Heteroannulation of nitroketene N,S-arylaminoacetals with POCL3: A novel highly regioselective synthesis of unsymmetrical 2,3-substituted quinoxalines

Article abstract of DOI:10.1021/ol0505095

(Chemical Equation Presented) A novel regioselective route for the synthesis of substituted and fused 3-chloro-2-(methylthio)quinoxalines through POCl₃-mediated heteroannulation of a range of α-nitroketene N,S-anilinoacetals has been reported.

Full text of DOI:10.1021/ol0505095

ORGANIC
LETTERS
2005
Vol. 7, No. 11
2169-2172
Heteroannulation of Nitroketene
N,S-Arylaminoacetals with POCl3: A
Novel Highly Regioselective Synthesis
of Unsymmetrical 2,3-Substituted
Quinoxalines†
C. Venkatesh,‡ B. Singh,‡ P. K. Mahata,‡ H. Ila,*,‡ and H. Junjappa§
Department of Chemistry, Indian Institute of Technology, Kanpur 208016, India, and
Bioorganics and Applied Materials PVt. Ltd., Νï. B-64/1, 3rd Stage, Peenya Industrial
Area, Peenya, Bangalore 560 058, India
hila@iitk.ac.in
Received March 9, 2005
ABSTRACT
A
novel regioselective route for the synthesis of substituted and fused 3-chloro-2-(methylthio)quinoxalines through POCl3-mediated
heteroannulation of a range of -nitroketene N,S-anilinoacetals has been reported.
r
Quinoxaline and its derivatives are an important class of
benzoheterocycles1 displaying a broad spectrum of biological
activities2 which have made them privileged structures in
combinatorial drug discovery libraries.3 They have also found
applications as dyes4 and building blocks in the synthesis of
organic semiconductors,5 and they also serve as useful rigid
subunits in macrocyclic receptors for molecular recognition6
and chemically controllable switches.7 These studies have
resulted in the appearance of a large number of publications
both in journals and patent literature related to the synthesis
and physiochemical/biological properties of quinoxaline and
their derivatives.1,8 Although a number of methods are
† Dedicated to Dr. S. Anand Kumar, Director, Astrazeneca Research
Foundation, Bangalore, India, on his 70th Birthday.
available for the synthesis of substituted quinoxalines,1,8,9
a
‡ Indian Institute of Technology.
§ Bioorganics and Applied Materials Pvt. Ltd.
review of the literature revealed that while the parent
molecules are easily prepared, the corresponding substituted
compounds are considerably more challenging. Probably the
most widely used method for the preparation of quinoxaline
derivatives is by condensation of aryl-1,2-diamines with
R-diketones, usually R-dicarbonyl compounds (Hinsberg
(1) Reviews: (a) Porter, A. E. In ComprehensiVe Heterocyclic Chemistry;
Katritzky, A. R., Rees, C. W., Eds; 1984; Vol. 3, part 2B, p 157. (b) Sato,
N. In ComprehensiVe Heterocyclic Chemistry II; Katritzky, A. R., Rees, C.
W., Scriven, E. F. V., Eds; Pergamon: Oxford, 1996; Vol. 6, p 233. (c)
Sakata, G.; Makino, K.; Kurasama, Y. Heterocycles 1988, 27, 2481. (d)
Cheeseman, G. W. H.; Werstiuk, E. S. G. AdV. Heterocycl. Chem. 1978,
22, 367.
(2) (a) Seitz, L. E.; Suling, W. J.; Reynolds, R. C. J. Med. Chem. 2002,
45, 5604. (b) Gazit, A.; App, H.; McMahon, G.; Chen, A.; Levitzki, A.;
Bohmer, F. D. J. Med. Chem. 1996, 39, 2170. (c) Monge, A.; Palop, J. A.;
Del Castillo, J. C.; Caldero, J. M.; Roca, J.; Romero, G.; Del Rio, J.;
Lasheras, B. J. Med. Chem. 1993, 36, 2745. (d) Toshima, K.; Takano, R.;
Ozawa, T.; Matsumara, S. Chem. Commun. 2002, 212.
(4) (a) Brock, E. D.; Lewis, D. M.; Yousaf, T. I.; Harper, H. H. (The
Proctor and Gamble Company) WO 9951688, 1999. (b) Sonawane, N. D.;
Rangnekar, D. W. J. Heterocycl. Chem. 2002, 39, 303. (c) Katoh, A.;
Yoshida, T.; Ohkando, J. Heterocycles 2000, 52, 911.
(3) (a) Wu, Z.; Ede, N. J. Tetrahedron Lett. 2001, 42, 8115. (b) Lee, J.;
Murray, W. V.; Rivero, R. A. J. Org. Chem. 1997, 62, 3874. (c) Holland,
R. J.; Hardcastle, I. R.; Jarman, M. Tetrahedron Lett. 2002, 43, 6435. (d)
Krchnak, V.; Smith, J.; Vagner, J. Tetrahedron Lett. 2000, 41, 2835. (e)
Uxey, T.; Tempest, P.; Hulme, C. Tetrahedron Lett. 2002, 43, 1637. (f)
Zaragoza, F.; Stephensen, H. J. Org. Chem. 1999, 64, 2555.
(5) (a) Dailey, S.; Feast, J. W.; Peace, R. J.; Sage, I. C.; Till, S.; Wood,
E. L. J. Mater. Chem. 2001, 11, 2238. (b) O’Brien, D.; Weaver, M. S.;
Lidzey, D. G.; Bradley, D. D. C. Appl. Phys. Lett. 1996, 69, 881.
(6) (a) Mizuno, T.; Wei, W.-H.; Eller, L. R.; Sessler, J. L. J. Am. Chem.
Soc. 2002, 124, 1134. (b) Elwahy, A. H. M. Tetrahedron 2000, 56, 897.
(7) Crossley, J. C.; Johnston, L. A. Chem. Commun. 2002, 1122.
10.1021/ol0505095 CCC: $30.25
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Published on Web 04/30/2005

condensation) or their equivalents.1,8a-f However, a major
drawback in this method is the lack of regioselectivity leading
to formation of isomeric products with unsymmetrically
substituted reactants.4c,8f,9b Among the various regioselective
routes to quinoxaline and derivatives,1,8-10 the method
involving nucleophilic substitution on o-nitrohalobenzene by
appropriately functionalized aliphatic amine followed by
reductive cyclization of the resulting o-nitroaminobenzene
derivatives has been most widely employed.3 The other most
promising route in terms of regiochemistry and generality
is the intramolecular cyclization of R-aryliminophenylhy-
drazone11 or oxime derivatives12-14 of R-dicarbonyl com-
pounds employing readily available substituted aniline
precursors instead of 1,2-diaminobenzene or o-halonitroben-
zene derivatives.14 However, these potentially useful methods
have not been thoroughly explored, and the existing few
examples are rather limited in scope and suffer from several
practical disadvantages such as extremely vigorous conditions
or low yields.11 During the course of our ongoing exploration
on synthetic applications of polarized ketene S,S- and N,S-
acetals as versatile building blocks for heterocycle synthe-
sis,15,16 we have now developed a novel, highly regioselective
and efficient route to 2,3-substituted quinoxalines through
N-heteroannulation of R-nitroketene N,S-anilinoacetals. The
results of these studies are presented in this letter.
Scheme 1. Synthesis of Quinoxalinea
a Reagents and conditions: (a) DMF, POCl3, Cl2CHCHCl2, 80-
90 °C, 60%; (b) POCl3, CH3CN, 80 °C, 70%.
2-(methylthio)quinoxaline 3a (Scheme 1). Subsequently, it
was found that the reaction proceeded smoothly in the
absence of DMF and under optimized conditions, the
quinoxaline 3a was obtained in improved yield (70%) when
N,S-acetal 1a was reacted with POCl3 in acetonitrile at 80
°C. The reaction was extended to other substituted R-ni-
troketene N,S-acetals 1b-j with a view to examine scope
of the reaction for a general quinoxaline synthesis and the
results are presented in the Table 1. In general, the nitro-
Table 1. Synthesis of Quinoxalines 3 and 5 by
POCl3-Promoted Cyclocondensation of R-Nitroketene
N,S-Acetals
We have recently reported an efficient general route to
3-aroyl-2-(methylthio)quinolines through cyclocondensation
of various R-oxo N,S-arylacetals with Vilsmeier reagents.17
These studies motivated us to extend this method for the
synthesis of 3-nitroquinolines by reaction of the correspond-
ing nitroketene N,S-acetals with Vilsmeier reagent. However
when the N,S-acetal 1a was exposed to Vilsmeier reaction
conditions, the product (60%) isolated was not the expected
quinoline 2a but was characterized as 3-chloro-7-methoxy-
(8) (a) Antoniotti, S.; Dunach, E. Tetrahedron Lett. 2002, 43, 3971 and
references therein. (b) Petukhov, P. A.; Tkachev, A. V. Tetrahedron 1997,
53, 9761. (c) Juncai, F.; Yang, L.; Qinghua, M.; Bin. L. Synth. Commun.
1998, 28, 193. (d) Raw, S. A.; Wilfred, C. D.; Taylor, R. J. K. Chem.
Commun. 2003, 2286. (e) Kaupp, G.; Naimi-Jamal, M. R. Eur. J. Org.
Chem. 2002, 1368. (f) Chen, P.; Barrish, J. C.; Iwanowicz, E.; Lin, J.;
Bednarz, M. S.; Chen, B.-C. Tetrahedron Lett. 2001, 42, 4293. (g)
Soderberg, B. C. G.; Wallace, J. M.; Tamariz, J. Org. Lett. 2002, 4, 1339.
(h) Suginome, M.; Collet, S.; Ito, Y. Org. Lett. 2002, 4, 351. (i)
Mukhopadhyay, R.; Kundu, N. G. Tetrahedron Lett. 2000, 41, 9927. (j)
Bunce, R. A.; Herron, D. M.; Ackerman, M. L. J. Org. Chem. 2000, 65,
2847. (k) Banik, B. K.; Banik, I.; Hackfeld, L.; Becker, F. F. Heterocycles
2002, 56, 467. (l) Goswami, S.; Adak, A. K. Chem. Lett. 2003, 32, 678.
(9) (a) Attanasi, O. A.; De Crescentini, L.; Fillippone, P.; Mantellini,
F.; Santeusanio, S. Synlett 2003, 1183. (b) Tanaka, K.; Takahashi, H.;
Takimoto, K.; Sugita, M.; Mitsuhashi, K. J. Heterocycl. Chem. 1992, 29,
771. (c) Popat, K. H.; Nimavat, K. S.; Thaker, K. M.; Joshi, H. S. J. Ind.
Chem. Soc. 2003, 80, 709. (d) Subba Rao, K. V.; Subrahmanyam, M. Chem.
Lett. 2002, 234.
(10) Kher, S. M.; Cai, S. X.; Weber, E.; Keana, J. F. J. Org. Chem.
1995, 60, 5838.
(11) McNab, H. J. Chem. Soc., Perkin Trans. 1 1982, 1941.
(12) (a) Xekoukoulotakis, N. P.; Hadjiantoniou-Maroulis, C. P.; Maroulis,
A. J. Tetrahedron Lett. 2000, 41, 10299. (b) Maroulis, A. J.; Domzaridou,
K. C.; Hadjiantoniou-Maroulis, C. P. Synthesis 1998, 1769. (c) Amesto,
D.; Horspool, W. M.; Apoita, M.; Gallego, M. G.; Ramos, A. J. Chem.
Soc., Perkin Trans. 1 1989, 2035.
(13) Rahman, A.; Ila, H.; Junjappa, H. J. Chem. Soc., Chem. Commun.
1984, 430.
(14) (a) Meth-Cohn, O.; Rhouati, S.; Tarnowski, B.; Robinson, A. J.
Chem. Soc. 1981, 1537. (b) Makino, K.; Sakata, G.; Morimoto, K.
Heterocycles 1985, 23, 2069. (c) Sakata, G.; Makino, K.; Morimoto, K.
Heterocycles 1985, 23, 143.
a The 4-methoxy group in the product 3d was found to be replaced by
chlorine.
2170
Org. Lett., Vol. 7, No. 11, 2005

ketene N,S-acetals 1a-c with an activating group para to
the site of cyclization gave the corresponding 3-chloro-2-
(methylthio)quinoxalines 3a-c in high yields (entries 1-3),
whereas moderate to good yields of the quinoxalines were
obtained from the N,S-acetals 1d-j (entries 4-10).The
corresponding (4-fluoroanilino) N,S-acetal 1j gave both the
regioisomers of the quinoxalines 3ja and 3jb formed by
heterocyclization at both para and ortho positions of fluorine
substituent (entry 10). Interestingly, the N,S-acetal 1k from
1-naphthylamine was transformed into the 3-chloro-2-
(methylthio)benzo[h]quinoxaline(3k) in excellent yield (80%)
under the standard reaction conditions (entry 11). Extension
of the method to N,S-acetal 4 derived from 3-aminopyridine
furnished the corresponding 3-chloro-2-(methylthio)pyrido-
[2,3-b]pyrazine 5 in a moderate yield of 45% (Table 1, entry
12). To further explore the generality and scope of this new
quinoxaline synthesis, the reaction was extended to bis-
(nitroketene N,S-acetals) 9 and 11 which afforded the novel
hitherto unknown pyrazinoquinoxalines 10 and 12 in 55%
and 45% yields, respectively, under identical conditions
(Scheme 2).
lective routes for 2,3-substituted quinoxalines through se-
quential nucleophilic substitution of 3-chloro- and 2-meth-
ylthio groups by various hetero and carbon nucleophiles. It
is pertinent to note that nucleophilic substitution on 2,3-
dichloroquinoxalines with various nucleophiles usually yields
a regioisomeric mixture of substituted quinoxalines.9b,19,20
However, our studies revealed displacement of only 3-chloro
group by various nucleophilic species (amines, phenol,
alcohols, thiols, etc.) in the quinoxaline 3a, whereas the
2-methylthio group remained inert even under drastic condi-
tions. The quinoxalines 3a and 3g were therefore transformed
into the corresponding more labile 3-chloro-2-(methylsul-
fonyl)quinoxalines 13a and 13g in high yields by oxidation
with m-CPBA. Subsequently, it has been possible to tune
up the reactivity of 2-chloro- and 3-(methylsulfonyl) groups
in 13a and 13g toward displacement by various nucleophiles
in a sequential manner, and the results of our preliminary
studies are presented in the Schemes 4 and 5. Thus, the
Scheme 4
Scheme 2
The probable mechanism18 for the conversion of N,S-
acetals 1 to quinoxalines 3 involves initial formation of
quinoxaline N-oxide 7 by dehydrative cyclization of 1
followed by subsequent chlorination at 3-position and
extrusion of oxygen through intermediate 8 (Scheme 3).
treatment of the quinoxaline 13a with n-butylamine at room
temperature afforded the corresponding 2-(n-butylamino)-
3-chloro-7-methoxyquinoxaline 14 in excellent yield. Sub-
sequent treatment of 14 with benzylamine in a pressure tube
gave the corresponding 3-(benzylamino)-2-(n-butylamino)-
7-methoxyquinoxaline 15 in 75% yield with high regiocontrol
(Scheme 4). Similarly, the regioisomeric 2-(benzylamino)-
3-(n-butylamino)-7-methoxyquinoxaline 17 could be obtained
in high yield from 13a through sequential displacement of
2-(methylsulfonyl) and 3-chloro groups by respective amines
(Scheme 4). Similarly, the 2-cyano-3-(N-benzylpiperazino)-
6-methoxyquinoxaline 19 displaying selective 5HT3 antago-
nist activity on guinea pig peripheral receptors2c and its 2-(N-
Scheme 3
With a number of substituted quinoxalines in hand, we
next focused our attention on the development of regiose-
(18) (a) Yoneda, F.; Sakuma, Y.; Shinozuka, K. J. Chem. Soc., Chem.
Commun. 1977, 681. (b) Sakuma, Y.; Matsushila, Y.; Yoneda, F. Hetero-
cycles 1978, 9, 1767.
(19) Katoh, A.; Ueda, S.; Junko, O.; Hirota, M.; Komine, H.; Mitsuhashi,
K. Heterocycles 1992, 34, 1965.
(20) Regioselective displacement by few amines have been observed in
some nitro and amino substituted quinoxalines: (a) Ford, E.; Brewster, A.;
Jones, G.; Bailey, J.; Sumner, N. Tetrahedron Lett. 2000, 41, 3197. (b)
Katoh, A.; Ueda, S.; Ohkando, J.; Hirota, M.; Komine, K.; Mitsuhanshi,
K. Heterocycles 1992, 34, 1965.
(15) Reviews: (a) Ila, H.; Junjappa, H.; Mohanta, P. K. Progress in
Heterocyclic Chemistry; Gribble, G. W., Gilchrist, T. L., Eds.; Pergamon:
New York, 2001; Vol. 13, Chapter 1, p 1. (b) Junjappa, H.; Ila, H.; Asokan,
C. V. Tetrahedron 1990, 46, 5423.
(16) Panda, K.; Suresh, J. R.; Ila, H.; Junjappa, H. J. Org. Chem. 2003,
68, 3498 and references therein.
(17) Mahata, P. K.; Venkatesh, C.; Syam Kumar, U. K.; Ila, H.; Junjappa,
H. J. Org. Chem. 2003, 68, 3966 and references therein.
Org. Lett., Vol. 7, No. 11, 2005
2171

Scheme 5. Synthesis of 5HT3 Antagonists
Scheme 6. Regioselective Synthesis of Unsymmetrical
Dialkyl/Diaryl Quinoxalines
benzylpiperazino)-3-cyano regioisomer 21 could be synthesized
from the corresponding 3-chloro-6-methoxy-2-(methylsul-
fonyl) quinoxaline 13g in excellent yields through sequential
nucleophilic displacement by N-benzylpiperazine and cyanide
ion (Scheme 4).
Finally, the 3-chloro and 2-methylthio groups in quinoxa-
line 3a could be displaced by alkyl or aryl groups by
sequential iron-21 and nickel-catalyzed22 cross-coupling reac-
tions with the appropriate Grignard reagents as shown in
Scheme 6. Thus, we could accomplish the synthesis of both
the regioisomers of the hitherto inaccessible unsymmetrical
2-(n-butyl)-3-methyl- or 3-(n-butyl)-2-methyl- (24a and 25a),
2-(n-butyl)-3-phenyl- or 3-(n-butyl)-2-phenyl- (24b and 25b),
and 2-(4′-methoxyphenyl)-3-phenyl- or 3-(4′-methoxyphen-
yl)-2-phenyl-7-methoxyquinoxalines (24c and 25c) in high
yields with full regiocontrol following the sequential reac-
tions (Scheme 6).
In summary, we have developed a novel highly regio-
selective approach for the synthesis of substituted and fused
3-chloro-2-(methylthio)quinoxalines through POCl3 mediated
heteroannulation of readily accessible R-nitroketene N,S-
anilinoacetals. The newly developed methodology is general
and provides quinoxalines in moderate to excellent yields
depending on the nature of the substituent on the aniline ring.
The presence of 3-chloro and 2-(methylthio) or 2-(methyl-
sulfonyl) functionalities further makes them useful substrates
for the synthesis of wide range of unsymmetrical 2,3-substi-
tuted quinoxalines with high regiocontrol via either sequential
nucleophilic substitution by various nucleophiles or via metal
catalyzed C-C bond formation. Our efforts in this direction
are underway and will be reported in due course.
(21) (a) Furstner, A.; Leitner, A.; Mendez, M.; Krause, H. J. Am. Chem.
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Acknowledgment. Financial assistance by Astrazeneca
Research Foundation, Bangalore, India, and DST, New Delhi,
is acknowledged.
Supporting Information Available: Analytical and
spectroscopic data of all compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL0505095
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