General and efficient copper-catalyzed three-component coupling reaction towards imidazoheterocycles: One-pot synthesis of alpidem and zolpidem

Article abstract of DOI:10.1002/anie.200907291

(Figure Presented) Three is not a crowd: A method for the construction of Imidazopyridine, imidazoquinoline, and imidazoisoquinoline frameworks has been developed. The synthetic utility of this method was demonstrated in a highly efficient one-pot synthesis of the drugs alpidem and Zolpidem (see scheme).

Full text of DOI:10.1002/anie.200907291

Angewandte
Chemie
DOI: 10.1002/anie.200907291
Multicomponent Reactions
General and Efficient Copper-Catalyzed Three-Component Coupling
Reaction towards Imidazoheterocycles: One-Pot Synthesis of Alpidem
and Zolpidem**
Natalia Chernyak and Vladimir Gevorgyan*
Imidazopyridine is an important pharmacophore, and is
widely found in many biologically active compounds.[1] In
particular, imidazo[1,2-a]pyridine is an essential fragment
present in pharmacologically important molecules, which
include several anxyolytic drugs,[2] such as alpidem (A),[2a,b]
necopidem (C), saripidem (D), and the drug used to treat
insomnia zolpidem (B)[2c,d] (Scheme 1). Although a variety of
Scheme 2. Synthesis of imidazopyridines by a TCC approach.
reaction of 2-aminopyridine 1, aldehyde 2, and terminal
alkyne 3.[6] Notably, the 5-exo-dig cyclization of 4 to 5 should
secure the formation of the imidazo[1,2-a]pyridylmethyl unit,
a common fragment of the previously mentioned, biologically
important molecules[2] (Scheme 1). To test this hypothesis, we
examined the reaction in the presence of different metal
Scheme 1. Imidazo[1,2-a]pyridine-based drugs.
catalysts. Accordingly, NaAuCl4, known to be an efficient
catalyst for the synthesis of indolizines through a TCC
reaction,[7] was first tested. However, no desired product
synthetic methods for the synthesis of these important
frameworks has been developed,[3] most of them are limited
in scope and require multistep preparation of the starting
materials.[4] Accordingly, development of straightforward and
general methods for the synthesis of imidazo[1,2-a]pyridines
from easily available precursors is highly warranted. Herein, a
general and efficient synthesis of imidazopyridines 5 by the
copper-catalyzed three-component coupling (TCC) reaction
of 2-aminopyridines 1 with aryl aldehydes 2 and alkynes 3 is
reported (Scheme 2).
was formed under these reaction conditions (Table 1, entry 1).
Further optimization revealed copper salts to be more
efficient catalysts for this transformation. Thus, reactions in
the presence of 5 mol% of Cu(OTf)2 produced 5a in 10%
Table 1: Optimization of the TCC reaction conditions.[a]
We reasoned that the imidazo[1,2-a]pyridyl core 5 could
be assembled by a p-philic metal-catalyzed 5-exo-dig cycliza-
tion[5] of propargylamine 4 (Scheme 2). The latter, in turn,
should be accessible through a three-component coupling
Entry
Catalyst (mol%)
Solvent
T [8C]
Yield of
5a [%][b]
1
2
3
4
5
6
7
8
NaAuCl4·2H2O (5)
Cu(OTf)2 (5)
CuCl (10)
toluene
toluene
toluene
toluene
MeCN
DMA
120
120
120
120
100
120
120
120
0
10
55
74
15
78
93
76[c]
CuCl (50)
[*] N. Chernyak, Prof. V. Gevorgyan
CuCl (5), Cu(OTf)2 (5)
CuCl (5), Cu(OTf)2 (5)
CuCl (5), Cu(OTf)2 (5)
CuCl (5), Cu(OTf)2 (5)
Department of Chemistry, University of Illinois at Chicago
845 West Taylor Street, Room 4500, Chicago, IL 60607 (USA)
Fax: (+1)312-355-0836
toluene
toluene
E-mail: vlad@uic.edu
Homepage: http://www.chem.uic.edu/vggroup
[a] Reaction conditions: 2-aminopyridine (0.1 mmol), benzaldehyde
(0.105 mmol), acetylene (0.11 mmol), CuCl (0.005 mmol), Cu(OTf)2
(0.005 mmol), solvent (1m, 0.1 mL), 16 h. [b] Yields were determined
by GC-MS analysis with pentadecane as an internal standard. [c] Reac-
tion was performed in air. DMA=N,N-dimethylacetamide.
[**] The support of the NIH (1P50 GM-086145) is gratefully acknowl-
edged.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.200907291.
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Table 2: Synthesis of imidazoheterocycles.[10]
yield (Table 1, entry 2). Meanwhile,
the use of 10 mol% of CuCl
resulted in a dramatic improvement
in the yield (55%; Table 1, entry 3).
However, reactions in the presence
of 50 mol% of CuCl produced 5a in
only 74% yield. (Table 1, entry 4).
Employment of the CuCl/Cu-
Entry
Product
Yield
[%][a]
Entry
Product
Yield
[%][a]
(OTf)2 binary catalytic system[9]
[8]
1
2
3
4
5a
5b
5c
5d
92
90
79
70
12
13
14
15
5l
89
80
90
86
in MeCN at 1008C provided the
desired product 5a in 15% yield
(78%; Table 1, entry 5). Surpris-
ingly, the use of DMA at 1208C
substantially improved the reaction
outcome (78%; Table 1, entry 6).
Finally, replacement of DMA with
the less polar toluene afforded imi-
dazopyridine 5a from 2-aminopyr-
idine 1a (1 equiv), aldehyde 2a
(1.05 equiv), and alkyne 3a
(1.5 equiv) in excellent yield
(93%; Table 1, entry 7). The reac-
tion performed in air provided 5a in
lower yield (76%; Table 1, entry 8).
Next, the generality of this
novel TCC reaction was examined
(Table 2). To our delight, we found
this transformation to be very gen-
eral for a wide range of aldehydes
and alkynes, and provided easy
access to densely substituted imida-
zopyridine derivatives 5. Thus,
employment of different alkyne
substrates, bearing aryl (Table 2,
entries 1, 2, 6–10, and 12–22), alkyl
(Table 2, entries 3–5), or silyl
(Table 2, entry 11) substituents,
produced imidazopyridines in good
to exellent yields. Aryl and alkyl
aldehydes also displayed good reac-
tivity in this reaction. A variety of
functional groups substituted at the
aromatic ring of the aldehyde sub-
strate, such as chloro (Table 2,
entry 6), bromo (Table 2, entry 12),
cyano (Table 2, entries 10, 13, and
5m
5n
5o
5
5e
44[b]
16
5p
50[c]
6
7
5 f
81
17
18
5q
5r
61
87
5g
56[b]
8
5h
5i
60
78
82
19
20
21
5s
5t
83
9
50[c]
70
10
5j
5u
11
5k
73
22
5v
65
[a] Yield of isolated product. [b] Product decomposes upon prolonged heating. [c] Some 2-amino-
pyridine and benzaldehyde did not react. [d] Corresponding imine was isolated in 48% yield. TBS=tert-
butyldimethylsilyl, TIPS=triisopropylsilyl.
18) and fluoro (Table 2, entries 14 and 15) groups were
tolerated. The reaction with propyl and isopropyl aldehydes
was uneventful, and furnished C2-alkyl-substituted imidazo-
pyridines 5g and 5h, respectively (Table 2, entries 7 and 8).
Employment of furan-2-carbaldehyde led to bishetaroaryl
compound 5i in 78% yield (Table 2, entry 9). Formaldehyde,
however, was less reactive and provided monosubstituted
imidazopyridine 5t in moderate yield (Table 2, entry 20).
Furthermore, 2-aminoquinoline and 2-aminoisoquinoline
reacted well in this transformation, thus affording imidazo-
quinoline 5u and imidazoisoquinoline 5v, respectively, in
good yields (Table 2, entries 21 and 22).
Next, we attempted the synthesis of alpidem (A) and
zolpidem (B) through this novel three-component coupling
reaction. It should be mentioned that these drugs are usually
synthesized by multistep procedures.[11] We hypothesized that
A and B could rapidly be accessed through a three-
component coupling reaction of the appropriate aminopyr-
idine, aldehyde, and corresponding propiolamide. We recog-
nized that employment of propiolamide as a starting material
would be challenging, as this Michael acceptor would not be
tolerated in the first step of the sequence. Thus, we performed
model studies of the TCC reaction with propiolates
(Scheme 3). It was found that imidazopyridines 6a–c could
be synthesized in good yields in a one-pot fashion, where ethyl
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Experimental Section
Typical procedure for the synthesis of imidazopyridines 5a–v: 2-
Aminopyridine 1 (0.5 mmol), CuCl (2.5 mg, 0.025 mmol, 5 mol%),
Cu(OTf)2 (9.04 mg, 0.025 mmol, 5 mol%), and aldehyde 2 (only
added at this point if solid) was added to a Weaton (1 mL)
microreactor in a glovebox under an inert atmosphere. Subsequently,
anhydrous toluene (500 mL, 1m), aldehyde 2 (0.525 mmol, 1.05 equiv),
and alkyne 3 (0.75 mmol, 1.5 equiv) were added to the mixture. The
microreactor was capped with a Teflon pressure cap and placed into a
preheated (1208C) aluminum heating block. The reaction mixture
was heated at 1208C until full consumption of 2-aminopyridine 1 (as
evident by GC-MS analysis). Upon completion (12–16 h) of the
reaction the mixture was filtered through a plug of neutral alumina
(eluent: EtOAc). The filtrate was concentrated under reduced
pressure to give the crude material, which was purified by column
chromatography on silica gel (eluent: Et3N/EtOAc/hexanes 4:17:84),
and afforded imidazopyridine 5.
Scheme 3. Model studies of the one-pot TCC reaction. M.S.=molecu-
lar sieves (4 ꢀ).
propyolate and copper catalysts were added to the reaction
mixture upon completion of the dehydrocondensation step.
By using the newly established protocol, the one-pot
syntheses of zolpidem and alpidem were carried out by
employing the corresponding propiolamides (Scheme 4).
Gratifyingly, the sequential TCC reaction of 2-amino-5-
Received: December 26, 2009
Published online: March 8, 2010
Keywords: cyclization · heterocycles · homogeneous catalysis ·
.
imidazopyridines · multicomponent reactions
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Scheme 4. One-pot synthesis of alpidem and zolpidem.
chloropyridine (1b) and p-chloroaldehyde (2b) with N,N-
dipropylpropiolamide produced alpidem (A) in 83% yield.
Likewise, the reaction of 2-amino-5-methylpyridine (1c), and
p-tolualdehyde (2c) with N,N-dimethylpropiolamide
afforded zolpidem (B) in 72% yield.
In conclusion, we have developed a general and highly
efficient method for the synthesis of imidazopyridine deriv-
atives by the copper-catalyzed three-component coupling
reaction of aryl, heteroaryl, and alkyl aldehydes with 2-
aminopyridines and terminal alkynes. The employment of 2-
aminoquinoline and 2-aminoisoquinoline as coupling part-
ners in this transformation led to imidazoquinoline and
imidazoisoquinoline frameworks in good yields. The synthetic
utility of this novel TCC reaction has been illustrated in a
highly efficient one-pot synthesis of alpidem and zolpidem.
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[8] Apparently, CuCl is a better catalyst for the synthesis of
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the corresponding 2-aminopyridine, aldehyde, and acetylene,
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