A novel isocyanide-based three-component reaction: Synthesis of highly substituted 1,6-dihydropyrazine-2,3-dicarbonitrile derivatives

Article abstract of DOI:10.1021/jo0707131

(Chemical Equation Presented) A novel multi-component synthesis of highly substituted 1,6-dihydropyrazine-2,3-dicarbonitrile derivatives starting from simple and readily available inputs is described. Thus, simply stirring an ethanol solution of 2,3-diami

Full text of DOI:10.1021/jo0707131

SCHEME 1. Synthesis of 1,6-Dihydropyrazine-2,3-dicar-
bonitrile Derivatives 4
A Novel Isocyanide-Based Three-Component
Reaction: Synthesis of Highly Substituted
1,6-Dihydropyrazine-2,3-dicarbonitrile
Derivatives
Ahmad Shaabani,* Ali Maleki, and Jafar Moghimi-Rad
Department of Chemistry, Shahid Beheshti UniVersity,
TABLE 1. Synthesis of 1,6-Dihydropyrazine-2,3-dicarbonitrile
Derivatives 4a-o
P.O. Box 19396-4716, Tehran, Iran
time yielda
product (min) (%)
a-shaabani@cc.sbu.ac.ir
entry
ketone
isocyanide
cyclohexyl
cyclohexyl
cyclohexyl
cyclohexyl
cyclohexyl
ReceiVed April 11, 2007
1
2
3
4
5
6
7
8
9
acetone
4a
4b
4c
4d
4e
4f
4g
4h
4i
90
100
100
90
90
94
98
88
82
85
82
92
94
93
84
82
80
87
80
2-butanone
2-pentanone
cyclopentanone
cyclohexanone
2-methylcyclohexanone cyclohexyl
acetophenone cyclohexyl
90
110
110
120
100
95
110
120
120
100
120
4-methylacetophenone cyclohexyl
4-bromoacetophenone cyclohexyl
10 acetone
11 cyclopentanone
12 4-methylacetophenone tert-butyl
13 2-methylcyclohexanone 2,6-(Me)2-phenyl
14 acetone
tert-butyl
tert-butyl
4j
4k
4l
A novel multi-component synthesis of highly substituted 1,6-
dihydropyrazine-2,3-dicarbonitrile derivatives starting from
simple and readily available inputs is described. Thus, simply
stirring an ethanol solution of 2,3-diaminomaleonitrile, a
ketone, and an isocyanide in the presence of a catalytic
amount of p-toluenesulfonic acid provided highly substituted
1,6-dihydropyrazine-2,3-dicarbonitrile derivatives in good to
excellent yields at ambient temperature.
4m
1,1,3,3-tetramethylbutyl 4n
1,1,3,3-tetramethylbutyl 4o
15 cyclohexanone
a Isolated yield.
zines,8 diazepines,9 and triazepines.3,10 Although the reaction
of DAMN with various carbonyl compounds has been reported
under classical two-component reactions, a careful literature
search reveals that the reaction of DAMN with carbonyl
compounds and isocyanide under a MCR strategy has not been
studied.
In continuing our interest in isocyanide-based multi-compo-
nent reactions,11 here we report a hitherto unknown reaction
which affords 1,6-dihydropyrazine-2,3-dicarbonitrile derivatives
4 via the three-component condensation of 2,3-diaminomale-
onitrile 1, a ketone 2, and an isocyanide 3 in the presence of a
catalytic amount of p-toluenesulfonic acid (p-TsOH‚H2O) in
ethanol at ambient temperature in excellent yields (Scheme 1).
Within the past decade, the resurgence of interest in multi-
component reactions (MCRs) has been driven, not only due to
their convergent nature, superior atom economy, and straight-
forward experimental procedures but also because of their value
to the pharmaceutical industry for construction of low molecular
weight compound libraries through combinatorial strategies and
parallel synthesis. Due to the unique reactivity of the isocyanide
functional group, MCRs involving isocyanides are among the
most versatile, in terms of the number and variety of compounds
which can be generated.1
Polyfunctionalized heterocyclic compounds play important
roles in the drug discovery process, and analysis of drugs in
late development or on the market shows that 68% of them are
heterocycles.1 Therefore, it is not surprising that research in the
field of synthesis of heterocyclic compounds has received special
attention.
(4) Alves, M. J.; Al-duaij, O.; Booth, B. L.; Carvalho, M. A.; Eastwood,
P.; Proenc¸a, M. F. J. R. P. J. Chem. Soc., Perkin Trans. 1 1994, 3571.
(5) (a) Schuman, R. F.; Shearin, W. E.; Tull, R. J. J. Org. Chem. 1979,
44, 4532. (b) Oro, J.; Kimball, A. P. Arch. Biochem. Biophys. 1962, 96,
293. (c) Yamada, Y.; Sakurai, M.; Kumashiro, I. U.S. Patent 3671649, 1972.
(d) Voet, A. B.; Schwartz, A. W.; Van Der Veen, M. Origins Life 1984,
14, 91. (e) Alves, M. J.; Booth, B. L.; Carvalho, M. A.; Pritchard, R. G.;
Proenc¸a, M. F. J. R. P. J. Heterocycl. Chem. 1997, 34, 739. (f) Al-Azmi,
A.; Booth, B. L.; Carpenter, R. A.; Carvalho, A.; Marrelec, E.; Pritchard,
R. G.; Proenc¸a, M. F. J. R. P. J. Chem. Soc., Perkin Trans. 1 2001, 2532.
(6) (a) Alves, M. J.; Carvalho, M. A.; Proenc¸a, M. F. J. R. P.; Booth, B.
L. J. Heterocycl. Chem. 2000, 37, 1041. (b) Alves, M. J.; Carvalho, M. A.;
Proenc¸a, M. F. J. R. P.; Booth, B. L.; Pritchard, R. G. J. Heterocycl. Chem.
1999, 36, 193. (c) Booth, B. L.; Costa, F. A. T.; Pritchrad, R. G.; Proenc¸a,
M. F. J. R. P. Synthesis 2000, 9, 1269.
(7) (a) Al-Azmi, A.; Booth, B. L.; Pritchard, R. G.; Proenc¸a, F. J. R. P.
J. Chem. Soc., Perkin Trans. 1 2001, 485. (b) Begland, R. W. U.S. Patent
3883532, 1974.
(8) (a) Ohtsuka, Y. J. Org. Chem. 1976, 41, 629. (b) Ohtsuka, Y.; Tohma,
E. J. Org. Chem. 1979, 44, 4871. (c) Tsuda, T.; Fujishima, K.; Ueda, H.
Agric. Biol. Chem. 1981, 45, 2129.
2,3-Diaminomaleonitrile (DAMN),2 a tetramer of hydrogen
cyanide, was considered as one of the versatile precursors to
the synthesis of various types of nitrogen heterocycles such as
imidazoles,3 oxazoles,4 purines,5 pyrroles,6 pyrimidines,7 pyra-
(1) (a) Do¨mling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3168. (b)
Do¨mling, A. Chem. ReV. 2006, 106, 17.
(2) Al-Azmi, A.; Elassar, A. A.; Booth, B. L. Tetrahedron 2003, 59,
2749.
(3) (a) Woodward, D. W. U.S. Patent 2534331, 1950. (b) Weigert, F. J.
U.S. Patent 3778446, 1973. (c) Ohtsuka, Y. J. Org. Chem. 1976, 41, 713.
(d) Ohtsuka, Y. J. Org. Chem. 1979, 44, 827. (e) Begland, R. W.; Hartter,
D. R.; Jones, F. N.; Sam, D. J.; Shepperd, W. A.; Webster, O. W.; Weigert,
F. J. J. Org. Chem. 1974, 39, 2341. (f) Johnson, S. J. Synthesis 1991, 75.
(g) Booth, B. L.; Proenc¸a, M. F. J. R. P. J. Chem. Soc., Chem. Commun.
1981, 788. (h) Booth, B. L.; Coster, R. D.; Proenc¸a, M. F. J. R. P. J. Chem.
Soc., Perkin Trans. 1 1987, 1521.
(9) Dias, A. M.; Proenc¸a, M. F. J. R. P.; Booth, B. L. J. Heterocycl.
Chem. 1996, 33, 855.
(10) Alves, M. J.; Booth, B. L.; Eastwood, P.; Pritchard, R. G.; Proenc¸a,
M. F. J. R. P. J. Chem. Soc., Chem. Commun. 1993, 834.
10.1021/jo0707131 CCC: $37.00 © 2007 American Chemical Society
Published on Web 07/04/2007
J. Org. Chem. 2007, 72, 6309-6311
6309

FIGURE 1. The structure of products 4a-o.
SCHEME 2. Reaction of DAMN with Isocyanide and Aldehyde
In a pilot experiment, 2,3-diaminomaleonitrile, acetone, and
cyclohexyl isocyanide in EtOH were stirred at room temperature
using a catalytic amount of p-toluenesulfonic acid. The progress
of the reaction was monitored by TLC. After completion of the
reaction after 90 min, an aqueous workup afforded 5-(cyclo-
hexylamino)-1,6-dihydro-6,6-dimethylpyrazine-2,3-dicarboni-
trile 4a in 90% yield. To evaluate the use of this approach, a
variety of aliphatic, alicyclic, and aromatic ketones were
condensed under similar circumstances. The results are shown
in Table 1. The reaction proceeds very cleanly at room
temperature, and no undesirable side reactions were observed.
In view of the success of the above reactions, we explored
the use of various alkyl and aryl isocyanides as a third
component in this reaction. Treatment of tert-butyl, 2,6-
dimethylphenyl-, or 1,1,3,3-tetramethylbutyl isocyanides with
DAMN in the presence of ketones in ethanol at ambient
temperature led to the formation of the corresponding 1,6-
dihydropyrazine-2,3-dicarbonitrile derivatives in high yields. The
results are summarized in Table 1.
m/z values. For example, the 1H NMR spectrum of 4h consisted
of a multiplet of signals for the cyclohexyl ring at δ 1.00-2.01
and two singlets for methyl groups at δ 1.64 and 2.26. A
multiplet was observed for the NH-CH at δ 3.85, an AB quartet
pattern for aromatic protons centered at δ 7.11 and 7.16, a
doublet for NH-CH at δ 7.36, and a fairly broad singlet was
1
observed for the NH group at δ 7.97. The H decoupled 13C
NMR spectrum of 4h showed 18 distinct resonances. Partial
assignment of these resonances is given in the Experimental
Section.
The reaction proceeds under mild conditions and is compat-
ible with a wide range of functional groups. Two substituents
in the products can be varied independently of each other.
Representative examples of this reaction are shown in Figure
1.
We extended this reaction to aldehyde; however, Schiff base
8 was generated from the aldehyde, and nucleophilic attack by
isocyanide does not occur. So, the isolated compound was
intermediate 8 (Scheme 2).
We have also investigated this reaction under Ugi four-
component reaction conditions using DAMN, isocyanide, al-
dehyde, or acetone in the presence of a stoichiometric amount
of HOAc. In both cases, the previously isolated products 4 and
8 were produced, respectively. Neither the classical Ugi four-
component product 9 (HOAc as acid component) nor the product
10 (HOAc as catalyst) was observed under the given reaction
conditions (Scheme 2).
The structures of the products 4a-o were deduced from their
IR, 1H NMR, and 13C NMR spectra. The mass spectra of these
compounds displayed molecular ion peaks at the appropriate
(11) (a) Shaabani, A.; Soleimani, E.; Maleki, A. Tetrahedron Lett. 2006,
47, 3031. (b) Shaabani, A.; Teimouri, M. B.; Arab Ameri, S. Tetrahedron
Lett. 2004, 45, 8409. (c) Shaabani, A.; Teimouri, M. B.; Bijanzadeh, H. R.
Tetrahedron Lett. 2002, 43, 9151. (d) Shaabani, A.; Yavari, I.; Teimouri,
M. B.; Bazgir, A.; Bijanzadeh, H. R. Tetrahedron 2001, 57, 1375. (e)
Shaabani, A.; Teimouri, M. B.; Bazgir, A.; Bijanzadeh, H. R. Mol. DiV.
2003, 6, 199. (f) Shaabani, A.; Bazgir, A.; Soleimani, K.; Bijanzadeh, H.
R. J. Fluorine Chem. 2002, 116, 93.
The possible mechanism for the formation of product is
shown in Scheme 3. It is conceivable that the initial event is
the formation of iminium 5 from DAMN and an activated
6310 J. Org. Chem., Vol. 72, No. 16, 2007

SCHEME 3. Possible Mechanism for the Formation of
Products 4a-o
derivatives. The biological activities of prepared 1,6-dihydro-
pyrazine-2,3-dicarbonitrile derivatives 4 are now under study.
Experimental Section
Typical Procedure for the Synthesis of 5-(Cyclohexylamino)-
1,6-dihydro-6-methyl-6-p-tolylpyrazine-2,3-dicarbonitrile (4h):
To a solution of DAMN (0.108 g, 1 mmol), 4-methylphenylacetone
(0.148 g, 1 mmol), and cyclohexyl isocyanide (0.109 g, 1 mmol),
in 3 mL of EtOH, was added p-TsOH‚H2O (0.095 g, 5 mol %).
The resulting mixture was stirred for 2 h at ambient temperature.
After completion of the reaction, as indicated by TLC (ethyl acetate/
n-hexane, 3/1), the product was precipitated by addition of 10 mL
of water. The precipitate was filtered off and washed with water,
and then crystallized from acetone to give 4h as light yellow crystals
(0.310 g, 92%): mp 250-253 °C; IR (KBr, cm-1) ν 3350, 2932,
2854, 2225, 2209, 1564, 1536; 1H NMR (300.13 MHz, DMSO-d6)
δ 1.00-2.01 (10H, m), 1.64 (3H, s), 2.26 (3H, s), 3.85 (1H, m),
7.11, 7.16 (4H, AB-q, JAB ) 7.5 Hz), 7.36 (1H, d, JHH ) 7.1
Hz), 7.97 (1H, br s); 13C NMR (75.47 MHz, DMSO-d6) δ 20.5,
24.7, 24.8, 25.2, 25.4, 31.3, 31.6, 50.2, 54.9, 109.8, 111.4, 114.2,
117.5, 124.6, 129.0, 137.0, 139.4, 153.0; MS m/z 333 (M+, 24),
318 (47), 251 (20), 236 (100), 209 (20), 160 (20), 117 (27), 91
(25), 65 (15), 55 (54), 41 (70). Anal. Calcd for C20H23N5: C, 72.04;
H, 6.95; N, 21.00. Found: C, 72.02; H, 6.96; N, 21.02.
ketone.12 On the basis of the well-established chemistry of
reaction of isocyanides with imines,1b intermediate 6 was
produced by nucleophilic attack of isocyanide 3 to iminium 5
followed by intramolecular nucleophilic attack by the NH2 group
on the activated nitrile moiety and production of compound 7.
Imine-enamine tautomerization of intermediate 7 produces the
product 4.
In summary, we have discovered a novel multi-component
reaction leading to polysubstituted 1,6-dihydropyrazine-2,3-
dicarbonitrile derivatives starting from simple and readily
available precursors. This novel reaction can be regarded as a
new approach for the preparation of pharmaceutically relevant,
highly substituted spiro-1,6-dihydropyrazine-2,3-dicarbonitrile
3
3
Acknowledgment. We gratefully acknowledge financial
support from the Research Council of Shahid Beheshti Univer-
sity.
(12) (a) Horiguchi, E.; Shirai, K.; Jaung, J.; Furusyo, M.; Takagi, K.;
Matsuoka, M. Dyes Pigm. 2001, 50, 99. (b) Yu, J.; Chen, Z.; Sone, M.;
Miyata, S.; Li, M.; Watanabe, T. Jpn. J. Appl. Phys. 2001, 40, 3201. (c)
Sun, Z.; Hosmane, R. Synth. Commun. 2001, 31, 549. (d) Shirai, K.;
Matsuoka, M.; Fukunishi, K. Dyes Pigm. 2000, 47, 107. (e) Handa, M.;
Farida, A.; Thompson, L.; Hayashibara, C.; Sugimori, T.; Hiromitsu, I.;
Kasuga, K. Mol. Cryst. Liq. Sci. Technol. 2000, 342, 75. (f) Morkved, E.;
Ossletten, H.; Kjosen, H.; Bjorlo, O. J. Prakt. Chem. 2000, 342, 83.
Supporting Information Available: Experimental procedures,
1
mass, IR, H NMR, and 13C NMR spectra for compounds 4a-o.
This material is available free of charge via the Internet at
http://pubs.acs.org.
JO0707131
J. Org. Chem, Vol. 72, No. 16, 2007 6311