Metal-Free Oxidative 1,2-Arylmethylation Cascades of N-(Arylsulfonyl)acrylamides Using Peroxides as the Methyl Resource

Article abstract of DOI:10.1021/acs.orglett.6b01419

A new, metal-free oxidative 1,2-arylmethylation cascades of N-(arylsulfonyl)acrylamides for the assembly of 2,2-disubstituted-N-arylbutanamides containing an all-carbon quaternary center is presented. This reaction enables the one-step formation of two ne

Full text of DOI:10.1021/acs.orglett.6b01419

Letter
pubs.acs.org/OrgLett
Metal-Free Oxidative 1,2-Arylmethylation Cascades of
N‑(Arylsulfonyl)acrylamides Using Peroxides as the Methyl Resource
Fang-Lin Tan,† Ren-Jie Song,*,‡ Ming Hu,† and Jin-Heng Li*,†,‡
†State Key Laboratory of Chemo/Biosensing and Chemometrics, Hunan University, Changsha 410082, China
‡Key Laboratory of Jiangxi Province for Persistent Pollutants Control and Resources Recycle, Nanchang Hangkong University,
Nanchang 330063, China
S
* Supporting Information
ABSTRACT: A new, metal-free oxidative 1,2-arylmethylation cascades of N-(arylsulfonyl)acrylamides for the assembly of 2,2-
disubstituted-N-arylbutanamides containing an all-carbon quaternary center is presented. This reaction enables the one-step
formation of two new C−C bonds through a sequence of methylation/1,4-aryl migration/desulfonylation using an organic
peroxide as the methyl resource with a broad substrate scope and excellent functional group tolerance.
Scheme 1. Difunctionalization Cascades of N-
(Arylsulfonyl)acrylamides
ifunctionalization of alkenes is one of the most important
Dmethods for increasing molecular complexity in synthesis,
which can simultaneously construct two new chemical bonds in
one-step.1,2 As a result, considerable efforts have been devoted to
develop new efficient strategies for the alkene difunctionaliza-
tion.3 Among them, oxidative dicarbo-functionalization are
particularly appealing, which enable the formation of two new
C−C bonds in a single reaction.4 However, approaches for the
oxidative 1,2-arylalkylation of alkenes are less abundant, and the
majority are restricted to transformations of N-arylacrylamides to
oxindoles and related heterocycles via a sequence of intra-
molecular C(sp2)−H functionalization and cyclization.5 Re-
cently, attention has been attracted on the difunctionalization of
N-(arylsulfonyl)acrylamides, which proceeded involving aryl
migration and desulfonylation.6 In 2013, Nevado and co-workers
first reported a copper-catalyzed 1,2-aryltrifluoromethylation of
the alkene moieties in N-(arylsulfonyl)acrylamides via a radical-
mediated trifluoromethylation, aryl migration/desulfonylation
tandem process6b leading to α-aryl-β-trifluoromethyl amides.7
Subsequently, some new radical-mediated strategies, including
1,2-arylphosphonylation,6a 1,2-arylazidation,6g and 1,2-arylalky-
lation,6e for the transformations of N-(arylsulfonyl)acrylamides
have been developed (Scheme 1a). Although the oxidative 1,2-
arylalkylation of N-(arylsulfonyl)acrylamides has been described
by the group of Zhu, it was limited to the use of cycloalkanes as
the alkyl resources. Further, to our knowledge, methods for the
1,2-arylmethylation cascades of N-(arylsulfonyl)acrylamides
have never been reported, despite the obvious synthetic utility
of the methylation reaction in chemistry, especially in medicinal
chemistry.8−10
the synthesis of 2,2-disubstituted-N-arylbutanamides containing
an all-carbon quaternary center. This radical-mediated reaction
employs peroxides as the methyl resource, thus enabling the one-
step formation of two C−C bonds through a sequence of
methylation, aryl migration, and desulfonylation (Scheme 1b).
We began our studies by examining the 1,2-arylmethylation
cascades of N,2-diphenyl-N-(phenylsulfonyl)acrylamide (1a)
with peroxides (Table 1). Pleasingly, treatment of acrylamide
1a with di-tert-butyl peroxide (DTBP; 2a) in PhCl under argon
atmosphere at 120 °C for 5 h afforded the desired product 3aa in
72% yield (entry 1). Encouraged by the results, a series of other
peroxides, including dicumylperoxide 2b (DCP), tert-butyl
peroxybenzoate 2c (TBPB), tert-butyl hydroperoxide 2d
(TBHP; in decane), and aqueous TBHP 2e, was examined
(entries 2−5): each of which could serve as the methyl resource
for the reaction but was less reactive than DTBP in terms of
yields. Notably, the use of DCP 2b exclusively resulted in the
Herein, we report a new metal-free oxidative 1,2-arylmethy-
Received: May 16, 2016
lation cascade of N-(arylsulfonyl)acrylamides with peroxides for
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b01419
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Letter
a
a
Table 1. Screening of Optimal Conditions
Scheme 2. Variation of the Acryl Sulfonamides (1)
b
entry
peroxide (equiv)
solvent
t (°C)
yield (%)
1
2
3
DTBP 2a (3)
DCP 2b (3)
TBPB 2c (3)
TBHP 2d (3)
TBHP 2e (3)
DTBP 2a (4)
DTBP 2a (2)
DTBP 2a (3)
DTBP 2a (3)
DTBP 2a (3)
DTBP 2a (3)
DTBP 2a (3)
DTBP 2a (3)
DTBP 2a (3)
DTBP 2a (3)
PhCl
120
120
120
120
120
120
120
120
120
120
120
120
130
110
120
72
67
38
15
14
70
52
38
29
21
64
trace
68
24
65
PhCl
PhCl
c
4
PhCl
d
5
PhCl
6
7
PhCl
PhCl
e
8
f
MeCN
toluene
DMF
PhCF3
t-BuOH
PhCl
9
10
11
12
13
14
PhCl
g
15
PhCl
a
Reaction conditions: 1a (0.2 mmol), 2, solvent (2 mL), argon, and 5
b
c
d
h. Isolated yield. TBHP (anhydrous, 5 M in decane). TBHP (70%
in water). A trace amount of cyano-containing product was detected
by GC−MS analysis. A trace amount of 1,2-benylmethylation product
was detected by GC−MS analysis. 1a (726 mg, 2 mmol) for 8 h.
e
f
g
a
Reaction conditions: 1a (0.2 mmol), 2 (3 equiv), PhCl (2 mL),
b
argon, 120 °C, and 5 h. 2-Hydroperoxy-2-methylbutane (2f) (0.4
mmol) was used as ethyl source.
formation of the 1,2-phenylmethylation product 3aa, not the 1,2-
phenylphenylation product (entry 2). A screen of the amount of
DTBP 2a revealed 3 equiv of DTBP as the best choice (entries 6
and 7). Among the effect of solvent examined, the use of PhCl
solvent turned out to be the most effective than the other
solvents, such as MeCN, toluene, DMF, PhCF3, and t-BuOH
(entries 8−12). Further screening on the reaction temperature
proved that the reaction at 120 °C gave the best yield (entries 1,
13, and 14). Gratifyingly, the scale of acrylamide 1a up to 2 mmol
was also viable for the synthesis of 3aa in moderate yield (entry
15).
With the optimized reactions in hand, we set out to explore the
scope of this oxidative 1,2-arylmethylation cascades protocol
with respect to the N-(arylsulfonyl)acrylamides 1, and the results
are summarized in Scheme 2. The optimal conditions were
compatible with a variety of N-aryl-N-(arylsulfonyl)acrylamides
1, providing the corresponding products 3ba−sa in moderate
yields. Importantly, several substituents, namely, Me, OMe, Cl, F,
and CN, on the aromatic ring of the N-aryl moiety were well-
tolerated, and the reactive order of the substituents was para >
meta > ortho in terms of yields (products 3ba−ia). While para-
Me-substituted substrate 1b gave 3ba in 75% yield, meta-Me-
substituted substrate 1g or ortho-Me-substituted substrate 1h
delivered the corresponding products 3ga and 3ha, respectively,
in lower yields. Notably, N-(naphthalen-1-yl)-substituted
substrate 1j was also proved to be viable for furnishing 3ja.
Subsequently, the substitution effect on the aromatic ring of the
N-(arylsulfonyl) moiety was investigated. Substrates 1k−n,
bearing a Me, a OMe, a Cl, or a CN group on the aryl ring of
the N-(arylsulfonyl) moiety, were efficiently converted to the
corresponding products 3ka−na in moderate to good yields.
Using substrates 1o or 1p with benzyl or methyl group at the 2
position of the acrylamides moiety smoothly assembled products
3oa and 3pa, respectively. In the case of N-phenyl-N-
(arylsulfonyl)-methacrylamides 1q−s, the reaction were success-
fully performed, giving 3qa−sa in moderate yield. Notably, Cl, F,
and Br groups could also survive, thereby facilitating additional
modifications at the halogenated position (products 3da−ea, 3ia,
3ma, and 3sa).
Gratifyingly, the optimal conditions were applicable to 1,2-
arylethylation cascades of N-(arylsulfonyl)acrylamides (products
3af and 3pf). For example, substrate 1a treated with 2-
hydroperoxy-2-methylbutane (2f) exclusively afforded the 1,2-
phenylethylation product 3af in 46% yield.
To understand the mechanism, some control experiments
were designed (Scheme 3). A mixture of two different acryl
sulfonamides 1b and 1l was reacted with DTBP (2a) under the
optimal conditions; no cross aryl-migrating products were
obtained (eq 1). The results demonstrate that 1,4-aryl migration
proceeds via an intramolecular process. To our surprise, N-alkyl
substrate 1t afford a cyclization product 3-ethyl-1,3-dimethy-
lindolin-2-one (3ta), in 62% yield (eq 2). Notably, the reaction of
N,2-diphenyl-N-(phenylsulfonyl)acrylamide (1a) with DTBP 2a
was completely inhibited when using a stoichiometric amount of
radical scavengers, including TEMPO, 2,6-di-tert-butyl-4-meth-
ylphenol (BHT), and hydroquinone. Moreover, 1-methoxy-
2,2,6,6-tetramethylpiperidine 5 was in situ detected by GC−MS
analysis. These results suggest that the reaction may involve a
radical process (eq 3).
The plausible mechanism of this metal-free oxidative 1,2-
arylmethylationcascades was proposed (Scheme 4).3,6−10 DTBP
readily generates methyl radical and acetone under heating.
Addition of the methyl radical across the C−C double bond in N-
(arylsulfonyl)acrylamides 1 affords the radical intermediate A,
B
DOI: 10.1021/acs.orglett.6b01419
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 3. Control Experiments
ACKNOWLEDGMENTS
■
We thank the Natural Science Foundation of China (Nos.
21402046 and 21472039) for financial support.
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In summary, we have developed new, metal-free oxidative 1,2-
arylmethylation cascades of N-(arylsulfonyl)acrylamides using
organic peroxides as the methyl source through a sequence of
methylation/aryl migration/desulfonylation. This reaction pro-
vides a simple and facile route to the straightforward synthesis of
2,2-disubstituted-N-arylbutanamides with a quaternary stereo-
center with excellent functional group tolerance.
́ ́
(6) (a) Fuentes, N.; Kong, W.-Q.; Fernandez-Sanchez, L.; Merino, E.;
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b01419.
Nevado, C. J. Am. Chem. Soc. 2015, 137, 964. (b) Kong, W.-Q.;
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■
S
Descriptions of experimental procedures for compounds
and analytical characterization (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
(7) (a) Kong, W.-Q.; Casimiro, M.; Fuentes, N.; Merino, E.; Nevado,
C. Angew. Chem., Int. Ed. 2013, 52, 13086. (b) Chen, Z.-M.; Bai, W.;
Wang, S.-H.; Yang, B.-M.; Tu, Y.-Q.; Zhang, F.-M. Angew. Chem., Int. Ed.
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Horberg, J.; Wallentin, C. J. Chem. - Eur. J. 2016, 22, 3292. (f) Gao, Y.-Z.;
*E-mail: srj0731@hnu.edu.cn.
*E-mail: jhli@hnu.edu.cn.
Notes
The authors declare no competing financial interest.
C
DOI: 10.1021/acs.orglett.6b01419
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