Oxidative radical 1,2-alkylarylation of alkenes with α-C(sp3)-H bonds of acetonitriles involving 1,2-aryl migration

Article abstract of DOI:10.1039/c4cc08902b

A novel metal-free oxidative 1,2-alkylarylation of unactivated alkenes with the α-C(sp³)-H bonds of acetonitriles for the synthesis of 5-oxo-pentanenitriles is presented. In the presence of TBPB (tert-butyl peroxybenzoate), a variety of α-aryl

Full text of DOI:10.1039/c4cc08902b

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COMMUNICATION
Oxidative Radical 1,2-Alkylarylation of Alkenes with
of Acetonitriles Involving 1,2-Aryl Migration
α
-C(sp3)-H Bonds
Yang Li,a Bang Liu,a Hai-Bing Li,a Qiuan Wang,*a and Jin-Heng Li*a
Received (in XXX, XXX) Xth XXXXXXXXX 200X, Accepted Xth XXXXXXXXX 200X
First published on the web Xth XXXXXXXXX 200X
DOI: 10.1039/b000000x
5
A novel metal-free oxidative 1,2-alkylarylation of unactivated
alkenes with the
synthesis of 5-oxo-pentanenitriles is presented. In the presence of
10 TBPB (tert-butyl peroxybenzoate), a variety of -aryl allylic
α
-C(sp3)-H bonds of acetonitriles for the
α
alcohols underwent the 1,2-alkylarylation reaction with
acetonitriles, giving 5-oxo-pentanenitriles in good to excellent
yields. This method proceeds via the C(sp3)-H oxidative coupling
with the C-C double bond and 1,2-aryl-migration, and represents
15 a new access to acyclic molecules through metal-free oxidative
alkene 1,2-alkylarylation.
The difunctionalization of alkenes has become a powerful
strategy for the assembly of more complex structures in
synthesis through simultaneously introduction of two
20 functional groups across alkenes.1 As a result, the discovery
of new efficient strategies for the alkene difunctionalization
has attracted much attention.1-4 Of particular interest are the
oxidative 1,2-alkylarylation transformations that proceed via
direct oxidative coupling of the C-C double bond with a
25 C(sp3)-H bond5 followed by incorporation of another aryl
group.2-4 However, the majority of these transformations
proceed through the aryl intramolecular incorporation, thereby
limiting to the synthesis of oxindoles and related
Scheme 1 Oxidative 1,2-Alkylarylation of Alkenes with Acetonitriles.
As shown in Table 1, the reaction between 1,1-
55 diphenylprop-2-en-1-ol (1a) and acetonitrile (2a) was chosen
as a model to explore the optimal reaction conditions. After a
series of trials, the best results were obtained with 3 equiv
TBPB at 100 oC under argon atmosphere for 20 h (entry 1).
Under the standard conditions, conversion of alkene 1a was
60 completed through C(sp3)-H oxidative coupling and 1,2-Ph-
mirgation, giving the target alkene difunctionalization product
3aa in 90% yield. Screening on the amount of TBPB revealed
that the presence of 2 equiv TBPB decreased the yield from
90% (entry 1) to 55% (entry 2), and 4 equiv TBPB (entry 3)
65 afforded the same results as those of 3 equiv TBPB. The
effect of the reaction temperatures was found to affect the
reaction (entry 1 vs. entries 4 and 5). Alkene 1a at 120 oC
remained high reactivity of (89% yield; entry 4). However, at
heterocycles.2,3 Moreover, only two papers using
α
-C(sp3)-H
30 bonds of acetonitriles for the oxidative alkylarylation of
alkenes have been reported.3 Liu and co-workers have first
described a palladium-catalyzed oxidative alkylarylation of
activated alkenes with acetonitriles to construct various
oxindoles (Scheme 1a).3a Subsequently, they have extended
35 this similar Pd-catalyzed oxidative strategy to alkylarylation
of unactivated alkenes.3b However, the two oxidative
alkylarylation methods are still restricted to the construction
of oxindoles and related heterocycles as well as the
requirement of expensive Pd catalysts. Thus, a new strategy
40 for general alkylarylation of alkenes under metal-free leading
to diverse complex molecules is highly desirable.
o
80 C it lowered dramatically, decreasing the yield of product
70 3aa to 34% (entry 5). It should be noted that the presence of
air suppresses the reaction, and decreases the yield to 72%
(entry 6). Finally, three other peroxides, including TBHP
(tert-buty hydroperoxide), DTBP (di-tert-butyl peroxide) and
BPO (benzoyl peroxide), were investigated (entries 7-9), and
75 the results showed that they were less effective than TBPB.
Both TBHP and DTBP had lower activity for the reaction in
terms of yield (entries 7 and 8). Although BPO had a lower
activity than TBPB, good yield of product 3aa was still
achieved (78% yield, entry 9).
Herein, we wish to report a new metal-free oxidative 1,2-
alkylarylation between the C-C double bonds of α-aryl allylic
alcohols4 and the
α
-C(sp3)-H bonds of acetonitriles using
45 TBPB as oxidant for the assembly of 5-oxo-pentanenitriles,
useful build blocks in synthesis6 (Scheme 1b); this method
achieves the alkene 1,2-alkylarylation by the C(sp3)-H
oxidative coupling with the C-C double bond and 1,2-aryl-
migration, and represents the first access to acyclic molecules
80
After determining the standard reaction conditions, we
next exploited the scope of this difunctionalization protocol
with respect to α-aryl allylic alcohols (1) and acetonitriles (2)
(Table 2). Initially, three other acetonitriles, including
butyronitrile (2b), 2-phenylacetonitrile (2c) and 2-
50 by metal-free oxidative 1,2-alkylarylation of alkenes with
C(sp3)-H bonds of acetonitriles.
α-
85 methoxyacetonitrile (2d), were examined in the presence of
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DOI: 10.1039/C4CC08902B
Table 1 Screening of the Optimal Conditionsa
45 halogenated positions (Products 3ca, 3da, 3fa, 3la, 3ma and
3oa). In alcohols 1p the migration of the Ph group had
precedence over naphthalen-2-yl group in 72% yield (product
3pa). The Ph- and pyridin-4-yl-substituted alcohol 1q also
worked well and mainly offered the pyridin-4-yl-migration
50 product 3qa in good yield. Gratifyingly, the reaction was
applicable to 2-(pyridin-4-yl)but-3-en-2-ol (1r), exclusively
furnishing the pyridin-4-yl-migrating product 3ra in 85%
yield.
Entry
Variation from the standard conditions
none
Isolated yield (%)
1
2
90
65
88
89
34
72
8
TBPB (2 equiv)
Table 2 ,2-Alkylarylation of Alkenes (1) with Acetonitriles (2)a
3
TBPB (4 equiv)
at 120 oC
4
at 80 oC
5
6
air (1 atm) instead of argon
TBHP (3 equiv) instead of TBPB
DTBP (3 equiv) instead of TBPB
BPO (3 equiv) instead of TBPB
7b
8
16
78
9
55
a
Reaction conditions: 1a (0.3 mmol), MeCN 2a (2 mL), and TBPB (3
5
equiv) under argon atmosphere at 100 oC for 20 h. TBHP (5 M in
b
O
O
decane).
CN
CN
R2 = R4 = Me,
3ba
, 75%
Ph
R2 = R4 = Cl, 3ca, 82%
Ph R3
R
2 = R4 = Br, 3da, 91%
1,1-diphenylprop-2-en-1-ol (1a) and TBPB (Products 3ab-ad).
Interestingly, butyronitrile (2b) was viable for reacting with
1,1-diphenylprop-2-en-1-ol (1a), furnishing the desired
10 product 3ab in 73% yield. However, both 2-phenylacetonitrile
(2c) and 2-methoxyacetonitrile (2d) had no reactivity for the
reaction (Products 3ac and 3ad).
Subsequently, a range of α-aryl allylic alcohols 1 were
investigated in the presence of acetonitrile (2a) and TBPB
15 (Products 3ba-sa). Screening of the substitution effect
suggests that which aryl group migration occurs depends on
the electronic and sterical hindrance properties of substituents
on the aryl ring: the aryl-migration reactivity based on the
electronic property decreased from electron-deficient aryl
20 groups to electron-rich aryl groups, and based on the sterical
hindrance property decreased from p-substituted-Ph and m-
substituted-Ph to Ph to o-substituted-Ph. Alcohols 1b-d,
which contain two same substituted aryl groups, such as two
R4
R3 = CH2CH3,
, 85% (1:1)
b
3ab
R3 = CH2Ph, 3ac, trace
O
R
3 = OMe, 3ad, trace
CN
R2
O
CN
CN
R2 = Me, 3ea, 83% (1.5:1)c
R2 = Cl,
, 90% (12:1)
c
3fa
R2
R2 = Ph, 3ga, 85% (30:1)c
R2 = CF3, 3ha, 81% (30:1)c
R2 = Me,
R2 = CF3, 3ja, 81% (9:1)c
, 82% (1.5:1)
c
3ia
R2
O
R4
O
Cl
O
CN
CN
R2
R4 = Me, 3ka, 81% (>99:1)c
R4 = Cl, 3la, 80% (30:1)c
R2
R2 = Me, 3na, 81% (2:1)c
R2 = Cl,
Cl
c
c
3oa
, 85% (30:1)
3ma
, 84% (50:1)
O
O
O
CN
CN
CN
Ph
4-MePh, two 4-ClPh or two 4-BrPh groups, on the
α position
N
N
25 delivered products 3ba-da in high yields. Alcohols 1e-h with
a Ph group and a p-substituted-Ph group underwent the p-
substituted-Ph group migration as the major process, giving
the corresponding products 3ea-ha in good yields. Similar
migration process took place for alcohols 1i and 1j with a Ph
30 group and a m-substituted-Ph group (Products 3ia and 3ja).
However, alcohols 1k and 1l with a Ph group and a o-
substituted-Ph group delivered the major Ph group-migration
products 3ia and 3ja in 82% and 81% yields. This migration
rule is suitable for alcohol 1m with two different aryl groups,
35 a p-substituted-Ph group and o-substituted-Ph group, which
assembled the p-substituted-Ph group-migration product 3ma
in good yield. Interestingly, alcohols 1n and 1o, which contain
two different substituted aryl groups, were also viable
substrates for the reaction, and selectivity of their products
40 3na and 3oa toward the migrating 3,4-disubstituted-Ph group.
It should be noteworthy that halogen functional groups, F, Cl
and Br, were well-tolerated under the optimal conditions,
thereby making the difunctionalization protocol more useful
in organic synthesis due to additional modifications at the
c,d
3pa, 72% (>99:1)c,d
, 75% (>99:1)
3qa
3ra
, 85%
a Reaction conditions: 1 (0.3 mmol), 2 (2 mL), and TBPB (3 equiv) under
argon atmosphere at 100 oC for 20 h. b The d.r. value ratio of product 3ab
is given in parenthesis determined by GC-MS analysis of the crude
c
60 product. The ratio of product 3/its isomer is given in parenthesis
determined by GC-MS analysis of the crude product. d For 30 h.
To understand the mechanism for the current reaction,
some control experiments were carried out (Scheme 2). As
shown in Scheme 2, a mixture two different α,α-diaryl allylic
65 alcohols 1a and 1c reacted with acetonitrile (2a) under the
standard conditions was conducted (Eq 1). The results
demonstrated that no cross aryl-migrating products were
observed, suggesting that the 1,2-aryl migration proceeds via
an intramolecular process. Moreover, among the reaction of
70 alcohol 1a with acetonitrile (2a), three radical inhibitors (4
equiv), TEMPO, hydroquinone and BHT, resulted in no
conversion of alcohol 1a into product 3aa (Eq 2), suggesting
that this current reaction may proceed via a radical process.
2
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DOI: 10.1039/C4CC08902B
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45
50
2
55
Scheme 2 Control Experiments.
The possible mechanism outlined in Scheme
3 was
proposed for the oxidative difunctionalization reaction.2-4
60
65
t
5
Initially, TBPB is split into BuO⋅ radical and PhCOO⋅ radical
under heating, supporting by the results of entries 1, 4 and 5
in Table 1. Subsequently, single-electron-transfer (SET) takes
place to form alkyl radical A, followed by addition to the C-C
double bond of substrate 1a affords new alkyl radical B.
10 Within alkyl radical intermediate B, 1,2-migration of aryl
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70
3
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85
15
Scheme 3 Possible Mechanism.
90
In summary, we have illustrated the first oxidative 1,2-
alkylarylation between the C-C double bonds of α-aryl allylic
alcohols and the
α
-C(sp3)-H bonds of acetonitriles using
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TBPB as oxidant under metal-free conditions. This method
95
20 achieves the C(sp3)-H oxidative coupling with the C-C double
bond and 1,2-aryl-migration, and provides an efficient and
highly atom-economic access to various acyclic molecules, 5-
oxo-pentanenitriles, through the oxidative 1,2-alkylarylation
of alkenes.
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This research was supported by the NSFC (Nos. 21172060
and 21472039) and Hunan Provincial Natural Science
Foundation of China (No. 13JJ2018).
Notes and references
a State Key Laboratory of Chemo/Biosensing and Chemometrics, College
30 of Chemistry and Chemical Engineering, Hunan University, Changsha
410082, China. Fax: 0086731 8871 3642; Tel: 0086731 8882 2286; Eꢀ
mail: jhli@hnu.edu.cn
† Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
35 DOI: 10.1039/b000000x/
6
‡ Footnotes should appear here. These might include comments relevant
to but not central to the matter under discussion, limited experimental and
spectral data, and crystallographic data.
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40
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