Rhodium-catalyzed arylthiolation reaction of nitroalkanes, diethyl malonate, and 1,2-diphenylethanone with diaryl disulfides: Control of disfavored equilibrium reaction

Article abstract of DOI:10.1016/j.tetlet.2012.07.132

In the presence of catalytic amounts of RhH(PPh₃)₄ and 1,2-bis(diphenylphosphino)ethane (dppe), 1-nitroalkanes reacted with a diaryl disulfide giving 1-arylthio-1-nitroalkanes in air. The equilibrium to form thermodynamically disfavored products was shifted by the rhodium-catalyzed oxidation of thiols to disulfides and water. The thiolation reaction of cyclic nitroalkanes proceeded in high yields provided that suitable diaryl disulfides were employed depending on the substrate: di(p-chlorophenyl) disulfide was used for the thiolation reaction of 1-nitroalkanes, 1-nitrocyclopentane and 1-nitrocycloheptane with acidic α-protons (pK_a 16 and 17); di(p-methoxyphenyl) disulfide for 1-nitrocyclobutane and 1-nitrocyclohexane with less acidic α-protons (pK_a ca. 18). Related reactivities were observed in the thiolation reactions of malonate and 1,2-diphenylethanone.

Full text of DOI:10.1016/j.tetlet.2012.07.132

Tetrahedron Letters 53 (2012) 5729–5732
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Tetrahedron Letters
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Rhodium-catalyzed arylthiolation reaction of nitroalkanes, diethyl malonate,
and 1,2-diphenylethanone with diaryl disulfides: control of disfavored
equilibrium reaction
⇑
⇑
Mieko Arisawa , Yuri Nihei, Masahiko Yamaguchi
Department of Organic Chemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Aoba, Sendai 980-8578, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
In the presence of catalytic amounts of RhH(PPh3)4 and 1,2-bis(diphenylphosphino)ethane (dppe),
1-nitroalkanes reacted with a diaryl disulfide giving 1-arylthio-1-nitroalkanes in air. The equilibrium
to form thermodynamically disfavored products was shifted by the rhodium-catalyzed oxidation of thiols
to disulfides and water. The thiolation reaction of cyclic nitroalkanes proceeded in high yields provided
that suitable diaryl disulfides were employed depending on the substrate: di(p-chlorophenyl) disulfide
was used for the thiolation reaction of 1-nitroalkanes, 1-nitrocyclopentane and 1-nitrocycloheptane with
Received 30 June 2012
Revised 24 July 2012
Accepted 30 July 2012
Available online 25 August 2012
Keywords:
Nitroalkane
Diaryl disulfide
Rhodium catalyst
Arylthiolation
Disfavored equilibrium
acidic
clohexane with less acidic
reactions of malonate and 1,2-diphenylethanone.
a
-protons (pKa 16 and 17); di(p-methoxyphenyl) disulfide for 1-nitrocyclobutane and 1-nitrocy-
a-protons (pKa ca. 18). Related reactivities were observed in the thiolation
Ó 2012 Elsevier Ltd. All rights reserved.
1-Organothio-1-nitroalkanes are an interesting group of
synthetic intermediates having a nitro group and an arylthio group
on the same carbon atom.1 Conventional synthesis of these
compounds generally employs the substitution reaction of 1-halo-
1-nitroalkanes and 1-sulfonyl-1-nitroalkane with sulfur nucleo-
philes.2 The thiolation reaction of nitroalkanes is more convenient,
because the starting materials are readily available. Such synthesis
is less common and has been conducted using a strong base and a
highly reactive thiolating reagent such as thiohalide or thioimide.3
Recently, arylthiolation reaction of nitroalkane with diaryl
disulfides reported, however, a stoichiometric amount of t-BuOK.4
Because of the high acidity of nitroalkanes, nitroate anions are
weakly nucleophilic. In addition, as will be noted in this work,
1-arylthio-1-nitroalkanes are thermodynamically disfavored
compared with 1-nitroalkanes in the presence of arenethiols. In
the conventional synthesis, an unfavorable equilibrium to form
1-arylthio-1-nitroalkanes probably is compensated for by the
formation of stable metal halides, which are undesired inorganic
waste materials.
yet known. Described herein is the rhodium-catalyzed arylthiola-
tion reaction of nitroalkanes and diaryl disulfides without using a
base. The equilibrium of 1-nitroalkane and diaryl disulfide to form
thermodynamically disfavored 1-arylthio-1-nitroalkane and are-
nethiol is shifted by the rhodium-catalyzed oxidation of arenethiol
to diaryl disulfide, regenerating the thiolating reagent.5 The reac-
tion employs readily available disulfides as the thiolating reagent
and proceeds without using a base.6 The use of favorable combina-
tions of nitroalkanes and diaryl disulfides was found to increase
yields of the products: di(p-chlorophenyl) disulfide was used for
the thiolation reaction of 1-nitroalkanes, 1-nitrocyclopentane,
and 1-nitrocycloheptane with acidic
di(p-methoxyphenyl) disulfide for 1-nitrocyclobutane and 1-nitro-
cyclohexane with less acidic -protons (pKa ca. 18).
a-protons (pKa 16 and 17);
a
When a mixture of 1-nitrohexane 1 and di(p-chlorophenyl)
disulfide 2d (2 equiv) was stirred in N,N-dimethylacetamide
(DMA) at room temperature for 3 h in air in the presence of
RhH(PPh3)4 (5 mol %) and 1,2-bis(diphenylphosphino)ethane
(dppe, 10 mol %), 1-(p-chlorophenylthio)-1-nitrohexane 3d was
obtained in 50% yield (Table 1). The rhodium complex and dppe
were both essential for the reaction; no reaction occurred in the
absence of either substance. The yield of 3d markedly decreased
to 1% in an argon atmosphere. The reaction of 1 with di(p-
methoxyphenyl) disulfide 2a, diphenyl disulfide 2c, and di(p-tri-
fluoromethylphenyl) disulfide 2e giving the products 3a, 3c, or
3e took place with lower yields. The reaction was applied to sev-
eral 1-nitroalkanes giving the corresponding 1-(p-chlorophenyl-
thio)-1-nitroalkanes.
A catalytic method of converting nitroalkanes into 1-arylthio-1-
nitroalkanes without using a base is attractive, when a stable inex-
pensive thiolating reagent is used. Such synthesis, however, is not
⇑
Corresponding authors. Tel.: +81 22 795 6814; fax: +81 22 795 6811 (M.A.); tel.:
+81 22 795 6812; fax: +81 22 795 6811 (M.Y.).
E-mail addresses: arisawa@m.tohoku.ac.jp (M. Arisawa), yama@m.tohoku.ac.jp
(M. Yamaguchi).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.07.132

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M. Arisawa et al. / Tetrahedron Letters 53 (2012) 5729–5732
Table 1
Table 2
Reaction of diaryl disulfides and nitroalkanes
Reaction of diaryl disulfides and nitrocycloalkanes
R
X
Isolated yield (%)
n-C5H11
n-C5H11
n-C5H11
n-C5H11
n-C3H7
n-C4H9
n-C9H19
1
1
1
1
p-MeO
H
2a
2c
2d
2e
2d
2d
2d
26
3a
3c
3d
3e
31
50
14
49
50
43
Isolated yield (%)
p-Cl
p-CF3
p-Cl
p-Cl
p-Cl
a
X
Thiol pKa
5 (17.8)b
6 (16.0)b
7 (17.9)b
8 (15.8)b
MeO
Me
H
Cl
CF3
2a
2b
2c
2d
2e
8.0
8.0
7.8
7.0
6.2d
89
88
85
70
35
42
49
75
83
16
80
85
66
56
17
23, 50c
48, 66c
45, 75c
67, 80c
50, 60c
a
b
c
pKa of RS-H.8
pKa of cyclonitroalkane.9
1H NMR yield.
pKa of p-CF3C6H4S-H measured by method of Ref. 8.
d
S–H proton (pKa 7.0)8 of p-chlorobenzenethiol; 5 and 7 with less
acidic
-protons (pKa 17.8 and 17.9)9 effectively reacted with
a
di(p-methoxyphenyl) disulfide 2a and di(p-tolyl) disulfide 2b, hav-
ing stronger S–S bonds, which were related to the less acidic S–H
protons (pKa 8.0)8 of p-methoxybenzenethiol and p-toluenethiol.
The interpretation is consistent with the reaction of 1-nitrohexane
(pKa 17.0 of nitropropane)10 (Scheme 1), which reacted with 2d in
a higher yield than 2a, 2c, and 2e.
Scheme 1.
The reverse nature of the reaction was examined (Scheme 1).
The treatment of equimolar amounts of 3d and p-chlorobenzeneth-
iol 4 with the catalyst in DMA at rt for 3 h under argon gave 1 and
2d in 95% and 86% (based on 3d plus 4) yields, respectively. Com-
pound 1 was obtained in 12% yield in the absence of the rhodium
complex and dppe ligand. The results showed an unfavorable equi-
librium to form 3d from 1 and 2d. The above observation that 3d
was obtained in air may be due to the oxidation of thiol 4 to the
disulfide 2d under rhodium catalysis conditions,5 which shifted
the equilibrium to the product 3d by removing 4 from the system.7
The arylthio exchange reaction of 1-arylthio-1-nitroalkane with
disulfide also occurred. The treatment of 3d with 2a in DMA at rt
for 3 h in the presence of RhH(PPh3)4 (5 mol %) and dppe
(10 mol %) in air gave the exchanged product 3a in 34% yield. The
C–S bond of the thionitroalkane could be cleaved by the rhodium
complex.
A rhodium complex catalyzed the 1-arylthiolation reaction of
nitroalkanes with diaryl disulfides giving 1-arylthio-1-nitroalkanes
in air. The equilibrium to form thermodynamically disfavored
products was shifted by the rhodium-catalyzed oxidation of thiols
to disulfides. 1-Arylthio-1-nitroalkanes were obtained effectively
by the judicious choice of diaryl disulfide with respect to the acid-
ity of nitroalkanes. In other words, the various 1-arylthio-1-nitro-
alkanes can synthesize using 2a or 2d without using a base.
A related correlation of the reactivity of diaryl disulfides and
substrates was observed in the thiolation reaction of carbonyl
compounds. Diethyl malonate 9 (pKa 16.4)11 showed a similar
tendency to 1 (pKa ca. 17), 6 (pKa 16.0), and 8 (pKa 15.8), which
reacted effectively with di(p-chlorophenyl) disulfide 2d. When 9
and 2d (2 equiv) were reacted in DMA at rt for 6 h in air in the
presence of RhH(PPh3)4 (10 mol %) and dppe (20 mol %), diethyl
The thiolation reaction was applied to nitrocycloalkanes, in
which a notable observation was made in regard to the combina-
tion of substrates (Table 2). When nitrocyclobutane 5 was reacted
a
-(p-chlorophenylthio)malonate 10d (65%) and diethyl a,a-bis
(p-chlorophenylthio)malonate 11d (17%) were obtained. The
rhodium complex and dppe were both essential for the reaction.
The yield of 10d decreased to 1% under an argon atmosphere. It
was noted that 9 reacted less effectively with 2a, 2b, and 2c, and
no reaction occurred with di(p-cyanophenyl) disulfide 2f (Table 3).
The thiolation reaction was applied to 1,2-diphenylethanone 12
with 2a, 2b, and 2c, a-arylthionitrocyclobutanes were obtained in
yields exceeding 80%. The yield decreased to 35% using 2e. Simi-
larly, nitrocyclohexane 7 effectively reacted with 2a and 2b, but
not with 2e. In contrast, nitrocyclopentane 6 reacted with 2c and
2d giving 1-thiolated products in 75 and 83% yields, respectively,
but the yield decreased with 2a, 2b, and 2e. Nitrocycloheptane 8
reacted with 2c and 2d, but less effectively with 2a. The seven-
membered ring products were unstable particularly under acidic
conditions, and isolated yields using basic silica gel chromatogra-
phy and reverse phase chromatography decreased when compared
with the crude NMR yields. Although the reaction of dibutyl disul-
fide and 5 gave 1-butylthio-1-nitrocyclobutane in 26% yield, the
reaction of 6, 7, and 8 did not proceed.
possessing less acidic
a
-protons (pKa 17.7)12 similarly to 5 (pKa
17.8) and 7 (pKa 17.9). When 12 and 2a (2 equiv) were reacted in
DMA at rt for 3 h in air in the presence of RhH(PPh3)4 (5 mol %)
and dppe (10 mol %), 1,2-diphenyl-2-(p-methoxyphenylthio)etha-
none 13 was obtained in 85% yield (Table 3). The yields were lower
with 2e and 2f.
Mechanistically, these reactions are under thermodynamic and
kinetic control. As noted above, the unfavorable equilibrium to
form arylthiolated products was shifted by the oxidation of a thiol
to a disulfide (Scheme 2). The favorable combinations of substrates
and thiolating reagents were ascribed to kinetic reasons. An in-
crease in the reaction rate is critical for efficient catalytic reactions,
because of the competitive deactivation of the catalyst. When a
rhodium complex activates C–H and S–S bonds at comparable
The reactivity of 5 and 7 was similar to that of 6 and 8 (Table 2).
This even/odd-ring number effect was explained by the acidity of
substrates and arenethiol. 6 and 8 with acidic
a-protons (pKa
16.0 and 15.8)9 effectively reacted with di(p-chlorophenyl) disul-
fide 2d, having weaker S–S bonds, which were related to the acidic

M. Arisawa et al. / Tetrahedron Letters 53 (2012) 5729–5732
5731
Table 3
Reaction of diethyl malonate 9 and 1,2-diphenylethanone 12 with diaryl disulfides
X
Isolated yield (%)
10/11
13
p-MeO
p-Me
H
p-Cl
p-CF3
p-NC
2a
2b
2c
2d
2e
2f
22/n.d.
20/n.d.
27/n.d.
65/17
40/2
n.d./n.d.
85
78
83
79
13
n.d.
n.d. not detected.
Scheme 3. Typical experimental procedures.
In a two-necked flask were placed tetrakis(triphenylphos-
phine)hydriderhodium (5 mol %, 14.5 mg), 1,2-bis(diphenylphos-
phino)ethane (10 mol %, 10.0 mg), di(p-methoxyphenyl) disulfide
2a (0.5 mmol, 139 mg), and nitrocyclobutane
5 (0.25 mmol,
25.3 mg) in DMA (0.5 mL) in air, and the mixture was reacted at
room temperature for 3 h. Then the reaction mixture was concen-
trated, and the residue was purified by flash column chromatogra-
phy on basic silica gel giving 1-(p-methoxyphenylthio)-1-
nitrocyclobutane (53.2 mg, 89%) and recovering 2a (102.1 mg,
73%).
Scheme 2.
rates, thiolation reactions should proceed smoothly. If the C–H
bond activation is much slower than S–S bond activation, the cat-
alyst preferentially interacts with the S–S bond, which retards the
total reaction, and suffers from catalyst deactivation. In regard to
the correlation of substrates, we consider that the use of an appro-
priate combination enhances the reaction rate and drives the reac-
tion to completion before catalyst deactivation.
Acknowledgments
This work was supported by Grant-in-Aid for Scientific Re-
search (No. 21229001) from JSPS, and the GCOE program. M. A. ex-
presses her thanks for financial support from the Grant-in-Aid for
Scientific Research from MEXT (No. 22689001), Japan Science
Technology Agency, and also to the Asahi Glass Foundation.
We developed several rhodium-catalyzed thiolation reactions
of organic compounds (Scheme 3).13 The
a
-methylthiolation of
-phenyl ketones 12
a-methylthio-p-cyanoacetophe-
a
-phenylthio ketones 14 (pKa ca. 17)12 and
a
Supplementary data
(pKa ca. 18)12 was conducted with
none 15. Methylthiolation of 1-triethylsilylalkyne 16 (pKa ca. 21)14
proceeded using dimethyl disulfide 17.6 Cyclohexanone 18 (pKa ca.
26)15 was methylthiolated by 2-methylthio-1,2-diphenyl-1-etha-
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2012.
07.132.
none 19.
a-(Methylthio)isobutyrophenone 21 transferred the
methylthio group to 1,3-benzothiazole 20 (pKa ca. 27),12 giving
2-methylthio-1,3-benzothiazole. Less acidic organic compounds
18 and 20 were thiolated using donors with C–S bonds. As shown
in this study, the thiolation reaction of acidic nitroalkanes 5–8 and
diethyl malonate 9 (pKa 16–18) proceeded using diaryl disulfides
with S-S bonds. Intermediate substrates 12, 14, and 16 were re-
acted with 2a, 15, or 17. The results support the idea that less reac-
tive thiolating reagents should be used for less acidic substrates.
The design of appropriate thiolating reagents is critical for the cat-
alyzed thiolation of organic compounds.
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