A facile access to 2-methylthio/alkoxy/amino-3-acylimidazo[1,2- a]pyridines based on cupric chloride promoted oxidative ring closure of α- oxoketene N,S-, N,O-, and N,N-acetals

Full text of DOI:10.1021/jo9916129

J . Org. Chem. 2000, 65, 1583-1587
1583
shown to be critically dependent on the nature of sub-
stituents at 2 and 3 positions.2,11a Thus there is a definite
need to develop a more structurally flexible method for
the synthesis of this class of compounds.
A F a cile Access to 2-Meth ylth io/Alk oxy/
Am in o-3-a cylim id a zo[1,2-a ]p yr id in es Ba sed
on Cu p r ic Ch lor id e P r om oted Oxid a tive
Rin g Closu r e of r-Oxok eten e N,S-, N,O-,
a n d N,N-Aceta ls
The most common approach for the synthesis of imi-
dazo[1,2-a]pyridines involves construction of imidazole
ring on suitably substituted pyridine precursors such as
2-aminopyridines12-14 (Tschitschibabin reaction), 2-halo-
1-phenacyl/alkyl pyridinium salts,15-17 pyridinium azome-
thine ylides,18 and other derivatives.18b,19,20 Approaches
based on the use of substituted imidazoles as starting
materials to construct the imidazopyridine nucleus have
also been described.3,21,22 However, most of these methods
suffer from drawbacks such as low yields, difficult
starting materials involving tedious work up procedure,
lengthy sequences, and lack of generality for incorpora-
tion of desired substituent in the imidazopyridine nucleus.
Therefore reactions involving direct electrophilic substi-
tution or Ullmann coupling on an imidazopyridine ring
have been developed recently for regiospecific introduc-
tion of acyl,23 aryl, and alkylthio groups24 which have
been recognized for their distinguishing features in
structure-activity relationship studies. During the course
of our continued interest on the synthetic application of
polarized ketene dithioacetals,25 we have recently de-
scribed the synthesis of novel (2-pyridylamino)-N,S- and
N,N-acetals via conjugate displacement on various R-oxo-
ketene dithioacetals by 2-(lithioamino)pyridine.26 Ready
availability of these N,S- and N,N-acetals and current
increasing interest in the synthesis of imidazo[1,2-a]-
pyridine derivatives for structure-activity studies
prompted us to investigate a new methodology for imi-
dazole annulation by intramolecular ring closure of these
intermediates. We herein describe a facile route to
3-aroylimidazo[1,2-a]pyridines with a range of function-
Okram Barun, H. Ila,* and H. J unjappa*
Department of Chemistry, Indian Institute of Technology,
Kanpur-208016, India
Okram Mukherjee Singh
Department of Chemistry, North-Eastern Hill University,
Shillong-793003, Meghalaya, India
Received October 15, 1999
Synthesis of imidazo[1,2-a]pyridines and their ana-
logues has attracted significant attention in recent years
as this class of compounds exhibit a broad range of
pharmacological activity.1-10 Substituted imidazo[1,2-a]-
pyridines have been recently identified as a new genera-
tion of potential antiviral agents in place of structurally
related benzimidazole derivatives, such as Enviroxime,
which failed as antiviral drugs in clinical trials because
of their poor bioavailability and undesirable side effects.11
The pharmacological profile of imidazo[1,2-a]pyridines is
* To whom correspondence should be addressed. E-mail:
hila@iitk.ac.in. Fax: 91-0512-597436, 91-0512-590260.
(1) (a) Montgomery, J . A.; Secrist, A. A. In Comprehensive Hetero-
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Chapter 4.10, p 607. (b) Mosby, W. L. In Chemistry of Heterocyclic
Compounds; Weissberger, A., Taylor, E. C., Eds.; Vol. 15, p 460,
Interscience Publishers: New York, 1961. (c) Gueiffer, A.; Viols, H.;
Blache, Y.; Chavignon, O.; Teulade, J . C.; Aumelas, A.; Chapat, J . P.
Heterocycles 1994, 38, 55.
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1992, 35, 3353 and references therein. (b) Yamanaka, M.; Miyake, K.;
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1997, 40, 3109-3118.
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Chem. 1990, 27, 1821.
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1999, 55, 541-548.
(25) (a) Kishore, K.; Reddy, K. R.; Suresh, J . R.; Ila, H.; J unjappa,
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H.; J unjappa, H. Tetrahedron Lett. 1999, 40, 3797-3800.
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1 1997, 3561.
10.1021/jo9916129 CCC: $19.00 © 2000 American Chemical Society
Published on Web 02/05/2000

1584 J . Org. Chem., Vol. 65, No. 5, 2000
Notes
Sch em e 1
Sch em e 3
Sch em e 2
Sch em e 4
3-aroylimidazo[1,2-a]pyridines 7c-f in high yields. A few
of the 2-methylthio derivatives (7a and 7c) were sub-
jected to reductive dethiomethylation in the presence of
Raney nickel to furnish the corresponding 2-unsubsti-
tuted-3-aroyl derivatives 10a and 10c in high yields. The
oxidative cyclization was found to be equally facile for
the corresponding N,O- and N,N-acetals derived from
secondary amines to yield the corresponding 2-methoxy-
(8c,d ) and 2-(N-cycloamino)-3-aroylimidazo[1,2-a]pyri-
dines (9a ,b) (Scheme 3). The N,N-acetals (3a -d , 6a ,b)
derived from primary amines also underwent smooth
cyclization under the identical conditions without forma-
tion of any side products yielding the respective 2-(2-
pyridylamino)- (11a -d ) or 2-anilino- (12a ,b) 3-aroylimi-
dazo[1,2-a]pyridines in 69-78% overall yields (Scheme
4). Interestingly, 3-aroyl-2-(2-pyridylamino)imidazo[1,2-
a]pyridines 11a -c underwent facile cyclodehydration in
the presence of boron trifluoride etherate to give novel
tetracyclic heteroaromatic salts 13a -c in which positive
charge is delocalized over two bridgehead nitrogen atoms.
Such compounds are potential DNA intercalators.27
alities at 2 position through an unusual cupric chloride
assisted oxidative ring closure of R-oxoketene N,S-, N,N-,
and N,O-acetals.
The desired N,S- (2a -f) and N,N-acetals (3a -d ) were
prepared in high yields according to our earlier reported
procedure,26 by displacement reaction on R-oxoketene S,S-
acetals (1a -f) with either 1 or 2 equiv of 2-(lithioamino)-
pyridine (Scheme 1). The N,S-acetals 2c and 2d under-
went facile displacement with sodium methoxide in
methanol to afford the corresponding N,O-acetals 4c and
4d in good yields. Similarly the mixed N,N-aminals 5a ,b
and 6a ,b derived from 2-aminopyridine and the respec-
tive cyclic secondary amines or aniline were synthesized
in good yields via direct displacement reactions on
oxoketene N,S-acetals 2a ,b by the corresponding lithio
derivatives of secondary amines or aniline (Scheme 2).
The reaction provides a useful procedure for the synthesis
of mixed N,N-aminals.
Our earlier attempts to cyclize 2a with a range of
oxidizing agents (K3FeCN6, MnO2, HgO, LTA, etc.) did
not meet with much success. However, when 2a was
refluxed with cupric chloride in THF (4 h), product
analysis showed formation of only one product character-
ized as 2-(methylthio)-3-benzoylimidazo[1,2-a]pyridine 7a
on the basis of spectral and analytical data. The other
substituted N,S-acetals (2c-f) also underwent facile ring
closure under these conditions to afford 2-(methylthio)-
The possible mechanism for the formation of imidazo-
[1,2-a]pyridines from N,S-, N,O-, or N,N-acetals is de-
picted in Scheme 6. Cupric chloride induced oxidative
(27) (a) Molina, A.; Vaquero, J . J .; Garcia-Navio, J . L.; Alvarez-
Builla, J .; de Pascual-Teresa, B.; Gago, F.; Rodrigo, M. M.; Ballesteros,
M. J . Org. Chem. 1996, 61, 5587. (b) Alvarez-Builla, J .; Gago, F.; de
Pascual-Teresa, B.; Pastor, M.; Rodrigo, M. M. J . Org. Chem. 1997,
62, 5476.

Notes
J . Org. Chem., Vol. 65, No. 5, 2000 1585
Sch em e 5
In summary, an efficient method for the synthesis of
biologically important 2,3-functionalized imidazo[1,2-a]-
pyridines has been described via an unprecedented
CuCl2-induced oxidative ring closure of novel R-oxoketene
N,S-, N,O-, and N,N-acetal intermediates. The methodol-
ogy allows regiospecific introduction of alkylthio, alkoxy,
primary, and secondary amino group in the 2-position of
imidazopyridine ring. These functionalities can be further
elaborated to construct novel fused heterocyclic ring
systems. The other advantages include mild reaction
conditions and easy accessibility of N,S-, N,O-, and N,N-
acetals, which can be prepared with large structural
variations from various aminoheterocycles, thus broad-
ening the scope of this methodology for the synthesis of
diverse class of bridgehead nitrogen heterocycles.
Sch em e 6
Exp er im en ta l Section
Gen er a l. n-Butyllithium (2.5 M in hexane) was purchased
from Aldrich Chemical Co. Cu(II)Cl2 (AR grade, moisture free)
and BF3‚Et2O were purchased from E-Merck India. Benzene (AR
grade) was purchased from Glaxo and used directly. Tetrahy-
drofuran (THF) was distilled twice over sodium/benzophenone
and stored on sodium wire before use. Unless otherwise stated
all reagents were purchased from local commercial sources and
used without purification.
All the R-oxoketene N,S- (2a -f) and N,N- (3a -d ) acetals were
prepared according to our reported26 procedure by reacting
2-(lithioamino)pyridine with corresponding R-oxoketenedithio-
acetals.
1-(4-Meth ylp h en yl)-3,3-bis-(2-p yr id yla m in o)p r op -2-en -1-
1
on e (3b): light yellow crystals; mp 102-103 °C; H NMR (400
MHz, CDCl3) δ 2.35 (s, 3H), 6.79-6.82 (m, 1H), 6.88-6.93 (m,
2H), 7.01 (d, 1H, J ) 8.0 Hz), 7.17 (s, 1H), 7.20 (d, 2H, J ) 8.4
Hz), 7.50-7.58 (m, 2H), 7.85 (d, 2H, J ) 8.4 Hz), 8.12-8.13 (m,
1H), 8.38-8.40 (m, 1H), 12.98 (brs, 1H), 14.59 (brs, 1H); 13C
NMR (CDCl3) δ 21.0, 80.4, 113.5, 114.8, 117.0, 118.2, 126.6,
128.5, 137.3, 137.6, 138.1, 140.4, 145.4, 148.0, 151.9, 154.1, 155.4,
180.6; IR (KBr) 3450, 1640, 1600, 1585, 1545 cm-1; MS m/z (%)
330 (M+, 56). Anal. Calcd for C20H18N4O: C, 72.71; H, 5.49; N,
16.96. Found: C, 72.96; H, 5.28; N, 16. 85.
1-(4-Ch lor op h en yl)-3,3-bis-(2-p yr id yla m in o)p r op -2-en -1-
on e (3c): yellow crystals; mp 111-112 °C; 1H NMR (400 MHz,
CDCl3) δ 6.95-6.98 (m, 1H), 7.01-7.06 (m, 2H), 7.13 (s, 1H),
7.14 (d, 1H, J ) 8.2 Hz), 7.38 (d, 2H, J ) 8.4 Hz), 7.66-7.73 (m,
2H), 7.85 (d, 2H, J ) 8.0 Hz), 8.25 (d, 1H, J ) 4.8 Hz), 8.48 (d,
1H, J ) 4.4 Hz), 13.12 (brs, 1H), 14.54 (brs, 1H); 13C NMR
(CDCl3) δ 80.7, 114.3, 115.6, 117.7, 119.0, 128.4, 136.5, 137.9,
138.8, 139.2, 145.9, 148.6, 152.2, 154.6, 156.4, 185.8; IR (KBr)
3400, 1655, 1610, 1580, 1540 cm-1; MS m/z (%) 350 (M+, 60).
Anal. Calcd for C19H15ClN4O: C, 65.05; H, 4.31, N, 15.97.
Found: C, 65.25; H, 4.21; N, 15.67.
Gen er a l P r oced u r e for th e P r ep a r a tion of N,O-Aceta ls
(4c,d ). To a stirred solution of methanolic sodium methoxide
(prepared from 0.46 g of Na metal in 15 mL of dry methanol, 15
mmol) was added the respective N,S-acetal (10 mmol) dissolved
in 15 mL of dry methanol, and the reaction mixture was stirred
at room temperature for 10 min, followed by refluxing for 2 h.
It was cooled to room temperature, quenched with saturated
NH4Cl solution, and extracted with chloroform. The combined
extracts were washed with water, dried (Na2SO4), and evapo-
rated to give the crude N,O-acetals, which were purified by
column chromatrography over silica gel using hexane/ethyl
acetate (9:1) as eluent.
abstraction of hydrogen via cation radical intermediate
14 may give resonance stabilized aminyl radical 15 which
undergoes facile intramolecular addition to the enamine
double bond followed by abstraction of a hydrogen radical
or proton to give the final product. Alternatively, electron
transfer from nitrogen to Cu(II) ion may take place in
the coordination sphere of initially formed copper complex
of type 17 to give metal-complexed aminyl radical inter-
mediate 1828 which on subsequent intramolecular cy-
clization may afford imidazo[1,2-a]pyridines (Scheme 6).
Cuprous and cupric salts in the presence of oxygen and
pyridine or amines are known to act as useful oxidizing
systems for cleavage of hydrazides,29 bishydrazone,30
o-phenylenediamine,31 and for dimerization of aromatic
amines.32 We are further exploring the mechanism of this
novel oxidative cyclization with CuCl2 and its application
for construction of other fused heterocycles.
(28) (a) Esker, J . L.; Newcomb, M. Adv. Heterocycl. Chem. 1993, 58,
1. (b) Falles, A. G.; Bniuza, I. M. Tetrahedron 1997, 53, 17543-17594
and references therein. (c) Baslable, J . W.; Hobson, J . D.; Ridell, W.
D. J . Chem. Soc., Perkin Trans. 1 1972, 2205. (d) Broka, C. A.; Eng,
K. K. J . Org. Chem. 1986, 51, 5043.
1-(4-Ch lor op h en yl)-3-m eth oxy-3-(2-p yr id yla m in o)p r op -
2-en -1-on e (4c): light yellow crystals; mp 137-138 °C; 1H NMR
(400 MHz, CDCl3) δ 3.90 (s, 3H), 5.60 (s, 1H), 6.90 (m,1H), 7.40
(d, 2H, J ) 9.0 Hz), 7.50-7.75 (m, 2H), 7.95 (d, 2H, J ) 9.0 Hz),
8.35 (dd, 1H, J ) 6.9, 1.8 Hz), 14.56 (brs, 1H); 13C NMR (CDCl3)
δ 46.5, 90.6, 114.5, 118.5, 128.5, 128.6, 137.3, 138.0, 138.4, 146.0,
152.2, 166.6, 184.5; IR (KBr) 3417, 1617, 1589, 1213; MS m/z
(%): 288 (M+, 80); Anal. Calcd for C15H13ClN2O2: C, 62.39; H,
4.53; N, 9.70. Found: C, 62.45; H, 4.42; N 9.61.
(29) Tsuji, J .; Nagashima, T.; Qui, N. T.; Takayanagi, H. Tetrahe-
dron 1980, 36, 1311-1315.
(30) Tsuji, J .; Takahashi, H.; Kajimoto, T. Tetrahedron Lett. 1973,
4573-4574.
(31) (a) Tsuji, J .; Takayanagi, H.; Toshida, Y. Chem. Lett. 1976, 147-
148. (b) Kajimoto, T.; Takahashi, H.; Tsuji, J . J . Org. Chem. 1976, 41,
1389-1393.
(32) (a) Kajimoto, T.; Takahashi, H.; Tsuji, J . Bull. Chem. Soc. J pn.
1982, 55, 3673. (b) J ackisch, J .; Legler, J .; Kauffmann, T. Chem. Ber.
1982, 115, 659.

1586 J . Org. Chem., Vol. 65, No. 5, 2000
Notes
3-Meth oxy-1-(4-m eth oxyph en yl)-3-(2-pyr idylam in o)pr op-
2-en -1-on e (4d ): light yellow crystals; mp 130-131 °C; 1H NMR
(400 MHz, CDCl3) δ 3.63 (s, 3H), 3.91 (s, 3H), 5.30 (s, 1H), 6.70
(m, 1H,), 7.10-7.50 (m, 4H), 7.80-8.15 (m, 3H,), 8.35 (dd, 1H,
J ) 6.9, 1.5 Hz), 14.0 (brs, 1H); 13C NMR (CDCl3) δ 46.4, 55.8,
87.6, 113.8, 113.9, 119.8, 129.0, 130.6, 131.0, 138.2, 147.8, 151.2,
162.0, 193.1; IR(KBr) 3458, 1627, 1599, 1339 cm-1; MS m/z (%)
284 (M+, 100). Anal. Calcd for C16H16N2O3: C, 70.85; H, 5.55;
N, 11.02. Found: C, 70.65; H, 5.60; N, 11.12.
Gen er a l P r oced u r e for th e P r ep a r a tion of Mixed N,N-
Am in a ls (5a ,b, 6a ,b). To a stirred solution of aniline (0.91 mL,
10 mmol) in dry THF (20 mL) was added n-butyllithium (15
mmol) under nitrogen atmosphere, over a period of 20 min at
room temperature (25 °C). The reaction mixture was stirred for
30 min at the same temperature, and the lithiation was indicated
by the appearance of reddish brown color. A solution of N,S-
acetal (10 mmol) in dry THF (25 mL) was added, and the
reaction mixture was refluxed for 4 h. It was then brought to
room temperature, poured into saturated aq NH4Cl solution, and
extracted with chloroform. The combined extracts were washed
with water, dried (Na2SO4), and evaporated to give crude
products which were purified by passing through a silica gel
column using ethyl acetate/hexane (1:9) as eluent.
through silica gel column using hexane/ethyl acetate (9:1) as
eluent, to afford pure imidazo[1,2-a]pyridines in high yields. The
analytical and spectral data for the purified compounds are
reported below:
3-Ben zoyl-2-(m eth ylth io)im idazo[1,2-a ]pyr idin e (7a): col-
orless crystals; mp 140-141 °C, lit.19a mp 139 °C; 1H NMR (300
MHz, CDCl3) δ 2.53 (s, 3H), 6.99 (ddd, 1H, J ) 6.9, 6.6, 0.9 Hz),
7.45 (dd, 1H, J ) 6.9, 0.9 Hz), 7.48-7.51 (m, 3H), 7.53-7.60 (m,
2H), 7.66 (dt, 1H, J ) 9.0, 0.9 Hz), 9.52 (dt, 1H, J ) 6.6, 0.9
Hz); 13C NMR (75.5 MHz, CDCl3) δ 14.8, 114.1, 115.7, 120.2,
128.2, 128.5, 128.6, 129.6, 131.5, 139.8, 148.0, 154.0, 185.5; IR
(KBr) 1627, 1590, 1224; MS m/z (%) 268 (M+, 25.3), 267 (M+
1, 100). Anal. Calcd for C15H12N2OS: C, 67.15; H, 4.51; N, 10.44.
Found: C, 67.34; H, 4.45; N, 10.55.
-
3-(4-Ch lor ob en zoyl)-2-(m et h ylt h io)im id a zo[1,2-a ]p yr i-
d in e (7c): colorless crystals; mp 152 °C; 1H NMR (300 MHz,
CDCl3) δ 2.55 (s, 3H), 7.05 (ddd, 1H, J ) 9.6, 6.9, 1.1 Hz), 7.47
(ddd, 1H, J ) 9.6, 6.9, 1.1 Hz), 7.50 (d, 2H, J ) 9.0 Hz), 7.61 (d,
2H, J ) 9.0 Hz), 7.66 (dt, 1H, J ) 9.6, 1.1 Hz), 9.53 (dt, 1H, J )
6.6, 1.1 Hz); 13C NMR (75.5 MHz, CDCl3) δ 14.8, 114.4, 115.8,
119.8, 128.6, 129.0, 129.7, 129.9, 137.9, 138.1, 148.1, 156.1, 184.1;
IR (KBr) 1670, 1627, 1599, 1221; MS m/z (%) 303 (M+, 100), 288
(M+ - 15, 14.40), 270 (M+ - 33, 51). Anal. Calcd for C15H11N2-
OCl: C, 59.5; H, 3.62; N, 9.21. Found: C, 59.63; H, 3.55; N, 9.33.
1-P h en yl-3-(1-p ip er id in o)-3-(2-p yr id yla m in o)p r op -2-en -
1-on e (5a ): yellow crystals; mp 117-118 °C; 1H NMR (400 MHz,
CDCl3) δ 1.58-1.60 (m, 2H), 1.73-1.79 (m, 4H), 3.05 (t, 4H, J
) 4.0 Hz), 5.45 (s, 1H), 7.01-7.03 (m, 1H), 7.13 (d, 1H, J ) 7.8
Hz), 7.35-7.39 (m, 3H), 7.41-7.45 (m, 1H), 7.77-7.81 (m, 2H),
8.40-8.44 (m, 1H), 12.71 (brs, 1H). 13C NMR (CDCl3) δ 23.8,
26.8, 55.1, 83.2, 115.0, 119.5, 127.8, 128.2, 130.4, 137.5, 140.8,
3-(4-Meth oxyben zoyl)-2-(m eth ylth io)im id a zo[1,2-a ]p yr i-
d in e (7d ): colorless crystals; mp 141 °C; 1H NMR (300 MHz,
CDCl3) δ 2.56 (s, 3H), 3.88 (s, 3H), 6.98 (ddd, 1H, J ) 6.8, 6.5,
0.9 Hz), 7.01 (d, 2H, J ) 9.0 Hz), 7.44 (ddd, 1H, J ) 9.6, 6.8, 0.9
Hz), 7.62 (dt, 1H, J ) 9.6, 0.9 Hz), 7.70 (d, 2H, J ) 9.0 Hz), 9.41
(dt, 1H, J ) 6.5, 0.9 Hz); 13C NMR (75.5 MHz, CDCl3) δ 15.0,
55.4, 113.8, 113.9, 115.8, 120.4, 128.3, 129.2, 130.8, 132.4, 147.8,
154.5, 162.8, 184.7; IR (KBr) 1670, 1604, 1339, 1222 cm-1; MS
m/z (%) 298 (M+, 19.7), 297 (M+ - 1, 100). Anal. Calcd for
147.8, 153.4, 160.1, 189.0; IR (KBr) 3405, 1605, 1560, 1490 cm-1
;
MS m/z (%) 307 (M+, 80). Anal. Calcd for C19H21N3O: C, 74.24;
H, 6.88; N, 13.67. Found: C, 74.45; H, 6.68; N, 13.88.
3-(4-Mor p h olin o)-1-p h en yl-3-(2-p yr id yla m in o)p r op -2-en -
1-on e (5b): light yellow crystals; mp 140-141 °C; 1H NMR (500
MHz, CDCl3) δ 3.36-3.38 (m, 4H), 3.80-3.81(m, 4H), 5.56 (s,
1H), 6.91-6.94 (m, 1H,), 7.10 (d, 1H, J ) 8.0 Hz), 7.40-7.46
(m, 3H), 7.60-7.63 (m, 1H), 7.81-7.87 (m, 2H), 8.31-8.33 (m,
1H), 12.62 (brs, 1H); 13C NMR (CDCl3) δ 48.6, 66.1, 82.5, 114.0,
118.2, 127.0, 128.2, 130.4, 138.0, 141.0, 148.5, 153.8, 160.6, 188.3;
IR (KBr) 3451, 1619, 1536, 1521, 1490 cm-1; HRMS m/z M+ calcd
C
16H14N2O2S: C, 64.41; H, 4.60; N, 9.39. Found: C, 64.60; H,
4.45; N, 9.48.
3-(2-F u r o y l)-2-(m e t h y lt h io )im id a zo [1,2-a ]p y r id in e
(7e): colorless crystals; mp 141-142 °C; 1H NMR (300 MHz,
CDCl3) δ 2.64 (s, 3H), 6.60 (dd, 1H, J ) 4.0, 2.0 Hz), 6.98 (ddd,
1H, J ) 6.9, 6.7, 1.1 Hz), 7.32 (d, 1H, J ) 4.0 Hz), 7.44 (ddd,
1H, J ) 9.6, 6.9, 1.1 Hz), 7.62 (dt, 1H, J ) 9.6, 1.1 Hz), 7.69 (d,
1H, J ) 3.0 Hz), 9.26 (dt, 1H, J ) 6.7, 1.1 Hz); 13C NMR (75.5
MHz, CDCl3) δ 15.0, 112.2, 114.1, 115.9, 118.2, 120.2, 128.1,
129.3, 146.2, 147.9, 151.6, 154.0, 171.9; IR (KBr) 1687, 1627,
1606, 1232 cm-1; MS m/z (%) 258 (M+, 100), 243 (M+ - 15, 21.8).
Anal. Calcd for C13H10N2O2S: C, 60.45; H, 3.90; N, 10.84.
Found: C, 60.56; H, 3.73; N, 10.90.
for
C18H19O2N3 309.147, found 309.146. Anal. Calcd. for
C18H19N3O2: C, 69.88; H, 6.19; N, 13.58. Found: C, 69.97; H,
5.95; N, 13.75.
3-An ilin o-1-p h en yl-3-(2-p yr id yla m in o)p r op -2-en -1-on e
(6a ): colorless crystals; mp 123-124 °C; 1H NMR (400 MHz,
CDCl3) δ 5.66 (s, 1H), 6.92-6.95 (m, 1H), 7.03 (d, 1H, J ) 8.5
Hz), 7.25-7.39 (m, 7H), 7.43-7.46 (m, 2H), 7.67 (dd, 1H, J )
7.3, 1.5 Hz), 7.74 (dd, 1H, J ) 4.8, 1.2 Hz), 8.19 (d, 1H, J ) 5.4
Hz), 12.19 (brs, 1H), 13.36 (brs, 1H); 13C NMR (CDCl3) δ 78.1,
114.2, 117.5, 125.7, 126.3, 126.7, 128.1, 129.5, 130.2, 137.4, 138.6,
141.0, 145.9, 154.8, 159.2, 185.7; IR (KBr) 3410, 1658, 1550, 1458
cm-1; MS m/z (%) 315 (M+, 58). Anal. Calcd for C20H17N3O: C,
76.17, H, 5.43; N, 13.32. Found: C, 76.33; H, 5.21; N, 13.88.
3-An ilin o-1-(4-m eth ylp h en yl)-3-(2-p yr id yla m in o)p r op -2-
en -1-on e (6b): yellow crystals; mp 111-112 °C; 1H NMR (400
MHz, CDCl3) δ 2.40 (s, 3H), 5.66 (s, 1H), 6.90-6.96 (m, 1H),
7.02 (d, 1H, J ) 8.4 Hz), 7.14 (d, 2H, J ) 7.5 Hz), 7.25-7.29 (m,
1H), 7.37 (d, 2H, J ) 8.0 Hz), 7.41-7.45 (m, 2H), 7.64-7.66 (m,
3H), 8.18 (d, 1H, J ) 8.0 Hz), 12.16 (brs, 1H), 13.13 (brs, 1H);
13C NMR (CDCl3) 21.3, 114.06, 117.4, 125.6, 126.1, 126.6, 128.8,
129.4, 137.4, 138.1, 138.5, 140.4, 145.9, 154.8, 159.0, 185.9; IR
(KBr) 3400, 1654, 1554, 1448, 1404 cm-1; MS m/z (%): 329 (M+,
65). Anal. Calcd for C21H19N3O: C, 76.57; H, 5.81; N, 12.75.
Found: C, 76.44; H, 5.69; N, 12.58.
Gen er a l P r oced u r e for Oxid a tive Cycliza tion of N,S-,
N,N-, a n d N,O- Aceta ls to Im id a zo[1,2-a ]p yr id in es. To a
stirred solution of respective N,S-, N,O-, or N,N-acetal (10 mmol)
in dry tetrahydrofuran (30 mL) was added anhydrous Cu(II)Cl2
(2.02 g, 15 mmol), and the reaction mixture was refluxed with
stirring for 3-4 h (monitored by TLC). The initial pale green
color of the reaction mixture faded away, and after 3 h it
gradually turned reddish brown. The reaction mixture after
cooling was poured into water and filtered to remove insoluble
impurities. The filtrate was extracted with chloroform, and the
organic layer was washed with water, dried (Na2SO4), and
evaporated to give crude viscous residue which was passed
2-(Me t h ylt h io)-3-(2-t h ie n oyl)im id a zo[1,2-a ]p yr id in e
(7f): light yellow crystals; mp 152-153 °C; 1H NMR (300 MHz,
CDCl3) δ 2.60 (s, 3H), 6.98 (ddd, 1H, J ) 6.9, 6.7, 1.1 Hz), 7.15
(dd, 1H, J ) 4.9, 3.8 Hz), 7.45 (ddd, 1H, J ) 9.2, 6.9, 1.1 Hz),
7.63 (dt, 1H, J ) 9.2, 1.2 Hz), 7.70 (dd, 1H, J ) 4.3, 1.2 Hz),
7.77 (dd, 1H, J ) 4.3, 1.2 Hz), 9.29 (dt, 1H, J ) 6.9, 1.1 Hz); 13
C
NMR (75.5 MHz, CDCl3) δ 15.1, 114.1, 115.8, 120.4, 127.4, 128.2,
129.3, 132.7, 133.0, 142.8, 147.9, 154.2, 177.4; IR (KBr) 1670,
1649, 1583, 1236 cm-1; MS m/z (%) 274 (M+, 100), 259 (M+
-
15, 13.9), 241 (M+ - 33, 84.4). Anal. Calcd for C13H10N2OS2: C,
56.91; H, 3.67; N, 10.21. Found: C, 56.80; H, 3.75; N, 11.65.
3-(4-Ch lor ob en zoyl)-2-m et h oxyim id a zo[1,2-a ]p yr id in e
(8c): yellow crystals; mp 156 °C; 1H NMR (400 MHz, CDCl3) δ
3.97 (s, 3H), 7.04 (ddd, 1H, J ) 6.9, 6.6, 1.1 Hz), 7.39 (d, 2H, J
) 9.0 Hz), 7.45-7.54 (m, 2H), 7.65 (d, 2H, J ) 9.0 Hz), 9.68 (dt,
1H, J ) 6.6, 1.1 Hz); 13C NMR (100 MHz, CDCl3) δ 56.0, 114.1,
115.4, 127.7, 129.0, 129.5, 130.0, 137.2, 137.9, 144.8, 163.3, 182.4;
IR (KBr) 1600, 1559, 1402, 1226 cm-1; MS m/z (%) 286 (M+, 100).
Anal. Calcd for C15H11N2O2Cl: C, 62.84; H, 3.87; N, 9.77.
Found: C, 62.78; H, 3.79; N, 9.95.
2-Me t h oxy-3-(4-m e t h oxyb e n zoyl)im id a zo[1,2-a ]p yr i-
d in e (8d ): white crystals; mp 109-110 °C; 1H NMR (300 MHz,
CDCl3) δ 3.88 (s, 3H), 4.01 (s, 3H), 6.95 (d, 2H, J ) 8.1 Hz), 7.04
(t, 1H, J ) 6.0 Hz), 7.47 (t, 1H, J ) 8.0 Hz), 7.55 (d, 1H, J ) 8.4
Hz), 7.77 (d, 2H, J ) 8.4 Hz), 9.65 (d, 1H, J ) 6.5 Hz); 13C NMR
(75.5 MHz, CDCl3) δ 55.3, 56.1, 112.9, 113.0, 114.1, 115.4, 128.9,
129.3, 131.0, 132.0, 144.7, 162.3, 162.9, 183.2; IR (KBr) 1605,
1556, 1406 cm-1; MS m/z (%) 282 (M+, 100). Anal. Calcd for
C16H14N2O3: C, 68.07; H, 5.00; N, 9.92. Found: C, 68.25; H, 4.89;
N, 10.01.

Notes
J . Org. Chem., Vol. 65, No. 5, 2000 1587
3-Ben zoyl-2-(1-p ip er id in o)im id a zo[1,2-a ]p yr id in e (9a ):
yellow crystals; mp 134-135 °C; H NMR (500 MHz, CDCl3) δ
1545, 1430, 1415 cm-1; MS m/z (%) 327 (M+, 100). Anal. Calcd
for C21H17N3O: C, 77.04; H, 5.23; N, 12.84. Found: C, 77.21; H,
5.21; N, 12.97.
1
1.14-1.18 (m, 4H), 1.33-1.38 (m, 2H), 3.11-3.13 (m, 4H), 6.92-
6.94 (m, 1H) 7.40-7.46 (m, 3H), 7.49-7.52 (m, 2H), 7.78(d, 2H,
J ) 7.5 Hz), 9.58 (d, 1H, J ) 5 Hz); 13C NMR (100 MHz, CDCl3)
δ 24.0, 24.9, 52.6, 109.7, 113.2, 114.9, 128.1, 128.3, 128.9, 129.4,
Gen er a l P r oced u r e for Ra n ey Nick el Deth iom eth yla -
tion of 7 to 10. To a stirred solution of 3-aroyl-2-(methylthio)-
imidazo[1,2-a]pyridines (7a or 7c) (2.5 mmol) in ethanol (25 mL)
was added Raney nickel (W2, three times by weight), and the
reaction mixture was refluxed with stirring for 6 h (monitored
by TLC). It was then filtered through a sintered glass funnel
and washed with ethanol (10 mL), and the filtrate was evapo-
rated under reduced pressure. The residue thus obtained was
diluted with chloroform, washed with water, dried (Na2SO4), and
evaporated to give crude products which were purified by passing
through silica gel column using hexane/ethyl acetate (9:1) as
eluent.
3-Ben zoylim id a zo[1,2-a ]p yr id in e (10a ): colorless crystals;
mp 135 °C; 1H NMR (300 MHz, CDCl3) δ 7.14 (ddd, 1H, J ) 6.9,
6.6, 1.0 Hz), 7.50-7.60 (m, 4H), 7.70 (m, 2H), 7.79 (dt, 1H, J )
8.8, 1.1 Hz), 8.21 (s, 1H), 9.74 (dt, 1H, J ) 6.6, 0.3 Hz); 13C NMR
(75.5 MHz, CDCl3) δ 115.1, 117.7, 123.5, 128.5, 128.8, 129.4,
130.2, 132.0, 138.4, 139.2, 145.6, 189.7; IR (KBr) 1689, 1597,
1223 cm-1; MS m/z (%) 222 (M+, 100). Anal. Calcd. for
131.4, 139.9, 146.3, 161.8, 185.0; IR (KBr) 1630, 1585, 1539 cm-1
;
HRMS m/z M+ calcd for C19H19N3O 305.152, found 305.1519.
Anal. Calcd for C19H19N3O: C, 74.79; H, 6.28; N, 13.77. Found:
C, 74.87; H, 6.01; N, 13.91.
3-B e n zo y l-2-(4-m o r p h o lin o )im id a zo [1,2-a ]p y r id in e
(9b): yellow crystals; mp 140-141 °C; 1H NMR (500 MHz,
CDCl3) δ 3.16 (t, 4H, J ) 7.5 Hz), 3.31 (t, 4H, J ) 7.2 Hz), 6.98
(dt, 1H, J ) 7.1, 1.5 Hz), 7.45-7.49 (m, 3H), 7.53-7.56 (m, 2H),
7.80-7.82 (m, 2H), 9.59 (d, 1H, J ) 5.0 Hz); 13C NMR (100 MHz,
CDCl3) δ 51.5, 65.9, 110.0, 113.7, 115.2, 128.2, 128.5, 128.9,
129.6, 131.8, 139.6, 146.1, 160.9, 184.9; IR (KBr) 1599, 1588,
1568, 1462 cm-1; HRMS m/z M+ calcd for C18H17N3O2 307.132,
found 307.131. Anal. Calcd for C18H17N3O2: C, 70.39; H, 5.58;
N, 13.68. Found: C, 70.21; H,5.42; N, 13.79.
3-Be n zoyl-2-(2-p yr id yla m in o)im id a zo[1,2-a ]p yr id in e
1
(11a ): colorless crystals; mp 125-126 °C; H NMR (400 MHz,
CDCl3) δ 6.85-6.92 (m, 2H), 7.26-7.56 (m, 3H), 7.61-7.69 (m,
5H), 8.16-8.19 (m, 1H), 8.20 (brs, 1H), 8.41(d, 1H, J ) 8.0 Hz),
8.92 (d, 1H, J ) 6.0 Hz); 13C NMR (100 MHz, CDCl3) δ 109.4,
113.0, 115.6, 118.5, 122.2, 128.0, 129.0, 129.5, 130.1, 131.1, 139.9,
140.0, 147.7, 155.7, 182.6; IR (KBr) 3350, 1585, 1540, 1490, 1465
cm-1; MS m/z (%) 314 (M+, 100). Anal. Calcd for C19H14N3O: C,
72.59; H, 4.49; N, 17.82. Found: C, 72.71; H, 4.23; N, 17.94.
3-(4-Meth ylben zoyl)-2-(2-p yr id yla m in o)im id a zo[1,2-a ]-
p yr id in e (11b): white crystals; mp 135-136 °C; 1H NMR (400
MHz, CDCl3) δ 2.46 (s, 3H), 6.88 (t, 2H, J ) 6.0 Hz), 7.35 (d,
2H, J ) 7.8 Hz), 7.44 (t, 1H, J ) 7.8 Hz), 7.49-7.56 (m, 1H),
7.59 (d, 2H, J ) 8 Hz), 7.65-7.70 (m, 1H), 8.19 (brs, 1H), 8.40
(d, 2H, J ) 6.5 Hz), 8.91 (d, 1H, J ) 6.0 Hz); 13C NMR (100
MHz, CDCl3) δ 21.6, 109.5, 112.9, 115.6, 118.6, 122.2, 127.3,
128.0, 129.0, 129.9, 130.0, 137.2, 140.0, 141.7, 147.6, 155.6, 182.8;
IR (KBr) 3300, 1610, 1590, 1565, 1490 cm-1; MS m/z (%) 328
(M+, 100). Anal. Calcd for C20H16N4O: C, 73.15; H, 4.91; N, 17.06.
Found: C, 73.29; H, 4.75; N, 17.22.
3-(4-Meth oxyben zoyl)-2-(2-p yr id yla m in o)im id a zo[1,2-a ]-
p yr id in e (11c): white crystals; mp 119-120 °C; 1H NMR (400
MHz, CDCl3) δ 3.89 (s, 3H), 6.87 (t, 2H, J ) 8 Hz), 7.03 (d, 2H,
J ) 7.2 Hz), 7.37-7.45 (m, 1H), 7.55(d, 2H, J ) 4.0 Hz), 7.68 (d,
2H, J ) 8.5 Hz), 8.18 (d, 1H, J ) 3.9 Hz), 8.30 (brs, 1H), 8.42 (d,
1H, J ) 8.0 Hz), 8.90 (d, 1H, J ) 6.8 Hz); 13C NMR (100 MHz,
CDCl3) δ 55.4, 109.5, 112.0, 113.3, 114.6, 115.6, 117.3, 128.1,
129.4, 129.8, 131.8, 137.8, 146.7, 148.0, 152.6, 153.0, 162.5, 182.7;
IR (KBr) 3110, 1645, 1590, 1541, 1465 cm-1; MS m/z (%) 344
(M+, 100). Anal. Calcd for C20 H16N4O2: C, 69.76; H, 4.68; N,
16.27. Found: C, 69.85; H, 4.45; N, 16.44.
C
14H10N2O: C, 75.66; H, 4.53; N, 12.60. Found: C, 75.70; H,
4.35; N, 12.50.
3-(4-Ch lor oben zoyl)im id a zo[1,2-a ]p yr id in e (10c): color-
less crystals; mp 129-130 °C; 1H NMR (300 MHz, CDCl3) δ
7.08-7.20 (m, 1H), 7.40-7.50 (m, 1H), 7.54 (d, 2H, J ) 8.0 Hz),
7.86 (d, 2H, J ) 8.4 Hz), 8.06-8.21 (m, 1H), 8.53 (s, 1H), 9.71-
9.86 (m, 1H); 13C NMR (75.5 MHz, CDCl3) δ 115.3, 117.8, 128.9,
129.5, 130.2, 130.3, 132.0, 137.6, 138.4, 145.6, 183.4; IR (KBr)
1650, 1585, 1500, 1470 cm-1; MS m/z (%) 256 (M+, 32), 222 (M+
- 34, 100). Anal. Calcd for C14H9ClN2O: C, 66.51; H, 3.53; N,
10.91. Found: C, 66.69; H, 3.45; N, 10.82.
Gen er a l P r oced u r e for BF 3‚Et2O-Assisted Cycliza tion
of 11a -c To Give Sa lts 13a -c. To a solution of 11 (10 mmol)
in dry benzene (30 mL) was added boron trifluoride etherate (3
mL), and the reaction mixture was refluxed with stirring for 1
h. On cooling, the yellow crystalline salt that separated was
filtered and washed with benzene and further purified by
crystallization from glacial acetic acid.
13a : yellow crystals; mp 219-220 °C; 1H NMR (400 MHz,
DMSO-d6) δ 7.31 (d, 1H, J ) 7.2 Hz), 7.41-7.42 (m, 1H), 7.51-
7.53 (m, 1H), 7.75-8.00 (m, 5H), 8.11-8.22 (m, 2H), 8.34-8.45
(m, 2H), 8.56 (d, 1H, J ) 6.5 Hz); 13C NMR (100 MHz, DMSO-
d6) δ 115.7, 118.0, 119.8, 120.2, 124.9, 126.7, 128.8, 129.2, 129.7,
131.8, 133.3, 137.9, 140.3, 140.8, 148.2, 158.9, 159.2; IR(KBr)
1650, 1580, 1521, 1460, 1060 cm-1; FAB MS m/z (%) 297 (M+
BF4, 100). Anal. Calcd for C19H13N4BF4: C, 59.41; H, 3.41, N,
14.59. Found: C, 59.67; H, 3.31; N, 14.66.
-
13b: yellow crystals; mp 234-235 °C; 1H NMR (400 MHz,
DMSO-d6) δ 2.59 (s, 3H), 7.33 (t, 1H, J ) 6.3 Hz), 7.51 (d, 1H,
J ) 6.0 Hz), 7.72-7.75 (m, 3H), 7.78 (d, 2H, J ) 8.2 Hz), 8.14
(d, 1H, J ) 8.1 Hz), 8.20-8.23 (m, 1H), 8.37 (m, 1H), 8.45 (d,
1H, J ) 8.4 Hz), 8.56 (d, 1H, J ) 8 Hz); 13C NMR (100 MHz,
DMSO-d6) δ 21.4, 115.7, 118.0, 119.6, 120.2, 121.9, 126.6, 129.0,
129.7, 131.7, 132.0, 137.9, 140.6, 140.7, 143.3, 148.1, 158.7, 159.0;
IR (KBr) 1584, 1519, 1510, 1468, 1065; FAB MS m/z (%) 311
(M+ - BF4, 100). Anal. Calcd for C20H15N4BF4: C, 60.33; H, 3.80;
N, 14.07. Found: C, 60.51; H, 3.65; N, 14.22.
13c: yellow crystals; mp 239-240 °C; 1H NMR (400 MHz,
DMSO-d6) δ 7.27 (t, 1H, J ) 5.4 Hz), 7.53 (dt, 1H, J ) 6.8, 1.2
Hz), 7.75 (d, 2H, J ) 8.4 Hz), 7.82 (d, 2H, J ) 8.5 Hz), 7.92-
8.05 (m, 1H), 8.17-8.28 (m, 1H), 8.35 (t, 1H, J ) 7.8 Hz), 8.44-
8.45 (m, 3H); 13C NMR (100 MHz, DMSO-d6) δ 114.7, 117.0,
119.1, 121.2, 124.5, 124.7, 128.6, 128.2, 128.7, 130.5, 132.3, 136.9,
141.3, 141.8, 149.2, 158.5, 159.2; IR(KBr) 1670, 1540, 1521, 1460,
1065 cm-1; FAB MS m/z (%) 331 (M+ - BF4, 100). Anal. Calcd
for C19H12ClN4BF4: C, 54.52; H, 2.89, N, 13.38. Found: C, 54.75;
H, 2.71; N, 13.56.
3-(4-Ch lor ob en zoyl)-2-(2-p yr id yla m in o)im id a zo[1,2-a ]-
p yr id in e (11d ): yellow crystals; mp 121-122 °C; 1H NMR (400
MHz, CDCl3) δ 6.90 (t, 2H, J ) 6.3 Hz), 7.27-7.50 (m, 1H), 7.56
(d, 2H, J ) 8.5 Hz), 7.57-7.59 (m, 1H), 7.64 (d, 2H, J ) 8.1 Hz),
7.69-7.72 (m, 1H), 8.21 (m, 1H), 8.33 (brs, 1H), 8.40 (d, 1H, J )
8.6 Hz), 8.83 (d, 1H, J ) 6.2 Hz); 13C NMR (100 MHz, CDCl3) δ
109.6, 114.4, 115.6, 117.6, 117.7, 119.9, 128.3, 136.6, 137.9, 138.7,
139.2, 145.9, 148.6, 152.2, 154.5, 156.3, 183.5; IR(KBr) 3125,
1655, 1599, 1555, 1535, 1460 cm-1; MS m/z (%) 348 (M+, 100).
Anal. Calcd for C19H13ClN4O: C, 65.43; H, 3.75; N, 16.06.
Found: C, 65.61; H, 3.59; N, 16.21.
2-An ilin o-3-ben zoylim id a zo[1,2-a ]p yr id in e (12a ): yellow
1
crystals; mp 123-124 °C; H NMR (400 MHz, CDCl3) δ 6.75-
6.77 (m, 1H), 6.98 (dt, 1H, J ) 7.0, 1.5 Hz), 7.25-7.32 (m, 2H),
7.36-7.40 (m, 1H), 7.49-7.52 (m, 1H), 7.53-7.62 (m, 7H), 8.10
(brs, 1H), 8.52 (d, 1H, J ) 5.1 Hz); 13C NMR (100 MHz, CDCl3)
δ 109.4, 113.0, 115.6, 118.5, 122.2, 127.1, 128.0, 129.0, 129.5,
130.1, 131.1, 139.9, 140.0, 147.7, 155.7, 182.6; IR (KBr) 3120,
1590, 1575 cm-1; MS m/z (%) 313 (M+, 100). Anal. Calcd for
C20H15N3O: C, 76.66; H, 4.82; N, 13.40. Found: C, 76.82; H,
4.92; N, 13.31.
2-An ilin o-3-(4-m et h ylb en zoyl)im id a zo[1,2-a ]p yr id in e
(12b): yellow crystals; mp 128-129 °C; 1H NMR (400 MHz,
CDCl3) δ 2.48 (s, 3H), 6.73-6.77 (m, 1H), 6.97-7.03 (m, 1H),
7.25-7.41 (m, 5H), 7.49-7.66 (m, 5H), 8.23 (brs, 1H), 8.49 (d,
1H, J ) 5.4 Hz); 13C NMR (75.5 MHz, CDCl3) δ 21.6, 109.4,
112.9, 115.6, 118.6, 122.1, 127.3, 128.0, 129.2, 129.8, 130.0, 137.2,
140.0, 141.6, 147.5, 155.6, 182.8; IR (KBr) 3150, 1610, 1580,
Ack n ow led gm en t. Financial assistance under DST
project is acknowledged. H.J . and O.B. thank CSIR,
New Delhi, for Emeritus Scientistship and Senior
Research Fellowship, respectively.
J O9916129