Free-radical cascade Alkylarylation of Alkenes with simple Alkanes: Highly efficient access to Oxindoles via selective (sp3)C-H and (sp 2)C-H Bond functionalization

Article abstract of DOI:10.1021/ol4032478

A copper-catalyzed alkylarylation of alkenes with simple alkanes was achieved, which not only provided an efficient method to prepare various alkyl-substituted oxindoles, but also represented a novel strategy for selective sp³ C-H functionalization/C-C bond formation via a free-radical cascade process. Additionally, selective activation of unactivated (sp ³)C-H and (sp²)C-H bonds by one single step is achieved in this system, which would also provide a novel strategy for raising efficiency in C-H bond functionalization.

Full text of DOI:10.1021/ol4032478

Letter
pubs.acs.org/OrgLett
Free-Radical Cascade Alkylarylation of Alkenes with Simple Alkanes:
Highly Efficient Access to Oxindoles via Selective (sp3)C−H and
(sp2)C−H Bond Functionalization
Zejiang Li, Ye Zhang, Lizhi Zhang, and Zhong-Quan Liu*
State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou Gansu 730000, P. R. China
S
* Supporting Information
ABSTRACT: A copper-catalyzed alkylarylation of alkenes
with simple alkanes was achieved, which not only provided an
efficient method to prepare various alkyl-substituted oxindoles,
but also represented a novel strategy for selective sp3 C−H
functionalization/C−C bond formation via a free-radical
cascade process. Additionally, selective activation of unac-
tivated (sp3)C−H and (sp2)C−H bonds by one single step is
achieved in this system, which would also provide a novel strategy for raising efficiency in C−H bond functionalization.
Scheme 1. Alkylarylation of Alkenes with Simple Alkanes
he construction of C−C bonds by direct C−H bond
Tactivation is of fundamental interest in modern synthetic
organic chemistry.1 Recently, various methods focused on C−C
bond formation through free-radical-initiated sp3-hybridized
C−H bond activation.2 However, most of these systems were
limited by activated C−H bonds such as α-(sp3)C−H of
alcohols, ethers, amines, nitroalkanes, and 2-(sp3)C−H of 1,3-
dicarbonyl compounds. Selective activation of the inactive C−
H bonds in simple alkanes to generate C−C bonds has
remained a challenging target.3 In the past several years, a series
of cross-dehydrogenative-coupling (CDC) reactions forming
C−C bonds by using simple alkanes were developed by Li and
co-workers.4 In addition, we5 and others6 have explored
alternative systems producing C(sp3)−C(sp2) bonds with
innate sp3 C−H bonds via radical addition−elimination
processes. Very recently, Antonchick and Burgmann7 reported
an efficient metal-free Minisci reaction of simple alkanes with
heteroarenes. Although these studies have considerably
improved this type of reactions, more efficient and selective
functionalization of inert sp3C−H/C−C bond formation would
be highly desirable. As part of our continuous investigations8 on
C−H bond activation, we began to design a radical cascade
reaction9 of alkenes with simple alkanes, which would concisely
synthesize various cyclic compounds using the strategy of
(sp3)C−H activation/C−C bond formation. Oxindoles and its
derivatives represent a large class of N-heterocycles, which
exhibit advanced pharmaceutical and bioactivities.10 Recently,
various transition metal-catalyzed cyclizations as well as radical-
initiated reactions have been developed to prepare these
molecules.11 However, to the best of our knowledge, the direct
1,2-alkylarylation of alkenes with simple alkanes to generate
oxindoles has never been reported. Herein, we report a free
radical cascade alkylarylation of alkenes with simple alkanes,
which allows for highly efficient access to alkyl-substituted
oxindoles by selective functionalization of innate (sp3)C−H
and (sp2)C−H bonds (Scheme 1).
Initially, we chose N-methyl-N-phenylmethacrylamide (1a)
and cyclohexane as the model substrates to optimize conditions
for this reaction (Table 1). It was found that the catalyst and
radical initiator critically affected the reaction efficiency. The
desired product was obtained in only 6% yield without any
catalyst (entry 1). The Cu2O used as catalyst was more efficient
than copper salts, such as CuBr and CuI, and copper powder
(entries 2−5). Addition of 1 mL, 2 mL and 10 mL of
cyclohexane as solvent led to the generation of the product in
32%, 44%, and 38% yields, respectively (entries 6−8).
Surprisingly, the yield decreased to 44% when a decane
solution of TBHP was used as the radical initiator (entry 9).
Other radical initiators such as di-tert-butyl peroxide (DTBP),
BPO, and K2S2O8 were proved to be less efficient than dicumyl
peroxide (DCP) (entries 10−13). No product was obtained
when 1,2-dichloroethane (DCE) and benzene were used as
solvent (entries 14 and 15). However, chlorobenzene can be
used as an alternative solvent other than the alkane despite of
low yield (entry 16). The reactions conducted at 80 and 130 °C
resulted in much lower yields (entries 17 and 18). The desired
product was isolated in 56% and 63% yields by using 2 and 10
mol % of the catalyst, respectively (entries 19 and 20).
With the modified conditions in hand, the scope of this
reaction with respect to N-arylacrylamides and alkanes was
studied (Table 2 and 3). As depicted in Table 2, the N-methyl,
Received: November 11, 2013
© XXXX American Chemical Society
A
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Letter
a
Table 1. Modification of the Typical Reaction Conditions
Table 3. Copper-Catalyzed Radical Cascade Reaction of N-
Arylacrylamides with Alkanes
a
b
entry
catalyst (mol %)
radical initiator
temp (°C)
yield (%)
1
2
3
4
5
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
110
110
110
110
110
110
110
110
110
110
110
110
110
110
110
110
80
6
33
30
40
72
32
44
38
44
42
93
CuBr (5)
CuI (5)
Cu (5)
Cu2O (5)
Cu2O (5)
Cu2O (5)
Cu2O (5)
Cu2O (5)
Cu2O (5)
Cu2O (5)
Cu2O (5)
Cu2O (5)
Cu2O (5)
Cu2O (5)
Cu2O (5)
Cu2O (5)
Cu2O (5)
Cu2O (2)
Cu2O (10)
c
6
d
7
e
8
f
9
TBHP
10
11
12
13
DTBP
DCP
BPO
K2S2O8
DCP
DCP
DCP
DCP
DCP
DCP
DCP
g
14
h
15
i
16
36
5
17
18
19
20
130
110
110
32
56
63
a
Reaction conditions: N-arylacrylamide (0.25 mmol), radical initiator
(0.75 mmol), 5 mL of cyclohexane as solvent, 22 h, unless otherwise
a
Reaction conditions: N-arylacrylamide (0.25 mmol), DCP (0.75
b
c
d
noted. Isolated yields. Cyclohexane (1 mL). Cyclohexane (2 mL).
mmol), 5 mL of alkane as solvent, 110 °C, 22 h, unless otherwise
e
f
g
b
c
Cyclohexane (10 mL). TBHP (in decane). 10 equiv of cyclohexane,
noted. Isolated yields. 10 equiv of adamantane, 5 mL of
chlorobenzene as solvent.
h
i
DCE as solvent. 10 equiv of cyclohexane, benzene as solvent. 10
equiv of cyclohexane, chlorobenzene as solvent.
Table 2. Copper-Catalyzed Radical Cascade Reaction of N-
Arylacrylamides with Cyclohexane
N-phenyl, and N-benzyl but not N-H substituted N-phenyl-
methacrylamides all gave the desired products in high yields
under the typical conditions (2a−d). Gratifyingly, the amides
with halogen atoms such as F, Cl, Br, and I substituents on the
para-position of the N-aryl moiety resulted in good to high
yields of the corresponding products (2e−h). When the
halogen atoms were replaced by electron-rich substituents such
as methyl and methoxyl groups, the yields decreased slightly (2i
and 2j). However, highly electron-deficient substituents such as
NO2 and CN groups on the N-aryl moiety did not result in any
products (2k and 2l). Notably, ortho-substituted substrates gave
moderate yields of the products (2m and 2n). In addition,
multisubstituted amides were also effective substrates, and the
expected products 2o and 2p were obtained in 76% and 60%
yields, respectively. Furthermore, N-methyl-N-naphthylmetha-
crylamide resulted in 30% yield of the desired product 2q. It is
noteworthy that CH2OAc groups at the 2 position of the
acrylamide core could be tolerated in this system (2r).
a
We next studied the reaction of N-methyl-N-phenyl-
methacrylamide with various simple alkanes as well as toluenes
under the typical reaction conditions (Table 3). Cycloalkanes
such as cyclopentane, cycloheptane, and cyclooctane all gave
high yields of the desired products (3a−c). Interestingly,
alkanes with high boiling points also resulted in good yields of
the products in chlorobenzene. For example, when adamantane
was used, 3d and 3d′ were isolated in a yield of 68% with a
ratio of 6/1. Acyclic alkanes gave moderate yields of products
(3e and 3f). It is noteworthy that highly selective alkylation
occurred at the C2 position of the linear alkane in spite of the
slightly small difference between C1 and C2 position in bond
a
Reaction conditions: N-arylacrylamide (0.25 mmol), DCP (0.75
b
mmol), 5 mL of cyclohexane as solvent, 110 °C, 22 h. Isolated yields.
c
46 h.
B
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Letter
dissociation energies (BDE).12 For pentane, the BDE of C(1)−
H is 100.2 kcal mol−1 and 99.2 kcal mol−1 at the C2 position.
Similarly, for hexane, the BDE of C(1)−H is 99.0 kcal mol−1
while the BDE of C(2)−H is 98.0 kcal mol−1. Therefore, the
reactivities of the sp3-hybridized C−H bonds in alkanes should
decrease in the order of tertiary > secondary > primary which
might be not due to the BDE of the sp3 C−H bond, but the
stability and the steric effect of the corresponding carbon-
centered radical.5,7 Finally, a series of toluene derivatives have
also been investigated. As a result, the corresponding products
were obtained in moderate to high yields (3g−m).13
Scheme 3. Possible Mechanism
To investigate the details of the mechanism for this copper-
catalyzed alkylarylation of acrylamides with alkanes, a series of
experiments were carried out. No desired product was observed
by addition of TEMPO as a radial inhibitor. In addition, an
intermolecular competing kinetic isotope effect (KIE) experi-
ment was carried out. As a result, a significant KIE was
observed with the kH/kD = 9.3 at a low conversion level
(Scheme 2). It indicates that the sp3 C−H bond cleavage
should be involved in the rate-determining step of this
procedure.
reaction of cumyloxyl radical with alkanes generates alkyl
radical and acetophenone,14 which can be isolated as a
byproduct. Radical intermediate A would be formed by
addition of alkyl radical to the CC bond. Cyclization of A
to benzene core would give radical B, which then is oxidized by
Cu(II) species to generate the product and regenerates the
Cu(I) species. Alternatively, the radical A can also be oxidized
by Cu(II) species to the corresponding carbocation, followed
by intramolecular electrophilic aromatic substitution giving the
product, which cannot be ruled out from the present system.
In conclusion, we developed a novel Cu-catalyzed oxidative
alkylarylation of acrylamides with simple alkanes. This method
not only provided a useful method for synthesis of alkyl-
substituted oxindoles but also represented a new strategy for
selective functionalization of simple alkanes via a free radical
cascade process. In addition, selective activation of unactivated
(sp3)C−H and (sp2)C−H bonds by one single step is achieved
in this system, which would also provide a novel strategy for
raising efficiency in C−H bond functionalization. Further
investigation of this strategy focusing on construction of other
bioactive cyclic compounds via selective sp3 C−H bond
functionalization of simple alkane is underway in our
laboratory.
Scheme 2. KIE Studies
Additionally, we tried to catch some radical intermediates by
electron spin resonance (ESR). The ESR signal of some Cu(II)
species was observed by using 2-methyl-2-nitrosopropane
(MNP) as a radical spin trap, which indicates that the Cu(I)
catalyst might be oxidized to Cu(II) species under this
condition (Figure 1).
A plausible mechanism that is consistent with the
experimental data and literature precedent is depicted in
Scheme 3. The Cu(I)-assited homolysis of DCP gives
cumyloxyl radical and Cu(II) species. Hydrogen abstraction
ASSOCIATED CONTENT
* Supporting Information
■
S
Full experimental details and characterization data for all
products. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: liuzhq@lzu.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This project is supported by the National Science Foundation
of China (Nos. 21002045, 21272096).
■
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