Iodine-Catalyzed Direct Olefination of 2-Oxindoles and Alkenes via Cross-Dehydrogenative Coupling (CDC) in Air

Article abstract of DOI:10.1021/acs.orglett.5b01662

A direct intermolecular olefination of sp³ C-H bond between 2-oxindoles and simple alkenes via a Cross-Dehydrogenative Coupling (CDC) strategy has been developed. In the absence of additional base, moderate to excellent yields have been obtaine

Full text of DOI:10.1021/acs.orglett.5b01662

Letter
pubs.acs.org/OrgLett
Iodine-Catalyzed Direct Olefination of 2‑Oxindoles and Alkenes via
Cross-Dehydrogenative Coupling (CDC) in Air
Hong-Yan Huang,†,‡ Hong-Ru Wu,†,‡ Feng Wei,†,‡ Dong Wang,† and Li Liu*,†
†Beijing National Laboratory for Molecular Sciences (BNLMS), CAS Key Laboratory of Molecular Recognition and Function,
Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China
‡University of Chinese Academy of Sciences, Beijing 100049, China
S
* Supporting Information
ABSTRACT: A direct intermolecular olefination of sp3 C−H bond between 2-oxindoles and simple alkenes via a Cross-
Dehydrogenative Coupling (CDC) strategy has been developed. In the absence of additional base, moderate to excellent yields
have been obtained by using a catalytic amount of iodine with atmospheric oxygen as the reoxidant. Based on the observation of a
radical capture experiment, the transformation is proposed to proceed via a radical process.
elective construction of C−C bonds through a cross-
dehydrogenative coupling (CDC) reaction of two C−H
Herein, we would like to report an I2-catalyzed olefination of
3-substituted-2-oxindoles with simple alkenes in an air
atmosphere to give 3-aryl- and 3-alkyl-3-alkenyl-2-oxindoles in
moderate to excellent yields. The coupling products could be
further converted into fused- and spiro-cyclic compounds
bearing an indole moiety.
S
bonds has become an important field in organic synthesis.1
Among them, direct CDC reactions of the sp3 C−H bond2
including the olefination reaction has attracted considerable
attention. As a highly effective and atom-economic approach to
forming sp2−sp3 C−C bonds, various direct olefination
strategies of sp3 C−H bonds such as the sp3 C−H bonds
adjacent to the heteroatom3 and alkane sp3 C−H bonds4 have
been developed. In 2006, Li and co-workers reported the CDC
reaction of tetrahydroisoquinolines with electron-deficient
alkenes via iminium ion intermediates.3a In 2014, the direct
olefination of simple ethers and olefins through a radical
process was reported by Lei and co-workers.3b For alkane
substrates, the olefination methods of the sp3 C−H bond in the
CDC strategy through metal insertion or a radical process were
respectively disclosed by Sanford,4a Yu,4b and Wei.4c Despite
these promising results, the direct olefination of other types of
sp3 C−H bonds has been less investigated.
Transition-metal catalysts were selected for CDC reactions in
priority.10 At first, the reaction of 3-phenyl-2-oxindole 1a with
styrene 2a in the presence of metal-catalyst Cu(OAc)2 was
carried out. Unfortunately, the product was a complicated
mixture including a polymer of styrene while no coupling
product was detected. Among the transition-metal-free
catalysts,11 iodine is a good candidate for corresponding
coupling reactions. It not only is an inexpensive, nontoxic, and
environmentally benign reagent but also is able to undergo the
electron transfer process in an oxidative process similar to the
transition-metal catalyst.12 So the reaction of 1a with 2a was
t
mediated by iodine (1.2 equiv) with additional base BuONa
(1.0 equiv) in a nitrogen atmosphere. The coupling product
(E)-3-phenyl-3-styryl-2-oxindole 3aa was obtained in 84% yield
(Table 1, entry 1). The exclusive (E)-stereoselectivity of the
reaction was observed (see Supporting Information). The
equivalent iodine and additional base were essential to the
coupling reaction in a N2 atmosphere (entries 2 and 3). To our
delight, if the reaction was performed in an air atmosphere,
only a catalytic amount (20 mol %) of iodine was needed
without the use of any additional base, affording the coupling
product 3aa in 68% yield (entry 5). The solvent had a strong
influence on the yield of the coupling product. When the mixed
solvent (PhMe/PhCl = 1:1) was used and the reaction
In recent years, functionalization of α-sp3 C−H bonds of the
carbonyl group has attracted widespread attention. The α-
olefination of carbonyl compounds with vinyl bromides or vinyl
triflates could be achieved under Pd- or Ni-catalysis.5
Meanwhile, the α-aromatization of sp3 C−H bonds of the
carbonyl group via a CDC reaction has made great progress.
Baran and co-workers accomplished the total syntheses of
various indole alkaloids by an intermolecular CDC of an α-sp3
C−H bond of the carbonyl group with indoles.6 Recently,
Kundig and Taylor’s groups independently explored the
̈
synthesis of oxindole derivatives via an intramolecular CDC
reaction under Cu (II)-promoted processes.7 It is noteworthy
that although the α-aromatization of carbonyl compounds has
been well developed,6−8 the direct α-olefinatioin of carbonyl
compounds through a CDC strategy is limited.9
Received: June 8, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b01662
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Letter
a
Table 1. Optimization of the Reaction Conditions
b
entry
base
NaOtBu (1.0)
iodine (mol %)
atmosphere
solvent
PhMe
temp (°C)
time (h)
yield of 3aa (%)
1
120
120
0
N2
N2
N2
air
air
air
air
air
air
air
air
O2
N2
100
100
100
100
100
100
100
120
120
120
120
120
120
12
15
12
24
24
24
24
12
12
12
12
12
12
84
21
2
−
PhMe
c
3
NaOtBu (1.0)
PhMe
NR
4
−
−
−
−
−
−
−
−
−
−
10
20
25
30
20
20
25
30
20
20
PhMe
30
68
58
52
71
80
83
81
42
trace
5
PhMe
6
PhMe
7
PhMe
8
PhCl
9
PhMe/PhCl (1:1)
PhMe/PhCl (1:1)
PhMe/PhCl (1:1)
PhMe/PhCl (1:1)
10
11
12
13
PhMe/PhCl (1:1)
a
b
c
Reaction conditions: 1a (0.1 mmol), 2a (1 mmol), solvent (2 mL). Isolated yields. NR = no reaction.
a b
,
temperature was changed to 120 °C, the yield of 3aa increased
from 68% to 80−83% (entry 5 vs entries 9−11). To our
surprise, the reaction of 1a with 2a performed under an oxygen
atmosphere gave a lower yield than that under an air
atmosphere (entry 12 vs 5). Moreover, under a nitrogen
atmosphere, the catalytic amount of iodine was demonstrated
to be ineffective for the coupling reaction (entry 13).
Scheme 1. Scope of 3-Substituted-2-oxindoles
Under the optimized reaction conditions, the approach of
iodine-catalyzed olefination was applied to the reactions of
various 3-substituted-2-oxindoles with 2a (Scheme 1). Both N-
protected and N-unprotected (R1 = CH3 and H)-2-oxindoles
were tolerant of the iodine-catalyzed CDC reaction. When the
group on N was changed from H to methyl, the yield of the
coupling product slightly increased (3aa vs 3ca). The
substituents on the C3 position (R2 = aryl and alkyl) of 2-
oxindoles were applicable, but with some influences on the
yields of coupling products. 3-Aryl-2-oxindoles provided better
yields of the coupling products than 3-benzyl-2-oxindoles
(3aa−3fa vs 3ia−3la).When an electron-withdrawing group
was located on the para-position of the phenyl group, the yields
decreased obviously (3ca vs 3fa). The electron-donating groups
on the para-positon of the benzyl group could remarkably
improve the yields (3ja vs 3ka). Furthermore, when R2 was an
aliphatic group, a moderate yield was obtained (3ga−3ha).
The scope of alkenes, which reacted with 1-methyl-3-(p-
tolyl)-2-oxindole 1e, was also explored (Scheme 2). All the
para-substituted styrenes provided high to excellent yields
(3ea−3ee). However, when a halogen atom was on the ortho-
or meta-position of the styrene moiety the yield decreased
remarkably (3ef−3eg). For the styrene derivatives with two
substituents on the double bond, the iodine-catalyzed CDC
reaction afforded the products (3eh−3ek) in low yields (41−
48%), except the product 3el from 1,1-diphenyl-ethylene. An
excellent yield of the product 3em (94%) was obtained by
using 2-vinylnaphthalene as a reaction partner. With methyl
acrylate as the substrate, no desired product was obtained.
To evaluate the practicality of this CDC reaction, a gram-
scale reaction of 1e and 2a was carried out. As shown in
a
Reaction conditions: 1a−1m (0.1 mmol), 2a (1.0 mmol), and I2
b
(0.02 mmol) in 2 mL of PhMe/PhCl (1:1) at 120 °C. Isolated yield.
Scheme 3, product 3ea was obtained in 86% yield under a 20
mol % catalyst loading.
The olefination products of 2-oxindoles could be further
converted to the indole alkloids bearing a fused cyclic amine
and spiro-cyclic 2-oxindoles. Starting from 3ha, pyrroloindo-
line13 4 was obtained in 70% overall yield (dr = 7.7:1) through
tandem reduction−cyclization in a one-pot process [Scheme 4,
eq 1]. Besides, an intramolecular Heck-type reaction of 3ia
catalyzed by Pd(OAc)2/PPh3 could effectively afford the
spirooxindole derivatives14 5 in 72% yield [Scheme 4, eq 2].
B
DOI: 10.1021/acs.orglett.5b01662
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a b
,
Although the exact reaction mechanism is unclear, one
possibility involving a radical pathway has been proposed
(Scheme 5). The reaction started with the generation of 2-
Scheme 2. Scope of alkenes
Scheme 5. Proposed Mechanism
oxindole radical intermediate A through the oxidization of 3-
substituted-2-oxindole by iodine. Then, A was immediately
trapped by styrene 2,15 forming a benzyl radical intermediate B.
which was quenched by an iodine radical to produce
intermediate C. The formation of radical B and an iodine-
trapped reaction were superior to other competitive reactions
such as homopolymerization of styrene and homodimerization
of intermediate B. Subsequently, intermediate C underwent
elimination of hydrogen iodide to give the desired coupling
product. Meanwhile, the generated HI was oxidized by
oxygen12d to produce iodine, and thus the catalytic cycle was
completed.
a
Reaction conditions: 1e (0.1 mmol), 2b−2m (1.0 mmol), and I2
b
(0.02 mmol) in PhMe/PhCl (1:1) 2 mL at 120 °C. Isolated yield.
c
Isolated yield when 0.5 mmol of alkenes were used.
Under the iodine-catalysis conditions, the addition of
TEMPO (radical scavenger) afforded the capture product 6
in 51% isolated yield (Scheme 6) with a trace of coupling
Scheme 3. Gram-Scale Reaction of 1e with 2a
Scheme 6. TEMPO Capture Reaction
Scheme 4. Subsequent Conversation of the Coupling
Products
product 3aa. The TEMPO-trapped reaction strongly supported
the formation of the intermediates B, in which the radical
located at the α-position of ethylbenzene.
In conclusion, an iodine-catalyzed olefination of 3-
substituted-2-oxindoles with simple alkenes in an air atmos-
phere through a CDC process has been developed to afford 3-
alkenyl-2-oxindoles in moderate to excellent yields. In the
course of the iodine-catalyzed olefination reaction, the
formation of radical intermediate B was confirmed by structural
analysis of the TEMPO-trapped product. This synthetic
method has a broad substrate scope with high atom economy.
The coupling products have great potential to be converted to
versatile indole alkaloids bearing fused- and spiro-cyclic
moieties.
C
DOI: 10.1021/acs.orglett.5b01662
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Organic Letters
Letter
1337. (g) Nicolaou, K. C.; Reingruber, R.; Sarlah, D.; Brase, S. J. Am.
̈
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b01662.
■
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1
Experimental procedures, characterization data, and H
NMR and 13C NMR spectra for new products (PDF)
AUTHOR INFORMATION
Corresponding Author
■
(11) Sun, C. L.; Shi, Z. J. Chem. Rev. 2014, 114, 9219.
*E-mail: lliu@iccas.ac.cn.
(12) (a) Tang, S.; Wu, Y.; Liao, W. Q.; Bai, R. P.; Liu, C.; Lei, A. W.
Chem. Commun. 2014, 50, 4496. (b) Kuepper, F. C.; Feiters, M. C.;
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Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Natural Science Foundation of China
(Nos. 21372224, 21420102003, and 21232008), the Ministry of
Science and Technology of China (973 Program
2011CB808600), Shandong Province independent innovation
and achievements transformation of special (2014XGC06001),
and the Chinese Academy of Sciences for financial support.
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