Cu(OTf)2-catalyzed synthesis of imidazo[1,2-a]pyridines from α-diazoketones and 2-aminopyridines

Article abstract of DOI:10.1016/j.tetlet.2007.08.090

α-Diazoketones undergo smooth coupling with 2-aminopyridines in the presence of 10 mol % of copper(II) triflate to produce the corresponding 2-substituted imidazo[1,2-a]pyridines (IPs) in excellent yields with high selectivity. Rh₂(OAc)₄

Full text of DOI:10.1016/j.tetlet.2007.08.090

Tetrahedron Letters 48 (2007) 7717–7720
Cu(OTf)2-catalyzed synthesis of imidazo[1,2-a]pyridines from
a-diazoketones and 2-aminopyridines
J. S. Yadav,* B. V. Subba Reddy, Y. Gopal Rao, M. Srinivas and A. V. Narsaiah
Division of Organic Chemistry, Indian Institute of Chemical Technology, Hyderabad 500 007, India
Received 28 June 2007; revised 31 July 2007; accepted 6 August 2007
Available online 30 August 2007
Abstract—a-Diazoketones undergo smooth coupling with 2-aminopyridines in the presence of 10 mol % of copper(II) triflate to pro-
duce the corresponding 2-substituted imidazo[1,2-a]pyridines (IPs) in excellent yields with high selectivity. Rh2(OAc)4 is also found
to be an equally effective catalyst for this transformation.
ꢀ 2007 Elsevier Ltd. All rights reserved.
Imidazo[1,2-a]pyridines (IPs) have received considerable
interest from the pharmaceutical industry because of
their interesting therapeutic properties,1 including
antibacterial,2 antifungal,3 antiviral,4 antiulcer,5 and
anti-inflammatory behavior.6 They have also been char-
acterized as selective cyclin-dependent kinase inhibi-
tors,7 calcium channel blockers,8 b-amyloid formation
inhibitors,9 and benzodiazepine receptor agonists,10
and they constitute a novel class of orally active nonpep-
tide bradykinin B2 receptor antagonists.11 Drug formu-
lations containing imidazo[1,2-a]pyridines such as
alpidem (anxiolytic), zolpidem (hypnotic), and zolim-
idine (antiulcer) are currently available.
The ready availability, relative stability, and facile
decomposition of a-diazocarbonyl compounds under
thermal, photochemical, acid, base, and transition metal
catalysis conditions make them useful intermediates in
organic synthesis.12 Interestingly, a-diazoketones under-
go a variety of transformations such as cyclopropana-
tion, aziridine formation, ylide formation, C–H and
X–H insertion reactions, and cyclization reactions.13
These reactions are chemoselective, which allow new
carbon-carbon and carbon-hetero atom bond formation
under mild conditions.14 However, there have been no
reports on the coupling of a-diazoketones with 2-amino-
pyridines to generate biologically potent imidazo[1,2-
a]pyridines (IPs).
N
In this Letter, we report a novel and efficient method for
the synthesis of substituted imidazo[1,2-a]pyridines (IPs)
via the coupling of 2-aminopyridines and a-diazoke-
tones using a catalytic amount of copper(II) triflate
under mild conditions. Accordingly, treatment of diazo-
acetophenone with 2-aminopyridine in the presence of
10 mol % Cu(OTf)2 in dichloroethane (DCE) at 80 ꢁC
afforded 2-phenylimidazo[1,2-a]pyridine 3a in 94% yield
(Scheme 1).
SO2Me
N
Zolimidine
N
N
Cl
Me
N
Cl
C3H7
N
Me
Me
Me
N
N
Zolpidem
C3H7
O
Alpidem
This remarkable catalytic activity of copper(II) triflate
provided the incentive for further study of reactions
with other a-diazocarbonyl compounds. Interestingly,
various a-diazoketones reacted smoothly with several
2-aminopyridines to give the corresponding 2-aryl- and
2-alkylimidazo[1,2-a]pyridine derivatives as the prod-
ucts of nitrogen insertion. The cis-cyhalothric acid
derived diazoketone also gave the nitrogen insertion
product (Table 1, entry p, Scheme 2).
O
Keywords: a-Diazoketones; Carbene insertion reactions; Imidazo[1,2-
a]pyridines.
Corresponding author. Tel.: +91 40 27193030; fax: +91 40
*
27160512; e-mail: yadav@iict.res.in
0040-4039/$ - see front matter ꢀ 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.08.090

7718
J. S. Yadav et al. / Tetrahedron Letters 48 (2007) 7717–7720
O
Cu(OTf)2
N2
N
+
N
NH2
N
°
DCE, 80 C
1
3a
2
Scheme 1.
Table 1. Cu(OTf)2-catalyzed synthesis of imidazo[1,2-a]pyridines from a-diazoketones and 2-aminopyridines
Entry
Diazoketone
2-Aminopyridine
Producta
Time (h)
2.0
Yieldb (%)
94
O
N
N
N2
a
N
NH2
CH3
O
H3C
N
N2
b
2.5
92
N
N
N
NH2
NH2
O
N
N
N2
c
2.5
3.0
91
87
Cl
Cl
O
N
N
N2
d
CH3
N
NH2
H3C
O
CH3
N
CH3
NH2
N2
e
f
2.5
2.5
90
91
CH3
F
N
N
N
H3C
O
N
N
N2
NH2
NH2
F
O
OMe
OMe
OMe
MeO
MeO
N2
N
N
g
2.0
92
N
OMe
N
N
N2
h
i
3.0
3.0
95
90
O
F
N
N
NH2
Ph
F
O
Ph
N
N
Cl
O
N2
NH2
CH3
NH2
Cl
CH3
N
j
2.0
91
N2
N
N
N
N
O
k
l
2.5
2.5
88
90
N2
N
N
NH2
NH2
Cl
Cl
N
N
O
Ph
N2
Ph
N
N
O
m
n
3.0
2.5
89
87
( )8
N2
N2
( )8
( )8
N
N
NH2
CH3
N
N
CH3
NH2
O
O
( )8
N
Br
N
o
p
3.0
2.5
86
90
Br
( )8
N2
( )8
N
NH2
Cl
O
Cl
N2
N
CF3
N
NH2
N
CF3
a All products were characterized by 1H NMR, 13C NMR, IR, and mass spectroscopy.
b Yield refers to pure products after chromatography.

J. S. Yadav et al. / Tetrahedron Letters 48 (2007) 7717–7720
7719
N
O
N
10 mol % Cu(OTf)2
Cl
Cl
N2
+
CF3
N
NH2
CF3
DCE, 80 °C
Scheme 2.
Both aromatic and aliphatic diazoketones participated
well in this conversion (Table 1). In all cases, the reac-
tions proceeded efficiently in the presence of 10 mol %
Cu(OTf)2 at 80 ꢁC in dichloroethane and the products
were obtained in high yields with high selectivity. No
side product arising from a Wolff rearrangement was
observed under these reaction conditions. Other side
products such as a-keto-O-triflates (the products of
OTf insertion) arising from Cu(OTf)2 were not detected
under these conditions. To determine the efficiency of
this procedure, we also performed the reaction with var-
ious other copper salts such as Cu(OAc)2, Cu(BF4)2,
CuBr2, and Cu(acac)2. Among these catalysts, Cu(OTf)2
was found to be the most effective. As solvent, dichloro-
ethane gave the best conversion. Alternatively, 5 mol %
of Rh2(OAc)4 was found to be an equally effective cata-
lyst for this transformation. Other Lewis acids such as
Sc(OTf)3, In(OTf)3, Bi(OTf)3, InBr3, and InCl3 failed
to give the desired products. Similarly, Bronsted acids
such as Montmorillonite K10, heteropoly acids, PMA,
and Amberlyst-15 also did not give the expected prod-
uct. The reaction may proceed via initial formation of
an imine followed by nitrogen insertion which would
result in the formation of the imidazo[1,2-a]pyridine
(Scheme 3).
Acknowledgment
Y.G.R. and M.S. thank CSIR, New Delhi, for the
award of fellowships.
References and notes
1. Katritzky, A. R.; Xu, Y.-J.; Tu, H. J. Org. Chem. 2003, 68,
4935, and references cited therein.
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Lhassani, M.; Chavignon, O.; Chezal, J.-M.; Teulade, J.-C.;
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Clercq, E.; Gueiffier, A. Eur. J. Med. Chem. 1999, 34, 271.
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A.; Cavender, D. E.; Olini, G. C.; Fahmy, B.; Siekierka, J.
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H. B. Bioorg. Med. Chem. Lett. 2005, 15, 1943.
8. Sanfilippo, P. J.; Urbanski, M.; Press, J. B.; Dubinsky, B.;
Moore, J. B., Jr. J. Med. Chem. 1991, 34, 2060.
9. Goodacre, S. C.; Street, L. J.; Hallett, D. J.; Crawforth, J.
M.; Kelly, S.; Owens, A. P.; Blackaby, W. P.; Lewis, R. T.;
Stanley, J.; Smith, A. J.; Ferris, P.; Sohal, B.; Cook, S. M.;
Pike, A.; Brown, N.; Wafford, K. A.; Marshall, G.;
Castro, J. L.; Atack, J. R. J. Med. Chem. 2006, 49, 35.
10. (a) Trapani, G.; Franco, M.; Ricciardi, L.; Latrofa, A.;
Genchi, G.; Sanna, E.; Tuveri, F.; Cagetti, E.; Biggio, G.;
Liso, G. J. Med. Chem. 1997, 40, 3109; (b) Trapani, G.;
Franco, M.; Latrofa, A.; Ricciardi, L.; Carotti, A.; Serra,
M.; Sanna, E.; Biggio, G.; Liso, G. J. Med. Chem. 1999,
42, 3934.
1
The structures of the products were established by H
NMR, 13C NMR, IR, and high resolution mass spec-
troscopy (HRMS). The scope and generality of this
procedure is illustrated with respect to various a-diazo-
ketones and 2-aminopyridines and the results are pre-
sented in Table 1.15
In summary, we have described a novel and efficient
protocol for the synthesis of 2-aryl- and 2-alkyl-
imidazo[1,2-a]pyridines (IP) via the coupling of a-di-
azoketones with 2-aminopyridines. In addition to its
simplicity and mild reaction conditions, this method
provides high yields of products with high selectivity
making it a useful and attractive strategy for the prepa-
ration of biologically relevant 2-susbtituted imidazo[1,2-
a]pyridines in a single step operation.
11. Abe, Y.; Kayakiri, H.; Satoh, S.; Inoue, T.; Sawada, Y.;
Imai, K.; Inamura, N.; Asano, M.; Hatori, C.; Katayama,
A.; Oku, T.; Tanaka, H. J. Med. Chem. 1998, 41, 564.
O
N2
N
N
Cu(OTf)2
+
NH2
N
+
-
+
N
N
N
..
..
-
N
N
N
Scheme 3.

7720
J. S. Yadav et al. / Tetrahedron Letters 48 (2007) 7717–7720
12. Doyle, M. P.; McKervey, M. A.; Ye, T. Modern Catalytic
Methods for Organic Synthesis with Diazo Compounds
from Cyclopropanes to Ylides; Wiley-Inter-Science: New
York, 1998.
13. (a) Ye, T.; McKervey, M. A. Chem. Rev. 1994, 94, 1091–
1160; (b) Padwa, A.; Hornbuckle, S. A. Chem. Rev. 1991,
91, 263–309; (c) Doyle, M. P. Chem. Rev. 1986, 86, 919–
939.
14. (a) Regitz, M.; Mass, G. Diazo Compounds—Properties
and Synthesis; Academic Press: New York, 1986, p 90; (b)
Jones, K.; Toutounji, T. Tetrahedron 2001, 57, 2427–
2431.
Brown semi-solid, IR (KBr): m 3415, 3112, 2925, 2854,
1645, 1523, 1452, 1342, 1274, 1149, 1019, 759, 712, 622,
;
436 cmÀ1 1H NMR (300 MHz, CDCl3): d 8.24 (d,
J = 6.4 Hz, 1H), 7.75 (br s, 1H), 7.51 (d, J = 8.5 Hz,
1H), 7.19 (dt, J = 1.4, 7.1 Hz, 1H), 7.69 (t, J = 7.1 Hz,
1H), 4.74 (s, 2H); 13C NMR (proton decoupled, 75 MHz,
CDCl3): d 145.1, 130.9, 127.9, 122.5, 121.7, 110.4, 108.1,
41.3; ESIMS: m/z: (M++H): 167; HRMS calcd for
C8H8N2Cl (M++H): 167.0376; found, 167.0375. Com-
pound 3n: Brown solid, mp 64–65 ꢁC; IR (KBr): m 2917,
2849, 1699, 1524, 1464, 1299, 1177, 939, 761, 721 cmÀ1; 1H
NMR (300 MHz, CDCl3): d 7.90 (d, J = 6.4 Hz, 1H), 7.27
(br s, 1H), 6.45 (d, J = 8.5 Hz, 1H), 6.15 (t, J = 8.5 Hz,
1H), 2.73 (t, J = 7.1 Hz, 2H), 1.60 (s, 3H, CH3), 1.65–1.67
(m, 2H), 1.45–1.10 (m, 24H), 0.83 (t, J = 8.5 Hz, 3H); 13C
NMR (proton decoupled, 75 MHz, CDCl3): d 145.6,
137.9, 129.2, 128.7, 122.9, 110.2, 108.0, 32.5, 30.1, 30.0,
29.7, 29.6, 29.5, 29.4, 29.2, 29.1, 29.0, 27.3, 25.7, 24.1, 19.3,
16.7, 13.3; ESIMS: m/z: (M++H): 343; HRMS calcd for
C23H39N2 (M++H): 343.3113; found: 343.3124. Com-
pound 3p: Colorless solid, mp 134–135 ꢁC, IR (KBr): m
3188, 3079, 2965, 1685, 1652, 1583, 1535, 1437, 1298, 1144,
1055, 951, 774 cmÀ1; 1H NMR (300 MHz, CDCl3): d 9.10
(br s, 1H); 8.23 (dd, J = 0.7, 1.9 Hz, 1H), 8.21 (dd, J = 0.7,
1.9 Hz, 1H), 7.69 (dt, J = 1.9, 6.8, Hz, 1H), 7.14 (dd,
J = 0.9, 9.4 Hz, 1H), 7.01 (ddd, J = 1.1, 2.4, 4.9 Hz, 1H),
2.19 (dt, J = 0.7, 8.4 Hz, 1H), 1.86 (d, J = 8.4 Hz, 1H),
1.38 (s, 3H), 1.31 (s, 3H); 13C NMR (proton decoupled,
75 MHz, CDCl3): d 168.2, 151.7, 147.3, 138.6, 130.3,
119.6, 114.7, 35.5, 31.1, 28.7, 28.5, 14.7; ESIMS: m/z:
(M++H): 315; HRMS calcd for C15H15N2F3Cl (M++H):
315.0875, found, 315.0882.
15. General procedure: A mixture of a-diazoketone (1 mmol),
2-aminopyridine (1 mmol) and Cu(OTf)2 (0.1 mmol) in
dichloroethane (10 mL) was stirred at 80 ꢁC for the
appropriate time (Table 1). After completion of the
reaction, as indicated by TLC, the reaction mixture was
quenched with water and extracted with ethyl acetate
(2 · 15 mL). Evaporation of the solvent followed by
purification on silica gel (Merck, 100–200 mesh, ethyl
acetate–hexane, 2–8) afforded the pure imidazo[1,2-a]pyr-
idine. Compound 3a: Gray solid, mp 131–133 ꢁC; IR
(KBr): m 2924, 2854, 1740, 1629, 1500, 1471, 1366, 1269,
1
1200, 1140, 1073, 1024, 915, 740, 692, 498, 426 cmÀ1; H
NMR (300 MHz, CDCl3): d 8.09 (d, J = 6.7 Hz, 1H), 7.91
(d, J = 7.5 Hz, 2H), 7.82 (s, 1H), 7.63 (d, J = 9.0 Hz, 1H),
7.40 (t, J = 7.5 Hz, 2H), 7.30 (d, J = 7.5 Hz, 1H), 7.14 (dd,
J = 6.7, 9.0 Hz, 1H), 6.74 (t, J = 6.7 Hz, 1H); 13C NMR
(proton decoupled, 75 MHz, CDCl3): d 145.6, 131.9,
128.7, 127.9, 126.0, 125.5, 124.7, 117.4, 116.2, 108.1;
ESIMS: m/z: (M++H): 195; HRMS calcd for C13H11N2
(M++H): 195.0922; found, 195.0921. Compound 3i: