Reactivity of 3-iodoimidazo[1,2-a]pyridines using a Suzuki-type cross-coupling reaction

Article abstract of DOI:10.1021/jo000698z

The influence of base and solvent in Suzuki cross-coupling reaction on various 2-substituted-3-iodoimidazo[1,2-a]pyridines was reported. The reactivity was largely influenced by nature of the substituent. Optimized yields and shortened times of reaction were obtained using strong bases in DME.

Full text of DOI:10.1021/jo000698z

6572
J . Org. Chem. 2000, 65, 6572-6575
Rea ctivity of 3-Iod oim id a zo[1,2-a ]p yr id in es Usin g a Su zu k i-Typ e
Cr oss-Cou p lin g Rea ction
Ce´cile Enguehard,† J ean-Louis Renou,† Vale´rie Collot,‡ Maud Hervet,† Sylvain Rault,‡ and
Alain Gueiffier*,†
Laboratoire de Chimie The´rapeutique, UFR des Sciences Pharmaceutiques, 31 avenue Monge,
37200 Tours, France, and Centre d′Etudes et de Recherche sur le Me´dicament de Normandie,
UFR des Sciences Pharmaceutiques, 5 rue Vaube´nard, 14032 Caen, France
gueiffier@univ-tours.fr
Received May 11, 2000
The influence of base and solvent in Suzuki cross-coupling reaction on various 2-substituted-3-
iodoimidazo[1,2-a]pyridines was reported. The reactivity was largely influenced by nature of the
substituent. Optimized yields and shortened times of reaction were obtained using strong bases in
DME.
Sch em e 1
In tr od u ction
Recently a new series of diaryl heterocycles including
rofecoxib and celecoxib have been developed as selective
cyclooxygenase-2 inhibitors for the treatment of acute
and chronic inflammatory diseases (Scheme 1).1 Selective
inhibition of this enzyme might avoid the side effects of
currently available nonsteroidal antiinflammatory drugs
while retaining their therapeutic efficacy. Recent clinical
trials have confirmed the superior gastrointestinal safety
profile of both compounds when compared to naproxen,2
diclofenac,3 or ibuprofen.4
In continuation of our studies on the reactivity of
nitrogen bridgehead heterocycles,5 we were then inter-
ested in the preparation and the pharmacological evalu-
ation of 2,3-diarylimidazo[1,2-a]pyridines. To develop a
convenient synthetic pathway in good agreement with
rapid pharmacomodulation, we were interested in study-
ing the Suzuki-type cross-coupling reaction. To the best
of our knowledge, the application of this reaction to these
series was only reported by R. E. Tenbrink on 6-bromo
derivatives,6 while 3-arylation was described by Y. Kawai
and A. Badger using the Stille coupling reaction.7 In this
work, we turned our interest to studying the reactivity
of the imidazo[1,2-a]pyridine ring system toward boronic
acid. In this way, the incidence of various parameters
was investigated: nature of the 2-substituent, nature of
the boronic acid, and conditions of the reaction (bases and
solvents).
It is well established that imidazo[1,2-a]pyridines un-
dergo electrophilic attack at the 3-position.8 Thus bro-
mination was achieved using NBS in CCl4,9 NBS in
CHCl3,10 bromine in NaOH,10 or bromine in acetic acid.11
The iodination reaction was in contrast poorly studied.
Iodination of 2-phenylimidazo[1,2-a]pyridine and (3-
nitrofuran-2-yl)imidazo[1,2-a]pyridine was reported using
iodine in ethanol12 or iodine in pyridine,13 respectively.
More recently, 2,6-dichloroimidazo[1,2-a]pyridine was
* To whom correspondence should be addressed. Fax (33) 02 47 36
72 88.
† Laboratoire de Chimie The´rapeutique.
‡ Centre d′Etudes et de Recherche sur le Me´dicament de Normandie.
(1) (a) Puig, C.; Crespo, M. I.; Godessart, N.; Feixas, J .; Ibarzo, J .;
J ime´nez, J .-M.; Soca, L.; Cardelu´s, I.; Heredia, A.; Miralpeix, M.; Puig,
J .; Beleta, J .; Huerta, J . M.; Lo´pez, M.; Segarra, V.; Ryder, H.; Palacios,
J . M. J . Med. Chem. 2000, 43, 214-223. (b) Talley, J . J .; Brown, D. L.;
Carter, J . S.; Graneto, M. J .; Koboldt, C. M.; Masferrer, J . L.; Perkins,
W. E.; Rogers, R. S.; Shaffer, A. F.; Zhang, Y. Y.; Zweifel, B. S.; Seibert,
K. J . Med. Chem. 2000, 43, 775-777.
14
iodinated using NIS in CHCl3 or in acetonitrile.15
(7) (a) Kawai, Y.; Satoh, S.; Yamasaki, H.; Kayakiri, N.; Yoshihara,
K.; Oku, T. P.C.T. WO 96/34866, 1996. (b) Badger, A.; Bender, P.; Esser,
K.; Griswold, D.; Nabil, H.; Lee, J .; Votta, B.; Simon, P. P.C.T. WO
91/00092, 1990.
(8) Almirante, L.; Polo, L.; Mugnaini, A.; Provinciali, E.; Rugarli,
P.; Biancotti, A.; Gamba, A.; Murmann, W. J . Med. Chem. 1965, 8,
305-312.
(9) Fischer, M. H.; Lusi, A. J . Med. Chem. 1972, 15, 5 (9), 982-985.
(10) Paolini, J . P.; Robins, R. K. J . Org. Chem. 1965, 30, 4085-
4090.
(2) Simon, L. S.; Weaver, A. L.; Graham, D. Y.; Kivitz, A. J .; Lipsky,
P. E.; Hubbard, R. C.; Isakson, P. C.; Verburg, K. M.; Yu, S. S.; Zhao,
W. W.; Geis, G. S. J AMA 1999, 282, 1921-1928.
(3) Emery, P.; Zeidler, H.; Kvien, T. K.; Guslandi, M.; Naudin, R.;
Stead, H.; Verburg, K. M.; Isakson, P. C.; Hubbard, R. C.; Geis, G. S.
Lancet 1999, 354, 2106-2111.
(4) Hawkey, C.; Laine, L.; Simon, T.; Beaulieu, A.; Maldonado-Cocco,
J .; Acevedo, E.; Shahane, A.; Quan, H.; Bolognese, J .; Mortensen, E.
Arthritis Rheum. 2000, 43, 370-377.
(11) Gueiffier, A.; Milhavet, J .-C.; Blache, Y.; Chavignon, O.; Teu-
lade, J .-C.; Madesclaire, M.; Viols, H.; Dauphin, G.; Chapat, J .-P. Chem.
Pharm. Bull. 1990, 38 (9), 2352-56.
(5) (a) Chavignon, O.; Teulade, J .-C.; Roche, D.; Madesclaire, M.;
Blache, Y.; Gueiffier, A.; Chabard, J .-L.; Dauphin, G. J . Org. Chem.
1994, 59, 6413-6418. (b) Chezal, J .-M.; Delmas, G.; Mavel S.; Elak-
maoui, H.; Me´tin, J .; Diez, A.; Blache, Y.; Gueiffier, A.; Rubiralta, M.;
Teulade, J .-C.; Chavignon, O. J . Org. Chem. 1997, 62, 4085-4087.
(6) Tenbrink, R. E. P.C.T. WO 96/25414, 1996.
(12) Hand, E. S.; Paudler, W. W. J . Org. Chem. 1978, 43 (4), 658-
663.
(13) Saldabol, N. O.; Giller, S. A. Chem. Heterocycl. Compd. 1976,
12, 1155-1162.
(14) Gudmundsson, K. S.; Drach, J . C.; Townsend, L. B. Tetrahedron
Lett. 1996, 37 (35), 6275-6278.
10.1021/jo000698z CCC: $19.00 © 2000 American Chemical Society
Published on Web 09/13/2000

Reactivity of 3-Iodoimidazo[1,2-a]pyridines
J . Org. Chem., Vol. 65, No. 20, 2000 6573
Ta ble 1a
Ta ble 2a
compd
R
R1
method time (h) yield (%)
compd
R
R1
method
time (h)
yield (%)
11
CO2C2H5 2-thienyl
CO2C2H5 3-thienyl
CO2C2H5 methyl
A
C
A
C
A
C
D
E
F
72
0.5
72
0.5
48
48
48
3
3
6
48
48
18
64
0
56
0
1, 6
CO2C2H5
H
A
C
A
B
C
D
A
A
B
C
D
A
D
48
0.5
48
20
4
0.5
48
48
48
7
73
91
44
71
75
71
47
39
28
66
77
48
69
12
13
14
2, 7
C6H5
H
0
C6H5
C6H5
2-thienyl
methyl
≈30b
70
53
85
5
3, 8
4, 9
pFC6H4
C(CH3)3
H
CH3
15
D
E
F
0
0.5
48
0.5
5, 10
H
H
a
Couplings were carried out at 75 °C in the presence of 5%
Pd(PPh3)4 and 2 equiv of Na2CO3 in toluene (method A) or 2 equiv
of Na2CO3 in DME (method C) or 2 equiv of NaOH in DME
(method D) or 2 equiv of Ba(OH)2 in DME (method E) or at reflux
in the presence of 2 equiv of Ba(OH)2 in THF (method F)
a
Couplings were carried out at 75 °C in the presence of 5%
Pd(PPh3)4 and 2 equiv of Na2CO3 in toluene (method A) or 2 equiv
of NaOH in toluene (method B) or 2 equiv of Na2CO3 in DME
(method C) or 2 equiv of NaOH in DME (method D).
b
Evaluated by TLC.
order deduced from Table 1. These reaction times were
markedly shortened by modifying the nature of the base
(NaOH, method D) leading to 7, 9, and 10 in 30 min in
around 70% yields.
Resu lts a n d Discu ssion
In a first approach, the iodination was attempted in
pyridine13 but purification was rather difficult and led
to a poor yield, thus we turned our interest to the
procedure using NIS in acetonitrile.15 Under these condi-
tions the diversely substituted imidazo[1,2-a]pyridines
afforded the expected iodinated compounds as a precipi-
tate in the reaction mixture. Only the ethyl imidazo[1,2-
a]pyridine-2-carboxylate appears to be poorly reactive
toward NIS.
First, the coupling reaction of benzeneboronic acid was
applied to 3-iodoimidazo[1,2-a]pyridine diversely substi-
tuted in the 2-position. The reaction was carried out in
a heterogeneous mixture of toluene and aqueous sodium
carbonate solution, in the presence of catalytic amount
of tetrakis(triphenylphosphine)palladium(0) at 75 °C for
2 days (method A). The use of higher temperatures in
order to improve the yield and shorten the reaction time
led to significant degradation of the heterocycle. From
the results reported in Table 1, we noted a marked effect
upon the nature of the substituent on the rate of coupling.
The presence of an ester group on the 2-position appeared
to favor the iodo substitution compared to 2-phenyl and
2-tert-butyl groups or hydrogen. These results could be
explained by the electronic-withdrawing effect of the
carbonyl group.
To optimize the reaction conditions, we decided to
investigate the reactivity of 3-iodoimidazo[1,2-a]pyridine
using various bases and solvents. We have observed that
whatever the base, the reaction time was greatly short-
ened and the yield markedly improved by replacement
of toluene by 1,2-dimethoxyethane. Thus, the coupling
was completed cleanly from 1 in 30 min using sodium
carbonate in DME (method C), leading to compound 6
(91% yield of isolated product after column chromatog-
raphy). Under the same conditions, a few hours were still
needed for an efficient coupling starting from 2 and 4 (4
and 7 h, respectively) in accordance with the reactivity
We then decided to exemplify the coupling reaction
with different boronic acids (Table 2). In our case, thien-
2-yl, thien-3-yl, and methylboronic acids appeared to be
less reactive than benzeneboronic acid since no reaction
occurred with method A conditions after a few days of
heating. Thienylboronic acids could be coupled to the
ester compound 1 using method C (Na2CO3/DME) but
provided lower yields (about 60%) than with benzenebo-
ronic acid. As far as the 2-phenyl compound 2 is con-
cerned, method D (NaOH/DME) was unable to give the
expected coupling product with thien-2-ylboronic acid in
good yield. From this observation, the reaction was then
performed using Ba(OH)2 in THF (method F) according
to the literature,16 giving 53% yield after 3 h of heating.
To determine the importance of the solvent, we investi-
gated the coupling reaction using Ba(OH)2 in DME in
70% yield.
Reaction of 1 with methylboronic acid was unsuccessful
through method C due to the long reaction time leading
to saponification of the ester function. Methyl coupling
was performed only starting from phenyl compound 2
using method D (NaOH, DME) after 6 h of heating in
good yield (85%). Attempt to shorten the reaction time
using Ba(OH)2 in DME or THF led to almost no reaction.
Con clu sion
After studying many different methods using varying
bases and solvents, the results led us to define the best
conditions of Suzuki reaction on 3-iodoimidazo[1,2-a]-
pyridine depending on the nature of boronic acid and
2-substituent. The base sensitivity of ester function
prevented us from using bases stronger than Na2CO3 or
too long reaction time under Suzuki conditions. However,
the good reactivity of 2-ester compound 1 allowed the
(15) Hamdouchi, C.; de Blas, J .; del Prado, M.; Gruber, J .; Heinz,
B. A.; Vance, L. J . Med. Chem. 1999, 42, 50-59.
(16) Ciufolini, M. A.; Mitchell, J . W.; Roschangar, F. Tetrahedron
Lett. 1996, 37, 8281-8284.

6574 J . Org. Chem., Vol. 65, No. 20, 2000
Enguehard et al.
126.1 (C-5), 118.0 (C-8), 115.7 (2J ) 21.6 Hz, Ph-3,5), 113.7
(C-6), 59.7 (C-3).
coupling reaction with phenyl and thienylboronic acids
to be carried out very efficiently in a short reaction time
using 2 equiv of Na2CO3 in DME (56-91% yields). In the
case of 2-phenyl and 2-alkyl analogues 2-4 the lower
reactivity but the higher stability led us to use NaOH or
Ba(OH)2 in DME with 70-85% yields. Methylboronic acid
appeared to be uncompatible with utilization of Ba(OH)2.
Further confirmation of this reactivity was obtained by
studying methods A and D on the parent heterocycle 5
(Table 1).
In conclusion, the Suzuki cross-coupling procedure
reported here represents a new general and convenient
synthetic approach in good agreement with rapid phar-
macomodulation of 3-arylimidazo[1,2-a]pyridines. The
extension of this method on other bridgehead nitrogen
heterocycles is in progress.
2-ter t-Bu tyl-3-iod o-7-m eth ylim id a zo[1,2-a ]p yr id in e (4):
68% yield; mp 120 °C; 1H NMR δ: 8.08 (d, 1H, J ) 7 Hz, H-5),
7.35 (d, 1H, J ) 1.6 Hz, H-8), 6.70 (d, 1H, H-6), 2.40 (s, 3H,
CH3), 1.57 (s, 9H, CH3); 13C NMR δ: 156.5 (C-2), 147.0 (C-8a),
135.9 (C-7), 125.3 (C-5), 116.2 (C-8), 115.6 (C-6), 55.6 (C-3),
33.6 (tBu), 30.6 (3C, tBu), 21.5 (CH3).
3-Iod oim id a zo[1,2-a ]p yr id in e (5): 87% yield; mp 167 °C;
1H NMR δ: 8.14 (dt, 1H, J ) 6.8 Hz, J ) 1.1 Hz, H-5), 7.70 (s,
1H, H-2), 7.66 (dt, 1H, J ) 9.1 Hz, J ) 1.1 Hz, H-8), 7.28 (ddd,
1H, J ) 6.8 Hz, H-7), 6.97 (td, 1H, H-6); 13C NMR δ: 147.7
(C-8a), 140.2 (C-2), 126.6 (C-7), 126.0 (C-5), 118.1 (C-8), 114.0
(C-6), 61.5 (C-3).
Gen er a l P r oced u r e for th e Su zu k i Rea ction . Meth od
A: To a mixture of 3-iodoimidazo[1,2-a]pyridine derivative (1
mmol) and Pd(PPh3)4 (58 mg, 0.05 mmol) in toluene (8 mL)
was added the corresponding aryl or alkyl boronic acid (1.1
mmol) followed by the addition of sodium carbonate (212 mg,
2 mmol) in water (4 mL). The reaction mixture was heated at
75 °C with vigorous stirring under nitrogen atmosphere, and
the rate of the reaction was followed by TLC. After 24 h of
stirring, a second portion boronic acid (1.1 mmol) was added.
After the starting aryl halide was consumed, the reaction
mixture was poured into water and then extracted with
dichloromethane (2 × 20 mL). The combined organic extracts
were washed with water (20 mL), dried over calcium chloride,
and concentrated to dryness under vacuo. The crude products
were purified by column chromatography (silica gel eluting
with dichloromethane).
Met h od B: To a mixture of 3-iodoimidazo[1,2-a]pyridine
derivative (1 mmol) and Pd(PPh3)4 (58 mg, 0,05 mmol) in
toluene (8 mL) was added phenylboronic acid (134 mg, 1.1
mmol) followed by the addition of sodium hydroxide (80 mg, 2
mmol) in water (4 mL). The reaction mixture was heated at
75 °C with vigorous stirring under nitrogen atmosphere. After
the starting aryl halide was consumed, the reaction mixture
was worked up as described in method A.
Meth od C: The reaction was carried out as described in
method B using the corresponding aryl or alkylboronic acid,
but the solvent was changed to dimethoxyethane and the base
to sodium carbonate.
Meth od D: The same conditions as described in method B
were applied using the corresponding aryl or alkylboronic acid,
but the solvent was changed to dimethoxyethane.
Meth od E: The reaction conditions described in method B
were applied using the corresponding aryl or alkylboronic acid,
but the solvent was changed to dimethoxyethane and the base
to barium hydroxide.
Meth od F : The reaction was carried out as described in
method B using 2-thienyl or 2-methylboronic acid, but the base
was changed to barium hydroxide and the solvent to tetrahy-
drofuran.
Exp er im en ta l Section
Gen er a l. Commercial reagents were used as received
without additional purification. Previously reported imidazo-
[1,2-a]pyridines were obtained using the described procedure:
Ethyl imidazo[1,2-a]pyridine-2-carboxylate,17 2-phenylimidazo-
[1,2-a]pyridine,18 2-(4-fluorophenyl)imidazo[1,2-a]pyridine,9
2-tert-butyl-7-methylimidazo[1,2-a]pyridine,19 imidazo[1,2-a]-
pyridine.20 NMR spectra were run at 200 MHz (1H) and 50
MHz (13C) in CDCl3. Possible inversion of two values in the
13C NMR spectra is expressed by an asterisk. Melting points
are uncorrected.
P r ep a r a tion of Iod o Com p ou n d s. Gen er a l P r oced u r e
for Rea ction w ith Iod in e. To a solution of ethyl imidazo-
[1,2-a]pyridine-2-carboxylate (15.8 mmol) in pyridine (10 mL)
was added iodine (6 g, 23.6 mmol). The reaction mixture was
heated at 50 °C for 5 h and then poured into water (20 mL).
The aqueous solution was extracted with dichloromethane. The
combined organic extracts were washed with water (3 × 20
mL) and dried over calcium chloride, and the solvent was
removed under reduced pressure. The residual material was
purified by column chromatography (neutral alumina, dichlo-
romethane as eluant).
Eth yl 3-iod oim id a zo[1,2-a ]p yr id in e-2-ca r boxyla te (1):
46% yield; mp 144 °C (brown powder); 1H NMR δ: 8.31 (dt,
1H, J ) 7 Hz, J ) 1.1 Hz, H-5), 7.72 (dt, 1H, J ) 9.2 Hz, J )
1.1 Hz, H-8), 7.38 (ddd, 1H, J ) 7 Hz, H-7), 7.05 (td, 1H, H-6),
4.54 (q, 2H, J ) 7.1 Hz, CH2), 1.51 (t, 3H, CH3); 13C NMR δ:
163.1 (CO), 148.2 (C-8a), 138.5 (C-2), 127.5 (C-5,C-7), 119.6
(C-8), 115.1 (C-6), 68.5 (C-3), 61.9 (CH2), 14.8 (CH3).
Gen er a l P r oced u r e for Rea ction w ith NIS. To a solution
of imidazo[1,2-a]pyridine (4 mmol) in dry acetonitrile (5 mL)
was added N-iodosuccinimide (0.95 g, 4 mmol). The reaction
mixture was stirred at room temperature for 30 min, and the
resulting white solid was filtered off, dried, and used without
further purification.
E t h yl 3-p h en ylim id a zo[1,2-a ]p yr id in e-2-ca r b oxyla t e
(6): colorless crystals; 91% yield (method C); mp 96 °C (lit.21
mp 88-90 °C); 13C NMR δ: 163.8 (CO), 144.7 (C-8a), 133.4
(C-2), 131.0 (3C, Ph-1,2,6), 129.8 (Ph-4), 129.2 (2C, Ph-3,5),
128.5 (C-3), 126.6 (C-7), 124.4 (C-5), 119.4 (C-8), 114.1 (C-6),
61.3 (CH2), 14.7 (CH3).
2,3-Dip h en ylim id a zo[1,2-a ]p yr id in e (7): colorless crys-
tals; 71% yield (method D); mp 150 °C (lit.22 mp 151.5-153
°C); 13C NMR δ: 145.2 (C-8a), 142.9 (C-2), 134.6 (Ph-1), 131.2
(2C, Ph′-2,6), 130.3 (Ph′-1), 130.0 (2C, Ph′-3,5), 129.3 (Ph′-4),
128.7 (2C, Ph-2,6*), 128.5 (2C, Ph-3,5*),127.9 (Ph-4), 125.1
(C-7), 123.7 (C-5), 121.5 (C-3), 118.0 (C-8), 112.7 (C-6).
2-(4-Flu or oph en yl)-3-ph en ylim idazo[1,2-a ]pyr idin e (8):
colorless crystals; 47% yield (method A); mp 104 °C; 1H NMR
δ: 7.97 (dt, 1H, J ) 7 Hz, J ) 1 Hz, H-5), 7.77-7.63 (m, 3H,
H-8, Ph-2,6), 7.57-7.43 (m, 5H, Ph′), 7.22 (ddd, 1H, J ) 9.2
Hz, J ) 7 Hz, H-7), 7.03 (t, 2H, J ) 8.9 Hz, Ph-3,5), 6.75 (td,
3-Iod o-2-p h en ylim id a zo[1,2-a ]p yr id in e (2): 83% yield;
mp 168 °C (lit.12 mp 166 °C); 13C NMR δ: 148.3 (C-2, C-8a),
133.5 (Ph-1), 129.3 (2C, Ph-2,6), 128.9 (C-7), 128.8 (2C, Ph-
3,5), 127.1 (Ph-4), 126.5 (C-5), 118.0 (C-8), 113.4 (C-6), 60.4
(C-3).
3-Iod o-2-(4-flu or op h en yl)im id a zo[1,2-a ]p yr id in e (3):
89% yield; mp 185 °C; 1H NMR δ: 8.22 (d, 1H, J ) 6.8 Hz,
H-5), 8.08 (dd, 2H, J ) 5.4 Hz, J ) 8.9 Hz, Ph-2,6), 7.63 (d,
1H, J ) 9 Hz, H-8), 7.28 (ddd, 1H, J ) 6.8 Hz, J ) 1.2 Hz,
H-7), 7.20 (t, 2H, J ) 8.9 Hz, Ph-3,5), 6.94 (td, 1H, H-6); 13C
NMR δ: 163.3 (1J ) 247.6 Hz, Ph-4), 148.5 (C-8a*), 147.7
(C-2*), 130.7 (3J ) 8 Hz, Ph-2,6), 130.1 (Ph-1), 126.9 (C-7),
(17) Lombardino, J . G. J . Org. Chem. 1965, 30, 2403-2405.
(18) Kaye, J . A.; Parris, G. L.; Burlant W. J . J . Am. Chem. Soc. 1953,
75, 748.
(19) Mavel, S.; Renou, J .-L.; Galtier, C.; Ibenmoussa, S.; Teulade,
J .-C.; Chavignon, O.; Essassi, E. M.; Snoeck, R.; Andrei, G.; Witvrouw,
M.; De Clerq, E.; Balzarini, J .; Gueiffier, A. Antiviral Res., submitted.
(20) Roe, A. M. J . Chem. Soc. 1963, 2195-2200.
(21) Mamedov, V. A.; Nuretdinov, I. A.; Sibgatullina, F. G. Bull.
Acad. Sci. USSR Div. Chem. Sci. 1990, 39, 2380-2382.
(22) Okuda, S.; Robinson, M. M. J . Am. Chem. Soc. 1959, 81, 740-
742.

Reactivity of 3-Iodoimidazo[1,2-a]pyridines
J . Org. Chem., Vol. 65, No. 20, 2000 6575
1H, H-6); 13C NMR δ: 162.8 (1J ) 247 Hz, Ph-4), 145.2 (C-8a),
141.9 (C-2), 131.1 (2C, Ph′-2,6), 130.8 (Ph-1*), 130.7 (Ph′-1*),
130.2 (3J ) 9 Hz, 2C, Ph-2,6), 130.1 (2C, Ph′-3,5), 129.4
(Ph′-4), 125.1 (C-7), 123.7 (C-5), 121.3 (C-3), 117.9 (C-8), 115.6
(C-2′), 127.8 (C-4′), 126.9 (C-7), 124.8 (C-5), 122.3 (C-3), 119.4
(C-8), 114.3 (C-6), 61.5 (CH2), 14.7 (CH3). Anal. Calcd for
C14H12N2O2S: C, 61.75; H, 4.44; N, 10.29. Found: C, 61.91; H,
4.47; N, 10.38.
(2J ) 21.6 Hz, 2C, Ph-3,5), 112.8 (C-6). Anal. Calcd for C19H13
-
Eth yl 3-(th ien -3-yl)im id a zo[1,2-a ]p yr id in e-2-ca r boxy-
la te (12): brown powder; 56% yield (method C); mp 134 °C;
1H NMR δ: 8.09 (dt, 1H, J ) 7 Hz, J ) 1.2 Hz, H-5), 7.74 (dt,
1H, J ) 9.2 Hz, J ) 1.2 Hz, H-8), 7.66 (dd, 1H, J ) 3.0 Hz, J
) 1.2 Hz, H-2′), 7.55 (dd, 1H, J ) 5 Hz, H-4′), 7.34 (dd, 1H,
H-5′), 7.29 (ddd, 1H, J ) 7 Hz, H-7), 6.87 (td, 1H, H-6), 4.40
(q, 2H, J ) 7.2 Hz, CH2), 1.39 (t, 3H, CH3); 13C NMR δ: 163.8
(CO), 144.8 (C-8a), 133.8 (C-2), 129.34 (C-5′), 128.0 (C-3′), 127.5
(C-2′), 126.5 (C-7), 126.4 (C-4′), 125.0 (C-3), 124.7 (C-5), 119.5
(C-8), 114.1 (C-6), 61.4 (CH2), 14.7 (CH3). Anal. Calcd for
FN2: C, 79.15; H, 4.54; N, 9.72. Found: C, 79.36; H, 4.38; N,
9.84.
7-Me t h yl-3-p h e n yl-2-t er t -b u t ylim id a zo[1,2-a ]p yr i-
d in e (9): colorless oil wich solidified upon standing; 77%
(method D); 1H NMR δ: 7.50-7.57 (m, 3H, Ph-2,6, H-5), 7.38-
7.41 (m, 4H, Ph-3,4,5, H-8), 6.48 (d, 1H, J ) 7.2 Hz, J ) 1.5
Hz, H-6), 2.40 (s, 3H, CH3), 1.34 (s, 9H, CH3); 13C NMR δ: 152.3
(C-2), 144.0 (C-8a), 134.9 (C-7), 132.5 (2C, Ph-2,6), 132.3
(Ph-1), 129.3 (2C, Ph-3,5), 129.2 (Ph-4), 123.0 (C-5), 119.5
(C-3), 115.7 (C-8), 114.4 (C-6), 33.9 (tBu), 31.7 (3C, tBu), 21.6
(CH3). Anal. Calcd for C18H20N2: C, 81.78; H, 7.63; N, 10.60.
Found: C, 81.91; H, 7.65; N, 10.60.
3-P h en ylim id a zo[1,2-a ]p yr id in e (10): colorless oil (lit.23
mp 97-98 °C); 69% yield (method D); 1H NMR δ: 8.38 (dt, 1H,
J ) 6.8 Hz, J ) 1.2 Hz, H-5), 7.74 (s, 1H, H-2), 7.72 (br d, 1H,
J ) 9.2 Hz, H-8), 7.65-7.45 (m, 5H, Ph), 7.24 (ddd, 1H, J )
6.8 Hz, H-7), 6.84 (td, 1H, J ) 1.2 Hz, H-6), 13C NMR δ: 146.6
(C-8a), 133.0 (C-2), 129.8 (Ph-1), 129.6 (2C, Ph-2,6), 128.8
(Ph-4), 128.5 (2C, Ph-3,5), 126.2 (C-3), 124.6 (C-7), 123.8
(C-5), 118.7 (C-8), 112.9 (C-6).
Eth yl 3-(th ien -2-yl)im id a zo[1,2-a ]p yr id in e-2-ca r boxy-
la te (11): brown powder; 64% yield (method C); mp 84 °C; 1H
NMR δ: 8.10 (dt, 1H, J ) 7 Hz, J ) 1.1 Hz, H-5), 7.74 (dt, 1H,
J ) 9.2 Hz, J ) 1.2 Hz, H-8), 7.62 (dd, 1H, J ) 5.1 Hz, J ) 1.3
Hz, H-5′), 7.33 (dd, 1H, J ) 3.5 Hz, J ) 1.3 Hz, H-3′), 7.31
(ddd, 1H, J ) 7 Hz, H-7), 7.25 (dd, 1H, J ) 5.1 Hz, J ) 3.5 Hz,
H-4′), 6.88 (t, 1H, J ) 7 Hz, H-6), 4.40 (q, 2H, J ) 7.1 Hz,
CH2), 1.36 (t, 3H, J ) 7.1 Hz, CH3); 13C NMR δ: 163.4
(CO), 145.2 (C-8a), 135.2 (C-2), 131.0 (C-3′), 129.2 (C-5′), 128.0
C
14H12N2O2S: C, 61.75; H, 4.44; N, 10.29. Found: C, 61.62; H,
4.51; N, 10.23.
2-P h en yl-3-(th ien -2-yl)im id a zo[1,2-a ]p yr id in e (14): col-
1
orless crystals; 70% yield (method E); mp 164 °C; H NMR δ:
8.03 (dt, 1H, J ) 6.8 Hz, J ) 1.2 Hz, H-5), 7.79 (m, 2H, Ph-
2,6), 7.72 (dt, 1H, J ) 9 Hz, J ) 1.2 Hz, H-8), 7.64 (dt, 1H, J
) 4.6 Hz, J ) 1.6 Hz, H-5′), 7.40-7.24 (m, 6H, Ph-3,4,5, H3′,
H4′, H-7), 6.83 (td, 1H, J ) 6.8 Hz, H-6); 13C NMR δ: 145.8
(C-8a), 144.9 (C-2), 134.2 (Ph-1), 130.7 (C-3′), 130.4 (|C-1′|),
129.3 (C-5′), 128.7 (2C, Ph-2,6*), 128.5 (C-4′), 128.4 (2C,
Ph-3,5*), 128.1 (Ph-4), 126.5 (C-3), 125.6 (C-7), 124.3 (C-5),
117.9 (C-8), 113.8 (C-6). Anal. Calcd for C17H12N2S: C, 73.89;
H, 4.38; N, 10.14. Found: C, 74.04; H, 4.40; N, 10.14.
3-Meth yl-2-p h en ylim id a zo[1,2-a ]p yr id in e (15): yellow
powder; 85% yield (method D); mp 157 °C (lit.9 mp 158-160
1
°C); H NMR δ: 7.94 (dt, 1H, J ) 6.8 Hz, J ) 1.2 Hz, H-5),
7.84 (m, 2H, Ph-2,6), 7.68 (dt, 1H, J ) 9 Hz, H-8), 7.35-7.56
(m, 3H, Ph-3,4,5), 7.21 (ddd, 1H, J ) 9 Hz, J ) 6.8 Hz, H-7),
6.89 (t, 1H, J ) 6.8 Hz, H-6), 2.68 (s, 3H, CH3); 13C NMR δ:
144.8 (C-8a), 142.9 (C-2), 135.3 (Ph-1), 128.9 (2C, Ph-2,6*),
128.8 (2C, Ph-3,5*), 127.8 (Ph-4), 123.9 (C-7), 123.3 (C-5), 117.9
(C-8), 116.30 (C-3), 112.4 (C-6).
(23) Gol′dfarb, Y. L.; Kondakova, M. S. J . Appl. Chem. 1942, 15,
151-163; Chem. Abstr. 1943, 2380-2381.
J O000698Z