Palladium(ii)-catalyzed intermolecular oxidative C-3 alkenylations of imidazo[1,2-a]pyridines by substrate-contolled regioselective C-H functionalization

Article abstract of DOI:10.1039/c4ra09669j

An efficient and highly regioselective palladium(ii)-catalyzed oxidative C-3 alkenylation of imidazo[1,2-a]pyridines with acrylate, acrylonitrile, or vinylarenes has been developed by using oxygen as an oxidant. Substrates such as acrylate and acrylonitrile tended to form β-product, while vinylarenes tended to form the sole α-products. This journal is

Full text of DOI:10.1039/c4ra09669j

RSC Advances
View Article Online
View Journal | View Issue
COMMUNICATION
Palladium(II)-catalyzed intermolecular oxidative
C-3 alkenylations of imidazo[1,2-a]pyridines by
substrate-contolled regioselective C–H
functionalization†
Cite this: RSC Adv., 2014, 4, 50137
Received 3rd September 2014
Accepted 30th September 2014
*
Hua Cao, Sai Lei, Jinqiang Liao, Jianping Huang, Huifang Qiu, Qinlin Chen,
DOI: 10.1039/c4ra09669j
Shuxian Qiu and Yaoyi Chen
www.rsc.org/advances
An efficient and highly regioselective palladium(II)-catalyzed oxidative efficient methods to synthesize imidazo[1,2-a]pyridines has
C-3 alkenylation of imidazo[1,2-a]pyridines with acrylate, acrylonitrile, continuously attracted the attentions of many chemists.12 We
or vinylarenes has been developed by using oxygen as an oxidant. have recently developed facile C–H transformation for the
Substrates such as acrylate and acrylonitrile tended to form b-product, preparation of imidazo[1,2-a]pyridine13 and other heterocyclic
while vinylarenes tended to form the sole a-products.
compounds. In this context, our attention is focused on the
development alkenylations of imidazo[1,2-a]pyridine to prepare
imidazo[1,2-a]pyridine derivatives (Scheme 1). Moreover, the
reaction has proceeded by using molecular oxygen as terminal
oxidant, which avoided the environmentally hazardous by-
products obtained with other oxidants.14
The metal-catalyzed Heck reaction which received the Nobel
Prize in 2010 has become one of the most widely used methods
in chemical synthesis.1 This approach offers the possibility for
catalytic transformation of unactivated C–H bonds into diverse
functionalities. Currently, direct oxidative alkenylation of
heterocycles has already achieved widespread acceptance
within the organic synthetic elds, because of its capacity to
utilize simpler and cheaper precursors for the preparation of
functionalized molecules. Consequently, the discovery of effi-
cient methods for the assembly of carbon–carbon bonds has
attracted attention in this eld, which avoided synthesis of
complex and expensive starting substrates. Since the pioneering
Fujiwara and co-workers2 have rst described a wealth of
palladium- and rhodium-catalyzed oxidative alkenylations.
Many elegant direct oxidative alkenylations3 have been achieved
without the need for prior halogenation or metallization in this
eld. Despite of several methods have been reported during the
last decades, there is still an intrinsic need for open new routes
to synthesize of diverse heterocycles molecules.
The initial screening studies have been carried out using 1a
and 2a as model substrate to identify and optimize many
different combinations of potential catalysts, oxidants, addi-
tives, and solvents in order to improve the yields of the reaction.
The results are summarized in Table 1. First, treatment of 1a
with 2a in the presence of PdCl2, Cu(OAc)2 and AcOH at 120 ꢀC
in dioxane, a trace of the desired directly alkenylation product
3a was observed (entry 1). Other Pd-catalyst was also tested
(entries 2–5), including Pd(O2CCF3)2, Pd(CH3CN)Cl2, Pd(dba)2,
Pd(OAc)2. Interestingly, the use of Pd(OAc)2 afforded the cor-
responding products 3a in 9% GC yield, while other palladium
sources gave poor yields. On changing the oxidants we observed
a signicant improvement by using Ag2CO3 as oxidant in the
reaction and the product 3a was obtained in 32% GC yield
(entry 6). Other silver salts, such as AgOAc or AgOTf, were also
employed and the desired product was obtained in 21%, 20%
yields respectively (Table 1, entries 7 and 8). Other oxidants,
such as BQ, DDQ, tBuOOBz, O2 and air were also tested (entries
Imidazo[1,2-a]pyridines are extremely important chemicals
that exhibit a wide range of biological activities4 and are used as
antiviral,5 antiulcer,6 antibacterial,7 antifungal,8 antiprotozoal,9
antiherpes,10 anti-inammatory.11 Since the wide application of
imidazo[1,2-a]pyridines in pharmaceutical research and drugs
including Alpidem, Zolpidem, Necopidem, Olprinone, Divalpon
and Zolimidine are available in the market, the development of
School of Chemistry and Chemical Engineering, Guangdong Pharmaceutical
University, Guangzhou 510006, P. R. China. E-mail: caohua@gdpu.edu.cn; Fax: +86
760 88207939
† Electronic supplementary information (ESI) available. See DOI:
10.1039/c4ra09669j
Scheme 1 Alkenylations of imidazo[1,2-a]pyridines.
RSC Adv., 2014, 4, 50137–50140 | 50137
This journal is © The Royal Society of Chemistry 2014

View Article Online
RSC Advances
Communication
Table 1 Optimization of reaction conditionsa
Entry
Catalyst
Oxidant
Additive
Solvent
t (h)
Yieldb (%)
1
2
3
4
5
6
7
8
PdCl2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
AgOAc
Ag2CO3
AgOTf
BQ
DDQ
tBuOOBz
O2 (1 atm)
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
PhCO2H
AcOH/Ac2O
Py
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Toluene
DMA
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
24
30
12
trace
5
trace
trace
9
32
21
20
NR
NR
NR
27
5<
69
12
81
40
12
Pd(O2CCF3)2
Pd(CH3CN)Cl2
Pd(dba)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
9
10
11
12
13
14c
15c
16c
17c
18c
19c
20c
21c
22c
23c
24c
Air (1 atm)
O2 (1 atm)/Ag2CO3
O2 (1 atm)/Ag2CO3
O2 (1 atm)/Ag2CO3
O2 (1 atm)/Ag2CO3
O2 (1 atm)/Ag2CO3
O2 (1 atm)/Ag2CO3
O2 (1 atm)/Ag2CO3
O2 (1 atm)/Ag2CO3
O2 (1 atm)/Ag2CO3
O2 (1 atm)/Ag2CO3
O2 (1 atm)/Ag2CO3
K2CO3
AcOH/Ac2O
AcOH/Ac2O
AcOH/Ac2O
AcOH/Ac2O
AcOH/Ac2O
AcOH/Ac2O
46
60
13
19
77
62
DMSO
DMF
Dioxane
Dioxane
a
b
Reaction conditions: 1a (0.5 mmol), 2a (2.5 mmol), catalyst (5% mol), oxidant (1.2 mmol), additive (0.5 mmol), solvent (3.0 mL). GC yields.
5 mol% Ag2CO3, O2 (500 mL).
c
9–13). The results showed that O2 was a choice for this trans- with 1 and led to the desired a-products 4a–4r in good yields.
formation. To our delight, the good yield was obtained, when The presence of electron-withdrawing groups, such as F and
the reaction was carried out by using Ag2CO3 (5 mol%) and O2 Cl, were tolerated in the reaction and afforded the desired
(with oxygen ballon) as co-oxidant (entry 14) in the presence of products smoothly.
Pd(OAc)2. These results encouraged us to adjust additives to
Subsequently, a variety of acrylates were examined. The
improve the yield (entries 15–18). We were pleased to nd that desired a-product was not formed, while only b-products
the yield of 3a could be observed in 81% by using AcOH and obtained under the optimized conditions. The results are
Ac2O as additives (entry 16). Effects of solvents and tempera- described in Table 3. A variety of acrylates were examined. It was
tures were also investigated in the following tests (entries 19– observed that alteration of an alkoxy part of acrylate did not
22). Among them, dioxane was demonstrated to be the best change the reaction efficiency, and a similar level of product
choice. Nonetheless, the yield could not be improved with the yields was obtained in the alkenylation of butyl, methyl, ethyl,
increasing reaction time to 30 h (entry 23). But decreasing the and cyclohexyl acrylate. The scope of various types of imidazo-
time to 12 h did affect the reaction efficiency and the low yields [1,2-a]pyridine substrates was also extensively surveyed. The
of 3a were obtained (entry 24).
imidazo[1,2-a]pyridine and its derivatives with electro-
With the optimized conditions in hand, we next investi- ndonating methyl groups at the 2-, 6-, 7-, and 8-positions were
gated the scope of this novel highly regioselective alkenyla- smoothly alkenylated at the 3-position with acrylate in good
tion of imidazo[1,2-a]pyridines with styrene for synthesis of yields. The substrate ethyl imidazo[1,2-a]pyridine-2-carboxylate
a-products. And the results are described in Table 2. A variety with electronwithdrawing CO2Et group at 2-positions also per-
of imidazo[1,2-a]pyridines with electrondonating methyl formed very well and afforded the desired product 4j in good
groups at the 2-, 6-, 7-, and 8-positions were smoothly alke- yield. Notably, high regioselectivity was observed, when the
nylated at the 3-position with styrene in good yields (Table 2). reactions were carried out by using 2,3-dihydro-imidazo[1,2-a]-
Thus, we turned our attention to examine the scope of pyridines with acrylate. All the results indicated that this
vinylarenes. Various substituted styrene was reacted well process is highly regioselective for C-3 alkenylation.
50138 | RSC Adv., 2014, 4, 50137–50140
This journal is © The Royal Society of Chemistry 2014

View Article Online
Communication
RSC Advances
Table 2 Alkenylations of imidazo[1,2-a]pyridines with styrenesa
Table 3 Alkenylations of imidazo[1,2-a]pyridines with acrylatesa
a
Isolated yields.
Scheme 2 Proposed mechanism.
through a palladium-catalyzed C–H functionalization reaction.
It represents a novel, regio- and stereoselective oxidative alke-
nylation process. This transformation using molecular oxygen
to avoid excessive silver levels also results in a clean and rather
waste-free process.
a
Isolated yields.
Acknowledgements
This research was nancially supported by National Natural
Science Foundation of China (21302023) and the Project of
Department of Education of Guangdong Province
(2013kjcx0111).
On the basis of the previous report and our results at this
stage, we have proposed two plausible pathways for the two
oxidative coupling reactions in Scheme 2. Path I:2,15 palladation
at C-3 of imidazo[1,2-a]pyridine (electrophilic substitution) was
thought to occur intermediate A with the aid of oxidant. Active
intermediate A then inserts into the methyl acrylate to give
intermediate B, which rapidly decomposes through b-elimina-
tion to generate the desired product and Pd catalyst (regular
Heck-reaction product); Path II:1b,3l,16 palladium(II) salts tend to
react with styrene to give the intermediate C, which then can
undergo an intermolecular nucleophilic attack of 1a (usually at
the more substituted vinylic carbon) to generate intermediate
D. The corresponding product is formed via b-hydride elimi-
nation from intermediate D and releases the Pd catalyst.
In summary, we have developed an efficient method for the
selective intermolecular alkenylation of substituted imidazo-
[1,2-a]pyridines with diverse acrylate, acrylonitrile, and styrenes
Notes and references
1 (a) A. B. Dounay and L. E. Overman, Chem. Rev., 2003, 103,
2945; (b) I. P. Beletskaya and A. V. Cheprakov, Chem. Rev.,
2000, 100, 3009; (c) A. d. Meijere and F. E. Meyer, Angew.
Chem., Int. Ed., 1994, 34, 2379.
2 (a) I. Moritani and Y. Fujiwara, Tetrahedron Lett., 1967, 8,
1119; (b) Y. Fujiwara, I. Moritani, S. Danno, R. Asano and
S. Teranishi, J. Am. Chem. Soc., 1969, 91, 7166.
3 (a) S. Murai, F. Kakiuchi, S. Sekine, Y. Tanaka, A. Kamatani,
M. Sonoda and N. Chatani, Nature, 1993, 366, 529; (b) C. Jia,
D. Piao, J. Oyamada, W. Lu, T. Kitamura and Y. Fujiwara,
This journal is © The Royal Society of Chemistry 2014
RSC Adv., 2014, 4, 50137–50140 | 50139

View Article Online
RSC Advances
Communication
Science, 2000, 287, 1992; (c) E. M. Beccalli, G. Broggini,
M. Martinelli and S. Sottocornola, Chem. Rev., 2007, 107,
5318; (d) L. Ackermann and J. Pospech, Org. Lett., 2011, 13,
4153; (e) L. Ackermann, A. V. Lygin and N. Hofmann, Org.
Lett., 2011, 13, 3278; (f) L. Ackermann and S. Fenner, Org.
Lett., 2011, 13, 6548; (g) L. Ackermann, L. Wang and
A. V. Lygin, Chem. Sci., 2012, 3, 177; (h) P. B. Arockiam,
C. Fischmeister, C. Bruneau and P. H. Dixneuf, Green
Chem., 2011, 13, 3075; (i) Y. H. Zhang, B. F. Shi and
J. Q. Yu, J. Am. Chem. Soc., 2009, 131, 5072; (j) X. Chen,
K. M. Engle, D. H. Wang and J. Q. Yu, Angew. Chem., Int.
Ed., 2009, 48, 5094; (k) H. Q. Do and O. Daugulis, J. Am.
Chem. Soc., 2007, 129, 12404; (l) Y. Yang, K. Cheng and
Y. Zhang, Org. Lett., 2009, 11, 5606; (m) J. J. Li, T. S. Mei
and J. Q. Yu, Angew. Chem., Int. Ed., 2008, 47, 6452; (n)
L. Y. Jiao and M. Oestreich, Org. Lett., 2013, 15, 5374; (o)
G. Broggini, V. Barbera, E. M. Beccalli, E. Borsini, S. Gallil,
Eur. J., 2011, 17, 6315; (e) V. Z. Parchinsky, O. Shuvalova,
O. Ushakova, D. V. Kravchenko and M. Krasavin,
Tetrahedron Lett., 2006, 47, 947; (f) F. Chen, M. Lei and
L. Hu, Tetrahedron, 2013, 69, 2954; (g) H. Zhou, W. Wang,
O. Khorev, Y. Zhang, Z. Miao, T. Meng and J. Shen, Eur. J.
Org. Chem., 2012, 5585; (h) V. Tyagi, S. Khan, V. Bajpai,
H. M. Gauniyal, B. Kumar and P. M. S. Chauhan, J. Org.
Chem., 2012, 77, 1414; (i) S. Husinec, R. Markovic,
M. Petkovic, V. Nasufovic and V. Savic, Org. Lett., 2011, 13,
2286; (j) Z. Fei, Y. P. Zhu, M. C. Liu, F. C. Jia and A. X. Wu,
Tetrahedron Lett., 2013, 54, 1222; (k) H. Y. Fu, L. Chen and
H. Doucet, J. Org. Chem., 2012, 77, 4473; (l) H. Yang,
L. Yang, Y. Li, F. Zhang, H. Liu and B. Yi, Catal. Commun.,
2012, 11; (m) J. Koubachi, S. El Kazzouli, S. Berteina-
Raboin, A. Mouaddib and G. Guillaumet, Synthesis, 2008,
2537; (n) J. Koubachi, S. Berteina-Raboin, A. Mouaddib and
G. Guillaumet, Synthesis, 2009, 271.
G. Lanza and G. Zecchi, Adv. Synth. Catal., 2012, 354, 159; 13 (a) H. Cao, H. Y. Zhan, Y. G. Lin, X. L. Lin, Z. D. Du and
(p) W. Raufa and J. M. Brown, Chem. Commun., 2013, 49,
8430; (q) R. C. Jones, M. Gał˛ezowski and D. F. O'Shea, J.
Org. Chem., 2013, 78, 8044.
4 (a) K. S. Gudmundsson and B. A. Johns, Org. Lett., 2003, 5,
1369; (b) C. Enguehard, F. Fauvelle, J. Debouzy,
H. F. Jiang, Org. Lett., 2012, 14, 1688; (b) H. Cao, Y. G. Lin,
H. Y. Zhan, Z. D. Du, X. L. Lin, Q. M. Liang and H. Zhang,
RSC Adv., 2012, 2, 5972; (c) H. Cao, X. H. Liu, L. M. Zhao,
J. H. Cen, J. X. Lin, Q. X. Zhu and M. L. Fu, Org. Lett.,
2014, 16, 146.
A. Peinnequin, I. Thery and D. V. A. Gueiffier, Eur. J. 14 (a) T. Punniyamurthy, S. Velusamy and J. Iqbal, Chem. Rev.,
Pharm. Sci., 2005, 24, 219.
5 G. Puerstinger, J. Paeshuyse, E. Declercq and J. Neyts, Bioorg.
Med. Chem. Lett., 2007, 17, 390.
2005, 105, 2329; (b) W. Q. Wu and H. F. Jiang, Acc. Chem. Res.,
2012, 45, 1736; (c) Z. Shi, C. Zhang, C. Tang and N. Jiao,
Chem. Soc. Rev., 2012, 41, 3381.
6 (a) J. J. Kaminsky and A. M. Doweyko, J. Med. Chem., 1997, 40, 15 (a) N. P. Grimster, C. Gauntlett, C. R. A. Godfrey and
427; (b) Y. Kaesura, S. Nishino, Y. Inoue, M. Tomoi and
H. Taksugi, Chem. Pharm. Bull., 1992, 40, 371.
7 Y. Rival, G. Grassy and G. Michel, Chem. Pharm. Bull., 1992,
40, 1170.
8 Y. Rival, G. Grassy, A. Taudou and R. Ecalle, Eur. J. Med.
Chem., 1991, 26, 13.
M. J. Gaunt, Angew. Chem., Int. Ed., 2005, 44, 3125; (b)
E. M. Beck, N. P. Grimster, R. Hatley and M. J. Gaunt, J.
Am. Chem. Soc., 2006, 128, 2528; (c) Y. Yang, H. Gong and
C. Kuang, Eur. J. Org. Chem., 2013, 5276; (d) H. Jiang,
Z. Feng, A. Wang, X. Liu and Z. Chen, Eur. J. Org. Chem.,
2010, 1227.
9 M. A. Ismail, R. K. Arafa, T. Wenzler, R. Brun, F. A. Tanious, 16 (a) W. Cabri and I. Candiani, Acc. Chem. Res., 1995, 28, 2; (b)
W. D. Wilson and D. W. Boykin, Bioorg. Med. Chem., 2008, 16,
681.
10 K. S. Gudmundsson and B. A. Johns, Bioorg. Med. Chem. Lett.,
2007, 17, 2735.
11 K. C. Rupert, J. R. Henry, J. H. Dodd, S. A. Wadsworth,
D. E. Cavender, G. C. Olini, F. Fahmy and J. J. Siekierka,
Bioorg. Med. Chem. Lett., 2003, 23, 347.
12 (a) A. K. Bagdi, M. Rahman, S. Santra, A. Majee and A. Hajra,
Adv. Synth. Catal., 2013, 355, 1741; (b) S. Santra, A. K. Bagdi,
A. Majee and A. Hajra, Adv. Synth. Catal., 2013, 355, 1065; (c)
N. Chernyak and V. Gevorgyan, Angew. Chem., Int. Ed., 2010,
49, 2743; (d) K. S. Masters, T. R. M. Rauws, A. K. Yasav,
W. A. Herrebout, B. V. Veken and B. U. W. Mases, Chem.–
J. Mo, L. Xu and J. Xiao, J. Am. Chem. Soc., 2005, 127, 751; (c)
H. Schenck, B. Akermark and M. Svensson, J. Am. Chem. Soc.,
2003, 125, 3503; (d) G. Broggini, E. M. Beccalli, A. Fasana and
S. Gazzola, Beilstein J. Org. Chem., 2012, 8, 1730; (e)
A. Ashimori, B. Bachand, M. A. Calter, S. P. Govek,
L. E. Overman and D. J. Poon, J. Am. Chem. Soc., 1998, 120,
6488; (f) R. J. Deeth, A. Smith and J. M. Brown, J. Am.
Chem. Soc., 2004, 126, 7144; (g) P. Fristrup, S. L. Quement,
D. Tanner and P.-O. Norrby, Organometallics, 2004, 23,
¨
6160; (h) C. Backtorp and P.-O. Norrby, Dalton Trans., 2011,
40, 11308; (i) E. M. Beccalli, G. Broggini, M. Martinelli and
S. Sottocornola, Chem. Rev., 2007, 107, 5318.
50140 | RSC Adv., 2014, 4, 50137–50140
This journal is © The Royal Society of Chemistry 2014