An I2-catalyzed oxidative cyclization for the synthesis of indolizines from aromatic/aliphatic olefins and α-picoline derivatives

Article abstract of DOI:10.1039/c5ra01234a

A novel I₂-catalyzed intermolecular oxidative tandem cyclization reaction of aromatic/aliphatic olefins and α-picoline derivatives has been achieved for the synthesis of indolizines under metal-free conditions. In this transformation, substituted indolizines are obtained in moderate to good yields through C-C/C-N bond formation in one pot. This journal is

Full text of DOI:10.1039/c5ra01234a

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An I2-catalyzed oxidative cyclization for the
synthesis of indolizines from aromatic/aliphatic
Cite this: RSC Adv., 2015, 5, 29424
olefins and a-picoline derivatives†
Received 21st January 2015
Accepted 17th March 2015
Likui Xiang, Fuming Zhang, Baohua Chen, Xiaobo Pang, Xiaodong Yang,
*
Guosheng Huang and Rulong Yan
DOI: 10.1039/c5ra01234a
www.rsc.org/advances
A novel I2-catalyzed intermolecular oxidative tandem cyclization
To overcome some of the disadvantages associated with
reaction of aromatic/aliphatic olefins and a-picoline derivatives has metal catalysts and complex substrates, a I2/TBHP reaction
been achieved for the synthesis of indolizines under metal-free system is an appropriate candidate for both academic and
conditions. In this transformation, substituted indolizines are industrial communities for our transformation.7 Iodine and
obtained in moderate to good yields through C–C/C–N bond olens, as common and easily available substrates, have been
formation in one pot.
widely used for constructing the scaffolds of heterocyclic
compounds.8 On the basis of our previous studies on the
synthesis of heterocyclic compounds,9 we envisaged that
substituted indolizines could be realized from olens and a-
picoline derivatives via I2-catalysis. With this in mind, our
initial investigation began by treating styrene (1a) and ethyl 2-
(pyridin-2-yl)acetate (2a) with I2 (10 mol%) and t-butyl hydro-
The synthesis of indolizines has attracted considerable interest
in organic synthesis due to their diverse and enhanced biolog-
ical activities. The skeleton of indolizine is an important key
structure in many pharmacological compounds1 and in mate-
rials science.2 As a result, great developments have been ach-
ieved in the synthesis of indolizines in recent years. Among
them, some elegant procedures have been accomplished using
cyclizations starting from pyridinium N-methylides and a
specic C2 functionalization of pyridines.3 With the develop-
ment of C–H bond activation, a metal-catalyzed direct func-
tionalization of indolizines was explored recently.4 From an
economic point of view, the oxidative tandem reaction has
emerged as a powerful and versatile synthetic tool for the
construction of indolizines through C–C/C–N bond formation.
More recently, the Lei group has reported a reagent-free oxida-
tive cyclization approach for the synthesis of indolizine deriv-
atives using a-picoline derivatives and nitroolens.5 Our group
has also reported a direct I2-mediated oxidative cyclization
method to synthesize indolizines from aromatic/aliphatic eno-
lizable aldehydes and 2-pyridyl acetates/acetone/acetonitrile
(Scheme 1).6 However, it is still a great challenge to synthesize
indolizines using readily accessible substrates through metal-
free oxidative tandem cyclization.
ꢀ
peroxide (TBHP) (3 equiv.) in DMF at 120 C. Gratifyingly, the
desired product ethyl 3-phenylindolizine-1-carboxylate (3aa)
was isolated in 54% yield (Table 1, entry 1). Herein, we report
interesting results from a direct I2-catalyzed oxidative cycliza-
tion protocol for the synthesis of substituted indolizines with
alkyl pyridines and aldehydes.
In order to improve the yield of 3aa, different solvents were
initially screened and NMP was found to be the best one for this
reaction (Table 1, entry 3). Aer changing the amount of I2, a
higher yield was achieved when 0.05 equiv. of I2 was used in the
transformation. Then various oxidants were also evaluated for
this reaction, and TBHP showed the highest activity for this
reaction (Table 1, entry 7). Further studies showed that the use
of N,N-ligands could promote the reaction, and the yield of 3aa
State Key Laboratory of Applied Organic Chemistry, Key Laboratory of Nonferrous
Metal Chemistry and Resources Utilization of Gansu Province, Department of
Chemistry, Lanzhou University, Lanzhou, 730000, China. E-mail: yanrl@lzu.edu.cn;
Fax: +86-931-8912596
† Electronic supplementary information (ESI) available: Experimental procedures
and spectroscopic data. See DOI: 10.1039/c5ra01234a
Scheme 1 The methods of synthesizing substituted indolizines.
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Table 1 Optimization of the reaction conditionsa
Table 2 Synthesis of substituted indolizines from substituted styrenes
and 2-pyridyl acetates/acetone/acetonitrilea
Catalyst
Entry (equiv.)
Yield
1
2
Additive
Oxidant
Solvent (%)b
Entry
R1
R2
Product
Yield (%)b
1
2
3
4
5
6
7
8
9
I2 (0.1)
I2 (0.1)
I2 (0.1)
I2 (0.1)
I2 (0.1)
I2 (0.6)
I2 (0.05)
I2 (0.05)
I2 (0.05)
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
DTBP
Benzoyl
peroxide
O2
DMF 54
DMSO 36
NMP 62
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
1g
1h
1i
H
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2b
2b
2b
2c
2d
COOEt
COOEt
COOEt
COOEt
COOEt
COOEt
COOEt
COOEt
COOEt
COOEt
COOEt
COOEt
COOEt
COOEt
COOEt
COOEt
COOEt
COOMe
COOMe
COOMe
COOMe
CN
3aa
3ba
3ca
3da
3ea
3fa
3ga
3ha
3ia
74
71
66
59
61
72
54
70
41
61
81
62
71
84
63
78
52
70
62
72
73
35
Trace
2-Me
3-Me
4-Me
4-tBu
2,5-DiMe
2,4,6-TriMe
4-OMe
4-CH2Cl
4-Ph
2-F
4-F
2-Cl
3-Cl
4-Cl
2-Br
4-Br
H
4-OMe
2-Cl
THF
MeCN 58
NMP
60
—
NMP 67
NMP Trace
NMP
—
9
10
11
12
13
14
I2 (0.05)
I2 (0.05)
I2 (0.05)
I2 (0.05)
I2 (0.05)
NMP Trace
NMP 69
NMP 70
NMP 74
NMP 71
10
11
12
13
14
15
16
17
18
19
21
22
23
24
1j
1k
1l
3ja
3ka
3la
Pyridine
Et3N
TMEDA
1,10-
Phenanthroline
PPh3
TBHP
TBHP
TBHP
TBHP
1m
1n
1o
1p
1q
1a
1h
1m
1n
1a
1a
3ma
3na
3oa
3pa
3qa
3ab
3hb
3mb
3nb
3ac
3ad
15
16
17
18
I2 (0.05)
I2 (1.0)
—
TBHP
NMP 60
NMP
NMP
NMP
—
—
—
TBHP
TBHP
—
TMEDA
a
Reaction conditions: 1a (1.0 mmol), 2a (0.5 mmol), additive (0.2
equiv.) and oxidant (3.0 equiv.) in 2 mL of solvent for 4 h at 120 ꢀC.
DMF = dimethyl formamide, DMSO = dimethyl sulfoxide, THF =
tetrahydrofuran, NMP = N-methyl-2-pyrrolidone. b Isolated yield.
3-Cl
H
H
COMe
a
Reaction conditions: 1a (1.0 mmol), 2a (0.5 mmol), I2 (0.05 equiv.),
TMEDA (0.2 equiv.) and TBHP (3.0 equiv.) in 2 mL NMP for 4 h.
b
Isolated yield.
was increased to 74% when 20 mol% of TMEDA was employed
as an additive (Table 1, entry 13). Moreover, I2 played an
important role in this reaction because no desired product was
generated without I2 (Table 1, entries 17 and 18).
(Table 3). Gratifyingly, the alkenes with different functional
groups displayed an efficient compatibility and produced the
target products in moderate yields. Vinylnaphthalenes (4a and
4b) and 2-vinylpyridine (4c) performed well and gave the
expected products for this process. Specially, aliphatic alkenes
could react under the optimized conditions and form the
desired products, except for cyclohexene. Interestingly, even
aliphatic alkenes bearing cyano and ester groups were well
tolerated in this transformation and offered the target products
in moderate yields.
In order to gain further insight into the mechanism, a
control experiment was investigated. A radical trapping experi-
ment was performed in the presence of 2,2,6,6-ter-
amethylpiperidine oxide (TEMPO). Indeed, the addition of 1.2
equivalents of TEMPO led to the oxidative process being
remarkably suppressed and a useful intermediate A was iso-
lated (Scheme 2). The presence of intermediate A gave powerful
evidence for the mechanism of the reaction.
With the optimized conditions in hand, the scope in terms of
the substituted styrenes and 2-pyridyl acetates/acetone/
acetonitrile was examined and the results are illustrated in
Table 2. It was gratifying to nd that a variety of substituted
styrenes could react with the 2-pyridyl acetates/acetonitrile
smoothly and furnished the desired products in moderate
yields. As shown in Table 2, the substituents on the aryl ring of
the styrene did not have a certain inuence on the formation of
the products. In particular, the styrenes bearing an electron
withdrawing group, such as F, Cl, Br, generated the desired
products in slightly higher yields than the electron-donating
ones. Moreover, when the substrate 2a was changed to 2b or
2c, the substrates underwent efficient cyclization and the
desired products were afforded in moderate yields. When 2-
pyridylacetone was employed for this reaction, only a trace
amount of the desired product was detected.
To further extend the substrate scope, we then paid attention
to some more challenging alkenes to evaluate the procedure
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Table 3 Synthesis of substituted indolizines from substituted alkenes
and 2-pyridyl acetates
Scheme 3 Proposed mechanism.
aromatic/aliphatic olens and a-picoline derivatives all can be
well tolerated in this transformation and generate the desired
products in moderate yields.
Acknowledgements
This work was supported by the National Natural Science
Foundation of China (21202067, 21372102) and the Funda-
mental Research Funds for the Central Universities (lzujbky-
2014-71).
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