Metal-Free Mediated Meerwein-Type Reaction: A Radical Cascade Arylation/Aryl Migration/Desulfonylation of Conjugated Alkenes

Article abstract of DOI:10.1021/acs.orglett.6b01041

A metal-free cascade arylation/aryl migration/desulfonylation of N-phenyl-N-(phenylsulfonyl)methacrylamide is described. The in situ generated diazonium salts from anilines and t-BuONO are used as aryl precursors. This process provides an efficient strategy for the synthesis of α-all-carbon quaternary stereocenters amides. A radical mechanism was proposed for this transformation.

Full text of DOI:10.1021/acs.orglett.6b01041

Letter
pubs.acs.org/OrgLett
Metal-Free Mediated Meerwein-Type Reaction: A Radical Cascade
Arylation/Aryl Migration/Desulfonylation of Conjugated Alkenes
Zhangqin Ni, Xin Huang, and Yuanjiang Pan*
Department of Chemistry, Zhejiang University, Hangzhou 310027, China
*
S Supporting Information
ABSTRACT: A metal-free cascade arylation/aryl migration/
desulfonylation of N-phenyl-N-(phenylsulfonyl)methacryl-
amide is described. The in situ generated diazonium salts
from anilines and t-BuONO are used as aryl precursors. This
process provides an efficient strategy for the synthesis of α-all-
carbon quaternary stereocenters amides. A radical mechanism
was proposed for this transformation.
lkenes are of great importance in organic synthesis
Scheme 1. Cascade Arylation/Aryl Migration/
Desulfonylation of N-Phenyl-N-
(phenylsulfonyl)methacrylamide
A
because of their potential for the introduction of various
functional groups to the CC bond. Numerous endeavors
have been paid to the development of novel difunctionalization
of alkenes since it can introduce two functional groups in a
1
−7
single step. On the other hand, though cascade reactions are
considered as efficient synthetic strategies, the desired product
can be obtained directly without the separation of reaction
8
intermediates. It has been widely used in the synthesis of
heterocyclic compounds. Recently, cascade reactions based on
phenylsulfonyl acrylamide have received increasing attention.
Nevado’s group first developed a novel radical cascade
aryltrifluoromethylation/aryl migration/desulfonylation of phe-
The results are summarized in Table 1. In the presence of tert-
butyl nitrite (3.5 equiv), tetrabutylammonium iodide (TBAI)
(10 mol %), and NaOAc (1 equiv), the target product 3a could
be obtained with 31% yield (entry 1). The structure of 3a was
confirmed by MS and NMR spectra. In order to increase the
yield, several different kinds of bases were screened in this
reaction, and the yield was improved (entries 2−5). Among the
bases tried, phenanthroline (Phen) gave the best result with
9a
nylsulfonyl acrylamide. Encouraged by Nevado’s pioneering
work, arylphosphonylation, arylazidation, arylalkylation, and
aryltrifluoromethylation of phenylsulfonyl acrylamide have
9
been developed by several groups. To the best of our
knowledge, the diarylation of phenylsulfonyl acrylamide has not
been investigated.
5
5% yield (entry 5). When the reaction was performed in the
absence of Phen, the yield of the target product decreased to
9% (entry 6). Subsequently, the effects of solvent were
Diazonium salts, which can be synthesized from commercial
available aniline, have proven to be good aryl radical providers.
Diazonium salts are prone to undergo a homolytic
dediazoniation to provide aryl radicals, and the in situ generated
aryl radicals can be trapped by other reactive species to form
the desired products. Various reactions based on the in situ
generated aryl radical from diazonium salts have been
3
investigated, and several different solvents were used instead of
MeNO2 (entries 7−10), while the results indicated that
MeNO2 was the most suitable solvent for this reaction.
Benzotrifluoride (BTF) had been used in arylative cyclization
14
10
of isocyanobiphenyls with anilines by Zhu. However, the
target product could be only isolated with 15% yield in our
reaction (entry 10). Then, two different nitrosating agents were
tested. When isoamyl nitrite was used instead of tert-butyl
nitrite, the target product could be obtained with 51% yield,
which is slightly lower than that with tert-butyl nitrite (entry
established, such as Sandmeyer-type reactions and Meer-
11
wein-type reactions. Recently, we developed a new approach
for the synthesis of 3,3-disubstituted oxindoles from anilines
1
2
3
nitrosated in situ. We also realized the C(Sp )−H bond
activation of acetonitrile using the in situ generated diazonium
13
salts as radical promoter. To further our investigation of the
in situ generated diazonium salts, a radical cascade reaction
using in situ generated diazonium salts and conjugated alkenes
was designed. In this communication, we describe a metal-free
cascade arylation/aryl migration/desulfonylation reaction of
phenylsulfonyl acrylamide (Scheme 1).
1
1). Sodium nitrite was inefficient for this transformation; no
product could be isolated (entry 12). If the reaction was
performed without the addition of H O, the yield would
2
decrease to 45% (entry 13). Further optimization focused on
Our study commenced with the reaction of N-phenyl-N-
phenylsulfonyl)methacrylamide 1a and p-chloroaniline 2a.
Received: April 11, 2016
(
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b01041
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 1. Optimization of Reaction Conditions
b
entry
additive
NaOAc
solvent
temp (°C)
yield (%)
1
2
3
4
5
6
7
8
9
MeNO2
MeNO2
MeNO2
MeNO2
MeNO2
MeNO2
DMSO
DMF
110
110
110
110
110
110
110
110
110
110
110
110
110
100
120
110
31
48
Na CO3
2
HMPA
NaHSO3
Phen
45
40
55
39
Phen
Phen
Phen
Phen
Phen
Phen
Phen
Phen
Phen
Phen
46
33
toluene
BTF
15
1
1
1
1
1
1
1
0
1
2
3
4
5
6
20
c
MeNO2
MeNO2
MeNO2
MeNO2
MeNO2
MeNO2
51
d
e
trace
45
48
52
f
43
a
Reaction conditions: 1a (0.5 mmol), 2a (3 equiv), t-BuONO (3.5
equiv), TBAI (10 mol %), additive (1 equiv), solvent (1 mL), H O (50
2
b
c
μL), N , 10 h. Isolated yield. Isoamyl nitrite instead of tert-butyl
2
d
Figure 1. Scope of aryl amines.
nitrite was used. sodium nitrite instead of tert-butyl nitrite was used.
e
f
Without the addition of H O. MeNO (2 mL).
2
2
the reaction temperature and concentration of the reactants.
The yield could not be improved when the reaction was
performed in either a higher or lower temperature (entries 14
and 15). The concentration of the reactants had an obvious
influence in this reaction. Increasing the volume of MeNO2
resulted in the decrease of the target product yield (entry 16).
With the optimized reaction conditions in hand, we then set
out to explore the substrate scopes of this radical cascade
reaction. N-Phenyl-N-(phenylsulfonyl)methacrylamide 1a was
reacted with various aryl amines 2a−k to give the
corresponding products 3a−k with moderate yields (Figure
1
). In this transformation, the electron-withdrawing substitu-
ents on anilines gave slightly higher yields than the electron-
donating ones (3a−f), which might be because the electron-
withdrawing substituents on the aromatic ring would favor
homolytic dediazoniations. Fortunately, chloro and bromo
groups were inert under these reaction conditions and would
allow further functionalization of the products. When the
aniline was substituted with a nitro group, which behaves as a
strong electron-withdrawing substituent, the yield of the
corresponding product decreased to 25% (3i). The effects of
the substituted position were also investigated. The steric
hindrance had obvious effects on this transformation. 3-
Chloroaniline 2j and 2-chloroaniline 2k only afforded the
desired products with 48% and 35% yields, which are lower
than that of 4-chloroaniline (3j, 3k).
A series of N-phenyl-N-(phenylsulfonyl)methacrylamides
were also investigated (Figure 2). First, the substituent effects
on the phenyl ring were investigated. When the phenyl ring was
substituted on the para-position, the electron-donating
substituents clearly gave higher yields than the electron-
withdrawing ones (3l−q). Then, the effects of steric hindrance
were studied. As anticipated, the steric hindrance had a
Figure 2. Scope of N-phenyl-N-(phenylsulfonyl)methacrylamides.
significant influence on this transformation. When the methyl
group substituted at the ortho- or meta-position instead of the
B
DOI: 10.1021/acs.orglett.6b01041
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
para-position, the yield of corresponding product decreased to
radical intermediate C. The 5-ipso-cyclization on the aromatic
ring generates intermediate D, and a rapid desulfonylation
affords the key amidyl radical E. Finally, radical intermediate E
abstracts a hydrogen atom to give the desired product.
In conclusion, we have developed a novel radical cascade
arylation/aryl migration/desulfonylation of N-phenyl-N-
(phenylsulfonyl)methacrylamide. The anilines could react
with t-BuONO to form diazonium salts, and the in situ
generated aryl radical from diazonium salts could add to the
CC bond. Through 5-ipso-cyclization and rapid desulfony-
lation, α-all-carbon quaternary stereocenters amides could be
obtained with moderate yield. This process provides a new
procedure for the synthesis of α-all-carbon quaternary stereo-
center amides.
3
9% or 51% (3r, 3s). We also tried to apply this strategy to
heteroaromatic ring substrate. When N-(phenylsulfonyl)-N-
quinolin-8-yl)methacrylamide was used in this reaction, the
(
target product could be obtained with 43% yield (3t).
Subsequently, the substituted effects on the phenysulfonyl
ring were investigated. The results implied that the electron-
withdrawing or -donating substituents had little effect on the
yield; instead, the target products could all be obtained with
moderate yields (3u−x). Fortunately, chloro and bromo groups
on either phenyl ring or phenylsulfonyl ring could be tolerated
and allow for further functionalization reactions. In addition,
3
the reaction could still proceed when R = H, although only
2
7% of the target product could be obtained (3y).
Unfortunately, when N-butyl-N-(phenylsulfonyl)methacryl-
amide or N-cyclohexyl-N-(phenylsulfonyl)methacrylamide was
used in this reaction, the target products could not be obtained
ASSOCIATED CONTENT
Supporting Information
■
*
S
(
3z).
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b01041.
To investigate the mechanism of this cascade reaction, the
control experiment was performed (Scheme 2). The 2,2,6,6-
Descriptions of experimental producedures for com-
pounds and analytical characterization (PDF)
Scheme 2. Control Experiment
AUTHOR INFORMATION
Corresponding Author
■
*
E-mail: panyuanjiang@zju.edu.cn.
Notes
The authors declare no competing financial interest.
tetramethylpiperidin-1-oxyl radical (TEMPO), which has been
widely used as radical scavenger, was added to the reaction
system. We found that the target product could not be obtained
and the starting material decomposed. We speculated the
reaction might undergo a radical process.
ACKNOWLEDGMENTS
■
We gratefully acknowledge the National Natural Science
Foundation of China (21532005, 21327010).
Based on the above-mentioned observations and previous
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DOI: 10.1021/acs.orglett.6b01041
Org. Lett. XXXX, XXX, XXX−XXX