Cerium oxide nanoparticle-catalyzed three-component protocol for the synthesis of highly substituted novel quinoxalin-2-amine derivatives and 3,4-dihydroquinoxalin-2-amines in water

Article abstract of DOI:10.1039/c4ra00717d

The syntheses of novel quinoxalin-2-amine derivatives were conducted in water using CeO₂ nanoparticle catalyzed three-component reactions of 1,2-diamines with aldehydes and isocyanides. A variety of 3,4-dihydroquinoxalin- 2-amine derivatives we

Full text of DOI:10.1039/c4ra00717d

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Cerium oxide nanoparticle-catalyzed three-
component protocol for the synthesis of highly
substituted novel quinoxalin-2-amine derivatives
and 3,4-dihydroquinoxalin-2-amines in water†
Cite this: RSC Adv., 2014, 4, 11459
*
Naushad Edayadulla and Yong Rok Lee
The syntheses of novel quinoxalin-2-amine derivatives were conducted in water using CeO2 nanoparticle
catalyzed three-component reactions of 1,2-diamines with aldehydes and isocyanides. A variety of 3,4-
dihydroquinoxalin-2-amine derivatives were also synthesized by reactions between 1,2-diamines,
ketones and isocyanides. This new method offers an environmentally benign and effective approach for
the synthesis of quinoxalin-2-amines and 3,4-dihydroquinoxalin-2-amines.
Received 4th December 2013
Accepted 7th February 2014
DOI: 10.1039/c4ra00717d
www.rsc.org/advances
Introduction
One of the central goals in organic synthesis is to discover and
identify reactions that enable processes to proceed in an envi-
ronmentally benign and sustainable way.1 The use of nano-
catalysis and green chemistry holds the answer of sustain-
ability.2 The main focus of green chemistry concerns the
avoidance of volatile organic solvents or their replacement with
non-ammable, non-volatile, non-toxic, and inexpensive green
alternatives.3 Water is the reaction medium used by nature for
biosynthesis, and has the advantage of being abundantly
available, non-hazardous, non-ammable, redox-stable, and
cheap. Thus, water is regarding as being an ideal green solvent,
and preferable to alternatives like ionic liquids.4 In addition,
water facilitates solvation and molecular assembly processes
that modulate reactivity and selectivity.5 On the other hand,
catalysis lies at the heart of innumerable chemical reactions,6
due to their unique properties and nano-catalysts have
considerably expanded the available possibilities.7
In particular, nano-catalysts have been widely used to
construct synthetic routes that are environmentally compatible,
safe, and high-yielding.8 Furthermore, metal oxide nano-
particles recently provide sustainable alternatives to conven-
tional catalysts in the organic chemistry sphere.9 Their
recyclability and ease of separation further increase their
potentials.10
Fig. 1 Selected natural and synthetic molecules bearing quinoxalines.
pharmacological properties.12 For example, compounds A and B
were isolated from beer,13 and the synthesized compound C
showed anti-leishmanial activity in vitro.14 In addition,
compounds D, (2-(4-(7-chloroquinoxalin-2-yl)-phenoxy]pro-
pionic acid (XK469), and E chloroquinoxaline-sulfonamide
(CQS) are well known topoisomerase IIb inhibitors15 and anti-
cancer reagents.16 Compound F has high RhoA inhibitor activity
and offers a basis for the development of new therapies for
cardiovascular diseases.17 In addition, naturally occurring
antibiotics such as echinomycin, actinomycin, and levomycin
with a quinoxaline skeleton show Gram-positive bacterial and
various transplantable tumor activities.18
Quinoxaline derivatives are also used as dyes, organic
semiconductors, and other materials.19 Due to their varied
biological activities and industrial applications, several
synthetic strategies have been developed for the preparation of
quinoxalines20 and dihydroquinoxalines.21 As shown in Scheme
1, the general method used to synthesize quinoxalines is cata-
lyzed aryl 1,2-amine to 1,2-dicarbonyl condensation; the cata-
lysts used include gallium(III) triate,22 montmorillonite K10,23
Molecules bearing a quinoxaline moiety are commonly
found in natural and synthetic materials (Fig. 1),11 and they
have been shown to possess a range of signicant biological and
School of Chemical Engineering, Yeungnam University, Gyeongsan 712-749, Republic
of Korea. E-mail: yrlee@yu.ac.kr; Fax: +82 53-810-4631; Tel: +82 53-810-2529
† Electronic supplementary information (ESI) available: Depiction of 1H, 13C NMR
spectra for all products 5a–5q, 7a–7i and 14a–14b. See DOI: 10.1039/c4ra00717d
Scheme 1 Reported general method for the synthesis of quinoxalines.
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sulfamic acid,24 cupric sulphate pentahydrate,25 Zn (L-proline),26
Cerium oxide nanoparticles (CeO2-NPs) are environmentally
I2,27 cellulose sulphuric acid,28 and zirconium tetrakis(dodecyl benign and economically feasible heterogeneous catalysts that
sulphate).29
offer several advantages, such as, sustainability in water, low
The three-component reactions between aryl 1,2-amines, cost, high catalytic reactivity, ease of handling, non-toxicity,
carbonyls, and isocyanides in the presence of a suitable catalyst reusability, and experimental simplicity.35 Because of their
such as p-TsOH,30 Fe(ClO4),31 ceric ammonium nitrate (CAN),32 importance, CeO2-NPs have been extensively used as catalysts,35
or Amberlyst-15 (Scheme 2)33 provide any alternative means of catalyst supports,36 sunscreens,37 gas sensors,38 and uorescent
synthesizing dihydroquinoxalines. In fact, we previously materials,39 and have been used as automotive catalysts,40 fuel
described the EDTA-catalyzed syntheses of a series of 3,4-dihy- cells,41 and heterogeneous catalytic ozonation reagents.42
droquinoxalin-2-amine derivatives involving three-component
coupling using one-pot condensation reactions.34 Importantly, the synthesis of quinoxaline-2-amines using CeO2-NPs as a
in these reactions, quinoxalin-2-amines were not produced. reusable heterocatalyst. Recently, in water medium, we have
To the best of our knowledge, no report has been issued on
Despite their own merits, many existing methods for the described environmentally benign and facile synthesis of 2H-
synthesis of quinoxalines and dihydroquinoxalines suffer from pyrans.43 In continuation with our studies on the development
shortcomings including toxic organic solvents, long reaction of a new methodology in water medium, we report herein an
times, the necessity of large amounts of expensive catalysts, and efficient and facile one-pot synthesis of quinoxalin-2-amines
harsh reaction conditions. Therefore, more environmentally and 3,4-dihydroquinoxalin-2-amines via a three-component
benign and efficient arsenals are still needed improving on condensation of diamines with aldehydes/ketones, and iso-
these shortcomings, which prompt us to develop new cyanides in the presence of catalytic amounts of CeO2 nano-
approaches relying on the use of green catalysts.
particles (Scheme 3).
Results and discussion
To afford quinoxaline-2-amines, treatment of o-phenylenedi-
amine (1a) with isovaleraldehyde (2a) and tert-butyl isocyanide
(3a) was rst attempted under several conditions. In the
absence of a catalyst at 80 ꢀC for 12 h in water, only a trace
amount of product 5a was formed and most of starting material
was recovered (entry 1, Table 1). With InCl3 or CeCl3$7H2O as
catalysts, the product 5a was isolated in 58 and 64% yield,
respectively (entries 2 and 3). With ceric ammonium nitrate
(CAN), 5a was isolated in 70% yield (entry 4). With CeO2-
nanoparticles, further reactions were investigated under several
solvents. Interestingly, the best yield (92%) was obtained in the
presence of 5 mol% or 10 mol% of CeO2-NPs in water (entry 7).
Importantly, in this reaction, only 5a was formed and the
Scheme
droquinoxalin-2-amines.
2 Reported method for the synthesis of 3,4-dihy-
Scheme 3 Three-component reactions for the synthesis of quinox-
alin-2-amines and 3,4-dihydroxyquinoxalin-2-amines.
Table 1 Optimization of reaction conditions for the synthesis of 5a
Yield (%)
Entry
Catalyst
Solvent
Temp.
Time (h)
4a
5a
1
2
3
4
5
6
7
8
9
—
H2O
H2O
H2O
H2O
H2O
H2O
H2O
Toluene
Ethanol
CH3CN
80 ꢀ
80 ꢀ
80 ꢀ
80 ꢀ
80 ꢀ
80 ꢀ
80 ꢀ
C
C
C
C
C
C
C
C
C
C
12
8
6
4
2
2
2
9
6
4
0
0
0
0
0
0
0
0
0
0
Trace
58
64
70
78
92
92
35
54
InCl3 (10 mol%)
CeCl3$7H2O (10 mol%)
(NH4)2Ce(NO3)6 (10 mol%)
CeO2-NPs (2 mol%)
CeO2-NPs (5 mol%)
CeO2-NPs (10 mol%)
CeO2-NPs (5 mol%)
CeO2-NPs (5 mol%)
CeO2-NPs (5 mol%)
100 ꢀ
78 ꢀ
80 ꢀ
10
68
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Table 2 Additional reactions of 1,2-diamines with several aldehydes and isocyanidesa
Entry
1
1,2-Diamine
Aldehyde
Isocyanide
Time (h)
2
Product
Yieldb (%)
81
2
3
2
2
86
76
4
5
6
7
8
9
2
2
2
2
2
2
84
91
76
82
82
87
3a
3b
3c
3d
3e
10
11
12
2
2
71
67
0
3a
12
13
14
15
2a
2b
2a
3a
3c
3a
2
2
2
81
77
67
16
2a
3d
2
66
a
Reaction conditions: 1,2-diamines (1.0 mmol), aldehyde (1.0 mmol), and isocyanide (1.0 mmol) catalyst CeO2-NPs (5 mol%), water (3.0 mL), 80 ꢀC.
Isolated yields aer column chromatography.
b
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expected 4a was not produced. The structure of 5a was deter- attempted. Reaction of 1b with isovaleraldehyde (2a) and tert-butyl
mined by 1H NMR, which showed 4 aromatic protons on a isocyanide (3a) afforded 5n in 81% yield (entry 13), whereas
quinoxaline ring at dH 7.78 (1H, dd, J ¼ 8.1, 0.9 Hz), 7.65 (1H, reaction between 1b with 2b and 3c provided 5o in 77% yield
dd, J ¼ 8.1, 0.9 Hz), 7.46 (1H, td, J ¼ 6.9, 1.5 Hz), and 7.30 (1H, (entries 14). In addition, reaction between diaminonaphthalene
td, J ¼ 6.9, 1.5 Hz) ppm. In the 13C NMR spectrum of 5a, 8 (1c) with 2a and 3a or 3d afforded 5p and 5q in 67 and 66% yield,
carbon peaks on a quinoxaline showed at dC 150.2, 147.5, 140.9, respectively (entries 15 and 16). Accordingly, these reactions were
136.0, 128.4, 128.0, 126.2, and 123.7 ppm.
found to provide a rapid route to the synthesis of a variety of
Additional reactions between various 1,2-diamines, aldehydes, quinoxaline-2-amine derivatives in good yield.
and isocyanides were carried out to determine the generality and
The generality and usefulness of this aqueous approach
efficiency under optimized conditions (Table 2). Reactions utilizing CeO2-NPs as a catalyst were further demonstrated by
between o-phenylenediamine (1a), isovaleraldehyde (2a), and n- reactions between 1,2-diamines, ketones, and isocyanides to form
butyl isocyanide (3b), 1,1,3,3-tetramethyl butyl isocyanide (3c), the corresponding 3,4-dihydroquinoxalin-2-amine derivatives.
cyclohexyl isocyanide (3d), or benzyl isocyanide (3e) in the pres- Further reactions between 1,2-diamines 1, various ketones 6, and
ence of 5 mol% of CeO2-NPs in water at 80 ꢀC for 2 h afforded the several isocyanides 3 were carried out in the presence of 5 mol%
corresponding quinoxalin-2-amine derivatives 5b–5e in 76–86% of CeO2 in water. Results are summarized in Table 3. All reactions
yield (Table 2, entries 1–4). Furthermore, treatment of 1a with were highly regioselective and no other products were observed.
isobutyraldehyde (2b) and isocyanides 3a–3e for 2 h provided the Reactions between o-phenylenediamine (1a), acetone (6a) or
expected products 5f–5j in 76–91% yield (Table 2, entries 5–9). propanone (6b), and tert-butyl isocyanide (3a) in water at 80 ꢀC for
With a,b-unsaturated aldehydes like 3-methyl-2-butenal (2c) or 1- 2 h provided the 3,4-dihydoquinoxalin-2-amines 7a and 7b in 94
cyclohexene-1-carboxaldehyde (2d), the desired products 5k and 5l and 93% yield, respectively (Table 3, entries 1 and 2). When
were formed in 71 and 67% yield, respectively (entries 10 and 11). cyclopentanone, cyclohexanone, or cycloheptanone were used, the
However, when benzaldehyde was used, the desired product 5m products 7c–7e were produced in 91, 89, and 83% yield, respec-
was not formed (entry 12). To investigate the scope and limita- tively (entries 3–5). Interestingly, when diaminomalenonitrile (1b)
tions of this cyclization, three-component reactions using dia- and diaminonaphthalene (1c) were used, the products 7f–7i were
minomaleonitrile (1b) or diaminonaphthalene (1c) were next obtained in 79–94% yield (entries 6–9). Accordingly, these
Table 3 Additional reactions of 1,2-diamines with several ketones and isocyanidesa
Entry
1
1,2-Diamine
Ketone
Isocyanide
Time (h)
2
Product
Yieldb (%)
94
2
3
4
2
2
2
93
91
89
5
2
83
6
7
8
6a
6c
6d
2
2
2
93
94
81
9
6e
2
79
a
Reaction conditions: 1,2-diamines (1.0 mmol), ketone (1.0 mmol), and isocyanide (1.0 mmol) catalyst CeO2-NPs (5 mol%), water (3.0 mL), 80 ꢀC.
Isolated yields aer column chromatography.
b
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reactions were found to provide rapid synthetic routes to a variety
of 3,4-dihydroquinoxalin-2-amine derivatives.
The aqueous nano-catalyzed three-component protocol
described above results in a potential medicinal scaffold,
conforms to the principles of green chemistry, and offers a
potential means of developing combinatorial libraries. Green
aspects of this reaction include high atom economy, its multi-
component nature, and the use of water as the reaction
medium. The movement of green chemistry has developed a
series of metrics to support and reinforce behaviour change in
both industry and academia in the move towards green and
more sustainable chemistry.44 Two most common green metrics
including atom economy and atom efficiency are calculated
below.
Scheme 4 Proposed mechanism for the formation of product 5.
Atom economy (A. Eco) is calculated below for:
(i) compound 5a
% A. Eco ¼ molecular mass of desired product/(molecular mass of all
reactants) ꢁ 100 ¼ 257.37/(108.14 + 86.13 + 83.13) ꢁ 100 ¼ 92.78%
(ii) compound 7a
% A. Eco ¼ molecular mass of desired product/(molecular mass of all
reactants) ꢁ 100 ¼ 231.33/(108.14 + 58.07 + 83.13) ꢁ 100 ¼ 92.77%
Scheme 5 Reaction of 1a with isatins 12a–12b and isocyanide 3a for
the synthesis of compounds 14a–14b.
Atom efficiency is calculated below for:
(i) compound 5a
iminium ion 8. Nucleophilic addition of isocyanide 3 to 8 would
give the intermediate 9, which undergoes intramolecular cyclo-
addition to afford other intermediate 10. Isomerization of 10
followed by subsequent oxidation would give the nal product 5.
Finally, to investigate further use of CeO2-NPs, reactions
between 1,2-diamine 1a, isatins, and isocyanides were also
attempted (Scheme 5). For example, the reaction between 1a,
isatin (12a) or N-methylisatin (12b), and tert-butyl isocyanide
(3a) afforded 14a and 14b in 94 and 95% yield, respectively,
without any formation of desired 13a and 13b. The structures of
compounds 14a and 14b were determined by comparing with
spectral data of previously reported results.45
% Atom efficiency ¼ (yield ꢁ A. Eco)/100 ¼ (92% ꢁ 92.78%)/100
¼ 85.35%
(ii) compound 7a
% Atom efficiency ¼ (yield ꢁ A. Eco)/100 ¼ (94% ꢁ 92.77%)/100
¼ 87.20%
Catalyst recyclability is an essential aspect of green chem-
istry. Aer completing reactions under optimized conditions,
the catalyst was recovered by ltering reaction mixtures,
washing residues with dichloromethane and/or water, and
drying at 80 ꢀC. The recovered catalyst was then reused to
perform the same reactions with fresh raw materials under
identical conditions. We found the effectiveness of CeO2-NPs
was not signicantly affected up to the fourth cycle, but product
yields were slightly reduced during the h cycle. A chart of the
catalytic potential of recycled CeO2-NPs is provided in Fig. 2.
A possible reaction mechanism is suggested as shown in
Scheme 4.We suggest that the carbonyl group of aldehyde 2 is
activated by coordination with oxygen of CeO2-NPs to give the
Conclusions
In summary, we have developed a novel one-pot three-compo-
nent reaction to the synthesis of quinoxalin-2-amine and 3,4-
dihydroquinoxaline-2-amine derivatives starting from various
simple and readily available 1,2-diamines, diverse carbonyl
compounds, and isocyanides. This multi-component reaction
allows the synthesis of medicinally important indophenazines,
which should nd various applications in the synthesis of
pharmaceuticals. This methodology offers several advantages,
including high product yield, ease of experimental procedure,
and an environmentally benign character.
Experimental section
All experiments were carried out under nitrogen. Merck pre-
coated silica gel plates (Art. 5554) with uorescent indicator
were used for analytical TLC. Flash column chromatography
1
Fig. 2 Recovery and reuse of CeO2-NPs for the synthesis of 5a.
was performed using silica gel 9385 (Merck). H NMR and 13C
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NMR spectra were recorded at 25 ꢀC on Bruker Avance DPX 300 42.7, 33.0, 26.8, 25.8, 24.8, 22.8; IR (KBr): 3454, 2929, 2857, 1574,
MHz spectrometer or a Varian VNS 300 MHz spectrometer in 1515, 1458, 1337, 1264, 1164, 1093, 1019, 890, 757 cmꢂ1; HRMS
CDCl3, DMSO-d6 as solvent. Multiplicities are abbreviated as s ¼ (EI+): m/z: calcd for C18H25N3: 283.2048, found 283.2047.
singlet, d ¼ doublet, t ¼ triplet, m ¼ multiplet. IR spectra were
N-Benzyl-3-isobutylquinoxalin-2-amine (5e). Liquid (245 mg,
1
recorded on a Jasco FTIR 5300 spectrophotometer. All melting 84%); H NMR (300 MHz, CDCl3) dH: 7.84 (1H, d, J ¼ 8.1 Hz),
points (uncorrected) were obtained on a Fischer-Johns melting 7.70 (1H, d, J ¼ 8.1 Hz), 7.52 (1H, t, J ¼ 7.2 Hz), 7.39–7.29 (6H,
point apparatus. HRMS was carried out at the Korean Basic m), 5.03 (1H, br s, NH), 4.79 (2H, d, J ¼ 4.5 Hz), 2.65 (2H, d, J ¼
Science Institute.
6.9 Hz), 2.37–2.28 (1H, m), 1.00 (6H, d, J ¼ 6.3 Hz); 13C NMR (75
MHz, CDCl3) dC: 150.4, 147.1, 140.9, 139.0, 136.9, 128.8, 128.7,
128.2, 127.9, 127.4, 125.9, 124.2, 45.4, 42.6, 26.7, 22.7; IR (neat):
3453, 3385, 3060, 2956, 1673, 1575, 1519, 1461, 1322, 1231,
1165, 1103, 1024, 948, 757 cmꢂ1; HRMS (EI+): m/z: calcd for
General procedure for the synthesis of quinoxalin-2-amine
derivatives (5a–5q)
To a solution of 1,2-diamine (1.0 mmol), aldehyde (1.0 mmol),
and isocyanide (1.0 mmol) in 3 mL of water was added CeO2-
C
19H21N3: 291.1735, found 291.1735.
N-tert-Butyl-3-isopropylquinoxalin-2-amine (5f). Solid (221
NPs (5 mol%). The resulting mixture was gently heated at 80 ꢀC. mg, 91%), mp 94–95 ꢀC; 1H NMR (300 MHz, CDCl3) dH: 7.81 (1H,
Reaction completion was monitored by TLC. The crude product d, J ¼ 8.1 Hz), 7.66 (1H, d, J ¼ 8.1 Hz), 7.47 (1H, dd, J ¼ 8.1, 1.2
was dissolved in ethyl acetate and puried by silica gel column Hz), 7.31 (1H, dd, J ¼ 8.1, 1.2 Hz), 4.76 (1H, br s, NH), 3.02–2.93
chromatography using hexane–ethyl acetate (9 : 1) as eluent to (1H, m), 1.57 (9H, s), 1.37 (6H, d, J ¼ 6.9 Hz); 13C NMR (75 MHz,
afford the desired compounds 5a–5q.
CDCl3) dC: 151.9, 149.2, 140.6, 136.1, 128.3, 128.2, 126.1, 123.6,
N-tert-Butyl-3-isobutylquinoxalin-2-amine
(5a).
Solid 51.9, 30.7, 28.9, 20.3; IR (KBr): 3444, 3071, 2964, 1517, 1458,
(237 mg, 92%), mp 47–49 ꢀC; 1H NMR (300 MHz, CDCl3) dH: 7.78 1317, 1214, 1080, 944, 758 cmꢂ1; HRMS (EI+): m/z: calcd for
(1H, dd, J ¼ 8.1, 0.9 Hz), 7.65 (1H, dd, J ¼ 8.1, 0.9 Hz), 7.46 (1H,
C
15H21N3: 243.1735, found 243.1732.
N-Butyl-3-isopropylquinoxalin-2-amine (5g). Solid (185 mg,
td, J ¼ 6.9, 1.5 Hz), 7.30 (1H, td, J ¼ 6.9, 1.5 Hz), 4.66 (1H, br s,
NH), 2.61 (2H, d, J ¼ 6.9 Hz), 2.34–2.20 (1H, m), 1.54 (9H, s), 1.01 76%), mp 52–54 ꢀC; 1H NMR (300 MHz, CDCl3) dH: 7.81 (1H, dd,
(6H, d, J ¼ 6.6 Hz); 13C NMR (75 MHz, CDCl3) dC: 150.2, 147.5, J ¼ 8.1, 0.9 Hz), 7.65 (1H, dd, J ¼ 8.1, 0.9 Hz), 7.47 (1H, td, J ¼
140.9, 136.0, 128.4, 128.0, 126.2, 123.7, 51.9, 43.0, 28.8, 26.9, 8.4, 1.5 Hz), 7.31 (1H, td, J ¼ 8.4, 1.5 Hz), 4.81 (1H, br s, NH),
22.8; IR (KBr): 3456, 2959, 2870, 1942, 1673, 1576, 1518, 1456, 3.59 (2H, q, J ¼ 6.9 Hz), 3.06–2.97 (1H, m), 1.70–1.63 (2H, m),
1362, 1215, 1169, 1098, 943, 759 cmꢂ1; HRMS (EI+): m/z: calcd 1.49–1.42 (2H, m), 1.37 (6H, d, J ¼ 6.6 Hz), 1.00–0.93 (3H, m);
for C16H23N3: 257.1892, found 257.1894.
13C NMR (75 MHz, CDCl3) dC: 151.8, 149.8, 140.9, 136.6, 128.6,
N-Butyl-3-isobutylquinoxalin-2-amine (5b). Liquid (208 mg, 128.3, 125.7, 123.8, 41.0, 31.5, 30.5, 29.6, 20.3, 14.1; IR (KBr):
1
81%); H NMR (300 MHz, CDCl3) dH: 7.80 (1H, d, J ¼ 8.1 Hz), 3402, 3061, 2926, 2861, 1573, 1521, 1465, 1311, 1229, 1090, 949,
7.66 (1H, d, J ¼ 8.1 Hz), 7.47 (1H, t, J ¼ 6.9 Hz), 7.31 (1H, td, J ¼ 805, 762 cmꢂ1; HRMS (EI+): m/z: calcd for C15H21N3: 243.1735,
8.1, 0.6 Hz), 4.72 (1H, br s, NH), 3.57 (2H, q, J ¼ 6.3 Hz), 2.63 found 243.1732.
(2H, d, J ¼ 6.6 Hz), 2.34–2.25 (1H, m), 1.71–1.62 (2H, m), 1.50–
3-Isopropyl-N-(2,4,4-trimethylpentan-2-yl)quinoxalin-2-amine
1.38 (2H, m), 0.95 (9H, m); 13C NMR (75 MHz, CDCl3) dC: 150.7, (5h). Solid (246 mg, 82%), mp 77–79 ꢀC; 1H NMR (300 MHz,
147.2, 141.2, 136.5, 128.2, 128.0, 126.0, 123.3, 42.7, 40.9, 31.4, CDCl3) dH: 7.80 (1H, dd, J ¼ 8.1, 0.9 Hz), 7.66 (1H, dd, J ¼ 8.1, 0.9
26.8, 26.5, 21.8, 20.2, 13.8; IR (neat): 3459, 2956, 2868, 1943, Hz), 7.47 (1H, td, J ¼ 8.4, 1.5 Hz), 7.30 (1H, td, J ¼ 8.4, 1.5 Hz), 4.81
1762, 1666, 1575, 1521, 1463, 1371, 1165, 1102, 948, 758 cmꢂ1
;
(1H, br s, NH), 3.01–2.92 (1H, m), 2.04 (2H, s), 1.62 (6H, s), 1.37
HRMS (EI+): m/z: calcd for C16H23N3: 257.1892, found 257.1894. (6H, d, J ¼ 6.6 Hz), 1.02 (9H, s); 13C NMR (75 MHz, CDCl3) dC:
3-Isobutyl-N-(2,4,4-trimethylpentan-2-yl)quinoxalin-2-amine 151.9, 149.2, 140.6, 136.0, 128.3, 128.2, 126.1, 123.5, 55.8, 51.5,
(5c). Liquid (270 mg, 86%); 1H NMR (300 MHz, CDCl3) dH: 7.77 31.7, 31.6, 30.6, 29.3, 20.5; IR (KBr): 3459, 3064, 2959, 2872, 1944,
(1H, dd, J ¼ 9.0, 0.9 Hz), 7.64 (1H, dd, J ¼ 9.0, 0.9 Hz), 7.46 (1H, 1572, 1517, 1468, 1420, 1306, 1220, 1127, 1081, 940, 755 cmꢂ1
;
td, J ¼ 6.9, 1.5 Hz), 7.29 (1H, td, J ¼ 6.9, 1.5 Hz), 4.71 (1H, br s, HRMS (EI+): m/z: calcd for C19H29N3: 299.2361, found 299.2364.
NH), 2.60–2.58 (2H, m), 2.35–2.22 (1H, m), 2.00 (2H, s), 1.59 (6H,
N-Cyclohexyl-3-isopropylquinoxalin-2-amine (5i). Solid (222
1
s), 1.02–0.99 (15H, m); 13C NMR (75 MHz, CDCl3) dC: 150.2, mg, 82%), mp 98–100 C; H NMR (300 MHz, CDCl3) dH: 7.80
147.4, 140.9, 135.9, 128.4, 128.0, 126.2, 123.6, 55.9, 51.5, 43.1, (1H, dd, J ¼ 8.1, 0.9 Hz), 7.63 (1H, dd, J ¼ 8.1, 0.9 Hz), 7.45 (1H,
31.8, 31.4, 29.3, 29.1, 26.6; IR (neat): 3469, 3057, 2955, 1762, td, J ¼ 8.1, 1.2 Hz), 7.39 (1H, td, J ¼ 8.1, 1.2 Hz), 4.71 (1H, d, J ¼
ꢀ
1670, 1576, 1517, 1465, 1365, 1237, 1163, 1056, 941, 757 cmꢂ1
;
6.9 Hz), 4.27–4.09 (1H, m), 3.05–2.96 (1H, m), 2.15–2.11 (2H, m),
HRMS (EI+): m/z: calcd for C20H31N3: 313.2518, found 313.2520. 1.78 (8H, m), 1.37 (6H, d, J ¼ 6.6 Hz); 13C NMR (75 MHz, CDCl3)
N-Cyclohexyl-3-isobutylquinoxalin-2-amine (5d). Semi solid dC: 151.7, 148.9, 141.0, 136.5, 128.5, 128.3, 125.7, 123.6, 49.0,
(216 mg, 76%); 1H NMR (300 MHz, CDCl3) dH: 7.79 (1H, dd, J ¼ 33.1, 30.5, 29.6, 25.8, 24.8, 20.3; IR (KBr): 3406, 2968, 2370, 1522,
9.0, 0.9 Hz), 7.64 (1H, dd, J ¼ 9.0, 0.9 Hz), 7.47 (1H, td, J ¼ 8.1, 1463, 1321, 1078, 915, 726 cmꢂ1; HRMS (EI+): m/z: calcd for
1.5 Hz), 7.30 (1H, td, J ¼ 8.1, 1.5 Hz), 4.62 (1H, d, J ¼ 7.2 Hz, NH),
4.21–4.09 (1H, m), 2.62 (2H, d, J ¼ 6.9 Hz), 2.35–2.22 (1H, m),
C
17H23N3: 269.1892, found 269.1893.
N-Benzyl-3-isopropylquinoxalin-2-amine (5j). Solid (241 mg,
2.14–2.09 (2H, m), 1.78–1.64 (3H, m), 1.55–1.42 (2H, m), 1.31– 87%), mp 96–98 ꢀC; 1H NMR (300 MHz, CDCl3) dH: 7.85 (1H, dd,
1.18 (3H, m), 1.01 (6H, d, J ¼ 6.6 Hz); 13C NMR (75 MHz, CDCl3) J ¼ 8.1, 0.9 Hz), 7.69 (1H, dd, J ¼ 8.1, 0.9 Hz), 7.50 (1H, td, J ¼
dC: 149.9, 147.2, 141.2, 136.5, 128.6, 128.1, 125.8, 123.7, 49.0, 8.1, 1.5 Hz), 7.43–7.27 (6H, m), 5.10 (1H, br s, NH), 4.80 (2H, d,
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J ¼ 5.1 Hz), 3.07–2.98 (1H, m), 1.37 (6H, d, J ¼ 6.9 Hz); 13C NMR NMR (75 MHz, CDCl3) dC: 149.9, 149.2, 138.8, 135.3, 133.9,
(75 MHz, CDCl3) dC: 151.7, 149.4, 140.7, 139.0, 136.9, 128.7, 130.5, 128.3, 127.3, 126.4, 125.8, 124.0, 121.9, 49.0, 42.9, 33.0,
128.3, 128.0, 127.4, 125.8, 124.1, 45.5, 40.9, 30.5, 20.4; IR (KBr): 29.6, 26.8, 25.8, 24.8, 22.8; IR (KBr): 3454, 3050, 2925, 2369,
3409, 2970, 2368, 1519, 1461, 1318, 1075, 915, 734 cmꢂ1; HRMS 1929, 1673, 1581, 1509, 1372, 1261, 1097, 877, 742 cmꢂ1; HRMS
(EI+): m/z: calcd for C18H19N3: 277.1579, found 277.1581.
N-tert-Butyl-3-(2-methylprop-1-enyl)quinoxalin-2-amine (5k).
Liquid (181 mg, 71%); 1H NMR (300 MHz, CDCl3) dH: 7.78 (1H,
d, J ¼ 8.1 Hz), 7.64 (1H, d, J ¼ 8.1 Hz), 7.47 (1H, t, J ¼ 8.1 Hz),
7.29 (1H, t, J ¼ 8.1 Hz), 6.12 (1H, s), 4.87 (1H, br s, NH), 1.99 (3H,
(EI+): m/z: calcd for C22H27N3: 333.2205, found 333.2202.
General procedure for the synthesis of 3,4-dihydroquinoxalin-
2-amine derivatives (7a–7i)
s), 1.85 (3H, s), 1.53 (9H, s); 13C NMR (75 MHz, CDCl3) dC: 150.2, To a solution of 1,2-diamine (1.0 mmol), ketone (1.0 mmol), and
145.2, 145.1, 141.0, 136.0, 128.7, 128.3, 126.2, 123.7, 119.2, 51.8, isocyanide (1.0 mmol) in 3 mL of water was added CeO2-NPs (5
28.7, 26.3, 19.9; IR (neat): 3430, 2969, 2316, 1763, 1644, 1567, mol%). The resulting mixture was gently heated at 80 ꢀC.
1516, 1452, 1313, 1242, 1056, 759 cmꢂ1; HRMS (EI+): m/z: calcd Reaction completion was monitored by TLC. The crude product
for C16H21N3: 255.1735, found 255.1737.
was dissolved in ethyl acetate and puried by silica gel column
N-tert-Butyl-3-cyclohexenylquinoxalin-2-amine (5l). Solid chromatography using hexane–ethyl acetate (7 : 3) as eluent to
(188 mg, 67%), mp 58–60 ꢀC; 1H NMR (300 MHz, CDCl3) dH: 7.78 afford the desired compounds 7a–7i.
(1H, dd, J ¼ 8.1, 0.9 Hz), 7.62 (1H, dd, J ¼ 8.1, 0.9 Hz), 7.46 (1H,
N-tert-Butyl-3,3-dimethyl-3,4-dihydroquinoxalin-2-amine (7a).
td, J ¼ 6.9, 1.5 Hz), 7.28 (1H, td, J ¼ 6.9, 1.5 Hz), 6.12 (1H, m), Solid (218 mg, 94%), mp 90–91 ꢀC; 1H NMR (300 MHz, CDCl3) dH:
5.20 (1H, br s, NH), 2.40–2.37 (2H, m), 2.24–2.21 (2H, m), 1.83– 7.03 (1H, m), 6.80–6.71 (2H, m), 6.52 (1H, m), 4.18 (1H, br s, NH),
1.71 (4H, m), 1.51 (9H, s); 13C NMR (75 MHz, CDCl3) dC: 149.4, 3.42 (1H, br s, NH), 1.46 (9H, s), 1.25 (6H, s); 13C NMR (75 MHz,
149.3, 141.1, 135.9, 135.9, 129.7, 128.8, 128.4, 126.1, 123.7, 51.7, CDCl3) dC: 157.4, 135.4, 134.7, 123.8, 122.5, 119.3, 113.4, 51.5,
28.9, 28.6, 27.4, 25.2, 22.6, 21.7; IR (KBr): 3430, 3061, 2937, 2372, 50.4, 28.9, 26.0; IR (KBr): 3438, 3370, 3047, 2869, 1619, 1585, 1511,
1518, 1454, 1410, 1359, 1315, 1220, 1138, 1014, 940, 756 cmꢂ1
;
1229, 748 cmꢂ1; HRMS (EI+): m/z: calcd for C14H21N3: 231.1735,
HRMS (EI+): m/z: calcd for C18H23N3: 281.1892, found 281.1889. found 231.1736.
5-(tert-Butylamino)-6-isobutylpyrazine-2,3-dicarbonitrile (5n).
N-tert-Butyl-3-ethyl-3-methyl-3,4-dihydroquinoxalin-2-amine
Semi solid (224 mg, 81%); 1H NMR (300 MHz, CDCl3) dH: 5.11 (1H, (7b). Solid (228 mg, 93%), mp 96–98 ꢀC; 1H NMR (300 MHz,
br s, NH), 2.43 (2H, d, J ¼ 6.9 Hz), 2.28–2.20 (1H, m), 1.47 (9H, s), CDCl3) dH: 6.99 (1H, d, J ¼ 6.9 Hz), 6.76–6.69 (2H, m), 6.48 (1H,
0.98 (6H, d, J ¼ 6.6 Hz); 13C NMR (75 MHz, CDCl3) dC: 151.8, 147.7, d, J ¼ 7.5 Hz), 4.13 (1H, br s, NH), 3.45 (1H, br s, NH), 1.58–1.50
129.6, 118.8, 114.8, 114.0, 53.6, 41.7, 28.3, 25.8, 22.6; IR (KBr): (2H, m), 1.45 (9H, s), 1.27 (3H, s), 0.90 (3H, t); 13C NMR (75 MHz,
3411, 2963, 2925, 2229, 1769, 1658, 1565, 1460, 1397, 1213, 1106, CDCl3) dC: 156.6, 135.0, 134.7, 123.7, 122.5, 118.9, 112.9, 53.5,
805, 692 cmꢂ1; HRMS (EI+): m/z: calcd for C14H19N5: 257.1640, 51.5, 31.2, 29.0, 24.1; IR (KBr): 3451, 3349, 2965, 1613, 1514,
found 257.1642.
5-Isobutyl-6-(2,4,4-trimethylpentan-2-ylamino)pyrazine-2,3- found 245.1896.
1267, 748 cmꢂ1; HRMS (EI+): m/z: calcd for C15H23N3: 245.1892,
1
dicarbonitrile (5o). Liquid (231 mg, 77%); H NMR (300 MHz,
N-tert-Butyl-10H-spiro[cyclopentane-1,20-quinoxalin]-30-amine
1
ꢀ
CDCl3) dH: 5.29 (1H, br s, NH), 2.84–2.75 (1H, m), 1.85 (2H, s), (7c). Solid (233 mg, 91%); mp 104–106 C; H NMR (300 MHz,
1.52 (6H, s), 1.25 (6H, d, J ¼ 6.6 Hz), 0.98 (9H, s); 13C NMR (75 CDCl3) dH: 7.03 (1H, dd, J ¼ 7.2, 1.5 Hz), 6.75–6.71 (2H, m), 6.51
MHz, CDCl3) dC: 149.0, 117.3, 114.4, 112.9, 108.3, 57.2, 57.1, (1H, dd, J ¼ 7.2, 1.5 Hz), 4.16 (1H, br s, NH), 3.61 (1H, br s, NH),
51.2, 42.2, 31.6, 31.4, 29.3, 28.8, 28.7, 18.7, 18.0; IR (neat): 3380, 1.76–1.68 (8H, m), 1.46 (9H, s); 13C NMR (75 MHz, CDCl3) dC:
2963, 2879, 2228, 1768, 1653, 1583, 1533, 1389, 1259, 1120, 157.1, 136.4, 135.0, 123.8, 122.3, 119.5, 113.6, 61.6, 51.5, 36.9,
1025, 803, 739 cmꢂ1; HRMS (EI+): m/z: calcd for C17H25N5: 28.9, 24.0; IR (KBr): 3462, 3297, 2960, 2879, 2343, 1614, 1582,
299.2110, found 299.2108.
1518, 1472, 1359, 1263, 1223, 1098, 1037, 803, 746 cmꢂ1; HRMS
N-tert-Butyl-3-isobutylbenzo[g]quinoxalin-2-amine
Semi solid (206 mg, 67%); H NMR (300 MHz, CDCl3) dH: 8.32
(5p). (EI+): m/z: calcd for C16H23N3: 257.1892, found 257.1894.
1
N-tert-Butyl-10H-spiro[cyclohexane-1,20-quinoxalin]-30-amine
1
ꢀ
(1H, s), 8.11 (1H, s), 7.92 (2H, t, J ¼ 9.3 Hz), 7.44–7.33 (2H, m), (7d). Solid (242 mg, 89%), mp 106–108 C; H NMR (300 MHz,
4.82 (1H, br s, NH), 2.66–2.64 (2H, d, J ¼ 6.9 Hz), 2.39–2.30 (1H, CDCl3) dH: 7.06 (1H, dd, J ¼ 7.2, 1.5 Hz), 6.85–6.75 (2H, m), 6.63
m), 1.59 (9H, s), 1.06 (6H, d, J ¼ 6.6 Hz); 13C NMR (75 MHz, (1H, dd, J ¼ 7.2, 1.5 Hz), 4.36 (1H, br s), 4.13 (1H, br s), 1.84–1.80
CDCl3) dC: 150.2, 149.4, 135.0, 133.9, 130.5, 128.3, 127.3, 126.3, (2H, m), 1.74–1.60 (3H, m), 1.50 (9H, s), 1.45–1.39 (4H, m), 1.29–
125.7, 124.0, 122.3, 52.1, 43.3, 29.7, 28.9, 27.0, 22.9; IR (KBr): 1.20 (1H, m); 13C NMR (75 MHz, CDCl3) dC: 157.4, 135.5, 133.9,
3463, 3051, 2924, 2857, 2354, 1676, 1581, 1510, 1455, 1359, 123.6, 122.2, 119.3, 113.6, 51.5, 51.4, 31.6, 28.9, 25.0, 20.7; IR
1262, 1218, 1095, 1030, 877, 742 cmꢂ1; HRMS (EI+): m/z: calcd (KBr): 3435, 2928, 2859, 1612, 1574, 1512, 1219, 741 cmꢂ1
;
for C20H25N3: 307.2048, found 307.2051.
HRMS (EI+): m/z: calcd for C17H25N3: 271.2048, found 217.2046.
N-(2,4,4-Trimethylpentan-2-yl)-10H-spiro[cycloheptane-1,20-
N-Cyclohexyl-3-isobutylbenzo[g]quinoxalin-2-amine
(5q).
Semi solid (220 mg, 66%); H NMR (300 MHz, CDCl3) dH: 8.34 quinoxalin]-30-amine (7e). Solid (284 mg, 83%), mp 79–81 ꢀC; 1H
(1H, s), 8.11 (1H, s), 7.90–7.89 (2H, m), 7.44–7.33 (2H, m), 4.80 NMR (300 MHz, CDCl3) dH: 7.01 (1H, dd, J ¼ 6.9, 1.5 Hz), 6.80–
(1H, d, J ¼ 6.9 Hz, NH), 4.27–4.12 (1H, m), 2.68 (2H, d, J ¼ 7.2 6.71 (2H, m), 6.54 (1H, dd, J ¼ 6.9, 1.5 Hz), 4.27 (1H, br s, NH),
Hz), 2.40–2.31 (1H, m), 2.19–2.15 (2H, m), 1.80–1.68 (3H, m), 3.78 (1H, br s, NH), 1.91 (2H, s), 1.76–1.71 (4H, m), 1.58–1.52
1.54–1.46 (2H, m), 1.30–1.22 (3H, m), 1.07–1.04 (6H, m); 13C (14H, m), 1.03 (9H, s); 13C NMR (75 MHz, CDCl3) dC: 158.1,
1
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135.7, 134.3, 123.5, 122.2, 119.2, 113.6, 55.7, 55.5, 52.0, 36.1, (1H, d, J ¼ 7.5 Hz), 8.21 (1H, d, J ¼ 8.1 Hz), 8.04 (1H, d, J ¼ 8.1
31.6, 30.5, 29.1, 22.8; IR (KBr): 3465, 3371, 2919, 2363, 1613, Hz), 7.77–7.63 (3H, m), 7.55 (1H, d, J ¼ 8.1 Hz), 7.33 (1H, t, J ¼
1511, 1366, 1211, 1074, 738 cmꢂ1; HRMS (EI+): m/z: calcd for 7.5 Hz); 13C NMR (75 MHz, DMSO) dC: 145.8, 143.9, 140.1, 139.7,
C
22H35N3: 341.2831, found 341.2828.
138.5, 131.1, 128.9, 128.6, 127.4, 128.8, 122.1, 120.5, 118.9,
6,6-Dimethyl-5-(2,4,4-trimethylpentan-2-ylamino)-1,6-dihy- 111.9; IR (KBr): 3154, 2363, 1950, 1610, 1465, 1407, 1207, 1131,
dropyrazine-2,3-dicarbonitrile (7f). Solid (267.2 mg, 93%), mp 1011, 751 cmꢂ1; HRMS (EI+): m/z: calcd for C14H9N3: 219.0796,
150–151 ꢀC; 1H NMR (300 MHz, CDCl3) dH: 4.69 (1H, br s, NH), found 219.0794.
3.87 (1H, br s, NH), 1.77 (2H, s), 1.42 (6H, s), 1.21 (6H, s), 0.96
6-Methyl-6H-indolo[2,3-b]quinoxaline (14b). Solid (220 mg,
(9H, s); 13C NMR (75 MHz, CDCl3) dC: 153.0, 116.8, 114.1, 113.5, 95%), mp 146–148 ꢀC; 1H NMR (300 MHz, CDCl3) dH: 8.45 (1H,
108.6, 57.0, 49.1, 32.4, 31.6, 30.6, 28.9, 23.8, 23.1; IR (KBr): 3414, d, J ¼ 7.8 Hz), 8.27 (1H, d, J ¼ 8.1 Hz), 8.11 (1H, d, J ¼ 8.1 Hz),
3346, 2962, 2369, 2217, 1552, 1454, 1360, 1316, 1222, 1133, 7.76–7.63 (3H, m), 7.42 (1H, d, J ¼ 8.1 Hz), 7.36 (1H, t, J ¼ 7.5
1033, 848, 711 cmꢂ1; HRMS (EI+): m/z: calcd for C16H25N5: Hz), 3.94 (3H, s); 13C NMR (75 MHz, CDCl3) dC: 145.6, 144.7,
287.2110, found 287.2111.
140.4, 139.9, 139.0, 130.8, 129.2, 128.6, 127.5, 125.8, 122.5,
10-(2,4,4-Trimethylpentan-2-ylamino)-6,9-diazaspiro[4.5]deca- 120.8, 119.1, 109.0, 27.3; IR (KBr): 3423, 3057, 2926, 1923, 1609,
7,9-diene-7,8-dicarbonitrile (7g). Solid (295 mg, 94%), mp 146– 1469, 1431, 1253, 1117, 753 cmꢂ1; HRMS (EI+): m/z: calcd for
147 ꢀC; 1H NMR (300 MHz, CDCl3) dH: 4.71 (1H, br s), 4.04 (1H, br
s), 1.77–1.67 (10H, m), 1.42 (6H, s), 0.95 (9H, s); 13C NMR (75 MHz,
CDCl3) dC: 151.7, 117.0, 114.4, 114.3, 108.5, 56.9, 51.2, 35.4, 31.6,
31.5, 31.4, 28.7, 28.6, 23.1; IR (KBr): 3436, 3343, 2964, 2214, 1676,
C15H11N3: 234.1031, found 234.1029.
Acknowledgements
1552, 1469, 1362, 1298, 1220, 1149, 1034, 978, 858, 701 cmꢂ1
;
This research was supported by the Nano Material Technology
HRMS (EI+): m/z: calcd for C18H27N5: 313.2266, found 313.2263. Development Program through the Korean National Research
N-(2,4,4-Trimethylpentan-2-yl)-1H-spiro[benzo[g]quinoxaline- Foundation (NRF) funded by the Korean Ministry of Education,
2,10-cyclohexan]-3-amine (7h). Solid (306 mg, 81%), mp 140–142 Science, and Technology (2012M3A7B4049675).
ꢀC; 1H NMR (300 MHz, CDCl3) dH: 7.58 (1H, d, J ¼ 7.5 Hz), 7.47
(1H, d, J ¼ 7.5 Hz), 7.35 (1H, s), 7.17–7.06 (2H, m), 6.85 (1H, s),
Notes and references
4.44 (1H, br s, NH), 4.41 (1H, br s, NH), 1.88 (2H, s), 1.88–1.54
(8H, m), 1.50 (6H, s), 1.40–1.33 (2H, m), 0.97 (9H, s); 13C NMR (75
MHz, CDCl3) dC: 159.0, 136.1, 135.0, 130.8, 129.5, 126.5, 124.8,
123.3, 121.9, 119.2, 107.5, 55.4, 51.7, 51.6, 41.6, 32.0, 31.4, 31.4,
28.9, 26.6, 24.7, 24.6, 20.4; IR (KBr): 3479, 3349, 2943, 1740, 1584,
1522, 1472, 1359, 1225, 1163, 867, 759 cmꢂ1; HRMS (EI+): m/z:
calcd for C25H35N3: 377.2831, found 377.2831.
1 F.-X. Zhu, W. Wang and H.-X. Li, J. Am. Chem. Soc., 2011, 133,
11632.
2 V. Polshettiwar and R. S. Varma, Green Chem., 2010, 12, 743.
3 F. M. Kerton and R. Marriot, Alternative Solvents for Green
Chemistry, RSC Green Chemistry Book Series, RSC
Publishing, Cambridge, UK, 2nd edn, 2013.
N-Cyclohexyl-1H-spiro[benzo[g]quinoxaline-2,10-cycloheptan]-
3-amine (7i). Solid (286 mg, 79%), mp 155–157 ꢀC; 1H NMR (300
MHz, CDCl3) dH: 7.56 (1H, d, J ¼ 8.1 Hz), 7.45 (1H, d, J ¼ 8.1 Hz),
7.35 (1H, s), 7.15–7.05 (2H, m), 6.79 (1H, s), 4.40 (1H, d, J ¼ 6.6
Hz, NH), 4.04–4.02 (2H, m), 2.01–1.95 (2H, m), 1.80–1.33 (16H,
m), 1.22–1.06 (4H, m); 13C NMR (75 MHz, CDCl3) dC: 161.7, 136.4,
135.7, 131.2, 129.7, 126.9, 125.0, 123.8, 122.2, 119.5, 107.9, 56.3,
48.2, 36.8, 32.9, 30.3, 25.7, 24.6, 22.8; IR (KBr): 3400, 3046, 2923,
2852, 1631, 1569, 1525, 1466, 1284, 1203, 1095, 1020, 875, 746
cmꢂ1; HRMS (EI+): m/z: calcd for C24H31N3: 361.2518, found
361.2515.
4 (a) U. M. Lindstrom, Chem. Rev., 2002, 102, 2751; (b)
¨
N. Shapiro and A. Vigalok, Angew. Chem., 2008, 120, 2891;
(c) C.-J. Li and T.-H. Chan, in Comprehensive Organic
Reactions in Aqueous Media, John Wiley & Sons, Inc.,
Hoboken, New Jersey, 2nd edn, 2007; (d) C. Wei and
C.-J. Li, Green Chem., 2002, 4, 39; (e) C.-J. Li, Chem. Rev.,
2005, 105, 3095; (f) A. Chanda and V. V. Fokin, Chem. Rev.,
2009, 109, 725; (g) K. H. Shaughnessy, Chem. Rev., 2009,
109, 643.
5 (a) V. K. Ahluwalia and R. S. Varma, Green Solvents for Organic
Synthesis, Alpha Science International, Abingdon, UK, 2009;
(b) A. Modak, J. Mondal, M. Sasidharan and A. Bhaumik,
Green Chem., 2011, 13, 1317.
6 R. A. van Santen and M. Neurock, Molecular Heterogeneous
Catalysis: A Conceptual and Computational Approach, Wiley-
VCH, Weinheim, 2007.
7 V. Polshettiwar, B. Baruwati and R. S. Varma, ACS Nano,
2009, 3, 728.
Synthesis of indophenazine (14a) and its derivative (14b)
To a solution of o-phenylenediamine (1.0 mmol), isatin (1.0
mmol), or N-methyl isatin (1.0 mmol), and isocyanide (1.0
mmol) in 3 mL of water was added CeO2-NPs (5 mol%). The
resulting mixture was gently heated at 80 ꢀC. Reaction
completion was monitored by TLC. The organic layer was
extracted with ethyl acetate (2 ꢁ 5 mL) and dried over Na2SO4.
Solvent was removed using a rotary evaporator and the crude
compounds were crystallized from hot ethyl acetate to give pure
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