Iodine-catalyzed regioselective sulfenylation of indoles with sodium sulfinates

Article abstract of DOI:10.1002/adsc.201300773

An iodine-catalyzed sulfenylation of free indoles with sodium sulfinates is described. The reaction selectively afforded 3-arylthioindoles in good to high yields in anisole under metal-free conditions. Functional groups such as halogens were well tolerated under the optimized reaction conditions.

Full text of DOI:10.1002/adsc.201300773

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DOI: 10.1002/adsc.201300773
Iodine-Catalyzed Regioselective Sulfenylation of Indoles with
Sodium Sulfinates
Fuhong Xiao,a Hao Xie,a Saiwen Liu,a and Guo-Jun Denga,b,*
a
Key Laboratory of Environmentally Friendly Chemistry and Application of Ministry of Education, College of Chemistry,
Xiangtan University, Xiangtan 411105, Peopleꢀs Republic of China
Fax : (+86)-0731-5829-2251; phone: (+86)-0731-5829-8601; e-mail: gjdeng@xtu.edu.cn
Key Laboratory of Molecular Recognition and Function, Institute of Chemistry, Chinese Academy of Sciences, Beijing
b
100080, Peopleꢀs Republic of China
Received: August 26, 2013; Revised: November 14, 2013; Published online: January 28, 2014
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201300773.
Abstract: An iodine-catalyzed sulfenylation of free
indoles with sodium sulfinates is described. The re-
action selectively afforded 3-arylthioindoles in good
to high yields in anisole under metal-free condi-
tions. Functional groups such as halogens were well
tolerated under the optimized reaction conditions.
make them under transition metal-free conditions.
Several approaches for direct sulfenylation of indoles
with disulfides under transition metal-free conditions
have been developed. Iodine,[13] N-bromosuccinimide
[15]
[16]
(NBS),[14] Cs2CO3 and K2CO3 were employed as
efficient promoters when disfulfides were used as sul-
fenylating agents. Additionally, sulfonyl hydrazides[17]
and arylsulfonyl chlorides[18] were also successfully
used as efficient sulfenylating agents with indoles
under metal-free conditions. Sodium sulfinates are
stable and easy to handle, and they have been widely
used as sulfonylating agents.[19] Recently, we and
others have developed various approaches using aro-
Keywords: indoles; iodine; sodium sulfinates; sul-
ACHTUNGTRENNUNGfenylation; transition metal-free conditions
Diaryl sulfides are of great importance as building matic sulfinic acids (or salts) as aryl sources via extru-
blocks for natural products, pharmaceuticals and func- sion of SO2.[20] To the best of our knowledge, there
tional materials.[1] Consequently, the development of are no examples describing the direct sulfenylation of
À
À
efficient methods for construction of C S bonds has heteroarene C H bonds using sodium sulfinates as
stimulated considerable interest. Among them, the sulfenylation reagents. Herein, we describe an iodine-
transition metal-catalyzed cross-coupling of aryl hal- catalyzed regioselective sulfenylation of free indoles
ides with thiols has become one of the most important with sodium sulfinates, affording 3-arylthioindoles in
methods for the synthesis of diaryl sulfides.[2] In good to high yields (Scheme 1).
À
recent years, the direct sulfenylation via C H func-
tionalization has attracted great interest since this
To get the optimized reaction conditions, the sul-
ACHTUNGTRENfNGNU enylation of indole (1a) with sodium benzenesulfi-
method can potentially lead to more efficient synthe- nate (2a; 2 equiv.) was selected as the model reaction
sis with a reduced number of synthetic operations. using diethyl phosphite as reagent in anisole. Several
Various sulfenylating agents such as quinone mono- iodide-containing catalysts were investigated, and
O,S-acetals,[3] disulfides,[4] sulfenyl halides,[5] N-thioar- among them I2 (10 mol%) showed the best efficiency
ylphthalimides,[6] thiols[7] and arylsulfonyl cyanides[8] to give the corresponding product 3a in 93% yield at
were smoothly coupled with electron-rich (hetero)- 1008C under an argon atmosphere (Table 1, entry 4).
arenes. This strategy has also been successfully em- The reaction was less efficient when other phosphorus
ployed for the sulfenylation of indoles, and selectively reagents were used (Table 1, entries 5–7). Replace-
afforded various 3-arylthioindoles which can be used
as potent drugs for cancer, HIV, heart disease and al-
lergies.[9] Thiols,[10] disulfides[11] and other activated
sulfur reagents[12] were able to couple with indoles
catalyzed by metals such as copper, iron, ruthenium
and palladium salts.
Due to the low threshold residual tolerance of
metals for pharmaceuticals, it is highly desirable to nates.
Scheme 1. Sulfenylation of indoles with aryl sodium sulfi-
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Iodine-Catalyzed Regioselective Sulfenylation of Indoles
Table 1. Optimization of the reaction conditions.[a]
Table 2. Sulfenylation of 1a with various sodium sulfinates.[a]
[a]
Conditions: 1a (0.5 mmol), 2a (1 mmol), catalyst
(10 mol%), reagent (2 equiv.), oxidant (3 equiv.), solvent
(1.2 mL), 1008C, Ar, 15 h; R1=(C2H5O)2POH, R2=
(PhO)3P, R3 =PhPO(OH)H, R4=PhPO(OH)2.
GC yield.
808C.
[b]
[a]
[c]
Conditions: 1a (0.5 mmol), 2 (1.0 mmol), I2 (0.05 mmol),
[d]
DMSO (1.5 mmol), diethyl phosphite (2 equiv.), anisole
Under air.
(1.2 mL), 1008C, argon, 15 h.
Isolated yield.
[b]
ment of DMSO with other oxidants such as oxygen,
peroxide and phenyl sulfoxide all decreased the reac-
tion yield (Table 1, entries 8–10). Other organic sol- yields, respectively (entries 7–9). It should be noted
vents such as dioxane, diglyme, NMP and toluene that no cleavage of the carbon-halogen bond was ob-
were less effective for this kind of reaction (Table 1, served. Arylsulfinic acid sodium salts bearing elec-
entries 11–14). Diethyl phosphite as additive and I2 tron-withdrawing trifluoromethyl and trifluorome-
are both necessary, and a very low yield was obtained thoxy groups reacted smoothly to give the products in
when the reaction was carried out in their absence high yields (entries 10 and 11). More bulky substrates
(Table 1, entries 15 and 16). Lower yields were ob- such as 2-naphthylsulfinic acid sodium salt (2l) also
tained when the reaction was run at 808C or in air efficiently reacted with 1a and gave the product in
(Table 1, entries 17 and 18). It should be noted that 85% yield (entry 12). To our delight, less reactive
only
a
trace amount of (methoxyphenyl)- sodium methanesulfinate (2m) also could couple with
ACHTUNGTRENNUNG(phenyl)sulfane by-product was observed when ani- indole to give the desired product in 65% yield
sole was used as solvent.
(entry 13).
With the optimized reaction conditions established,
The influence of the substituents on the indole
the substrate scope with respect to sodium sulfinates moiety was also evaluated and the results are present-
was examined, and the results are summarized in ed in Table 3. Indoles with a methyl group at C-2, C-4
Table 2. Arylsulfinic acid sodium salts with alkyl sub- and C-7 all smoothly coupled with 2a and gave the
stituents smoothly reacted with indole to give the cor- desired products in 87%, 89% and 86% yields, respec-
responding 3-arylthioindoles in good to high yields tively (entries 1–3). The reaction yields decreased dra-
(entries 2–5). Halogen functional groups such as matically when halogen groups were presented at the
fluoro, chloro and bromo were well tolerated under C-5 position in indole (entries 5–7). Better yields
the optimized reaction conditions, and the sulfenyla- were obtained if the halogen subsituents were located
tion products were obtained in 86%, 93% and 91% at C-6 (entries 8 and 9). Under the optimized reaction
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Fuhong Xiao et al.
Table 3. Sulfenylation of various indoles with 2a.[a]
[a]
Conditions: 1 (0.5 mmol), 2a (1.0 mmol), I2 (0.05 mmol),
DMSO (1.5 mmol), diethyl phosphite (2 equiv.), anisole
(1.2 mL), 1008C, argon, 15 h.
[b]
Isolated yield.
Scheme 2. Control experiments under various conditions.
conditions, the direct sulfenylation occurred exclusive-
ly at the C-3 position of the indole moiety. When the
C-3 position of indole was occupied by a methyl
group, no C-2 sulfenylation product was observed in the presence of I2 and diethyl phosphite, which is
(entry 10). Protected 1-methylindole also could similar to Pinnick and co-workersꢀ observations.[21] No
couple with 2a and gave the desired product in 82% desired product was obtained when 6a was treated
yield (entry 11).
with indole (Scheme 2, d). Further treatment of 1,2-
To gather more information, some control experi- di-p-tolyldisulfane (4b) with indole afforded the de-
ments were set up under various reaction conditions. sired product 3b in 45% yield and bis-subsituted by-
No reaction occurred upon treatment of sodium ben- product 3b’ in 17% yield (Scheme 2, e). This means
zenesulfinate (2a) with iodine in the absence of dieth- that the direct sulfenylation reaction of indole with
yl phosphite (Scheme 2, a). S-Phenyl phosphoro- 1,2-di-p-tolyldisulfane showed poor selectivity. During
thioate 6a was obtained as the major product when the optimization of the reaction, a large amount of di-
the reaction was carried out in the absence of I2 and phenylsulfane was observed when phenyl sulfoxide
DMSO (Scheme 2, b). Treatment of 2a with I2 under was used as the oxidant (Table 1, entry 10). This
similar conditions without DMSO for 12 h gave the means DMSO (similar to phenyl sulfoxide) was re-
1,2-diphenyldisulfane (4a), S-phenyl benzenesulfono- duced to dimethylsulfane and acted as an oxidant.
thioate (5a) and S-phenyl phosphorothioate (6a) in Based on these observations, a plausible mechanism
30%, 5% and 3% GC yields, respectively (Scheme 2, to rationalize this transformation is illustrated in
c). This means that 1,2-diphenyldisulfane (4a) was Scheme 3. Initially, 1,2-diphenyldisulfane (4a) is gen-
generated from sodium benzenesulfinate (2a) possi- erated from 2a in the presence of I2 and diethyl phos-
blely via intermediate S-phenyl phosphorothioate (6a) phite.[21] Then 4a reacts with I2 to form an electrophil-
366
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Adv. Synth. Catal. 2014, 356, 364 – 368

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Iodine-Catalyzed Regioselective Sulfenylation of Indoles
acetate=9:1) to give 3a as white solid; yield: 95.6 mg
(85%).
Acknowledgements
This work was supported by the National Natural Science
Foundation of China (21172185, 21372187), the Hunan Pro-
vincial Natural Science Foundation of China (11JJ1003,
12JJ7002), the New Century Excellent Talents in University
from Ministry of Education of China (NCET-11-0974) and
the Hunan Provincial Innovative Foundation for Postgradu-
ates (CX2012B250).
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