A novel one-pot pseudo-five-component synthesis of 4,5,6,7-tetrahydro-1H-1, 4-diazepine-5-carboxamide derivatives

Article abstract of DOI:10.1021/jo8002612

(Chemical Equation Presented) A novel one-pot pseudo-five-component synthesis of 4,5,6,7-tetrahydro-1H-1,4-diazepine-5-carboxamide derivatives starting from simple and readily available inputs including 2,3- diaminomaleonitrile, a cyclic or acyclic ketone, an isocyanide, and water in the presence of a catalytic amount of p-toluenesulfonic acid in aqueous medium at ambient temperature in high yields is described.

Full text of DOI:10.1021/jo8002612

TABLE 1. Synthesis of 4,5,6,7-Tetrahydro-1H-1,4-diazepine-5-
carboxamide Derivatives 5a-l
A Novel One-Pot Pseudo-Five-Component
Synthesis of 4,5,6,7-Tetrahydro-1H-
1,4-diazepine-5-carboxamide Derivatives
time yielda
product (h) (%)
entry
ketone
isocyanide
cyclohexyl
1
2
3
4
5
6
7
cyclohexanone
cyclohexanone
cyclopentanone
cyclopentanone
5a
5b
5c
5d
5e
5f
16 92
18 84
20 82
20 80
16 85
24 85
24 80
Ahmad Shaabani,* Ali Maleki, Hamid Mofakham, and
Jafar Moghimi-Rad
tert-butyl
cyclohexyl
tert-butyl
4-tert-butylcyclohexanone cyclohexyl
Department of Chemistry, Shahid Beheshti UniVersity,
cyclohexanone
cyclopentanone
benzyl
P.O. Box 19396-4716, Tehran, Iran
1,1,3,3-Tetramethyl- 5g
butyl
a-shaabani@cc.sbu.ac.ir
8
9
acetophenone
4′-methylacetophenone
cyclohexyl
cyclohexyl
cyclohexyl
cyclohexyl
tert-butyl
5h
5i
5j
5k
5l
24 82
24 84
22 90
20 92
20 90
10 4′-bromoacetophenone
11 acetone
12 acetone
ReceiVed February 1, 2008
a Isolated yield.
of many spirocenter-containing natural compounds over the
years. On the other hand, spirocyclic systems are structurally
interesting.3
2,3-Diaminomaleonitrile (DAMN)4 was considered as one of
the versatile precursors for the synthesis of various types of
nitrogen heterocycles such as imidazoles,5 oxazoles,6 purines,7
pyrroles,8pyrimidines,9pyrazines,10 diazepines,11 andtriazepines.5,12
Although many reactions of DAMN have been reported under
classical two-component reactions,4 to the best of our knowl-
edge, only one reaction of it with isocyanides under MCR
strategy has been studied.13a
A novel one-pot pseudo-five-component synthesis of 4,5,6,7-
tetrahydro-1H-1,4-diazepine-5-carboxamide derivatives start-
ing from simple and readily available inputs including 2,3-
diaminomaleonitrile, a cyclic or acyclic ketone, an isocyanide,
and water in the presence of a catalytic amount of p-tol-
uenesulfonic acid in aqueous medium at ambient temperature
in high yields is described.
In continuing our interest in I-MCRs,13 here we report a
hitherto unknown reaction that affords 4,5,6,7-tetrahydro-1H-
1,4-diazepine-5-carboxamide derivatives 5a-l especially spi-
rocyclic 4,5,6,7-tetrahydro-1H-1,4-diazepine-5-carboxamide-2,3-
Sequential transformations and one-pot multicomponent reac-
tions (MCRs) are always resource effective and environmentally
acceptable and thus greener as compared to multistep reactions.1
They offer significant advantages over conventional linear step
syntheses, by reducing time and saving money, energy, and raw-
materials thus resulting in both economical and environmental
benefits. At the same time, diversity can be achieved for building
up libraries by simply varying each component.1 Because of
the unique reactivity of the isocyanide functional group,
isocyanide-based MCRs (I-MCRs) are among the most versatile,
in terms of the number and variety of compounds which can
be generated.1
(3) (a) Sannigrahi, M. Tetrahedron 1999, 55, 9007. (b) Heathcock, C. H.;
Graham, S. L.; Pirrung, M. C.; Plavac, F.; White, C. T. Spirocyclic Systems. In
The Total Synthesis of Natural Products; Simon, J., Ed.; John Wiley and Sons:
New York, 1983; Vol. 5, p 264.
(4) Al-Azmi, A.; Elassar, A. Z. A.; Booth, B. L. Tetrahedron 2003, 59, 2749.
(5) (a) Ohtsuka, Y. J. Org. Chem. 1976, 41, 713. (b) Ohtsuka, Y. J. Org.
Chem. 1979, 44, 827. (c) Begland, R. W.; Hartter, D. R.; Jones, F. N.; Sam,
D. J.; Shapperd, W. A.; Webster, O. W.; Weigert, F. J. J. Org. Chem. 1974, 39,
2341. (d) Booth, B. L.; Proenc¸a, M. F. J. R. P. J. Chem. Soc., Chem. Commun.
1981, 788. (e) Booth, B. L.; Coster, R. D.; Proenc¸a, M. F. J. R. P. J. Chem.
Soc., Perkin Trans. 1 1987, 1521.
(6) Alves, M. J.; Al-duaij, O.; Booth, B. L.; Carvalho, M. A.; Eastwood, P.;
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E.; Pritchard, R. G.; Proenc¸a, M. F. J. R. P. J. Chem. Soc., Perkin Trans. 1
2001, 2532.
Spirocyclic structures are found in wide range of natural
compounds isolated from various sources.2 The complexity of
these ring structures is represented by the quaternary carbon
center and two fused rings. Stereoselective methodologies for
the construction of the spirocenter have allowed total syntheses
(8) (a) Alves, M. J.; Carvalho, M. A.; Proenc¸a, M. F. J. R. P.; Booth, B. L.
J. Heterocycl. Chem. 2000, 37, 1041. (b) Booth, B. L.; Costa, F. A. T.; Pritchard,
R.; Proenc¸a, M. F. J. R. P. Synthesis 2000, 9, 1269.
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J. Chem. Soc., Perkin Trans. 1 2001, 485.
(10) (a) Ohtsuka, Y. J. Org. Chem. 1976, 41, 629. (b) Ohtsuka, Y.; Tohma,
E.; Kojima, S.; Tomita, N. J. Org. Chem. 1979, 44, 4871. (c) Tsuda, T.;
Fujishima, K.; Ueda, H. Agric. Biol. Chem. 1981, 45, 2129.
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1996, 33, 855.
(1) (a) Do¨mling, A. Chem. ReV. 2006, 106, 17. (b) Do¨mling, A.; Ugi, I.
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Multicomponent Reactions, Wiley-VCH: Weinheim, 2005.
(2) (a) Conroy, H.; Chakrabarti, J. K. Tetrahedron 1959, 4, 6. (b) Sakabe,
N.; Takada, S.; Okabe, K. J. J. Chem. Soc., Chem. Commun. 1967, 6, 259. (c)
Cui, C. B.; Kakeya, H.; Osada, H. Tetrahedron 1996, 52, 12651. (d) Cui, C. B.;
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Osada, H. Tetrahedron 1997, 53, 59.
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M. F. J. R. P. J. Chem. Soc., Chem. Commun. 1993, 834.
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6309. (b) Shaabani, A.; Soleimani, E.; Maleki, A. Tetrahedron Lett. 2006, 47,
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10.1021/jo8002612 CCC: $40.75
Published on Web 04/05/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 3925–3927 3925

FIGURE 1. The structure of products 5a-l.
SCHEME 1. Possible Mechanism for the Formation of Products 5a-l
dicarbonitriles 5a-g via the one-pot pseudo-five-component
condensation of 2,3-diaminomaleonitrile 1, a cyclic or acyclic
ketone 2, an isocyanide 3, and water 4 in the presence of a
catalytic amount of p-toluenesulfonic acid (p-TsOH·H2O) in
water at ambient temperature in high yields (eq 1).
and no undesirable side reactions were observed under these
reaction conditions. Representative structures of products are
shown in Figure 1.
The possible mechanism for the formation of products 5a-l
is shown in Scheme 1. It is conceivable that the initial event is
the formation of diimine 6 from condensation between DAMN
and ketones.1,14 Then an intramolecular imine-enamine cy-
clization of 6 affords seven-membered ring 7.5c,10a,15 On the
basis of the well-established chemistry of reaction of isocyanides
with imines,1 intermediate 8 was produced by nucleophilic attack
of isocyanide 3 to iminium 7 followed by nucleophilic attack
of an H2O molecule on the nitrilium moiety and production of
compound 9. Finally, tautomerization of intermediate 9 produces
the 4,5,6,7-tetrahydro-1H-1,4-diazepine-5-carboxamide deriva-
tives 5a-l.
It is important to note that the proposed mechanism is
supported by characterization of isolated seven-member-ring
In a pilot experiment, 2,3-diaminomaleonitrile and cyclohex-
anone were stirred in water at room temperature with a catalytic
amount of p-toluenesulfonic acid. The progress of the reaction
was monitored by TLC. After 4 h, cyclohexyl isocyanide was
added to the reaction mixture and stirring was continued for
12 h. After completion of the reaction, an aqueous workup
afforded compound 5a in 92% yield.
In view of the success of the above reaction, we explored
the scope of this promising reaction by varying the structure of
the ketone and isonitrile component (Table 1). The reaction
proceeds very cleanly under mild conditions at room temperature
1
intermediate 7 by mass spectroscopy, IR, H NMR, and 13C
NMR spectra (see the Supporting Information). Finally, the
structure of 5a was confirmed unambiguously by single-crystal
X-ray analysis (see the Supporting Information).16
(14) (a) Horiguchi, E.; Shirai, K.; Jaung, J.; Furusyo, M.; Takagi, K.;
Matsuoka, M. Dyes Pigments 2001, 50, 99. (b) Shirai, K.; Matsuoka, M.;
Fukunishi, K. Dyes Pigments 2000, 47, 107. (c) Handa, M.; Farida, A.;
Thompson, L.; Hayashibara, C.; Sugimori, T.; Hiromitsu, I.; Kasuga, K. Mol.
Cryst. Liq. Sci. Technol. 2000, 342, 75.
(15) Mague, J. T.; Eduok, E. E. J. Chem. Crystallogr. 2000, 30, 311.
3926 J. Org. Chem. Vol. 73, No. 10, 2008

The 1H NMR of crude product of 5a showed only one
stereoisomer. The molar ratio of the second stereoisomer of
compounds 5h to 5j was negligible to estimate its molar ratio
32.3, 32.6, 36.3, 38.6, 47.6, 48.2, 59.8, 65.0, 105.7, 113.4, 117.0,
118.0, 174.6. MS m/z 396 (M+ + 1, 30), 298 (100), 269 (84), 208
(15), 98 (18), 81 (22), 67 (20), 55 (50), 41 (55). Anal. Calcd for
C23H33N5O: C, 69.84; H, 8.41; N, 17.71. Found C, 69.81; H, 8.43;
N, 17.72.
1
by H NMR.
In conclusion, we have discovered a novel pseudo-five-
component condensation reaction leading to 4,5,6,7-tetrahydro-
1H-1,4-diazepine-5-carboxamide derivatives starting from simple
and readily available precursors. This novel reaction can be
regarded as a new approach for the preparation of synthetically
and pharmaceutically relevant spirocyclic systems. This reaction
includes some important aspects like the use of water as a
reaction component and a “green” reaction medium, high atom
economy, and mild reaction conditions.
Typical Procedure for the Synthesis of Compound 5l. First,
a solution of DAMN (0.108 g, 1 mmol) and acetone (0.116 g, 2
mmol) in the presence of p-TsOH.H2O (0.095 g, 5 mol%) was
stirred for 5 h in 5 mL of H2O at ambient temperature. After
completion of the reaction, as indicated by TLC (ethyl acetate/n-
hexane, 2/1; Rf 0.50), tert-butyl isocyanide (0.083 g, 1 mmol) was
added to the reaction mixture. Then the resulting mixture was stirred
for 15 h at ambient temperature. After completion of the reaction,
as indicated by TLC (ethyl acetate/n-hexane, 3/1; Rf 0.40), the
product was filtered off, washed further with water, and then
crystallized from acetone to give 5l as colorless crystals (0.260 g,
90%): mp 164-166 °C. IR (KBr) cm-1 3415, 3320, 2978, 2927,
2857, 2216, 1664, 1622, 1511, 1453. 1H NMR (300.13 MHz,
DMSO-d6) δ 1.07-1.24 (18H, m), 1.50 (1H, d, J ) 13.9 Hz), 2.40
(1H, d, J ) 14.2 Hz), 5.75 (2H, br s), 6.81 (1H, br s). 13C NMR
(75.47 MHz, DMSO-d6) δ 28.7, 28.9, 29.6, 32.1, 47.9, 50.8, 54.5,
62.5, 108.6, 111.2, 117.2, 117.8, 173.9. MS m/z 290 (M+ + 1,
10), 234 (2), 189 (100), 133 (60), 59 (24), 43 (50). Anal. Calcd for
C15H23N5O: C, 62.26; H, 8.01; N, 24.20. Found C, 62.33; H, 7.94;
N, 24.35.
Experimental Section
Typical Procedure for the Synthesis of Compound 5a. First,
a solution of DAMN (0.108 g, 1 mmol) and cyclohexanone (0.196
g, 2 mmol) in the presence of p-TsOH.H2O (0.095 g, 5 mol%) was
stirred for 4 h in 5 mL of H2O at ambient temperature. After
completion of the reaction, as indicated by TLC (ethyl acetate/n-
hexane, 2/1; Rf 0.45), cyclohexyl isocyanide (0.109 g, 1 mmol)
was added to the reaction mixture. Then the resulting mixture was
stirred for 12 h at ambient temperature. After completion of the
reaction, as indicated by TLC (ethyl acetate/n-hexane, 3/1; Rf 0.35),
the product was filtered off, washed further with water, and then
crystallized from acetone to give 5a as colorless crystals (0.363 g,
92%): mp 181-184 °C. IR (KBr) cm-1 3382, 3295, 2933, 2853,
2220, 2202, 1634, 1617, 1543, 1446. 1H NMR (300.13 MHz,
DMSO-d6) δ 1.00-2.00 (28H, m), 2.20-2.30 (1H, m), 3.55 (1H,
m), 4.68 (1H, m), 5.87 (1H, m), 7.00 (1H, br s). 13C NMR (75.47
MHz, DMSO-d6) δ 21.1, 21.4, 21.5, 23.9, 25.2, 25.6, 25.7, 26.0,
Acknowledgement. We gratefully acknowledge financial
support from the Research Council of Shahid Beheshti University.
Supporting Information Available: Crystallographic data
for 5a (CIF), experimental procedures, and mass, IR, 1H NMR,
and 13C NMR spectra for compounds 5a-l and 7. This material
is available free of charge via the Internet at http://pubs.acs.org.
(16) Stoe & Cie, X-STEP32, Version 1.07b: Crystallographic package 2000.
JO8002612
J. Org. Chem. Vol. 73, No. 10, 2008 3927