A one-pot synthesis of imidazo[1,5-a]pyridines

Article abstract of DOI:10.1016/j.tetlet.2009.06.061

A one-pot synthesis of imidazo[1,5-a]pyridines starting from a carboxylic acid and 2-methylaminopyridines allowing introduction of various substituents at the 1- and 3-positions is achieved using propane phosphoric acid anhydride in ethyl or n-butyl aceta

Full text of DOI:10.1016/j.tetlet.2009.06.061

Tetrahedron Letters 50 (2009) 4916–4918
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A one-pot synthesis of imidazo[1,5-a]pyridines
b
James M. Crawforth a, , Melissa Paoletti
*
a Pfizer Global Research and Development, Ramsgate Road, Sandwich, Kent CT13 9NJ, UK
b University of Camerino, Department of Chemical Sciences, Via S. Agostino, 162032 Camerino (MC), Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
A one-pot synthesis of imidazo[1,5-a]pyridines starting from a carboxylic acid and 2-methylaminopyri-
dines allowing introduction of various substituents at the 1- and 3-positions is achieved using propane
phosphoric acid anhydride in ethyl or n-butyl acetate at reflux.
Received 8 April 2009
Revised 1 June 2009
Accepted 12 June 2009
Available online 16 June 2009
Ó 2009 Elsevier Ltd. All rights reserved.
The imidazo[1,5-a]pyridines are an important class of heterocy-
clic compounds owing to their photophysical and biological prop-
erties. They have found utility in a number of areas of research
including potential applications in organic light-emitting diodes
(OLED)1 and thin-layer field effect transistors (FET).2 In addition
they have been investigated in a wide range of potential pharma-
ceutical applications, including HIV-protease inhibitors,3 and
Thromboxane A2 synthesis inhibitors.4 Therefore, a widely applica-
ble and convenient method for the synthesis of this ring system
would be of interest. Existing synthetic routes target the imi-
dazo[1,5-a]pyridines from the corresponding N-2-pyridylmethyla-
mides with Filmier-type cyclisations5 and strong acid
condensations.3 Alternative methods include the cyclisation of N-
2-pyridylmethyl thioamides with DCC,6 mercury(II) acetate,7 or
more recently, iodine.8
er temperature using n-butyl acetate as solvent. This gave 3-
phenyl-imidazo[1,5-a]pyridine 1 in an improved 85% isolated
yield, but more importantly, a greatly reduced reaction time of
18 h. In order to confirm that the final ring closing dehydration
was mediated by T3PÒ and not just a thermal process, a control
experiment was undertaken (Scheme 2). N-Pyridin-2-ylmethyl-
benzamide 13 was prepared via a standard amide coupling reac-
tion. Subsequent heating at reflux in n-butyl acetate for 24 h and
monitoring by LC–MS showed no reaction. Addition of 1.5 equiv
of T3PÒ to the reaction and heating for a further 24 h, gave 3-phe-
nyl-imidazo[1,5-a]pyridine 1 in 82% isolated yield. Turning our
attention to the scope of the reaction, a number of experiments
with different substrates were carried out (Table 1).11 The reaction
appears very general, with not only alkyl groups, compounds 1–5,
but also heterocyclic groups being well tolerated, products 9–12.
It is interesting to note that an imidazole moiety required no
protection and gave a reasonable yield of 3-(1H-imidazol-2-yl)-
imidazo[1,5-a]pyridine 12. The methyl ester 6 also gave a good
yield with no sign of hydrolysis, indicating the mild nature of the
conditions. The reaction could also be performed using quinolin-
2-yl-methylamines to furnish the imidazo[1,5-a]quinoline ring
system in products 14 and 15 in good yield (Table 2).
Herein we report a new and simple one-pot procedure to access
imidazo[1,5-a]pyridines starting from carboxylic acids and 2-
methylaminopyridines using propane phosphoric acid anhydride
(T3PÒ) in ethyl or n-butyl acetate.
The general synthetic route is outlined in Scheme 1 and can be
regarded as amide formation followed by dehydration. Propane
phosphoric acid anhydride (T3PÒ) has been widely used in peptide
and amide synthesis;9 however, it can also act as a water scavenger
and has been used in the synthesis of nitriles from either a primary
amide, or a carboxylic acid and ammonium chloride directly.10 We
envisaged that these two properties could be combined to provide
a concise one-pot route to imidazo[1,5-a]pyridines and our initial
experiments demonstrated that a one-pot approach to this ring
system was feasible.
In conclusion, we have presented a new and efficient one-pot
synthesis of the imidazo[1,5-a]pyridine and imidazo[1,5-a]quino-
line ring systems in good yields which allows the introduction of
various substituents at the 1 and 3 positions. We are presently
expanding the scope of the reaction to other ring systems.
Reaction of 2-methylaminopyridine and benzoic acid in ethyl
acetate at reflux furnished 3-phenyl-imidazo[1,5-a]pyridine 1 in
76% isolated yield, albeit requiring an extended reaction time, (Ta-
ble 1). To address this the reaction was repeated running at a high-
R1
R1
T3P, EtOAc or n-BuOAc
RT to reflux
N
NH2
N
R2
N
R2CO2H
* Corresponding author. Tel.: +44 1304649703.
E-mail address: james.m.crawforth@pfizer.com (J.M. Crawforth).
Scheme 1.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.06.061

J. M. Crawforth, M. Paoletti / Tetrahedron Letters 50 (2009) 4916–4918
4917
Table 1
Table 1 (continued)
R1
Synthesis of imidazo[1,5-a]pyridines
R1
R2
Product
Time/yielda (%)
17 h/52c
R1
Entry
T3P, EtOAc or n-BuOAc
N
N
RT to reflux
H
N
NH2
N
12
H
2-Imid
12
R2
N
R2CO2H
N
N
Entry
1
R1
H
R2
Product
Time/yielda (%)
a
N
Isolated yield.
T3PÒ was added to a suspension of the 2-methylaminopyridine and acid in
b
Ph
1
96 h/76b
18
EtOAc at rt and then the mixture was heated at reflux.
N
c
n-BuOAc was used as solvent.
O
CF3
n-BuOAc, reflux, 24 h
No reaction
N
h/85c
N
N
N
2
3
4
CF3
Me
H
Ph
2
24 h/33c
H
N
n-BuOAc, T3P (1.5 eq),
reflux, 24 h, 82%
N
13
1
N
N
Ph
3
3 h/88c
Scheme 2. Control experiment.
N
Table 2
Synthesis of imidazo[1,5-a]quinolines
t-Bu
4
18 h/88c
N
Me
NH2
N
T3P, n-BuOAc
N
R1
R1
RT to reflux
N
MeCO2H
+
3 h/82c
N
Entry
1
R1
Product
Time/yielda (%)
3 h/73b
5
Ph
Me
5
N
N
N
N
c-Pent
14
15
N
N
6
7
H
H
p-MeCO2Ph
6
48 h/60b
18 h/72c
N
3 h/66b
CO2Me
2
Bn
N
4-py
7
N
N
a
Isolated yield.
n-BuOAc was used as solvent.
b
N
8
9
H
H
H
H
2-Furan
2-Thienyl
2-py
8
24 h/75c
5 h/78c
O
N
Acknowledgements
N
N
We thank Mr. Cris Lapthorn for HR-MS analysis.
9
10
11
N
S
N
References and notes
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10
11
18 h/72c
18 h/67c
N
N
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Abstr. 2005, 142, 440277.
N
3-py
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Malkowitz, L.; Gould, S. L.; DeMartino, J. A.; Springer, M. S.; Hazuda, D.; Miller,
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4918
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J. M. Crawforth, M. Paoletti / Tetrahedron Letters 50 (2009) 4916–4918
was added T3PÒ (Aldrich 50% solution in EtOAc, 7.5 ml), and after complete
addition, the solution was stirred at rt for 1 h, before being heated at reflux for
17 h. The cooled reaction mixture was washed with saturated sodium
bicarbonate solution (2 Â 30 ml), the organic phase dried (MgSO4) and
concentrated in vacuo to a colourless oil. The residue was purified by flash
chromatography over silica gel to yield 3-pyridin-3-yl-imidazo[1,5-a]pyridine
11 (600 mg, 67%).1H NMR (400 MHz, CDCl3) d 6.64 (1H, t, J = 6.8 Hz) 6.79 (1H,
dd, J = 9.2, 6.4 Hz) 7.47 (1H, dd, J = 8.0, 4.9 Hz) 7.54 (1H, d, J = 9.0 Hz) 7.62 (1H,
s) 8.12–8.16 (1H, m) 8.26 (1H, d, J = 7.0 Hz) 8.68 (1H, dd, J = 4.7, 1.6 Hz) 9.10
(1H, d, J = 2.3 Hz) ppm. 13C NMR (100 MHz, CDCl3) d 113.7, 119.1, 119.6, 121.0,
121.8, 124.1, 127.0, 132.3, 135.4, 148.7, 149.8 ppm. HR-MS (ESI) m/z 196.0875
[M+H]+. Calcd for C12H10N3 m/z 196.0873.
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methylaminopyridine (500 mg, 4.6 mmol) in n-butyl acetate (25 ml) at rt was
added 3-pyridinecarboxylic acid (588 mg, 5.3 mmol). To the resulting slurry