AlCl3 as an efficient catalyst toward the synthesis of 1,6-dihydropyrazine-2,3-dicarbonitrile derivatives

Article abstract of DOI:10.1080/00397911.2013.769602

Aluminium chloride has been shown to be an efficient catalyst for the multicomponent reactions of diaminomaleonitrile (DAMN), ketones or aldehydes, and isocyanides for the synthesis of 1,6-dihydropyrazine-2,3-dicarbonitrile derivatives using comparative s

Full text of DOI:10.1080/00397911.2013.769602

This article was downloaded by: [Colorado State University]
On: 05 September 2013, At: 04:13
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered
office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK
Synthetic Communications: An
International Journal for Rapid
Communication of Synthetic Organic
Chemistry
Publication details, including instructions for authors and
subscription information:
http://www.tandfonline.com/loi/lsyc20
AlCl3 as an Efficient Catalyst Toward the
Synthesis of 1,6-Dihydropyrazine-2,3-
dicarbonitrile Derivatives
Shrikar M. Bhosale a , Nilesh H. Naik a & Radhika S. Kusurkar a
a Department of Chemistry , University of Pune , Pune , India
Accepted author version posted online: 03 Jul 2013.Published
online: 04 Sep 2013.
To cite this article: Shrikar M. Bhosale , Nilesh H. Naik & Radhika S. Kusurkar (2013) AlCl3 as an
Efficient Catalyst Toward the Synthesis of 1,6-Dihydropyrazine-2,3-dicarbonitrile Derivatives,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, 43:23, 3163-3169, DOI: 10.1080/00397911.2013.769602
To link to this article: http://dx.doi.org/10.1080/00397911.2013.769602
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the information (the
“Content”) contained in the publications on our platform. However, Taylor & Francis,
our agents, and our licensors make no representations or warranties whatsoever as to
the accuracy, completeness, or suitability for any purpose of the Content. Any opinions
and views expressed in this publication are the opinions and views of the authors,
and are not the views of or endorsed by Taylor & Francis. The accuracy of the Content
should not be relied upon and should be independently verified with primary sources
of information. Taylor and Francis shall not be liable for any losses, actions, claims,
proceedings, demands, costs, expenses, damages, and other liabilities whatsoever or
howsoever caused arising directly or indirectly in connection with, in relation to or arising
out of the use of the Content.
This article may be used for research, teaching, and private study purposes. Any
substantial or systematic reproduction, redistribution, reselling, loan, sub-licensing,
systematic supply, or distribution in any form to anyone is expressly forbidden. Terms &

Conditions of access and use can be found at http://www.tandfonline.com/page/terms-
and-conditions

Synthetic Communications1, 43: 3163–3169, 2013
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397911.2013.769602
AlCl3 AS AN EFFICIENT CATALYST TOWARD
THE SYNTHESIS OF 1,6-DIHYDROPYRAZINE-2,3-
DICARBONITRILE DERIVATIVES
Shrikar M. Bhosale, Nilesh H. Naik, and Radhika S. Kusurkar
Department of Chemistry, University of Pune, Pune, India
GRAPHICAL ABSTRACT
Abstract Aluminium chloride has been shown to be an efficient catalyst for the multicom-
ponent reactions of diaminomaleonitrile (DAMN), ketones or aldehydes, and isocyanides
for the synthesis of 1,6-dihydropyrazine-2,3-dicarbonitrile derivatives using comparative
study with various catalysts. Unprecedented use of aromatic and aliphatic aldehydes in this
multicomponent reaction (MCR) was demonstrated.
[Supplementary materials are available for this article. Go to the publisher’s online
edition of Synthetic Communications1 for the following free supplemental resources: Full
experimental and spectral details.]
Keywords AlCl3; diaminomaleonitrile; 1,6-dihydropyrazine-2,3-dicarbonitrile; multi-
component reaction
INTRODUCTION
Heterocycles are a very important class of organic compounds, because of their
wide application in medicine, agriculture, and technology.[1] It is observed that 68%
of the total drugs in the market are heterocycles.[2] Therefore, research in the
synthesis of heterocyclic compounds has become of great interest. Among nitrogen
heterocycles, pyrazine is an important moiety that has a basic skeletal system used in
various natural products and biologically active molecules,[3–13] including anticancer
multidrug resistance reversal agents such as ardeemin and AV-200.[14] Consequently,
there is a need to develop a new and convenient synthetic approach for pyrazine-
based compounds.
In recent years, multicomponent reactions (MCRs)[15–17] have become impor-
tant because of their better atom economy, straightforward experimental procedures,
Received August 24, 2012.
Address correspondence to Radhika S. Kusurkar, Department of Chemistry, University of Pune,
Pune 411007, India. E-mail: rsk@chem.unipune.ac.in
3163

3164
S. M. BHOSALE, N. H. NAIK, AND R. S. KUSURKAR
and value in the pharmaceutical industry. Particularly, because of unique reactivity
of isocyanides, multicomponent reactions involving isocyanides[18] have become
one of the most efficient tools for rapid scaffold construction and introduction of
molecular diversity.
Literature survey indicated only one report[19] of a MCR for the synthesis of
1,6-dihydropyrazine-2,3-dicarbonitrile derivatives. The present work describes the
investigation of AlCl3 as an efficient catalyst for this synthesis.
RESULTS AND DISCUSSION
In the first part of this study, the MCR leading to substituted 1,6-
dihydropyrazine-2,3-dicarbonitrile was carried out using various catalysts at room
temperature. Thus, diaminomaleonitrile (DAMN), acetone, and cyclohexyl isocya-
nide were dissolved in acetonitrile (Scheme 1), and a series of catalysts were screened
for this MCR (Table 1). The product obtained was characterized as
5-(cyclohexylamino)-1,6-dihydro-6,6-dimethylpyrazine-2,3-dicarbonitrile
(3a,
Table 2, entry 1) by analyzing the spectral data and comparing it with reported[19]
values. Comparison of the reaction time and yield using various catalysts indicated
that copper bromide and aluminium chloride gave similar results. The reaction was
completed in 5 min in both the cases; however, the yield in copper bromide reaction
(95%) was little less than that in the aluminium chloride reaction (98%).
To explore the scope of the reaction and generality of the present transform-
ation, we extended the procedure to various aromatic, alicyclic, and aliphatic ketones
and aldehydes in the second part, using CuBr2 and AlCl3, separately as a catalyst,
Scheme 1. Synthesis of 1,6-dihydropyrazine-2,3-dicarbonitrile derivatives.
Table 1. Reaction time and yield of 3a using various catalysts
Entry
Catalyst
Time (min)
Yield (%)
1
2
CAN
5
5
5
5
5
5
5
5
5
5
5
87
89
90
88
77
98
79
81
86
90
95
Bi(NO3).5 H2O
FeCl3-SiO2
FeCl3
3
4
5
LiCl
AlCl3
MgCl2
6
7
8
Montmorillonite
CuI
InCl3
9
10
11
CuBr2

1,6-DIHYDROPYRAZINE-2,3-DICARBONITRILE
3165
Table 2. Reaction time and yield for the synthesis of 1,6-dihydropyrazine-2,3-dicarbonitrile derivatives
Ketone=
aldehyde 1
Time
Isocyanide 2 (min)
Yield
(%)
Entry
Product 3
Catalyst
i) AlCl3
ii) CuBr2
98
95
1a
Acetone
Cyclohexyl
5
i) AlCl3
ii) CuBr2
97
90
2a
3a
4
Cyclopentanone
Cyclohexyl
Cyclohexyl
Cyclohexyl
5
6
i) AlCl3
ii) CuBr2
94
92
Cyclohexanone
i) AlCl3
ii) CuBr2
90
84
4-Methyl-2-pentanone
10
i) AlCl3
ii) CuBr2
94
88
5a
2-Butanone
Cyclohexyl
Cyclopentyl
6
5
6
Cyclohexanone
i) AlCl3
95
i) AlCl3
ii) CuBr2
93
87
7
2-Butanone
Cyclopentyl
7
i) AlCl3
ii) CuBr2
96
93
8
9
Cyclopentanone
Cyclopentyl
5
4
i) AlCl3
ii) CuBr2
94
90
Acetone
Benzyl
(Continued )

3166
S. M. BHOSALE, N. H. NAIK, AND R. S. KUSURKAR
Table 2. Continued
Ketone=
aldehyde 1
Time
Isocyanide 2 (min)
Yield
(%)
Entry
10
Product 3
Catalyst
i) AlCl3
ii) CuBr2
95
90
Cyclohexanone
Benzyl
5
5
i) AlCl3
ii) CuBr2
96
91
11a
Cyclopentanone
Ter- Butyl
12a
Acetone
Ter- Butyl
Cyclohexyl
5
i) AlCl3
97
i) AlCl3
ii) CuBr2
65
00
13a
Acetophenone
30
i) AlCl3
ii) CuBr2
70
00
14
p-Methoxy acetophenone Cyclohexyl
20
15
16
17
Isobutaraldehyde
Cyclohexyl
Cyclohexyl
Cyclohexyl
30
20
15
i) AlCl3
98
97
n-Propanal
i) AlCl3
i) AlCl3
ii) CuBr2
70
00
Benzaldehyde
(Continued )

1,6-DIHYDROPYRAZINE-2,3-DICARBONITRILE
3167
Table 2. Continued
Ketone=
aldehyde 1
Time
Isocyanide 2 (min)
Yield
(%)
Entry
Product 3
Catalyst
i) AlCl3
ii) CuBr2
80
00
18
Benzaldehyde
Isopropyl
20
i) AlCl3
ii) CuBr2
80
00
19
20
Benzaldehyde
Tert-butyl
Tert-butyl
20
30
n-Heptyl aldehyde
i) AlCl3
93
21
Vanillin
Isopropyl
120
i) AlCl3
47b
22
23
p-Anisaldehyde
Tert-butyl
Tert-butyl
180
180
i) AlCl3
<10b
Furfuraldehyde
i) AlCl3
32b
aRef. [19].
bIntermediate imine isolated.
with alicyclic and aromatic isocyanides and DAMN (Scheme 1). All these reactions
led to the formation of the corresponding 1,6-dihydropyrazine-2,3-dicarbonitrile
derivatives 3a–3w in good to excellent yield in very short time intervals (Table 2).
It is noted that in contrast to the earlier report[19] where aldehydes failed to give
the expected product, the reaction with aldehydes using AlCl3 was successfully
achieved, affording new products 3o–3w (Table 2). In general, it was observed that

3168
S. M. BHOSALE, N. H. NAIK, AND R. S. KUSURKAR
aromatic aldehydes and ketones reacted slowly giving less yield than the aliphatic
aldehydes and aliphatic and alicylic ketones. However, using CuBr2 as a catalyst,
reaction with aromatic aldehyde and ketones failed to give the expected product
and the reaction stopped at the intermediate imine step. Thus, reactions using
aluminium chloride with different types of aldehydes and ketones could be carried
out successfully with good yield in a very short time. This can be attributed to the
stronger catalytic activity of aluminium chloride as a Lewis acid. Considering the
versatile use of aluminium chloride in the reactions, it was shown to be the best
catalyst for this MCR among all the catalysts used.
The probable mechanism would be similar to that described in the earlier
report[19] and involves ketone or aldehyde activated by the catalyst used.
CONCLUSIONS
For the first time aromatic and aliphatic aldehydes were successfully used in the
MCR for the synthesis of 1,6-dihydropyrazine-2,3-dicarbonitrile derivatives. AlCl3 was
shown to be the most efficient catalyst among the chosen catalysts for the present MCR.
EXPERIMENTAL
Melting points are uncorrected. Mass spectra were recorded at an ionization
1
potential of 70 eV. H NMR spectra were recorded on a Varian Mercury 300-MHz
instrument. The spectra are presented in the order of chemical shifts (d scale) in parts
per million (ppm), multiplicity, approximate coupling constant (J value) in hertz
(Hz), and number of protons. Signals were characterized as s (singlet), d (doublet),
t (triplet), m (multiplet), and br s (broad signal). The 13C NMR spectra were recorded
on a Varian Mercury 75.00-MHz instrument. Chemical shifts (d scale) are reported
in parts per million (ppm). All the products are characterized by infrared (IR),
1H NMR and 13C NMR spectra, mass spectral data, and elemental analysis.
General Procedure for the Synthesis of 1,6-Dihydropyrazine-2,3-
dicarbonitriles
AlCl3 (15 mol%) was added to a solution of DAMN (1 mmol), ketone (1 mmol)
and isocyanide (1 mmol), in 5 ml of CH3CN. The resulting mixture was stirred for an
appropriate time at room temperature. After completion of the reaction, as indicated
by thin-layer chromatography (TLC; ethyl acetate=n-hexane 3=1), the product was
precipitated by addition of 10 ml of water. The precipitate was filtered off, washed
with water, and then recrystallized from acetone. In the case of aromatic aldehyde,
precipitate after filtration was loaded on column chromatography with 20% ethyl
acetate–hexane as an eluent system to furnish the product.
5-(Cyclohexylamino)-1,6-dihydro-6-methyl-6-butyl-pyrazine-2,3-
dicarbonitrile (3d)
Yield 94%; light yellow crystal; mp 190–192ꢀC; IR (KBr) cmꢁ1: 3385, 3346,
1
2210, 1575; H NMR (300.00 MHz, DMSO-d6): d 0.084–1.00 (m, 9H, 3 ꢂ CH3),

1,6-DIHYDROPYRAZINE-2,3-DICARBONITRILE
3169
1.00–1.90 [m, 13H, -(CH2)6- & CH], 3.80 (m, 1H, cyclohexyl CH), 6.85 (brs, 1H,
D2O exchangeable, -N-H), 7.07 (brs, 1H, D2O exchangeable, -N-H); 13C NMR
(75.00 MHz, DMSO-d6): d 23.14, 23.65, 23.90, 24.42, 24.79, 25.25, 31.35, 31.65,
44.30, 49.49, 52.63, 108.95, 109.76, 114.20, 117.96, 154.46; MS m=z 299 (M þ 1). Anal.
calcd. for C17 H25N5: C: 68.19; H, 8.42; N, 23.39. Found: C, 68.53; H, 8.12; N, 23.95
SUPPORTING INFORMATION
1
Full experimental details and H and 13C NMR spectra can be found via the
Supplementary Content section of this article’s Web page.
ACKNOWLEDGMENTS
We are grateful to J. P. Chaudhary for NMR spectra and D. Gurav for IR
spectra. S. M. B. is thankful to the Council of Scientific and Industrial Research,
New Delhi, for financial support.
REFERENCES
1. Pozharski, A. F.; Soldatankov, A. T.; Katrizky, A. R. Heterocycles in Life and
society—An Introduction to Heterocyclic and Biochemistry and the Role of Heterocycles
in Science, Technology, Medicine, and Agriculture; John Wiley and Sons: New York, 1997.
2. Domling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3168–3210.
3. Chen, Z.; Fan, J.; Kende, A. S. J. Org. Chem. 2004, 69, 79–85.
4. Zimmermann, P. J.; Christofbrehm, B. W.; Palmer, A. M.; Volz, J.; Simon, W. A. Bioorg.
Med. Chem. 2008, 16, 536–541.
5. Sloot, D.; Hendrik, J.; Hofmann, H. J. J. Agri. Foodchem. 1975, 23, 358–358.
6. Wang, D.; Kim, L.; Beconi, M. J. Med. Chem. 2005, 48, 141–151.
7. Pei, Z.; Li, X.; Geldern, V.;Thomas, W. J. Med. Chem. 2006, 49, 6439–6442.
8. Niculescu-Duvaz, I.; Roman, E.; Whittakar, S. R. J. Med. Chem. 2006, 49, 407–416.
9. Kysil, V.; Tkachenko, S.; Khvat, A.; Williams, C.; Tsirulnikov, S.; Churakova, M.;
Ivachtchenko, A. Tetrahedron Lett. 2007, 48, 6239–6244.
10. Guedat, P.; Boissy, G. EP1749822 A1, 2007.
11. Nuss, J. M.; Ramurthy, S. WO2001044206, 2001.
12. Kuo, G. H.; Connolly, P. WO2002024681, 2002.
13. Gaillard, P.; Quattropani, A.; Pomel, V.; Rueckle, T.; Klicic, J.; Church, D.
WO2007023186, 2007.
14. Mendez-vidal, C.; Quesada, A. R. Cancer Lett. 1998, 132, 45–50.
15. (a) Shaabani, A.; Maleki, A.; Mofakham, H.; Khavasi, H. R. J. Comb. Chem. 2008, 10,
323–326; (b) Musonda, C. C.; Litple, S.; Yardley, V.; Chibale, K. Bioorg. Med. Chem. Lett.
2007, 17, 4733–4734; (c) Teimouri, M. B.; Bezhrang, R. Bioorg. Med.Chem. Lett. 2006, 16,
3697–3701; (d) Rafied, E.; Jafari, H. Bioorg. Med.Chem. Lett. 2006, 16, 2463–2466.
16. Zhu, J.; Bienzyme, H. (Eds.); Multicomponent Reaction; Wiley-VCH: Weinheim, 2005.
17. Domling, A. Chem. Rev. 2006, 106, 17–89.
18. (a) Heravi, M. M.; Moghimi, S. J. Iran. Chem. Soc. 2011, 8, 306–373; (b) Ruijter, E.;
Scheffelaar, R.; Orru, R. V. A. Angew. Chem. Int. Ed. 2011, 50, 6234–6246; (c) Shabani,
A.; Maleki, A.; Rezawan, A. H.; Sarvary, A. Mol. Divers. 2011, 15, 41–68.
19. Shaabani, A.; Maleki, A.; Moghimi-Rad. J. Org. Chem. 2007, 72, 6309–6311.