Iodine-catalyzed regioselective sulfenylation of indoles with sulfonyl hydrazides

Article abstract of DOI:10.1002/anie.201301437

New S in town: Sulfonyl hydrazides smoothly undergo sulfenylation with indoles in the presence of 10 mol % I₂ to give structurally diverse indole thioethers in moderate to excellent yields with extremely high regioselectivity. This study paves the way for the use of sulfonyl hydrazides as unique sulfur electrophiles in chemical synthesis. Copyright

Full text of DOI:10.1002/anie.201301437

Angewandte
Chemie
DOI: 10.1002/anie.201301437
Synthetic Methods
Iodine-Catalyzed Regioselective Sulfenylation of Indoles with Sulfonyl
Hydrazides**
Fu-Lai Yang and Shi-Kai Tian*
The indole moiety is present in many biologically relevant
molecules, and consequently, much attention has been paid to
the synthesis of substituted indoles through either construc-
tion or modification of indole rings.[1] The electron-rich nature
of indole rings enable them to undergo direct carbon–
hydrogen bond functionalization with electrophiles to form
carbon–carbon and carbon–heteroatom bonds. In this regard,
the sulfenylation of indoles has been developed for the
synthesis of indole thioethers, some of which serve as potent
agents to treat cancer[2] and allergies,[3] from sulfenylating
agents such as sulfenyl halides,[4] N-thioimides,[5] sulfonium
salts,[6] thiols,[7] disulfides,[8] quinone mono-O,S-acetals,[9] and
arylsulfonyl chlorides.[10] Nevertheless, many of these sulfe-
nylating agents are unstable to air and moisture, are
expensive, or possess unpleasant odors. Moreover, previously
reported sulfenylation reactions of indoles frequently require
excess sulfenylating agents, excess additives, or high temper-
ature, suffer from a narrow substrate scope, or yield by-
products unfriendly to the environment. To address such
issues, it is highly desirable to explore new sulfenylating
agents and reaction conditions for the sulfenylation of indoles.
Sulfonyl hydrazides are readily accessible and exist as
stable solids, and they have been widely employed to form
hydrazones and heterocycles which have versatile applica-
tions.[11] Moreover, sulfonyl hydrazides can be utilized as
reductants[12] and sulfonyl sources[13] through the cleavage of
their sulfur–nitrogen bonds, and very recently as aryl sources
through the cleavage of their carbon–sulfur bonds.[14] In sharp
contrast, little has been published on the cleavage of the
sulfur–oxygen bonds of sulfonyl hydrazides for chemical
synthesis. In this context, we envisioned that the reductive
nature of the NHNH2 group in the sulfonyl hydrazide might
be utilized to remove the two oxygen atoms of the sulfonyl
group under certain reaction conditions, and consequently,
sulfonyl hydrazides could serve as effective sulfur electro-
philes for the sulfenylation of indoles, wherein water and
molecular nitrogen are expected to be generated as environ-
mentally benign by-products [Eq. (1)].
The sulfenylation of indole (1a) with p-toluenesulfonyl
hydrazide (2a; 1.2 equiv) was selected as the model reaction
to test our hypothesis. Initially, the reaction did not occur in
ethanol in the presence of 10 mol% iodine and open to air at
room temperature. To our delight, heating the mixture at
708C led to the formation of 3-(p-tolylthio)-1H-indole (3a) in
86% yield as a single regioisomer. For comparison, the
reaction was performed under nitrogen and gave 3a in
a slightly lower yield (81%). Reducing the catalyst loading to
5 mol% resulted in a much lower yield (52%). A number of
common solvents were examined, but no better yield was
obtained.[15] Moreover, replacing iodine with N-iodosuccin-
imide (NIS) decreased the yield to 41%,[16] and even no
desired product was obtained when replacing iodine with N-
bromosuccinimide (NBS), N-chlorosuccinimide (NCS), or
Bu4NI.
In the presence of 10 mol% iodine, a range of aryl-,
heteroaryl-, and alkylsulfonyl hydrazides smoothly under-
went sulfenylation with indoles in ethanol to give structurally
diverse thioethers in moderate to excellent yields with
extremely high regioselectivity (Table 1).[17] In general, the
sulfenylation reaction took place at the C3 position of the
indole ring (Table 1, entries 1–25). However, the C2 position
of the indole ring was the reaction site of choice when the C3
position was occupied by a substituent (Table 1, entries 26–
28). Notably, the reaction tolerated a variety of functional
groups such as alkoxy, fluoro, chloro, bromo, iodo, nitro, ester,
and nitrile. In a few cases sulfonyl hydrazides decomposed
significantly because of slow sulfenylation (see below), and to
our delight, acceptable yields were obtained by increasing the
amounts of sulfonyl hydrazides from 1.2 to 2 equivalents
(Table 1, entries 18, 23, and 28).
[*] F.-L. Yang, Prof. Dr. S.-K. Tian
Department of Chemistry
University of Science and Technology of China
Hefei, Anhui 230026 (China)
E-mail: tiansk@ustc.edu.cn
Prof. Dr. S.-K. Tian
While the decomposition of sulfonyl hydrazides pro-
ceeded very slowly in ethanol at 708C,[13f] it was dramatically
accelerated by iodine. Treatment of 2a with 10 mol% iodine
gave the sulfonothioate 5a and disulfide 6a in 44 and 33%
yields, respectively (Scheme 1). Moreover, 5a could be
reduced to give 6a under the same reaction conditions but
in only 15% yield, which suggested that there was at least one
more intermediate leading to 6a. To gain more insights, we
carried out electron-spray ionization (ESI) mass spectromet-
ric analysis of the iodine-catalyzed reaction mixture of 1a and
Key Laboratory of Synthetic Chemistry of Natural Substances,
Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, Shanghai 200032 (China)
[**] We are grateful for the financial support from the National Natural
Science Foundation of China (21232007 and 21172206), the
National Basic Research Program of China (973 Program
2010CB833300), and the Program for Changjiang Scholars and
Innovative Research Team in University (IRT1189).
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201301437.
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Table 1: Iodine-catalyzed regioselective sulfenylation of indoles with
Table 2: Reactions of indole (1a) with the four decomposition products
of sulfonyl hydrazide 2a.[a]
sulfonyl hydrazides.[a,b]
Entry
1 (R1)
2 (R2)
3 or 4
Yield [%][c]
1
2
3
4
5
6
7
8
1a (H)
1a (H)
1a (H)
1a (H)
1a (H)
1a (H)
1a (H)
1a (H)
1a (H)
1a (H)
1a (H)
1a (H)
1a (H)
1a (H)
1a (H)
1a (H)
1b (1-Me)
1c (2-Me)
1d (2-Ph)
1e (4-Br)
1 f (5-OMe)
1g (5-Br)
1h (5-NO2)
1i (5-CO2Me)
1j (6-Cl)
1k (3-Me)
1l (3-CHPh2)
1m (3-CH2CN)
2a (4-MeC6H4)
2b (Ph)
3a
3b
3c
3d
3e
3 f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
3r
84
79
75
72
88
82
81
89
90
85
63
90
66
69
58
67
88
67
87
82
80
89
59
70
89
91
76
56
Entry
S source
Yield [%][b]
3a
9a
10a
5a
6a
2c (4-MeOC6H4)
2d (4-FC6H4)
2e (4-ClC6H4)
2 f (4-BrC6H4)
2g (4-IC6H4)
2h (4-O2NC6H4)
2i (3-O2NC6H4)
2j (2,5-Cl2C6H3)
2k (2,4,6-Me3C6H2)
2l (2-naphthyl)
2m (2-thienyl)
2n (Me)
2o [(CH2)7Me]
2p (CH2Ph)
2b (Ph)
2b (Ph)
2b (Ph)
2b (Ph)
2b (Ph)
2b (Ph)
2b (Ph)
2b (Ph)
2b (Ph)
2b (Ph)
2b (Ph)
1
2
3
4
5a
6a
7a
8a
48
29
28
62
20
–
12
14
–
–
11
–
–
–
14
–
–
–
trace
–
[a] Reaction conditions: indole (1a) (0.20 mmol), S source (1 equiv),
iodine (10 mol%), ethanol (0.5 mL), 708C, open to air, 5 h. [b] Yield of
isolated product.
9
10
11
12
13
14
15
16
17
18[d]
19
20
21
22
23[d]
24
25
26
27
28[d]
dithioether 9a and sulfone 10a, which were not detected in
the corresponding iodine-catalyzed sulfenylation reaction.
Thus, it is unlikely for these decomposition products of the
sulfonyl hydrazide to serve as major intermediates for the
formation of the corresponding indole thioether.
Furthermore, it is unlikely for an indolyl sulfone to serve
as an intermediate in the sulfenylation reaction. As shown in
Equation (2), our reaction conditions failed to reduce the
3s
3t
3u
3v
3w
3x
3y
4a
4b
4c
2b (Ph)
[a] Reaction conditions: indole 1 (0.40 mmol), sulfonyl hydrazide 2
(0.48 mmol), iodine (10 mol%), ethanol (1.0 mL), 708C, open to air, 5 h.
[b] No regioisomer was detected by 1H NMR analysis. [c] Yield of
isolated product. [d] 0.80 mmol of sulfonyl hydrazide 2 was used and the
reaction was run for 8 h.
sulfone 11a to give 3a. This result suggests that the removal of
the two oxygen atoms from the sulfonyl group occurs prior to
the carbon–sulfur bond formation between the indole and the
sulfonyl hydrazide.
The reaction mixture of 1a with 2a became weakly acidic
(pH 4–5) as determined by using pH paper. Moreover, the
reaction conditions allowed N-Boc-N’-sulfonylhydrazine
(12a) to be transformed into 3a in 72% yield by taking
advantage of the weak acidity to remove the Boc group
[Eq. (3)]. In sharp contrast, no reaction was observed with N-
Scheme 1. Decomposition of the sulfonyl hydrazide 2a.
2a, and tentatively identified two minor decomposition
products of 2a, 4-MeC6H4SO2H (7a), and 4-MeC6H4SO2Et
(8a), according to the high-resolution mass data.[15]
benzoyl-N’-sulfonylhydrazine (13a) under the same reaction
conditions. These results suggest that the NHNH2 group is
essential for the sulfonyl hydrazide to serve as an effective
sulfenylating agent.
On the basis of the above experimental results, we
propose the major reaction pathways as depicted in
Scheme 2 for the iodine-catalyzed sulfenylation of indoles
with sulfonyl hydrazides. Stepwise removal of the hydrogen
and oxygen atoms from the SO2NHNH2 group in 2 with
iodine leads to the formation of the thiodiazonium 17,[18]
Additional experiments were carried out under the
developed reaction conditions to determine whether the
decomposition products of sulfonyl hydrazides could be
transformed into indole thioethers. As demonstrated by the
results summarized in Table 2, the four decomposition
products of 2a, 5a, 6a, 7a, and 8a, were all transformed
into 3a, albeit in much lower yields than that from the
reaction of 1a with 2a (Table 1, entry 1). Moreover, some of
these reactions gave additional by-products, such as the
2
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way for the use of sulfonyl hydrazides as unique sulfur
electrophiles in chemical synthesis.
Received: February 19, 2013
Published online: && &&, &&&&
Keywords: heterocycles · hydrazides · iodine · regioselectivity ·
.
synthetic methods
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Scheme 3. Proposed reaction pathways for the iodine-promoted
decomposition of sulfonyl hydrazides.
extrusion of molecular nitrogen gives 7,[13f] which undergoes
esterification with ethanol (solvent) under acidic conditions
to give the sulfinate ester 8. Alternatively, 7 undergoes
nucleophilic substitution with 17 (or 18) to give the sulfono-
thioate 5. Reduction of 17, 18, or 5, by ethanol/iodine gives 6.
The generation of HI and 7 as by-products in small amounts
by such a reaction pathway accounts for the weak acidity of
the reaction mixture.
In summary, we have developed an unprecedented
sulfenylation reaction of indoles with sulfonyl hydrazides
through the cleavage of sulfur–oxygen and sulfur–nitrogen
bonds. In the presence of 10 mol% iodine, a range of aryl-,
heteroaryl-, and alkylsulfonyl hydrazides smoothly under-
went sulfenylation with indoles to give structurally diverse
indole thioethers in moderate to excellent yields with
extremely high regioselectivity. The current study paves the
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[15] For details, see the Supporting Information.
[16] The reaction mixture turned purple, and it suggested that iodine
was generated from NIS.
[17] Under the same reaction conditions the reaction with pyrrole
and aniline afforded unsatisfactory yields. Moreover, no desired
reaction was observed with less reactive aromatic compounds
such as furan, phenol, and anisole.
[18] Since the reaction was not affected by the addition of a stoichio-
metric amount of 1,1-diphenylethene, a radical intermediate
might not be involved in the formation of 17.
4
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Angew. Chem. Int. Ed. 2013, 52, 1 – 5
These are not the final page numbers!

Angewandte
Chemie
Communications
Synthetic Methods
New S in town: Sulfonyl hydrazides
smoothly undergo sulfenylation with
indoles in the presence of 10 mol% I2 to
give structurally diverse indole thioethers
in moderate to excellent yields with
extremely high regioselectivity. This study
paves the way for the use of sulfonyl
hydrazides as unique sulfur electrophiles
in chemical synthesis.
F.-L. Yang, S.-K. Tian*
&&&& — &&&&
Iodine-Catalyzed Regioselective
Sulfenylation of Indoles with Sulfonyl
Hydrazides
Angew. Chem. Int. Ed. 2013, 52, 1 – 5
ꢀ 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!