Catalyst-free direct arylsulfonylation of N-arylacrylamides with sulfinic acids: A convenient and efficient route to sulfonated oxindoles

Article abstract of DOI:10.1039/c4gc00231h

A simple, efficient and catalyst-free procedure has been developed for the construction of sulfonated oxindoles via the direct arylsulfonylation of N-arylacrylamides with sulfinic acids. The present protocol, which simply utilizes cheap oxidants, readily-available starting materials, and catalyst-free conditions, provides an alternative and highly attractive approach to a series of sulfonated oxindoles with high atom efficiency and excellent functional group tolerance. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4gc00231h

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Catalyst-free direct arylsulfonylation of
N-arylacrylamides with sulfinic acids: a convenient
and efficient route to sulfonated oxindoles†
Cite this: Green Chem., 2014, 16,
2988
Received 12th February 2014,
Accepted 15th March 2014
Wei Wei, Jiangwei Wen, Daoshan Yang, Juan Du, Jinmao You and Hua Wang*
DOI: 10.1039/c4gc00231h
www.rsc.org/greenchem
A simple, efficient and catalyst-free procedure has been developed properties and widespread synthetic applications for various
for the construction of sulfonated oxindoles via the direct arylsul- organic transformations.11 So far, various sulfonylating agents
fonylation of N-arylacrylamides with sulfinic acids. The present such as sulfonyl chlorides, sulfinates, sulfonyl selenides, sulfo-
protocol, which simply utilizes cheap oxidants, readily-available nyl cyanides, sulfonylazides and sulfonyl hydrazides have been
starting materials, and catalyst-free conditions, provides an used for the construction of organic sulfone compounds.12
alternative and highly attractive approach to a series of sulfonated
Nevertheless, most sulfonylation reactions usually suffer
oxindoles with high atom efficiency and excellent functional group from low atom-efficiency and relatively harsh or complex reac-
tolerance.
tion conditions. Recently, sulfinic acids as stable and readily
available sulfonylating agents have alternatively emerged for
constructing sulfone compounds with high atom-efficiency.13
For example, Lei and co-workers described pyridine mediated
aerobic oxysulfonylation of alkenes with arylsulfinic acids
leading to β-hydroxysulfones.13a In 2013, Li et al. reported
KI/18-crown-6 (20 mol%) catalyzed oxidative arylsulfonylation of
activated alkenes with p-toluenesulfonylhydrazide (TsNHNH2)
in the presence of 3 equiv. TBHP.14 To the best of our knowl-
edge, there are no examples describing the direct arylsulfonyla-
tion of alkenes to access sulfonated oxindoles using sulfinic
acids as sulfonylating reagents. Owing to our continued inter-
est in the construction of sulfone-containing organic com-
pounds,13c,15 herein, we wish to report a new and efficient
catalyst-free direct arylsulfonylation of arylacrylamides with
sulfinic acids towards sulfonated oxindoles by simply using
the cheap K2S2O8 (1 equiv.) as the oxidant (eqn (1)). The
present methodology provides a convenient and highly attrac-
tive approach to a diverse range of sulfonated oxindoles in
moderate to high yields with high atom efficiency and excel-
lent functional group tolerance.
Oxindoles are an important class of heterocycles with unique
biological activity that are frequently found in many natural
products and biologically active compounds.1 In particular,
the functionalized oxindoles have elicited considerable syn-
thetic interest because of their important applications in asym-
metric synthesis, library design and drug discovery.2 So far, a
number of effective synthetic methods have been established,
among them the recently developed transition-metal catalyzed
or metal-free oxidative difunctionalization of activated alkenes
offer particularly appealing approaches to various functional
oxindoles.3–9 Through this methodology, many functional
groups such as cyano,3 carbonyl,4 hydroxyl,5 phosphoryl,6 tri-
fluoromethyl,7 azidyl,8 and nitro9 groups have been success-
fully incorporated into the oxindole framework. Gracefully
successive as these recent studies on difunctionalization of
activated alkenes could be, there is still a great demand for the
development of a simple, convenient, efficient and highly
atom-economic oxidative difunctionalization system to offer
other important functionalized oxindoles.
The sulfone functionality, as the key structural motif,
widely exists in a variety of natural products, clinical pharma-
ceuticals, and synthetic intermediates.10 The incorporation of
sulfone groups into organic molecules has drawn increasing
attention from chemists in view of their important biological
ð1Þ
The Key Laboratory of Life-Organic Analysis and Key Laboratory of Pharmaceutical
Intermediates and Analysis of Natural Medicine, School of Chemistry and Chemical
Initially, the model reaction of N-arylacrylamide 1a with
benzenesulfinic acid 2a was conducted in CH3CN–H2O (1 : 2)
at 80 °C under air (Table 1, entry 1). To our delight, the
desired sulfonated oxindole 3aa was obtained in 58% yield.
Engineering, Qufu Normal University, Qufu 273165, Shandong, China.
E-mail: huawang_qfnu@126.com
†Electronic supplementary information (ESI) available: Experimental details.
See DOI: 10.1039/c4gc00231h
2988 | Green Chem., 2014, 16, 2988–2991
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Table 1 Optimization of the reaction conditionsa
Table 2 Results for catalyst-free arylsulfonylation of N-arylacrylamide
with sulfinic acidsa,b
Entry
Oxidant
Solvent
Yieldb (%)
1
2
3
4
5
6
7
8
Air (O2)
CH3CN–H2O (1/2)
CH3CN–H2O (1/2)
CH3CN–H2O (1/2)
CH3CN–H2O (1/2)
CH3CN–H2O (1/2)
CH3CN–H2O (1/2)
CH3CN–H2O (1/2)
DCE–H2O (1/2)
DME–H2O (1/2)
DMSO–H2O (1/2)
DMF–H2O (1/2)
1,4-Dioxane–H2O (1/2)
DMA–H2O (1/2)
Toluene–H2O (1/2)
NMP–H2O (1/2)
CH3CN–H2O (1/1)
CH3CN–H2O (2/1)
CH3CN–H2O (1/4)
H2O
58
81
80
87
63
57
28
83
70
77
64
69
64
63
65
73
66
82
66
42
81
80
Tracec
76d
(NH4)2S2O8 (1)
Na2S2O8(1)
K2S2O8(1)
TBHP (1)
DTBP (1)
H2O2 (1)
K2S2O8 (1)
K2S2O8 (1)
K2S2O8 (1)
K2S2O8 (1)
K2S2O8 (1)
K2S2O8 (1)
K2S2O8 (1)
K2S2O8 (1)
K2S2O8 (1)
K2S2O8 (1)
K2S2O8 (1)
K2S2O8 (1)
K2S2O8 (1)
K2S2O8 (1.5)
K2S2O8 (2)
K2S2O8 (1)
K2S2O8 (1)
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
CH3CN
CH3CN–H2O (1/2)
CH3CN–H2O (1/2)
CH3CN–H2O (1/2)
CH3CN–H2O (1/2)
a Reaction conditions: 1a (0.25 mmol), 2a (0.75 mmol), oxidant
(1–2 equiv.), solvent (3 mL), 80 °C, 12 h, under air. TBHP: tert-butyl
hydroperoxide, 70% solution in water; DTBP: di-tert-butyl peroxide;
DCE:
1,2-dichloroethane; DME:
1,2-dimethoxyethane; DMA:
N,N-dimethylacetamide; NMP: N-methyl-2-pyrrolidone. b Isolated yields
based on 1a. c 25 °C. d 60 °C.
Then, the effects of other oxidants (1 equiv.) such as
(NH4)2S2O8, Na2S2O8, K2S2O8, TBHP, DTBP and H2O2 were
investigated. The results showed that this arylsulfonylation
reaction could also occur in the presence of the above oxi-
dants, while the reactivity of K2S2O8 was better than others to
form the desired product in 87% yield (Table 1, entries 2–7).
Further optimization of solvents showed that the reaction per-
formed in CH3CN–H2O (1 : 2) was found to be superior for the
formation of 3aa (Table 1, entries 8–18). Notably, this arylsulfo-
nylation reaction was also conducted effectively in water
(Table 1, entry 19). In contrast, product 3aa was obtained in
relatively low yield when the reaction was performed in sole
CH3CN (Table 1, entry 20). Increasing the amount of K2S2O8
did not improve this reaction yield (Table 1, entries 21 and 22).
Only a trace amount of 3aa was detected at room temperature,
and the best yield was isolated when the reaction was con-
ducted at 80 °C (Table 1, entries 4, 23–24).
a Reaction conditions: 1 (0.25 mmol), 2 (0.75 mmol), K2S2O8 (1 equiv.),
CH3CN–H2O (3 mL, 1/2), 80 °C, 12–24 h. b Isolated yields based on 1.
Under the optimized conditions, the scope and limitations
of the reaction of various N-arylacrylamides with sulfinic acids
were investigated and the results are shown in Table 2. In
general, N-arylacrylamides containing electron-donating or
-withdrawing groups on the aryl rings were suitable for this
protocol, and the corresponding products were obtained in
moderate to good yields (3aa–3la). A wide range of functional-
ities such as halogen, carbonyl, and cyano groups were all
tolerated in this reaction, thereby facilitating possible
further modifications (3ea–3ia). ortho-Substituted arylacryl-
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amide, which could not be effectively used in the previous was converted into an oxygen-centered radical 4 resonating
reported system,14 was compatible with this reaction, affording with the sulfonyl radical 5 via the single electron transfer (SET)
the desired product 3ja in good yield. The substituent group at and deprotonation process in the presence of K2S2O8.16 Sub-
the meta-position of the phenyl ring afforded a mixture of two sequently, the addition of the sulfonyl radical 5 to N-arylacryl-
regioselective products (3ka/3ka′) and (3la/3la′) and 4-substi- amide 1 generated the alkyl radical 6. Intramolecular cyclization
tuted indolinones were obtained as the major products (3ka of intermediate 6 with an aryl ring would lead to the formation
and 3la). It is noteworthy that the cyclization of tetrahydroqui- of radical intermediate 7. Finally, the oxidation of 7 afforded
noline could afford tricyclic oxindole 3ma in 76% yield. N-Aryl- the corresponding carbocation, which lost H+ to produce the
acrylamides with different functional groups such as alcohol sulfonated oxindole 3.
could also be used in the reaction to give the expected product
In summary, a convenient and efficient method has been
3na in 92% yield. Investigations of different N-protection developed for the construction of sulfonated oxindoles via a
groups showed that substrates bearing both alkyl and aryl pro- catalyst-free direct arylsulfonylation reaction of arylacrylamides
tecting groups on the nitrogen are suitable for this reaction with sulfinic acids using the simple and cheap K2S2O8 as the
(3aa–3oa), whereas N-free and acetyl N-arylacrylamides failed oxidant. Taking into account the combination of desirable fea-
to afford the desired products. In addition to benzenesulfinic tures, such as operation simplicity, product diversity, catalyst-
acid, various substituted benzenesulfinic acids bearing either free conditions, and high atom efficiency, this reaction system
electron-rich or electron-deficient groups were all suitable for is expected to provide an alternative and attractive approach to
this reaction to give the corresponding products in good yields a series of biologically important sulfonated oxindoles from
(3ab–3ag). The sterically-hindered substituted arylsulfinic sulfinic acids. The detailed scope, mechanism, and synthetic
acids such as 2-bromobenzenesulfinic acid and 2-(trifluoro- application of this reaction are under investigation.
methyl)benzenesulfinic acid were also tolerated in this
process, leading to the desired products in good yields (3ah
and 3ai). Naphthalene-1-sulfinic acid could also be used in the
reaction to give the desired product 3aj in 70% yield.
Acknowledgements
A radical pathway was proposed in the oxidative addition This work was supported by the National Natural Science
reaction of sulfinic acids to alkenes leading to β-hydroxysul- Foundation of China (no. 21302109, 21375075, and 21302110),
fones by Lei,13a the corresponding mechanism was proved by the Taishan Scholar Foundation of Shandong Province, the
radical trapping experiments with TEMPO (2,2,6,6-tetramethyl- Excellent Middle-Aged and Young Scientist Award Foundation
1-piperidinyloxy, a well-known radical scavenger). As shown of Shandong Province (BS2013YY019), and the Scientific
in eqn (2), when TEMPO was added in this reaction system, Research Foundation of Qufu Normal University (BSQD
the arylsulfonylation reaction was extremely inhibited, which 2012020).
suggested that a radical process might be involved in the
present reaction.
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