Indolizine Synthesis via Oxidative Cross-Coupling/Cyclization of Alkenes and 2-(Pyridin-2-yl)acetate Derivatives

Article abstract of DOI:10.1021/acs.orglett.5b01334

A novel copper/I₂-mediated oxidative cross-coupling/cyclization of 2-(pyridin-2-yl)acetate derivatives and simple olefins is developed, which provides a straightforward and efficient access to structural diversely indolizines. A series of 1,3-d

Full text of DOI:10.1021/acs.orglett.5b01334

Letter
pubs.acs.org/OrgLett
Indolizine Synthesis via Oxidative Cross-Coupling/Cyclization of
Alkenes and 2‑(Pyridin-2-yl)acetate Derivatives
Ren-Rong Liu, Jian-Jun Hong, Chuan-Jun Lu, Meng Xu, Jian-Rong Gao, and Yi-Xia Jia*
College of Chemical Engineering, Zhejiang University of Technology, Hangzhou 310014, China
S
* Supporting Information
ABSTRACT: A novel copper/I2-mediated oxidative cross-
coupling/cyclization of 2-(pyridin-2-yl)acetate derivatives and
simple olefins is developed, which provides a straightforward
and efficient access to structural diversely indolizines. A series of
1,3-di- and 1,2,3-trisubstituted indolizines are easily synthesized
in modest to excellent yields.
ndolizine derivatives are one of the major classes of
heterocycles. Functionalized indolizines have found wide
applications in natural products and synthetic pharmaceuticals,
which are associated with a broad spectrum of biological
activities, such as antifungal, anticancer, and SGL T1
antagonists (Figure 1).1 Other attractive bioactivities of
aminooxygenation, aminofluorination, and so on.10 Recently,
I
difunctionalization of alkenes has been successfully applied as
an important strategy for the synthesis of heterocycle
compounds, such as furans, oxazoles, and quinolones.11
However, to the best of our knowledge, the construction of
indolizines from simple alkenes by oxidative difunctionalization
has not been reported. As a part of our continuing interest in
the synthesis of functionalized indolizine,12 we report herein a
copper/I2-mediated oxidative cross-coupling/cyclization of
alkenes and 2-(pyridin-2-yl)acetate derivatives that provides a
straightforward and efficient access to structural diversely
indolizines in modest to excellent yields.13
Our initial efforts were focused on the oxidative cross-
coupling/cyclization reaction using ethyl 2-(pyridin-2-yl)-
acetate 1a and styrene 2a as the model substrates (Table 1).
It was found that the reaction afforded the desired product 3aa
in 15% yield by employing Cu(OAc)2·H2O as a mediator in
DCE at 100 °C after 24 h (Table 1, entry 1). A series of
additives were then introduced to the reaction system to
improve the yield. The introduction of different ammonium
compounds slightly improved the yields, and the desired
product was isolated in 31% yield when 1.0 equiv of NBu4Cl
was added (Table 1, entries 2−5). To our delight, the addition
of 1.0 equiv of molecular iodine remarkably enhanced the yield
to 52% (Table 1, entry 7). Following this result, other iodine
salts (NaI, KI, KIO3) were tested; however, no further increase
of the yields was observed (Table 1, entries 8−10). It was noted
that no desired product was detected in the absence of
Cu(OAc)2·H2O, even with TBHP as the oxidant (Table 1,
entries 11 and 12). Reducing the amount of Cu(OAc)2·H2O
led to a decreased yield (Table 1, entry 13). A lower yield was
also observed when the amount of molecular iodine was
increased to 2.0 equiv (Table 1, entry 14). Subsequent
optimization showed that the combination of NBu4Cl and
molecular iodine could further improve the product yield to
70% (Table 1, entry 15). Other copper salts were then
Figure 1. Selected structures bearing an indolizine core.
indolizines include antitubercular, phosphatase inhibitive,
antioxidant, or anti-inflammatory.2 Consequently, the develop-
ment of efficient methods for rapid construction and
functionalization of indolizines has gained much attention.
Documented approaches to indolizines mainly include the
following: Scholtz reaction,3 Tschitschibabin reaction,4 dipolar
cycloadditions of pyridinium and related heteroaromatic ylides
with electron-deficient alkynes or alkenes,5 cyclization of
pyridines with alkenyldiazoacetates,6 C−H functionalization
reaction,7 transition-metal-catalyzed cycloisomerizations of
alkynylpyridine derivatives,8 and transannulations of pyrido-
triazoles with alkynes.9 Despite primordial importance in
synthetic chemistry, these methods often involve multistage
synthesis and suffer from limited substrate availability in some
cases. Therefore, a straightforward, convenient, and regiose-
lective route to synthesize indolizines using basic chemical
materials is highly attractive.
Alkenes have been recognized as important starting materials
in synthetic chemistry because of their low cost and ready
availability. Selective oxidative difunctionalization of alkenes is
an extremely powerful chemical transformation as evidenced by
the extensively developed transformations, such as diamination,
Received: May 7, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b01334
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
a
Table 1. Optimization of the Reaction Conditions
Scheme 1. Scope of Styrene
b
entry
copper salt
additive
yield (%)
1
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
15
25
2
NBu4F
NBu4Cl
NBu4I
NBu4Br
Ag2O
3
31
4
20
5
23
6
13
7
I2
52
8
NaI
22
9
KI
30
10
11
12
KIO3
32
I2
0
I2/TBHP
I2
trace
31
c
13
Cu(OAc)2·H2O
Cu(OAc)2·H2O
Cu(OAc)2·H2O
CuI
d
14
I2
40
15
16
17
I2/NBu4Cl
I2/NBu4Cl
I2/NBu4Cl
I2/NBu4Cl
70
trace
trace
80
CuCl2
e
18
Cu(OAc)2·H2O
a
Reaction conditions: 1a (0.2 mmol), 2a (2.0 equiv), 3.0 equiv of
copper salt, and 1.0 equiv of additive in DCE (1.0 mL) at 100 °C for
b
c
d
24 h. Isolated yield. 1.0 equiv of Cu(OAc)2·H2O was used. 2.0
e
equiv of I2 was used. 2a (0.2 mmol) and 1a (0.4 mmol, 2.0 equiv)
were used.
examined, while CuI and CuCl2 showed almost no catalytic
activity in this reaction (Table 1, entries 16 and 17). As 2-
(pyridin-2-yl)acetate 1a was partially decomposed under the
above conditions, we thus modified the molar ratio of 1a/2a
from 1:2 to 2:1, which improved the product yield to 80%
based on the amount of styrene (Table 1, entry 18).
With the optimal reaction conditions in hand (Table 1, entry
17), we then examined the scope of this reaction by varying the
styrenes, and the results are summarized in Scheme 1.
Generally, the reactions produced the corresponding indoli-
zines in good yields. Styrenes bearing electron-withdrawing
substituents on the benzene ring furnished the desired product
in higher yields than those bearing electron-donating
substituents (Scheme 1, 3aj−ak vs 3ad−ae). No obvious steric
effect was observed for the substituted groups on the benzene
ring of styrene in this reaction, and the expected indolizines
were afforded in modest yields for the ortho-substituted
styrenes (3ap−ar,at,aw). Several important functional groups
such as −NO2 (3aj,ar), −CN (3ak), and halogens −F, −Cl,
−Br (3ag−ai,an−ap,at−av) were well tolerated, which allows
further functionalization toward the synthesis of structural
diversely indolizines. Additionally, terminal alkenes containing a
naphthalene moiety were also employed to produce the
indolizine products in modest yields (3aw−ay).
a
Reaction conditions: 1a (0.4 mmol), 2 (0.2 mmol), 3.0 equiv of
Cu(OAc)2·H2O, 1.0 equiv of I2, and 1.0 equiv of NBu4Cl in DCE (1.0
mL) at 100 °C for 24 h.
indolizine 3aa′ in 40% yield. Moreover, the reaction of trans-
1,2-diphenylethene 2b′ produced indolizine 3ab′ in 35% yield.
Aliphatic alkene was also tested in the reaction, whereas the
corresponding indolizine 3ac′ was obtained in a relatively lower
yield.
Next, we investigated the scope of the pyridine derivatives
under the optimized conditions, and the results are listed in
Scheme 3. Different 2-(pyridin-2-yl)acetates 1 reacted well with
styrene 2a to deliver the corresponding indolizines in modest to
good yields (78% for methyl ester 3ba and 65% for isopropyl
ester 3ca). Notably, substrate 1 containing a CN group was
found to be a suitable substrate, and its reaction with styrene 2a
afforded the product 3da in 35% yield. Nevertheless, no
reaction occurred for the substrate 1 without an additional
electron-withdrawing group (for example, R′ = Me, 3ea),
In addition to styrenes, other types of alkenes were also
examined in the reaction (Scheme 2). When alkene 2z was
used, indolizine 3az bearing a carbazole motif was isolated in
45% yield. Gratifyingly, 1,2-disubstituted alkenes were also
suitable substrates for the reaction to generate the correspond-
ing 1,2,3-trisubstituted indolizines. Thus, the reaction of 1H-
indene 2a′ with 1a produced a tetracyclic polysubstituted
B
DOI: 10.1021/acs.orglett.5b01334
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 2. Scope of Substituted Olefin
Scheme 4. Plausible Mechanism
functionalized indolizines in modest to excellent yields. Due to
easy availability of the starting materials and wide substrate
scope, this protocol would be highly prospective in organic
synthesis.
a
Reaction conditions: 1a (0.4 mmol), 2 (0.2 mmol), 3.0 equiv
Cu(OAc)2·H2O, 1.0 equiv I2, and 1.0 equiv. NBu4Cl in DCE (1.0 mL)
at 100 °C for 24 h.
a
ASSOCIATED CONTENT
* Supporting Information
Scheme 3. Scope of Pyridine Derivative
■
S
Complete experimental procedure and characterization data for
the prepared compounds. The Supporting Information is
available free of charge on the ACS Publications website at
DOI: 10.1021/acs.orglett.5b01334.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: yxjia@zjut.edu.cn.
Notes
The authors declare no competing financial interest.
a
Reaction conditions: 1 (0.4 mmol), 2a (0.2 mmol), 3.0 equiv of
Cu(OAc)2·H2O, 1.0 equiv of I2, and 1.0 equiv of NBu4Cl in DCE (1.0
mL) at 100 °C for 24 h.
ACKNOWLEDGMENTS
■
We are grateful for financial support from the National Natural
Science Foundation of P.R. China (21372202 and 21402175),
the New Century Excellent Talents in University (NCET-12-
1086), and Zhejiang Natural Science Fund for Distinguished
Young Scholars (R14B020005).
showing the limitation of the present reaction. Moreover, the
reaction of 2-(quinolin-2-yl)acetate substrate with styrene 2a
proceeded well to furnish the corresponding product benz[e]-
indolizines 3fa in 85% yield.
The control experiment showed that product 3aa was not
observed when a radical scavenger 2,2,6,6-tetramethylpiperidin-
1-yloxyl (TEMPO) was added to the reaction system (eq 1),
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DOI: 10.1021/acs.orglett.5b01334
Org. Lett. XXXX, XXX, XXX−XXX