Au-catalyzed domino process synthesis of imidazo[1,2-a]pyridines from 2-aminopyridine and N-tosylhydrazones: An efficient C[sbnd]N bond formation reaction

Article abstract of DOI:10.1016/j.catcom.2016.10.033

A novel Au-catalyzed domino reaction for the synthesis of imidazo[1,2-a]pyridines from 2-aminopyridine and N-tosylhydrazones has been developed using molecular oxygen. It represents a new strategy for the formation of C[sbnd]N bonds. This transformation demonstrated a broad tolerance toward the substrates and allowed the generation of a diverse imidazo[1,2-a]pyridine derivatives with good yields.

Full text of DOI:10.1016/j.catcom.2016.10.033

Au-catalyzed domino process synthesis of Imidazo[1,2-a]pyridines
from 2-aminopyridine and N-tosylhydrazones: An efficient C¡ce:glyph
name=”sbnd”/¿N bond formation reaction
Pengfeng Guo, Shuyu Huang, Jiaxian Mo, Xiaoyan Chen, Hangqi Jiang,
Weifeng Chen, Hehuan Cai, Haiying Zhan
PII:
DOI:
Reference:
S1566-7367(16)30407-1
doi:10.1016/j.catcom.2016.10.033
CATCOM 4838
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Catalysis Communications
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Accepted date:
12 August 2016
25 October 2016
26 October 2016
Please cite this article as: Pengfeng Guo, Shuyu Huang, Jiaxian Mo, Xiaoyan Chen,
Hangqi Jiang, Weifeng Chen, Hehuan Cai, Haiying Zhan, Au-catalyzed domino process
synthesis of Imidazo[1,2-a]pyridines from 2-aminopyridine and N-tosylhydrazones: An
efficient C¡ce:glyph name=”sbnd”/¿N bond formation reaction, Catalysis Communications
(2016), doi:10.1016/j.catcom.2016.10.033
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ACCEPTED MANUSCRIPT
Au-Catalyzed Domino Process Synthesis of Imidazo[1,2-a]pyridines
From 2-aminopyridine and N-tosylhydrazones: An Efficient C-N
bond Formation Reaction
Pengfeng Guo,a Shuyu Huang,a Jiaxian Mo,a Xiaoyan Chen,a Hangqi Jiang,a Weifeng
Chen,a Hehuan Cai,a Haiying Zhan*a
a
School of Chemistry and Chemical Engineering, Guangdong Pharmaceutical
University, Zhongshan 528458, P.R. of China
Fax: (+) 86-760-88207939
E-mail: nancyzhy@foxmail.com
Abstract: A novel Au-catalyzed domino reaction for the synthesis of
imidazo[1,2-a]pyridines from 2-aminopyridine and N-tosylhydrazones has been
developed using molecular oxygen. It represents a new strategy for the formation of
C-N bonds. This transformation demonstrated a broad tolerance toward the substrates
and allowed the generation of a diverse imidazo[1,2-a]pyridine derivatives with good
yields.
Keywords: Au-Catalyzed; Imidazo[1,2-a]pyridines; Synthesis; Molecular oxygen
1. Introduction
Transition metal-catalyzed organic reactions are powerful tools for the formation of C-N bonds
to synthesize sophisticated N-fused heterocyclic compounds[1-3] which are important chemicals
that exhibit a wide range of biological activities.[4-5] Due to their great application value it has
attracted significant interest in modern organic chemists. Many novel transformations have
been developed to prepare those N-fused heterocyclic compounds, such as indoles,[6-7]
pyrroles,[8-9] imidazo[1,2-a]pyridines,[10-11] triazoles,[12-14] pyridines[15-16] et al. Those strategies
encouraged us to develop new route for the synthesis of N-fused heterocyclic compounds.
In this context, imidazo[1,2-a]pyridines have emerged as an important class of organic
compounds (See Scheme 1) and are frequently used as pharmaceuticals.[17-19] Anumber of drugs
in the market were including the imidazo[1,2-a]pyridine core moiety, such as zolpidem,
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zolimidine, olprinone, necopidem, alpidem, and saripidem. Thus, the development of new
methods for the preparation of these compounds is of significant interest. There are mainly two
routes to construct imidazo[1,2-a]pyridine derivatives. One way is to functionalize
imidazo[1,2-a]pyridines via direct cross-coupling reactions, such as arylation,[20-21]
thiolation,[22-23] alkenylation,[24-25] and carbonylation[26-27] et al. The other is to cyclize
pyridin-2-amine.[28-30] Several reports[31-32] have been developed to prepare
imidazo[1,2-a]pyridines in this field. Despite all these advances, the development of more
direct synthetic methods to access to this skeleton is in high favorable. Herein, we report a new
Au-catalyzed reaction[33] for the synthesis of imidazo[1,2-a]pyridines from 2-aminopyridine
and N-tosylhydrazones, which could be carried out under mild conditions to give desired
product in good yields.
Scheme 1. Important imidazo[1,2-a]pyridines
2. Results and discussion
At the onset of our investigation, we employed 2-aminopyridine (1a) and
4-methyl-N'-(1-phenylethylidene)benzenesulfonohydrazide (2a) as the substrates. The results
are outlined in Table 1. Interestingly, the reaction of 1a with 2a in toluene catalyzed by 5 mol%
of Ph3PAu(I)OTf furnished the product 3a as a single regioisomer in 67% yield in the presence
of Cs2CO3 at 110 ℃for 12 h (Table 1,entry 1). The same reaction catalyzed by 5 mol% of
Ph3PAuCl or Ph3PAu(I)BF4 or Ph3PAu(I)SbF6 or Ph3PAu(I)PF6 or Ph3PAu(I)NTf2 gave lower
yields of the desired product 3a (Table 1, entries 2-6). Moreover, Cu(OAc)2, CuI or AgOAc was
2

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next employed(Table 1, entries 7-9). Compared with Ph3PAu(I)OTf, low yield 3a was obtained.
After that, screening of suitable bases for this transformation revealed that CsOAc gave the best
yield of the desired product 3a (Table 1,entry 10). Other bases, such as NaOAc, NaOH,
NaHCO3, and Na3PO4, furnished the inferior results (Table 1,entries 11-14). After obtaining
discouraging results for this C-N bonds formation reaction, we next investigated the oxidant.
Replacement of air by AgOAc or DDQ or K2S2O8 decreased the yield (Table 1,entries 15-17).
To our delight, the desired product 3a was generated in 88% yield by using O2 as a oxidant
(Table 1,entry 18). Different solvents was then employed and the results indicated that other
solvents (dioxane, ClCH2CH2Cl, DMSO, DMF, Toluene) reduced the catalytic effect resulting
in lower conversion (Table 1,entries 19-23).
Table 1. Model Reaction and Optimizationa
NNHTs
N
catalyst, additive
+
NH2
N
solvent, oxidant, 12 h
N
1a
2a
3a
Entry
1
Catalyst
Additive
Cs2CO3
Oxidantb Solvent
Yield(%)c
67
air
Toluene
Ph3PAu(I)OTf
Ph3PAuCl
2
3
Cs2CO3
Cs2CO3
air
air
Toluene
Toluene
16
37
Ph3PAu(I)BF4
4
5
6
7
8
9
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
air
air
air
air
air
air
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
43
46
61
32
15
-
Ph3PAu(I)SbF6
Ph3PAu(I)PF6
Ph3PAu(I)NTf2
Cu(OAc)2
CuI
AgOAc
3

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10
11
12
13
14
15
16
17
18
19
20
21
22
23
CsOAc
NaOAc
NaOH
air
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
dioxane
72
63
20
43
35
32
12
32
88
82
Ph3PAu(I)OTf
Ph3PAu(I)OTf
Ph3PAu(I)OTf
Ph3PAu(I)OTf
Ph3PAu(I)OTf
Ph3PAu(I)OTf
Ph3PAu(I)OTf
Ph3PAu(I)OTf
Ph3PAu(I)OTf
Ph3PAu(I)OTf
Ph3PAu(I)OTf
Ph3PAu(I)OTf
Ph3PAu(I)OTf
-
air
air
NaHCO3
Na3PO4
CsOAc
CsOAc
CsOAc
CsOAc
CsOAc
CsOAc
CsOAc
CsOAc
CsOAc
air
air
AgOAc
DDQ
K2S2O8
O2
O2
O2
ClCH2CH2Cl 81
O2
DMSO
DMF
69
64
-
O2
O2
Toluene
a Reaction conditions: 1a (0.6 mmol), 2a (0.5 mmol), catalyst (5 mol %), additives (10 mol %), solvents 3 mL; 110 °C for 12 h;
bCarried out in a sealed tube; c Yields determined by GC analysis using n-octadecane as internal standard.
With optimized conditions in hand (Table 1, entry 18), we tested the substrate scope for this
Au-catalyzed transformation. The N-tosylhydrazones scope for the synthesis of
imidazo[1,2-a]pyridines was investigated under the optimized conditions and the results are
summarized in Table 2. As expected, a variety of N-tosylhydrazones 2 were tolerated well with
2-aminopyridine 1a to give imidazo[1,2-a]pyridine derivatives 3 in moderated to good yields.
Generally, both electron-donating groups, like methyl, isobutyl, PhCH2O, CH3CONH, 4-methoxy,
methoxy, and phenyl, and electron-withdrawing groups, such as OCF3, Cl, and F, reacted well under
4

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the
optimal
conditions.
In
addition,
the
substrates,
such
as
(2j),
and
4-methyl-N'-(1-(naphthalen-2-yl)ethylidene)benzenesulfonohydrazide
4-methyl-N'-(1-(naphthalen-1-yl)ethylidene)benzenesulfonohydrazide
(2k),
N'-(1-(furan-2-yl)ethylidene)-4-methylbenzenesulfonohydrazide (2n), were also employed and the
corresponding products (3j, 3k, 3n) was formed in this reaction. The scope of N-tosylhydrazones
for this transformation was further explored by changing groups R2. Interestingly, the corresponding
products (3o, 3p, 3q) were also formed in 73%, 70%, 49% yields, respectively, when the H (R2 ) in
N-tosylhydrazones was replaced by CH3, Ph.
Table 2. Scope for the Formation of Imidazo[1,2-a]pyridines from 2-aminopyridine and
N-tosylhydrazonesa
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N
N
N
N
N
N
3c 83%
3b 82%
3a 85%
N
N
NHCOCH3
O
O
N
N
N
3e 76%
3d 80%
N
N
N
N
OCF3
N
OCH3
3h 70%
3g72%
3f 77%
N
N
N
Ph
Cl
N
N
N
N
3j 86%
3i 81%
3k 84%
N
N
O
N
F
N
N
3n 77%
3m 81%
3l 83%
N
N
N
N
OCH3
N
N
Ph
3q 49%
3p 70%
3o 73%
a Isolated yields
In order to explore the scope of this Au-catalyzed reaction, a variety of pyridin-2-amines with
different N-tosylhydrazones were evaluated under the optimized reaction conditions. The
results are presented in Table 3. Different substituents on the pyridine ring, such as CH3, Cl, Br,
I, and F, led to a beneficial effect on the reaction outcome and led to the corresponding product
4a−4i in moderate to good yields. For the orthogonality of gold and palladium catalysis, which
allows the use of aryl bromides and iodides in gold catalysis without competing oxidative
addition.[34] It was indicated that pyridin-2-amines substituted with both electron-rich groups
and electron-poor groups were suitable partners.
Table 3. Au-Catalyzed Synthesis of Imidazo[1,2-a]pyridinesa
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An important marketed drug zolimidine which was an antiulcer drug has been synthesized
under our reaction conditions in Scheme 2. The reaction was carried out by using 1a and
4-methyl-N'-(1-(4-(methylsulfonyl)phenyl)ethylidene)benzenesulfonohydrazide
as
the
substrates, and the desired product was formed in 68% yield under optimized conditions. This
is a new route for the synthesis of drug zolimidine.
Scheme 2. Synthesis of Zolimidine
According to the results of this transformation and the recent report[35], a proposed mechanism
for the formation of imidazo[1,2-a]pyridines has been described in Scheme 3. 2a underwent
Michael type addition of 1a to give the intermediate A which underwent elimination of
TsNHNH2 to form the intermediate B. A gold(III) intermediate C was easily generated in the
presence of Ph3PAu(I)OTf and O2. Subsequently, reductive elimination of C given intermediate
D and released the gold catalyst. Finally, intermediate D then converted to product 3a via the
abstraction of the hydrogen with the help of CsOAc.
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NNHTs
N
Ph
+
N
Ph
N
N
H
A
NHNHTs
N
NH2
H
B
1a
2a
O2
Ph3PAuIOTf
HX or H2O
Au (I)
LAuIII
AcO
H
N
H
N
N
N
Ph
N
Ph
N
Ph
3a
C
D
Scheme 3. Possible Mechanism
3. Conclusion
In conclusion, we have developed an efficient Au(I)-catalyzed domino process for the
construction of C-N bonds to prepare imidazo[1,2-a]pyridines which are broadly applicable for
the synthesis of biologically active compounds. This reaction proceeds smoothly with broadly
scope and gives the products in moderate to good yields. In particular, our strategy is
applicable to the synthesis of zolimidine which is an important antiulcer drug. Further
investigations to extend the substrate scope and discover synthetic applications are ongoing in
our laboratory.
Acknowledgment
The work was financially Supported by National Natural Science Foundation of China
(21302023), the Project of Department of Education of Guangdong Province (2013kjcx0111),
the financial support of the Science and Technology Program of Guangzhou,
China(1563000282), the Innovation and Strong School Project of Guangdong Pharmaceutical
University (2014KTSCX120), and the Project of Innovation for Enhancing Guangdong
Pharmaceutical University, Provincial Experimental Teaching Demonstration Center of
Chemistry & Chemical Engineering.
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NNHTs
N
Ph3PAu (I)OTf, CsOAc
R
toluene, O2, 110 OC, 12 h
R
+
R1
N
R2
N
NH2
R1
R2
Graphical abstract
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Highlights
Gold(I)-catalyzed synthesis of imidazo[1,2-a]pyridines;
The formation of C-N bonds;
Green oxidation with O2;
12