Sulfenylation of nitroalkanes and hydroxyaryls

Article abstract of DOI:10.1016/j.tetlet.2011.10.053

The sulfenylation of nitroalkanes and hydroxyaryls in DMSO using aryl disulfides as sulfenylating reagents was studied. The corresponding arylthionitroalkanes and arylthiohydroxyaryls were obtained in moderate to good yields in very mild conditions, thus improving the reported procedures for the synthesis of these compounds.

Full text of DOI:10.1016/j.tetlet.2011.10.053

Tetrahedron Letters 52 (2011) 7061–7063
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Sulfenylation of nitroalkanes and hydroxyaryls
⇑
Guillermo A. Blanco, Maria T. Baumgartner
INFIQC, Dpto. Química Orgánica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Ciudad Universitaria, Córdoba 5000, Argentina
a r t i c l e i n f o
a b s t r a c t
Article history:
The sulfenylation of nitroalkanes and hydroxyaryls in DMSO using aryl disulfides as sulfenylating
reagents was studied. The corresponding arylthionitroalkanes and arylthiohydroxyaryls were obtained
in moderate to good yields in very mild conditions, thus improving the reported procedures for the syn-
thesis of these compounds.
Received 25 August 2011
Revised 6 October 2011
Accepted 10 October 2011
Available online 20 October 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Sulfenylation
Disulfides
Nitroalkanes
Hydroxyaryls
Dimethylsulfoxide
O
C
The sulfur atom behaves as an electrophile when it is present in a
species in which it has electron deficiency. These type of compounds
are widely used as sulfur transfer agents to introduce a sulfur moiety
into nucleophilic species like ketones, 1,3-diketones, b-keto esters,
amides, etc. in basic conditions. There has been developed a wide
range of sulfur transfer agents, some of them are disulfides,1 sulfenyl
chloride,2 methylmethanethiosulfate,3 sulfenamides,4 N-phen-
ylthiocaprolactam,5 and N-phenylthiosuccinimide6 (Scheme 1).
However, disulfides are often preferred because of their stability,
low cost, and commercial availability.
O
C
R'
SR''
+
R'
X
SR''
R
R
R' = Alkoxy, alkyl, aryl
R'' = Alkyl, Ph
O
O
X =
Cl, SO2CH3, N
,
,
N
SR'',
N
O
Many sulfur-containing compounds are particularly useful as
synthetic intermediates and have biological activity. For instance,
Scheme 1. Common sulfur transfer agents.
a
-sulfenylated carbonyl species are especially interesting since
they can be used in numerous organic transformations,4 thus, many
these procedures are highly complex and require non commercial,
unstable starting materials.
protocols to obtain these species have been widely studied.1–6 Re-
cently, the enantioselective synthesis of
a-sulfenylated carbonyl
compounds has received much attention.7 Many studies concerning
the sulfenylation of other species like indoles,8,9 phosphonates,10
b-amino esters,11 and nitriles12 have also been developed.
PhSCl
NaCH2NO2
ð1Þ
PhS CH2NO2
THF/EtOH
To our knowledge, no research has been reported about the
sulfenylation of nitroalkanes with stable commercial sulfenylating
reagents as disulfides. As it was said, these latter compounds are
desirable but constitute weaker electrophiles than the other sulfur
transfer agents mentioned.4 Some sulfenylated nitroalkanes are
important synthetic intermediates.13
In the case of hydroxyaryls, the electrophilic reaction of a hin-
dered phenol with sulfenyl chloride to give the corresponding aryl-
thiolated phenol in good yie1d was reported.16 Additionally, a
series of 4-arylthio-2,6-dialkylphenols have been prepared with
aryl disulfides in basic media, with long periods of reaction at high
temperatures.17 However, the only report about the synthesis of
On the other hand, less research has been reported on the sulf-
enylation of nitroalkanes and hydroxyaryls. For instance, the prep-
aration of phenylthionitromethane was carried out by the reaction
of nitromethane anion with sulfenyl chloride (Eq. 1),13 from the
nitration of the dianion derived from phenylthio acetic acid,14 or
from ethyl nitroacetate and N-phenylthio morpholine.15 All of
⇑
Corresponding author. Tel.: +54 351 4334170/73; fax: +54 351 4333030.
E-mail addresses: tere@mail.fcq.unc.edu.ar, tere@fcq.unc.edu.ar (M.T. Baumgart-
ner).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.10.053

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G. A. Blanco, M. T. Baumgartner / Tetrahedron Letters 52 (2011) 7061–7063
1-sulfenylated-2-naphthols involves a different protocol in which
these compounds are obtained in moderate yields with a vana-
dium-catalyzed reaction, using thiols as sulfenylating reagents.9
These products may be used as agricultural chemicals for powdery
mildew.9
S
CH2NO2
10
Figure 1. 2-Naphthylthionitromethane.
In this work, a sulfenylation protocol in mild conditions is de-
scribed for nitroalkanes and hydroxyaryls with stable and cheap
commercial reagents as disulfides.
Table 1 summarizes the results obtained from the study of the
reactions of nitroalkanes and disulfides in basic media. Firstly,
the reaction of nitromethane anion formed by deprotonation of
nitromethane (1) with potassium t-butoxide, and diphenyldisul-
fide (2) was analyzed. When a mixture of 1, 2, and base (ratio
10:1:10.5) was allowed to react for 2 h in DMSO, phenylthioni-
tromethane (3) in 82% yield was obtained (Eq. 2) (Table 1, entry 1).
In order to explore the use of disulfides as sulfenylating reagents
for nitroalkanes, the behavior of other nitroalkanes in this system
was also examined. Therefore, under analogous conditions, the
reactions of 1-nitropropane (11) with disulfides 2, 5, and 6 were
tested, in which the corresponding products (12–14) were obtained
with moderate to good yields (Eq. 2) (Table 1, entries 11–13).
However, the reaction of 2-nitropropane with disulfide 2 affor-
ded a very low yield (approx. 10%) of 1-phenylthio-2-nitropropane,
characterized by CG–MS.
R
S
1) DMSO, KOC(CH3)3
CHNO2
ð2Þ
X
S
+ R CH2NO2
+ X
SH
X
2) HCl
2
On the other hand, 1-nitropentane (15) reacted with disulfide 2
affording 1-phenylthio-1-nitropentane (16) in 99% yield (Table 1,
entry 14).
In all reactions the thiol formed (Eq. 2) dimerized to the corre-
sponding disulfide after the work-up. This latter product may be
recovered easily, for further use, in the purification process. The
equivalents of disulfide recovered in each reaction are also in
agreement with the expected values taking into account the equiv-
alents of disulfide coming from thiol dimerization and unreacted
disulfide.
The effective sulfenylation of nitroalkanes with disulfides in ba-
sic media may be possible because of the enhanced nucleophilicity
of nitroanions in DMSO compared with other solvents like water or
alcohols.18 This solvent is not much desirable in large-scale syn-
thetic procedures, however, it can be removed easily from the reac-
tion crude since it stays in the water phase in a dichloromethane/
water extraction.
Thus, this is the first study about the sulfenylation of nitroalk-
anes with disulfides with synthetic purpose, which shows impor-
tant advantages from the procedures reported for the synthesis
of sulfenylated nitroalkanes.
In order to improve the synthetic conditions of the reaction, the
nitroalkane concentration was decreased by a factor of 5. Thus,
when a mixture of 1, 2, and base (ratio 2:1:2.5) was allowed to re-
act for 22 h, a 45% yield of product 3 was obtained (Table 1, entry
2). In addition, di-(phenythio)methane (4) was observed in these
conditions in 46% yield. Product 4 may be formed by disubstitution
of nitromethane anion with subsequent loss of the nitro group.
With the aim of improving product yield, the effect of the reac-
tion time (Table 1, entries 3–5) was analyzed. The best result, 65%
yield of 3, was obtained in 5 h, product 4 not being observed.
When the nitroalkane concentration was decreased even more
to a ratio 1:2:base of 1:1:1, a 30% yield of product 3 was observed
in a 5 h reaction.
The procedure was extended to other disulfides, thus with di-(p-
methylphenyl)disulfide (5) and di-(p-chlorophenyl) disulfide (6)
the corresponding products, p-methyl-phenylthionitromethane
(7) and p-chlorophenylthio-nitromethane (8), were obtained with
yields of 80% and 55%, respectively (Eq. 2) (Table 1, entries 7 and 9).
Additionally, di-(2-naphthyl)disulfide (9) reacted with 1 (ratio
1:9:base = 10:1:10.8) affording 2-naphthylthionitromethane (10)
in 84% yield (Fig. 1).
Table 1
Reactions of nitroalkanes with disulfides in DMSO
Entry
Nitroalkane RCH2NO2
Disulfide (p-X-C6H4S)2
2, X = H
Ratio nitroalkane:disulfide
Reaction time (h)
Product p-X-C6H4S–CH(R)NO2
3, R = H, X = H
Yielda (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
1, R = H
10:1b
2:1d
2:1
2:1
2:1
1:1
10:1
2:1
10:1
2:1
10:1
10:1
10:1
2:1
2
82c
45e
51e
65e
47e
30e
80c
46e
55c
45e
46c
71c
84c
99c
22
8½
5
2
5
2
5
2
5
2
2
2
5
5, CH3
6, Cl
7, R = H, X = CH3
8, R = H, X = Cl
11, R = CH2CH3
2, X = H
5, CH3
6, Cl
12, R = CH2CH3, X = H
13, R = CH2CH3, X = CH3
14, R = CH2CH3, X = Cl
16, R = (CH2)3CH3, X = H
15, R = (CH2)3CH3
2, X = H
a
b
c
Yields refer to initial moles of disulfide.
[1] = 0.82 M, [2] = 0.08 M.
Quantified by gas chromatography with the internal standard method.
[1] = 0.16 M, [2] = 0.08 M.
d
e
Isolated yield.

G. A. Blanco, M. T. Baumgartner / Tetrahedron Letters 52 (2011) 7061–7063
7063
Table 2
Reactions of 2-naphthol (17) with 2 in DMSO
Entry
Ratio 2:17
Reaction time (h)
Yielda of 18 (%)
S
1
2
3
1:6b
1:2c
1:2
2
2
7
75
56
72
OH
OH
S
a
Determined by gas chromatography using the internal standard method and
19
20
refer to initial moles of disulfide.
b
[2] = 0.08 M, [17] = 0.48 M.
c
[2] = 0.08 M, [17] = 0.16 M.
Figure 2. 1-(2-Naphthylthio)-2-naphthol and 1-phenylthio-9-phenanthrol.
The use of disulfides as sulfenylating reagents was also tested
with hydroxyaryls. The reaction of 2-naphthol (17) and disulfide
2 (ratio 2:17 = 1:6), in the presence of potassium t-butoxide, affor-
ded 1-phenylthio-2-naphthol (18) in 75% yield (Eq. 3) (Table 2, en-
try 1). When a smaller concentration of 17 was used (ratio
2:17 = 1:2), product 18 was obtained with yields of 56% and 72%
at different reaction times, 2 and 7 h, respectively (Table 2, entries
2 and 3).
Supplementary data
Supplementary data (general methods, materials, experimental
procedures and 1H NMR, 13C NMR and MS of products 4, 7, 8, 10,
12, 13, 14, 16, 18, 19 and 20) associated with this article can be
found, in the online version, at doi:10.1016/j.tetlet.2011.10.053.
References and notes
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ð3Þ
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Acknowledgments
This work was supported by Agencia Córdoba Ciencia (ACC),
Consejo Nacional de Investigaciones Científicas y Técnicas (CONI-
CET) and Secretaría de Ciencia y Tecnología (SECyT), Universidad
Nacional de Córdoba, Argentina. G.A.B. thanks CONICET for the
award of a fellowship.