Arylsulfenylation of heterocyclic compounds with arylsulfenamides in the presence of phosphorus(V) oxochloride

Article abstract of DOI:10.1007/s10593-010-0629-4

The electrophilic sulfenylation of a series of indoles and pyrroles with arylsulfenamides in the presence of phophorus(V) oxohalide has been studied. It has been shown that arylsulfenylation of indoles led to products with substitution at position 3, while in the case of pyrrole it occurred at position 2.

Full text of DOI:10.1007/s10593-010-0629-4

Chemistry of Heterocyclic Compounds, Vol. 46, No. 9, 2010
ARYLSULFENYLATION OF HETEROCYCLIC
COMPOUNDS WITH ARYLSULFENAMIDES IN THE
PRESENCE OF PHOSPHORUS(V) OXOCHLORIDE*
R. L. Antipin1**, A. N. Chernysheva1, E. K. Beloglazkina1, and N. V. Zyk1
The electrophilic sulfenylation of a series of indoles and pyrroles with arylsulfenamides in the presence
of phophorus(V) oxohalide has been studied. It has been shown that arylsulfenylation of indoles led to
products with substitution at position 3, while in the case of pyrrole it occurred at position 2.
Keywords: indoles, pyrroles, electrophilic substitution, sulfenylation.
Sulfur-containing indoles are widely known compounds with a variety of biological activity. Indoles
with substitutions in position 3 are effective in the treatment of a wide range of illnesses, such as obesity [1],
oncological diseases [2], diseases of the heart and bacterial infections [3]. They are also starting materials in the
synthesis of preparations with antiHiv activity [4], inhibitors of 5-lipoxygenases [5], and in addition they are
used in the synthesis of organic compounds possessing nonlinear optical properties [6].
Arylsulfenyl halides are usually used for sulfenylation of five-membered aromatic heterocyclic
compounds [7-12]. However the basic problem with their use is the instability of the arylsulfenyl halides starting
materials.
We have shown previously that the reactions of arylsulfenamides with alkenes, alkynes, and dienes in
the presence of phosphorus(V) and sulfur(IV) oxohalides leads to the formation of β-halosulfides in quantitative
yields. The mechanism of the reaction includes preliminary coordination of the phosphorus atom to the sulfur
atom of the sulfenamide starting material [13, 14]. In the present work we report a simple method for the
sulfenylation of a series of indoles and pyrroles with arylsulfenamides 1-3 in the presence of a phosphorus(V)
oxohalide.
O
+
–
Ar
S
ArS NR2 + POCl3
P
Hal
Hal
Hal
NR2
1–3
A
1 Ar = Ph, NR2 = NEt2; 2 Ar = 2-O2NC6H4, NR2 = N(CH2CH2)O;
3 Ar = 4-O2NC6H4, NR2 = N(CH2CH2)O
_______
* Presented to Academician N. D. Zefirov by his grateful colleagues to celebrate his 75th jubilee.
** To whom correspondence should be addressed, e-mail: roman.antipin@gmail.com.
1M. V. Lomonosov Moscow State University, Moscow 119992, Russia.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, 1329-1334, September, 2010.
Original article submitted March 17, 2010.
0009-3122/10/4609-1071©2010 Springer Science+Business Media, Inc.
1071

We have shown previously that the interaction of arylsulfenamides with phosphorus(V) or sulfur(IV)
oxohalides led to the formation not of arylsulfenhalides but to the donor-acceptor complex A which is the
immediate electrophilic reagent [14].
In the cases of interaction with indoles or pyrroles intermediate A may react to form the corresponding
sulfides:
SAr
R = H, R1 = Me
R1
R
NR
R
R1
4a–c
5a–c
N
H
R = Me, R1 = H
4–6
A
SAr
NR1
R
R = R1 = Me
R1
N
SAr
6a–c
46 a Ar = Ph, b Ar = o-O2NC6H4, c Ar = p-O2NC6H4
As a result of the interaction of indoles and pyrroles with arylsulfenamides in the presence of
phosphorus oxohalides a series of unsymmetrical sulfides were obtained. The results of the sulfenylation
reactions are summarized in Table 1.
TABLE 1. Results of Sulfenylation of Indoles and Pyrroles with
Arylsulfenamides in the Presence of Phosphorus(V) Oxohalide
Found, %
Calculated, %
——————
Sulfen-
amide
Reaction
product
Empirical
formula
mp,
°C
Yield,
%
Substrate
C
H
N
4
1
2
3
1
2
3
1
2
3
1
2
3
4a
С15H13NS
75.02 5.46
75.31 5.46
63.19 4.33
63.38 4.23
63.30 4.28
63.38 4.23
75.00 5.47
75.31 5.46
63.40 4.23
63.38 4.23
63.20 4.16
63.38 4.23
5.65
5.86
9.80
9.86
9.77
9.86
5.77
5.86
9.86
9.86
9.78
9.86
147
153
133
98
61
86
97
96
95
99
81
78
79
97
96
99
4b
4c
С15H12N2O2S
С15H12N2O2S
С15H13NS
5
6
7
5a
5b
5c
С15H12N2O2S
С15H12N2O2S
C6H15NS
125
113
—
6a
—
—
—
—
—
—
—
—
—
—
—
—
6b
6c
C16H14N2O2S
C16H14N2O2S
C11H11NS
165
—
7a +7d
7b
7c
—
C11H10N2O2S
C11H10N2O2S
56.49 4.37
56.47 4.35
56.30 4.29
56.47 4.35
11.80
11.97
11.81
11.97
—
79
1072

1073

As expected, interactions of complex A with indoles unsubstituted at position 3 gave compounds
substituted at this position. At the same time indoles substituted at position 3 formed the corresponding
2-indolyl aryl sulfides [15-17]. The corresponding indolylaryl sulfides were obtained with yields from good to
quantitative.
Reactions with 2,3-disubstituted indoles led to products of N-sulfenylation, which were formed in much
smaller yields than in the case of 2- or 3-monosubstituted indoles.
Arylsulfenylation of N-methylpyrrole led to the formation of 2-arylthiopyrroles in quantitative yield.
However in the case of the reaction of N-methylpyrrole with arylsulfenamide 1 a mixture of 2- and 3-substituted
pyrroles 7a and 7d was obtained in a ratio of 2:3.
Thus the proposed method of sulfenylation of indoles and pyrroles with arylsulfenamides in the
presence of phosphorus oxohalides is a suitable simple preparative method foe the preparation of the required
compounds in high yields. In most cases sulfenylation led to the formation of just one regioisomer. In the course
of investigating the reaction mixtures formation of by-products was not observed which makes possible the use
of this method for the sulfenylation of a range of nitrogen-containing five-membered heterocyclic compounds.
N Me
SAr
7
A
+
SAr
N
N
Me
7a–c
Me
7d
7 a,d Ar = Ph, b Ar = o-O2NC6H4, c Ar = p-O2NC6H4
TABLE 3. 1H NMR Spectra of the Products of Sulfenylation of N-Methyl-
pyrrole
Chemical shifts, , ppm (J, Hz)
Com-
pound
H-3 (1Н, d,
J = 2.8)
NR
H-2
—
H-4 (1Н)
H-5 (1Н, d)
Ar
(3Н, s)
7a
3.64
6.12
6.10 (dd,
J = 2.8,
J = 3.1)
6.80 (J = 3.0)
7.10-7.52
(5H, m)
7d
7b
3.64
3.75
6.05
(1Н, d, s)
—
6.10 (d,
J = 2.8)
6.84 (J = 2.8)
6.90 (J = 3.1)
7.10-7.55
(5H, m)
—
6.08
6.12 (dd,
J = 2.8,
J = 3.1)
7.05-7.90
(4H, m)
7c
3.74
—
6.05
6.14 (dd,
J = 2.8,
J = 2.9)
6.87 (J = 2.9)
7.18 (2Н, d,
J = 9.0);
8.00 (2Н, d,
J = 9.0 )
TABLE 4. 13C NMR Spectra of Products of Sulfenylation of Indoles and
N-Methylpyrrole
Compound
Chemical shifts, , ppm
4b
4с
5a
7c
135.8, 133.2, 129.9, 125.8, 124.7, 123.0, 121.0, 119.7, 115.6, 110.0
149.7, 124.9, 124.0, 122.8, 121.2, 118.5, 111.0, 37.0
137.5, 137.0, 129.5, 129.0, 127.0, 126.0, 124.0, 121.5, 120.0, 111.0, 41.0
134.0, 129.5, 127.5, 127.0, 126.5, 125.9, 125.0, 120.8, 109.0, 34.0
1074

EXPERIMENTAL
1H and 13C NMR spectra were recorded on a Bruker AVANCE (400 and 100 MHz, respectively) in
CDCl3 as solvent and internal standard. Elemental analyzes of the synthesized compounds were carried on a
Carlo-Erba CHN-analyzer.
General Method. To a solution of heterocyclic compound (2.5 mmol) in absolute methylene chloride
(10 ml), a solution of arylsulfenamide 1-3 (2.5 mmol) in CH2Cl2 was added at room temperature. The mixture
formed was stirred for 10 min and then a solution of phosphorus(V) oxochloride (2.5 mmol) in the same solvent
(10 ml) was added and stirring was continued for 4 h. The solution was passed through a layer of silica gel
(height 3 cm). After removing the solvent in vacuum, solid crystalline substances were obtained, the products of
the electrophilic substitution.
NMR swpectroscopic data for the compounds synthesized are given in Tables 2-4.
This work was carried out with financial support from the RFFI (project 08-03-00707).
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