Heteroaromatic imidazo[1,2-a]pyridines synthesis from C-H/N-H oxidative cross-coupling/cyclization

Article abstract of DOI:10.1039/c2cc35927h

A novel silver-mediated highly selective C-H/N-H oxidative cross-coupling/cyclization between 2-aminopyridines and terminal alkynes has been demonstrated. This approach provided a simple way to construct heteroaromatic imidazo[1,2-a]pyridines. By using this protocol, the marketed drug zolimidine (antiulcer) could be synthesized easily.

Full text of DOI:10.1039/c2cc35927h

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Chemical Communications
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Volume 48 | Number 90 | 21 November 2012 | Pages 11037–11152
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Aiwen Lei et al.
Heteroaromatic imidazo[1,2-a]pyridines synthesis from C–H/N–H oxidative cross-coupling/cyclization

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Heteroaromatic imidazo[1,2-a]pyridines synthesis from C–H/N–H
oxidative cross-coupling/cyclizationw
Chuan He,a Jing Hao,a Huan Xu,a Yiping Mo,a Huiying Liu,a Juanjuan Hana and
Aiwen Lei*ab
Received 16th August 2012, Accepted 12th September 2012
DOI: 10.1039/c2cc35927h
A novel silver-mediated highly selective C–H/N–H oxidative cross-
coupling/cyclization between 2-aminopyridines and terminal
alkynes has been demonstrated. This approach provided a simple
Scheme 1 Silver-mediated C–H/N–H oxidative cross-coupling/
way to construct heteroaromatic imidazo[1,2-a]pyridines. By
cyclization.
using this protocol, the marketed drug zolimidine (antiulcer)
could be synthesized easily.
and region-defined routes for constructing 2-arylimidazo-
[1,2-a]pyridines from basic chemical materials, such as pyridine
derivatives and terminal alkynes, are highly attractive. Herein, we
communicate our effort in silver-mediated synthesis of hetero-
aromatic imidazo[1,2-a]pyridines through C–H/N–H oxidative
cross-coupling/cyclization between 2-aminopyridines and terminal
alkynes (Scheme 1).
Direct C–H functionalization towards the formation of C–C
and C–heteroatom (N, O and S, etc.) bonds is of great
significance and a challenge, and application of these strategies
to construct heterocycles is especially attractive.
Compared to the classical transition-metal-catalyzed coupling
reactions, the direct oxidative coupling between two different C–H
or heteroatom-H bonds has an inherent advantage such as
avoiding pre-functionalization of the substrates, and represents
an ideal chemical synthesis.1 In this emerging field, the highly
efficient and selective cross-coupling reactions involving terminal
alkynes are still challenging. Under the oxidative conditions, the
reactions usually suffer from the inevitable homocoupling of
terminal alkynes (Glaser–Hay coupling).2 Recently, some insights
into the direct oxidative C–H functionalization/alkynylation have
been realized.3 However, the challenge of selectivity still remains in
such reactions. Only few examples could avoid the homocoupling
of terminal alkynes. Very recently, silver salts have shown great
potential in the highly selective chemical syntheses involving
terminal alkynes.3f,i,j
We reasoned that the imidazo[1,2-a]pyridine frameworks
could be assembled by a direct C–H/N–H oxidative cross-
coupling/cyclization between 2-aminopyridines and terminal
alkynes in the presence of suitable transition metal catalysts
and oxidants. Our initial efforts focused on the reaction of
2-aminopyridine 1a and phenylacetylene 2a by using copper(II),
iron(III), and silver(I) salts, etc. After some attempts, when silver(I)
salts were employed, the corresponding target 2-phenylimidazo-
[1,2-a]pyridine 3aa was obtained with perfect selectivity and in good
yield (Scheme 1 and Table 1). This interesting one-step transforma-
tion to the imidazoheterocycles encouraged us to further examine
the feasibility of this efficient C–H/N–H oxidative cross-coupling/
cyclization.
The simplest was the best. Only employing Ag2CO3 (2.0 equiv.)
in dioxane at 110 1C, the C–H/N–H oxidative cross-coupling/
cyclization could proceed smoothly in good yield (Table 1, entry 8).
To enhance the conversion of terminal alkyne, 2 equiv. of
2-aminopyridine was employed in the reaction. Even if the two
substrates were added in one-pot, no terminal alkyne homo-
coupling and other byproducts were observed under these oxidative
reaction conditions. Neither base nor acid additives could improve
the yields, such as KOAc, NaOAc, K2CO3, Cs2CO3, DBU, HOAc,
and HOPiv (Table 1, entries 1–7). Ag2O could also produce the
desired product in 63% yield, while AgNO3 was totally ineffective
(Table 1, entries 9 and 10). The reaction could proceed in other
solvents, such as polar solvents DMF, DMSO and NMP, albeit in
lower yields (Table 1, entries 11–13). When DCE was used, only
15% yield was obtained (Table 1, entry 14). When 1.0 equiv. of
Ag2CO3 was employed, only 41% yield was afforded (Table 1,
entry 15). An attempt to utilize O2 as the oxidant in the reaction
was also unsuccessful (Table 1, entry 16).
Imidazoheterocycles represent an important class of heterocycles
prevalent in a myriad of natural products and biologically active
compounds.4 In particular, imidazo[1,2-a]pyridine with important
therapeutic properties is the key structural moiety in several
pharmaceutical drugs, such as the hugely successful and valuable
molecules zolpidem, alpidem and zolimidine, etc.5 In addition,
some abnormal N-heterocyclic carbenes are also prepared based
on imidazo[1,2-a]pyridines.6 Although some methods are available
for the synthesis of this important scaffold,5a,7 the straightforward
a College of Chemistry and Molecular Sciences, Wuhan University,
430072, P. R. China. E-mail: aiwenlei@whu.edu.cn;
Fax: +86-27-68754067
b State Key Laboratory for Oxo Synthesis and Selective Oxidation,
Lanzhou Institute of Chemical Physics, Chinese Academy of
Sciences, 730000, Lanzhou, P. R. China
w Electronic supplementary information (ESI) available. See DOI:
10.1039/c2cc35927h
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 11073–11075 11073

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Table 1 Optimization conditions for the reaction of 2-aminopyridine
1a and phenylacetylene 2a
the possibility for further functionalization (Scheme 2, 3ea–3ga).
Moreover, 1-aminoisoquinoline 1h and 2-aminoquinoline 1i could
also be readily introduced in the transformation, affording imidazo-
isoquinoline and imidazoquinoline, respectively, albeit in lower
yields (Scheme 2, 3ha and 3ia). Interestingly, 2-aminopyridine
with imidazole moieties could also be employed to afford the
imidazo[1,2-a]pyridine scaffold in 40% yield (Scheme 2, 3ja).
Varied terminal alkynes 2 were also tested to access the
imidazo[1,2-a]pyridines (Scheme 3). Either electron-withdrawing
and -donating substituted groups or halogen groups at the
aromatic ring of aryl alkynes were well tolerated in the
reactions, such as Me, OMe, Cl, Br, and CO2Et (Scheme 3,
3ab–3ac, 3ad–3ag, 3bb, 3bg and 3eg). Meanwhile, aryl alkynes
with substituents at the ortho, meta, or para position of the
aromatic ring could react satisfactorily to afford the desired
products in moderate to good yields. Terminal alkynes containing
benzodioxole and thiophene moieties could also be transformed
into the imidazo[1,2-a]pyridines scaffold in 32% and 14% yields
respectively (Scheme 3, 3ah and 3ai). Moreover, alkyl terminal
alkyne prop-2-ynyl pivalate 2j could react with 1a producing
the target product 3aj in 25% yield.
Entry
[Ag]
Additive
Solvent
Yielda (%)
1b
2
3
4
5
6
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2O
AgNO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
KOAc
NaOAc
K2CO3
Cs2CO3
DBU
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
DMF
DMSO
NMP
DCE
Dioxane
Dioxane
71
63
62
53
43
51
Trace
71
63
0
45
31
43
15
41
13
HOAc
HOPiv
7
8c
9
10
11
12
13
14
15d
16e
None
Zolimidine (antiulcer) could be synthesized in a concise
route. As shown in Scheme 4, by utilizing 2-aminopyridine
1a and 4-ethynylphenylmethylsulfane 2k, the cyclization product
3ak could be generated smoothly in 60% yield under the
Ag-mediated conditions. The SMe functional group could be
well tolerated in the reaction. Further oxidation of 3ak using
a
b
Isolated yields. Reactions were carried out on the scale of 0.25 mmol
of 2a in the presence of 2.0 equiv. of Ag2CO3 and 2.0 equiv. of additives
in 6 mL of solvent at 110 1C for 10 h, N2 atmosphere (entries 1–7).
c
Reactions were carried out on the scale of 0.5 mmol of 2a in the
presence of 2.0 equiv. of [Ag] in 6 mL of solvent at 110 1C for 10 h, N2
d
e
atmosphere (entries 8–16). 1.0 equiv. of Ag2CO3. 0.5 equiv. of
Ag2CO3, O2 atmosphere.
Under the optimized reaction conditions, various 2-amino-
pyridines 1 were found to be suitable reaction partners with
phenylacetylene 2a to provide the corresponding imidazopyridine
derivatives 3 (Scheme 2). 2-Aminopyridines substituted at different
positions with methyl group could react with phenylacetylene 2a in
good yields. The position of substituents almost had no influence
on the chemical yields (Scheme 2, 3ba–3da). Halogen groups
substituted at the aromatic ring of 2-aminopyridine, such as chloro,
bromo and even iodo, were all well tolerated, which provided
Scheme 3 Substrate scope for the reaction of 2-aminopyridines 1 and
terminal alkynes 2. Reactions conditions: 1.0 mmol of 1 and 0.5 mmol
of 2 in the presence of 1.0 mmol of Ag2CO3 in 6 mL of dioxane at
110 1C for 10 h, N2 atmosphere. Isolated yields.
Scheme 2 Substrate scope for the reaction of 2-aminopyridines 1 and
phenylacetylene 2a. Reactions conditions: 1.0 mmol of 1 and 0.5 mmol
of 2a in the presence of 1.0 mmol of Ag2CO3 in 6 mL of dioxane at
110 1C for 10 h, N2 atmosphere. Isolated yields.
Scheme 4 Preparation of zolimidine.
c
11074 Chem. Commun., 2012, 48, 11073–11075
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20973132) and the 973 Program (2012CB725302). The authors
also thank the support from ‘‘the Fundamental Research
Funds for the Central Universities’’, Program for New Century
Excellent Talents in University (NCET) and Program for
Changjiang Scholars and Innovative Research Team in
University (IRT1030).
Scheme 5 Reaction of 1a and silver phenylacetylide.
Notes and references
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Scheme 6 Proposed mechanism.
mCPBA as the oxidant could simply produce the target
product zolimidine 4ak in 68% yield. Actually, a one-pot reaction
sequence enables convenient access to zolimidine in about 40%
overall yield.
Moreover, we have also tested some internal alkynes such as
prop-1-ynylbenzene, 1,2-diphenylethyne and dimethyl but-2-
ynedioate instead of terminal alkynes. However, no corre-
sponding imidazo[1,2-a]pyridine products could be observed
under the current conditions. Accordingly, we envisioned that
silver acetylide might be the key intermediate in the reaction.
As shown in Scheme 5, the prepared silver acetylide was
allowed to react with 1a under the standard conditions. In
the presence of additional Ag2CO3, silver phenylacetylide
could indeed react with 1a giving 40% yield of 3aa. Without
additional Ag2CO3, only 9% yield was obtained.
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A putative mechanism for this Ag-mediated C–H/N–H
oxidative cross-coupling/cyclization is outlined in Scheme 6.
Initially, silver acetylide complex A is formed by the reaction of
terminal alkyne 2a with Ag(I). Then, through the silver-promoted
nucleophilic attack of 2-aminopyridine 1a on complex A, the crucial
intermediate B is obtained,8 possibly aggregated with additional
Ag(I).9 Finally, silver-induced oxidative cyclization of B affords the
product 3aa via two single-electron oxidation. Although 2.0 equiv.
of Ag2CO3 was employed in the reaction, actually, the silver species
after the reaction could be recycled conveniently by filtration and
treating with nitric acid and Na2CO3.3i
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In summary, we have developed a novel silver-mediated
highly selective C–H/N–H oxidative cross-coupling/cycliza-
tion between 2-aminopyridines and terminal alkynes. This
approach provides a simple way to construct heteroaromatic
imidazo[1,2-a]pyridines from basic chemical materials. Only
promoted by silver species, various 2-aminopyridines could
react smoothly with terminal alkynes in perfect selectivity and
in moderate to good yields. In this oxidative transformation,
no terminal alkyne homocoupling byproduct was observed. By
using this protocol, the marketed drug zolimidine (antiulcer) could
be easily synthesized in a concise route. Further mechanistic
studies on this oxidative transformation are currently ongoing
in our laboratory.
8 S. Ueda and H. Nagasawa, J. Am. Chem. Soc., 2009, 131,
15080–15081.
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This work was supported by the National Natural Science
Foundation of China (21025206, 20832003, 20972118, and
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 11073–11075 11075