Microwave-assisted organic synthesis of 3-substituted-imidazo[1,5-a]pyridines

Article abstract of DOI:10.1016/j.tetlet.2009.10.137

3-Substituted-imidazo[1,5-a]pyridines were conveniently synthesized in two steps from commercially available picolinic esters under microwave irradiation conditions.

Full text of DOI:10.1016/j.tetlet.2009.10.137

Tetrahedron Letters 51 (2010) 284–286
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Microwave-assisted organic synthesis of 3-substituted-imidazo[1,5-a]pyridines
Venkata Satyanarayana Arvapalli, Guangwu Chen, Sergey Kosarev, Meifen Evonne Tan, Dejian Xie,
*
Larry Yet
AMRI Singapore Research Centre, Pte. Ltd, 61 Science Park Road, #05-01 The Galen, Science Park III, 117525, Singapore
a r t i c l e i n f o
a b s t r a c t
Article history:
3-Substituted-imidazo[1,5-a]pyridines were conveniently synthesized in two steps from commercially
available picolinic esters under microwave irradiation conditions.
Ó 2009 Elsevier Ltd. All rights reserved.
Received 1 October 2009
Revised 27 October 2009
Accepted 28 October 2009
Available online 5 November 2009
The imidazo[1,5-a]pyridine skeleton (2-azaindolizines) has
potential applications in organic light-emitting diodes (OLEDs),1
in organic thin-layer field effect transistors (FETs),2 and as precur-
sors of N-heterocyclic carbenes.3 Pharmaceutical applications such
as cardiotonic agents,4 aromatase inhibitors in estrogen-dependent
diseases,5 thromboxane A2 synthetase inhibitors,6 and angiotensin
II receptor antagonists7 have also been reported in the literature. A
variety of methods have been employed in the synthesis of these 2-
azaindolizines. Most routes relying on traditional Vilsmeier-type
cyclizations of N-2-pyridylmethyl amides are only modestly effi-
cient.8–10 N-2-Pyridylmethyl thioamides have also been cyclized
tate at reflux allowed the introduction of various substituents at
the 1- and 3-positions.19
We now report a convenient microwave-assisted organic syn-
thesis of 3-substituted-imidazo[1,5-a]pyridines and describe the
scope and limitation of this method. Methyl picolinate (1) was re-
acted with various amines under microwave irradiation at 200 °C
in anhydrous 1,4-dioxane to give picolinamides 2,20 which after
isolation were then cyclized in phosphorus oxychloride also
under microwave conditions at 150 °C for 45 min or at 180 °C
for 10 min to give 3-substituted-imidazo[1,5-a]pyridines 321
(Scheme 1).
RCH2NH2
POCl3
H
1,4-dioxane
OCH3
150 ºC, 45 min
or 180 ºC, 10 min
microwave irradiation
N
N
R
N
200 ºC, 1–2 h
N
N
microwave irradiation
O
R
O
1
3
2
Scheme 1. Microwave-assisted organic synthesis of 3-substituted-imidazo[1,5-a]pyridines.
with dicyclohexylcarbodiimide,11 mercuric salts,12 and iodine/pyr-
idine.13 These general methods either give low to moderate yields,
require harsh prolonged thermal reaction conditions giving tarry
materials, or use environmentally toxic reagents. Other methods
of preparing 2-azaindolizines include the use of imine deriva-
tives,14 benzotriazoles,15 2,20-pyridils,16 and dipyridylketones.17
Recently, an oxidative condensation-cyclization of aldehydes and
aryl-2-pyridylmethylamines in the presence of elemental sulfur
as an oxidant afforded a variety of 1,3-diarylated imidazo[1,5-
a]pyridines18, and a one-pot synthesis of imidazo[1,5-a]pyridines
starting from a carboxylic acid and 2-methylaminopyridines using
propane phosphoric acid anhydride (T3P) in ethyl or n-butyl ace-
The reactions of methyl picolinate (1) with a series of substi-
tuted benzylamines were first investigated and the results are
shown in Table 1. N-Benzyl picolinamides 2a–e having hydrogen,
halogen, and electron-withdrawing substituents all provided
cyclized products 3a–e in good yields (entries 1–5). The yields
for 3a (R = phenyl, 92%) and 3d (R = 4-Cl-phenyl, 64%) under micro-
wave conditions were higher than those reported previously for
the same thermal reaction of the N-benzylpicolinamides in phos-
phorus pentachloride in chloroform or pyridine where 3a and 3d
were obtained in yields of 20% and 31%, respectively.22 N-Benzyl
picolinamides 2f–h electron-donating benzylamines such as
4-methoxy, 4-N,N-dimethylamino, and 3,4-methylenedioxy failed
to provide any of the desired cyclized products 3f–h, respectively
(entries 6–8). 2-Methoxybenzylamine (entry 9) afforded cyclized
product 3i in poor yield.
* Corresponding author.
E-mail address: Larry.Yet@amriglobal.com (L. Yet).
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.10.137

V. S. Arvapalli et al. / Tetrahedron Letters 51 (2010) 284–286
285
Table 1
Synthesis of picolinamides and conversion to phenyl-substituted imidazo[1,5-a]pyridines
RCH2NH2
POCl3
1,4-dioxane
H
150 ºC, 45 min
OCH3
N
R
N
N
200 ºC, 1–2 h
N
N
or 180 ºC, 10 min
microwave irradiation
O
microwave irradiation
O
2a-i
R
1
3a-i
Entry
R
2 (% yield)
3 (% yield)
1
2
3
4
5
6
7
8
9
Phenyl
4-CF3-phenyl
4-CN-phenyl
4-Cl-phenyl
4-F-phenyl
4-OMe-phenyl
4-NMe2-phenyl
3,4-Methylenedioxyphenyl
2-OMe-phenyl
2a (60)
2b (48)
2c (37)
2d (94)
2e (95)
2f (98)
2g (37)
2h (97)
2i (63)
3a (92)
3b (89)
3c (98)
3d (64)
3e (96)
3f (NR)
3g (NR)
3h (NR)
3i (11)
The introduction of substituents other than phenyl or substi-
tuted phenyl groups at the 3-position of the imidazo[1,5-a]pyri-
dine ring system were then investigated and the results are
shown in Table 2. 4-Pyridylmethylamine (entry 1) gave 3-(4-pyri-
dyl)imidazo[1,5-a]pyridine (3j) in moderate yield. Aliphatic
amines such as ethylglycine hydrochloride (entry 2) and isocya-
nomethanamine (entry 3) afforded ester and cyano derivatives
3k and 3l, respectively. However, 2,2-dimethoxyethanolamine
(entry 4) failed to give the acetal product 3m, which is a useful
precursor to the aldehyde functionality.
The scope of this method was expanded by investigating
substitution on the pyridine ring system. Dimethyl pyridine-2,5-
dicarboxylate (4) was converted to the picolinamides 5a–c23 via
a
magnesium–chloride-mediated coupling with 4-substituted
benzylamines. Microwave irradiation of 7 with phosphorus oxy-
chloride provided methyl 3-substituted-imidazo[1,5-a]pyridine-
7-carboxylates 6a–c (Scheme 2). The ester group provides a useful
handle for further elaboration of these molecules.
The proposed mechanism of the cyclization step outlined in
Scheme 3 was previously presented and validated by deuterium-
Table 2
Synthesis of picolinamides and conversion to 3-substituted imidazo[l,5-a]pyridines
POCl3
RCH2NH2
1,4-dioxane
H
150 ºC, 45 min
or 180 ºC, 10 min
microwave irradiation
OCH3
N
N
R
N
200 ºC, 1–2 h
N
N
O
microwave irradiation
O
R
1
3j-m
2j-m
Entry
R
2 (% yield)
3 (% yield)
l
4-Pyridyl
CO2Et
CN
2j (65)
2k (45)
2l (36)
2m (63)
3j (62)
2
3
4
3k (70)
31 (29)
3m (NR)
CH(OMe)2
O
R
O
R
H2N
H3CO
H3CO
H
OCH3
N
N
N
MgCl2, THF, 25 ºC
O
O
4
5a R = H (72%)
5b R = F (49%)
5c
R = Cl (55%)
POCl3
150 ºC, 1 h or
180 ºC, 10 min
microwave irradiation
N
N
O
OCH3
6a R = H (43%)
6b R = F (89%)
R
6c
R = Cl (97%)
Scheme 2. Microwave-assisted organic synthesis of methyl 3-substituted-imidazo[1,5-a]pyridine-7-carboxylates.

286
V. S. Arvapalli et al. / Tetrahedron Letters 51 (2010) 284–286
H
POCl3
- HCl
N
R
N
R
N
N
N
N
R
O
Cl
7
8
2
N
N
N
N
N
R
N
R
R
9
3
10
Scheme 3. Proposed mechanism of the cyclization step.
labeling NMR experiments.22 Picolinamides 2 is converted to
imidoyl chlorides 7 which upon loss of hydrogen chloride gener-
ates nitrile ylides 8–10 in different resonance forms, which then
cyclized to 3-substituted-imidazo[1,5-a]pyridines 3.
In conclusion, we have applied a convenient microwave-as-
sisted organic synthesis to the preparation of 3-substituted-imi-
dazo[1,5-a]pyridines. The scope and limitations of this method
were presented.
14. (a) Krapcho, A. P.; Powell, J. R. Tetrahedron Lett. 1986, 27, 3713; (b) Bluhm, M.
E.; Ciesielski, M.; Gorls, H.; Doring, M. Angew. Chem., Int. Ed. 2002, 41, 2962.
15. Katritzky, A. R.; Qiu, G. J. Org. Chem. 2001, 66, 2862.
16. Wang, J.; Mason, R.; VanDerveer, D.; Feng, K.; Bu, X. R. J. Org. Chem. 2003, 68,
5415.
17. (a) Siddiqui, S. A.; Potewar, T. M.; Lahoti, R. J.; Srinivasan, K. V. Synthesis 2006,
2849; (b) Wang, J.; Dyers, L., Jr.; Mason, R., Jr.; Amoyaw, P.; Bu, X. R. J. Org.
Chem. 2005, 70, 2353.
18. Shibahara, F.; Sugiura, R.; Yamaguchi, E.; Kitagawa, A.; Murai, T. J. Org. Chem.
2009, 74, 3566.
19. Crawforth, J. M.; Paoletti, M. Tetrahedron Lett. 2009, 50, 4916.
20. A representative procedure for the synthesis of N-benzylpicolinamide (2a) is
presented as follows: Methyl picolinate (1, 568 mg, 4.15 mmol) and
benzylamine (488 mg, 4.56 mmol) in 1,4-dioxane (2 mL) were heated with
stirring at 200 °C for 1 h in the Biotage InitiatorTM microwave reactor. After
cooling, the contents of the reaction vessel were poured onto water and the
aqueous mixture was extracted with methylene chloride. The organic phase
was washed with saturated aqueous brine solution, dried over Na2SO4, and
concentrated in vacuo. The residue was purified by column chromatography
(silica gel, ethyl acetate/hexanes) to give N-benzylpicolinamide (2a, 529 mg,
60%): 1H NMR (CDCl3, 300 MHz): d 4.67 (d, J = 6.1 Hz, 2H), 7.26–7.44 (m, 6H),
7.85 (td, J = 7.7 Hz, 1.7 Hz, 1H), 8.23 (dd, J = 7.8 Hz, 0.9 Hz, 1H), 8.38 (br s, 1H),
8.52 (ddd, J = 4.7 Hz, 1.6 Hz, 0.9 Hz, 1H), ESI-MS: m/z 213 [M+H]+.
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A representative procedure for the synthesis of a 3-phenylimidazo[1,5-
a]pyridine (3a) is presented as follows: A mixture of N-benzylpicolinamide
(2a, 100 mg, 0.471 mmol) and phosphorus oxychloride (2 mL, 21.5 mmol) was
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reactor. After cooling, the mixture was concentrated in vacuo, and water
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300 MHz):
d 6.55 (td, J = 7.4 Hz, 1.2 Hz, 1H), 6.72 (ddd, J = 9.1 Hz, 6.4 Hz,
0.8 Hz, 1H), 7.42–7.56 (m, 5H), 7.80 (dd, J = 3.5 Hz, 1.5 Hz, 2H), 8.26 (dd,
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