Pd-catalyzed oxidative cross-coupling of imidazo[1,2-a]pyridine with arenes

Article abstract of DOI:10.1016/j.tetlet.2014.01.069

A facile method for direct Pd(OAc)₂-catalyzed oxidative cross-coupling of unactivated imidazo[1,2-a]pyridine with simple arenes has been developed. The reaction shows good reaction efficiency, high regioselectivity, and good functional-group compatibility. This approach provides a useful protocol for the preparation of imidazo[1,2-a]pyridine-arene structure of interest in biological and pharmaceutical materials.

Full text of DOI:10.1016/j.tetlet.2014.01.069

Accepted Manuscript
Pd-Catalyzed Oxidative Cross-Coupling of Imidazo[1,2-a]pyridine with Arenes
Shaohua Wang, Wenjie Liu, Jinghe Cen, Jinqiang Liao, Jianping Huang,
Haiying Zhan
PII:
S0040-4039(14)00103-8
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.01.069
TETL 44102
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
1 November 2013
13 January 2014
20 January 2014
Please cite this article as: Wang, S., Liu, W., Cen, J., Liao, J., Huang, J., Zhan, H., Pd-Catalyzed Oxidative Cross-
Coupling of Imidazo[1,2-a]pyridine with Arenes, Tetrahedron Letters (2014), doi: http://dx.doi.org/10.1016/j.tetlet.
2014.01.069
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers
we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and
review of the resulting proof before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Graphical Abstract
Pd-Catalyzed Oxidative Cross-Coupling of
Imidazo[1,2-a]pyridine with Arenes
Leave this area blank for abstract info.
Shaohua Wang, Wenjie Liu,* Jinghe Cen, Jinqiang Liao, Jianping Huang, Haiying Zhan*
Ph
H
Pd(OAc)2
Ag(I)/O2
N
N
R1
H
R2
+
R1
R2
PivOH
N
N
A novel Pd-catalyzed C(sp2)-H/C(sp2)-H cross-coupling of unactivated imidazo[1,2-a]pyridines with simple arenes
utilizing a combination of Ag(I) and O2 as oxidants exclusively yields C-3 arylated imidazo[1,2-a]pyridines.

1
Tetrahedron Letters
j o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m
Pd-Catalyzed Oxidative Cross-Coupling of Imidazo[1,2-a]pyridine with Arenes
Shaohua Wang, Wenjie Liu,* Jinghe Cen, Jinqiang Liao, Jianping Huang, Haiying Zhan*
School of Chemistry and Chemical Engineering, Guangdong Pharmaceutical University, Guangzhou 510006, P.R. of China
ARTICLE INFO
ABSTRACT
Article history:
Received
A facile method for direct Pd(OAc)2-catalyzed oxidative cross-coupling of unactivated
imidazo[1,2-a]pyridine with simple arenes has been developed. The reaction shows good
reaction efficiency, high regioselectivity and good functional-group compatibility. This
approach provides a useful protocol for the preparation of imidazo[1,2-a]pyridine-arene
structure of interest in biological and pharmaceutical materials.
Received in revised form
Accepted
Available online
2009 Elsevier Ltd. All rights reserved.
eywords:
Dehydrogenative cross-coupling
Birayls
Imidazo[1,2-a]pyridine
Unactivated arenes
activities (Figure 1). Current strategies for preparing
imidazo[1,2-a]pyridine derivatives are focused on the
construction of the fused ring with desired aryl substitutents at
oriented position in advance.12 Herein, we described the first
example of direct Pd(OAc)2-catalyzed oxidative cross-coupling
of imidazo[1,2-a]pyridine with completely unactivated arenes.
Biaryl moiety as a key structural motif was found in many
natural products, bioactive molecules, and functional materials.1
Thus, the development of new and efficient transformation to
prepare biaryl structures has already attracted a great deal of
attention. During the last decades, transition metal-catalyzed
cross-coupling reactions have become one of the most powerful
tools in modern organic chemistry for the synthesis of biaryl
molecules. Many successful strategies, such as Stille, Suzuki,
Kumada and Negishi reaction, have been developed with a
variety of metal catalysts.1a,2 These processes require
functionalized starting materials (aryl halides and aryl metals)
that are often not commercially available or are relatively
expensive, resulting in longer synthetic sequences and severe
environmental problems. Currently, organic chemists have
focused on direct dehydrogenative cross-coupling of C–H bonds
of arenes and heteroarenes, because this transformation is more
atom-economical and minimize the costs of prefunctionalization.3
N
N
O
O
Cl
O
S
H3C
N
N
N
Cl
CH3
CH3
N
N
O
N
alpidem
zolimidine
zolpidem
Figure 1 Imidazo[1,2-a]pyridine derivatives with biology and
medicinal activity.
Here we began this study by choosing imidazo[1,2-a]pyridine
1a and benzene 2a as model substrates to optimize the reaction
conditions (Table 1). The effects of different palladium sources,
oxidants, additives, and solvents were systematically examined.
The desired coupling product was observed in the presence of 5
mol % of Pd(OAc)2, 1.2 equiv of Cu(OAc)2 as an oxidant, 0.15
equiv of HOAc as an additive in N,N-dimethylacetamide (DMA)
at 130 °C (entry 1). Remarkably, the yield of product 3a could be
nearly trebled to 41% by replacing Cu(OAc)2 with Ag2CO3(entry
2). Among other oxidants tested, AgOAc and Ag2O was less
effective, while benzoquinone (BQ), oxone and pure O2 or non-
oxidant was totally ineffective (entries 3-8). It was noticeable that
the combination of Ag2CO3/O2 was better choice, which had
synergistic effect on improving the reaction efficiency (entries
9,10). Thus, the results demonstrated that Ag2CO3 and O2 played
a key role in the catalytic cycle. Moreover, the additive of pivalic
Therefore, the formation of the biaryl C-C bond via direct
dehydrogenative cross-coupling of arenes and heteroarenes is one
of the most efficient strategies for the synthesis of bicyclic
heteroarenes. Recently, elegant transition metal-catalyzed direct
dehydrogenative cross-coupling reactions including the
(hetero)arylations of indole,4 benzofurans,5 pyrrols,4b azoles,6
benzo[h]quinolines,7 perfluoroarenes,8 xanthines,9 and pyridine-
N-oxides,10 were reported with good yields. Among the
transition-metal, palladium is the most versatile and widely
applied catalytic metal in this field due to its synthetic efficiency.
Molecules containing imidazo[1,2-a]pyridine ring play an
important role in a wide range of natural products and drugs.11 In
particular, imidazo[1,2-a]pyridine derivatives with a biaryl motif
such as alpidem (anxiolytic), zolimidine (antiulcer) and zolpidem
(hypnotic) show excellent biological and pharmaceutical

2
Tetrahedron
acid (PivOH) showed better results than HOAc and 2,2,2-
mainly at less hindered meta- and para-positions (entries 16-18).
Fluorobenzene with electron-withdrawing group also could be
used as a coupling partner and the desired product 3q was
isolated in 43% yield (entry 17). Methoxybenzene showed good
regiocontrol (meta/para = 1:5) than fluorobenzene and toluene
(entry 18).
trifluroacetic acid (TFA) (entries 11,12). We next investigated
the influence of solvents and found that N,N-dimethylformamide
(DMF) could dramatically enhance the reaction efficiency (entry
13). The use of other solvents such as N-methyl-2-pyrrolidone
(NMP), dioxane and dimethyl sulfoxide (DMSO) lead to lower
yields (entries 16-18). Poor results were obtained if Pd(OAc)2
was substituted by PdCl2(CH3CN)2 or Pd(TFA)2 (entries 14,15).
It was clearly demonstrated that the best yield of coupling
product of 3a (78%, entry 13) was obtained by using 5 mol %
Pd(OAc)2 as the catalyst, a combination of Ag2CO3 and O2 as
oxidant, pivalic acid as an additive in DMF.
Table 2 Oxidative cross-coupling of imidazo[1,2-a]pyridine
derivatives with arenesa
Entry
1
2
Product
Ph
Yieldb
N
N
1
74
Table 1 Optimization of the intermolecular cross-coupling of
1a and 2aa
N
N
2a
2a
1a
3a
Ph
H
cat. Pd, oxidant
additive, 130 oC
Ph
N
N
H
H
+
H
N
N
N
N
2
3
4
79
77
75
N
N
1a
2a
3a
Solvent Yield (%)b
1b
3b
Entry
Cat
Oxidant
Cu(OAc)2
Ag2CO3
Oxone
Additive
HOAc
HOAc
HOAc
HOAc
HOAc
HOAc
HOAc
HOAc
HOAc
HOAc
PivOH
TFA
1
2
3
4
5
6
7
8
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMF
15
41
-
Ph
N
N
N
2a
2a
N
BQ
-
O2
<5
36
31
-
1c
3c
AgOAc
Ag2O
Ph
N
N
-
N
9c Pd(OAc)2
10c Pd(OAc)2
11c Pd(OAc)2
12c Pd(OAc)2
13c Pd(OAc)2
Ag2CO3/O2
Ag2CO3/air
Ag2CO3/O2
Ag2CO3/O2
Ag2CO3/O2
53
42
68
11
78
28
32
61
37
26
N
1d
3d
Ph
N
N
Ph
N
N
5
6
2a
2a
72
63
PivOH
PivOH
PivOH
PivOH
PivOH
PivOH
Ph
N
14c PdCl2(CH3CN)2 Ag2CO3/O2
DMF
N
3e
1e
15c Pd(TFA)2
16c Pd(OAc)2
17c Pd(OAc)2
18c Pd(OAc)2
Ag2CO3/O2
Ag2CO3/O2
Ag2CO3/O2
Ag2CO3/O2
DMF
Ph
NMP
CF3
Dioxane
CF3
N
DMSO
N
3f
1f
a Reaction conditions: imidazo[1,2-a]pyridine 1a (1.0 mmol), benzene (2a)
(1 mL), catalyst (5 mol%), oxidant (1.2 eq), additive (0.15 eq), O2 (gas bag),
in 2 mL of solvent at 130 °C for 20 h.
Ph
N
b
N
Yields are determined by GC.
c Ag2CO3 (5 mol%).
N
7
2a
73
N
To further expand the scope of this novel methodology, we
tested simple arenes as coupling partners with different
imidazo[1,2-a]pyridine compounds. The arylated imidazo[1,2-
a]pyridine could be isolated with yields ranging from 26% to
79% (Table 2). Most of the reactions ran for 20 h to achieve
complete conversion with good regioselectivity and no
homocoupling products were detected. It is noteworthy that the
cross-coupling of compounds 1a-c and 1k was regioselectively
occurred at C-3 but not C-2 position in the imidazo[1,2-
a]pyridine rings. The method appeared to have good functional
group tolerance. Imidazo[1,2-a]pyridine ring substituted at C-2
position with methyl, tetra-butyl, phenyl, or trifluoromethyl
group was compatible with the reaction conditions. Benzene was
sufficiently reactive, affording the desired products in moderate
isolated yield (entries 1-7). The reactions were sensitive to steric
hindrance. For example, m-xylene and o-xylene reacted at the
less hindered positions to generate single coupling products with
good efficiency (entries 8-13, 19, 20). However, reactions using
mesitylene proceeded at a sluggishly rate and low yield (entries
14, 15). For monosubstituted arene, C-H activation took place
1g
1a
3g
8
71
N
N
3h
2b
2b
9
1b
73
N
N
3i

3
10
1e
2b
66
19
1a
72
N
N
Ph
2g
N
N
3j
3s
N
11
2b
58
N
N
20
1k
2g
75
N
1h
N
3k
N
3t
a Reaction conditions: All reaction were performed with 1 (1.0 mmol), 2 (1
mL), Pd(OAc)2 (5 mol%), Ag2CO3 (5 mol%), PivOH (0.15 eq), O2 (gas bag)
in 2 mL of DMF at 130 °C for 20 h.
N
12
2b
69
N
b Isolated yield after column chromatography of the crude and the ratios of
N
isomers were determined by 1H NMR.
c m/p = 1:1.7. d m/p = 1.4:1. e m/p = 1:5.
1i
N
3l
On the basis of the preliminary studies, we proposed the
following mechanism for the dehydrogenative cross-coupling of
imidazo[1,2-a]pyridine with benzene (Figure 2). In the first
metalation step, we speculated that the abstraction of hydrogen
from imidazo[1,2-a]pyridine should be easily take place. The
intermediate I was generated by electrophilic C-H substitution of
Pd(OAc)2. Then, the key heterocoupling intermediate II was
formed by C-H activation of simple arenes through concerted
metalation deprotonation (CMD) process, which might be the
rate determining step in the catalytic cycle. The desired cross-
coupling product was obtained by a reductive elimination from
intermediate II. Finally reoxidation of Pd(0) by oxidant
regenerated the catalytically active Pd(II) species to finish the
reaction cycle.
N
13
2b
64
N
N
N
1j
3m
14
1a
26
N
2c
N
3n
H
N
N
15
2c
29
N
N
N
Pd(OAc)2
1k
HOAc
N
oxidant
3o
Me
OAc
Pd
N
Pd(0)
16
1a
70c
N
N
I
2d
N
Pd
3p
cross-coupling
product
H
N
F
N
F
HOAc
II
17
1a
43d
N
Figure 2 Possible mechanism for oxidative C-H/C-H cross-coupling
of imidazo[1,2-a]pyridine with benzene.
N
2e
3q
In conclusion, we have developed the Pd-catalyzed direct C-H
arylation of unactivated imidazo[1,2-a]pyridine with simple
arenes for the first time. It represents an efficient way to prepare
imidazo[1,2-a]pyridine derivatives in good yields and high
selectivity. Further studies to expand the substrate scope and their
application as well as investigations of the reaction mechanism
are currently underway.
OMe
OMe
18
1a
62e
N
2f
N
3r

4
Tetrahedron
131, 9651. (c) Lynos, T. W.; Hull, K. L.; Sanford, M. S. J. Am.
Chem. Soc. 2011, 133, 4455.
Acknowledgments
8. (a) He, C.-Y.; Fan, S.; Zhang, X. J. Am. Chem. Soc. 2010, 132,
12850. (b) Wei, Y.; Su, W. J. Am. Chem. Soc. 2010, 132, 16377.
(c) Li, H.; Liu, J.; Sun, C.-L.; Li, B.-J.; Shi, Z.-J. Org. Lett. 2011,
13, 276. (d) Do, H. Q.; Daugulis, O. J. Am. Chem. Soc. 2011, 133,
13577. (e) He, C.-Y.; Min, Q.-Q.; Zhang, X. Organometallics
2012, 31, 1335.
9. (a) Malakar, C. C.; Schmidt, D.; Conrad, J.; Beifuss, U. Org. Lett.
2011, 13, 1378. (b) Wang, Z.; Li, K.; Zhao, D.; Lan, J.; You, J.
Angew. Chem. Int. Ed. Engl. 2011, 50, 5365. (c) Xi, P.; Yang, F.;
Qin, S.; Zhao, D.; Lan, J.; Gao, G.; Hu, C.; You, J. J. Am. Chem.
Soc. 2010, 132, 1822.
The work was financially supported by the Foundation for
Distinguished Young Talents in Higher Education of Guangdong
(2012LYM_0086), Natural Science Foundation of Guangdong
Province (S2013040012962) and the National Natural Science
Foundation of China (21302023, 21373061).
References and notes
1. (a) Corbet, J.-P.; Mignani, G. Chem. Rev. 2006, 106, 2651. (b)
Hassan, J.; Sévignon, M.; Gozzi, C.; Schulz, E.; Lemaire, M.
Chem. Rev. 2002, 102, 1359. (c) Meyer, E. A.; Castellano, R. K.;
Diederich, F. Angew. Chem. Int. Ed. Engl. 2003, 42, 1210. (d)
Kozlowski, M. C.; Morgan, B. J.; Linton, E. C. Chem. Soc. Rev.
2009, 38, 3193.
10. (a) Cho, S. H.; Hwang, J.; Chang, S. J. Am. Chem. Soc. 2008, 130,
9254. (b) Gong, X.; Song, G.; Zhang, H.; Li, X. Org. Lett. 2011,
13, 1766.
11. (a) Trapani, G.; Franco, M.; Latrofa, A.; Ricciardi, L.; Carotti, A.;
Serra, M.; Sanna, E.; Biggio, G.; Liso, G. J. Med. Chem. 1999, 42,
3934. (b) Linton, A.; Kang, P.; Ornelas, M.; Kephart, S.; Hu, Q.;
Pairish, M.; Jiang, Y.; Guo, C. J. Med. Chem. 2011, 54, 7705. (c)
Bode, M. L.; Gravestock, D.; Moleele, S. S.; van der Westhuyzen,
C. W.; Pelly, S. C.; Steenkamp, P. A.; Hoppe, H. C.; Khan, T.;
Nkabinde, L. A. Bioorg. Med. Chem. 2011, 19, 4227. (d) Dahan-
Farkas, N.; Langley, C.; Rousseau, A. L.; Yadav, D. B.; Davids,
H.; de Koning, C. B. Eur. J. Med. Chem. 2011, 46, 4573.
12. (a) Toure, B. B.; Lane, B. S.; Sames, D. Org. Lett. 2006, 8, 1979.
(b) Dai, W.; Petersen, J. L.; Wang, K. K. J. Org. Chem. 2005, 70,
6647. (c) Cai, L.; Brouwer, C.; Sinclair, K.; Cuevas, J.; Pike, V. W.
Synthesisi 2006, 133. (d) Husined, S.; Markovic, R.; Petkovic, M.;
Nasufovic, V.; Savic, V. Org. Lett. 2011, 13, 2286. (e) Cao, H.;
Zhan, H.; Lin, Y.; Lin, X.; Du, Z.; Jiang, H. Org. Lett. 2012, 14,
1688. (f) Fu, H. Y.; Chen, L.; Doucet, H. J. Org. Chem. 2012, 77,
4473. (g) Jamal, K.; Saïd, E. K.; Sabine, B.-R.; Abderrahim, M.;
Gérald, G. Synlett 2006, 19, 3237.
2. (a) Martin, R.; Buchwald, S. L. Acc. Chem. Res. 2008, 41, 1461.
(b) de Meijere, A.; Diederich, F. Wiley-VCH; Weinheim,
Germany, 2004. (c) Zhang, S.-S.; Wang, Z.-Q., Xu, M.-H., Lin,
G.-Q. Org. Lett. 2010, 12, 5546.
3. (a) Yeung, C. S.; Dong, V. M. Chem. Rev. 2011, 111, 1215. (b)
Liu, C.; Zhang, H.; Shi, W.; Lei, A. Chem. Rev. 2011, 111, 1780.
(c) Kuhl, N.; Hopkinson, M. N.; Wencel-Delord, J.; Glorius, F.
Angew. Chem. Int. Ed. Engl. 2012, 51, 10236. (d) Chen, X.;
Engle, K. M.; Wang, D. H.; Yu, J. Q. Angew. Chem. Int. Ed. Engl.
2009, 48, 5094. (e) Yu, D.-G.; Li, B. J.; Shi, Z.-J. Tetrahedron
2012, 68, 5130. (f) Liu, C., Jin, L.; Lei, A. Synlett 2010, 2527.
4. (a) Stuart, D. R.; Fagnou, K. Science 2007, 316, 1172. (b) Stuart,
D. R.; Villemure, E.; Fagnou, K. J. Am. Chem. Soc. 2007, 129,
12072.
5. (a) Dwight, T. A.; Rue, N. R.; Charyk, D.; Josselyn, R.; Deboef,
B. Org. Lett. 2007, 7, 3137. (b) Potavathri, S.; Pereira, K. C.;
Gorelsky, S. I.; Pike, A.; LeBris, A. P.; DeBoef, P. J. Am. Chem.
Soc. 2010, 132, 14676. (c) Kitahara, M.; Umeda, N.; Hirano, K.;
Satoh, T.; Miura, M. J. Am. Chem. Soc. 2011, 133, 2160.
6. (a) Wu, G.; Zhou, J.; Zhang, M.; Su, W. Chem. Commun. 2012,
48, 8964. (b) Nishino, M.; Hirano, K.; Satoh, T.; Miura, M.
Angew. Chem. Int. Ed. 2012, 51, 6993. (c) Li, Z.; Ma, L.; Xu, J.;
Kong, L.; Wu, X.; Yao, H. Chem. Commun. 2012, 48, 3763.
7. (a) Hull, K. L.; Sanford, M. S. J. Am. Chem. Soc. 2007, 129,
11904. (b) Hull, K. L.; Sanford, M. S. J. Am. Chem. Soc. 2009,
Supplementary Material
1H and 13C NMR spectra of compounds 3a-3t.