Synthesis of polysubstituted imidazo[1,2-a]pyridines via microwave-assisted one-pot cyclization/Suzuki coupling/palladium-catalyzed heteroarylation

Article abstract of DOI:10.1021/jo0712603

(Chemical Equation Presented) A new and efficient method for the synthesis of 2,3,6-trisubstituted imidazo[1,2-a]pyridine derivatives using a microwave-assisted one-pot, two-step Suzuki/heteroarylation or one-pot, three-step cyclization/Suzuki/heteroarylation was developed. Polysubstituted compounds are obtained in good yield from 2-amino-5-halogenopyridines, 2-halogenocarbonyl derivatives, boronic acids, and heteroaryl bromides.

Full text of DOI:10.1021/jo0712603

Synthesis of Polysubstituted Imidazo[1,2-a]pyridines via
Microwave-Assisted One-Pot Cyclization/Suzuki Coupling/
Palladium-Catalyzed Heteroarylation
Jamal Koubachi,†,‡ Sa¨ıd El Kazzouli,†,‡ Sabine Berteina-Raboin,*,†
Abderrahim Mouaddib,‡ and Ge´rald Guillaumet†
Institut de Chimie Organique et Analytique, UMR CNRS 6005, UniVersite´ d’Orle´ans, BP 6759,
45067 Orle´ans Cedex 2, France, and Faculte´ des Sciences et Te´chniques de Be´ni-Mellal,
UniVersite´ Cadi-Ayyad, BP 523, 23000 Be´ni-Mellal, Morocco
sabine.berteina-raboin@uniV-orleans.fr
ReceiVed June 13, 2007
A new and efficient method for the synthesis of 2,3,6-trisubstituted imidazo[1,2-a]pyridine derivatives
using a microwave-assisted one-pot, two-step Suzuki/heteroarylation or one-pot, three-step cyclization/
Suzuki/heteroarylation was developed. Polysubstituted compounds are obtained in good yield from
2-amino-5-halogenopyridines, 2-halogenocarbonyl derivatives, boronic acids, and heteroaryl bromides.
SCHEME 1. Heteroarylation on
6-Chloroimidazo[1,2-a]pyridines 1 and 2
Introduction
Imidazo[1,2-a]pyridine derivatives have been shown to
exhibit a diverse range of therapeutic properties such as
melatonin receptor ligands,1 antiviral,2 antiulcer,3 antibacterial,4
† Universite´ d’Orle´ans.
‡ Universite´ Cadi-Ayyad.
(1) Guillaumet, G.; Berteina-Raboin, S.; El Kazzouli, S.; Delagrange,
P.; Caignard, D.-H. PCT, Int. Appl. WO 027474, 2006; Chem. Abstr. 2006,
144, 254132.
antifungal,5 agonist of benzodiazepine receptor,6 calcium channel
(2) (a) Elhakmoui, A.; Gueiffier, A.; Milhavet, J. C.; Blache, Y.; Chapat,
J. P. Bioorg. Med. Chem. Lett. 1994, 4, 1937. (b) Gueiffier, A.; Lhassani,
M.; Elhakmoui, A.; Snoeck, R.; Andrei, G.; Chavignion, O.; Teulade, J.
C.; Kerbal, A.; Essassi, M.; Debouzy, J. C.; Witurowo, J. P.; Blache, Y.;
Balzarini, J.; De Clercq, E.; Chapat, J. P. J. Med. Chem. 1996, 39, 2856.
(c) Lhassani, M.; Chavignion, O.; Chezal, J. M.; Teulade, J. C.; Chapat, J.
P.; Snoeck, R.; Andrei, G.; Balzarini, J.; De Clercq, E.; Gueiffier, A. J.
Med. Chem. 1999, 34, 271. (d) Gudmundsson, K. S.; Drach, J. C.;
Townsend, L. B. J. Org. Chem. 1997, 62, 3453. (e) Pan, S.; Wang, G.;
Shinazi, R. F.; Zhao, K. Tetrahedron Lett. 1998, 39, 2695. (f) Hamdouchi,
C.; de Blas, J.; del Prado, M.; Gruber, J.; Heinz, B. A.; Vance, L. J. Med.
Chem. 1999, 42, 50. (g) Gudmundsson, K. S.; Williams, J. D.; Drach, J.
C.; Townsend, L. B. J. Med. Chem. 2003, 46, 1449.
blocker,7 â-amyloid formation inhibitor,8 or ligand for detecting
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9631 509, 1996; Chem. Abstr. 1997, 126, 8117j. Abiegnente, E. Act. Chim.
Therap. 1991, 18, 1253.
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Med. Chem 1991, 34, 2060. (b) G. Trapani, M. Franco, A. Latrofa, L.
Ricciardi, A. Carotti, M. Serra, E. Sanna, G. Biggio, G. Liso, J. Med. Chem.
1999, 42, 3934. (c) G. Trapani, M. Franco, L. Ricciardi, A. Latrofa, G.
Genchi, E. Sanna, F. Tuveri, E. Gagetti, G. Biggio, G. Liso, J. Med. Chem.
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10.1021/jo0712603 CCC: $37.00 © 2007 American Chemical Society
Published on Web 09/05/2007
7650
J. Org. Chem. 2007, 72, 7650-7655

Synthesis of Polysubstituted Imidazo[1,2-a]pyridines
FIGURE 1. Trisubstituted imidazoles and imidazopyrimidines.
TABLE 1. Optimization of Heteroarylation on
6-Chloroimidazo[1,2-a]pyridines 1 and 2
TABLE 2. Results of One-Pot Suzuki/Heteroarylation or
Heteroarylation/Suzuki on 1
reaction time (h)
conv yield
reaction
time
reaction
time
entry R 1 catalyst system
/T (°C)
compd (%)
(%)
% yield
entry catalyst system method
(step 1)
(step 2)
(3/5/6)
1
2
3
4
H
H
Pd(PPh3)4
Pd(OAc)2/PPh3
3/150
2/150
3/150
2/150
3
3
4
4
80
100
45
61
80
29
91
1
2
3
4
Pd(PPh3)4
Aa
1 h 15 min 3 h
0/42/25
Ph Pd(PPh3)4
Ph Pd(OAc)2/PPh3
Bb
3 h
3 h
2 h
1 h 15 min 0/40/23
2 h
3 h
100
Pd(OAc)2/PPh3
A′ a
B′ b
53/0/20
51/0/22
a One-pot Suzuki/heteroarylation. b One-pot heteroarylation/Suzuki.
SCHEME 2. Suzuki Cross-Coupling on
6-Chloroimidazo[1,2-a]pyridines 1
developed a one-pot synthesis of these substrates by tandem
cyclization, Suzuki coupling, and heteroarylation reactions using
2-amino-5-bromopyridine as starting material. As far as we
know, the previous published methods toward making 2,3,6-
trisubstituted imidazo[1,2-a]pyridines required four separate
steps: cyclization,18 Suzuki19 or Stille coupling20 at the 6-posi-
tion, preparation of 3-halogenoimidazo[1,2-a]pyridines,2f,21 and
then Suzuki22 or Stille23 coupling at the 3-position. Therefore,
within the area of heteroaromatic systems, palladium is often
used to catalyze only one single reaction; hence, a few examples
of one-pot coupling are known.24
â-amyloid9 and constitute a novel class of orally active
nonpeptide bradykinin B2 receptor antagonists.10 Moreover, the
imidazo[1,2-a]pyridine derivative zolpidem was commercialized
as a hypnotic.11
Recently, new trisubstituted imidazoles and imidazopyrim-
idines have been described as kinase inhibitors (compounds I,
II,12 and V,13 Scheme 1), acyl-COAs (cholesterol O-acyltrans-
ferase) (compound III,14 Figure 1), and ALK5 inhibitors
(compound IV,15 Figure 1). Interestingly, all of these compounds
show strong similarity to 3,6-di- or 2,3,6-tri(hetero)arylimidazo-
[1,2-a]pyridines VI (Figure 1). For this reason, we focused our
attention on an expeditious approach to compounds VI.
In continuation with our research on imidazo[1,2-a]pyridine
derivatives,1,16 we recently reported a versatile ring transforma-
tion providing access to 3-(hetero)arylimidazo[1,2-a]pyridines.17
In this paper, we report a microwave-assisted one-pot Suzuki/
heteroarylation preparation of 2,3,6-tri(hetero)arylimidazo[1,2-
a]pyridines from 6-halogeno-2-substituted imidazo[1,2-a]-
pyridines, boronic acids, and heteroaryl bromides. We have also
Results and Discussion
One-Pot Suzuki/Heteroarylation or Heteroarylation/Su-
zuki on 6-Chloroimidazo[1,2-a]pyridines. The required imi-
(13) Dodd, J. H.; Henry, J. R.; Rupert, K. C. PCT Int. Appl. WO 01/
34605; Chem. Abst. 2001, 134, 366888.
(14) Astles, P. C.; Ashton, M. J.; Bridge, A. W.; Harris, N. V.; Hart, T.
W.; Parrott, D. P.; Porter, B.; Riddel, D.; Smith, C.; Williams, R. J. J. Med.
Chem. 1996, 39, 1423.
(15) Callahan, J. F.; Burgess, J. L.; Fornwald, J. A.; Gaster, L. M.;
Harling, J. D.; Harrington, F. P.; Heer, J.; Kwon, C.; Lehr, R.; Mathur, A.;
Olson, B. A.; Weinstock, J.; Laping, N. J. J. Med. Chem. 2002, 45, 999.
(16) (a) El Kazzouli, S.; Berteina-Raboin, S.; Mouaddib, A.; Guillaumet,
G. Tetrahedron Lett. 2003, 45, 3193. (b) El Kazzouli, S.; Berthaut, A.;
Berteina-Raboin, S.; Mouaddib, A.; Guillaumet, G. Lett. Org. Chem. 2005,
2, 184.
(8) Fuchs, K.; Romig, M.; Mendla, K.; Briem, H.; Fechteler, K. WO 14
131; Chem. Abstr. 2002, 136, 183824r.
(9) Zhuang, Z. P.; Kung, M. P.; Wilson, A.; Lee, C. W.; Plo¨ssl, K.; Hou,
C.; Holtzman, D. M.; Kung, H. F. J. Med. Chem. 2003, 46, 237.
(10) Abe, Y.; Kayakiri, H.; Satoh, S.; Inoue, T.; Sawada, Y.; Imai, K.
H. J. Med. Chem. 1998, 41, 564.
(17) Koubachi, J.; El Kazzouli, S.; Berteina-Raboin, S.; Mouaddib, A.;
Guillaumet, G. Synlett. 2006, 3237.
(18) Gueiffier, A.; Mavel, S.; Lhassani, M.; Elhakmaoui, A.; Snoeck,
R.; Andrei, G.; Chavignon, O.; Teulade, J.-C.; Witvrouw, M.; Balzarini,
J.; De Clercq, E.; Chapat, J.-P. J. Med. Chem. 1998, 41, 5108.
(19) Enguehard, C.; The´ry, I.; Hervet, M.; Renou, J. L.; Fauvelle, F.;
Gueiffier, A. HelV. Chim. Acta 2001, 84, 3610.
(20) Hervet, M.; The´ry, I.; Gueiffier, A.; Enguehard, C. HelV. Chim. Acta
2003, 86, 3461.
(21) (a) Paolini, J. P.; Robins, R. K. J. Org. Chem. 1965, 30, 4085. (b)
Fischer, M. H.; Lusi, A. J. Med. Chem. 1972, 15, 982. (c) Hand, E. S.;
Paudler, W. W. J. Org. Chem. 1978, 43, 2900. (d) Gudmundsson, K. S.;
Drach, J. C. Tetrahedron Lett. 1996, 37, 6275.
(11) Holm, K. J.; Goa, K. L. Drugs 2000, 59, 865.
(12) (a) Wilson, K. P.; McCaffrey, P. G.; Hsiao, K.; Pazhanisamy, S.;
Galillo, V.; Bemis, G. W.; Fitzgibbn, M. J.; Caron, P. R.; Murcko, M. A.;
Su, M. S. Chem. Biol. 1997, 4, 423. (b) McLay, I. M.; Halley, F.; Souness,
J. E.; McKenna, J.; Benning, V.; Birrel, M.; Burton, B.; Belvisi, M.; Collis,
A.; Constan, A.; Foster, M.; Hele, D.; Jayyosi, Z.; Kelly, M.; Maslen, C.;
Miller, G.; Ouledlhkim, M. C.; Page, K.; Phipps, S.; Pollock, K.; Porter,
B.; Ratcliffe, A. J.; Redford, E. J.; Webber, S.; Slater, B.; Thybaud, V.;
Wilsher. Bioorg. Med. Chem. 2001, 9, 537.
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J. Org. Chem, Vol. 72, No. 20, 2007 7651

Koubachi et al.
SCHEME 3. One-Pot Suzuki/Heteroarylation or Heteroarylation/Suzuki on Compound 1
SCHEME 4. Suzuki Cross-Coupling on
6-Bromoimidazo[1,2-a]pyridines 7
dazo[1,2-a]pyridine intermediates 1 and 2 were prepared by
condensation of the suitable 2-amino-5-substituted pyridines
with R-halogenocarbonyl derivatives in refluxing ethanol ac-
cording to a literature procedure.18
Heteroarylation. In our previous work, we mentioned that
the chloro substituent survived during the (hetero)arylation
reaction conditions on 6-chloroimidazo[1,2-a]pyridines.17 We
anticipated that this chloro substituent would react in the same
pot (one-pot polycoupling) with boronic acid in the presence
of Pd(0) which could be generated in situ after the heteroary-
lation reaction. To explore the potential of this approach, first,
we sought to investigate the best methods reported for Suzuki
coupling21 [Pd(Ph3)4] and heteroarylation reactions17 [Pd(OAc)2/
PPh3] on 6-chloroimidazo[1,2-a]pyridines in the heteroarylation
reaction under microwave irradiation (Scheme 1). Thus, the
reactions between starting material 1 or 2 and 3-bromopyridine
in the presence of Pd(PPh3)4 at 150 °C for 3 h in a mixture of
dioxane/EtOH gave the desired compounds 3 and 4 in 61% and
29% yields, respectively (Table 1, entries 1 and 3). Interestingly,
the use of Pd(OAc)2/PPh3 under similar reaction conditions
(150 °C, 2 h) also proceeded smoothly, and the expected
compounds 3 and 4 were obtained in 80% and 91% yields
(Table 1, entries 2 and 4).
Suzuki Cross-Coupling. The scope and limitation of the
Suzuki cross-coupling under the optimized heteroarylation
conditions was then investigated. The coupling between 6-chlor-
oimidazo[1,2-a]pyridine 1 and p-thiomethylphenylboronic acid
(Scheme 2) using Pd(PPh3) resulted in total conversion after 1
h 15 min and in 82% yield, while the Pd(OAc)2/PPh3 catalyst
system only led to incomplete conversion (62% after 3 h) and
compound 5 was obtained in only 45% yield.
while 53% yield of monocoupled side product 3 was obtained
using method A′. In contrast, the desired compound 6 was only
isolated in 25% and 20% yield (Table 2, entries 1 and 3).
Switching of the reaction sequence (conditions B and B′) gave
similar results (Table 2, entries 2 and 4). It is noteworthy that
the advantage of using 6-chloroimidazo[1,2-a]pyridine 1 as
starting material was that the reaction could be carried out in
two different directions: Suzuki/heteroarylation (A, A′) and
heteroarylation/Suzuki (B, B′). Unfortunately, a major limitation
with this substrate is the poor yield of the expected double
coupled compound 6.
One-Pot Suzuki/Heteroarylation on 6-Bromoimidazo[1,2-
a]pyridines. Suzuki Cross-Coupling. To overcome these
limitations, an alternative strategy was then investigated. This
approach is based on the use of 6-bromoimidazo[1,2-a]pyridine
derivatives as starting material (Scheme 4). In this case, it was
essential to start with Suzuki cross-coupling17 to achieve this
catalytic process in the same pot. We found the coupling on
6-bromoimidazo[1,2-a]pyridine 7 afforded the desired com-
pound 5 in excellent yields and quickly using both catalyst
systems [Pd(PPh3)4 (method A), 20 min] in 87% yield or [Pd-
(OAc)2/PPh3 (method A′), 20 min] in 89% yield.
One-Pot Reaction. The one-pot cross-coupling (Scheme 5)
between 7, p-thiomethylphenylboronic acid, and 3-bromopyri-
dine under reaction conditions A (Pd(PPh3)4) afforded a mixture
of 5 and expected product 6 in moderate yield (30 and 35%,
respectively) while the use of method A′ (Pd(OAc)2/PPh3) gave
3,6-disubstituted imidazo[1,2-a]pyridine 6 in 71% yield without
traces of monosubstituted compound 5.
With a suitable protocol in hand (Pd(OAc)2/PPh3 as catalyst
in a mixture of dioxane/EtOH at 150 °C, MW), the scope of
the one-pot tandem Suzuki and heteroarylation coupling was
extended to the synthesis of various polysubstituted imidazo-
[1,2-a]pyridine analogues. In all cases, the starting materials
7,18 8,18 and 918 (Scheme 6) were first treated with various
boronic acids for 20 min, and then heteroaryl bromides were
added and the reactions were irradiated for 2 h (150 °C). The
expected products (Table 3, entries 1-9) were obtained in good
yields.
One-Pot Reaction. We studied these palladium catalysts on
the one-pot cross-coupling using 1 as starting substrate to
identify the best routes to lead to disubstituted compound 6
(Scheme 3). We investigated different ways: methods A and
A′ (one-pot Suzuki/heteroarylation) or B and B′ (one-pot
heteroarylation/Suzuki). Thus, when 1 was treated under condi-
tions A or A′ (Table 2, Scheme 3), two different compounds
was generated in each case. The monocoupled side product 5
was formed as the major compound in 42% yield (method A),
(23) (a) Kawai, Y.; Satoh, S.; Yamasaki, H.; Kayakiri, N.; Yoshihara,
K.; Oku, T. P. C. T. WO 96/34866; Chem. Abstr. 1996, 126, 74840. (b)
Badger, A.; Bender, P.; Esser, K.; Griswold, D.; Nabil, H.; Lee, J.; Votta,
B.; Simon, P. P. C. T. WO 91/00092; Chem. Abstr. 1991, 115, 64756.
(24) For some examples of multifunctional Pd catalysts that promote
sequential one-pot processes, see: (a) Kasawasaki, I.; Yamashita, M.; Ohta,
S. J. Chem. Soc., Chem. Commun. 1994, 2085. (b) Heynderickx, A.; Samat,
A.; Guglielmetti, R. Synthesis 2002, 213. (c) Duan, X.-F.; Li, X. -H.; Li,
F.-Y.; Huang, C.-H. Synthesis 2004, 2614. (d) Handy, T.-S.; Sabatini, J.-J.
Org. Lett. 2006, 8, 1537. (e) DiMauro, E. F.; Vitullo, J. R. J. Org. Chem.
2006, 71, 3959.
One-Pot Cyclization/Suzuki Coupling/Palladium-Cata-
lyzed Heteroarylatio. In the final phase of our studies, we
generated the desired 2,3,6-trisubstituted imidazo[1,2-a]pyridines
in a one-pot, three-step reaction starting from the commercially
7652 J. Org. Chem., Vol. 72, No. 20, 2007

Synthesis of Polysubstituted Imidazo[1,2-a]pyridines
TABLE 3. Results of the One-Pot, Two-Step Suzuki/Heteroarylation
SCHEME 5. One-Pot Reaction on 6-Bromoimidazo[1,2-a]pyridines 7
SCHEME 6. One-Pot, Two-Step Suzuki/Heteroarylation
without workup with R-halogenocarbonyl derivatives (cycliza-
tion for 20 min). After cooling to ambient temperature,
palladium acetate, triphenylphosphine, and boronic acids were
added, and the reaction mixture was irradiated for 20 min
(Suzuki coupling), and finally, after another cooling to room
temperature, pyridine bromide derivatives were added and the
reaction mixture was irradiated again for 2 h (heteroarylation
reaction). These sequences afforded desired 2,3,6-trisubstituted
imidazo[1,2-a]pyridines in nearly quantitative conversions. This
whole sequence was carried out under microwave irradiation
at 150 °C (Scheme 7). The compounds 6, 10, 16, and 18-20
were isolated in good overall yields (Table 4, entries 1-6).
available 2-amino-5-bromopyridine by tandem cyclization/
Suzuki cross-coupling/palladium-catalyzed heteroarylation. After
careful screening of the reaction conditions, we found the
optimized procedure. Thus, under microwave irradiation, 2-amino-
5-bromopyridine was treated successively in the same pot
J. Org. Chem, Vol. 72, No. 20, 2007 7653

Koubachi et al.
SCHEME 7. One-Pot, Three-Step Cyclization/Suzuki/Heteroarylation
TABLE 4. Results of the One-Pot, Three-Steps Cyclization/Suzuki/Heteroarylation
of a mixture of 1,4-dioxane/ EtOH (2/1, v/v) in a vial microwave
tube with a stir bar were added 3-bromopyridine (1.5 equiv),
potassium carbonate (2 equiv), triphenylphosphine (0.2 equiv), and
palladium(II) acetate (0.1 equiv) under argon, and then the tube
was sealed with a silicon septum and subjected to microwave
irradiation at 150 °C with stirring. The reaction vessel was allowed
to cool to room temperature, and the solution was diluted with
dichloromethane (15 mL) and extracted (3×). The combined organic
layers were dried over MgSO4 and concentrated under vacuum.
The residue was purified by column chromatography on silica gel
(EtOAc/PE) to give the desired products 3 and 4.
In conclusion, we have developed a novel and rapid approach
for the synthesis of 3,6-di- or 2,3,6-tri(hetero)arylimidazo[1,2-
a]pyridines by a microwave-assisted one-pot, two-step Suzuki
coupling/palladium-catalyzed heteroarylation or one-pot, three-
step cyclization/Suzuki coupling/palladium-catalyzed heteroary-
lation reaction. We found optimal conditions using the Pd-
(OAc)2/PPh3 system as catalyst in the mixture of dioxane/EtOH
at 150 °C. This approach has the potential to be of great benefit
in the rapid and convergent synthesis of substituted imidazo-
[1,2-a]pyridines. The overall process represents the first example
of the one-pot cyclization/Suzuki cross-coupling/regioselective
heteroarylation under microwave irradiations. We are currently
working on the extension of this method to include other
heterocyclic systems and other palladium and/or copper cross-
coupling reactions.
Method 2. The reaction was carried out as described in method
1 using the corresponding 3-bromopyridine (1.5 equiv); in this case,
the catalyst (Pd(OAc)2/PPh3) was changed to Pd(PPh3)4.
Procedure for Suzuki Cross-Coupling Reaction of 6-Chloro-
or 6-Bromoimidazo[1,2-a]pyridine and p-Methylsulfanylphe-
nylboronic Acid under Microwave Irradiation (Scheme 2).
Method 3. To a solution of 6-chloro- or 6-bromoimidazo[1,2-a]-
pyridine (0.1 g) dissolved in 2 mL of a mixture of 1,4-dioxane/
EtOH (2/1, v/v) in a vial microwave tube with a stir bar were added
p-methylsulfanylphenylboronic acid (1.2 equiv), potassium carbon-
ate (2 equiv), triphenylphosphine (0.2 equiv), and palladium(II)
acetate (0.1 equiv) under argon. The reaction vessel was sealed
with a silicon septum and subjected to microwave irradiation at
Experimental Section
Procedure for Heteroarylation of 6-Chloroimidazo[1,2-a]-
pyridine or 6-Chloro-2-phenylimidazo[1,2-a]pyridine and 3-Bro-
mopyridine under Microwave Irradiation (Scheme 1, Table 1).
Method 1. To a solution of 6-chloroimidazo[1,2-a]pyridine or
6-chloro-2-phenylimidazo[1,2-a]pyridine (0.1 g) dissolved in 2 mL
7654 J. Org. Chem., Vol. 72, No. 20, 2007

Synthesis of Polysubstituted Imidazo[1,2-a]pyridines
150 °C with stirring. The reaction mixture was then allowed to
cool to room temperature, diluted with dichloromethane (15 mL),
and extracted (3×). The combined organic layers were dried over
MgSO4 and concentrated under reduced pressure. The crude
material was purified by column chromatography on silica gel
(EtOAc/PE) to give 6-(4-methylsulfanylphenyl)imidazo[1,2-a]py-
ridine 5.
Method 4. The reaction was carried out as described in method
3 using the corresponding p-methylsulfanylphenylboronic acid (1.2
equiv); in this case, the catalyst (Pd(OAc)2/PPh3) was changed to
Pd(PPh3)4.
General Procedure for One-Pot Suzuki/Heteroarylation on
6-Bromoimidazo[1,2-a]pyridines (Scheme 3, Table 2). Method
A′. To a solution of 6-bromoimidazo[1,2-a]pyridine (0.1 g) in 2
mL of a mixture of 1,4-dioxane/ EtOH (2/1, v/v) in a vial
microwave tube were added arylboronic acid (1.2 equiv), potassium
carbonate (2 equiv), triphenylphosphine (0.2 equiv), and palladium-
(II) acetate (0.1 equiv) under argon. The reaction vessel was sealed
with a silicon septum and subjected to microwave irradiation for
20 min at 150 °C with stirring. After the mixture was cooled to
room temperature, heteroaryl bromide (1.5 equiv) was injected into
the tube via a syringe, and the reaction mixture was subjected again
to microwave irradiation at 150 °C for 2 h. The reaction vessel
was cooled to room temperature, diluted with dichloromethane (15
mL), and extracted (3×). The combined organic layer was dried
over MgSO4 and concentrated under vacuum. The crude material
thus obtained was purified by column chromatography on silica
gel (EtOAc/PE) to give polysubstitued imidazo[1,2-a]pyridine
derivatives 6 and 10-17.
microwave irradiation for 20 min at 150 °C with stirring. After
being cooled to room temperature, the reaction vessel was unsealed,
and arylboronic acid (1.2 equiv), triphenylphosphine (0.2 equiv),
and palladium(II) acetate (0.1 equiv) were added under argon. The
reaction vessel was sealed again with a silicon septum and irradiated
for 20 min at 150 °C with stirring. After another cooling to room
temperature, heteroaryl bromide (1.5 equiv) was injected into the
tube via syringe and the reaction mixture was irradiated at 150 °C
for 2 h. Finally, the mixture was cooled to room temperature, diluted
with dichloromethane (15 mL), and extracted (3×). The combined
organic layers were dried over MgSO4 and solvents removed under
reduced pressure. The crude material obtained was purified by
column chromatography on silica gel (EtOAc/PE) to give polysub-
stitued imidazo[1,2-a]pyridine derivatives 6, 15, 16, 18 , and 20.
All yields mentioned in the tables are isolated yields.
6-(4-Methylsulfanylphenyl)-3-pyridin-3-ylimidazo[1,2-a]py-
ridine 6: yellow solid; one-pot, three-steps, 51% yield; mp 124-
1
125 °C; H NMR (CDCl3, 250 Hz) δ 2.50 (s, 3H), 7.31 (d, 1H, J
) 8.4 Hz), 7. 46 (m, 4H), 7.75 (d, 2H, J ) 10.6 Hz), 7.91 (dt, 1H,
J ) 1.9, 7.8 Hz), 8.39 (s, 1H), 8.67 (dd, 1H, J ) 1.5, 4.7 Hz), 8.89
(d, 1H, J ) 1.5 Hz); 13C NMR (CDCl3, 62.5 Hz) δ 15.9, 118.5,
120.0, 122.9, 124.2, 125.6, 125.8, 127.2, 127.3, 127.5, 133.9, 134.2,
135.4, 139.1, 146.1, 149.1, 149.5; HRMS calcd for C19H15N3S (M+)
317.09867, found 317. 0967.
Note Added after ASAP Publication: Reference 21b was
incorrect in the version published September 5, 2007; the correct
version was published September 7, 2007.
General Procedure for One-Pot Cyclization/Suzuki/Het-
eroarylation Reaction (Scheme 7, Table 4). To a solution of
2-amino-5-bromopyridine (0.1 g) in 2 mL of a mixture of
1,4-dioxane/EtOH (2/1, v/v) in a vial microwave tube with a stir
bar were added potassium carbonate (2 equiv) and R-halgeno ketone
(1.05 equiv) under argon. The reaction mixture was subjected to
Supporting Information Available: Full characterization data
for compounds 3-6 and 10-20. This material is available free of
charge via the Internet at http://pubs.acs.org.
JO0712603
J. Org. Chem, Vol. 72, No. 20, 2007 7655