Fe-promoted radical cyanomethylation/arylation of arylacrylamides to access oxindoles via cleavage of the sp3 C-H of acetonitrile and the sp2 C-H of the phenyl group

Article abstract of DOI:10.1039/c4ob02172j

Radical cyanomethylation/arylation of arylacrylamides to access oxindoles with acetonitrile as the radical precursor is described. This reaction involves dual C-H bond functionalization, including the sp³ C-H of acetonitrile and the sp²

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Fe-promoted radical cyanomethylation/arylation of arylacrylamides to
access oxindoles via cleavage of the sp3 C–H of acetonitrile and the sp2
C–H of phenyl group
Changduo Pan, Honglin Zhang and Chengjian Zhu*
5
Received (in XXX, XXX) Xth XXXXXXXXX 20XX, Accepted Xth XXXXXXXXX 20XX
DOI: 10.1039/b000000x
CH3CN in the presence of radical initiator such as DTBP, TBHP
and BPO at 120 C. To our delight, the desired product 3-(1,3-
Radical cyanomethylation/arylation of arylacrylamides to
access oxindoles by acetonitrile as the radical precursor is
discribed. This reaction involved dual C–H bonds
10 functionalization, including the sp3 C–H of acetonitrile and
the sp2 C–H of phenyl group. A variety of functional groups,
such as methoxy, ethyloxy carbonyl, chloro, bromo, iodo,
nitro, trifluoromethoxy and trifluoromethyl groups are
toleratedwell.
o
50 dimethyl-2-oxoindolin-3-yl)propanenitrile 3aa was obtained in
21% yield in the presence of DTBP (Table 1, entry 1), along with
byprouct 5aa by carbomethylation of phenylacrylamide. Then,
we attempted to promote the yield by adding some metal such as
FeCl3, FeCl2, Fe(acac)2, and CuI. To our delight, the yield was
55 increased to 78% when 5 mol % of Fe(acac)2 was subjected to the
procedure (Table 1, entry 6).
15
The difunctionalization of activated alkenes has emerged as a
powerful strategy in organic synthesis.1 Recently, this strategy
was applied for the synthesis of functionalized oxindoles by
oxidative C–H functionalization/carbocyclization of N-
arylacrylamides. Generally, there are two pathways for this
Scheme 1. Radical cyanomethylation/arylationofarylacrylamide
20 transformation. The first is palladium-catalyzed cyclizations of
N-arylacrylamides with different nucleophiles.2 Another pathway
is radical-initiated cyclizations with different radical precursors.3
Very recently, radical oxidative 1,2-alkylarylation of N-
arylacrylamides with an alkyl radical that formed from the
25 cleavage of sp3 C–H in the presence of radical initiator was
developed but still less. For example, Li explored an iron-
catalyzed oxidative alkylarylation of N-arylacrylamides with a
sp3 C–H bond adjacent to a heteroatom and an aryl sp2 C–H.4
Duan and Li reported the Cu-catalyzed and IrCl3 facilitated 1,2-
30 benzylarylation of N-arylacrylamides with benzylic sp3 C−H
bond and aryl sp2 C−H bond, respectively.5 Liu described a Cu-
catalyzed oxidative alkylarylation of acrylamides with simple
alkanes.6
60 Table 1. Screeningthe optimal conditions.
The formations of LnM-CH2CN complexes by stoichiometric
35 amounts of a transition metal (M = Rh, Ni, Ru etc.) to activate the
sp3 C−H bond of acetonitrile have been documented.7 Recently,
Pd-catalyzed the sp3 C-H bond cleavage of acetonitrile was also
developed.2a,8 However, to the best of our knowledge, the sp3
C−H bond cleavage of acetonitrile through the radical pathway is
Entry
[M]
radical initiator
Yield (%)a
1
2
3
4
5
6
7
8
9
---
---
DTBP
TBHP
BPO
3aa/5aa = 21/18
0
trace
---
FeCl2
FeCl3
Fe(acac)2
Cu(OAc)2
CuI
DTBP
DTBP
DTBP
DTBP
DTBP
DTBP
3aa/5aa = 60/12
3aa/5aa = 52/15
3aa/5aa = 78/10
trace
40 less reported.9 Herein, we report
a novel Fe-promoted
cyanomethylation/arylation of arylacrylamides with acetonitrile
to access oxindoles through a radical-type pathway (Scheme 1).
trace
0b
Recently,
we
reported
the
alkylarylation10
and
Fe(acac)2
trifluoromethylation/arylation11 of N-arylacrylamides by visible-
45 light photoredox catalysis. Based on our interest in
difunctionalization of N-arylacrylamide, initially, we examined
the reaction of N-methyl-N-phenylmethacrylamide (1a) with
a
Reaction conditions: 1a (0.2 mmol), [M] (5 mol %), radical initiator
(0.6 mmol) and 2a (2 mL) under air for 12 h at 120 oC. TBHP = 70%
solution in water. DTBP = di-tert-butyl peroxide. BPO = benzoyl
65 peroxide. b 80oC.
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With the optimized reaction conditions in hand, we attempted
The effect of the protecting group on the nitrogen atom was
to investigate the scope of N-arylacrylamides. As shown in Table
investiged. The substrates bearing an alkyl on N atom (4aa-4ba,
2, electron-donating groups such as methoxy and methyl as well 25 Table 3) proceeded higher yields than the substrate with aryl
as electron-withdrawing groups such as chloro, bromo, iodo,
ethyloxy carbonyl, nitro, trifluoromethoxy and trifluoromethyl
were tolerated well on the aryl rings, affording the products in
good yields. Notably, halogen group (F, Cl, Br, I) in the
group on N atom (4ca). Substrates with various olefins were also
examined. For substrates without a substituent at the α position
(R2=H) of the olefin, the desired product was not obtained.
Substrates with benzyl, methoxymethyl, acetoxymethyl and
5
oxindoles offers the potential further transformation by cross- 30 phenyl groups at the α position afforded the products 4ea–4ha in
coupling reactions. Steric hindrance on the aryl rings had some
moderate yields. Substrates with trisubstituted olefins also
provided the corresponding products in moderate yields (4ia-4ja).
Notably, isobutyronitrile (2b) was also good partner.
10 effect on the reaction. For example, arylacrylamides with ortho
substituents such as 1e-1f performed less reactive. To investigate
the regioselectivity of the cyclization, a mixture of two expected
regioisomers (3ga/3g’a = 2:1) was obtained for meta-substituted
arylacrylamide 1g. Importantly, the pyridine group was also
15 suitable for this transformation, providing the product 3ta in
moderate yield.
Table 3. Scope of other arylacrylamides
Table 2. Scope of arylacrylamides
35
a
Reaction conditions: 1a (0.2 mmol), Fe(acac)2 (5 mol %), DTBP (0.6
mmol) and2 (2 mL)under air for12h at 120 oC.
40
To gain insight into the mechanism for this
difunctionalization of arylacrylamides, some control experiments
were conducted. Intramolecular and intermolecular experiments
were carried out. The results demonstrated that there is no kinetic
isotope effect in either intramolecular (kH/kD = 1.1) (Scheme 2, eq.
45 1) or intermolecular experiments (kH/kD= 1.0) (Scheme 2, eq. 2).
When 2.0 equivalents of 2,2,6,6-tetramethylpiperidine oxide
(TEMPO) was added as a radical inhibitor, no desired product
was observed. The KIE result of the experiment between CH3CN
and CD3CN (kH/kD = 3.5) and KIE (kH/kD = 2.9) of individual
50 reaction in CH3CN and CD3CN indicated that the sp3 C−H bond
20 Reaction conditions: 1a (0.2 mmol), Fe(acac)2 (5 mol %), DTBP (0.6
mmol) and2a (2mL)under air for12 h at 120 oC.
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cleavage of acetonitrile is the rate-determining step (Scheme 2, eq.
25
In
conclusion,
we
have
developed
a
radical
3).12
cyanomethylation/arylation of arylacrylamides to access
oxindoles by acetonitrile as the radical precursor. This reaction
involved dual C–H bonds functionalization, including the sp3 C–
H of acetonitrile and the sp2 C–H of phenyl group. The procedure
Scheme 2. Preliminary mechanismstudies
30 was simple and tolerated a variety of functional groups, such as
methoxy, ethyloxy carbonyl, chloro, bromo, iodo, nitro,
trifluoromethoxy and trifluoromethyl groups.
This work is supported by the National Natural Science
Foundation of China (21172106 and 21372114), the National
35 Basic Research Program of China (2010CB923303) and the
Research Fund for the Doctoral Program of Higher Education
of China (20120091110010). Pan thanks the support of
Natural Science Foundation of China (21272178).
Notes and references
40
a State Key Laboratory of Coordination Chemistry, School of Chemistry
and Chemical Engineering, Nanjing University, Nanjing 210093, P. R.
China; E-mail: cjzhu@nju.edu.cn
† Electronic Supplementary Information (ESI) available: See
DOI: 10.1039/b000000x/
5
Based on the above experimental results, a possible
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10 cyanomethyl radical A to arylacrylamide 1a form the radical B,
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Path b provided the byproduct 3-ethyl-1,3-dimethylindolin-2-one
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