A novel and facile synthesis of 2-(cyclohexylamino)-6,7-dihydro-3-aryl-1H-indole-4(5H)-ones via a one-pot multi-component reaction

Article abstract of DOI:10.1016/j.tetlet.2008.08.012

A simple and efficient synthesis of 2-(cyclohexylamino)-6,7-dihydro-3-aryl-1H-indole-4(5H)-ones was achieved via a one-pot multi-component reaction of cyclohexyl isocyanide, an aldehyde, a 1,3-dicarbonyl compound, and ammonium acetate in the presence of a catalytic amount of KHSO₄ in acetonitrile.

Full text of DOI:10.1016/j.tetlet.2008.08.012

Tetrahedron Letters 49 (2008) 6101–6103
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Tetrahedron Letters
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A novel and facile synthesis of 2-(cyclohexylamino)-6,7-dihydro-3-aryl-1H-
indole-4(5H)-ones via a one-pot multi-component reaction
*
Majid M. Heravi , Bita Baghernejad, Hossein A. Oskooie, Rahim. Hekmatshoar
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:
A simple and efficient synthesis of 2-(cyclohexylamino)-6,7-dihydro-3-aryl-1H-indole-4(5H)-ones was
achieved via a one-pot multi-component reaction of cyclohexyl isocyanide, an aldehyde, a 1,3-dicarbonyl
compound, and ammonium acetate in the presence of a catalytic amount of KHSO4 in acetonitrile.
Ó 2008 Elsevier Ltd. All rights reserved.
Received 26 May 2008
Revised 28 July 2008
Accepted 5 August 2008
Available online 8 August 2008
Keywords:
Cyclohexyl isocyanide
1,3-Dicarbonyl compound
Multi-component reaction
1H-Indole-4(5H)-ones
1. Introduction
larly for the synthesis of substituted indole rings.14,15 Thus, the
development of high-throughput methods for the synthesis of
There has been tremendous interest in developing highly effi-
cient transformations for the preparation of organic compounds,
as well as, biologically active materials, with potential application
in the pharmaceutical or agrochemical industries from commer-
cially available compounds. There is also a need for synthetic
chemists to find new, efficient, and strategically important pro-
cesses, which are environmentally benign and lead to greater
structural variation in short period of times with high yields and
simple work-up procedures. Significant advances have been made
to chemical processes to achieve the ultimate goal of hazard-free,
waste-free, and energy-efficient syntheses.1 In this context, multi-
component reactions (MCRs)2 have played an important role in
these processes.3,4 Since the pioneering work by Strecker in 1850
describing the first reported MCR,5 this well-known concept6 has
been used extensively in both liquid-phase2e and solid-phase7
chemistry for the rapid assembly of complex heterocyclic structures
for pharmaceutical development.8 Isocyanide-based MCRs,2,9
introduced in 1921 by Passerini,10 generally predominate for the
construction of widely diverse heterocycles.11
indoles remains an important topic. Therefore, we decided to use
a MCR for the synthesis of 2-(cyclohexylamino)-6,7-dihydro-3-
aryl-1H-indole-4(5H)-ones.
Herein, we report a mild, practical, and highly efficient proce-
dure for the preparation of the title compounds using KHSO4 as a
catalyst under refluxing conditions (Scheme 1).
2-(Cyclohexylamino)-6,7-dihydro-3-aryl-1H-indole-4(5H)-ones
were obtained by the MCR of cyclohexyl isocyanide, an aldehyde,
dimedone or 1,3-cyclohexandione, and ammonium acetate in the
presence of a catalytic amount of KHSO4 in acetonitrile (Scheme
1) in good yields (Table 1). To the best of our knowledge, there
are no reports on the synthesis of these compounds via MCR using
KHSO4 as the catalyst. KHSO4 is one of the components of a triple
salt with the formula 2KHSO5ÁKHSO4ÁK2SO4 which is known as
Oxone, and is used as a highly efficient oxidant in many organic
reagents.16 Very recently, we reported the use of KHSO4 as an
efficient catalyst for the synthesis of 1,1-diacetates,17 the aromati-
zation of Hantzsch 1,4-dihydropyridines, and the synthesis of
quinoxalines.18 We evaluated the amount of KHSO4 required for
this transformation and found that as little as 10 mol % of KHSO4
catalyzed the reaction to some extent, but a longer reaction time
(>3 h) was required. The use of an increased amount of catalyst
did not improve the yield significantly. The scope of the reaction
with respect to the aldehyde component was examined. As shown
in Table 1, aromatic aldehydes containing both electron-donating
or -withdrawing groups gave excellent yields of the product. In
each reaction, the yield was a function of the reaction time which
was optimized at 4 h at reflux.
The indole nucleus is an important substructure found in
numerous natural alkaloids.12,13 The diversity of the structures
encountered, as well as their biological and pharmaceutical rele-
vance, has motivated research aimed at the development of new,
economical, efficient, and selective synthetic strategies, particu-
* 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.2008.08.012

6102
M. M. Heravi et al. / Tetrahedron Letters 49 (2008) 6101–6103
NC
O
O
Ar
CH3CN
+
ArCHO
NH4OAc
+
+
N
reflux
R
R
H
N
H
KHSO4
O
R
R
2
3
4
1a R=H
1b
CH
5
R=H
CH
R=
R=
6
3
3
Scheme 1.
Table 1
easy work-up, use of an easy to handle and safe catalyst, and high
yields of products.
Synthesis of 2-(cyclohexylamino)-6,7-dihydro-3-aryl-1H-indole-4(5H)-ones using
various aldehydes
Entry
Substrate
Product
Ar
Yielda (%)
2. Preparation of 2-(cyclohexylamino)-6,7-dihydro–3-aryl-1H-
indole-4(5H)-ones: typical procedure
1
2
3
4
5
6
7
8
9
1a
1a
1a
1a
1a
1a
1b
1b
1b
1b
1b
1b
5a
5b
5c
5d
5e
5f
6a
6b
6c
6d
6e
6f
C6H5
90
85
85
83
90
91
87
90
84
88
90
90
4-Cl–C6H4
2-NO2–C6H4
4-NO2–C6H4
4-CH3–C6H4
4-CH3O–C6H4
C6H5
4-Cl–C6H4
2-NO2–C6H4
4-NO2–C6H4
4-CH3–C6H4
4-CH3O–C6H4
To a magnetically stirred solution of 1,3-dicarbonyl compound
(1 mmol), aldehyde (1 mmol), ammonium acetate (1.5 mmol),
and KHSO4 (10 mol %) in acetonitrile (5 mL) was added cyclohexyl
isocyanide (1 mmol), and the reaction mixture was refluxed for 4 h.
The progress of the reaction was monitored by TLC (ethyl acetate–
hexane 1:3). After completion of the reaction, acetonitrile was
removed in vacuo and then diethyl ether was added to the solid
residue in order to separate the catalyst from the mixture The
filtrate was washed twice with 5% NaHCO3 (5 mL) and dried over
MgSO4. The solvent was evaporated under reduced pressure and
the product was recrystallized from CH2Cl2–EtOH (1:2) to give
the pure product.
10
11
12
a
Yield of isolated products.
O
O
Ar
2.1. 2-(Cyclohexylamino)-6,7-dihydro-3-phenyl-1H-indole-
4(5H)-one (5a)
ArCHO
NH4OAc
+
+
Mp: 168 °C. IR (KBr) (m
max, cmÀ1): 1630 (C@N), 1670 (C@O),
O
O
3320 (N–H). 1H NMR (CDC13, 300 MHz) dH (ppm): 1.11–1.99
(10H, m), 2.44 (2H, m), 2.71 (2H, t, J = 5.9), 2.90 (2H, t, J = 6.0),
3.02 (1H, m), 7.45–7.53 (5H, m, arom), 8.22 (1H, s, NH), 9.48 (1H,
s, NH). 13C NMR (CDC13, 125 MHz) dC (ppm): 21.91, 24.96, 25.13,
26.67, 27.08, 34.22, 34.09, 42.70, 55.10, 121.25, 128.32 (arom.
and 2CH), 129.46 (arom. and 2CH), 131.02, 145.11, 146.98 (C–
NO2), 154.43, 156.92 (C–N), 194.45 (C@O). GC/MS: 308 (M+). Anal.
Calcd for C20H24N2O: C, 77.89; H, 7.84; N, 9.08. Found: C, 77.88; H,
7.81; N, 9.05.
O
O
Ar
Ar
H
N
+
N
H
NH
-
C
+
N
2.2. 2-(Cyclohexylamino)-6,7-dihydro-3-(2-nitrophenyl)-1H-
indole-4(5H)-one (5c)
O
Ar
Mp: 181 °C. IR (KBr) (m
max, cmÀ1): 1325 and 1515 (NO2), 1630
N
H
(C@N), 1670 (C@O), 3320 (N–H). 1H NMR (CDC13, 300 MHz) dH
(ppm): 1.11–1.96 (10H, m), 2.38 (2H, m), 2.68 (2H, t, J = 6.1), 2.89
(2H, t, J = 5.9), 3.20 (1H, m), 7.45–7.84 (4H, m, arom), 8.08 (1H, s,
NH), 9.32 (1H, s, NH). 13C NMR (CDC13, 125 MHz) dC (ppm):
22.81, 24.92, 25.05, 26.66, 27.10, 34.11, 34.09, 42.65, 65.08,
122.11, 124.33, 125.55, 125.98, 130.12, 139.45, 141.25, 144.32
(C–NO2), 152.41, 153.97 (C–N), 193.46 (C@O). GC/MS: 353 (M+).
Anal. Calcd for C20H23N3O3: C, 67.97; H, 6.56; N, 11.89. Found: C,
67.89; H, 6.66; N, 11.84.
N
H
Scheme 2.
A plausible mechanism for this reaction is suggested in Scheme
2. The first step may involve adduct formation by condensation of
1,3-cyclohexanedione with the aromatic aldehyde, followed by
attack of ammonium acetate to give the intermediate 2-benzylidi-
ene-3-imino-cyclohexanone. Reaction of cyclohexyl isocyanide
with this intermediate then gives the desired product.
In summary, we have reported an efficient process for the
synthesis of potentially biologically interesting functionalized
2-(cyclohexylamino)-6,7-dihydro-3-aryl-1H-indole-4(5H)-ones
starting from readily available and inexpensive reagents. The
advantages of the present procedure are experimental simplicity,
2.3. 2-(Cyclohexylamino)-6,7-dihydro-3-(4-nitrophenyl)-1H-
indole-4(5H)-one (5d)
Mp: 175 °C. IR (KBr) (m
max, cmÀ1): 1320 and 1505 (NO2), 1630
(C@N), 1670 (C@O), 3320 (N–H). 1H NMR (CDC13, 300 MHz) dH
(ppm): 1.15–2.01 (10H, m), 2.42 (2H, m), 2.73 (2H, t, J = 6.1), 2.94

M. M. Heravi et al. / Tetrahedron Letters 49 (2008) 6101–6103
6103
(2H, t, J = 6.2), 3.12 (1H, m), 7.35 (2H, d, J = 8.2), 7.91 (2H, d, J = 8.2),
8.13 (1H, s, NH), 9.50 (1H, s, NH). 13C NMR (CDC13, 125 MHz) dC
(ppm): 22.91, 25.12, 25.15, 26.70, 27.12, 34.14, 34.19, 42.61,
55.10, 120.21, 125.92 (arom. and 2CH), 129.33 (arom. and 2CH),
130.05, 145.11, 145.21 (C–NO2), 153.42, 154.96 (C–N), 193.39
(C@O). GC/MS: 353 (M+). Anal. Calcd for C20H23N3O3: C, 67.97; H,
6.56; N, 11.89. Found: C, 67.94; H, 6.59; N, 11.81.
and 2CH), 130.06, 145.1, 145 (C–NO2), 153.4, 154.9 (C–N), 193.3
(C@O). GC/MS: 381 (M+). Anal. Calcd for C22H27N3O3: C, 69.27; H,
7.13; N, 11.01. Found: C, 69.15; H, 7.24; N, 10.94.
2.7. 2-(Cyclohexylamino)-6,7-dihydro-6,6-dimethyl-3(4-
methoxyphenyl)-1H-indole-4(5H)-one (6f)
Mp: 198 °C. IR (KBr) (m
max, cmÀ1): 1622 (C@N), 1669 (C@O),
2.4. 2-(Cyclohexylamino)-6,7-dihydro-3-(4-methylphenyl)-1H-
indole-4(5H)-one (5e)
3324 (N–H). 1H NMR (CDC13, 300 MHz) dH (ppm): 1.17 (6H, s,
2CH3), 1.21–1.99 (10H, m), 2.40 (2H, s), 2.63 (2H, s), 3.25 (1H,
m), 4.59 (3H, s, CH3), 7.23 (2H, d, J = 8.2), 7.88 (2H, d, J = 8.2),
8.16 (1H, s, NH), 9.08 (1H, s, NH). 13C NMR (CDC13, 125 MHz) dC
(ppm): 21.91, 25.11, 25.22, 26.69, 27.22, 27.98, 28.05, 34.24,
36.39, 39.60, 40.25, 58.34, 120.54, 124.65 (arom. and 2CH),
127.43 (arom. and 2CH), 130.14, 145.12, 145.25 (C–NO2), 153.42,
154.91 (C–N), 192.22 (C@O). GC/MS: 366 (M+). Anal. Calcd for
C23H30N2O2: C, 75.38; H, 8.25; N, 7.64. Found: C, 75.35; H, 8.24;
N, 7.54.
Mp: 168 °C. IR (KBr) (m
max, cmÀ1): 1628 (C@N), 1678 (C@O),
3339 (N–H). 1H NMR (CDC13, 300 MHz) dH (ppm): 1.12–1.97
(10H, m), 2.37 (2H, m), 2.68 (2H, t, J = 6.1), 2.85 (2H, t, J = 6.0),
3.25 (1H, m), 4.01 (3H, s, CH3), 7.30 (2H, d, J = 8.2), 7.91 (2H, d,
J = 8.2), 8.18 (1H, s, NH), 9.45 (1H, s, NH).13C NMR (CDC13,
125 MHz) dC (ppm): 23.41, 25.66, 25.83, 26.72, 27.02, 34.16,
34.29, 42.66, 55.19, 59.12, 120.91, 124.98 (arom. and 2CH),
125.62 (arom. and 2CH), 130.05, 145.15, 144.91 (C-NO2), 152.94,
153.99 (C–N), 192.25 (C@O). GC/MS: 322 (M+). Anal. Calcd for
References and notes
C21H26N2O: C, 78.22; H, 8.13; N, 8.69. Found: C, 78.22; H, 8.12;
N, 8.61.
1. Adams, D. J.; Dyson, P. J.; Tavener, S. J. Chemistry in Alternative Reaction Media;
Wiley-VCH Verlag GmbH & Co.: Weinheim, 2004.
2.5. 2-(Cyclohexylamino)-6,7-dihydro-6,6-dimethyl-3-phenyl-
1H-indole-4(5H)-one (6a)
2. (a) Zhu, J.; Bienayme, H. Multicomponent Reactions; Wiley-VCH: Weinheim,
2005; (b) Bienayme, H.; Hulme, C.; Oddon, G.; Schmitt, P. Chem. Eur. J 2000, 6,
3321; (c) Domling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3168; (d) Zhu, J.
Eur. J. Org. Chem. 2003, 1133; (e) Orru, R. V.; de Greef, M. Synthesis QSAR Comb.
Sci 2006, 25, 432–438; (f) Ramon, D. J.; Yus, M. Angew. Chem., Int. Ed. 2005, 44,
1602.
3. Weber, L.; Illgen, M.; Almstetter, M. Synlett 1999, 366.
4. Wender, P. A.; Handy, S. T.; Wright, D. L. Chem. Ind. 1997, 765.
5. Strecker, A. Liebigs Ann. Chem. 1850, 75, 27.
Mp: 201 °C. IR (KBr) (m
max, cmÀ1): 1610 (C@N), 1660 (C@O),
3300 (N–H). 1H NMR (CDC13, 300 MHz) dH (ppm): 1.18 (6H, s,
2CH3), 1.20–2.12 (10H, m). 2.48 (2H, s), 2.53 (2H, s), 3.31 (1H,
m), 7.42–7.63 (5H, m, arom), 8.07 (1H, s, NH), 9.24 (1H, s, NH).
13C NMR (CDC13, 125 MHz) dC (ppm): 25.21, 25.28, 25.51, 27.92,
30.12, 33.96, 33.98, 37.11, 43.16, 53.45, 58.19, 110.91, 123.75
(arom. and 2CH), 125.42, 126.91, 129.56 (arom. and 2CH),
134.79, 150.90, 154.13 (C–N), 190.51 (C@O). GC/MS: 336 (M+).
Anal. Calcd for C22H28N2O: C, 78.53; H, 8.39; N, 8.32. Found: C,
78.42; H, 8.40; N, 8.28.
6. Posner, G. H. Chem. Rev. 1986, 86, 831.
7. Dax, S. L.; McNally, J. J.; Youngman, M. A. Curr. Med. Chem. 1999, 6, 255.
8. Nefzi, A.; Ostresh, J. M.; Houghten, R. A. Chem. Rev. 1997, 97, 449.
9. (a) Domling, A. Curr. Opin. Chem. Biol. 2000, 4, 318; (b) Domling, A. Curr. Opin.
Chem. Biol. 2002, 6, 306.
10. (a) Passerini, M. Gazz. Chim. Ital. 1921, 51, 126; (b) Passerini, M. Gazz. Chim. Ital.
1921, 51, 181.
11. Ugi, I.; Domling, A.; Werner, B. J. Heterocycl. Chem. 2000, 37, 647.
12. Sundberg, R. J. Indoles; Academic Press: London, 1996.
13. Joule, J. A. In Science of Synthesis; Thomas, E. J., Ed.; Thieme: Stuttgart, 2001;
Vol. 10, p 361.
14. Sundberg, R. J. In Comprehensive Heterocyclic Chemistry; Katritzky, A. R., Rees, C.
W., Eds.; Pergamon: Oxford, 1984; Vol. 4, p 314.
15. Tois, J.; Franzen, R.; Koskinen, A. Tetrahedron 2003, 59, 5395.
16. (a) Travis, B. R.; Sivakumar, M.; Hollist, G. O.; Borhan, B. Org. Lett. 2003, 5, 1031;
(b) Bolm, C.; Magnus, A. S.; Hildebrand, J. P. Org. Lett. 2000, 2, 1173; (c)
Thottumkara, A. P.; Bowsher, M. S.; Vinod, T. K. Org. Lett. 2005, 7, 2933.
17. Heravi, M. M.; Bakhtiari, Kh.; Taheri, Sh.; Oskooie, H. A. Green Chem. 2005, 7,
867.
18. (a) Heravi, M. M.; Bakhtiari, K.; Oskooie, H. A. Monatsh. Chem. 2007, 38, 875;
(b) Heravi, M. M.; Bakhtiari, K.; Oskooie, H. A. J. Chin. Chem. Soc. 2007, 54,
579.
2.6. 2-(Cyclohexylamino)-6,7-dihydro-6,6-dimethyl-3-
(4-nitrophenyl)-1H-indole-4(5H)-one (6d)
Mp: 221 °C. IR (KBr) (m
max, cmÀ1): 1328 and 1515 (NO2), 1610
(C@N), 1665 (C@O), 3300 (N–H). 1H NMR (CDC13, 300 MHz) dH
(ppm): 1.17 (6H, s, 2CH3), 1.19–1.98 (10H, m), 2.40 (2H, s), 2.63
(2H, s), 3.28 (1H, m), 7.25 (2H, d, J = 8.3), 7.91 (2H, d, J = 8.3),
8.09 (1H, s, NH), 9.44 (1H, s, NH).13C NMR (CDC13, 125 MHz) dC
(ppm): 21.91, 25.02, 25.12, 26.66, 27.02, 27.93, 28.15, 34.14,
36.19, 39.61, 58.34, 120.21, 124.82 (arom. and 2CH), 127.36 (arom.