Conversion of pyridine to imidazo[1,2-a]pyridines by copper-catalyzed aerobic dehydrogenative cyclization with oxime esters

Article abstract of DOI:10.1021/ol403105p

A rapid and environmentally friendly conversion of pyridine to imidazo[1,2-a]pyridines has been developed via copper-catalyzed aerobic dehydrogenative cyclization with ketone oxime esters.

Full text of DOI:10.1021/ol403105p

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Conversion of Pyridine to
Imidazo[1,2‑a]pyridines by
Copper-Catalyzed Aerobic Dehydrogenative
Cyclization with Oxime Esters
Huawen Huang, Xiaochen Ji, Xiaodong Tang, Min Zhang, Xianwei Li, and Huanfeng Jiang*
School of Chemistry and Chemical Engineering, South China University of Technology,
Guangzhou 510640, P. R. China
jianghf@scut.edu.cn
Received October 29, 2013
ABSTRACT
A rapid and environmentally friendly conversion of pyridine to imidazo[1,2-a]pyridines has been developed via copper-catalyzed aerobic
dehydrogenative cyclization with ketone oxime esters.
Intensive attention has been paid to the transformation
of pyridine and its derivatives, which provided convenient
access to a broad range of functionalized N-containing
organic molecules. However, in most cases, more reactive
pyridinium salts were indispensable for the success of the
transformation.1 Direct functionalization of pyridine re-
mains a significant challenge owing to the lower energy of
the π-system relative to benzene.2 In recent years, the
transition-metal-catalyzed transformation of unactivated
pyridine has triggered widespread interest due to the
desirable synthetic flexibility and overall efficiency.3,4
On the other hand, the construction of pyridine-contain-
ing heteropolycycles from pyridine derivatives has been
widely reported.1,5 In particular, imidazo[1,2-a]pyridines,
which represent an important class of natural products,
(1) Bull, J. A.; Mousseau, J. J.; Pelletier, G.; Charette, A. B. Chem.
Rev. 2012, 112, 2642.
(2) Katritzky, A. R.; Taylor, R. Adv. Heterocycl. Chem. 1990, 47, 1.
(3) For recent examples of transition-metal-catalyzed addition reaction
of unactivated pyridine, see: (a) Oshima, K.; Ohmura, T.; Suginome, M.
J. Am. Chem. Soc. 2012, 134, 3699. (b) Oshima, K.; Ohmura, T.; Suginome,
M. J. Am. Chem. Soc. 2011, 133, 7324. (c) Gutsulyak, D. V.; van der Est, A.;
Nikonov, G. I. Angew. Chem., Int. Ed. 2011, 50, 1384. (d) Osakada, K.
Angew. Chem., Int. Ed. 2011, 50, 3845.
(4) For recent examples of transition-metal-catalyzed CÀH function-
alization of unactivated pyridine, see: (a) Lewis, J. C.; Bergman, R. G.;
Ellman, J. A. J. Am. Chem. Soc. 2007, 129, 5332. (b) Berman, A. M.;
Lewis, J. C.; Bergman, R. G.; Ellman, J. A. J. Am. Chem. Soc. 2008, 130,
14926. (c) Godula, K.; Sezen, B.; Sames, D. J. Am. Chem. Soc. 2005, 127,
3648. (d) Kawashima, T.; Takao, T.; Suzuki, H. J. Am. Chem. Soc. 2007,
129, 11006. (e) Murphy, J. M.; Liao, X.; Hartwig, J. F. J. Am. Chem. Soc.
2007, 129, 15434. (f) Fischer, D. F.; Sarpong, R. J. Am. Chem. Soc. 2010,
132, 5926. (g) Nakao, Y.; Kanyiva, K. S.; Hiyama, T. J. Am. Chem. Soc.
2008, 130, 2448. (h) Tsai, C.-C.; Shih, W.-C.; Fang, C.-H.; Li, C.-Y.;
Ong, T.-G.; Yap, G. P. A. J. Am. Chem. Soc. 2010, 132, 11887. (i) Nakao,
Y.; Yamada, Y.; Kashihara, N.; Hiyama, T. J. Am. Chem. Soc. 2010,
132, 13666. (j) Ye, M.; Gao, G.-L.; Yu, J.-Q. J. Am. Chem. Soc. 2011,
133, 6964. (k) Johnson, D. G.; Lynam, J. M.; Mistry, N. S.; Slattery,
J. M.; Thatcher, R. J.; Whitwood, A. C. J. Am. Chem. Soc. 2013, 135,
2222.
(5) For selective examples of indolizine synthesis from pyridines, see:
ꢀ
ꢀ
(a) Barluenga, J.; Lonzi, G.; Riesgo, L.; Lopez, L. A.; Tomas, M. J. Am.
Chem. Soc. 2010, 132, 13200. (b) Li, Z.; Chernyak, D.; Gevorgyan, V.
Org. Lett. 2012, 14, 6056. (c) Jung, Y.; Kim, I. Tetrahedron 2012, 68,
8198. (d) Kel’in, A. V.; Sromek, A. W.; Gevorgyan, V. J. Am. Chem. Soc.
2001, 123, 2074. (e) Seregin, I. V.; Gevorgyan, V. J. Am. Chem. Soc.
2006, 128, 12050. (f) Schwier, T.; Sromek, A. W.; Yap, D. M. L.;
Chernyak, D.; Gevorgyan, V. J. Am. Chem. Soc. 2007, 129, 9868.
(6) (a) Enguehard-Gueiffier, C.; Gueiffier, A. Mini-Rev. Med. Chem.
2007, 7, 888. (b) Lhassani, M.; Chavignon, O.; Chezal, J. M.; Teulade,
J. C.; Chapat, J. P.; Snoeck, R.; Andrei, G.; Balzarini, J.; Clercq, E. D.;
Gueiffier, A. Eur. J. Med. Chem. 1999, 34, 271. (c) Rupert, K. C.; Henry,
J. R.; Dodd, J. H.; Wadsworth, S. A.; Cavender, D. E.; Olini, G. C.;
Fahmy, B.; Siekierka, J. J. Bioorg. Med. Chem. Lett. 2003, 13, 347.
(7) For synthesis of imidazo[1,2-a]pyridine from 2-aminopyridines
based on condensation, see: (a) Vilchis-Reyes, M. A.; Zentella, A.;
ꢀ
ꢀ
Martı
´
Gallegos, J. L. V.; Dı
nez-Urbina, M. A.; Guzman, A.; Vargas, O.; Apan, M. T. R.;
´
az, E. Eur. J. Med. Chem. 2010, 45, 379. (b) Yadav,
J. S.; Reddy, B. V. S.; Rao, Y. G.; Srinivas, M.; Narsaiah, A. V.
Tetrahedron Lett. 2007, 48, 7717. (c) Chernyak, N.; Gevorgyan, V.
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Wink, D. J.; Gevorgyan, V. Org. Lett. 2013, 15, 956. (e) Nair, D. K.;
Mobin, S. M.; Namboothiri, N. N. Org. Lett. 2012, 14, 4580.
r
10.1021/ol403105p
XXXX American Chemical Society

pharmaceuticals, and bioactive compounds,6 were inten-
sively synthesized based on 2-aminopyridines7,8 through
condensation or/and oxidative coupling of the CÀN bond.
Instead of utilizing 2-aminopyridines, traditionally derived
from pyridine, direct conversion of simple pyridine intothe
target heterocycles would be of great significance. How-
ever, there have been only a few examples designed toward
imidazo[1,2-a]pyridines through direct conversion of pyr-
idine. Recently, Fabio et al. reported a novel solvent- and
catalyst-free reaction of pyridine-like heterocycles with
1,2-diaza-1,3-dienes, directly leading to imidazo[1,2-a]-
pyridines, -quinolines, and -isoquinolines in good yields
(Scheme 1a).9 Despite the synthetic efficiency, this reaction
suffers the limitation of inaccessible and substituent-
restricted 1,2-diaza-1,3-dienes. During our preparation of
this munascript, Fu et al. reported an efficient Cu-catalyzed
aerobic cyclization of pyridine and N-(alkylidene)-4H-1,2,4-
triazol-4-amines for the synthesis of imidazo[1,2-a]pyridines
with triazole as a leaving group (Scheme 1b).10 As our
continuing interest in N-heterocycle synthesis under a
Cu/O2 catalytic system,11 herein, we describe a Cu-catalyzed
aerobic cyclization of pyridine with easily accessible oxime
esters for the preparation of imidazo[1,2-a]pyridine com-
pounds (Scheme 1c). Compared with previous work, the
present protocol features high efficiency and good functional
group tolerance. Furthermore, the use of an environmentally
friendly oxidant and the green byproducts generated make
this transformation very practical and atom-economical.
We initially found that the imidazo[1,2-a]pyridine moiety
canbeformedwithapromising32%yieldfrompyridine(1a,
3.0 equiv) and acetophenone oxime acetate (2a, 1.0 equiv)
with CuI (20 mol %) in N,N-dimethylformamide (DMF)
under air at 95 °C for 2.0 h (Table 1, entry 1). Enhancement
in yield was not observed upon screening other copper(I)
catalysts such as CuBr (entry 2), CuCl (entry 3), and CuOTf
(entry 4). Notably, Cu(II) catalysts such as Cu(OTf)2
(entry 5) and Cu(OAc)2 (entry 6) did not afford the imidazo-
[1,2-a]pyridine product. Inorganic base additives, which
would affect the interaction between Cu(I) and oxime esters,12
proved to significantly influence this transformation. While
NaOAc decreased the yield of 3aa, NaHSO3 and NaHCO3
Scheme 1. Direct Transformation of Pyridine to
Imidazo[1,2-a]pyridines
Table 1. Optimization of Reaction Conditionsa
oxime
ester
cat.
additive
yield
(%)b
entry
(20 mol %)
(20 mol %)
1
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2c
2d
CuI
none
32
20
18
9
2
CuBr
CuCl
CuOTf
Cu(OTf)2
Cu(OAc)2
CuI
none
3
none
4
none
5
none
trace
0
6
none
7
NaOAc
NaHSO3
NaHCO3
Na2CO3
Li2CO3
DABCO
Li2CO3
Li2CO3
Li2CO3
Li2CO3
25
49
45
33
89
trace
88
15
62
40
(8) For synthesis of imidazo[1,2-a]pyridine from 2-aminopyridines
based on oxidative coupling, see: (a) Yan, R.-L.; Yan, H.; Ma, C.; Ren,
Z.-Y.; Gao, X.-A.; Huang, G.-S.; Liang, Y.-M. J. Org. Chem. 2012, 77,
2024. (b) Zeng, J.; Tan, Y. J.; Leow, M. L.; Liu, X.-W. Org. Lett. 2012,
14, 4386. (c) He, C.; Hao, J.; Xu, H.; Mo, Y.; Liu, H.; Han, J.; Lei, A.
Chem. Commun. 2012, 48, 11073. (d) Wang, H. G.; Wang, Y.; Peng,
C. L.; Zhang, J. C.; Zhu, Q. J. Am. Chem. Soc. 2010, 132, 13217. (e)
Wang, H. G.; Wang, Y.; Liang, D. D.; Liu, L. Y.; Zhang, J. C.; Zhu, Q.
Angew. Chem., Int. Ed. 2011, 50, 5678. (f) Ma, L.; Wang, X.; Yu, W.;
Han, B. Chem. Commun. 2011, 47, 11333. (g) Bagdi, A. K.; Rahman, M.;
Santra, S.; Majee, A.; Hajra, A. Adv. Synth. Catal. 2013, 355, 1741. (h)
Mohan, D. C.; Donthiri, R. R.; Rao, S. N.; Adimurthy, S. Adv. Synth.
Catal. 2013, 355, 2217. (i) Cai, Z.-J.; Wang, S.-Y.; Ji, S.-J. Adv. Synth.
Catal. 2013, 355, 2686.
8
CuI
9
CuI
10
11
12
13c
14
15
16
CuI
CuI
CuI
CuI
CuI
CuI
CuI
a Unless otherwise indicated, the reaction was performed with oxime
ester (0.3 mmol, 1.0 equiv), pyridine (0.9 mmol, 3.0 equiv), copper
catalyst (0.06 mmol, 20 mol %), additive (0.06 mmol, 20 mol %) in DMF
(1.0 mL) at 95 °C under air for 2.0 h. b Determined by GC analysis with
tridecane as an internal standard. c Under an O2 atmosphere.
(9) Attanasi, O. A.; Bianchi, L.; Campisi, L. A.; Crescentini, L. D.;
Favi, G.; Mantellini, F. Org. Lett. 2013, 15, 3646.
(10) Yu, J.; Jin, Y.; Zhang, H.; Yang, X.; Fu, H. Chem.;Eur. J.
201310.1002/chem.201302737.
(11) (a) Jiang, H.; Li, X.; Pan, X.; Zhou, P. Pure. Appl. Chem. 2012,
84, 553. (b) Li, X.; He, L.; Chen, H.; Wu, W.; Jiang, H. J. Org. Chem.
2013, 78, 3636. (c) Li, X.; Huang, L.; Chen, H.; Wu, W.; Huang, H.;
Jiang, H. Chem. Sci. 2012, 3, 3463. (d) Huang, H.; Ji, X.; Wu, W.; Huang,
L.; Jiang, H. J. Org. Chem. 2013, 78, 3774.
enhanced the yield to 49% and 45%, respectively. A marginal
improvement was observed upon running the reaction with
Na2CO3. To our delight, addition of Li2CO3 in this reaction
B
Org. Lett., Vol. XX, No. XX, XXXX

Scheme 2. Scope of Ketone Oxime Estersa
Scheme 3. Scope of Pyridines and Isoquinolinea
a Unless otherwise indicated, reaction conditions: see Table 1, entry 11.
b Within 1.5 h.
a Unless otherwise indicated, reaction conditions: see Table 1, entry 11.
b Within 1.5 h.
ketones were also productive, leading to the products
(3ap and 3aq) in 82% and 78% yield, respectively. Oximes
derived from other aryl ketones such as propiophenone,
1,1,1-trifluoro-3-phenylpropan-2-one, and 2-phenylaceto-
phenone afforded the products 3atÀ3av, respectively, in
moderate yields. Besides, oximes derived from methyl pyr-
uvate and aliphatic ketone could efficiently afford imidazo-
[1,2-a]pyridines 3ar and 3as. Unfortunately, oximes derived
from nonmethyl alkyl ketones such as pentan-3-one and
cyclohexanone did not work. Among the oximes investi-
gated, relatively electron-rich oximes, such as with methoxyl
(3af and 3aj), naphthalen-1-yl (3ao), and aliphatic (3as)
groups, enabled the reaction time to be reduced to 1.5 h.
The substrate scope in substituted pyridines was also
evaluated (Scheme 3). Generally, lower yields relative to
pyridine were obtained with substituted pyridines. Inter-
estingly, 3-substituted pyridines afforded products in mod-
erate yield (3bÀ3d), with the C2-position of the pyridines
participating rather than the C6-position. Unfortunately,
C2-substituted pyridines did not prove fruitful when run-
ning the reaction with even more than 5 equiv of pyridines.
system gave a dramatic improvement, with the yield of 3aa
increasing up to 89% (entry 11). Unexpectedly an organic
base such as DABCO completely prevented this transforma-
tion (entry 12). This reaction under an oxygen atmosphere led
no obvious change in the yield (entry 13). Finally, other
different acetophenone oxime esters (2bÀ2d) were tested
under the catalytic system, and no further improvement in
yield was observed (entries 14À16).
With the optimized reaction conditions in hand, we next
set out to investigate the generality of the Cu-catalyzed
cyclization with a variety of ketone oxime acetates (Scheme 2).
A number of oximes derived from aryl methyl ketones
smoothly participated in the reaction, affording the corre-
sponding imidazo[1,2-a]pyridines 3aaÀ3am in moderate
to good yields, with tolerance of functional groups, includ-
ing fluoro, chloro, bromo, trifluoromethyl, methoxyl, and
methylsulfonyl groups. 1- or 2-naphthalenylethanone oxi-
mes afforded the products 3ao and 3an, respectively, in good
yields. Oximes derived from thiophen-2-yl and furan-2-yl
(12) (a) Ren, Z.-H.; Zhang, Z.-Y.; Yang, B.-Q.; Wang, Y.-Y.; Guan,
Z.-H. Org. Lett. 2011, 13, 5394. (b) Guan, Z.-H.; Zhang, Z.-Y.; Ren,
Z.-H.; Wang, Y.-Y.; Zhang, X. J. Org. Chem. 2011, 76, 339. (c) Wei, Y.;
Yoshikai, N. J. Am. Chem. Soc. 2013, 135, 3756. (d) Tang, X.; Huang, L.;
Qi, C.; Wu, W.; Jiang, H. Chem. Commun. 2013, 49, 9597.
(13) Previous work on the transformation of 2-aminopyridines and
methyl ketones (see ref 8gÀ8i) generally requires 24 h.
(14) See Supporting Information for details.
Org. Lett., Vol. XX, No. XX, XXXX
C

Pyridine-like heterocycles such as quinoline and isoquino-
line were also subjected to these reaction conditions. While
quinoline, just like a C2 substituted pyridine, could not
work, isoquinoline was an effective substrate for this
aerobic cyclization. When treated with various oximes de-
rived from aryl methyl ketones, methyl pyruvate, and
aliphatic ketone, isoquinoline reacted smoothly to afford
moderate to good yields of substituted imidazo[2,1-a]-
isoquinoline products (3eÀ3j), whereas oximes derived from
nonmethyl ketones such as propiophenone and 2-phenyla-
cetophenone featured very low activities (<15% yield).
Compared with pyridine, other N-containing heteroaro-
matic compounds, such as pyrazine, pyrimidine, and 1,3,5-
triazine, did not work in this aerobic cyclization.
Scheme 4. Plausible Reaction Mechanism
To gain mechanistic insight into this reaction, some
control experiments were conducted. Addition of a free
radical scavenger TEMPO or ethene-1,1-diyldibenzene
could not prohibit the cyclization (eqs 1 and 2), which
indicated this reaction did not proceed through a radical
mechanism. The intermolecular competition reaction was
conducted using equal amounts of 1a and D-labeled
pyridine d5-1a, corresponding to a KIE = 1 (eq 3), which
was determined by 1H NMR analysis of the isolated prod-
ucts. The measured KIE suggested that the H-abstraction
from pyridine was not the rate-determining step during the
oxidative cyclization. Additionally, ketone oxime esters
could serve as an internal oxidant to promote this transfor-
matiion because this reaction could afford a 41% yield of
imidazo[1,2-a]pyridine 3aa under a N2 atmosphere (eq 4).
oxidative addition of Cu(I) to oxime esters. Then, insertion
of pyridine into the CuÀN bond of B takes place at the 1,2-
positions of the pyridine ring with a new CuÀN bond
formation to afford intermediate D. Intramolecular H-ab-
straction ofE, the tautomer of D, byCu(III) results in a six-
membered copper ring intermediate F. Finally, reductive
elimination and oxidative aromatization lead to the final
imidazo[1,2-a]pyridine product and regeneration of Cu(I).
Additionally, pyridine aromatization of D, followed by oxi-
dative cyclization, could also lead to the final product.8gÀi
However, the high efficiency of this reaction13 (within 2 h)
indicated it is more likely to proceed through direct reductive
elimination of intermediate F. Moreover, intermediate F
may provide the basis for the regioselectivity obtained with
C3-subsituted pyridines.14
In conclusion, we have developed a highly efficient Cu-
catalytic system for the direct transformation of pyridine
to imidazo[1,2-a]pyridine derivatives with ketone oxime
esters. This protocol features advantages including high
efficiency, an inexpensive catalyst (CuI), an economic and
environmentally friendly oxidant (air), and green byprod-
ucts (HOAc and H2O). Moreover, it might open up a new
way to design complex molecules through direct conver-
sion of unactivated pyridine.
Acknowledgment. We thank the National Natural
Science Foundation of China (20932002 and 21172076),
National Basic Research Program of China (973 Program)
(2011CB808600), Doctoral Fund of Ministry of Education
of China (20090172110014), and Guangdong Natural Science
Foundation (10351064101000000) for financial support.
Supporting Information Available. Experimental proce-
dure and characterization of compounds 3. This material is
available free of charge via the Internet at http://pubs.acs.org.
Based on the above experimental results and previous
reports in terms of the Cu(I)-catalyzed transformation of
oxime esters,12 a possible mechanism is proposed as shown
in Scheme 4. A Cu(III)-imino species B is formed via
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX