Synthesis of imidazo[1,5-a]pyridines from 1,1-dibromo-1-alkenes

Article abstract of DOI:10.1016/j.tetlet.2009.12.013

An efficient method is developed for the synthesis of imidazo[1,5-a]pyridine from the reaction of 1,1-dibromo-1-alkenes with 2-aminomethylpyridines. The reaction requires an inorganic base, such as Na₂CO₃, and moderate heating in DMF to proceed. Moderate to good yields are obtained. As demonstrated by the authors and others, 1,1-dibromo-1-alkenes are employed as synthons for activated carboxyl groups.

Full text of DOI:10.1016/j.tetlet.2009.12.013

Tetrahedron Letters 51 (2010) 828–831
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Tetrahedron Letters
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Synthesis of imidazo[1,5-a]pyridines from 1,1-dibromo-1-alkenes
*
Aimin Zhang, Xiaoling Zheng, Junfa Fan, Wang Shen
KanionUSA Inc., 3916 Trust Way, Hayward, CA 94545, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient method is developed for the synthesis of imidazo[1,5-a]pyridine from the reaction of 1,1-
dibromo-1-alkenes with 2-aminomethylpyridines. The reaction requires an inorganic base, such as
Na2CO3, and moderate heating in DMF to proceed. Moderate to good yields are obtained. As demon-
strated by the authors and others, 1,1-dibromo-1-alkenes are employed as synthons for activated car-
boxyl groups.
Received 17 November 2009
Revised 3 December 2009
Accepted 3 December 2009
Available online 11 December 2009
Ó 2009 Elsevier Ltd. All rights reserved.
Fused heteroaromatic compounds containing ring-junction
nitrogen atoms are important for the preparation of biologically ac-
tive molecules.1 One such heteroaromatic class of compounds, imi-
dazo[1,5-a]pyridines have been found in antibiotic cribrostatin-6
isolated from blue marine sponge2 and in important synthetic bio-
active molecules.3
Initially, the optimized reaction conditions for benzimidazole
preparation11 were applied to the reaction of methyl 4-(2,2-dib-
romovinyl)benzoate (1a) and 2-aminomethylpyridine (2a), as
shown in Scheme 2. However, only low yield (15%) of methyl 4-
(imidazo[1,5-a]pyridin-3-ylmethyl)benzoate (3a) was isolated,
along with low yields of amide (4a) and amidine (5a).
The most common synthesis of imidazo[1,5-a]pyridines em-
ploys a two-step sequence of acylation or thioacylation of 2-ami-
nomethylpyridines, followed by cyclization.4 An efficient one-pot
procedure with propane phosphoric acid anhydride was recently
reported.5 Another general route for the preparation of imi-
dazo[1,5-a]pyridines involves condensation of 2-aminomethyl-
pyridines with aldehydes under oxidative conditions.6 Another
multistep preparation of imidazo[1,5-a]pyridines is also reported,
such as sequential van Leusen/intramolecular Heck reactions,7a
benzotriazole-mediated reaction,7b and ammonium acetate-medi-
ated condensation of pyridyl ketones with aldehydes.7c
These poor results prompted us to optimize the reaction condi-
tions for the formation of (3a, Table 1). Contrary to previously re-
ported reaction conditions for the synthesis of amides9a or
benzimidazoles,11 organic bases (Table 1, entries 1 and 2) were
not suitable for this transformation.12 On the other hand, heating
the reaction with anhyd NaHCO3 in DMF gave a good yield of the
desired product (3a) based on HPLC analysis. This led us to exam-
ine other inorganic bases, and it was found that aq Na2CO3 in DMF
gave the best yield. The product (3a) was partially hydrolyzed at
90 °C (Table 1, entry 6), and that problem could be overcome with
lower reaction temperature (Table 1, entry 8).
These preparations of imidazo[1,5-a]pyridines often employ
either toxic, strongly acidic, corrosive reagents, or involve multi-
step syntheses. Therefore alternative methods are still of interest
to organic and medicinal chemists. Previously in our laboratory,
1,1-dibromo-1-alkenes were found to be versatile intermediates8
in the synthesis of isocoumarins,8a trisubstituted alkenes, unsym-
metrical alkynes,8b,d and 1,3-dialkynes.8c More recently, we and
others reported that 1,1-dibromo-1-alkenes could be employed
as synthons for activated carboxylic acids, to prepare amides9
and amidines10 in excellent yields from 2-aryl-1,1-dibromoethenes
and alkyl amines under mild reaction conditions (Scheme 1). This
versatility of 1,1-dibromo-1-alkenes was further demonstrated in
the preparation of benzimidazoles.11 We now report an effective
synthesis of imidazo[1,5-a]pyridines from 1,1-dibromo-1-alkenes
under mild basic conditions.
With the optimized reaction conditions, the scope of the reac-
tion was examined, and the results are summarized in Table 2.
The reaction is sensitive to steric hindrance (Table 2, entry 1). A
significant amount of amide (4b) was formed. When the reaction
R1
N
R1R2NH2
Ar
Ar
R2
R2
DMF, H2O
O
R1
N
N
R1 = H
R2
R1R2NH2
neat
Ar
Br
Ar
HN
R2
N
R1
R2
Br
H
N
R1
N
R1
R2
H2N
R2
DABCO, DMF
N
Ar
* Corresponding author. Tel.: +1 510 781 0700; fax: +1 510 781 0707.
E-mail address: wshen@kanionusa.com (W. Shen).
Scheme 1. 2-Aryl-1,1-dibromoethenes as equivalents to activated carboxylic acids.
0040-4039/$ - see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2009.12.013

A. Zhang et al. / Tetrahedron Letters 51 (2010) 828–831
829
Br
H2N
DABCO, DMF
100 oC, 12 h
+
Br
N
MeO2C
2a
1a
N
(1.2 equiv)
N
O
N
N
+
+
MeO2C
HN
HN
MeO2C
N
MeO2C
N
3a (15%)
4a (22%)
5a (9%)
Scheme 2. Synthesis of imidazo[1,5-a]pyridine 3a with DABCO base.
Table 1
Optimization of reaction conditionsa
Br
N
N
conditions
+
Br
H2N
N
MeO2C
MeO2C
1a
2a
3a
Entry
Solvent
Base (equiv)
T (°C), t (h)
Yieldb (%)
1
2
3
4
5
7
6
8
DMF
DMF
DMF
DMSO
DMF
DMF
DMF
DMF
DIEA (3)
90, 12
90, 6
90, 6
90, 6
90, 6
90, 6
90, 6
80, 20
23c
37c
54
49
79
DABCO (3)
NaHCO3 (3)
NaHCO3 (3)
Na2CO3 (2)
K2CO3 (2)
21
Na2CO3 (2, 1.0 M, aq)
Na2CO3 (2, 1.0 M, aq)
72, 9 (acid)d
86 (69%)e
a
Reaction conditions: 1a (0.50 mmol), 2a (0.60 mmol), solvent (2.5 mL). After 1a was consumed, 4-phenyl-2-cyanopyridine (0.0 mmol) was added to the mixture as an
internal standard, and the reaction mixture was analyzed by HPLC–MS.
b
Yield was calculated based on HPLC analysis with 4-phenylpyridine as the internal standard.
Small amount of amide 4a was also detected by LC–MS.
Aqueous solution of Na2CO3 (2.0 M) was used, and the corresponding acid was detected from HPLC–MS analysis.
Yield in parentheses (69%) is the isolated yield.
c
d
e
Table 2
Preparations of imidazo[1,5-a]pyridines14
N
Br
N
N
R
R
H2N
R1
+
R1
N
Br
1
2
3
Entry Dibromide 1
Amine 2
Temp,
time
Product
Yield (%)
Br
H
N
H2N
N
MeO
Br
1a
+
O
80 °C,
20 h
3b (36), 4b
(31)
2b
1
MeO2C
N
N
O
MeO2C
MeO2C
3b
4b
4c
MeO
H
N
H2N
N
N
+
O
80 °C,
20 h
3c (0), 4c
(40)
MeO2C
N
2
3
OMe
2c
N
MeO
3c
H2N
80 °C,
20 h
N
3d (64)
N
2d
N
MeO2C
3d
(continued on next page)

830
A. Zhang et al. / Tetrahedron Letters 51 (2010) 828–831
Table 2 (continued)
Entry Dibromide 1
Amine 2
Temp,
time
Product
Yield (%)
Ph
Ph
O
H2N
N
N
80 °C,
20 h
4
5
3e (52)
N
N
2e
N
MeO2C
MeO2C
3e
H2N
O
80 °C,
20 h
3f (51)
3g (43)
N
2f
3f
N
80 °C,
20 h
6
7
H2N
H2N
N
MeO2C
N
3g
2g
NH2
NH
N
80 °C,
20 h
3h (0)
3i (49)
3j (59)
HN
2h
MeO2C
S
NH2
3h
S
Br
Br
N
80 °C,
20 h
8
2a
2a
Br
1b
N
3i
N
80 °C,
20 h
9
Br
N
N
1c
N
3j
Br
N
80 °C,
20 h
10
2a
3k (41)
Br
MeO
Ph
N
1d
MeO
Ph
3k
Ph
Br
O
N
+
80 °C,
20 h
3l (36), 4l
(19)
11
12
2a
2a
Br
HN
N
1e
N
4b
3b
Br
Br
Br
N
80 °C,
20 h
3m (60)
Br
1f
N
3m
Br
EtO2C
80 °C,
10 h
N
EtO2C
13
14
2a
2e
3n (46)
3o (62)
Br
1g
3n
N
Ph
3o
N
80 °C,
10 h
EtO2C
N
was run with anhyd Na2CO3, the yield of the desired product (3b)
did not improve, and instead of amide (4b), amidine (5b) was
formed (Scheme 3).
Furthermore, when 2-aminomethyl-6-methoxypyridine (2c)
was used, no desired product (3c) but only amide (4c) was isolated
(Table 2, entry 2). Significantly lower nucleophilicity of pyridyl ‘N’
(relative to pyridine) from 6-methoxy substitution,13 in addition to
the steric hindrance of 6-substitution, may be the reason for this
observation. The steric sensitivity was further shown by dibromide
1e (Table 2, entry 11). Even though the phenyl group is not imme-
diately next to the reaction center, a significant amount of by-
product amide (4l) was isolated. However, 2-aminomethyl-6-
Br
N
Na2CO3
anhydrous
+
Br
H2N
MeO2C
1a
2b
DMF
N
N
+
N
HN
MeO2C
N
MeO2C
N
3b (33%)
5b
(41%)
Scheme 3. Influence of steric hinderance on the reaction.

A. Zhang et al. / Tetrahedron Letters 51 (2010) 828–831
831
4. Cyclization with Burgess reagent: (a) Li, J. J.; Li, J. J.; Li, J.; Trehan, A. K.; Wong, H.
S.; Krishnananthan, S.; Kenedy, L. J.; Gao, Q.; Ng, A.; Robl, J. A.;
Balasubramanian, B.; Chen, B.-C. Org. Lett. 2008, 10, 2897; Cyclization with
POCl3: (b) Bower, J. D.; Ramage, G. R. J. Chem. Soc. 1955, 2834; Cyclization with
polyphosphoric acid: (c) Winterfeld, K.; Franzke, H. Angew. Chem. 1963, 75,
1101; Cyclization of thioamide with DCC: (d) Bourdais, J.; Omar, A.-M. M. E. J.
Heterocycl. Chem. 1980, 17, 555; Cyclization of thioamide with Hg(II) salt: (e) El
Khadem, H. S.; Kawai, J.; Swartz, D. L. Heterocycles 1989, 28, 239; Cyclization of
thioamide with I2: (f) Shibahara, F.; Kiagawa, A.; Yamaguchi, E.; Murai, T. Org.
Lett. 2006, 8, 5621.
5. Crawforth, J. M.; Paoletti, M. Tetrahedron Lett. 2009, 50, 4916.
6. Copper catalyzed oxidation with oxygen: (a) Bluhm, M. E.; Ciesielski, M.; Gorls,
H.; Doring, M. Angew. Chem., Int. Ed. 2002, 41, 2962; Oxidation with sulfur: (b)
Shibahara, F.; Sugiura, R.; Yamaguchi, E.; Kitagawa, A.; Murai, T. J. Org. Chem.
2009, 74, 3566.
7. (a) Beebe, X.; Gracias, V.; Djuric, S. W. Tetrahedron Lett. 2006, 47, 3225; (b)
Katritzky, A. R.; Qiu, G. J. Org. Chem. 2001, 66, 2862; (c) Wang, J.; Dyers, L., Jr.;
Mason, R., Jr.; Amoyaw, P.; Bu, X. R. J. Org. Chem. 2005, 70, 2353.
8. (a) Wang, L.; Shen, W. Tetrahedron Lett. 1998, 39, 7625; (b) Shen, W.; Wang, L. J.
Org. Chem. 1999, 64, 8873; (c) Shen, W.; Thomas, S. A. Org. Lett. 2000, 2, 2857;
(d) Shen, W. Synlett 2000, 737.
9. (a) Shen, W.; Kunzer, A. Org. Lett. 2002, 4, 1315; (b) Huh, D. H.; Jeong, J. S.; Lee,
H. B.; Ryn, H.; Kim, Y. G. Tetrahedron 2002, 58, 9925.
10. Huh, D. H.; Ryu, H.; Kim, Y. G. Tetrahedron 2004, 60, 9857.
11. Shen, W.; Kohn, T.; Fu, Z.; Jiao, X.-Y.; Lai, S.; Schmitt, M. Tetrahedron Lett. 2008,
49, 7284.
methoxyquinoline (2f) afforded good yield of the desired product
(3f) without the corresponding amide. Neutral substitutions at
positions other than ‘C-6’ of 2-aminomethylpyridine are well toler-
ated (Table 2, entries 3, 4, 14).
Substitutions on the aryl ring of 2-aryl-1,1-dibromoethene are
well tolerated, as both electron-donating (1d) and electron-with-
drawing (1a, 1c) substrates gave good yields of the corresponding
products. Heteroaromatic substitutions (1b, 1c) are also tolerated.
Bromine substitution on aryl ring (1f) does not affect the reaction,
while it may provide a handle for further manipulation of the result-
ing product (3m). Finally, an ester group in place of aryl ring gave
good yields of products (entries 13 and 14). This would broaden
the scope of this reaction.
In summary, a facile synthesis of imidazo[1,5-a]pyridines is de-
scribed. This method employs a mild inorganic base and moderate
heating, which are different from existing reaction conditions for
the preparation of this class of compounds. Therefore, the method
should complement the existing synthesis of imidazo[1,5-a]pyri-
dines, and will find applications in both synthetic organic and
medicinal chemistry.
12. Besides di(isopropyl)ethylamine (DIEA) and DABCO, 4-methylmorpholine,
DBU, tetramethylguanidine also failed to give good yields of the desired
product.
Acknowledgments
13. The nucleophilicity of pyridinyl ‘N’ is parallel to its basicity: 2-
Methoxypyridine is a significantly weaker base than pyridine or 2-methy
pyridine (pKa’s are 3.3 for 2-methoxypyridine, 5.2 for pyridine, and 6.0 for 2-
methylpyridine): Joule, J. A.; Mills, K. Heterocyclic Chemistry, 4th ed.; Blackwell:
Oxford, 2000. Chapter 5.
The authors are grateful to Jack Maung for proof reading of this
manuscript.
14. Typical reaction procedure: A mixture of methyl 4-(2,2-dibromovinyl)benzoate
(1a, 320 mg, 1.0 mmol) and 2-aminomethylpyridine (2a, 119 mg, 1.1 mmol) in
DMF (5 mL) and Na2CO3 (1.0 M, 2.0 mmol) was heated at 80 °C for 20 h. The
reaction mixture was cooled to room temperature, diluted with ethyl acetate
(80 mL), washed with water (10 mL) and brine (5 mL), dried over anhyd
Na2SO4, and concentrated. The residue was subjected to silica gel
chromatography using 10% methanol in dichloromethane to give methyl 4-
(imidazo[1,5-a]pyridin-3-ylmethyl)benzoate (3a, 184 mg, 69%). 1H NMR
(CDCl3, 300 MHz) d 7.96 (d, J = 8.1 Hz, 2H),7.56 (d, J = 7.5 Hz, 1H), 7.44 (t,
J = 4.4 Hz, 2H), 7.26 (d, J = 8.1 Hz, 2H), 6.66 (t, J = 7.8 Hz, 1H), 6.47 (t, J = 6.8 Hz,
1H), 4.49 (s, 2H), 3.90 (s, 3H); LC–MS (ESI+) m/z: 267 (M+H).
References and notes
1. Reviews: (a) Hamama, W. S.; Zoorob, H. H. Tetrahedron 2002, 58, 6143; (b)
Swinbourne, J. F.; Hunt, H. J.; Klinkert, G. Adv. Heterocycl. Chem. 1979, 23, 103.
2. Isolation and characterization of cribrostatin-6: (a) Pettit, G. R.; Collins, J. C.;
Knight, J. C.; Herald, D. L.; Nieman, R. A.; Williams, M. D.; Pettit, R. K. J. Nat. Prod.
2003, 66, 544; A recent total synthesis: (b) Knueppel, D.; Martin, S. F. Angew.
Chem., Int. Ed. 2009, 48, 2569.
3. As thromboxane synthetase inhibitor: (a) Brännström, K.; Arendshorst, W. J.
Am. J. Physiol. 1999, 276, F758; b As Mek Kinase inhibitor: Price, S.; Heald, R.;
Savy, P. P. A. WO2009085980, 2009. Chem. Abstr. 2009, 151, 123,970.