A novel three-component reaction for the synthesis of N-cyclohexyl-3-aryl-quinoxaline-2-amines

Article abstract of DOI:10.1016/j.tetlet.2008.11.123

Ferric perchlorate catalyzes the three-component condensation reaction of o-phenylenediamine, aromatic aldehydes, and cyclohexyl isocyanide to afford the corresponding N-cyclohexyl-3-aryl-quinoxaline-2-amines in good yields.

Full text of DOI:10.1016/j.tetlet.2008.11.123

Tetrahedron Letters 50 (2009) 767–769
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
A novel three-component reaction for the synthesis
of N-cyclohexyl-3-aryl-quinoxaline-2-amines
*
Majid M. Heravi , Bita Baghernejad, Hossein A. Oskooie
Department of Chemistry, School of Science, Azzahra University, Vanak, Tehran, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 22 July 2008
Revised 3 November 2008
Accepted 28 November 2008
Available online 6 December 2008
Ferric perchlorate catalyzes the three-component condensation reaction of o-phenylenediamine, aro-
matic aldehydes, and cyclohexyl isocyanide to afford the corresponding N-cyclohexyl-3-aryl-quinoxa-
line-2-amines in good yields.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
O-Phenylenediamine
N-Cyclohexyl-3-aryl-quinoxaline-2-amines
Ferric perchlorate
Cyclohexyl isocyanide
Three-component reactions
1. Introduction
To the best of our knowledge, there is no report on the synthesis
of these compounds with cyclohexyl isocyanide and aldehydes.
Among the various classes of nitrogen-containing heterocyclic
compounds, quinoxalines display a broad spectrum of biological
activity.1–4 This has contributed to their usefulness in combinato-
rial drug discovery libraries.5–10 Quinoxalines play an important
role as a basic skeleton for the design of a number of antibiotics
such as echinomycin, actinomycin, and leromycin. It has been re-
ported that these compounds inhibit the growth of gram-positive
bacteria, and are active against various transplantable tumors.11,12
The quinoxaline ring is also a constituent of many pharmaco-
logically and biologically active compounds such as insecticides,
fungicides, herbicides, and anthelminitics.13,14 Quinoxaline deriva-
tives have found application in dyes,15 electron luminescent mate-
rials,16 organic semiconductors,17 chemically controllable
switches,18 as building blocks for the synthesis of anion recep-
tors,19 cavitands,20 dehydroannulenes,21 DNA cleaving agents,22
and also serve as useful rigid subunits in macrocyclic receptors
or in molecular recognition.23
The application of ferric perchlorate as a catalyst is becoming more
widespread. It is used in organic chemistry for the protection of
alcohols and deprotection of tetrahydropyranyl ethers,31 acetyla-
tion of alcohols and phenols,32 aromatization of Hantzsch 1,4-dihy-
dropyridines,33 synthesis of 1,5-benzodiazepine derivatives,34
direct acetylation of THP ethers,35 conversion of oximes to aryl
and alkyl hydrazones,36 and for the synthesis of
a-aminonitriles
using trimethylsilylcyanide.37 In this Letter, and in continuation
of our research, we report ferric perchlorate as an efficient catalyst
for the synthesis of N-cyclohexyl-3-aryl-quinoxaline-2-amines in
good yields from o-phenylenediamine, aromatic aldehydes, and
cyclohexyl isocyanide (Scheme 1).
In recent years, multicomponent reactions (MCRs) have become
important tools in modern preparative synthetic chemistry be-
cause they increase the efficiency by combining several operational
steps without isolation of intermediates or changing the reaction
conditions.38,39 MCRs have emerged as valuable tools for the prep-
aration of structurally diverse chemical libraries of drug-like het-
erocyclic compounds.40–42 Isocyanide-based MCRs are especially
important in this area.43
The MCR of cyclohexyl isocyanide, an aromatic aldehyde, and
o-phenylenediamine in the presence of a catalytic amount of
ferric perchlorate in acetonitrile was complete within 2 h to
afford N-cyclohexyl-3-aryl-quinoxaline-2-amines in good yields
(Table 1). The yields of the reactions increased as the reaction
temperature was raised, and refluxing conditions were found
to be optimum. Importantly, aromatic aldehydes carrying either
Despite remarkable efforts,3,4 the development of an effective
method for the synthesis of quinoxalines is still an important chal-
lenge. A number of synthetic strategies have been developed for
the preparation of substituted quinoxalines.24–29 The most com-
mon method relies on the condensation of an aryl 1,2-diamine
with a 1,2-dicarbonyl compound in refluxing ethanol or acetic acid
for 2–12 h, and this typically gives yields of 34–70%.30
* Corresponding author. Tel.: +98 2188041344; fax: +98 2188047861.
E-mail address: mmh1331@yahoo.com (M.M. Heravi).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.11.123

768
M. M. Heravi et al. / Tetrahedron Letters 50 (2009) 767–769
R
NC
R
NH2
NH2
Fe(ClO4)3
N
N
+
+
CHO
reflux
acetonitrile
N
H
1
4
2
3
Scheme 1.
Table 1
highly selective Lewis acid. The oxidation potential of ferric per-
chlorate in methanol is 0.70 eV.45
Synthesis of N-cyclohexyl-3-aryl-quinoxaline-2-amines
Entry
Substrate
Product
Time (h)
Yielda (%)
2. Preparation of N-cyclohexyl-3-aryl-quinoxaline-2-amines:
general procedure
1
2
3
4
5
6
7
Benzaldehyde
4a
4b
4c
4d
4e
4f
2
2
2
2
2
2
2
92
92
91
93
92
92
92
3-Nitrobenzaldehyde
4-Chlorobenzaldehyde
4-Methoxybenzaldehyde
4-Nitrobenzaldehyde
4-Hydroxybenzaldehyde
4-Methylbenzaldehyde
To a mixture of o-phenylenediamine (1 mmol), benzaldehyde
(1 mmol), and cyclohexyl isocyanide (1 mmol) in acetonitrile
(5 mL), a catalytic amount of ferric perchlorate (0.2 mmol) was
added and the mixture was refluxed for 2 h. The progress of the
reaction was monitored by TLC (ethyl acetate–hexane 1:3). After
completion of the reaction, acetonitrile was removed and the reac-
tion mixture was diluted with water (10 mL), and CH2Cl2 (10 mL)
was added. The organic layer was separated and dried over MgSO4.
The solvent was evaporated under reduced pressure, and the prod-
uct was obtained without any further purification.
4g
a
Yield of isolated product.
electron-donating or -withdrawing substituents afforded good
yields of the expected products. The reaction proceeds cleanly
and is free from side products. A possible reaction mechanism
is suggested in Scheme 2.
The first step may involve reaction of the aromatic aldehyde
with o-phenylenediamine followed by attack of cyclohexyl isocya-
nide on the resulting intermediate. Following rearrangement and
catalytic oxidation by ferric perchlorate,33 the product is obtained.
In conclusion, we have demonstrated a very simple, efficient,
clean, and practical method for the synthesis of N-cyclohexyl-3-
aryl-quinoxaline-2-amines in good yields (91–93%) in the presence
of ferric perchlorate as an efficient catalyst.
3. N-Cyclohexyl-3-phenyl-quinoxaline-2-amine (4a)
Mp 187 °C; IR (KBr) (m
max, cmÀ1): 3200, 1632, 1620; 1H NMR
(CDCl3, 300 MHz) dH (ppm): 1.11–2.12 (m, 10H), 3.24 (m, 1H),
4.75 (s, 1H, NH), 7.51–8.02 (m, 9H, arom). 13C NMR (CDCl3, 125
MHz) dC (ppm): 24.81, 26.53 (2CH2), 33.30 (2CH2), 51.24, 126.26
(2CH), 128.21, 128.62, 129.13, 131.55 (2CH), 131.5, 132.2, 134.7,
136.5 (C@N), 141.1, 142.1, 145.4 (NH–C@N). GC/MS: 303 (M+).
Anal. Calcd for C20H21N3: C, 79.17; H, 6.98; N, 13.85. Found: C,
79.11; H, 6.92; N, 13.81.
Although Fe(III) reagents are known to be strong oxidants,44 fer-
ric perchlorate in this reaction behaves solely as a powerful and
R
R
+
NH2
NH
Fe(ClO4)3
CH
CHO
+
NH2
NH2
C-
+
R
H
N
N
+
R
H
N
NH2
N
+
N
N
H
R
R
H
N
N
-2H
N
N
H
catalytic
dehydrogenation33
N
N
H
Scheme 2.

M. M. Heravi et al. / Tetrahedron Letters 50 (2009) 767–769
769
150.93 (C–NO2). GC/MS: 317 (M+). Anal. Calcd for C21H23N3: C,
79.46; H, 7.30; N, 13.24. Found: C, 79.14; H, 7.25; N, 13.08.
4. N-Cyclohexyl-3-(3-nitrophenyl)-quinoxaline-2-amine (4b)
max, cmÀ1): 3165, 1635, 1628; 1H NMR
Mp 195 °C; IR (KBr) (
m
(CDCl3, 300 MHz) dH (ppm): 1.24–2.29 (m, 10H), 3.40 (m, 1H),
4.51 (s, 1H, NH), 7.51–8.43 (m, 8H, arom). 13C NMR (CDCl3,
125 MHz) dC (ppm): 25.22, 26.15 (2CH2), 33.53 (2CH2), 52.10,
127.56, 128.42, 129.91, 129.12, 129.96, 130.11, 131.16, 132.20,
132.94, 134.12, 138.55 (C@N), 141.51, 142.23 (NH–C@N), 150.95
(C–NO2). GC/MS: 348 (M+). Anal. Calcd for C20H20N4O2: C, 68.95;
H, 5.79; N, 16.08. Found: C, 68.88; H, 5.81; N, 16.11.
Acknowledgments
M.M. Heravi is thankful for partial financial support from the
presidential office for Project No. 87066/26.
References and notes
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(CDCl3, 300 MHz) dH (ppm): 1.12–2.20 (m, 10H), 3.49 (m, 1H),
4.45 (s, 1H, NH), 7.42–8.46 (m, 8H, arom). 13C NMR (CDCl3,
125 MHz) dC (ppm): 23.34, 26.15 (2CH2), 33.71 (2CH2), 52.18,
127.32, 128.82, 128.55, 129.73, 130.15, 131.19, 132.67, 133.39,
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Mp 179 °C; IR (KBr) (m
max, cmÀ1): 3168, 1642, 1638; 1H NMR
(CDCl3, 300 MHz) dH (ppm): 1.20–2.29 (m, 10H), 2.68 (s, 3H),
3.44 (m, 1H), 4.51 (s, 1H, NH), 7.27–8.29 (m, 8H, arom). 13C NMR
(CDCl3, 125 MHz) dC (ppm): 25.49, 26.31 (2CH2), 32.97 (2CH2),
33.67, 51.97, 123.37 (2CH), 127.64, 128.43 (2CH), 121.41, 130.07,
131.27, 134.46, 138.59 (C@N), 141.77, 142.21 (NH–C@N), 148.87,
150.97 (C–NO2). GC/MS: 333 (M+). Anal. Calcd for C21H23N3O: C,
75.65; H, 6.95; N, 12.60. Found: C, 75.57; H, 7.02; N, 12.56.
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Mp 209 °C; IR (KBr) (m
max, cmÀ1): 3150, 1622, 1610; 1H NMR
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4.38 (s, 1H, NH), 7.49–8.33 (m, 8H, arom). 13C NMR (CDCl3,
125 MHz) dC (ppm): 25.43, 26.48 (2CH2), 33.21 (2CH2), 52.68,
127.71 (2CH), 128.78, 129.36 (2CH), 121.27, 130.08, 131.33,
134.42, 138.57 (C@N), 141.91, 142.28 (NH–C@N), 148.92, 150.86
(C–NO2). GC/MS: 348 (M+). Anal. Calcd for C20H20N4O2: C, 68.95;
H, 5.79; N, 16.08. Found: C, 68.86; H, 5.77; N, 16.02.
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Mp 176 °C; IR (KBr) (m
max, cmÀ1): 3143, 1642, 1638; 1H NMR
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CDCl3, 300 MHz) dH (ppm): 1.18–2.19 (m, 10H), 3.24 (m, 1H),
4.32 (s, 1H, NH), 4.86 (s, 1H, OH), 7.41–8.62 (m, 8H, arom). 13C
NMR (CDCl3, 125 MHz) dC (ppm): 24.44, 25.97 (2CH2), 33.07
(2CH2), 52.43, 126.94 (2CH), 128.31, 129.17 (2CH), 121.27,
130.91, 131.32, 133.31, 137.79 (C@N), 139.91, 143.01 (NH–C@N),
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N, 13.24.
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Mp 201 °C; IR (KBr) (m
max, cmÀ1): 3163, 1638, 1622; 1H NMR
(CDCl3, 300 MHz) dH (ppm): 1.17–2.39 (m, 10H), 2.59 (s, 3H),
3.34 (m, 1H), 4.37 (s, 1H, NH), 7.22–8.27 (m, 8H, arom). 13C NMR
(CDCl3, 125 MHz) dC (ppm): 24.13, 25.57 (2CH2), 30.17 (2CH2),
39.84, 52.51, 126.67 (2CH), 128.51, 128.47 (2CH), 129.97, 130.74,
131.27, 134.17, 138.56 (C@N), 141.97, 141.09 (NH–C@N), 142.97,
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