Heteroaromatic annulation of 2-methyl/2-cyanomethylbenzimidazole dianions with α-oxoketene dithioacetals: A highly regioselective synthetic protocol for 1,2-and 2,3-substituted/annulated pyrido[1,2-a]benzimidazoles

Article abstract of DOI:10.1021/jo026786w

A highly efficient and regioselective annulation protocol for a series of linearly 2,3- and angularly 1,2-substituted and annulated pyrido[1,2-α]benzimidazoles involving [3 + 3] cyclocondensation of the dianions generated from 2-methyl (2A) and 2-cyanomet

Full text of DOI:10.1021/jo026786w

Heter oa r om a tic An n u la tion of 2-Meth yl/
2-Cya n om eth ylben zim id a zole Dia n ion s w ith r-Oxok eten e
Dith ioa ceta ls: A High ly Regioselective Syn th etic P r otocol for 1,2-
a n d 2,3-Su bstitu ted /An n u la ted P yr id o[1,2-a ]ben zim id a zoles†
Kausik Panda, J . R. Suresh, H. Ila,* and H. J unjappa*
Department of Chemistry, Indian Institute of Technology, Kanpur 208 016, India
hila@iitk.ac.in
Received November 30, 2002
A highly efficient and regioselective annulation protocol for a series of linearly 2,3- and angularly
1,2-substituted and annulated pyrido[1,2-a]benzimidazoles involving [3 + 3] cyclocondensation of
the dianions generated from 2-methyl (2A) and 2-cyanomethyl (3A) benzimidazoles with a variety
of R-oxoketene dithioacetals has been reported. Thus the dianion 2A derived from 2-methylbenz-
imidazole has been shown to undergo regioselective 1,2-addition with various R-oxoketene
dithioacetals derived from acyclic (4a -d ) and cyclic ketones (13a ,b, 20, 29 and 32) to afford various
carbinol acetals which on intramolecular cyclocondensation in the presence of phosphoric acid
furnish the corresponding 1-methylthio-2,3-substituted (5a -c) and 2,3-fused linear polycyclic (14a ,b,
21, 30, and 33) pyrido[1,2-a]benzimidazoles in high yields. Similarly the dianion 3A from
2-cyanomethylbenzimidazole undergoes one-pot conjugate addition-elimination and cycloconden-
sation with these R-oxoketene dithioacetals to give 4-cyano-3-(methylthio)-1(or 1,2-)-substituted
(6a -d ) and the corresponding angularly 1,2-fused (16a ,b, 23, 31, and 34) polycylic analogues of
pyrido[1,2-a]benzimidazoles in execellent yields.
In tr od u ction
system did not receive much attention until the past
decade5 when some of its derivatives found pharmaceuti-
cal applications.6 Thus many of the pyrido[1,2-a]benz-
imidazolium salts and their 1-azino derivatives are
shown to be intercalating agents,7 whereas structures
such as 1a -c are shown (Scheme 1) to exhibit antipro-
Compounds containing azaindole ring systems have
attracted considerable attention in recent years because
of their promising biological activities and use as impor-
tant building blocks in natural and synthetic bioactive
compounds through their isosterism with indole.1 Among
them, the imidazo[1,2-a]pyridine (IP)2 and related struc-
tures such as imidazo[1,2-a]pyrimidine (IPM),2b imidazo-
[1,2-a]quinoxaline (IQ),3 or imidazo[2,1-a]isoquinoline
(IIQ)4 frameworks have been extensively studied because
of their wide range of pharmacological activities, which
has prompted chemists to develop many synthetically
attractive methods for this class of compounds. In
contrast, the related pyrido[1,2-a]benzimidazole ring
(3) (a) Molina, P.; Alajarin, M.; Vidal. A. J . Org. Chem. 1992, 57,
6703 and references therein. (b) Chavignon, O.; Teulade, J . C.; Roche,
D.; Madesclaire, M.; Blache, Y.; Gueiffier, A.; Chabard, J . L.; Dauphin,
G. J . Org. Chem. 1994, 59, 6413. (c) Chezal, J . M.; Delmas, G.; Mavel,
S.; Elhakmaoui, H.; Metin, J .; Diez, A.; Blache, Y.; Gueiffier, A.;
Rubiralta, M.; Teulade, J . C.; Chavignon, O. J . Org. Chem. 1997, 62,
4085. (d) Takahashi, T.; Shibasaki, J . J . Pharm. Soc. J pn. 1949, 69,
496. (e) Almirante, L.; Mugnaini, A.; De Toma, N.; Murmann, W. Boll.
Chim. Farm. 1971, 110, 322. (f) Rees, C. W.; Smith, D. J . Chem. Soc.,
Perkin Trans. 1 1987, 1159.
(4) (a) Henn, L.; Hickey, D. M. B.; Moody, C. J .; Rees, C. W. J . Chem.
Soc., Perkin Trans. 1 1984, 2189. (b) Hickey, D. M. B.; Moody, C. J .;
Rees, C. W. J . Chem. Soc., Perkin Trans. 1 1986, 1119. (c) Ning, R. Y.;
Blount, J . F.; Madan, P. B.; Fryer, R. I. J . Org. Chem. 1977, 42, 1791.
(d) Takamura, T.; Chiba, T.; Tejima, S. Chem. Pharm. Bull. 1978, 26,
2924. (e) Saint-Ruf, G.; Loukakou, B.; Nzouzi, C. J . Heterocycl. Chem.
1981, 18, 1565. (f) Hashimoto, Y.; Shudo, K.; Okamoto, T. J . Am. Chem.
Soc. 1982, 104, 7637. (g) Bohacek, R.; De Lombaert, S.; McMartin, C.;
Priestle, J .; Grutter, M. J . Am. Chem. Soc. 1996, 118, 8231.
(5) (a) Morgan, G.; Stewart, J . J . Chem. Soc. 1938, 1292. (b) Morgan,
G.; Stewart, J . J Chem. Soc. 1939, 1057.
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Chem. 1991, 28, 497.
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Rodrigo, M. M.; Ballesteros, M.; Alvarez-Builla. J . Biorg. Med. Chem.
Lett. 1995, 5, 3043. (b) Postor, J .; Siro, J . G.; Garcia-Navio, J . L.;
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Pastor, M.; Rodrigo, M. M. J . Org. Chem. 1997, 62, 5476. (c) Feigon,
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† Dedicated to Prof. M. V. George on his 75th birthday.
(1) Chezal, J . M.; Moreau, E.; Delmas, G.; Gueiffier, A.; Blache, Y.;
Grassy, G.; Lartigue, C.; Chavignon, O.; Teulade, J . C. J . Org. Chem.
2001, 66, 6576 and references therein.
(2) (a) Barun, O.; Ila, H.; J unjappa, H.; Singh, O. M. J Org. Chem.
2000, 65, 1583 and references therein. (b) Almirante, L.; Polo, L.;
Mugnaini, A.; Provinciali, E.; Rugarli, P.; Biancotti, A.; Gamba, A.;
Murmann, W. J . Med. Chem. 1965, 8, 305. (c) Yamamoto, T.; Tsuji,
K.; Kosuge, T.; Okamoto, T.; Shudo, K.; Takeda, K.; Itaka, Y.;
Yamaguchi, K.; Seino, Y.; Yahagi, T.; Nagao, M.; Sugimura, T. Proc.
J pn. Acad. B 1978, 54, 248. (d) Davey, D.; Erhardt, P. W.; Lumma, W.
C., J r.; Wiggins, J .; Sullivan, M.; Pang, D.; Cantor, E. J . Med. Chem.
1987, 30, 1337. (e) Kaminski, J . J .; Hilbert, J . M.; Pramanik, B. N.;
Solomon, D. M.; Conn, D. J .; Rizvi, R. K.; Elliott, A. J .; Guzik, H.; Lovey,
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10.1021/jo026786w CCC: $25.00 © 2003 American Chemical Society
Published on Web 03/27/2003
3498
J . Org. Chem. 2003, 68, 3498-3506

Pyrido[1,2-a]benzimidazoles
SCHEME 1
SCHEME 2
liferative activity.8 Some of these compounds also display
interesting photophysical and fluorescent properties.9
While there are many elegant approaches for imidazo-
[1,2-a]pyridine2 and related systems,1-4 the synthetic
routes for pyrido[1,2-a]benzimidazoles are less common,
which in part can be attributed to the difficulty in the
preparation of these heterocycles, often requiring a
lengthy and low yielding synthesis.10
or generality over a wide range of substrates. Therefore
development of new general regiospecific methods for this
class of compounds is highly desirable.
During the course of our heteroaromatic annulation
studies involving [3 + 3] cyclocondensation of R-oxoketene
dithioacetals (1,3-bielectrophilic components) with vari-
ous heteroallyl anions (1,3-binucleophilic components),14we
had the opportunity to explore regiospecific formation of
substituted and annulated pyrido[1,2-a]benzimidazoles
by coupling of these oxoketene dithioacetals with dianions
2A and 3A derived from 2-methyl- or 2-cyanomethylbenz-
imidazoles retrosynthetically depicted in the Scheme 2.
We have demonstrated in our earlier studies that it is
possible to tune up reactivity of ambident heteroallyl
anions derived from various methyl-substituted hetero-
cycles toward R-oxoketene dithioacetals in either a re-
giospecific 1,2-fashion or a conjugate 1,4-addition-
elimination pathway.15 In general the heteroallyl anions
stabilized by an electron-withdrawing group such as
nitrile are shown to add to R-oxoketene dithioacetals
initially in conjugate addition-elimination fashion15a,b,h,i
whereas the corresponding lithiomethyl species gener-
ated by deprotonation of methyl-substituted heterocycles
Assembly of the pyrido[1,2-a]benzimidazole framework
can be accomplished in a variety of ways with several
approaches described in an extensive 1980 review.11 Only
a few new variations have been reported6b,7a,b,12,13 since
then, and to our knowledge, no additional review has
appeared. The most common route to pyrido[1,2-a]ben-
zimidazoles involves ring closure reactions of 1,2,3-
substituted benzimidazole derivatives.10,11 Thus substi-
tuted pyrido[1,2-a]benzimidazoles are formed in low
yields in uncatalyzed thermal reactions of 1,2-alkyl-
substituted benzimidazoles with either methyl propiolate
or dimethyl acetylenedicarboxylate (DMAD).11a Base-
induced cycloannulation of N-unsubstituted benzimida-
zoles having an active methylene substituent (CH2CN)
at the C(2) position with 1,3-dicarbonyl compounds has
been reported to give various substituted pyrido[1,2-a]-
benzimidazoles in moderate to high yields.11a However,
use of unsymmetrically substitued 1,3-dicarbonyl com-
pounds or substituted benzimidazoles in this type of
condensation is complicated by formation of isomeric
mixtures as a result of availability of several modes of
ring closure. The other important approaches make use
of ring closure reactions of pyridine derivatives such as
2-aminopyridine with either o-chloronitrobenzene, p-
benzoquinone, or 2-chlorocyclohexanone yielding substi-
tuted pyrido[1,2-a]benzimidazoles in moderate to high
yields.11a However, all these methods suffer from some
limitations such as low yields, drastic reaction conditions,
(12) Fletcher, N. C.; Abeln, D.; von Zelewsky, A. J . Org. Chem. 1997,
62, 8577.
(13) (a) Alajarin, M.; Vidal, A.; Tovar, F. Tetrahedron Lett. 2000,
41, 7029. (b) Alajarin, M.; Vidal, A.; Tovar, F.; Conesa, C. Tetrahedron
Lett. 1999, 40, 6127.
(14) Review: (a) Ila, H.; J unjappa, H.; Mohanta, P. K. In Progress
in Heterocyclic Chemistry; Gribble, G. W., Gilchrist, T. L., Eds.;
Pergamon Press: Oxford, UK, 2001; Vol. 13, Chapter 1, p 1. (b)
J unjappa, H.; Ila, H.; Patro, B.; Rao, Ch. S. J . Indian Chem Soc. 1994,
71, 501.
(15) (a) Suresh, J . R.; Syam Kumar, U. K.; Ila, H.; J unjappa, H.
Tetrahedron 2001, 57, 781. (b) Suresh, J . R.; Barun, O.; Ila, H.;
J unjappa, H. Tetrahedron 2000, 56, 8153. (c) Barun, O.; Patra, P. K.;
Ila, H.; J unjappa, H. Tetrahedron Lett. 1999, 40, 3797. (d) Basaveswara
Rao, M. V.; Syam Kumar, U. K.; Ila, H.; J unjappa, H. Tetrahedron
1999, 55, 11563. (e) Kishore, K.; Reddy, K. R.; Suresh, J . R.; Ila, H.;
J unjappa, H. Tetrahedron. 1999, 55, 7645. (f) Patra, P. K.; Suresh, J .
R.; Ila, H.; J unjappa, H. Tetrahedron 1998, 54, 10167. (g) Syam Kumar,
U. K.; Patra, P. K.; Ila, H.; J unjappa, H. Tetrahedron Lett. 1998, 39,
2029. (h) Suresh, J . R.; Patra, P. K.; Ila, H.; J unjappa, H. Tetrahedron
1997, 53, 14737. (i) Patra, P. K.; Suresh, J . R.; Ila, H.; J unjappa, H.
Tetrahedron Lett. 1997, 38, 3119. (j) Reddy, K. R.; Roy, A.; Ila, H.;
J unjappa, H. Tetrahedron 1995, 51, 10941. (k) Roy, A.; Nandi, S.; Ila,
H.; J unjappa, H. Org. Lett. 2001, 3, 229. (l) Satyanarayana, J .; Reddy,
K. R.; Ila, H.; J unjappa. H. Tetrahedron Lett. 1992, 33, 6173. (m)
Reddy, K. R.; Ila, H.; J unjappa, H. Synthesis 1995, 929. (n) Balu, M.
P.; Pooranchand, D.; Ila, H.; J unjappa, H. Tetrahedron Lett. 1988, 29,
501. (o) Pooranchand, D.; Satyaranayana, J .; Ila, H.; J unjappa, H.
Synthesis. 1993, 241.
(8) (a) Koenigsmann, M.; Zafferani, M.; Danhauser-Rield, S.; Reuti,
B.; Houlihan, W. J .; Thiel, E.; Berdel, W. E. Cancer Lett. 1992, 67,
145. (b) Brana, M. F.; Castellano, J . M.; Keilhauer, G.; Machuca, A.;
Martin, Y.; Redondo, C.; Schlick, E.; Walker, N. Anticancer Drug Res.
1994, 9, 527.
(9) (a) Bangar, R. B.; Varadarajan, T. S. Appl. Phys. B: Lasers Opt.
1994, B58, 79. (b) Bangar, R. B.; Varadarajan, T. S. Spectrosc. Lett.
1993, 26, 1953.
(10) (a) Knolker, H. J .; Boese, R.; Hitzemann, R. Chem. Ber. 1990,
123, 327. (b) Ohta, S.; Yuasa, T.; Narita, Y.; Kawasaki, I.; Minamii,
E.; Yamashita, M. Heterocycles 1991, 32, 1923. (c) Schaefer, H.; Gruner,
M.; Grossmann, G.; Gewald, K. Monatsh. Chem. 1991, 122, 959.
(11) (a) Tennant, G. In The Chemistry of Heterocyclic Compunds;
Weissberger, A., Taylor, E. C., Eds.; Interscience Publishers: New
York, 1980; Vol. 40, Part 2, p 257. (b) Mosby, W. L. In The Chemistry
of Heterocyclic Compunds; Weissberger, A., Taylor, E. C., Eds.;
Interscience Publishers: New York, 1961; Vol. 15, p 507.
J . Org. Chem, Vol. 68, No. 9, 2003 3499

Panda et al.
SCHEME 3
SCHEME 4
SCHEME 5
were found to be less discriminate, displaying either a
1,2- or a 1,4-addition pattern.14,15 Subsequent acid-
induced (or spontaneous) cycloaromatization of these
adducts leads to formation of either linearly substituted/
annulated (1,2-addition) or angularly substituted/annu-
lated (conjugate addition-elimination) benzoheterocycles
(or bridged azaheterocycles) in highly regiospecific fash-
ion. We therefore envisaged in line with these earlier
studies that it should be possible to develop a general
protocol for regioselective synthesis of either 2,3-substi-
tuted/annulated (5) or the corresponding angularly 1,2-
substituted/fused (6) pyrido[1,2-a]benzimidazoles by cy-
cloannulation of R-oxoketene dithioacetals with respective
2-substituted benzimidazole dianions 2A and 3A as
shown in the Scheme 2. We have successfully achieved
these objectives and report our findings in the present
paper.
established by its Raney-Ni dethiomethylation to afford
sulfur-free compound 8a in 68% yields (Scheme 4). The
corresponding 4-bis(methylthio)-3-buten-2-one (4b) also
underwent 1,2-addition with 2A followed by acid-induced
cyclization of the resulting carbinol acetal 7b under
identical conditions to furnish the corresponding 3-meth-
yl-1-(methylthio)pyrido[1,2-a]benzimidazole (5b) in 70%
yield (Scheme 3). Attempted reductive dethiomethylation
of 5b resulted in concomitant reduction of the pyridine
ring also to give 3-methyl-1,2,3,4-tetrahydropyrido-
[1,2-a]benzimidazole (8b) in 74% yield (Scheme 4).
We next investigated the cycloannulation of dianion
3A derived from 2-cyanomethylbenzimidazole 3 with the
acyclic ketene dithioacetals 4a ,b (Scheme 3). Thus when
4a or 4b was reacted with 3A, workup of the reaction
mixture gave only a single product in both cases, which
Resu lts a n d Discu ssion
Cycloannulation of dianion 2A derived from 2-meth-
ylbenzimidazole 2 with acyclic R-oxoketene dithioacetals
4a -d was first investigated (Schemes 3-5). Dianion 2A
was generated by deprotonation of 2 with BuLi followed
by its reaction with ketene dithioacetal 4a to afford the
carbinol acetal 7a in nearly quantitative yield. When 7a
was subjected to cycloaromatization in the presence of
H3PO4, workup and TLC analysis of the reaction mixture
showed formation of a single product (70%) characterized
as 1-(methylthio)-3-phenylpyrido[1,2-a]benzimidazole (5a)
on the basis of its spectral and analytical data (Scheme
3).The regiochemistry of the product 5a was further
3500 J . Org. Chem., Vol. 68, No. 9, 2003

Pyrido[1,2-a]benzimidazoles
SCHEME 6
were characterized as 4-cyano-1-phenyl(or 1-methyl)-3-
(methylthio)-pyrido[1,2-a]benzimidazoles 6a (76%) and
6b (72%), respectively (Scheme 3). Our attempts to isolate
conjugate adducts 9a ,b under various conditions in the
presence of different bases (NaH, BuLi) were not suc-
cessful. The regiochemistry of one of the products 6a was
established by its acid-induced hydrolysis-decarboxyla-
tion to 10a and also by its Raney-Ni dethiomethylation-
reduction to the product 11a (Scheme 4). The character-
istic spectral feature that distinguished the two regio-
isomers 5a and 10a was the chemical shift of the H-9
proton, which appeared at higher field (δ 6.47, d, J )
only an intractable mixture of products. This may be due
to the presence of a bulkier phenyl group in the carbinol
7d , which sterically inhibits formation of cyclic planar
transition state for cyclization. On the other hand, both
4c and 4d underwent smooth cyclization with dianion
3A yielding 1,2,3,4-tetrasubstituted pyrido[1,2-a]benz-
imidazoles 6c,d in high yields under identical conditions
to those described earlier (Scheme 5).
After successfully achieving and establishing the syn-
thesis of regioselectively substituted pyrido[1,2-a]benz-
imidazoles 5a -c and 6a -d , we next undertook the
synthesis of linearly and angularly fused [1,2-a]pyrido-
benzimidazoles as depicted in Schemes 6-9. Cyclocon-
densation of cyclic R-oxoketene dithioacetals 13a ,b de-
rived from cyclohexanone and cyclopentanone with
dianions 2A and 3A was first investigated (Scheme 6).
Thus the linearly fused 12-(methylthio)-2,3-cyclohexapy-
rido[1,2-a]benzimidazole 14a was obtained in 68% yield
when 13a was reacted with dianion 2A under earlier
described conditions followed by acid-induced cyclization
of the resulting carbinol 13A.17 The product 14a was
converted to the sulfur-free pyrido[1,2-a]benzimidazole
15a by treatment with Raney-Ni. The corresponding 2,3-
cyclopentapyrido[1,2-a]benzimidazole 14b was also ob-
tained from 13b and 2A following the identical conditions
(Scheme 6). Similarly, the one-step cycloannulation of
dianion 3A with 13a and 13b afforded the angularly 1,2-
fused substituted pyrido[1,2-a]benzimidazoles 16a ,b in
66% and 65% yields, respectively (Scheme 6). Reductive
dethiomethylation of one of the products 16a with Raney-
Ni yielded 17a in which the connectivity between the
6-methyl group and the H-5 proton was established by
1
8.5 Hz) in the H NMR spectrum of 10a in comparison
to 5a (δ 8.67, d, J ) 8.6 Hz) presumably due to the
shielding effect of the 1-phenyl group in 10a .16 The
product 10a was further desulfurized to give parent
1-phenylpyrido[1,2-a]benzimidazole (12a ) in 64% yield
(Scheme 4).
The methodology was next extended for the synthesis
of tetrasubstituted pyrido[1,2a]benzimidazoles by sub-
jecting the R-oxoketene dithioacetals 4c,d to cyclocon-
densation with 2A and 3A (Scheme 5). Thus the ketene
dithioacetal 4c from ethylmethyl ketone underwent
smooth 1,2-addition with the dianion 2A followed by
cyclization of the resulting carbinol 7c to afford 2,3-
dimethyl-1-(methylthio)pyrido[1,2-a]benzimidazole 5c in
62% yield. However, the carbinol dithioacetal 7d from
ketene dithioacetal 4d (from propiophenone) failed to
cyclize to the corresponding 2-methyl-3-phenyl derivative
5d under similar conditions or in the presence of other
Lewis and protic acids (BF3‚Et2O, TFA, PTSA) yielding
(16) The 1H NMR spectra of all the newly synthesized 1-phenyl-
pyrido[1,2-a]benzimidazole 6a , 6d , and 11-12a displayed a higher field
shift of the H-9 proton (δ 5.92-6.44) due to the shielding effect of the
1-phenyl group.
(17) All the carbinols obtained by 1,2-addition of anion 2A to various
oxoketene dithioacetals were characterized with the help of 1H and
13C NMR spectral data.
J . Org. Chem, Vol. 68, No. 9, 2003 3501

Panda et al.
SCHEME 7
SCHEME 8
SCHEME 9
pentacyclic pyrido[1,2-a]benzimidazoles 30 and 31 in
good yields on treatment with dianions 2A and 3A,
respectively, under identical conditions (Scheme 8).
Finally, the versatility of this annulation methodology
was evident from the synthesis of planar hexacyclic
pyrido[1,2-a]benzimidazoles 33 and 34 which were ob-
tained in good yields by cycloannulation of anions 2A and
3A with ketenedithioacetal 32 derived from acenaphthen-
1-one (Scheme 9) under the described conditions. The
angularly fused product 34 was subjected to acid-induced
hydrolysis-decarboxylation to provide 35 in 62% yield.
the NOE difference experiment thus confirming the
regiochemical assignments. The product 16a was sub-
jected to acid-induced hydrolysis-decarboxylation to give
18a followed by its Raney-Ni dethiomethylation to afford
19a in 62% yield (Scheme 6).
Further scope of the methodology is demonstrated by
the synthesis of linearly and angularly fused pentacyclic
pyrido[1,2-a]benzimidazoles 21 and 23 by performing
cycloannulation reactions on oxoketene dithioacetal 20
derived from R-tetralone with dianions 2A and 3A,
respectively (Scheme 7). Thus when oxoketene dithioac-
etal 20 was reacted with dianion 2A, the corresponding
carbinol 20A was isolated in 91% yield. Subsequent
cyclization of 20A with H3PO4 under earlier described
conditions afforded the pentacyclic pyrido[1,2-a]benzimi-
dazole 21 in 72% yield. The reaction of 20 with dianion
3A also followed the similar conjugate addition-cycliza-
tion trend affording the corresponding angularly 1,2-
fused pentacyclic pyridobenzimidazole 23 in high yield
under identical conditions. The regiochemistry of the
products 21 and 23 was established by desulfurization
of 21 to 22 and acid-assisted hydrolysis-decarboxylation
of 23 to 24. The product 21 was converted to the linearly
fused parent pentacyclic pyrido[1,2-a]benzimidazoles 26
by subjecting it to successive dehydrogenation (DDQ) and
dethiomethylation with Raney-Ni (Scheme 7). The an-
gularly fused parent pyrido[1,2-a]benzimidazole 28 was
also obtained from 24 following a similar two-step
sequence (Scheme 7). The methodology was also extended
to cyclic ketene dithioacetal 29 available from indanone,
which produced the expected linearly and angularly fused
Con clu sion
In summary, we have demonstrated a highly efficient
and regiospecific annulation protocol for a series of
linearly 2,3- and angularly 1,2-substituted and annulated
pyrido[1,2-a]benzimidazoles involving [3 + 3] cyclocon-
densation of the dianions derived from 2-methyl- (2A) and
2-cyanomethyl- (3A) benzimidazole with a variety of
R-oxoketene dithioacetals via a highly regioselective 1,2-
addition (with 2A) or 1,4-addition-elimination (with 3A)
pathway (Scheme 2). Depending on the structures of
acyclic and cyclic R-oxoketene dithioacetals the methodol-
ogy allows access to a wide range of hitherto unknown
novel planar polycyclic (tetra, penta, hexa) linearly or
angularly fused pyrido[1,2-a]benzimidazole ring systems,
some of which may prove useful as potential DNA
binders. A few of these newly synthesized pyrido[1,2-a]-
benzimidazoles display fluorescent properties which are
under investigation. We are currently studying the
generality of this cycloannulation process for regiospecific
construction of other bridged azaindoles such as pyrido-
[1,2-a]imidazoles and pyrido[1,2-a]pyrroles which will be
published later.
3502 J . Org. Chem., Vol. 68, No. 9, 2003

Pyrido[1,2-a]benzimidazoles
124.6, 125.2 126.0, 127.2, 128.3, 128.6, 135.3, 136.6, 146.6,
151.2; MS (m/z, %) 290 (100), 275 (90).
Exp er im en ta l Section
Gen er a l. 1H (400 MHz) and 13C NMR (100 MHz) spectra
were recorded in CDCl3 and TMS was used as an internal
reference. Melting points are uncorrected. Chromatographic
purification was done by column chromatography, using 60-
120 mesh silica gel obtained from Acme Synthetic Chemicals.
All reactions were monitored by TLC on glass plates coated
with silica gel (Acme) containing 13% calcium sulfate as binder
and visualization was effected with short-wavelength UV light
(254 nm) or acidic KmnO4 solution. THF was dried over sodium
wire with benzophenone and distilled.
Gen er a l P r oced u r e for H3P O4-In d u ced Cycliza t ion
of t h e Ca r b in ols 7a -d : Syn t h esis of 2,3-Su b st it u t ed
(5a -c) a n d 2,3-An n u la ted P yr id o[1,2-a ]ben zim id a zoles
(14a ,b, 21, 30, a n d 33). The crude carbinols (∼8 mmol)
obtained from the earlier reactions were dissolved in H3PO4
(85%, 20 mL) and the solution was heated at 90-100 °C for
4-5 h (monitored by TLC). The reaction mixture was brought
to room temparature, poured into ice-cold water (50 mL) and
extracted with CHCl3 (3 × 50 mL). The combined organic
extracts were washed with water (3 × 50 mL), dried (Na2SO4),
and evaporated to give crude products which were purified by
column chromatography over silica gel with hexanes-EtOAc
(8:2) as eluent.
The chemically pure diisopropylamine, ethanol, H2SO4,
AcOH, ammonia solution, and dioxane were purchased from
standard firms and further dried whenever needed by standard
procedures.
1-(Meth ylth io)-3-ph en ylpyr ido[1,2-a ]ben zim idazole (5a).
Yield 70% (1.62 g); yellow crystals (chloroform-hexane); mp
146 °C; Rf 0.3 (8:2 hexanes-EtOAc); IR (KBr) 3173, 3057,
All the ketones, i.e., acetophenone, propiophenone, acetone,
ethylmethyl ketone, cyclohexanone, and cyclopentanone, re-
quired for the preparation of R-oxoketene dithioacetals were
purchased from the standard firms whereas the R-tetralone,18a
indan-1-one,18b acenaphthene-1-one,18c and 2-methyl-18d and
2-cyanomethylbenzimidazoles18e were prepared according to
the reported procedures. All the known R-oxoketene dithioac-
etals 4a -d , 13a ,b, 20, and 29 and the unknown 32 were
prepared from the appropriate ketones according to our earlier
reported method.18f
1
2985, 1991, 1673 cm-1; H NMR (400 MHz, CDCl3) δ 2.70 (s,
3H, SCH3), 6.92 (d, J ) 1.4 Hz, 1H, ArH), 7.34 (dd, J ) 3.6,
4.4 Hz, 1H, ArH), 7.41-7.54 (m, 4H, ArH), 7.69 (d, J ) 8.2
Hz, 2H, ArH), 7.73 (dd, J ) 0.48, 0.72 Hz, 1H, ArH), 7.94 (d,
J ) 7.5 Hz, 1H, ArH), 8.67 (d, J ) 8.6 Hz, 1H, ArH); 13C NMR
(100 MHz, CDCl3) δ 16.7, 109.7, 111.3, 115.8, 119.3, 120.7,
125.3, 126.9, 128.8, 129.1, 129.9, 138.2, 140.3, 141.4,145.4,
150.0; MS (m/z, %) 290 (M+, 100), 275 (45.6). Anal. Calcd for
3-(Bism eth ylth io)a cen a p h th en e-1-on e (32). Yield 72%;
yellow crystals (chloroform-hexane); mp 78 °C; Rf 0.6 (9:1
C
18H14N2S (290.38): C, 74.45; H, 4.86; N, 9.65. Found: C,
74.28; H, 4.98; N, 9.44.
1
hexanes-EtOAc); IR (KBr) 1676, 1506, 1420, 1362 cm-1; H
3-Met h yl-1-(m et h ylt h io)p yr id o[1,2-a ]b en zim id a zole
(5b). Yield 70% (1.27 g); white crystals (chloroform-hexane);
mp 130 °C; Rf 0.3 (8:2 hexanes-EtOAc); IR (KBr) 3528, 3445,
NMR (400 MHz, CDCl3) δ 2.55 (s, 3H, SCH3), 2.63 (s, 3H,
SCH3), 7.60 (t, J ) 7.36 Hz, 1H, ArH), 7.66 (t, J ) 7.56 Hz,
1H, ArH), 7.76 (d, J ) 8.32 Hz, 1H, ArH), 8.00 (dd, J ) 8.04,
6.84 Hz, 2H, ArH), 8.36 (d, J ) 7.08 Hz, 1H, ArH); 13C NMR
(100 MHz, CDCl3) δ 19.3, 19.4, 121.0, 121.3, 124.5, 127.6,
128.2, 130.3, 130.8, 133.4, 135.0, 137.1, 156.2, 189.4: MS (m/
z, %) 272 (M+, 100), 255 (14.9). Anal. Calcd for C15H12OS2
(272.40): C, 66.14; H, 4.40. Found: C, 66.43; H, 4.21.
1642, 1488, 1451 1323 cm-1 1H NMR (400 MHz, CDC13) δ
;
2.41 (s, 3H, CH3), 2.63 (s, 3H, SCH3), 6.46 (s, 1H, ArH), 7.28
(s, 1H, ArH), 7.29 (t, J ) 8.3 Hz, 1H, ArH), 7.49 (t, J ) 8.0
Hz, 1H, ArH), 7.89 (d, J ) 8.0 Hz, 1H, ArH), 8.62 (d, J ) 8.5
Hz, 1H, ArH); 13C NMR (100 MHz, CDCl3) δ 16.6, 21.5, 112.3,
112.9, 115.7, 119.1, 120.2, 125.1, 130.0, 139. 5, 139.9, 145.0,
150.1; MS (m/z, %) 228 (M+, 5.6), 214 (100). Anal. Calcd for
Gen er a l P r oced u r e for th e Ad d ition of Dia n ion 2A to
R-Oxok eten e Dith ioa ceta ls. To a stirring solution of 2-me-
thylbenzimidazole (1.0 g, 8 mmol) in THF (30 mL) at 0 °C was
added BuLi (15%, 7.5 mL, 20 mmol) under nitrogen atmo-
sphere. The reaction mixture immediately developed a yel-
lowish brown color, indicating the formation of monoanion,
that changed to a curdy white suspension within 5 min
showing the formation of dianion. After further stirring for 1
h, a solution of appropriate ketene dithioacetal (8 mmol) in
THF (15 mL) was added at 0 °C and the reaction mixture was
brought to room temperature and left overnight under stirring
(monitored by TLC). It was then poured into a cold saturated
NH4Cl solution (50 mL) and extracted with CHCl3 (3 × 50 mL),
and the combined organic layer was washed with water (3 ×
50 mL), dried (Na2SO4), and evaporated to give the corre-
sponding carbinols in almost quantitative yields which were
C
13H12N2S (228.31): C, 68.38; H, 5.26; N, 12.26. Found: C,
68.24; H, 5.42; N, 12.59.
12-(Meth ylth io)-1,2,3,4-tetr a h yd r oben zim id a zo[1,2-b]-
isoqu in olin e (14a ). Yield 68% (1.45 g); yellow crystals
(chloroform-hexane); mp 115 °C; Rf 0.3 (8:2 hexanes-EtOAc);
IR (KBr) 3040, 3005, 2937, 2855, 1776 cm-1 1H NMR (400
;
MHz, CDCl3) δ 1.72-1.79 (m, 4H, CH2), 2.29 (s, 3H, SCH3),
2.81 (t, J ) 6.3 Hz, 2H, CH2), 3.02 (t, J ) 6.3 Hz, 2H,CH2),
7.19-7.23 (m, 1H, ArH), 7.35 (s, 1H, ArH), 7.40 (t, J ) 7.8
Hz, 1H, ArH), 7.80 (d, J ) 7.8 Hz, 1H, ArH), 8.92 (d, J ) 8.0
Hz, 1H, ArH); 13C NMR (100 MHz, CDCl3) δ 17.3, 22.0, 23.0,
27.0, 30.2, 116.3, 119.1, 120.4, 124.9, 128.7, 130.2, 132.7, 141.7,
144.9, 148.8, 152.7; MS (m/z, %) 268 (M+, 100), 253 (25.9). Anal.
Calcd for C16H16N2S (268.38): C, 71.60; H, 6.01; N, 10.43.
Found: C, 71.48; H, 6.13; N, 10.40.
1
pure enough to be characterized by H and 13C NMR spectra
5,6-Dih yd r o-7-(m eth ylth io)ben zim id a zo[1,2-b]ben zo[f]-
isoqu in olin e (21). Yield 72% (1.82 g); bright yellow crystals
(chloroform-hexane); mp 161 °C; Rf 0.3 (8:2 hexanes-EtOAc);
and used as such for further transformation. Analytically pure
samples of few carbinols were obtained by column chroma-
tography over silica gel with hexanes-EtOAc (8:2) as eluent.
2-[4-Bis(m et h ylt h io)-2-h yd r oxy-2-p h en ylb u t -3-en e-1-
yl]ben zim id a zole (7a ). Yield 94% (2.67 g); brown crystals
(chloform-hexane); mp 134 °C; Rf 0.3 (9:1 hexanes-EtOAc);
IR (KBr) 3780, 3687, 2833, 1441 cm-1 1H NMR (400 MHz,
;
CDCl3) δ 2.43 (s, 3H, SCH3), 2.94 (t, J ) 7.0 Hz, 2H, CH2),
3.35 (t, J ) 6.6 Hz, 2H, CH2), 7.26-7.38 (m, 4H, ArH), 7.50
(dd, J ) 7.32, 7.08 Hz, 1H, ArH), 7.87 (d, J ) 7.5 Hz, 1H, ArH),
7.93 (d, J ) 8.28 Hz, 1H, ArH), 8.05 (s, 1H, ArH), 9.04 (d, J )
8.56 Hz, 1H, ArH); 13C NMR (100 MHz, CDCl3) δ 18.0, 26.2,
29.1, 112.4, 116.3, 119.5, 121.0, 124.9, 125.1, 127.4, 128.2,
128.4, 129.2, 130.6, 132.2, 132.5, 136.9, 138.2, 145.4, 149.3;
MS (m/z, %) 316 (M+, 100), 301 (15.28). Anal. Calcd for
IR (KBr) 3355, 3161, 2920, 1674, 1582 cm-1 1H NMR (400
;
MHz, CDCl3) δ 2.00 (s, 3H, SCH3), 2.12 (s, 3H, SCH3), 3.37 (d,
J ) 14 Hz, 1H, CH), 3.50 (d, J ) 15.2 Hz, 1H CH), 6.38 (s, 1H,
ArH), 7.19-7.23 (m, 3H, ArH), 7.25-7.32 (m, 2H, ArH), 7.46
(d, J ) 8.0 Hz, 2H, ArH), 7.51-7.53 (m, 2H, ArH); 13C NMR
(100 MHz, CDCI3) δ 16.8, 16.8, 43.9, 114.7, 115.5, 119.0, 122.2,
C
20H16N2S (316.42): C, 75.91; H, 5.09; N, 8.85. Found: C,
75.83; H, 5.05; N, 8.73.
(18) (a) Olson, C. E.; Bader, A. R. Org. Synth. 1955, 35, 95-96. (b)
Arcus, C. L.; Barett, G. C. J . Chem. Soc. 1958, 2740. (c) Fieser, F J .
Am. Chem. Soc. 1940, 62, 432. (d) Vogel, A. I. Textbook of Organic
Chemistry, 5th ed.; ELBS: London, UK, 1988; p 1162. (e) Copeland,
R. A. B.; Day, A. R. J . Org. Chem. 1943, 65, 1072. (f) Chauhan, S. M.
S.; J unjappa, H. Tetrahedron 1976, 32, 1779.
14-(Meth ylth io)ben zim id a zo[1,2-f]flu or a n th en e (33).
Yield 78% (2.11 g); yellow crystals (chloroform-hexane) mp
192 °C; Rf 0.37 (8:2 hexanes-EtOAc); IR (KBr) 3046, 2916,
1746, 1646, 1595, cm-1; 1H NMR (400 MHz, CDCl3) δ 2.44 (s,
3H, SCH3), 7.27 (t, J ) 7.3 Hz, 1H, ArH), 7.42 (t, J ) 7.3 Hz,
J . Org. Chem, Vol. 68, No. 9, 2003 3503

Panda et al.
1H, ArH), 7.47-7.57 (m, 2H, ArH), 7.67 (d, J ) 8.08 Hz, 1H,
ArH), 7.71 (d, J ) 8.08 Hz, 1H, ArH), 7.76 (dd, J ) 8.28, 10.96
Hz, 2H, ArH), 7.88 (s, 1H, ArH), 8.51 (d, J ) 7.5 Hz, 1H, ArH),
8.93 (d, J ) 8.2 Hz, 1H, ArH); 13C NMR (100 MHz, CDCl3) δ
17.8, 109.4, 116.2, 119.6, 119.8, 121.5, 122.8, 125.1, 126.1
127.4, 127.9, 128.4, 130.3, 130.4, 130.8, 131.0, 133.7, 134.4,
136.3, 141.5, 145.5, 149.5; MS (m/z, %) 338 (M+, 65), 323 (72).
Anal. Calcd for C22H14N2S (338.43): C, 78.08; H, 4.16; N, 8.27.
Found: C, 78.05; H, 4.22; N, 8.39.
Gen er a l P r oced u r e for th e Cycliza tion of Dia n ion 3A
w ith R-Oxok eten e Dith ioa ceta ls: Syn th esis of 1,2-Su b-
stitu ted an d An n u lated P yr ido[1,2-a ]ben zim idazole (6a-
d , 16a ,b, 23, 31, a n d 34). To a stirring solution of LDA [8.0
mmol, prepared from diisopropylamine (2.5 mL, 8.0 mmol),
BuLi (15%, 6 mL, 8.0 mmol) in 10 mL of THF] at 0 °C was
added a solution of 2-cyanomethylbenzimidazole (0.5 g, 3.2
mmol) in THF (10 mL) when the reaction mixture indicated
the formation of dianion 3A as a deep red solution. It was
further stirred for 1 h at 0 °C followed by addition of a solution
of oxoketene dithioacetal (3.2 mmol) in THF (15 mL). The
reaction mixture was left for overnight stirring and then
quenched with cold saturated NH4Cl (50 mL) followed by
extraction with CHCl3 (3 × 50 mL). The combined organic
extracts were washed with water (3 × 50 mL), dried (Na2SO4),
and evaporated to give crude pyrido[1,2-a]benzimidazoles as
solids which were further purified by passing through a silica
gel column with hexanes-EtOAc (8:2) as eluent.
7.8 Hz, 1H, ArH), 8.03 (d, J ) 8.3 Hz, 1H, ArH); 13C NMR
(100 MHz, CDCl3) δ 18.9, 25.5, 28.5, 115.0, 115.5, 120.5, 120.8,
125.1, 125.4, 125.9, 126.2, 127.1, 128.0, 128.0, 129.6, 131.2,
138.5, 139.2 145.2, 148.2, 148.6; MS (m/z, %) 341 (M+, 100),
326 (11.65). Anal. Calcd for C21H15N3S (341.43): C, 73.87; H,
4.42; N, 12.30. Found: C, 73.74; H, 4.50; N, 12.53.
8-Cya n o-7-(m e t h ylt h io)b e n zim id a zo[1,2-e]flu or a n -
th en e (34). Yield 75% (0.87 g); red crystals (chloroform-
hexane); mp 165 °C; Rf 0.35 (8:2 hexanes-EtOAc); IR (KBr)
3233, 3055, 2218, 1556 cm-1 1H NMR (400 MHz, CDCl3) δ
;
2.82 (s, 3H, SCH3), 7.41 (dd, J ) 7.0, 8.2 Hz, 1H, ArH), 7.53-
7.60 (m, 2H, ArH), 7.65 (t, J ) 7.3 Hz, 1H, ArH), 7.80 (d, J )
8.2 Hz, 1H, ArH), 7.98 (d, J ) 8.0 Hz, 1H, ArH), 8.03 (d, J )
7.8 Hz, 1H, ArH), 8.50 (d, J ) 8.5 Hz, 1H, ArH), 8.58 (d, J )
7.8 Hz, 1H, ArH), 8.64 (d, J ) 7.3 Hz, 1H, ArH); 13C NMR
(100 MHz, CDCl3): δ 19.7, 113.8, 114.9, 115.2, 120.8, 121.8,
123.1, 126.0, 126.5, 126.9, 127.0, 127.5, 127.9, 128.5, 129.0,
129.4, 131.9, 132.4, 135.6, 140.4, 145.0, 145.6, 148.4; MS (m/
z, %) 364 (M+, 100). Anal. Calcd for C23H13N3S (363.44): C,
76.01; H, 3.60; N, 11.56. Found: C, 76.11; H, 3.51; N, 11.33.
Gen er a l P r oced u r e for Ra n ey-Ni Deth iom eth yla tion -
Red u ction of P yr id o[1,2-a ]ben zim id a zoles 5a ,b, 6a , 14a ,
16a , a n d 21. To an ethanolic solution (20 mL) of appropriate
pyrido[1,2-a]benzimidazole (5 mmol) was added Raney-Ni (W2)
(∼3 g) and the suspension was refluxed with stirring for 6-7
h (monitored by TLC). It was then filtered through a sintered
glass funneland washed with hot ethanol and the filtrate was
concentrated to afford viscous residue, which was purified by
column chromatography over silica gel with hexanes-ethyl
acetate (8:2) as eluent.
4-Cya n o-3-(m eth ylth io)-1-p h en ylp yr id o[1,2-a ]ben zim i-
d a zole (6a ). Yield 76% (0.76 g); yellow crystals (chloroform-
hexane); mp 248 °C; Rf 0.25 (8:2 hexanes-EtOAc); IR (KBr)
3613, 3590, 2214, 1588 cm-1 1H NMR (400 MHz, CDCl3) δ
;
3-P h en ylp yr id o[1,2-a ]ben zim id a zole (8a ). Yield 68%
(0.83 g); yellow crystals (chloroform-hexane); mp 175 °C; Rf
0.25 (8:2 hexanes-EtOAc); IR (KBr) 3432, 3240, 3023, 1680,
2.67 (s, 3H, SCH3), 6.44 (d, J ) 8.5 Hz, 1H, ArH), 6.58 (s, 1H,
ArH), 6.96 (dd, J ) 8.28, 1.2 Hz, 1H, ArH), 7.40 (t, J ) 8.3
Hz, 1H, ArH), 7.58-7.60 (m, 2H, ArH), 7.63-7.73 (m, 3H,
ArH), 7.89 (d, J ) 8.2 Hz, 1H, ArH); 13C NMR (100 MHz,
CDCl3) δ 15.2, 95.2, 108.2, 113.8, 114.2, 120.0, 121.3, 126.0,
126.2, 128.4, 129.3, 131.0, 132.7, 144.1, 145.1, 147.3, 151.4;
MS (m/z, %) 315 (M+, 100). Anal. Calcd for C19H13N3S
(315.30): C, 72.37; H, 4.15; N, 13.32. Found: C, 72.13; H, 4.32;
N, 13.55.
1
1643 cm-1; H NMR (400 MHz, CDCl3) δ 7.16 (dd, J ) 7.08,
0.96, Hz, 1H, ArH), 7.30 (t, 6.8 Hz, 1H, ArH), 7.32(t, J ) 7.8
Hz, 1H, ArH), 7.39 (d, J ) 7.3 Hz, 1H, ArH), 7.43-7.50 (m,
3H, ArH), 7.65 (d, J ) 7.5 Hz, 1H, ArH), 7.90 (s, 1H, ArH),
7.91 (d, J ) 8.8 Hz, 1H, ArH), 7.94 (d, J ) 8.0 Hz, 1H, ArH),
8.45 (d, J ) 7.3 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 110.3,
110.5, 114.2, 119.6, 121.1, 125.0, 125.8, 126.7, 126.9, 126.9,
128.9, 129.1, 138.2, 142.4, 148.8; MS (m/z, %) 244 (M+, 100).
Anal. Calcd for C17H12N2 (244.36): C, 83.58; H, 4.95; N, 11.46.
Found: C, 83.44; H, 4.94; N, 11.58.
4-Cya n o-1-m eth yl-3-(m eth ylth io)p yr id o[1,2-a ]ben zim i-
d a zole (6b). Yield 70% (0.56 g); yellow crystals (chloroform-
hexane); mp 258 °C; Rf 0.3 (8:2 hexanes-EtOAc); IR (KBr)
3452, 2214, 1623, 1476, 1517 cm-1; 1H NMR (400 MHz, CDCl3)
δ 2.66 (s, 3H, CH3), 3.04 (s, 3H, SCH3), 6.47 (s, 1H, ArH), 7.31
(t, J ) 7.3 Hz, 1H, ArH), 7.52 (t, J ) 7.5 Hz, 1H, ArH), 7.95
(d, J ) 8.2 Hz, 2H, ArH); 13C NMR (100 MHz, CDCl3) δ 15.1,
21.7, 105.7, 107.1, 113.9, 114.3, 120.0, 121.8, 126.2, 129.8,
142.8, 145.1, 148.0, 151.6; MS (m/z, %) 253 (M+, 100), 207 (2.3).
Anal. Calcd for C14H11N3S (253.33): C, 66.37; H, 4.40; N, 16.58.
Found: C, 66.13; H, 4.33; N, 16.65.
4-Met h yl-l-p h en ylp yr id o[1,2-a ]b en zim id a zole (11a ).
Yield 60% (0.77 g); yellow low melting solid; Rf 0.25 (8:2
hexanes-EtOAc); IR (CCl4) 3038, 2921, 2854, 1740, 1696 cm-1
;
1H NMR (400 MHz, CDCl3) δ 2.68 (s, 3H, CH3), 6.50 (d, J )
8.5 Hz, 1H, ArH), 6.53 (d, J ) 6.8 Hz, 1H, ArH), 6.88 (dd, J )
7.5, 8.28 Hz, 1H, ArH), 7.21 (d, J ) 6.8 Hz, 1H, ArH), 7.28-
7.34 (m, 1H, ArH), 7.44-7.54 (m, 5H, ArH), 7.89 (dd, J ) 0.52,
8.3 Hz, 1H, ArH); 13C NMR (100 MHz, CDCl3) δ 17.6, 112.1,
114.6, 119.6, 120.3, 124.9, 125.9, 126.2, 127.7, 129.1, 129.6,
129.8, 134.5, 138.9, 144.3, 149.7; MS (m/z, %) 258 (M+, 100),
243 (15). Anal. Calcd for C18H14N2 (258.32): C, 83.69; H, 5.46;
N, 10.84. Found: C, 83.76; H, 5.48; N, 10.62.
6-Cyan o-5-(m eth ylth io)-1,2,3,4-tetr ah ydr oben zim idazo-
[1,2-a ]qu in olin e (16a ). Yield 66% (0.61 g); yellow crystals
(chloroform-hexane); mp 235 °C; Rf 0.3 (8:2 hexanes-EtOAc);
1
IR (KBr) 3710, 2932, 2360, 2337, 2218, 1550 cm-1; H NMR
(400 MHz, CDCl3) δ 1.92-1.96 (m, 2H, CH2), 2.04-2.10 (m,
2H, CH2), 2.83 (s, 3H, SCH3), 2.87 (t, J ) 6.1 Hz, 2H, CH2),
3.43 (t, J ) 6.3 Hz, 2H, CH2), 7.31 (t, J ) 8.0 Hz, 1H, ArH),
7.52 (t, J ) 7.8 Hz, 1H, ArH), 7.99 (d, J ) 8.3 Hz, 1H, ArH),
8.05 (d, J ) 8.2 Hz, 1H, ArH); 13C NMR (100 MHz, CDCl3) δ
18.8, 21.6, 26.3, 29.0, 125.8, 107.7, 109.8, 115.3, 119.6, 120.3,
120.3, 121.5, 125.8, 125.8, 141.3, 145.0, 145.0; MS (m/z %) 293
(M+, 100), 278 (11.7). Anal. Calcd for C17H15N3S (293.39): C,
69.59; H, 5.15; N, 14.32. Found: C, 69.75; H, 5.19; N, 14.13.
1,2,3,4-Tetr ah ydr oben zim idazo[1,2-b]isoqu in olin e (15a).
Yield 67% (0.74 g); yellow crystals (chloroform-hexane); mp
152 °C; Rf 0.2 (8:2 hexanes-EtOAc); IR (KBr) 3207, 3042,
1
2940, 1700, 1600 cm-1; H NMR (400 MHz, CDCl3) δ 1.84 (s,
4H, CH2 ), 2.82 (s, 2H, CH2), 2.90 (s, 2H, CH2), 7.26 (t, J ) 7.8
Hz, 1H, ArH), 7.34 (s, 1H, ArH), 7.46 (t, J ) 7.3 Hz, 1H, ArH),
7.78 (d, J ) 8 Hz, 1H, ArH), 7.86(d, J ) 8.0 Hz, 1H, ArH),
8.11(s, 1H, ArH); 13C NMR (100 MHz, CDCl3) δ 22.4, 22.6, 26.3,
29.5, 110.1, 114.7, 119.2, 119.9, 121.3, 121.9, 125.1, 128.3,
142.3, 144.6, 148.4; MS (m/z, %) 222 (M+, 100%). Anal. Calcd
for C15H14N2 (222.29): C, 81.05; H, 6.34; N, 12.60. Found: C,
81.14; H, 6.30; N, 12.53.
8-Cya n o-5,6-d ih yd r o-7-(m eth ylth io)ben zim id a zo[1,2-a ]-
ben zo[h ]qu in olin e (23). Yield 76% (0.83 g); orange crystals
(cloroform-hexane); mp 300 °C; Rf 0.32 (8:2 hexanes-EtOAc);
1
IR (KBr) 3647, 3611, 3043, 2223, 1480, 1443 cm-1; H NMR
6-Meth yl-1,2,3,4-tetr a h yd r oben zim id a zo[1,2-a ]qu in o-
lin e (17a ). Yield 54% (0.63 g); yellow low melting solid; Rf 0.2
(8:2 hexanes-EtOAc); IR (CCl4) 2945, 2865, 2739, 1682, 1642
(400 MHz, CDCl3) δ 2.56 (t, J ) 6.4 Hz, 1H, CH2), 2.81 (s, 3H,
SCH3), 2.96 (t, J ) 6.4 Hz, 2H, CH2), 3.47 (d, J ) 15.8 Hz, 1H,
CH2), 7.15-7.19 (m, 1H, ArH), 7.29-7.37 (m, 1H, ArH), 7.43-
7.52 (m, 3H, ArH), 7.73 (d, J ) 8.5 Hz, 1H, ArH), 7.91 (d, J )
1
cm-1; H NMR (400 MHz, CDCl3) δ 1.80-1.86 (m, 2H, CH2),
1.98-2.04 (m, 2H, CH2), 2.67 (s, 3H, CH3), 2.75 (t, J ) 6.1 Hz,
3504 J . Org. Chem., Vol. 68, No. 9, 2003

Pyrido[1,2-a]benzimidazoles
2H, CH2), 3.35 (t, J ) 6.3 Hz, 2H, CH2), 7.08 (s, 1H, ArH),
7.25 (t, J ) 8.2 Hz, 1H, ArH), 7.46 (dd, J ) 7.3, 8.0 Hz, 1H,
ArH), 8.03 (d, J ) 8.5 Hz, 1H, ArH), 8.09 (d, J ) 8.5 Hz, 1H,
ArH); 13C NMR (100 MHz, CDCl3) δ 17.3, 21.5, 22.3, 27.8, 28.0,
115.5, 118.4, 121.4, 122.9, 125.7, 128.6, 129.6, 133.0, 135.6,
143.1, 153.7; MS (m/z, %) 236 (M+, 100), 221 (35). Anal. Calcd
for C16H16N2 (236.31): C, 81.31; H, 6.82; N, 11.85. Found: C,
81.40; H, 6.70; N, 11.67.
16.3). Anal. Calcd for C20H16N2S (316.42): C, 75.91; H, 5.09;
N, 8.85. Found: C, 75.73; H, 5.16; N, 8.93.
Red u ctive Deth iom eth yla tion of 10a , 18a , a n d 24 w ith
Ra n ey-Ni. Reductive dethiomethylation were carried out as
reported earlier.
1-P h en ylp yr id o[1,2-a ]ben zim id a zole (12a ). Yield 58%
(1.09 g); yellow low melting solid; Rf 0.2 (8:2 hexanes-EtOAc);
IR (CCl4) 3056, 2927, 1686, 1642, 1599 cm-1 1H NMR (400
;
MHz, CDCl3) δ 6.49 (d, J ) 8.5 Hz, 1H, ArH), 6.59 (d, J ) 6.8
Hz, 1H, ArH), 7.33 (dd, J ) 7.08, 8.04 Hz, 1H, ArH), 7.39 (dd,
J ) 6.84, 9.28 Hz, 1H, ArH), 7.45-7.58 (m, 5H, ArH), 7.64 (d,
J ) 9.0 Hz, 1H, ArH), 7.82 (d, J ) 8.3 Hz, 1H, ArH); 13C NMR
(100 MHz, CDCl3) δ 112.1, 114.1, 116.7, 119.5, 120.3, 125.1,
128.0, 128.9, 129.0, 129.2, 130.0, 134.3, 141.2, 144.6, 149.3;
MS (m/z, %) 244 (M+, 98), 243 (100). Anal. Calcd for C17H12N2
(244.30): C, 83.58; H, 4.95; N, 11.46. Found: C, 83.75; H, 4.73;
N, 11.38.
5,6-Dih yd r ob en zim id a zo[1,2-b]b en zo[f]isoq u in olin e
(22). Yield 66% (0.89 g); yellow crystals (chloroform-hexane);
mp 133-134 °C; Rf 0.2 (8:2 hexanes-EtOAc); IR (KBr) 3417,
3053, 2852, 1698, 1627 cm-1 1H NMR (400 MHz, CDCl3) δ
;
2.75 (s, 2H, CH2), 2.85 (s, 2H, CH2), 7.07 (t, J ) 8.0 Hz, 1H,
ArH), 7.23-7.26 (m, 2H, ArH), 7.29-7.32 (m, 1H, ArH), 7.32
(s, 1H, ArH), 7.39 (t, J ) 7.3 Hz, 1H, ArH), 7.55 (d, J ) 9.2
Hz, 1H, ArH), 7.80 (d, J ) 8.5 Hz, 1H, ArH), 7.87 (s, 1H, ArH),
7.87 (t, J ) 6.8 Hz, 1H, ArH); 13C NMR (100 MHz, CDCl3) δ
27.8, 28.8, 115.7, 116.8, 119.4, 119.7, 124.3, 124.5, 125.1, 125.7,
127.9, 128.1, 129.3, 129.8, 130.9, 132.4, 135.3, 138.2, 144.5;
MS (m/z, %) 270 (M+, 71.2). Anal. Calcd for C19H14N2
(270.33): C, 84.41; H, 5.21; N, 10.36. Found: C, 84.28; H, 5.34;
N, 10.49.
1,2,3,4-Tetr a h yd r oben zim id a zo[1,2-a ]qu in olin e (19a ).
Yield 62% (0.68 g); yellow low melting solid; Rf 0.2 (8:2
hexanes-EtOAc); IR (CCl4) 3052, 2935, 2860, 2308, 1734 cm-1
;
1H NMR (400 MHz, CDCl3) δ 1.78-1.84 (m, 2H, CH2), 1.96-
2.02 (m, 2H, CH2), 2.74 (t, J ) 6.1 Hz, 2H, CH2), 3.32 (t, J )
6.3 Hz, 2H, CH2), 7.13 (d, J ) 9.2 Hz, 1H, ArH), 7.20 (t, J )
8.0 Hz, 1H, ArH), 7.41 (t, J ) 7.3 Hz, 1H, ArH), 7.48 (d, J )
9.2 Hz, 1H, ArH), 7.85 (d, J ) 8.1 Hz, 1H, ArH), 8.06 (d, J )
8.56 Hz, 1H, ArH); 13C NMR (100 MHz, CDCl3) δ 21.6, 22.3,
28.0, 29.6, 114.4, 115.3, 119.2, 119.3, 120.4, 124.8, 129.8,132.8,
137.5, 144.1, 148.4; MS (m/z; %) 222 (M+, 100), 194 (85). Anal.
Calcd for C15H14N2 (222.28): C, 81.04; H, 6.34; N, 12.60.
Found: C, 81.13; H, 6.22; N, 12.53.
Gen er a l P r oced u r e for Acid -In d u ced Hyd r olysis-
Deca r boxyla tion of P yr id o[1,2-a ]ben zim id a zoles 6a , 16a ,
23, a n d 34: Syn th esis of 10a , 18a , 24, a n d 35. A suspension
of cyano-substituted pyrido[1,2-a]benzimidazole (5 mmol) in
water (5 mL), AcOH (5 mL), and concentrated H2SO4 (5 mL)
was refluxed with stirring at 180 °C for 8 h (monitored by
TLC). It was then cooled, poured into ice-cold water (25 mL),
neutralized with saturated NaHCO3 solution, and extracted
with CHCl3 (3 × 50 mL). The combined organic layer was dried
(Na2SO4) and evaporated to give crude viscous residue that
was purified by column chromatography over silica gel with
hexanes-EtOAc (8:2) as eluent to give the pure product.
5,6-Dih yd r op yr id oben zim id a zo[1,2-a ]ben zo[h ]qu in o-
lin e (27). Yield 58% (0.48 g); brown crystals (chloroform-
hexane); mp 162 °C; Rf 0.4 (8:2 hexanes-EtOAc); IR (KBr)
2960, 2930, 2860, 2359, 1728 cm-1; 1H NMR (400 MHz, CDCl3)
δ 2.80 (t, J ) 8.0 Hz, 2H, CH2), 2.99 (t, J ) 8.0 Hz, 2H, CH2),
7.22-7.28 (m, 1H, ArH), 7.47 (t, J ) 8.8 Hz, 1H, ArH), 7.60-
7.68 (m, 3H, ArH), 7.82 (d, J ) 8.5 Hz, 2H, ArH), 7.92 (d, J )
8.5 Hz, 1H, ArH), 8.23 (d, J ) 7.3 Hz, 2H, ArH); 13C NMR
(100 MHz, CDCl3) δ 19.2, 27.7, 105.3, 109.5, 116.7, 120.4,
120.5, 121.2, 124.4, 127.5, 127.9, 128.4, 128.7, 128.7, 130.3,
131.0, 133.7, 135.9, 152.2; MS (m/z, %) 270 (M+, 100), 269 (80).
Anal. Calcd for C19H14N2 (270.33): C, 84.41; H, 5.21; N, 10.36.
Found: C, 84.27; H, 5.34; N, 10.51.
Gen er a l P r oced u r e for Deh yd r ogen a tion of 21 a n d 27
w ith DDQ. To a solution of either 21 or 27 (0.25 g, 0.8 mmol)
in dry dioxane (25 mL) was added DDQ (0.5 g, 2.4 mmol) and
the reaction mixture was stirred with refluxing for 5 h
(monitored by TLC). The dioxan was removed under reduced
pressure and the residue was dissolved in CHCl3 (50 mL). The
CHCl3 solution was washed with water (3 × 50 mL), dried
(Na2SO4), and evaporated to give crude residue that was
purified by column chromatography over silica gel with hex-
anes-EtOAc (7:3) as eluent to give pure 25 and 28.
3-(Met h ylt h io)-1-p h en ylp yr id o[1,2-a ]b en zim id a zole
(10a ). Yield 62% (0.90 g); light yellow crystals (chloroform-
hexane); mp 170 °C; Rf 0.2 (8:2 hexanes-EtOAC); IR (KBr)
3451, 2982, 2924, 1693 cm-1 1H NMR (400 MHz, CDCl3) δ
;
2.61 (s, 3H, SCH3), 6.47 (d, J ) 8.5 Hz, 1H, ArH), 6.53 (d, J )
1.4 Hz, 1H, ArH), 6.92 (t, J ) 8.2 Hz, 1H, ArH), 7.37 (t, J )
7.5 Hz, 1H, ArH), 7.40 (d, J ) 1.9 Hz, 1H, ArH), 7.52-7.66
(m, 5H, ArH), 7.83 (d, J ) 8.28 Hz, 1H, ArH); 13C NMR (100
MHz, CDCl3) δ 14.5, 108.1, 111.8,111.9, 114.1, 118.9, 120.2,
125.1, 128.9, 129.1, 130.2, 133.6, 139.9, 143.3, 144.5, 149.6;
MS (m/z, %) 290 (M+, 100). Anal. Calcd for C18H14N2S
(290.38): C, 74.45; H, 4.85; N, 9.64. Found: C, 74.32; H, 4.98;
N, 9.68.
5-(Met h ylt h io)-1,2,3,4-t et r a h yd r ob en zim id a zo[1,2-a ]-
qu in olin e (18a ). Yield 68% (0.91 g); yellow crystals (chloro-
form-hexane); mp 168 °C; Rf 0.2 (8:2 hexanes-EtOAc); IR
(KBr) 3438, 3265, 2856, 1993, 1735 cm-1; 1H NMR (400 MHz,
CDCl3) δ 1.88-1.94 (m, 2H, CH2), 2.01-2.07 (m, 2H, CH2),
2.54 (s, 3H, SCH3), 2.71 (t, J ) 6.12 Hz, 2H, CH2), 3.38 (t, J )
6.12 Hz, 2H, CH2), 7.22 (t, J ) 7.56 Hz, 1H, ArH), 7.26 (s, 1H,
ArH), 7.45 (t, J ) 7.32 Hz, 1H, ArH), 7.86 (d, J ) 8.28 Hz, 1H,
ArH), 8.05 (d, J ) 8.28 Hz, 1H, ArH); 13C NMR (100 MHz,
CDCl3) δ 14.4, 21.6, 21.9, 24.8, 28.2, 106.4, 115.0, 117.1, 119.0,
119.8, 124.6, 129.8, 136.5, 145.0, 148.7, 154.2; MS (m/z; %) 268
(M+, 7.0), 266 (75). Anal. Calcd for C16H16N2S (268.37): C,
71.60; H, 6.01; N, 10.44. Found: C, 71.41, H, 6.12; N, 10.52.
7-(Me t h ylt h io)b e n zim id a zo[1,2-b]b e n zo[f]isoq u in o-
lin e (25). Yield 48% ( 0.41 g); yellow low melting solid; Rf 0.4
(8:2 hexanes-EtOAc); IR (CCl4) 3047, 2919, 2849, 1733, 1589
1
cm-1; H NMR (400 MHz, CDCl3) δ 2.77 (s, 3H, SCH3), 7.56
(t, J ) 7.5 Hz, 1H, ArH), 7.66-7.70 (m, 2H, ArH), 7.79 (t, J )
6.8 Hz, 1H, ArH), 7.97 (d, J ) 8.0 Hz, 1H, ArH), 8.02 (s, 1H,
ArH), 8.03 (d, J ) 8.0 Hz, 1H, ArH), 8.11 (d, J ) 7.5 Hz, 1H,
ArH), 8.41 (d, J ) 6.8 Hz, 1H, ArH), 8.67 (d, J ) 8.0 Hz, 1H,
ArH), 8.73 (d, J ) 8.0 Hz, 1H, ArH); 13C NMR (100 MHz,
CDCl3) δ 18.8, 118.8, 121.1, 124.8, 126.1, 126.3, 126.4, 126.6,
126.7, 127.7, 128.4, 129.1, 129.6, 130.2, 133.6, 134.8, 136.0,
137.0, 137.9, 140.9; MS (m/z, %) 314 (M+, 100). Anal. Calcd
for C20H14N2S (314.42): C, 75.91; H, 5.06; N, 8.85. Found: C,
75.82; H, 5.15; N, 8.72.
5,6-Dih yd r o-7-(m et h ylt h io)b en zim id a zo[1,2-a ]b en zo-
[h ]qu in olin e (24). Yield 55% (0.87 g); yellow crystals (chlo-
roform-hexane); mp 225 °C; Rf 0.3 (8:2 hexanes-EtOAc); IR
(KBr) 3552, 3061, 2360, 1708, 1614, 1570 cm-1; 1H NMR (400
MHz, CDCl3) δ 2.23-2.40 (m, 2H, CH2), 2.52 (s, 3H, SCH3),
2.85 (s, 2H, CH2), 7.02 (t, J ) 8.0 Hz, 1H, ArH), 7.27 (s, 1H,
ArH), 7.30-7.38 (m, 4H, ArH), 7.67 (d, J ) 8.3 Hz, 1H, ArH),
7.80 (d, J ) 8.5 Hz, 1H, ArH), 7.82 (d, J ) 7.8 Hz, 1H, ArH);
13C NMR (100 MHz, CDCl3) δ 14.6, 24.3, 28.5, 108.2, 108.3,
115.5, 115.9, 119.2, 123.0, 124.8, 125.0, 125.6, 127.8, 129.5,
131.4, 134.3, 136.3, 138.0, 143.9, 144.4; MS (m/z, %) 316 (M+,
Ben zim id a zo[1,2-a ]ben zo[h ]qu in olin e (28). Yield 55%
(0.56 g); yellow crystals; mp 151 °C; Rf 0.5 (8:2 hexanes-
EtOAc); IR (CCl4) 3056, 2923, 2854, 1641, 1598 cm-1; 1H NMR
(400 MHz, CDCl3) δ 7.24-7.27 (m, 1H, ArH), 7.49 (t, J ) 6.3
Hz, 1H, ArH), 7.63-7.70 (m, 4H, ArH), 7.85 (d, J ) 8.8 Hz,
J . Org. Chem, Vol. 68, No. 9, 2003 3505

Panda et al.
2H, ArH), 7.95 (d, J ) 8.8 Hz, 2H, ArH), 8.27 (d, J ) 8.8 Hz,
2H, ArH); 13C NMR (100 MHz, CDCl3) δ 109.1, 109.6, 116.8,
120.3, 120.5, 120.6, 120.6, 121.3, 127.5, 127.9, 128.4, 128.6,
128.6, 128.7, 128.8, 130.4, 131.1, 133.8, 135.1; MS (m/z, %) 268
(M+, 100). Anal. Calcd for C19H12N2 (268.38): C, 71.60; H, 6.01;
N, 10.43. Found: C, 71.58; H, 6.11; N, 10.31.
NMR (100 MHz, CDCl3) δ 105.4, 109.1, 109.5, 116.8, 120.3,
120.5, 120.6, 121.3, 127.5, 127.9, 128.4, 128.6, 128.6, 128.7,
128.8, 130.4, 131.1, 131.1, 133.8; MS (m/z, %) 268 (M+, 100).
Anal. Calcd for C19H12N2 (268.38): C, 71.60; H, 6.01; N, 10.43.
Found: C, 71.67; H, 6.04; N, 10.31.
Red u ctive Deth iom eth yla tion of 25 to 26 w ith Ra n ey-
Ni. Reductive dethiomethylation was carried out as reported
earlier.
Ack n ow led gm en t. K.P. and J .R.S. thank CSIR
New Delhi for a Senior Research Fellowship. Financial
assistance under DST is also acknowledged.
Ben zim id a zo[1,2-b]ben zo[f]isoqu in olin e (26). Yield 53%
(0.43 g); yellow crystals (chloroform-hexane); mp 155 °C; Rf
0.3 (8:2 hexanes-EtOAc); IR (CCl4) 3048, 2849, 2681, 1734,
Su p p or tin g In for m a tion Ava ila ble: Characterization
data of products 7b, 7d , 20A, 5c, 14b, 30, 6c, 6d , 16b, 31, 8b,
and 35 and NOE for products 11a and 17a . This material is
available free of charge via the Internet at http://pubs.acs.org.
1
1508 cm-1; H NMR (400 MHz, CDCl3) δ 7.35 (d, J ) 6.3 Hz,
1H, ArH), 7.39-7.48 (m, 4H, ArH), 7.55 (t, J ) 7.0 Hz, 1H,
ArH), 7.67 (d, J ) 7.0 Hz, 2H, ArH), 7.93 (t, J ) 7.8 Hz, 2H,
ArH), 8.11 (s, 1H, ArH), 8.61 (d, J ) 6.8 Hz, 1H, ArH); 13C
J O026786W
3506 J . Org. Chem., Vol. 68, No. 9, 2003