Highly efficient synthesis of 5,6-disubstituted-5H-pyrrolo[2,3-b]pyrazine- 2,3-dicarbonitriles through a one-pot palladium-catalyzed coupling reaction/cyclization in water

Article abstract of DOI:10.1016/j.tetlet.2012.04.016

A highly efficient one-pot synthesis of 5,6-disubstituted-5H-pyrrolo[2,3-b] pyrazine-2,3-dicarbonitriles is presented. The reaction of 5-(alkyl-arylamino)- 6-chloropyrazine-2,3-dicarbonitriles with phenylacetylene, catalyzed by Pd-Cu, in the presence of SDS as the surfactant in water, leads to the desired products in good-to-high yields.

Full text of DOI:10.1016/j.tetlet.2012.04.016

Tetrahedron Letters 53 (2012) 3126–3130
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Highly efficient synthesis of 5,6-disubstituted-5H-pyrrolo[2,3-b]-
pyrazine-2,3-dicarbonitriles through a one-pot palladium-catalyzed
coupling reaction/cyclization in water
⇑
Ali Keivanloo , Mohammad Bakherad, Hossein Nasr-Isfahani, Somayeh Esmaily
School of Chemistry, Shahrood University of Technology, Shahrood, Iran
a r t i c l e i n f o
a b s t r a c t
Article history:
A highly efficient one-pot synthesis of 5,6-disubstituted-5H-pyrrolo[2,3-b]pyrazine-2,3-dicarbonitriles is
presented. The reaction of 5-(alkyl-arylamino)-6-chloropyrazine-2,3-dicarbonitriles with phenylacety-
lene, catalyzed by Pd–Cu, in the presence of SDS as the surfactant in water, leads to the desired products
in good-to-high yields.
Received 7 February 2012
Revised 28 March 2012
Accepted 4 April 2012
Available online 12 April 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Palladuim catalyzed
Pyrrolo[2,3-b]pyrazine
Cross-coupling
Phenylacetylene
Surfactant
Pyrrolo[2,3-b]pyrazines have gained significant attention as
they exhibit diverse biological activities and clinical applications.
They show antibronchospastic effects1 and the ability to inhibit
the activity of p38 MAP kinase.2 These compounds also inhibit cy-
clin-dependent kinases (CDKs), thereby exhibiting antiproliferative
effects.3,4 Due to the potential applications of CDK inhibitors as no-
vel agents for a variety of neurodegenerative disorders such as Alz-
heimer’s disease, this family of compounds were named the
‘aloisines’ following the first name (Aloiz) of Dr. Alzheimer.3b CDKs
are involved in numerous biological processes such as cellular dif-
ferentiation, transcription, apoptosis, and cell cycle control.5,6 Fur-
thermore, CDKs have been linked to several diseases, for example,
cancer, neurodegenerative diseases, and diabetes.7
a more general and safer practical approach to the synthesis of
substituted pyrrolo[2,3-b]pyrazines is required.
Sonogashira cross-coupling with subsequent cyclization has
been successfully utilized for the synthesis of carbocylic12 and het-
erocyclic compounds.13 The use of water or aqueous solutions rep-
resents
a technique to overcome the economical and the
environmental problems caused by the use of toxic and harmful
organic solvents in chemical reactions.14 Several examples of Pd-
catalyzed Sonogashira reactions in aqueous medium have already
been reported.15
In continuation of our studies16 on the Pd-catalyzed synthesis of
new heterocyclic compounds of biological significance, and in par-
ticular the efficient synthesis of pyrrolo[2,3-b]quinoxalines,17 we
became interested in developing a synthetic route to 5,6-disubsti-
tuted-5H-pyrrolo[2,3-b]pyrazine-2,3-dicarbonitriles in water. In
order to introduce two substituents on the pyrrolo[2,3-b]pyra-
zine-fused ring system, our retrosynthetic analysis revealed the
use of 5-(alkyl-arylamino)-6-chloropyrazine-2,3-dicarbonitriles
and phenylacetylene as the starting materials (Scheme 1). The pal-
ladium-catalyzed cross-coupling reaction is the key step in this
synthesis.
Several approaches for the synthesis of pyrrolo[2,3-b]pyrazine
cores have been developed, such as condensation of a benzonitrile
derivative with an
a
-lithiated alkyl pyrazine,4,8 palladium-cata-
lyzed cyclization of 2-chloro-3-(methanesulfonamido)pyrazine
with substituted alkynes under thermal9 or microwave-assisted
conditions,10 and reaction of commercially available 2,3-dichloro-
pyrazine with
a-lithiated ketones, esters, and nitriles followed by
cyclization with primary amines or hydrazines.11 However, these
methods have their own shortcomings concerning yields, nature
of the substituents, and the use of toxic solvents and bases. Thus,
The starting materials 1a–h were prepared from commercially
available diaminomaleonitrile and oxalyl chloride in several steps
via literature procedures (Scheme 2).18
When compounds 1a–h were reacted with phenylacetylene (2)
in the presence of bistriphenylphosphine palladium(II) chloride,
copper(I) iodide, sodium lauryl sulfate (SDS), and potassium
⇑
Corresponding author. Fax: +98 2733395441.
E-mail
addresses:
keivanloo@shahroodut.ac.ir,
akeivanloo@yahoo.com
(A. Keivanloo).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.04.016

A. Keivanloo et al. / Tetrahedron Letters 53 (2012) 3126–3130
3127
Ph
NC
NC
N
N
NC
NC
N
N
Cl
NC
NC
N
N
Ph
Ph
CH
+
N
NH
R
NH
R
R
Scheme 1. Retrosynthetic analysis of 5,6-disubstituted-5H-pyrrolo[2,3-b]pyrazine-2,3-dicarbonitriles.
H
NC
NC
N
O
O
NC
NC
N
N
Cl
Cl
NC
NC
N
Cl
NC
NH2
NH2
(COCl)2
RNH2
THF
SOCl2
1,4-dioxane
N
H
N
NH
R
NC
1a-h
Scheme 2. Synthesis of 5-(alkyl-arylamino)-6-chloropyrazine-2,3-dicarbonitriles from diaminomaleonitrile and oxalyl chloride.
NC
NC
N
N
NC
NC
N
N
Cl
Pd(Ph3P)2Cl2, CuI, SDS
K2CO3, H2O, 70 °C
+
N
R
NH
R
R = alkyl, aryl
3a-h
1a-h
2
Scheme 3. Sonogashira coupling/cyclization of 5-(alkyl-arylamino)-6-chloropyrazine-2,3-dicarbonitriles with phenylacetylene. Reagents and conditions: Compound 1a–h
(0.556 mmol), 2 (1.11 mmol), K2CO3 (1.67 mmol), Pd(Ph3P)2Cl2 (5 mol %), CuI (10 mol %), SDS (10 mol %), distilled H2O (5 mL), 70 °C, 24 h, argon atmosphere.
Table 1
Synthesis of 5,6-disubstituted-5H-pyrrolo[2,3-b]pyrazine-2,3-dicarbonitriles
Entry
Amine 2
Product
Mp
Yield (%)
NC
N
N
N
N
Cl
NC
N
NC
NC
NH
3a
1
156
87
NC
NC
N
N
Cl
N
N
NC
NC
N
O
NH
2
148
82
75
3b
O
CH3
H3C
N
N
N
N
NC
NC
Cl
NC
NC
N
NH
3
4
180
133
CH3
H3C
CH3
H3C
3c
Cl
NC
NC
N
N
NC
NC
N
N
N
NH
68
CH3
CH3
H3C
3d
CH3
(continued on next page)

3128
A. Keivanloo et al. / Tetrahedron Letters 53 (2012) 3126–3130
Table 1 (continued)
Entry
Amine 2
Product
Mp
Yield (%)
NC
N
N
Cl
NC
N
N
N
NC
NC
NH
5
6
147
78
3e
O
O
NC
NC
N
N
Cl
NC
NC
N
N
N
NH
230
241
220
96
93
90
3f
NC
NC
N
N
Cl
N
N
NC
NC
N
NH
7
3g
3h
CH3
CH3
Cl
N
N
N
N
NC
NC
NC
NC
N
NH
8
Cl
Cl
Table 2
Effect of various catalysts on the reaction of 5-(benzylamino)-6-chloropyrazine-2,3-dicarbonitrile with phenylacetylenea
Ph
NC
NC
N
N
Cl
NC
NC
N
N
NC
NC
N
N
catalyst
Ph
Ph
CH
+
+
K2CO3, H2O, 70 °C
N
NH
NH
2
1a
3a
4
Entry
Catalyst
Yieldb (%)
3
4
1
2
3
4
5
PdCl2, Ph3P, CuI
Pd(Ph3P)2Cl2, CuI
Pd(Ph3P)2Cl2
PdCl2, Ph3P
Pd/C, Ph3P, CuI
75
87
—
—
20
—
—
65
53
60
a
Reaction conditions: 1a (0.556 mmol), 2 (1.11 mmol), K2CO3 (1.67 mmol), Pd catalyst (5 mol %), CuI (10 mol %), SDS (10 mol %),
distilled H2O (5 mL), 70 °C, 24 h, argon atmosphere.
carbonate at 70 °C in water under an argon atmosphere, 5,6-disub-
stituted-5H-pyrrolo[2,3-b]pyrazine-2,3-dicarbonitriles 3a–h were
obtained in good-to-high yields (Scheme 3). The results are shown
in Table 1.
The effect of the catalyst also studied, and the results are pre-
sented in Table 2. Pd(Ph3P)2Cl2 and CuI were found to be the best
catalyst system (entry 2). Addition of copper(I) iodide was essen-
tial as the co-catalyst. The reactions carried out without CuI
(entries 3 and 4), led only to 5-(benzylamino)-6-(phenyleth-
ynyl)pyrazine-2,3-dicarbonitrile (4) and no cyclization product
was formed. When Pd/C, CuI was used as the catalyst system (entry
5), a mixture of products of 3 and 4 was formed (Scheme 4).
Potassium carbonate was found to be a suitable base for the
reaction, giving cleaner products and better yields. The inclusion
of the surfactant was also critical for the success of the reaction,
and the yields decreased significantly when no surfactant was
used.
The structural assignments of compounds 3a–h were based on
elemental analyses, and spectroscopic data. The 1H NMR spectrum
of 3d showed an aromatic proton at d 7.25, which was characteristic

A. Keivanloo et al. / Tetrahedron Letters 53 (2012) 3126–3130
3129
Ph
NC
NC
N
N
Cl
NC
NC
N
N
NC
NC
N
N
Pd/C, CuI, SDS
Ph
Ph
CH
+
+
K2CO3, H2O, 70 °C
N
NH
NH
2
1a
3a
4
Scheme 4. Pd/C-catalyzed reaction of 5-(alkyl-arylamino)-6-chloropyrazine-2,3-dicarbonitriles with phenylacetylene. Reagents and conditions: Compound 1a (0.556 mmol),
2 (1.11 mmol), K2CO3 (1.67 mmol), Pd/C (5 mol %), CuI (10 mol %), SDS (10 mol %), distilled H2O (5 mL), 70 °C, 24 h, argon atmosphere.
NC
NC
N
N
Cl
NC
NC
N
N
H
CH
Pd(Ph3P)2Cl2, CuI, SDS
K2CO3, H2O, 70 °C
+
NH
NH
H3C
1a
5
Scheme 5. Reaction of 1a with an aliphatic alkyne to give the dechlorinated product. Reagents and conditions: Compound 1a (0.556 mmol), hex-1-yne (1.11 mmol), K2CO3
(1.67 mmol), Pd(Ph3P)2Cl2 (5 mol %), CuI (10 mol %), SDS (10 mol %), distilled H2O (5 mL), 70 °C, 24 h, argon atmosphere.
of a fused pyrrole ring. The other five aromatic protons appeared
at d 7.63–7.79. In the aliphatic region, two doublets at d 0.61
and d 4.33 and a multiplet at d 1.79 were assigned to the iso-butyl
group.
The use of phenylacetylene was necessary as aliphatic alkynes,
due to their low reactivity, gave only reduced products under the
reaction conditions (Scheme 5). This was confirmed from the 1H
5-(Benzylamino)pyrazine-2,3-dicarbonitrile (5)
White solid; 1H NMR (500 MHz, DMSO-d6): d 4.60 (d, J = 6.2 Hz,
2H, CH2), 7.16–7.39 (m, 5H, 5CH), 7.50 (s, 1H, CH pyrazine), 8.22 (t,
J = 6.2 Hz, 1H, NH); 13C NMR (125 MHz, DMSO-d6): d 153.66,
145.56, 139.94, 129.98, 128.28, 127.88, 127.26, 120.22, 115.21,
114.67, 43.97; IR (KBr): 3300 (NH), 3100, 2900, 2210 (CN), 1605,
1546, 1490, 995 cmÀ1; Anal. Calcd for C13H9N5: C, 66.37; H, 3.86;
N, 29.77. Found: C, 66.36; H, 3.85; N, 29.79.
NMR spectrum of 5-benzylaminopyrazine-2,3-dicarbonitrile
5
which showed a characteristic singlet at d 7.50 for the aromatic
proton.
In conclusion, the chemistry outlined here provides a simple,
one-pot, and highly efficient method for the synthesis of 5,6-disub-
stituted-5H-pyrrolo[2,3-b]pyrazine-2,3-dicarbonitriles in water
from readily available starting materials in good-to-high yields.
Acknowledgment
We express our thanks to the Research Council of Shahrood
University of Technology for the financial support of this work.
Supplementary data
General procedure for the preparation of 5,6-disubstituted-5H-
pyrrolo[2,3-b]pyrazine-2,3-dicarbonitriles 3a–h
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.04.
016.
A mixture of 5-(alkyl-arylamino)-6-chloropyrazine-2,3-dicar-
bonitrile 1 (0.556 mmol), Pd(Ph3P)2Cl2 (0.0278 mmol, 5 mol %),
CuI (0.0556 mmol, 10 mol %), sodium lauryl sulfate (0.0389 mmol,
7 mol %), and K2CO3 (1.67 mmol) in H2O (5 mL) under an argon
atmosphere was treated with phenylacetylene (2) (1.11 mmol)
slowly, and the resulting mixture was stirred at 70 °C for 24 h.
After completion of the reaction, the mixture was filtered, and
the remaining solid washed with H2O and dried. The crude product
was purified by column chromatography using CHCl3–CH3OH
(99:1) as eluent.
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