Dipolar cycloaddition of ethyl isocyanoacetate to 3-chloro-2-(methylthio)/ 2-(methylsulfonyl)quinoxalines: Highly regio- and chemoselective synthesis of substituted imidazo[1,5-a]quinoxaline-3-carboxylates

Article abstract of DOI:10.1021/jo070590k

(Chemical Equation Presented) An efficient route for regio- and chemoselective synthesis of substituted 3-(carboedioxy)imidazo[1,5-a] quinoxalines and novel diimidazo[1,5-a:5′,1′-c]quinoxalines via base-induced cycloaddition of ethyl isocyanoacetate to un

Full text of DOI:10.1021/jo070590k

of biologically important and therapeutically useful agents. Thus,
they have been used as a template for the synthesis of GABA/
benzodiazepine receptor agonists/antagonists,7 cAMP and cGMP
phosphodiesterase inhibitors,8 A1- and A2a-adenosine receptor
agonists,9 and several other pharmacologically active com-
pounds.2a,10-12 More recently, 4-[(2-chloro-6-methylphenyl)-
amino]-7,8-dimethoxyimidazo[1,5-a]quinoxaline (BMS-238497)
has emerged as a novel and potent inhibitor of Src-family kinase
p56Lck, displaying excellent enzymatic activity against Lck (IC50
) 2 nM) and good potency in blocking T-cell proliferation (IC50
) 0.67 µM).13-14
Dipolar Cycloaddition of Ethyl Isocyanoacetate to
3-Chloro-2-(methylthio)/
2-(methylsulfonyl)quinoxalines: Highly Regio-
and Chemoselective Synthesis of Substituted
Imidazo[1,5-a]quinoxaline-3-carboxylates†
G. S. M. Sundaram, B. Singh, C. Venkatesh, H. Ila,* and
H. Junjappa
Department of Chemistry, Indian Institute of Technology,
Kanpur-208016, India
hila@iitk.ac.in
ReceiVed March 22, 2007
Mainly two approaches have been reported in the literature for
the construction of the imidazo[1,5-a]quinoxalin-4-one ring sys-
tem. In the first approach, an appropriately substituted imidazole
derivative is introduced into a substituted o-halonitrobenzene
derivative followed by intramolecular cyclization of the resulting
ortho-substituted imidazobenzene.8,12,15 The second approach
involves annulation of an imidazole ring to N-protected quinox-
alin-2-one mediated by a dipolar cycloaddition of tosylmethyl
or benzyl isocyanide as the key step.3,7,16 Whereas the first
approach is not feasible for the synthesis of imidazoquinoxalines
with electron-donating substituents (OMe), the second approach
suffers from several drawbacks such as a lack of regioselectivity
encountered in the formation of quinoxalin-2-ones from unsym-
metrical phenylene-1,2-diamines and poor chemoselectivity (N
vs O-alkylation) observed in the N-protection step.16 Also, the
method requires not easily accessible, air-sensitive, unstable phen-
ylene-1,2-diamines as initial precursors. During the course of
our ongoing studies on polarized ketene S,S- and N,S-acetals,17,18
we have recently reported a novel highly regioselective synthesis
of unsymmetrical 2,3-substituted quinoxalines.19 The overall
strategy involves POCl3-mediated heterocyclization of the read-
ily accessible R-nitroketene N,S-anilino acetals, furnishing
regiospecifically substituted 3-chloro-2-(methylthio)quinoxalines
An efficient route for regio- and chemoselective synthesis
of substituted 3-(carboethoxy)imidazo[1,5-a]quinoxalines and
novel diimidazo[1,5-a:5′,1′-c]quinoxalines via base-induced
cycloaddition of ethyl isocyanoacetate to unsymmetrically
substituted 3-chloro-2-(methylthio)/2-(methylsulfonyl)qui-
noxalines has been reported.
Compounds containing azole-fused quinoxalines such as
pyrrolo[1,2-a]quinoxalines,1 imidazo[1,2-a]quinoxalines,2 imi-
dazo[1,5-a]quinoxalines,3 [1,2,4]triazolo[4,3-a]quinoxalines,2a,4,5
and 1H-imidazo[4,5-b]quinoxalines6 are known to exhibit a wide
range of biological activities. Among these compounds, imidazo-
[1,5-a]quinoxalines and the related imidazo[1,5-a]quinoxalin-
4-ones are common structural arrays that are found in a number
(7) Jon Jacobsen, E.; Stelzer, L. S.; Belonga, K. L.; Carter, D. B.; Im,
W. B.; Sethy, V. H.; Tang, A. H.; VonVoigtlander, P. F.; Petke, J. D. J.
Med. Chem. 1996, 39, 3820.
† Dedicated to Prof. Miguel Yus on his 60th birthday.
(8) Davey, D. D.; Erhardt, P. W.; Cantor, E. H.; Greenberg, S. S.;
Ingebretsen, W. R.; Wiggins, J. J. Med. Chem. 1991, 34, 2671.
(9) Colotta, V.; Cecchi, L.; Catarzi, D.; Filacchioni, G.; Martini, C.;
Tacchi, P.; Lucacchini, A. Eur. J. Med. Chem. 1995, 30, 133.
(10) Tenbrink, R. E.; Jacobsen, E. J.; Gammill, R. B. U.S. Patent
5541324, July 30, 1996; Chem. Abstr. 1996, 125, 195687.
(11) Hansen, H. C.; Frank, W. EP 344943 A1, Dec 6, 1989; Chem. Abstr.
1990, 112, 216962.
(12) Lee, T. D.; Brown, R. E. U.S. Patent 4440929, April 3, 1984; Chem.
Abstr. 1984, 101, 7202.
(13) Barrish, J. C.; Chen, P.; Das, J.; Iwanowicz, E. J.; Norris, D. J.;
Padmanaba, R.; Roberge, J. Y.; Schieven, G. L. U.S. Patent 6235740, May
22, 2001.
(14) Chen, P.; Norris, D.; Iwanowicz, E. J.; Spergel, S. H.; Lin, J.; Gu,
H. H.; Shen, Z.; Wityak, J.; Lin, T.-A.; Pang, S.; De Fex, H. F.; Pitt, S.;
Shen, D. R.; Doweyko, A. M.; Bassolino, D. A.; Roberge, J. Y.; Poss, M.
A.; Chen, B.-C.; Scheiven, G. L.; Barrish, J. C. Bioorg. Med. Chem. Lett.
2002, 12, 1361.
(15) Norris, D.; Chen, P.; Barrish, J. C.; Das, J.; Moquin, R.; Chen, B.-
C.; Guo, P. Tetrahedron Lett. 2001, 42, 4297.
* To whom correspondence should be addressed. Fax: 91-0512-2597436,
91-0512-2590260.
(1) (a) Campiani, G.; Morelli, E.; Gemma, S.; Nacci, V.; Butini, S.;
Hamon, M.; Novellino, E.; Greco, G.; Cagnotto, A.; Goegan, M.; Cervo,
L.; Valle, F. D.; Fracasso, C.; Caccia, S.; Mennini, T. J. Med. Chem. 1999,
42, 4362.
(2) (a) Ohmori, J.; Shimizu-Sasamata, M.; Okada, M.; Sakamoto, S. J.
Med. Chem. 1997, 40, 2053. (b) Deleuze-Masque´fa, C.; Gerebtzoff, G.;
Subra, G.; Fabreguettes, J.-R.; Ovens, A.; Carraz, M.; Strub, M.-P.; Bompart,
J.; George, P.; Bonnet, P.-A. Biorg. Med. Chem. 2004, 12, 1129. (c) Parra,
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Michel, A.; Chapat, J.-P.; Bonnet, P.-A. Eur. J. Med. Chem. 2001, 36, 255.
(3) Chen, B.-C.; Zhao, R.; Bednarz, M. S.; Wang, B.; Sundeen, J. E.;
Barrish, J. C. J. Org. Chem. 2004, 69, 977 and references therein.
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P. A.; Koe, B. K. J. Med. Chem. 1990, 33, 2240.
(5) Unciti-Broceta, A.; Pineda-de-las-Infantas, J.; Diaz-Mocho´n, J. J.;
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2005, 70, 2878.
(6) Catarzi, D.; Cecchi, L.; Colotta, V.; Filacchioni, G.; Martini, C.;
Tacchi, P.; Lucacchini, A. J. Med. Chem. 1995, 38, 1330.
(16) Chen, P.; Barrish, J. C.; Iwanowicz, E.; Lin, J.; Bednarz, M. S.;
Chen, B.-C. Tetrahedron Lett. 2001, 42, 4293.
10.1021/jo070590k CCC: $37.00 © 2007 American Chemical Society
Published on Web 06/01/2007
5020
J. Org. Chem. 2007, 72, 5020-5023

SCHEME 1
SCHEME 2
in moderate to excellent yields depending on the nature of the
substituents on the aniline ring.19 This new heteroannulation
protocol avoids phenylene-1,2-diamines as precursors, and the
3-chloro and 2-methylthio (or 2-methylsulfonyl) functionalities
in these newly synthesized quinoxalines can be smoothly
replaced by various heteronucleophiles or carbon nucleophiles
in a highly regio- and chemoselective fashion via sequential
nucleophilic substitution or metal-catalyzed cross-coupling,
yielding a wide range of unsymmetrically 2,3-substituted
quinoxalines with high regiocontrol.19 In continuation of these
studies, we became interested in investigating dipolar cycload-
dition of these newly synthesized 3-chloro-2-(methylthio)/2-
(methylsulfonyl)quinoxalines with activated methyl isocyanides
with a view to develop a regioselective synthesis of unsym-
metrically substituted imidazo[1,5-a]quinoxalines because of the
broad spectrum of biological activity displayed by this class of
compounds. We have successfully achieved this goal, and herein
we describe the results of our studies.
The desired substituted 3-chloro-2-(methylthio)quinoxalines
2a-i were prepared according to our reported procedure via
intramolecular cyclization of nitroketene N,S-anilino acetals 1a-i
in the presence of POCl3 in acetonitrile at 70-80 °C (Scheme
1).19 All the 3-chloro-2-(methylthio)quinoxalines 2a-iwere trans-
formed into 2-(methylsulfonyl)quinoxalines 3a-i via mCPBA
oxidation at room temperature. We selected ethyl isocyanoace-
tate (4) as a dipolarophile for cycloaddition studies with a few
selected 3-chloro-2-(methylthio)quinoxalines 2 (Scheme 1). Thus,
the reaction of 2a with 4 was optimized in the presence of vari-
ous bases (NaH, K+-t-BuO-, DBU, n-BuLi, NaHMDS) and sol-
vents. The best results were obtained when 2a was reacted with
4 in the presence of DBU in DMF at 80 °C for 4-5 h, furnishing
only one product (75%) which was characterized as ethyl 7,8-
dimethoxy-4-(methylthio)imidazo[1,5-a]quinoxaline-3-carboxyl-
ate (5a) on the basis of spectral and analytical data (Scheme 1).
The product 5a is apparently formed by dipolar cycloaddition of
ethyl isocyanoacetate to the more activated 3,4-NdCsCl bond
of 2a, whereas no reaction is observed with the 1,2-NdCsSMe
bond. A similar trend was also observed when other substituted
quinoxalines 2b-i were reacted with 4 under identical condi-
tions, yielding substituted 4-(methylthio)imidazo[1,5-a]quinoxa-
line-3-carboxylates 5b-i in high yields (Scheme 1). Two of
the imidazoquinoxalines, 5d and 5g, were subjected to Raney
Ni dethiomethylation, yielding the regioisomeric 4-unsubstituted
8-methoxy-substituted (6d) and 7-methoxy-substituted (6g)
imidazo[1,5-a]quinoxalines in good yields (Scheme 1).
The quinoxalines 3a-i having a more activated 2-(methyl-
sulfonyl) functionality were next subjected to cycloaddition with
ethyl isocyanoacetate with a view to examine the effect of the
substituents on the chemo- and regioselectivity of the reaction
(Schemes 2 and 3).20 Thus, the reaction of symmetrically
substituted 3-chloro-6,7-dimethoxy-2-(methylsulfonyl)quinoxa-
line (3a) with ethyl isocyanoacetate (1.0 equiv) was found to
be very facile, proceeding smoothly at room temperature with
the disappearance of the starting materials within 3 h. Workup
and analysis of the reaction mixture showed formation of only
one major product (87%), which, after isolation, was character-
(17) Review: (a) Ila, H.; Junjappa, H.; Mohanta, P. K. In 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.
(18) Recent papers: (a) Peruncheralathan, S.; Khan, T. A.; Ila, H.;
Junjappa, H. J. Org. Chem. 2005, 70, 10030. (b) Peruncheralathan, S.;
Yadav, A. K.; Ila, H.; Junjappa, H. J. Org. Chem. 2005, 70, 9644. (c) Panda,
K.; Venkatesh, C.; Ila, H.; Junjappa, H. Eur. J. Org. Chem. 2005, 2045.
(d) Sundaram, G. S. M.; Venkatesh, C.; Syam, Kumar, U. K.; Ila, H.;
Junjappa, H. J. Org. Chem. 2004, 69, 5760. (e) Peruncheralathan, S.; Khan,
T. A.; Ila, H.; Junjappa, H. Tetrahedron 2004, 60, 3457. (f) Mahata, P. K.;
Venkatesh, C.; Syam, Kumar, U. K.; Ila, H.; Junjappa, H. J. Org. Chem.
2003, 68, 3966. (g) Panda, K.; Suresh, J. R.; Ila, H.; Junjappa, H. J. Org.
Chem. 2003, 68, 3498.
(20) For the substituent effect on 2,3-dichloroquinoxalines, see: Ford,
E.; Brewster, A.; Jones, G.; Bailey, J.; Sumner, N. Tetrahedron Lett. 2000,
41, 3197.
(19) Venkatesh, C.; Singh, B.; Mahata, P. K.; Ila, H.; Junjappa, H. Org.
Lett. 2005, 7, 2169.
J. Org. Chem, Vol. 72, No. 13, 2007 5021

SCHEME 3
SCHEME 4
ized as ethyl 4-chloro-6,7-dimethoxy-imidazo[1,5-a]quinoxaline-
3-carboxylate (7a) on the basis of spectral and analytical data
(Scheme 2). Similarly, the corresponding unsubstituted qui-
noxaline 3b and 6,7-dichloro-2-(methylsulfonyl)-3-chloroqui-
noxaline (3c) also furnished only regioisomeric imidazo[1,5-
a]quinoxalines 7b,c as the main products, which are evidently
derived by cycloaddition of ethyl isocyanoacetate anion to the
1,2-NdCsSO2Me bond of the quinoxalines 3b,c in a highly
chemoselective fashion (Scheme 2).
a Yields in parentheses represent yields of 9 obtained in reaction of 3
with 1.0 equiv of ethyl isocyanoacetate.
SCHEME 5
A further detailed investigation of cycloaddition studies on
unsymmetrically substituted 3-chloro-2-(methylsulfonyl)qui-
noxalines 3d-i displayed an interesting substituent effect on
the chemo- and regioselectivity of the reaction. Thus, the
quinoxalines 3d and 3e having an electron-donating methoxy
or methyl group in the 6-position reacted with ethyl isocy-
anoacetate (1 equiv) under the earlier described conditions to
give exclusively 4-(methylsulfonyl)imidazo[1,5-a]quinoxalines
8d,e (formed by cycloaddition of 4 to the 3,4-NdCsCl bond),
whereas the corresponding 7-methoxy-substituted (3g) and
7-methyl-substituted (3h) 2-(methylsulfonyl)quinoxalines, on the
other hand, underwent cycloaddition to the 1,2-NdCsSO2Me
double bond in a highly chemoselective fashion, furnishing the
regioisomeric products imidazo[1,5-a]quinoxalines 7g and 7h
in 82% and 81% yields, respectively (Scheme 3). Interestingly,
the order of chemoselectivity was found to be reversed in the
case of 6-chloro- and 7-chloro-2-(methylsulfonyl)quinoxalines
3f and 3i, which on reaction with 1 equiv of ethyl isocyanoace-
tate under standard reaction conditions afforded the respective
4,7-dichloroimidazo[1,5-a]quinoxaline-3-carboxylate 7f (75%)
and the corresponding 7-chloro-4-(methylsulfonyl) derivative
8i (72%), which are apparently derived from cycloaddition of
4 to the 1,2-NdCsSO2Me and 3,4-NdCsCl double bonds of
3f and 3i, respectively (Scheme 3).
These observations can be explained in terms of the electronic
effects of various substituents present in the quinoxalines 3a-
i. Thus, in the case of unsubstituted and symmetrically substi-
tuted quinoxalines 3a-c, the electron-withdrawing effect of the
2-(methylsulfonyl) group appears to predominate over that of
the 3-chloro substituent, thus directing the cycloaddition of the
ethyl isocyanoacetate anion to the 1,2-double bond of quinoxa-
lines 3a-c, yielding 4-chloroimidazoquinoxalines 7a-c exclu-
sively in high yields (Scheme 2). On the other hand, the presence
of electron-releasing 6-methoxy or 6-methyl groups increases
the electron density at the 2-position of the quinoxalines 3d,e,
resulting in the attack of the ethyl isocyanoacetate anion on the
more electrophilic 3,4-NdCsCl bond to give the products
imidazoquinoxalines 8d,e exclusively in excellent yields (Scheme
3). Formation of the products 7g,h from the 7-methoxy- and
7-methylquinoxalines 3g,h can also be explained in a similar
manner. On the other hand, reversal of the regio- and chemose-
lectivity observed in the cycloaddition of 6- and 7-chloro-
substituted quinoxalines 3f and 3i to give 7f and 8i, respectively,
appears to be probably due to predominance of the electron-
withdrawing effect of the chloro group over its +M effect.
In all the reactions of substituted 3-chloro-2-(methylsulfonyl)-
quinoxalines with 1 equiv of ethyl isocyanoacetate, formation
of minor products (2-10%) was observed, which were char-
acterized as the bis(imidazo)quinoxalinedicarboxylates 9a-i on
the basis of their spectral and analytical data. These hitherto
unreported tetracyclic diimidazo[1,5-a:5′,1′-c]quinoxalines 9a-i
were obtained as exclusive products in excellent yields when
the quinoxalines 3a-i were reacted with 2.2 equiv of ethyl
isocyanoacetate for a prolonged time (10-12 h) at room
temperature (Scheme 4).
To further demonstrate the scope and versatility of this pro-
cedure for regiospecific synthesis of unsymmetrically substituted
imidazo[1,5-a]quinoxalines, regioisomeric 4-(cycloamino)- and
4-alkyl/arylimidazo[1,5-a]quinoxalines were synthesized as
shown in Schemes 5 and 6. Thus, the cycloaddition of ethyl
isocyanoacetate (1.1 equiv) to 3-(N-benzylpiperazino)-6-meth-
oxy-2-(methylsulfonyl)- and 3-(N-benzylpiperazino)-6-methyl-
2-(methylsulfonyl)quinoxalines 10d,e under the earlier described
conditions afforded the corresponding 7-substituted 4-(N-
benzylpiperazino)-imidazo[1,5-a]quinoxaline-3-carboxylates 11d
and 11e in excellent yields (Scheme 5). The N-benzylpiperazino-
substituted quinoxalines 10d,e were prepared in good yields by
chemoselective nucleophilic displacement on the corresponding
3-chloro-2-(methylsulfonyl)quinoxalines 3d and 3e. Alterna-
tively, the regioisomeric 4-(N-benzylpiperazino)-8-methoxy- and
5022 J. Org. Chem., Vol. 72, No. 13, 2007

SCHEME 6
dition of activated methyl isocyanides to the -CdN bond of
the quinoxalines. Also the previous methods suffer from several
limitations such as poor regio- and chemoselectivity and air
sensitivity of electron-rich phenylene-1,2-diamine precursors.
Whereas 3-chloro-2-(methylthio)quinoxalines 2a-i undergo
exclusive cycloaddition to the 3,4-NdCsCl bond, in the case
of substituted 3-chloro-2-(methylsulfonyl)quinoxalines 3a-i, the
regio- and chemoselectivity is governed by the nature and
position of the substituent on the benzene ring of quinoxaline.
The cycloaddition of 2 equiv of ethyl isocyanoacetate to both
the 1,2- and 3,4-NdC bonds of 3-chloro-2-(methylsulfonyl)-
quinoxalines affords novel hitherto unreported diimidazo[1,5-
a:5′,1′-c]quinoxalines in excellent yields. The methodology is
also useful for regioselective synthesis of alkyl/aryl- and amino-
substituted imidazo[1,5-a]quinoxalines which can be derivatized
for creating further points of diversity on the quinoxaline
template.
4-(N-benzylpiperazino)-8-methylimidazo[1,5-a]quinoxalines 11g
and 11h could be obtained by direct nucleophilic displacement
of the 4-methylsulfonyl group in the previously synthesized
8-substituted imidazoquinoxaline derivatives 8d and 8e, respec-
tively, by N-benzylpiperazine (Scheme 5).
Finally, the application of our method for the synthesis of
regioisomeric 4-alkyl/aryl-7- or 8-methoxyimidazo[1,5-a]qui-
noxalines 20-23 is depicted in Scheme 6. The desired regioi-
someric 3-alkyl/aryl-6-methoxy-2-(methylsulfonyl)- and 3-alkyl/
aryl-7-methoxy-2-(methylsulfonyl)quinoxalines 16-19 were
prepared by our earlier reported procedure19 via iron-catalyzed
cross-coupling of n-butyl- and (4-methoxyphenyl)magnesium
halides on the quinoxalines 2d and 2g followed by mCPBA
oxidation of the resulting 3-alkyl/aryl-2-(methylthio)quinoxalines
12-15 to the corresponding 2-(methylsulfonyl)quinoxalines
16-19, respectively. Subsequent cycloaddition of ethyl isocy-
anoacetate on 3-alkyl/aryl-6-methoxy-2-(methylsulfonyl)qui-
noxalines 16 and 17 or the corresponding 7-methoxy analogues
18 and 19 furnished the regioisomeric 4-alkyl/arylimidazoquinox-
alines 20 and 21 or 22 and 23 in excellent yields (Scheme 6).
In summary, we have developed a highly regio- and chemose-
lective approach for the synthesis of substituted 3-(carboethoxy)-
imidazo[1,5-a]quinoxalines via base-induced cycloaddition of
ethyl isocyanoacetate to unsymmetrically substituted 3-chloro-
2-(methylthio)/2-(methylsulfonyl)quinoxalines. It should be
noted that the earlier cycloaddition routes to this heterocyclic
template involve reaction of either tosylmethyl or benzyl
isocyanides with the activated 3,4-double bond of N-substituted
quinoxalin-2-ones, furnishing only imidazo[1,5-a]quinoxaline-
4-one derivatives, whereas there is no report of direct cycload-
Exprimental Section
General Procedure for the Base-Induced Cycloaddition
Reaction of Ethyl Isocyanoacetate to 3-Chloro-2-(methylthio)-
quinoxalines 2a-i. An oven-dried 100 mL two-necked flask was
charged with the corresponding 2,3-disubstituted quinoxalines (1.5
mmol), ethyl isocyanoacetate (1.65 mmol), and DMF (10 mL) under
a N2 atmosphere and the solution stirred for 5 min at room
temperature. DBU (3.75 mmol) was added to this stirring solution,
and the resulting mixture was heated at 80 °C for 5 h (monitored
by TLC). It was then cooled and poured into water (100 mL). The
mixture was extracted with chloroform (3 × 50 mL), dried over
anhydrous Na2SO4, concentrated under reduced pressure, adsorbed
onto silica gel, and purified using hexane-EtOAc as the eluent to
give 3-(carboethoxy)imidazo[1,5-a]quinoxalines 5a-i in good
yields.
Acknowledgment. G.S.M.S. thanks IIT Kanpur for senior
research fellowships. Financial assistance under DST and
AstraZeneca Research Foundation, Bangalore project are also
acknowledged.
Supporting Information Available: Additional experimental
procedures and spectral characterization data. This material is
available free of charge via the Internet at http://pubs.acs.org.
JO070590K
J. Org. Chem, Vol. 72, No. 13, 2007 5023