,4ꢀdioxane compared to that of THF
could be due to the chelation effect of the two oxygen atoms in
the former to form the HB with the NH2 group more effectively.
The inferior yields in DMF, MeCN and toluene are also reflection
45 of the unfavourable hydrogen bond donor/acceptor ability of
these solvents.
Entry Catalystb
(mol%)
Solvent
Temp Time
(A:B)c yield (%)d
(oC)
(h)
A
B
80
85
90
1
2
3
4
5
6
Pyridine (10)
ꢀꢀꢀ
βꢀCD (1 equiv) Water
TMSCl (1 equiv) Water
CTAB (20)
HClO4ꢀSiO2
(50 mg)
THF
PEGꢀ400
rt
2
8
3
8
8
1
20:80 25 45
83:17 65 15
79:21 63 21
86:14 51 12
34:65 25 62
22:77 15 63
80
70
70
10
rt
Water
MeCN
7
TBAB (20)
Water
rtꢀ70
4.5
72:28 51 18
+ K2CO3 (2 equiv)
8
9
DABCO (20)
ꢀꢀꢀ
THF
Water
rt
110
1
7
32:67 12 62
58:42 33 41e
aI (1 mmol) was treated with 2a under the various reported reaction
conditions. bLit ref: 4a, 4eꢀj, and 5c for entries 1ꢀ8, respectively.
cRegioisomeric distribution based on Ha and Hb proton integration value
1
d
in the H NMR of the crude reaction mixture. Isolated yield after flash
95 column chromatography. eData generated under the condition of the
present study.
Although the quinoxaline formation by a direct condensation of 6
with 2a becomes feasible in water under catalystꢀfree condition,
the reaction of unsymmetrical oꢀphenylenediamine with phenacyl
Conclusions
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DOI: 10.1039/C4RA16568C
A new synthetic strategy of ‘all water’ tandem aroylmethylationꢀ
nitro reductionꢀcyclocondensation is reported for the first and
400 mesh size, 2.5 g), and eluted with hexaneꢀEtOAc (95:5) to
obtain
analytically
pure
2ꢀ((2ꢀnitrophenyl)amino)ꢀ1ꢀ
generalized regioselective synthesis of 2ꢀaryl quinoxalines. Water 60 phenylethanone (Table 2, Entry 1) (3a) as Yellow solid (236 mg,
plays the critical role through hydrogen bond driven ‘synergistic
electrophile nucleophile dual activation’ during the Nꢀ
aroylmethylation and provides the basis of quinoxaline formation
in regiodefined manner. Water also exerts beneficial effect during
92 %); mp = 147ꢀ149 °C; IR (KBr)
= 3433, 2926, 2872,
max
5
1735, 1619, 1570, 1514, 1453, 1352, 1259, 1106, 951, 749 cmꢀ1;
1H NMR (CDCl3, 400MHz, TMS) δ: 8.92 (bs, 1H), 8.25 (dd,
J=1.5, 8.5Hz, 1H), 8.07ꢀ8.05 (m, 2H), 7.69ꢀ7.65 (m, 1H), 7.58ꢀ
the nitro reductionꢀcyclocondensation cascade and makes this 65 7.48 (m, 3H), 6.84ꢀ6.82 (m, 1H), 6.76ꢀ6.72 (m, 1H), 4.80 (d,
synthetic strategy a true example of ‘allꢀwater chemistry.’
J=4.4Hz, 2H); 13C NMR (CDCl3, 100MHz, TMS) δ: 192.71,
143.97, 136.22, 134.44, 134.22, 132.70, 129.04, 127.89, 127.08,
115.98, 114.14, 49.42; MS (APCI) m/z: 257 (M+H)+. HRMS
(ESI) m/z calcd for C14H12N2O3Na+ [M+Na+], 279.0740; Found
70 279.0740.
10 Experimental section
General remarks: The glasswares used were thoroughly washed
and dried in an oven and the experiments were carried out with
required precautions. Chemicals and all solvents were
commercially available and used without further purification. The
15 TLC experiments were performed on silica gel GFꢀ254 and
visualized under UV at 254 nm. Evaporation of solvent was
performed at reduced pressure using a rotary evaporator. Melting
points were measured using a melting point apparatus and were
Typical procedure for the cascade reductionꢀcondensation of
3a to 5a: To the mixture of 2ꢀ[(2ꢀnitrophenyl)amino]ꢀ1ꢀ
phenylethanone 3a (256 mg, 1 mmol) in water (2 mL) was added
In metal (287 mg, 2.5 mmol, 2.5 equiv) and 2N HCl (2.5 mL, 5
75 mmol, 5 equiv), and the mixture was stirred magnetically at 110
°C (oilꢀbath) for 3 h (TLC). The reaction mixture was extracted
with EtOAc (3 × 5 mL). The combined EtOAc extracts were
dried (anh Na2SO4), filtered, and the filtrate was concentrated
under rotary vacuum evaporation. The crude product was
80 adsorbed on silica gel (230ꢀ400 mesh size, 500 mg), charged on
to a flash chromatography column of silicaꢀgel (230ꢀ400 mesh
size, 2.5 g), and eluted with hexaneꢀEtOAc (99:1) to obtain
analytically pure 5a as a pale orange solid (185 mg, 90%)4a
(Table 4).
1
uncorrected. The H and 13C NMR spectra were recorded on a
20 400 MHz NMR spectrometer in CDCl3 with residual
undeuterated solvent (CHCl3: 7.26/77.0) using Me4Si as an
internal standard. The chemical shift (δ) values are given in ppm
and J values are given in Hz. The 13C NMR spectra were fully
decoupled and were referenced to the middle peak of the solvent
25 CDCl3 at 77.00 ppm. Splitting pattern were designated as s,
singlet; bs, broad singlet; d, doublet; dd, doublet of doublet; t,
triplet; dt, doublet of triplet and m, multiplet. The mass spectra
(MS) were recorded under atmospheric pressure chemical
ionization (APCI) and electrospray ionization (ESI). The high
30 resolution mass spectra (HRMS) were recorded under
electrospray ionization (ESI). The infraꢀred (IR) spectra were
recorded in the range of 4000ꢀ600 cmꢀ1 as KBr pellets for all solid
samples.
85 Typical procedure for ‘all water’ oneꢀpot tandem Nꢀ
aryolmethylationꢀreductionꢀcondensation for synthesis of 2ꢀ
aryl quinoxalines. Synthesis of 5a: The mixture of oꢀ
nitroaniline 1a (138 mg, 1 mmol) and αꢀbromacetophenone 2a
(199 mg, 1 mmol, 1 equiv) in water (2 mL) was stirred
90 magnetically at 110 °C (oilꢀbath) for 3 h followed by addition of
In (287 mg, 2.5 mmol, 2.5 equiv), 2N HCl (2.5 mL, 5 mmol, 5
equiv) and the reaction mixture was allowed to stir till the
completion of reaction (2 h, TLC). The reaction mixture was
extracted with EtOAc (3 × 5 mL). The combined EtOAc extracts
95 were dried (anh Na2SO4), filtered, and the filtrate was
concentrated under rotary vacuum evaporation. The crude
product was recrystallized from EtOH to afford analytically pure
2ꢀphenylquinoxaline (Table 8, Entry 1) (5a) as a pale orange
solid (177 mg, 86 %). mp = 75ꢀ76 °C; max = 3005, 2325, 1275,
Preparation of Pure water (15 Mꢁꢀcm resistivity at 25 °C):
35 The pure water was prepared by subjecting the tap water for
reverse osmosis and ionic/organic removal by passing through
preꢀpacked cartridge.
Preparation of Ultrapure water (18.2 Mꢁꢀcm resistivity at 25
°C): The ultrapure water was prepared by subjecting the pure
40 water for UV treatment (185/254 nm UV Lamp), deionization by
passing through deionization cartridge followed by ultra
membrane filtration (0.01um) under pressures up to 145 psi (10
bar). Ultrapure water (UPW) is generally considered to be ≥ 18.2
Mꢁꢀcm resistivity at 25ºC, low ppt in metals, less than 50 ppt in
45 inorganic anions and ammonia, less than 0.2 ppb in organic
anions, and below 1 ppb total organic carbon (TOC) and silica
(dissolved and colloidal).
Typical procedure for selective monoꢀNꢀbenzoylmethylation
of oꢀnitroaniline (1a): The mixture of oꢀnitroaniline 1a (138 mg,
50 1 mmol) and αꢀbromacetophenone 2a (199 mg, 1 mmol, 1 equiv)
in water (2 mL) was stirred magnetically at 110 °C (oilꢀbath).
After completion of the reaction (3 h, TLC), the reaction mixture
was extracted with EtOAc (3 × 5 mL). The combined EtOAc
extracts were dried (anh Na2SO4), filtered, and the filtrate was
55 concentrated under rotary vacuum evaporation. The crude
product was adsorbed on silica gel (230ꢀ400 mesh size, 500 mg),
charged on to a flash chromatography column of silicaꢀgel (230ꢀ
1
100 1260, 764, 750 cmꢀ1; H NMR (CDCl3, 400MHz, TMS) δ: 9.26
(s, 1H), 8.15ꢀ8.05 (m, 4H), 7.72ꢀ7.65 (m, 2H), 7.52ꢀ7.45 (m, 3H);
13C NMR (CDCl3, 100MHz, TMS) δ: 151.68, 143.26, 142.21,
141.53, 136.69, 130.19, 130.13, 129.57, 129.45, 129.07, 127.48;
MS (ESI) m/z: 207 (M+H)+.4a
105
In an alternative purification procedure the crude product was
adsorbed on silica gel (230ꢀ400 mesh size, 500 mg), charged on
to a flash chromatography column of silicaꢀgel (230ꢀ400 mesh
size, 2.5 g), and eluted with hexaneꢀEtOAc (99:1) to obtain
analytically pure 2ꢀphenylquinoxaline (Table 8, Entry 1) (5a) as a
110 pale orange solid (173 mg, 84 %).
In general, the purification was made by crystallization except
for low melting (< 65 °C) compounds wherein the purification
was made through column chromatography.
Experimental procedure for the various attempts for the
115 synthesis of 2ꢀ((2ꢀaminophenyl)amino)ꢀ1ꢀphenylethanone
6
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(4a):
(M+H)+.17a
PdꢀCatalysed hydrogenation of 2ꢀ[(2ꢀnitrophenyl)amino]ꢀ1ꢀ 55 Step 2 (Scheme 7): Synthesis of tertꢀbutyl (2ꢀ[(2ꢀoxoꢀ2ꢀ
phenylethanone (3a) (Scheme 5). Pd/C (5%) (10 mg) was added
to the of 3a (256 mg, 1 mmol) in toluene (10 mL) and kept under
H2 atmosphere at room temperature at 40 psi pressure. After 6 h,
the Pd/C was removed by filtration and the filtrate was
phenylethyl)aminophenyl]carbamate (8a) from 7a. The
mixture of tertꢀbutyl2ꢀaminophenylcarbamate (7a) (208 mg,
1mmol) and αꢀbromacetophenone (2a) (199 mg, 1 mmol, 1
equiv) in water (2 mL) was stirred magnetically at rt. After
5
concentrated under rotary vacuum evaporation. The crude 60 completion of the reaction (12 h, TLC), the reaction mixture was
product was adsorbed on silica gel (230ꢀ400 mesh size, 500 mg),
charged on to a flash chromatography column of silicaꢀgel (230ꢀ
extracted with EtOAc (3 × 5 mL). The combined EtOAc extracts
were dried (anh Na2SO4), filtered, and the filtrate was
concentrated under rotary vacuum evaporation. The crude
product was adsorbed on silica gel (230ꢀ400 mesh size, 500 mg),
αꢀ 65 charged on to a flash chromatography column of silicaꢀgel (230ꢀ
400 mesh size, 2.5 g), and eluted with hexaneꢀEtOAc (94:6) to
obtain analytically pure 8a as a light yellow solid (189 mg, 58
%); mp = 130ꢀ132 °C; IR (KBr) max = 3368, 2925, 1698, 1607,
1498, 1449, 1356, 1248, 1166, 1048, 739 cmꢀ1; 1H NMR (CDCl3,
10 400 mesh size, 2.5 g), and eluted with hexaneꢀEtOAc (99:1) to
obtain analytically pure 5a as a pale orange solid (72 mg, 35%).4a
Reaction
of
oꢀphenylenediaimine
(6)
with
bromoacetophenone (2a) (Scheme 6):
To the mixture of oꢀphenylenediaimine (6) (108 mg, 1 mmol) and
15 αꢀbromacetophenone (2a) (199 mg, 1 mmol, 1 equiv) in MeCN
(2 mL) was added K2CO3 (276 mg, 2 mmol, 2 equiv) and stirred
magnetically under reflux condition. After completion of the 70 400MHz, TMS) δ: 8.03 (d, J=7.4Hz, 2H), 7.64 (t, J=7.36Hz, 1H),
reaction (4 h, TLC), the reaction mixture was extracted with
EtOAc (3 × 5 mL). The combined EtOAc extracts were dried
20 (anh Na2SO4), filtered, and the filtrate was concentrated under
rotary vacuum evaporation. The crude product was adsorbed on
7.53 (t, J=7.72Hz, 2H), 7.39 (t, J=7.04Hz, 1H), 7.15ꢀ7.11 (m,
1H), 6.81 (t, J=7.44Hz, 1H), 6.74 (d, J=7.96Hz, 1H), 6.27 (s,
1H), 4.99 (bs, 1H), 4.61 (bs, 2H), 1.56 (s, 9H); 13C NMR (CDCl3,
100MHz, TMS) δ: 195.22, 154.16, 141.16, 134.93, 133.89,
silica gel (230ꢀ400 mesh size, 500 mg), charged on to a flash 75 128.92, 127.78, 126.58, 125.60, 124.68, 118.59, 112.93, 80.57,
chromatography column of silicaꢀgel (230ꢀ400 mesh size, 2.5 g),
and eluted with hexaneꢀEtOAc (99:1) to obtain analytically pure
25 5a as a pale orange solid (123 mg, 60%).4a
50.75, 28.36; MS (ESI) m/z: 237 (M+H)+. HRMS (ESI) m/z
calcd for C19H22N2O3Na+ [M+Na+], 349.1528; Found 349.1545.
Experimental procedure for the synthesis of 5a from 8a
(Scheme 8): The mixture of tertꢀbutyl (2ꢀ[(2ꢀoxoꢀ2ꢀ
Experimental procedure for the synthesis of tertꢀbutyl (2ꢀ[(2ꢀ
oxoꢀ2ꢀphenylethyl) aminophenyl]carbamate (8a) (Scheme 80 phenylethyl)aminophenyl]carbamate (8a) (326 mg, 1 mmol) in
7/Table 7):
water (3 mL) was stirred magnetically at 110 °C (oilꢀbath) After
completion of the reaction (2 h, TLC), the reaction mixture was
extracted with EtOAc (3 × 5 mL). The combined EtOAc extracts
were dried (anh Na2SO4), filtered, and the filtrate was
Step 1: Preparation of tertꢀbutyl (2ꢀaminophenyl) carbamate
30 (7a). oꢀPhenyldiamine (6) (108 mg, 1 mmol) was stirred at 30 oC
in absolute EtOH (2 mL), and diꢀtertꢀbutyl dicarbonate (218 mg,
1.1 mmol, 1.1 equiv), dissolved in absolute EtOH (2 mL), was 85 concentrated under rotary vacuum evaporation. The crude
added dropwise to the reaction mixture. After 30 min, the solvent
was evaporated to dryness, and the crude material. The crude
35 product was adsorbed on silica gel (230ꢀ400 mesh size, 500 mg),
charged on to a flash chromatography column of silicaꢀgel (230ꢀ
product was adsorbed on silica gel (230ꢀ400 mesh size, 500 mg),
charged on to a flash chromatography column of silicaꢀgel (230ꢀ
400 mesh size, 2.5 g), and eluted with hexaneꢀEtOAc (99:1) to
obtain analytically pure 5a as a pale orange solid (168 mg,
400 mesh size, 2.5 g), and eluted with hexaneꢀEtOAc (96:4) to 90 82%).4a
obtain analytically pure tertꢀbutyl (2ꢀaminophenyl)carbamate
(7a) as a white solid (147 mg, 71%); mp = 110ꢀ113 °C; IR (KBr)
Experimental procedure for the synthesis of 5a from 8a
(Scheme 8):The mixture of tertꢀbutyl (2ꢀ[(2ꢀoxoꢀ2ꢀ
phenylethyl)aminophenyl]carbamate (8a) (326 mg, 1mmol) in
TFE (3 mL) was stirred magnetically at 90 °C (oilꢀbath). After
40
= 3414, 3356, 2973, 1896, 1682, 1595, 1490, 1456, 1387,
max
1366, 1162, 1054, 1027, 850, 749 cmꢀ1; 1H NMR (CDCl3,
400MHz, TMS) δ: 7.28ꢀ7.27 (m, 1H), 7.00 (dt, J=1.36, 7.6Hz, 95 completion of the reaction (24 h, TLC), the reaction mixture was
1H), 6.81ꢀ6.75 (m, 2H), 6.35 (bs, 1H), 3.75 (bs, 2H), 1.52 (s, 9H);
13C NMR (CDCl3, 100MHz, TMS) δ: 153.91, 139.99, 126.13,
45 124.77, 119.56, 117.57, 80.50, 28.35; MS (ESI) m/z: 209
(M+H)+. HRMS (ESI) m/z calcd for C11H16N2O2Na+ [M+Na+],
231.1109; Found 231.1114.17e
extracted with EtOAc (3 × 5 mL). The combined EtOAc extracts
were dried (anh Na2SO4), filtered, and the filtrate was
concentrated under rotary vacuum evaporation. The crude
product was adsorbed on silica gel (230ꢀ400 mesh size, 500 mg),
100 charged on to a flash chromatography column of silicaꢀgel (230ꢀ
400 mesh size, 2.5 g), and eluted with hexaneꢀEtOAc (99:1) to
obtain analytically pure 5a as a pale orange solid (31 mg, 15%).4a
1ꢀ(4ꢀChlorophenyl)ꢀ2ꢀ[(2ꢀnitrophenyl)amino]ethanone (Table
Diꢀtertꢀbutyl 1,2ꢀphenylenedicarbamate (7b). white solid (65
mg, 22%); mp = 105ꢀ106 °C; IR (KBr) max = 3307, 2978, 2931,
1
50 1699, 1601, 1527, 1457, 1248, 1158, 1049, 1025, 749 cmꢀ1; H
NMR (CDCl3, 400MHz, TMS) δ: 7.47 (bs, 2H), 7.11 (s, 2H),
3, Entry 2): Yellow solid (266 mg, 91 %); mp = 153ꢀ156 °C; ; IR
1
6.89 (s, 2H), 1.52 (s, 18H); 13C NMR (CDCl3, 100MHz, TMS) δ: 105 (KBr)
= 2981, 1275, 1260, 1054, 1033, 764, 750 cmꢀ1; H
max
153.90, 130.29, 125.31, 124.22, 80.76, 28.46; MS (ESI) m/z: 309
NMR (CDCl3, 400MHz, TMS) δ: 8.87 (bs, 1H), 8.24 (dd, J=1.52,
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8.52Hz, 1H), 7.99 (dd, J=1.84, 6.8Hz, 2H), 7.53ꢀ7.46 (m, 3H),
142.30, 141.20, 130.14, 129.39, 129.26, 129.07, 129.01,
6.81ꢀ6.72 (m, 2H), 4.76 (d, J=4.4Hz, 2H); 13C NMR (CDCl3, 60 128.95,114.56, 55.41; MS (ESI) m/z: 237 (M+H)+.
100MHz, TMS) δ: 191.64, 143.86, 140.80, 138.96, 136.24,
129.45, 129.30, 127.17, 116.17, 114.05, 49.43; MS (APCI) m/z:
291 (M+H)+. HRMS (ESI) m/z calcd for C14H11ClN2O3Na+
[M+Na+], 313.0350; Found 313.0349.
2ꢀ(3ꢀMethoxyphenyl)quinoxaline (Table 8, Entry 3)5k: Light
yellowish orange solid (198 mg, 84 %); mp = 87ꢀ88 °C; IR (KBr)
max = 3434, 2918, 2846, 2225, 1733, 1275, 1260, 1022, 750 cmꢀ
5
1
1; H NMR (CDCl3, 400MHz, TMS) δ: 9.36 (s, 1H), 8.19ꢀ8.13
2ꢀ[(4ꢀChloroꢀ2ꢀnitrophenyl)amino]ꢀ1ꢀphenylethanone (Table 65 (m, 2H), 7.92 (dd, J=1.8,7.64 Hz, 1H), 7.80ꢀ7.74 (m, 2H), 7.52ꢀ
3, Entry 3): Yellow solid (258 mg, 89 %); mp = 158ꢀ160 °C; IR
7.48 (m, 1H), 7.22ꢀ7.17 (m, 1H), 7.09 (d, J=8.24 Hz, 1H), 3.93 (s,
3H); 13C NMR (CDCl3, 100MHz, TMS) δ: 157.40, 152.23,
147.30, 142.71, 141.06, 131.61, 131.44, 129.76, 129.55, 129.37,
129.07,126.56, 121.54, 111.43, 55.65; MS (ESI) m/z: 237
(KBr)
= 3342, 3005.58, 1691, 1628, 1561.90, 1517, 1402,
max
10 1351, 1275, 1261,1156, 1070, 808, 764, 750 cmꢀ1;1H NMR
(CDCl3, 400MHz, TMS) δ: 8.89 (bs, 1H), 8.24 (d, J=2.36Hz,
1H), 8.04 (d, J=7.52Hz, 2H), 7.67 (t, J=7.4Hz, 1H), 7.55 (t, 70 (M+H)+.
J=7.76Hz, 2H), 7.44 (dd, J=2.36, 9.04Hz, 1H), 6.79 (d,
J=9.04Hz, 1H), 4.77 (d, J=4.24Hz, 2H); 13C NMR (CDCl3,
15 100MHz, TMS) δ: 192.30, 142.62, 136.28, 134.38, 134.30,
129.11, 127.92, 126.32, 120.83, 115.54, 49.44; MS (APCI) m/z:
2ꢀ(4ꢀChlorophenyl)quinoxaline (Table 8, Entry 4)4a: Light
orange solid (197 mg, 82 %); mp = 120ꢀ122 °C; IR (KBr)
=
max
3004, 2325, 1260, 1275, 764, 750 cmꢀ1; 1H NMR (CDCl3,
400MHz, TMS) δ: 9.31 (s, 1H), 8.19ꢀ8.13 (m, 4H), 7.83ꢀ7.75 (m,
291 (M+H)+. HRMS (ESI) m/z calcd for C14H11ClN2O3Na+ 75 2H), 7.57ꢀ7.54 (m, 2H); 13C NMR (CDCl3, 100MHz, TMS) δ:
[M+Na+], 313.0350; Found 313.0350.
150.59, 142.87, 142.22, 141.66, 136.59, 135.19, 130.48, 129.79,
129.60, 129.41, 129.17, 128.78; MS (ESI) m/z: 241 (M+H)+.
2ꢀ(4ꢀBromophenyl)quinoxaline (Table 8, Entry 5)5k: Light
brown solid (238 mg, 84 %); mp = 138 °C; 1H NMR (CDCl3, 400
2ꢀ[(5ꢀChloroꢀ2ꢀnitrophenyl)amino]ꢀ1ꢀphenylethanone (Table
20 3, Entry 4): Yellow solid (262 mg, 90 %); mp = 155ꢀ158 °C; IR
(KBr) max = 3362, 2924, 1695, 1623, 1491, 1275, 1259, , 1078,
1
750 cmꢀ1; H NMR (CDCl3, 400MHz, TMS) δ: 9.00 (bs, 1H), 80 MHz, TMS) δ: 9.29 (s, 1H), 8.15ꢀ8.07 (m, 4H), 7.82ꢀ7.74 (m,
8.20 (d, J=9.08Hz, 1H), 8.06 (d, J=1.2Hz, 2H), 7.69 (t, J=7.44Hz,
1H), 7.57 (t, J=8Hz, 2H), 6.84 (d, J=1.96Hz, 1H), 6.72 (dd, J=2,
25 9.14Hz, 1H), 4.78 (d, J=4.28Hz, 2H); 13C NMR (CDCl3,
100MHz, TMS) δ: 192.12, 144.41, 142.70, 134.41, 134.23,
2H), 7.71ꢀ7.68 (m, 2H); 13C NMR (CDCl3, 100MHz, TMS) δ:
150.66, 142.83, 142.22, 141.68, 135.62, 132.80, 130.37, 131.88,
130.52, 129.84, 129.60,129.18, 129.02, 125.00; MS (ESI) m/z:
284 (M+H)+.
130.17, 129.28, 129.11, 128.52, 128.32, 127.96, 116.48, 113.71 85 7ꢀChloroꢀ2ꢀphenylquinoxaline (Table 8, Entry 6)5i: Light
49.39; MS (ESI) m/z: 291 (M+H)+. HRMS (ESI) m/z calcd for
C14H11ClN2O3Na+ [M+Na+], 313.0350; Found 312.1499.
30 2ꢀ[(4ꢀMethylꢀ2ꢀnitrophenyl)amino]ꢀ1ꢀphenylethanone (Table
3, Entry 5): Light yellow solid (248 mg, 92 %); mp = 162ꢀ164
orange solid (194 mg, 81 %); mp = 104ꢀ106 °C; IR (KBr)
=
max
3047, 2922, 2852. 1606, 1539, 1483,1449, 1404, 1314, 1131,
1073,958, 913,834, 758, 686, 666 cmꢀ1; 1H NMR (CDCl3,
400MHz, TMS) δ: 9.30 (s, 1H), 8.20ꢀ8.14 (m, 3H), 8.04 (d,
°C; IR (KBr) max = 3362, 2923, 1742, 1692, 1637, 1561, 1528, 90 J=8.92Hz, 1H), 7.68 (dd, J=2.16, 8.84Hz, 1H), 7.58ꢀ7.55 (m,
1
1275, 1155, 750 cmꢀ1; H NMR (CDCl3, 400MHz, TMS) δ: 8.78
(bs, 1H), 8.06 (d, J=7.56Hz, 3H), 7.67 (t, J=7.36Hz, 1H), 7.56 (t,
35 J=7.56Hz, 2H), 7.33 (d, J=8.52Hz, 1H), 6.75 (d, J=8.6Hz, 1H),
4.78 (d, J=4.28Hz, 2H), 2.31 (s, 3H); 13C NMR (CDCl3, 100MHz,
3H); 13C NMR (CDCl3, 100MHz, TMS) δ: 152.48, 143.38,
142.62, 140.07, 136.27, 136.07, 130.56, 130.48, 130.34, 129.21,
128.95, 128.49, 127.84, 127.60; MS (ESI) m/z: 240 (M)+.
7ꢀChloroꢀ2ꢀ(4ꢀmethoxyphenyl)quinoxaline (Table 8, Entry
TMS) δ: 192.91, 142.19, 137.62, 134.52, 134.17, 132.33, 129.03, 95 7)5i: Offꢀwhite solid (216 mg, 80 %); mp = 103ꢀ105 °C; IR (KBr)
127.89, 126.44, 125.59, 114.12, 49.55, 20.01; MS (APCI) m/z:
271 (M+H)+. HRMS (ESI) m/z calcd for C15H14N2O3Na+
40 [M+Na+], 293.0897; Found 293.0785.
= 2922, 1607, 1539, 1487, 1258, 1225, 1181, 1125, 1071,
max
1025, 957, 914, 841, 827, 750, 571, 515 cmꢀ1; H NMR (CDCl3,
400MHz, TMS) δ: 9.30 (d, J=5.92Hz, 1H), 8.19 (dd, J=3.04,
8.76Hz, 2H), 8.12 (dd, J=2.12, 10.88Hz, 1H), 8.08ꢀ8.03 (m, 1H),
1
1ꢀ(4ꢀMethoxyphenyl)ꢀ2ꢀ[(4ꢀmethylꢀ2ꢀ
nitrophenyl)amino]ethanone (Table 3, Entry 6): Yellowish 100 7.73ꢀ7.66 (m, 1H), 7.10 (d, J=8.72Hz, 2H), 3.93 (s, 3H); 13C
orange solid (270 mg, 90 %); mp = 128ꢀ130 °C; IR (KBr)
=
NMR (CDCl3, 100MHz, TMS) δ: 161.77, 143.88, 143.15,
135.97, 131.21, 130.61, 130.29, 130.00, 129.10, 128.99, 128.79,
128.28, 128.03, 114.68, 55.49; MS (APCI) m/z: 271 (M+H)+.
HRMS (ESI) m/z calcd for C15H11ClN2ONa+ [M+Na+], 293.0452;
max
3364, 2912, 1676, 1632, 1600, 1560, 1524, , 1424, 1348, 1262,
1
45 1241, 1181, 764 cmꢀ1; H NMR (CDCl3, 400MHz, TMS) δ: 8.75
(bs, 1H), 8.01 (s, 2H), 7.99 (d, J=1.96Hz, 1H), 7.28 (dd, J=2,
14.5Hz, 1H), 6.99 (d, J=1.9Hz, 2H), 6.71 (d, J=8.6Hz, 1H), 4.68 105 Found 293.0452.
(d, J=4.4Hz, 2H), 3.88 (s, 3H), 2.27 (s, 3H); 13C NMR (CDCl3,
100MHz, TMS) δ: 191.31, 164.26, 142.30, 137.59, 132.32,
50 132.20, 127.51, 126.42, 125.42, 114.18, 113.75, 55.61,49.15,
20.00; MS (ESI) m/z: 301 (M+H)+. HRMS (ESI) m/z calcd for
C16H16N2O4Na+ [M+Na+], 323.1008; Found 323.1005.
7ꢀChloroꢀ2ꢀ(4ꢀchlorophenyl)quinoxaline (Table 8, Entry 8):
Light orange solid (225 mg, 82 %); mp = 180ꢀ182 °C; IR (KBr)
1
= 2922, 1521, 1275, 1260, 1022, 764, 750 cmꢀ1; H NMR
max
(CDCl3, 400MHz, TMS) δ: 9.30 (s, 1H), 8.18ꢀ8.15 (m, 3H), 8.07
110 (d, J=8.92Hz, 1H), 7.72 (dd, J=2.32, 8.92Hz, 1H) 7.58ꢀ7.55 (m,
2H); 13C NMR (CDCl3, 100MHz, TMS) δ: 151.30, 142.92,
142.56, 140.17, 137.01, 136.33, 134.70, 131.53, 130.77, 130.39,
129.48, 128.82, 128.73, 128.45; MS (APCI) m/z: 275 (M+H)+.
HRMS (ESI) m/z calcd for C14H8Cl2N2Na+ [M+Na+], 296.9957;
2ꢀ(4ꢀMethoxyphenyl)quinoxaline (Table 8, Entry 2)5k: Light
yellow solid (377 mg, 83 %); mp = 97ꢀ98 °C; IR (KBr)
=
max
1
55 2926, 1606, 1584, 1274, 1252, 1175, 1028, 834, 763 cmꢀ1; H
NMR (CDCl3, 400 MHz, TMS) δ: 9.28 (s, 1H), 8.18ꢀ8.07 (m,
4H), 7.76ꢀ7.67 (m, 2H), 7.08ꢀ7.04 (m, 2H), 3.87 (s, 3H); 13C 115 Found 297.1305.
NMR (CDCl3, 100MHz, TMS) δ: 161.45, 151.37, 143.04,
2ꢀ(4ꢀBromophenyl)ꢀ7ꢀchloroquinoxaline (Table 8, Entry 9)5c:
8
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Light brown solid (256 mg, 80 %); mp = 144ꢀ146 °C; IR (KBr)
(d, J=14.28Hz 1H), 7.62ꢀ 7.55 (m, 1H), 7.10 (d, J=8.44Hz 2H),
= 2922, 2075, 1633, 1421, 1176, 1075, 957, 880, 835, 775, 55 3.92 (s, 3H), 2.62 (s, 3H); 13C NMR (CDCl3, 100MHz, TMS) δ:
max
711 cmꢀ1; 1H NMR (CDCl3, 400 MHz, TMS) δ: 9.28 (s, 1H), 8.13
161.30, 142.99, 142.19, 139.57, 132.48, 131.37, 129.51, 128.92,
128.82, 128.58, 128.29, 127.97, 114.56, 55.45, 21.80; MS (ESI)
m/z: 251 (M+H)+.
(d, J=2.24Hz, 1H), 8.09ꢀ8.04 (m, 3H), 7.72ꢀ7.68 (m, 3H); 13C
NMR (CDCl3, 100MHz, TMS) δ: 151.40, 142.89, 142.58,
140.21, 136.37, 135.16, 132.46, 130.82, 130.41, 129.06, 128.97,
128.47, 128.13, 125.44; MS (APCI) m/z: 321 (M+2H)+.
5
2ꢀ(4ꢀBromophenyl)ꢀ7ꢀmethylquinoxaline (Table 8, Entry
60 15)5c: Yellowish orange (238 mg, 80 %); mp = 96ꢀ98 °C; IR
6ꢀChloroꢀ2ꢀphenylquinoxaline (Table 8, Entry 10)5i: Colorless
(KBr)
= 2920, 2851, 1624, 1587, 1488, 1436, 1131, 1072,
max
1
crystal (199 mg, 83 %); mp = 125ꢀ127 °C; IR (KBr)
=
1009, 960, 834, 777 cmꢀ1; H NMR (CDCl3, 400MHz, TMS) δ:
9.22 (s, 1H), 8.06 (dd, J=1.92, 6.64Hz, 2H), 7.99 (d, J=8.56Hz,
1H), 7.91 (s, 1H), 7.68 (dd, J=1.84, 6.72Hz, 2H), 7.58 (dd,
max
10 3367, 2162, 1276, 1256, 752 cmꢀ1; H NMR (CDCl3, 400MHz,
1
TMS) δ: 9.34 (s, 1H), 8.21ꢀ8.19 (m, 2H), 8.13ꢀ8.09 (m, 2H), 7.74
(dd, J=2.36, 8.96Hz, 1H), 7.62ꢀ7.55 (m, 3H); 13C NMR (CDCl3, 65 J=1.84, 8.56Hz, 1H), 2.61 (s, 3H); 13C NMR (CDCl3, 100MHz,
100MHz, TMS) δ: 151.95, 144.16, 141.82, 140.85, 136.38,
135.26, 131.34, 130.85, 130.45, 129.24, 128.09, 127.53; MS
15 (APCI) m/z: 241 (M+H)+.
TMS) δ: 150.58, 142.31, 141.92, 141.11, 140.21, 135.82, 132.32,
132.18, 128.97, 128.89, 128.66, 128.43, 124.83, 21.91; MS
(APCI) m/z:
C15H11BrN2Na+ [M+H+], 299.0106; Found 299.0178.
299 (M+H)+. HRMS (ESI) m/z calcd for
6ꢀChloroꢀ2ꢀ(4ꢀmethoxyphenyl)quinoxaline (Table 8, Entry
11)5i:Offꢀwhite solid (219 mg, 81 %); mp = 140ꢀ142 °C; IR 70 7ꢀMethoxyꢀ2ꢀphenylquinoxaline
(Table
8,
Entry
(KBr)
= 2930, 2837, 1674, 1606, 1577, 1538, 1519, 1454,
16)5i:Colorless crystal (193 mg, 82 %); mp = 86ꢀ88 °C; IR (KBr)
max
1
1309, 1287, 1273, 1257, 1171, 1066, 1026, 957, 827, 764, 750,
20 570, 515 cmꢀ1; 1H NMR (CDCl3, 400MHz, TMS) δ: 9.29 (s, 1H),
8.18 (dd, J=1.84, 7Hz, 2H), 8.09 (d, J=2.2Hz, 1H), 8.05 (d,
= 2917, 2840, 1733, 1459, 1260, 1078, 1025, 750 cmꢀ1; H
max
NMR (CDCl3, 400MHz, TMS) δ: 9.19 (s, 1H), 8.20ꢀ8.18 (m,
2H), 8.02 (d, J=9.12Hz, 1H), 7.61ꢀ7.54 (m, 3H), 7.45 (d,
J=8.96Hz, 1H), 7.71 (dd, J=2.28, 8.92Hz, 1H), 7.09 (dd, J=1.76, 75 J=2.72Hz, 1H), 7.42 (dd, J=2.76, 9.12Hz, 1H), 4.02 (s, 3H); 13C
6.92Hz, 2H), 3.92 (s, 3H); 13C NMR (CDCl3, 100MHz, TMS) δ:
161.68, 151.53, 143.84, 141.42, 140.87, 134.66, 131.18, 130.60,
25 128.97, 128.86, 128.02, 114.67, 55.46; MS (APCI) m/z: 271
(M+H)+. HRMS (ESI) m/z calcd for C15H11ClN2ONa+ [M+Na+],
293.0452; Found 293.0451.
NMR (CDCl3, 100MHz, TMS) δ: 161.09, 151.98, 143.99,
140.79, 137.81, 137.03, 130.06, 129.14, 127.53, 122.92, 106.90,
55.86; MS (ESI) m/z: 237 (M+H)+.
Acknowledgement
6ꢀChloroꢀ2ꢀ(4ꢀchlorophenyl)quinoxaline (Table 8, Entry 12):
Yellowish orange solid (225 mg, 82 %); mp = 130ꢀ132 °C; IR
80 Financial support from UGC (SRF to BT) and CSIR (RA to DK),
New Delhi is thankfully acknowledged.
30 (KBr)
= 2917, 2849, 1275, 1260, 750 cmꢀ1; 1H NMR
max
(CDCl3, 400MHz, TMS) δ: 9.32 (s, 1H), 8.17 (dd, J=1.92,
6.72Hz, 2H), 8.14 (d, J=2.28Hz, 1H), 8.09 (d, J=8.96Hz, 1H),
Notes and references
7.76 (dd, J=2.28, 8.96Hz, 1H), 7.57 (dd, J=1.96, 6.68Hz, 2H); 13
C
aDepartment of Medicinal Chemistry, National Institute of
Pharmaceutical Education and Research (NIPER), Sector 67, S. A. S.
85 Nagar 160 062, Punjab, India. Eꢀmail: akchakraborti@niper.ac.in
† Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/b000000x/
NMR (CDCl3, 100MHz, TMS) δ: 150.70, 143.67,141.88,
35 140.76, 139.29, 136.88, 135.55, 134.77, 131.55, 130.80, 129.49,
128.73, 128.12, 114.07; MS (APCI) m/z: 275 (M+H)+. HRMS
(ESI) m/z calcd forC14H8Cl2N2Na+ [M+Na+], 296.9957; Found
297.1298.
90 (1) (a) A. Cartra, P. Corona and M. Loriga, Curr. Med. Chem. 2005, 12,
2259; (b) A. Cartra, S. Piras, G. Loriga and G. Paglietti, Mini Rev.
Med. Chem. 2006, 6, 1179; (c) R. M. Rajurkar, V. A. Agrawal, S.
S. Thonte and R. G. Ingale, Pharmacophore 2010, 1, 65; (d) M.
González and H. Cerecetto, Expert Opin. Ther. Pat. 2012, 22, 1289;
2ꢀ(4ꢀBromophenyl)ꢀ6ꢀchloroquinoxaline (Table 8, Entry 13):
40 Offꢀwhite solid (257 mg, 83 %); mp = 175ꢀ177 °C; IR (KBr)
= 3049, 2923, 2849, 1604, 1539, 1476, 1328, 1275, 1176,
max
1004, 919, 825, 750, 569 cmꢀ1; 1H NMR (CDCl3, 400MHz, TMS)
δ: 9.27 (s, 1H), 8.09 (d, J=2.24Hz, 1H), 8.06 (d, J=8.48Hz, 3H),
7.73ꢀ7.67 (m, 3H); 13C NMR (CDCl3, 100MHz, TMS) δ: 150.74,
45 143.61, 141.90, 140.76, 135.58, 135.20, 132.45, 131.56, 130.81,
130.40, 129.04, 128.95, 128.12, 125.29; MS (APCI) m/z: 321
(M+H)+. HRMS (ESI) m/z calcd for C14H8BrClN2Na+ [M+Na+],
340.9452; Found 341.1820.
95
100
105
(e) R. G. Ingle and R. P. Marathe, Pharmacophore 2012, 3, 109.
(2) Vareniciline (a) S. D. Shah, L. A. Wilken, S. R. Winkler and S. J.
Lin, J. Am. Pharm. Assoc. (2003), 2008, 48, 659; Carbadox (b) B.
Emmert, S. Schauder, H. Palm, E. Hallier and S. Emmert, Ann.
Agric. Environ. Med. 2007, 14, 329; Brimonidine (c) C. B. Toris, C.
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Heterocycl. Chem. 2002, 39, 303; Electroluminescence (b) C. T.
Chen, J. S. Lin, M. V. R. K. Moturu, Y. W. Lin, W. Yi, Y. T. Tao
and C. H. Chien, Chem. Commun. 2005, 3980; Semiconductor (c) S.
Dailey, J. W. Feast, R. J. Peace, I. C. Sage, S. Till and E. L. Wood,
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(d) S. Ott aand R. Faust, Synlett 2004, 1509; Electron transport
2ꢀ(4ꢀMethoxyphenyl)ꢀ7ꢀmethylquinoxaline (Table 8, Entry
50 14)4e: Light yellow solid (200 mg, 80 %); mp = 52ꢀ57 °C; IR
(KBr)
= 2917, 2857, 2307, 1956, 1739, 1618, 1451, 1384,
max
1179, 1050, 746 cmꢀ1; H NMR (CDCl3, 400MHz, TMS) δ: 9.26
1
(s, 1H), 8.19ꢀ8.16 (m, 2H), 8.01 (dd, J=8.52,12.32 Hz, 1H), 7.97
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DOI: 10.1039/C4RA16568C
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DOI: 10.1039/C4RA16568C
Graphical Abstract
An “all-water” strategy for regiocontrolled synthesis of 2-aryl
quinoxalines
Babita Tanwar, Priyank Purohit, Banothu Naga Raju, Dinesh Kumar, Damodara N. Kommi and
Asit K. Chakraborti *
Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and
Research (NIPER), Sector 67, S. A. S. Nagar 160 062, Punjab, India.
E. mail: akchakraborti@niper.ac.in; akchakraborti@rediffmail.com
Cascade N-aroylmethylation–reduction–condensation process as novel strategy of “all water chemistry” for first
generalized regioselective synthesis of 2-aryl quinoxalines.