A new synthesis of 2-(hetero)aryl-substituted pyrazines

Article abstract of DOI:10.1016/j.tetlet.2009.01.110

2-Chloropyrazine showed remarkable reactivity towards AlCl₃-mediated heteroarylation of arenes and heteroarenes providing direct access to a variety of 2-aryl and heteroaryl-substituted pyrazines, respectively, in good to excellent yields under

Full text of DOI:10.1016/j.tetlet.2009.01.110

Tetrahedron Letters 50 (2009) 1618–1621
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Tetrahedron Letters
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A new synthesis of 2-(hetero)aryl-substituted pyrazines
Arumugam Kodimuthali a,b, B. Chandra Chary a, Padala Lakshmi Prasunamba b, Manojit Pal a,
*
a New Drug Discovery, R&D Center, Matrix Laboratories Ltd., Anrich Industrial Estate, Bollaram, Jinnaram Mandal, Medak District, Andra Pradesh 502 325, India
b Department of Chemistry, University College of Science, Osmania University, Hyderabad 500 007, India
a r t i c l e i n f o
a b s t r a c t
Article history:
2-Chloropyrazine showed remarkable reactivity towards AlCl3-mediated heteroarylation of arenes and
heteroarenes providing direct access to a variety of 2-aryl and heteroaryl-substituted pyrazines, respec-
tively, in good to excellent yields under mild reaction conditions.
Received 12 December 2008
Revised 16 January 2009
Accepted 20 January 2009
Available online 23 January 2009
Ó 2009 Elsevier Ltd. All rights reserved.
The first AlCl3-induced C–C bond-forming reaction between
2-chloropyrazine and (hetero)arenes is described here, such reac-
tions being only known using transition metal catalysts (Fig. 1).1a
Pyrazine derivatives have attracted wide pharmaceutical inter-
ests because of their potential uses in the treatment of psychiatric
disorders, neurological diseases (e.g., stress, anxiety and depres-
sion), and cardiovascular disorders. They are reported to modulate
the activity of CRF1 (corticotropin-releasing factor 1) receptors.1b,1c
Besides, they are also versatile building blocks in the synthesis of
VCAM-1 (vascular cell adhesion molecule-1) inhibitors,2 pyrazine
alkaloids (antineoplasmic activity),3 and imidazopyrazin coelen-
terazine (bioluminescent).4 Because of their medicinal and syn-
thetic value, a number of methods have been developed for the
synthesis of pyrazine derivatives, especially 2-(hetero)aryl pyra-
zines. These include the cross-coupling of 2-chloropyrazine with
(a) ArMgX in the presence of (PPh3)2PdCl2/ZnCl2,5 (b) ArSnBu3 in
the presence of PdCl2(PPh3)2/PPh3, (c) Ar4Sn (generated in situ
from ArMgX and SnCl4) in the presence of Pd(PPh3)4,6 (d) ArBF3K
in the presence of PdCl2(dppf), (e) ArZnCl in the presence of
PdCl2(PPh3)27, or (f) ArB(OH)3 in the presence of PdCl2(dppb)/
Na2CO3.8 2-(Hetero)aryl pyrazines can also be prepared via the
cross-coupling of vinyl triflate with 2-pyrazinylzincbromide in
the presence of Pd(PPh3)4, coupling of 2-pyrazinylthioether with
ArSnBu3 in the presence of Pd(PPh3)4/Cu(I)-3-methylsalicylate,
coupling of 2-pyrazinyl tributyltin with ArBr in the presence of
Pd(PPh3)4. The utility of these methodologies, particularly the reac-
tion under Suzuki conditions,3 has been demonstrated in the syn-
thesis of pyrazine alkaloids, for example, Botryllazines A–B that
showed cytotoxicity against human tumor cells. While these meth-
odologies involved mild conditions and displayed increased func-
tional group tolerance, most of them, however, often required
the use of expensive catalysts and reagents. Additionally, the re-
quired organo-metallic reagents are either not available commer-
cially in many cases or their preparations often involve
cumbersome procedures. Recently, we have reported a AlCl3-in-
duced heteroarylation of arenes and heteroarenes as an alternative,
but less expensive strategy for the synthesis of various nitrogen-
containing heterocyclic compounds.9–13 A further exploration of
ArMgX or ArSnBu3 or Ar4Sn or ArBF3K or
ArZnCl or ArB(OH)3 (when X = Cl)
ROTf (when X = ZnBr)
ArSnBu3 (when X = SPh)
ArBr (when X = SnBu3)
N
N
N
N
Ar
X
Figure 1. Pd-catalyzed C–C bond-forming reaction between 2-chloropyrazine and
arenes.
OH
OH
AlCl3
solvent
N
+
N
80 ºC
N
Cl
N
3a
1
2a
Scheme 1. AlCl3-Induced heteroarylation of 1-naphthol (2a) with 1.
Table 1
Heteroarylation of 2a with 1 under various conditions
Entry
Solvent
Time (h)
Yielda (%)
1
2
3
4
5
6
7
ClCH2CH2Cl
CHCl3
CH2Cl2
CH3CN
EtOAc
8
79
70
66
70
69
20
14
24
15
20
32
56
THF
Toluene
* Corresponding author. Tel.: +91 08458279301; fax: +91 08458279305.
E-mail addresses: manojitpal@rediffmail.com, Manojit.Pal@matrixlabs india.com
(M. Pal).
No reaction
a
Yield of isolated products.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.01.110

A. Kodimuthali et al. / Tetrahedron Letters 50 (2009) 1618–1621
1619
Table 2
Synthesis of 2-(hetero)aryl-substituted pyrazines (3)
Entry
Reactant (2)
Product (3)
Conditions
Yielda (%)
OH
OH
1
3a
80 °C, 8 h
79
N
N
2a
OH
Me
OH
Me
2
3b
80 °C, 8 h
73
HO
OH
N
N
2b
OMe
OMe
3
3c
80 °C, 12 h
69
MeO
OMe
N
N
2c
OMe
OMe
4
3d
80 °C, 10 h
70
MeO
OMe
MeO
2d
OMe
N
N
OMe
OMe
5
6
7
8
3e
80 °C, 14 h
80 °C, 8 h
80 °C, 15 h
80 °C, 10 h
76
80
76
N
2e
N
OH
HO
3f
N
2f
N
OMe
MeO
3g
N
2g
N
OH
OH
3h
53
35
N
H
N
H
N
N
2h
N
N
+
OH
3ha
N
H
a
Yield of isolated products.

1620
A. Kodimuthali et al. / Tetrahedron Letters 50 (2009) 1618–1621
this strategy led us to develop a novel, inexpensive, and scalable
method for the synthesis of 2-(hetero)aryl pyrazines.
responding product 2-arylpyrazines (3a–g) was isolated in good
yields after the usual work-up followed by purification using col-
umn chromatography.14,15 The free phenolic hydroxyl group was
well tolerated in the case of 2a, 2b, 2f, and 2h, and the heteroary-
lation occurred at the ring carbon rather than oxygen (or nitrogen).
The use of 4-hydroxycarbazole (2h) afforded a mixture of products,
that is, 3h and its regioisomer 3ha in 53% and 35% yields, respec-
tively (Table 2, entry 8).16
The presence of the free phenolic hydroxyl group in a number of
products allowed us to use this as a handle for further chemical
transformations. For example, compound 3a was converted to a
thiazolidinedione (TZD) derivative 4, of potential pharmacological
interest (Scheme 3).17
The heteroarylation reaction seems to proceed via the complex-
ation of AlCl3 with the nitrogen of –C(Cl)@N- moiety of 1, thereby
activating the chloro-group to facilitate a nucleophilic attack by
arenes or heteroarenes (2) at the chlorine-bearing carbon atom
(Fig. 2).18 This nucleophilic attack is possibly favored by the elec-
tron-withdrawing effect of the second nitrogen of the pyrazine
ring.
In conclusion, we have developed a novel, operationally simple
and single-step method for the preparation of 2-(hetero)aryl pyra-
zines from readily available starting materials and reagents. The
methodology does not require the use of expensive transition me-
tal catalysts or organometallic reagents, and therefore has the po-
tential to become useful alternative towards the direct synthesis of
novel 2-(hetero)aryl pyrazines.
For our initial study, we chose commercially available 2-chloro-
pyrazine (1) as a heteroaryl halide, and 1-naphthol (2a) as an arene
component (Scheme 1) to examine the AlCl3-induced heteroaryla-
tion reaction. The results are summarized in Table 1. Thus, when a
mixture of 1 (1 equiv), 2a (1 equiv), and AlCl3 (1.2 equiv) in dichlo-
roethane (5 ml) was stirred at 80 °C for 8 h, the desired 4-pyrazin-
2-yl-naphthalen-1-ol (3a) was isolated in 79% yield (Table 1, entry
1). The compound 3a was characterized by spectral data. To estab-
lish the optimum conditions, we then examined the effect of time
and solvents on this heteroarylation process. A variety of solvents
other than dichloroethane were examined (Table 1, entries 2–7). In
spite of increasing and varying the reaction time from 14 to 56 h
and maintaining the temperature at 80 °C, none of these solvents
provided a better yield of 3a than dichloroethane (70–20% vs
79%). The reaction did not proceed in toluene (Table 1, entry 7).
Thus, dichloroethane was found to be the best suitable solvent
for the heteroarylation of 2a with 2-chloropyrazine.
Having established the optimum conditions for the AlCl3-in-
duced heteroarylation reaction of 2-chloropyrazine with 2a, we
then decided to examine the reactivity of 2-chloropyrazine with
other arenes and heteroarenes. Accordingly, a number of arenes
were reacted with 2-chloropyrazine (Scheme 2), and the results
are summarized in Table 2. Arenes such as 2-methyl-benzene-1,
3-diol (2b), 1,3-dimethoxybenzene (2c), 1,3,5-trimethoxybenzene
(2d), 1-methoxynaphthalene (2e), 2-naphthol (2f), and
2-methoxynaphthalene (2g) were employed successfully to afford
the desired products 3b–g (Table 2, entries 2–7) in good yields.
Thus, in a typical procedure 1.0 equiv of 2-chloropyrazine was re-
acted with 1.0 equiv of arene (2a–g) in the presence of 1.2 equiv of
anhydrous AlCl3 using dichloroethane as solvent at 80 °C. The cor-
Acknowledgment
The authors thank the management of Matrix Laboratories Lim-
ited for continuous support and encouragement.
Supplementary data
N
AlCl3
N
+
RH
1
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2009.01.110.
dichloroethane
80 °C
8-15 h
R
3
2
References and notes
Scheme 2. AlCl3-Induced heteroarylation of 2 with 1.
1. (a) Li, J. J.; Gribble, G. W. Palladium in Heterocyclic Chemistry, Pyrazines and
Quinoxalines, Published by Elsevier, 2006, ISBN 0080451160. (Chapter 10, pp
353–373).; (b) Yoon, T., Ge, P., Delombaert, S., Horvath, R. World Application
WO 2004/018437 A1, 4 March 2004.; (c) Ge, P., Horvath, R. F., Zhang, L. Y.,
Yamaguchi, Y., Kaiser, B., Zhang, X., Zhang, S., Zhao, H., John, S., Moorcroft, N.,
Shutske, G. Word Application WO 2005/023806 A2, 17 March 2005.
2. Weingarten, M. D.; Liming, N. I.; Sikorski, J. A. World Application WO 2004/
056727 A2, 8 July 2004.
3. Buron, F.; Ple, N.; Turck, A.; Queguiner, G. J. Org. Chem. 2005, 70, 2616–2621.
4. Kakoi, H. Chem. Pharm. Bull. 2002, 50, 301–302.
5. (a) Adamczky, M.; Akireddy, S. R.; Johnson, D. D.; Mattingly, P. G.; Pan, Y.;
Rajarathnam, E. R. Tetrahedron 2003, 59, 8129–8142; (b) For a Ni-catalyzed
reaction, see: Godek, D. M.; Rosen, T. J. WO 91/18878; Chem. Abstr. 1992, 116,
106106.
6. Namamura, H.; Takeuchi, D.; Murai, A. Synlett 1995, 1227–1228.
7. Amat, M.; Hadida, S.; Pshenichnyi, G.; Bosch, J. J. Org. Chem. 1997, 62, 3158–
3175.
8. Jones, K.; Keenan, M.; Hibbert, F. Synlett 1996, 509–510.
9. (a) Pal, M.; Batchu, V. R.; Dager, I.; Swamy, N. K.; Padakanti, S. J. Org. Chem.
2005, 70, 2376–2379; (b) Kodimuthali, A.; Nishad, T. C.; Prasunamba, P. L.; Pal,
M. Tetrahedron Lett. 2009, 50, 354–358.
O
O
1. BrCH2CH2OH, K2CO3
DMF, 60 ºC, 12 h, 72%
COCH3
3a
2. PBr3, 61%
thiazolidine-2,4-dione
3. p-OHC6H4COCH3
K2CO3, DMF, rt, 24 h
67%
piperidine
N
benzoic acid
toluene, reflux
48h, 39%
N
S
O
O
O
NH
N
O
N
4
10. Pal, M.; Batchu, V. R.; Parasuraman, K.; Yeleswarapu, K. R. J. Org. Chem. 2003, 68,
6806–6809.
Scheme 3. Synthesis of TZD derivative 4 from 3a.
11. Pal, M.; Batchu, V. R.; Khanna, S.; Yeleswarapu, K. R. Tetrahedron 2002, 58,
9933–9940.
12. Pal, M.; Khanna, I.; Subramanian, V.; Padakanti, S.; Pillarisetti, S. World Patent
Application WO 2006/058201 A2, June 1, 2006.
13. (a) Pal, M.; Rao, Y. K.; Khanna, I.; Swamy, N. K.; Subramanian, V.; Batchu, V. R.;
Iqbal, J.; Pillarisetti, S. U.S. Patent Application US 2006/0128729 A1, June 15,
2006.; (b) See also: Hentrich, W.; Hardtmann, M.; Knoche, R. U.S. Patent
Application US 1780879, November 4, 1930.
AlCl3
N
AlCl3
N
R
Cl
RH
3
N
N
AlCl3
HCl
14. Typical procedure for the synthesis of 2-(hetero)arylpyrazine (3): A mixture of 2-
chloropyrazine (1.0 equiv), arene/heteroarene (2a–h) (1.0 equiv), and
Figure 2. Proposed mechanism for AlCl3-induced heteroarylation of 2 with 1.

A. Kodimuthali et al. / Tetrahedron Letters 50 (2009) 1618–1621
1621
anhydrous AlCl3 (1.2 equiv) in dichloroethane (5 mL) was stirred according to
the conditions mentioned in Table 2. After completion of the reaction, the
mixture was poured into ice-cold water (15 mL), stirred for 10 min, and then
extracted with ethyl acetate (3 Â 5 mL). The organic layers were collected,
combined, washed with water (3 Â 10 mL), dried over anhydrous Na2SO4, and
concentrated under vacuum. The residue was purified by column
chromatography to afford the expected products.
159.0, 158.8, 152.5, 141.7, 140.7, 139.6, 124.6, 111.2, 108.3, 107.1, 8.1; HPLC
purity 99.29%. Compound 3d: Off-white solid; mp 124–126 °C; 1H NMR
(300 MHz, DMSO-d6) d 8.65 (d, J = 1.5 Hz, 1H), 8.48–8.46 (m, 2H), 6.34 (s,
2H), 3.84 (s, 3H, OCH3), 3.67 (s, 6H, OCH3); mmax (KBr, cmÀ1): 1610, 1587,
1471; Mass (ESI method, i-butane): 247 (M++1, 100%); 13C NMR (75 MHz,
DMSO-d6) 161.7, 158.6 (2C), 150.3, 147.0, 144.0, 142.0, 108.0, 90.9 (2C), 55.7
(2C), 55.4; HPLC purity 99.99%.
15. Spectral data for selected compounds: Compound 3a: pale yellow solid; mp
188–190 °C; 1H NMR (300 MHz, DMSO-d6) d 10.57 (s, 1H, OH), 8.87 (s, 1H),
8.77 (s, 1H), 8.64 (d, J = 2.3 Hz, 1H), 8.27–8.24 (m, 1H), 8.14–8.11 (m, 1H),
7.57–7.50 (m, 3H), 7.01 (d, J = 7.8 Hz, 1H); mmax (KBr, cmÀ1): 1623, 1582,
1522, 1494, 1448; Mass (ESI method, i-butane): 223 (M++1, 100%); 13C NMR
(75 MHz, DMSO-d6) 154.6, 154.5, 145.2, 143.7, 142.3, 131.7, 129.3, 127.0,
125.0, 124.8, 124.7 (2C), 122.4, 107.6; HPLC purity 98.41%. Compound 3b:
Pale yellow solid; mp 198–200 °C; 1H NMR (300 MHz, DMSO-d6) d 13.32 (s,
1H), 9.88 (s, 1H), 9.35 (s, 1H), 8.52 (m, 2H), 7.84 (d, J = 8.8 Hz, 1H), 6.48 (d,
J = 8.8 Hz, 1H), 2.02 (s, 3H, CH3); mmax (KBr, cmÀ1): 3427, 1613, 1518, 1468;
Mass (ESI method, i-butane):203 (M++1, 100%); 13C NMR (75 MHz, DMSO-d6)
16. While the corresponding isomeric products were not isolated from the reaction
mixtures of 1 and 2a–g, their formation cannot be ruled out completely as the
yields of pure desired products, that is, 3a–g were not very high.
17. Rao, Y. K.; Pal, M.; Sharma, V. M.; Venkateswarlu, A.; Pillaresetti, R. U.S. Patent
Application US 2005/0119269 A1, June 2, 2005.
18. A possible alternative pathway for a phenol heteroarylation may be proposed
which includes initial formation of an O-heteroaryl ether followed by its
subsequent catalytic isomerization to the desired product. However, this
pathway can be ruled out because of the fact that the intermediate ether was
not isolated even in trace quantity from the reaction mixture of 1 and a phenol,
for example, 2a or 2b or 2f.