Convenient preparation of a novel class of imidazo[1,5-a]pyridines: Decisive role by ammonium acetate in chemoselectivity

Article abstract of DOI:10.1021/jo0342020

A facile and one-pot straightforward methodology has been developed to prepare a novel class of imidazo[1,5-a]pyridines. A key role played by ammonium acetate in chemoselectivity has been examined.

Full text of DOI:10.1021/jo0342020

such as LDA,12 MeLi,13 TiCl4,14 dicyclohexylcarbodiimide
(DCC),7 phosphoric oxychloride,8,15 or PCl5.16 The forma-
tion of the fused ring framework usually takes two or
more steps to complete. Additional steps would be
required when functional motif groups are introduced.1,2,9,11
We report here a new and straightforward one-pot
approach; this simple methodology does not involve the
use of highly sensitive reagents.
Con ven ien t P r ep a r a tion of a Novel Cla ss of
Im id a zo[1,5-a ]p yr id in es: Decisive Role by
Am m on iu m Aceta te in Ch em oselectivity
J ie Wang,† Richard Mason,† Donald VanDerveer,‡
Ke Feng,† and Xiu R. Bu†,*
Department of Chemistry and NASA Center for High
Performance Polymers and Composites, Clark Atlanta
University, Atlanta, Georgia 30314, and School of
Chemistry and Biochemistry, Georgia Institute of
Technology, Atlanta, Georgia 30322
Treatment of benzaldehyde with 2,2′-pyridil in the
presence of ammonium acetate in acetic acid gave 1-(2-
pyridoyl)-3-phenylimidazo[1,5-a]pyridine 1a and 4,5-bis-
(2-pyridyl)-2-phenylimidazole 2a (Scheme 1). Generally,
1 showed up as a yellow spot in TLC, which can be easily
recognized and separated by chromatography in a silica
column. Further purification was obtained by recrystal-
lization from ethyl acetate/hexane. Compound 1 pos-
sessed good solubility in most polar organic solvents such
as chloroform, THF, and ethyl acetate. Examination of
the IR band showed that the CdO vibration of 1a was
at 1643 cm-1. The chemical shift of CdO in the 13C NMR
spectrum was 186.6 ppm. The structure of 1a by X-ray
crystallographic determination revealed that two fused
rings were perfectly coplanar (Figure S1). The phenyl
group at the 3-position is twisted 36.07(5)° from the
imidazole ring. The carbonyl group is twisted from the
pyridyl ring by 46.20(4)°. This group is also not coplanar
with the imidazole ring, and the deviation is 9.17(7)°. The
twist between the imidazole ring and the pyridyl ring is
50.53(4)°.
Optimization of the reaction conditions was initiated
on the preparation of 1a , based on the fact that 2a was
a major product, and 1a was obtained but in a very low
yield. The initial reaction condition included a 1:1 molar
ratio of 2,2′-pyridil and benzaldehyde, 118 °C reaction
temperature, and 24 h reaction time. A lower reaction
temperature (65 °C) was also used. In both cases, the
yield was ca. 2%. Compounds 1b (4.1%, yield), 1c (2.3%),
1d (2.4%), 1e (3.9%), and 1f (4.5%) were also obtained in
low yields (118 °C, 24 h). Shortening the reaction time
to 6 h did not affect the yields. Further investigation was
carried out using different ratios of 2,2′-pyridil to benz-
aldehyde at 6 h and 118 °C. The use of 1.5:1 of 2,2′-pyridil
to benzaldehyde gave 1a in 8.2% yield. When a 2:1 ratio
was used, the yield was further increased to 12.1%. This
ratio seems to give the best yield because a 2.5:1 ratio
gave 1a in 11.9% yield. The need of excess 2,2′-bipyridil
probably originates from its reactivity. In addition to 2
formed from these reactions, the formation of black and
insoluble tar side products was also observed. Most likely,
xbu@cau.edu
Received February 14, 2003
Abstr a ct: A facile and one-pot straightforward methodology
has been developed to prepare a novel class of imidazo-
[1,5-a]pyridines. A key role played by ammonium acetate
in chemoselectivity has been examined.
The chemistry of fused nitrogen heterocyclic imidazo-
[1,5-a]pyridines and the closely related isomers has
attracted increasing attention due to their medicinal
significance.1 Imidazo[1,5-a]pyridines possess thrombox-
ane A2 synthetase inhibiting property.2 The isomers such
as imidazo[1,2-a]pyridines and pyrazolo[1,5-a]pyridines
possess antiviral,3 antiulcer,4 and D4 receptor antago-
nistic properties.5 Many other structurally closely related
molecules possessing fused imidazoles are also biologi-
cally active. For example, imidazo[1,5-a]pyrazines and
imidazo[1,2-a]pyrimidones exhibit potent corticotropin
releasing hormone (CRH) receptor and GnRH receptor
antagonistic effects, respectively.6
The previous synthesis of imidazo[1,5-a]pyridines mainly
involves the use of R-2-pyridylalkylamine, followed by
subsequent functionalization to anchor various electro-
philic reagents.2,7-11 Other approaches include the use
of imine derivatives,12 2-cyanopyridine,13 and recently,
benzotriazoles.14 Most syntheses require strict reaction
conditions because of the use of highly sensitive reagents
† Clark Atlanta University
‡ Georgia Institute of Technology
(1) Montgomery, J . A.; Secrist, J . A., III. In Comprehensive Hetero-
cyclic Chemistry; Katritzky, A. R., Rees, C. W., Eds.; Pergamon Press:
Oxford, 1984; Vol. 5, p 614.
(2) Ford, N. F.; Browne, L. J .; Campell, T.; Gemenden, C.; Goldstein,
R.; Gude, C.; Waley, J . W. F. J . Med. Chem. 1985, 28, 164.
(3) Gueiffier, A.; Lhassani, M.; Elhakmaoui, A.; Snoeck, R.; Andrei,
G.; Chavignon, O.; Teulade, J .-C.; Kerbal, A.; Essassi, E. M.; Debouzy,
J .-C.; Witvrouw, M.; Blache, Y.; Balzarini, J .; Clercq, E. D.; Chapet,
J .-P. J . Med. Chem. 1996, 39, 2856-2859.
(4) Kaminki, J . J .; Bristol, J . A.; Lovey, R. G.; Elliot, A. J .; Duzik,
H.; Solomon, D. M.; Conn, D. J .; Domalski, M. S.; Wong, S.-C.; Gold,
E. H.; Long, J . F.; Chiu, P. J . S.; Steinberg, M.; McPhail, A. T. J . Med.
Chem. 1985, 28, 876.
(5) Lo¨ber, S.; Hu¨bner, H.; Gmeiner, P. Bioorg. Med. Chem. Lett.
1999, 9, 97-102.
(6) (a) Hartz, R. A.; Gilligan, P. J .; Nanda, K. K.; Tebben, A. J .;
Fitzgerald, L. W.; Miller, K. Bioorg. Med. Chem. Lett. 2002, 12, 291.
(b) Gross, T. D.; Zhu, Y.-F.; Saunders: J .; Wilcoxen, K. M.; Gao, Y.;
Connors, P. J ., J r.; Guo, Z.; Struthers, R. S.; Reinhart, G. J .; Chen. C.
Bioorg. Med. Chem. Lett. 2002, 12, 2185.
(7) Bourdais, J .; Omar, A.-M. E. J . Heterocycl. Chem. 1980, 17, 555.
(8) Bower, J . D.; Ramage, G. R. J . Chem. Soc. 1955, 2834.
(9) Fuentes, O.; Paudler, W. W. J . Org. Chem. 1975, 40, 1210.
(10) Abushanab, E.; Bindra, A. P. J . Org. Chem. 1973, 38, 2049.
(11) For substitutions in different positions of the ring system, see:
(a) Montgomery, J . A.; Secrist, J . A., III. In Comprehensive Heterocyclic
Chemistry; Katritzky, A. R., Rees, C. W., Eds.; Pergamon Press:
Oxford, 1984; Vol. 5, p 634. (b) Blatcher, P.; Middlemiss, D. Tetrahedron
Lett. 1980, 21, 2195. (c) Hlasta, D. Tetrahedron Lett. 1990, 31, 5833.
(d) Hlasta, D. J .; Silbernagel, M. Heterocycles 1998, 48, 1015.
(12) Krapcho, A. P.; Powell, J . R. Tetrahedron Lett. 1986, 27, 3713.
(13) Palacios, F.; Alonso, C.; Rubiales, G. Tetrahedron 1995, 51,
3683.
(14) Katritzky, A. R.; Qiu, G. J . Org. Chem. 2001, 66, 2862.
(15) Browne, L. J .; Gude, C.; Rodriguez, H.; Steele, R. E.; Bhatnager,
A. J . Med. Chem. 1991, 34, 725.
(16) Benincori, T.; Brenna, E.; Sannicolo, F. J . Chem. Soc., Perkin
Trans. 1 1993, 675.
10.1021/jo0342020 CCC: $25.00 © 2003 American Chemical Society
Published on Web 05/29/2003
J . Org. Chem. 2003, 68, 5415-5418
5415

SCHEME 1
TABLE 1. Yield s of 1a Obta in ed fr om Use of Differ en t
Mola r Ra tios of Rea cta n ts
SCHEME 2
run
molar ratioa
yield of 1a (%)
1
2
3
4
5
6
7
8
9
1:1:1
1:1:2
2:1:1
2:1:1.5
2:1:2
2:1:2.5
2:1:4
2:1:6
2:1:8
16.7
14.7
28.9
29.4
67.2
52.1
41.7
40.5
12.1
a
2,2′-pyridil/benzaldehyde/ammonium acetate.
TABLE 2. Yield s of 1 a n d 2 Obta in ed in Differ en t
Con d ition s
an excessive amount of 2,2′-pyridil compensates the
consumption by side reactions. Ammonium acetate used
in all of the reactions is 8 equiv to aldehyde.
entry
R
yielda of 1 (%)
yieldb of 2 (%)
1
2
3
4
5
6
7
8
H
CH3
CH2CH3
CH(CH3)2
OCH3
Cl
1a : 67.2
1b: 51.3
1c: 57.1
1d : 42.4
1e: 68.1
1f: 55.7
1g: 65.2
1h : 52.2
2a : 37.5
2b: 41.7
2c: 33.9
2d : 25.6
2e: 31.7
2f: 34.4
2g: 41.7
2f: ndc
Further optimization was based on the following
rationales: (1) the reaction led to the formation of 2 as
the major product; and (2) the formation of 1 mol of 2
would require 2 mol of ammonia, whereas the formation
of 1 mol of 1 would require only 1 mol of ammonia
(Scheme 2). Thus, we beg one innocent question: will
ammonium acetate have a dramatic effect on the reac-
tion? Ammonium acetate is a solid source of ammonia,
which can be conveniently generated in situ through the
dissociation of ammonium acetate. Usually, the amount
of ammonium acetate used is loosely controlled. A large
excess is often used for two reasons: one is that it is
water-soluble and any leftover can be easily removed
during a workup, and the other is that it is a neutral
salt and not a significantly active species other than as
an ammonia source. We envision that the formation of 1
may depend on the amount of ammonium acetate. That
means that ammonium acetate is not merely used as
ammonia source, and most importantly, the amount may
hold the key to chemoselectivity. If all of the prior results
obtained are due to the use of 8 equiv ammonium acetate,
which favors the formation of 2 because the amount was
far excessive, then a reduced amount of ammonia acetate
would favor the formation of 1. To prove this theory, a
series of experiments have been focused on the use of a
reduced amount of ammonium acetate. Table 1 lists the
results obtained from varied equivalence of ammonium
acetate to benzaldehyde. The reduced amount of am-
monium acetate was applied to the previously established
2:1 ratio of 2,2′-pyridil to benzaldehyde (vide supra).
When ammonium acetate was reduced to 6 equiv, the
yield of 1a was increased to 40.5% (run 8, Table 1), a
F
NO2
a
Obtained from 2:1:2 ratio of pyridil, aldehyde, and ammonium
b
acetate. Obtained from 1:1:8 ratio of pyridil, aldehyde, and
ammonium acetate. c Not determined.
significant jump compared to 12.1% from 8 equiv (run 9,
Table 1). This revealed an important and critical role
played by the amount of ammonium acetate. Further
investigation showed that 2 equiv of ammonium acetate
gave the highest yield (67.2%, run 5, Table 1). Equally
significantly, the present reaction condition has to con-
sider the reactivity of 2,2′-pyridil as discussed previously.
It is clear that the optimal results can be achieved only
when the ratio of 2,2′-pyridil to benzaldehyde is main-
tained at 2:1. A simple use of 2 equiv of ammonium
acetate without the optimal ratio of 2,2′-pyridil to benz-
aldehyde will lead to a compromised result. The reaction
from 2,2′-pyridil, benzaldehyde, and ammonium acetate
in a 1:1:2 ratio reduced yield to 14.7% (run 2, Table 1), a
significant decrease compared to 67.2% from a ratio of
2:1:2. Therefore, 2,2′-pyridil, benzaldehyde, and am-
monium acetate at a molar ratio of 2:1:2 is an optimal
combination for the requisite imidazo[1,5-a]pyridines.
Table 2 lists results using various benzaldehyde ana-
logues. In all of these cases, 1 was obtained as the major
products in good yields. The formation of 2 was also
observed, but the yield was significantly low. The isolated
5416 J . Org. Chem., Vol. 68, No. 13, 2003

2H), 7.14 (m, 1H), 6.76 (t, J ) 6.8 Hz, 1H), 2.60 (q, J ) 7.7 Hz,
2H), 1.19 (t, J ) 7.7 Hz, 3H); 13C NMR (CDCl3) δ 186.4, 155.9,
149.4, 146.0, 139.2, 137.1, 136.2, 129.3, 128.7, 128.5, 128.2, 126.3,
126.0, 125.6, 125.2, 122.6, 120.9, 115.2, 28.7, 15.4; MS 327 (M+).
Anal. Calcd for C21H17N3O: C, 77.04; H, 5.23; N, 12.84. Found:
C, 77.17; H, 5.28; N, 12.75.
yield of 2a was less than 4%. Table 2 also lists yields of
2 obtained from the 1:1:8 ratio (pyridil, aldehyde, and
ammonium acetate) for comparison. The dramatically
different results from the two reaction conditions high-
light the importance of the amount of ammonium acetate
in controlling chemoselectivity and thus the outcome of
the reactions.
1-(2-P yr id oyl)-3-(4-isop r op ylp h en yl)im id a zo[1,5-a ]p yr i-
d in e (1d ). Recrystallized from benzene/hexanes 5/1 (v/v); yellow
crystal, mp 154-155 °C; IR(KBr) νmax 1626 cm-1 1H NMR
;
Theoretically, the formation of 1 only needs 1 equiv of
ammonia, but practically 2 equiv of ammonium acetate
is utilized. This seeming contradiction likely comes from
the fact that not all ammonia generated in situ from
dissociation of ammonium acetate participates in the
requisite reaction. Free ammonia is a gas, and some of
it may escape in gaseous state during the reaction.
In summary, a novel class of imidazo[1,5-a]pyridines
with a pyridoyl unit has been obtained. The condensation
of 2,2′-pyridil, aldehydes, and ammonium acetate was
found to be dictated by the amount of ammonium acetate.
A 2:1:2 ratio of 2,2′-pyridil, aldehydes, and ammonium
acetate offers the desirable chemoselectivity for the
synthesis of the requisite imidazo[1,5-a]pyridines. The
present method provides one-step direct condensation
using commercially available and inexpensive starting
materials to achieve structurally rather complex imidazo-
[1,5-a]pyridines.
(CDCl3) δ 8.71 (d, J ) 4.2 Hz, 1H), 8.44 (d, J ) 9.0 Hz, 1H), 8.31
(d, J ) 7.8 Hz, 1H), 8.27 (d, J ) 7.0 Hz, 1H), 7.75 (m, 1H), 7.63
(d, J ) 8.1 Hz, 2H), 7.32 (m, 3H), 7.14 (m, 1H), 6.75 (m, 1H),
2.87, (m, 1H), 1.22 (d, J ) 7.0 Hz, 6H); 13C NMR (CDCl3) δ186.5,
162.3, 155.9, 150.6, 149.4, 139.2, 136.2, 135.4, 128.7, 127.9, 127.1,
126.6, 126.5, 126.0, 125.5, 125.2, 123.8, 120.9, 115.2, 34.0, 23.8;
MS 341 (M+). Anal. Calcd for C22H19N3O: C, 77.40; H, 5.61; N,
12.31. Found: C, 77.58; H, 5.67; N, 12.30.
1-(2-P yr id oyl)-3-(4-m eth oxyp h en yl)im id a zo[1,5-a ]p yr i-
d in e (1e). Recrystallized from benzene/hexanes 5/1 (v/v); yellow
crystal, mp 132-134 °C; IR(KBr) νmax 1643 cm-1 1H NMR
;
(CDCl3) δ 8.71 (d, J ) 4.1 Hz, 1H), 8.39 (d, J ) 8.9 Hz, 1H), 8.27
(d, J ) 7.9 Hz, 1H), 8.20 (d, J ) 7.0 Hz, 1H), 7.75 (t, J ) 7.7 Hz,
1H), 7.61 (d, J ) 8.5 Hz, 2H), 7.32 (m, 1H), 7.12 (t, J ) 7.8 Hz,
1H), 6.93 (d, J ) 8.5 Hz, 2H), 6.75 (t, J ) 6.8 Hz, 1H), 3.75 (s,
3H); 13C NMR (CDCl3) δ 186.2, 160.5, 155.7, 149.2, 139.1, 137.0,
136.3, 130.5, 130.1, 129.1, 126.0, 125.6, 125.2, 121.3, 122.6, 120.9,
115.2, 114.4, 55.7; MS 329 (M+). Anal. Calcd for C20H15N3O2:
C, 72.94; H, 4.59; N, 12.76. Found: C, 73.09; H, 4.66; N, 12.67.
1-(2-P yr id oyl)-3-(4-ch lor op h e n yl)im id a zo[1,5-a ]p yr i-
d in e (1f). Recrystallized from ethyl acetate/hexanes 3/1 (v/v);
yellow crystal, mp 158-159 °C; IR(KBr) νmax 1643 cm-1; 1H NMR
(CDCl3) δ 8.73 (d, J ) 4.4 Hz, 1H), 8.44 (d, J ) 9.1 Hz, 1H), 8.25
(d, J ) 7.1 Hz, 2H), 7.78 (m, 1H), 7.67 (d, J ) 8.5 Hz, 2H), 7.43
(d, J ) 8.4 Hz, 2H), 7.36 (m, 1H), 7.20 (m, 1H), 6.84 (t, J ) 6.8
Hz, 1H); 13C NMR (CDCl3) δ 186.5, 155.8, 149.3, 137.8, 137.2,
136.3, 135.5, 129.9, 129.3, 127.5, 126.2, 125.3, 122.3, 121.1, 115.6;
MS 333 (M+). Anal. Calcd for C19H12ClN3O: C, 68.37; H, 3.62;
N, 12.59. Found: C, 68.32; H, 3.63; N, 12.49.
Exp er im en ta l Section
Gen er a l P r oced u r e for P r ep a r a tion of 1. A mixture
consisting of 2,2′-pyridil (1.06 g, 5.00 mmol), 4-substituted
benzaldehyde (2.50 mmol), and NH4OAc (0.385 g, 5.00 mmol)
in 25 mL of glacial acetic acid was stirred at 110 °C under N2.
The reaction was monitored by the TLC. After 6 h, the reaction
mixture was cooled to room temperature, poured into 100 mL
of water, and then neutralized with a 20% NaOH aqueous
solution to pH 11-12. The solid was filtered, redissolved in CH2-
Cl2, and washed with water and brine. The organic layer was
separated and dried over Na2SO4. Upon removal of solvent, the
brown residue was purified using flash chromatography on a
silica column with an eluent of 2:1:0.1 CH2Cl2/ethyl acetate/
MeOH (v/v/v) to give 1, which was further purified by crystal-
lization from solvents to afford analytically pure compounds.
Yields of 1 are listed in Table 2.
1-(2-P yr id oyl)-3-p h en yl-im id a zo[1,5-a ]p yr id in e (1a ). Re-
crystallized from ethyl acetate/hexanes 3/1 (v/v); yellow crystal,
mp 128-130 °C; IR (KBr) νmax 1643 (CdO) cm-1; 1H NMR (400
MHz, CDCl3) δ 8.75 (d, J ) 4.5 Hz, 1H), 8.48 (d, J ) 9.0 Hz,
1H), 8.31 (d, J ) 7.4 Hz, 2H), 7.79 (m, 1H), 7.74 (d, J ) 7.0 Hz,
2H), 7.50-7.43 (m, 3H), 7.38 (m, 1H), 7.21 (m, 1H), 6.83 (t, J )
6.5 Hz, 1H); 13C NMR (CDCl3) δ 186.6, 155.9, 149.3, 139.1, 137.2,
136.3, 129.5, 129.0, 128.7, 126.1, 125.5, 125.3, 122.5, 121.1, 115.3;
MS (EI) 299 (M+). Anal. Calcd for C19H13N3O: C, 76.24; H, 4.38;
N, 14.04. Found: C, 76.33; H, 4.42; N, 14.11.
1-(2-P yr id oyl)-3-(4-flu or op h e n yl)im id a zo[1,5-a ]p yr i-
d in e (1g). Recrystallized from ethyl acetate/hexanes 3/1 (v/v);
yellow crystal; mp 143-145 °C; IR (KBr) νmax 1643 cm-1 1H
;
NMR (CDCl3) δ 8.68 (d, J ) 4.4 Hz, 1H), 8.39 (d, J ) 9.0 Hz,
1H), 8.20 (t, J ) 8.0 Hz, 2H), 7.75 (t, J ) 7.7 Hz, 1H), 7.69 (m,
2H), 7.32 (m, 1H), 7.13 (m, 3H), 6.79 (t, J ) 6.8 Hz, 1H); 13C
NMR (CDCl3) δ 186.5, 164.4, 162.0, 155.8, 149.2, 138.1, 137.1,
136.3, 130.8, 129.3, 126.2, 125.3, 122.3, 120.9, 116.3, 116.0, 115.5;
MS 317 (M+). Anal. Calcd for C19H12FN3O: C, 71.92; H, 3.81;
N, 13.24. Found: C, 71.87; H, 3.97; N, 13.13.
1-(2-P yr id oyl)-3-(4-n it r op h e n yl)im id a zo[1,5-a ]p yr i-
d in e (1h ). Recrystallized from ethanol; yellow solid, mp 229-
230 °C; IR(KBr) νmax 1651 cm-1; 1H NMR (CDCl3) δ 8.73 (d, J )
4.3 Hz, 1H), 8.48 (d, J ) 9.1 Hz, 1H), 8.38 (d, J ) 7.1 Hz, 1H),
8.30 (d, J ) 8.6 Hz, 2H), 8.24 (d, J ) 7.7 Hz, 1H), 7.98 (d, J )
8.5 Hz, 2H), 7.82 (t, J ) 7.7 Hz, 1H), 7.39 (m, 1H), 7.28 (m, 1H),
6.95 (t, J ) 6.8 Hz, 1H); 13C NMR (CDCl3) δ 186.6, 155.5, 149.3,
147.7, 137.6, 136.4, 135.2, 130.3, 129.0, 126.8, 125.8, 125.3, 124.2,
122.3, 121.3, 116.4; MS 344 (M+). Anal. Calcd for C19H12N4O3:
C, 66.28; H, 3.51; N, 16.27. Found: C, 66.13; H, 3.59; N, 16.15.
Gen er a l P r oced u r e for P r ep a r a tion of 2. To a 100-mL
round-bottom flask were added 20 mL of glacial acetic acid and
2,2-pyridil (1.00 g, 4.71 mmol). The mixture was allowed to stir
at room temperature until all of the solid was dissolved.
Aldehyde (4.71 mmol) was then added, followed by the addition
of ammonium acetate (2.90 g, 37.68 mmol). The reaction mixture
was magnetically stirred at 118 °C for 6 h and then cooled to
room temperature. The mixture was poured into 200 mL of ice
water and neutralized with a 10% sodium carbonate solution to
a pH of 6.5-7.0. The formed precipitate was collected and
redissolved in methylene chloride. The organic phase was
washed with water (100 mL and then 2 × 75 mL) and then dried
over sodium sulfate. Upon removal of solvent under reduced
pressure, the residue was run on a silica column using an eluent
of CH2Cl2/EtOAc (1:10, v/v) to remove other undesirable com-
ponents first and then using (CH2Cl2/EtOAc, 3:1, v/v) to obtain
1-(2-P yr id oyl)-3-(4-m et h ylp h en yl)im id a zo[1,5-a ]p yr i-
d in e (1b). Recrystallized from benzene/hexanes 5/1 (v/v); yellow
crystal, mp 140-141°C; IR(KBr) νmax 1643 cm-1 1H NMR
;
(CDCl3) δ 8.72 (d, J ) 4.5 Hz, 1H), 8.43 (d, J ) 9.1 Hz, 1H), 8.30
(d, J ) 7.8 Hz, 1H), 8.26 (d, J ) 7.1 Hz, 1H), 7.77 (t, J ) 8.6 Hz,
1H), 7.59 (d, J ) 8.1 Hz, 2H), 7.33 (m, 1H), 7.24 (d, J ) 8.0 Hz,
2H), 7.16 (m, 1H), 6.78 (t, J ) 6.8 Hz, 1H), 2.34 (s, 3H); 13C NMR
(CDCl3) δ 186.4, 155.9, 149.4, 139.7, 139.2, 137.1, 136.2, 129.3,
128.6, 126.1, 125.4, 125.2, 122.6, 120.9, 115.2, 21.3; MS 313 (M+).
Anal. Calcd for C20H15N3O: C, 76.66; H, 4.82; N, 13.41. Found:
C, 76.45; H, 4.79; N, 13.40.
1-(2-P yr id oyl)-3-(4-e t h ylp h e n yl)im id a zo[1,5-a ]p yr i-
d in e (1c). Recrystallized from benzene/hexanes 5/1 (v/v); yellow
crystal, mp 136-138 °C; IR(KBr) νmax 1634 cm-1 1H NMR
;
(CDCl3) δ 8.72 (d, J ) 4.4 Hz, 1H), 8.44 (d, J ) 9.1 Hz, 1H), 8.31
(d, J ) 7.9 Hz, 1H), 8.26 (d, J ) 7.1 Hz, 1H), 7.75 (t, J ) 7.7 Hz,
1H), 7.62 (d, J ) 7.9 Hz, 2H), 7.32 (m, 1H), 7.27 (d, J ) 8.0 Hz,
J . Org. Chem, Vol. 68, No. 13, 2003 5417

1. After 1 was eluted out, EtOAc/CH2Cl2 (3:1,v/v) was used to
obtain 2. Both 1 and 2 were further purified by recrystallization.
Conditions used for the purification of 1 were the same as that
described above. Yields of 1 have been discussed in the text, and
yields of 2 are listed in Table 2. Compounds 2a , 2b, 2e, and 2g
obtained in this way have been compared to the reported values
in the literature.17,18
NCC3-910), and DOE (DE-FC02-02EW15254) is grate-
fully acknowledged.
Su p p or tin g In for m a tion Ava ila ble: X-ray crystal struc-
ture of 1a and complete sets of structural parameters including
coordinates, bonding distances, and angles; general experi-
mental procedures and full characterization of 2c, 2d , and 2f
including data from 1H NMR, 13C NMR, MS, IR, elemental
analysis, and melting points; and recrystallization conditions
for the purification of each of these compounds. This material
is available free of charge via the Internet at http://pubs.acs.org.
Ack n ow led gm en t. Financial support in part by the
U.S. Army (DAAD19-01-0746), NASA (NCC3-552 and
(17) Lombardino, J .; Wiseman, E. H. J . Med. Chem. 1974, 17, 1182.
(18) Nakashima, K.; Fukuzaki, Y.; Nomura, R.; Shimoda, R.; Na-
kamura, Y.; Kuroda, N.; Akiyama, S. A.; Irgum, K. Dyes Pigments 1998,
38, 127.
J O0342020
5418 J . Org. Chem., Vol. 68, No. 13, 2003