Copper-catalyzed formation of sulfur-nitrogen bonds by dehydrocoupling of thiols with amines

Article abstract of DOI:10.1002/ejoc.201000167

Copper-catalyzed formation of sulfur-nitrogen bonds can be performed by a dehydrocoupling of aryl thiols with amines. Sulfenamides or sulfonamides can be produced by the use of a copper catalyst in air or under oxygen atmosphere. Furthermore, a reaction involving the combination of a palladium catalyst and a copper catalyst selectively afforded sulfinamides.

Full text of DOI:10.1002/ejoc.201000167

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201000167
Copper-Catalyzed Formation of Sulfur–Nitrogen Bonds by Dehydrocoupling of
Thiols with Amines
Nobukazu Taniguchi*[a]
Keywords: Sulfur / Sulfenamides / Dehydrocoupling reactions / Copper / Palladium / Amines
Copper-catalyzed formation of sulfur–nitrogen bonds can be
performed by a dehydrocoupling of aryl thiols with amines.
Sulfenamides or sulfonamides can be produced by the use of
a copper catalyst in air or under oxygen atmosphere. Further-
more, a reaction involving the combination of a palladium
catalyst and a copper catalyst selectively afforded sulfin-
amides.
disulfides as homocoupling products and/or of an inactive
metal-thiolate complex. As a natural result, direct synthesis
of sulfenamides by using thiols has not been explored so
far. To construct these sulfur–nitrogen bonds, generation of
disulfides by oxidation of thiols or of thiolate-copper com-
plexes considered as intermediates is required (Scheme 2).[8]
Introduction
Transition-metal-catalyzed syntheses of organosulfur
compounds with sulfur–nitrogen bonds are important pro-
cedures,[1] and the herein obtained derivatives have found
wide utilization as intermediates[2] or reagents in organic
synthesis.[3] Application of these compounds are also ex-
pected in material science.[4] However, the formation of sul-
fur–nitrogen bonds have usually been carried out by classic
procedures.[5,6] For instance, sulfenamides are produced
from sulfenyl chlorides with amines.[1] This is an inefficient
method because for the synthesis of sulfenyl chlorides, it is
necessary to employ disulfide with chlorine or N-chlorosuc-
cinimide. Therefore, the development of a convenient and
useful synthetic method that uses thiols is desired. It was
previously reported that sulfenamides from disulfides can
be obtained with a copper catalyst (Scheme 1).[7] However,
the developed method cannot control the dehydrocoupling
of thiols with amines. Furthermore, catalytic coupling of
thiols with amines has not been developed to date. To
achieve this, it was envisaged to carry out the reaction by
using a transition-metal catalyst. Generally, regulation of
the present reaction is very difficult owing to formation of
Scheme 2. Strategy for metal-catalyzed synthesis of sulfenamides
by using thiols.
To solve these problems, numerous methods involving
combinations of copper catalysts with amine ligands were
researched under oxidative conditions, and it was found
that copper-catalyzed coupling of thiols with amines was
successful. In this paper, the synthetic methodology for the
preparation of sulfenamides, sulfinamides and sulfonamides
from thiols and amines with the use of a copper catalyst is
described.
Results and Discussion
Initially, a large variety of Cu catalysts and ligands
(Table 1) were examined. In the reaction of 4-MeC6H4SH
(1a) with tert-butylamine (2a), when no ligands were added,
N-(4-methylphenylthio)-N-(tert-butyl)amine 3aa was ob-
tained in only 43% yield (Entry 1). Systematically, the effect
of amine ligands was investigated. The use of TMEDA re-
sulted in 48% yield (Entry 2); however, the system CuI-
bpy (1:1, 5 mol-%) afforded sulfenamides 3aa in 90% yield
without the formation of disulfide (Entry 3). On the con-
trary, other solvents such as DMF or toluene could not
Scheme 1. Copper-catalyzed coupling of disulfides with amines.
[a] Department of Chemistry, Fukushima Medical University,
Fukushima 960-1295, Japan
Fax: +81-24-5471369
E-mail: taniguti@fmu.ac.jp
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201000167.
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Copper-Catalyzed Formation of Sulfur–Nitrogen Bonds
promote the reaction satisfactorily (Entries 4 and 5). When
Attention was then focused on the direct formation of
other copper salts [CuIBr, CuIICl2, CuII(OAc)2] were used, sulfonamides or sulfinamides from thiols with amines in
the yield decreased slightly (Entries 6–8).
one pot. As a general rule, these compounds are synthesized
by reaction of sulfonyl chlorides with amines or by oxi-
dation of sulfenamides, but strong oxidants are neces-
sary.[11] Accordingly, a method that used the copper catalyst
under mild conditions was investigated. Firstly, a copper-
catalyzed preparation of sulfonamides was examined. To
achieve this, it was necessary to study the system CuI-bpy
(1:1, 10 mol-%) under an oxygen atmosphere (Table 3). For-
tunately, when tBuNH2 was employed as an amine, N-
(phenylsulfonyl)-N-(tert-butyl)amine was obtained in 90%
yield with trace amounts of sulfenamide and sulfinamide
(Entry 1). The present method can take advantage of vari-
ous aryl thiols (Entries 2–5). On the contrary, the use of
other amines did not result in the corresponding sulfon-
amides, and the formation of complex mixtures was often
observed (Entries 6–7).
Table 1. Investigation of suitable conditions for the synthesis of sul-
fenamides.
Entry [Cu]
L
Solvent
DMSO
3aa/4[a]
3 [%][b]
1
2
3
4
5
6
7
8
CuI
none
TMEDA DMSO
bpy
bpy
bpy
bpy
bpy
50:50
50:50
100:0
28:72[c]
0:100[c]
83:17
83:17
77:23
43
48
90
21
0
73
78
72
DMSO
DMF
PhCH3
DMSO
DMSO
DMSO
CuBr
CuCl2
Cu(OAc)2 bpy
[a] Determined by 1H NMR spectroscopy. [b] Isolated yield after
silica gel chromatography. [c] A trace of sulfinamide was also de-
tected.
Table 3. Synthesis of sulfonamides with the use of a copper cata-
lyst.[a]
On the basis of the method described above, reactions of
various thiols with different amines were carried out
(Table 2). In most cases, expected sulfenamides 3 were pro-
duced in excellent yields, and it was clear that the reaction
of thiophenol could employ various alkylamines (Entries 1–
5).[9] Not only alkylamines but also arylamines were used
in the procedure (Entries 6–8). The corresponding sulfen-
amides 3 were obtained in 40–55% yields. The yields of
these reactions were slightly lower on account of oxidation
of anilines.[10] Similarly, reactions of other aryl thiols with
tBuNH2 afforded satisfactory results (Entries 9–13). Regret-
tably, the use of 4-O2NC6H4SH or nBuSH did not promote
the reaction (Entries 14–15).
Entry
ArSH
R2NH
6 [%][b]
1[c]
2[c]
3[c]
4[c]
5[c]
6
PhSH
tBuNH2
tBuNH2
tBuNH2
tBuNH2
tBuNH2
Et2NH
90
71
70
45[d]
60
0[e]
0
4-MeC6H4SH
4-MeOC6H4SH
4-ClC6H4SH
2-MeC6H4SH
PhSH
7
4-MeC6H4SH
iPrNH2
[a] The mixture of ArSH (0.3 mmol), R1R2NH (0.3 mmol), and
CuI-bpy (1:1, 10 mol-%) in DMSO (0.2 mL) was treated at 60 °C
under oxygen. [b] Isolated yields after silica gel chromatography. [c]
Formation of trace amounts of sulfenamide and sulfinamide was
also observed. [d] The disulfide of 1 was also obtained in 42%
yield. [e] The sulfenamide was obtained in 80% yield.
Table 2. Copper-catalyzed coupling of thiols with amines.[a]
The preparation of sulfinamides was then examined
(Table 4). When a mixture of ArSH with tert-butylamine
was treated with only the CuI-bpy catalyst, the desired
sulfinamide was not selectivity produced.[12] Similarly, the
palladium catalyst only also did not afford the correspond-
ing sulfinamide (Entry 1). Noteworthy, the combination of
PdCl2 (3 mol-%) and CuI (5 mol-%) afforded N-(phenyl-
sulfinyl)-N-(tert-butyl)amine in 68% yield with trace
amounts of sulfenamide and disulfide (Entry 2). Various
aryl thiols could also be used in the procedure (Entries 3–
6).[13] The reaction with 2-MeC6H4SH required the use of
10 mol-% of PdCl2 under an oxygen atmosphere owing to
the slow oxidation of the sulfenamides (Entry 6). Further-
more, this procedure can also use disulfides (Entries 7–8).
In order to deduce the reaction mechanism, the reaction
in the absence of oxygen was examined and the reactivity
of PhSCuI (an intermediate) was considered. As shown in
Scheme 3, when the reaction of thiophenol (1b) with
tBuNH2 (2a) was performed under nitrogen, the corre-
Entry
1
R1R2NH
Time [h]
3 [%][b]
1
2
3
PhSH
Et2NH
18
18
18
24
18
85
87
88
73
piperidine
tBuNH2
nBuNH2
iPrNH2
4[c]
5[c]
6[c]
7[c]
8[c]
9
82
4-MeC6H4NH2 18
55[d]
40[d]
52[d]
83
4-MeC6H4SH
4-ClC6H4NH2
PhNHMe
tBuNH2
tBuNH2
tBuNH2
tBuNH2
tBuNH2
tBuNH2
tBuNH2
36
18
18
18
18
18
18
18
18
2-MeC6H4SH
2-BrC6H4SH
4-MeC6H4SH
4-MeOC6H4SH
4-ClC6H4SH
4-O2NC6H4SH
nBuSH
10
11
12
13
14
15
74
90
82
83
trace
trace
[a] The mixture of ArSH (0.3 mmol), R1R2NH (0.3 mmol), and
CuI-bpy (1:1, 5 mol-%) in DMSO (0.2 mL) was treated at 60 °C in
air. [b] Isolated yields after distillation. [c] 10 mol-% of CuI-bpy
was used and 0.4 mL of DMSO was used. [d] Isolated yields after
silica gel chromatography.
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N. Taniguchi
SHORT COMMUNICATION
Table 4. Synthesis of sulfinamide by use of the combination of a cle B: After (PhS)2 is produced by the oxidation of PhSH,
copper and a palladium catalyst.[a]
sulfenamides are produced from disulfides with amines by
a copper catalyst. Finally, PhSCuII(I)Ln is formed.[7]
Furthermore, the reaction under oxygen affords sulfon-
amides by the oxidation of sulfenamides. On the contrary,
in the synthesis of sulfinamides, it seems that the conversion
of sulfenamides to sulfonamides is restrained by the ad-
Entry ArSH
7 [%][b] Sulfenamide Disulfide [%][b]
dition of a palladium catalyst. Further investigations on the
exact details of the mechanism are now in progress.
1[c]
2
3
PhSH
PhSH
4-MeC6H4SH
0
0
72
68
75
trace
trace
trace
trace
trace
trace
trace
trace
trace
trace
50
4
5
4-MeOC6H4SH 65
Conclusions
4-ClC6H4SH
2-MeC6H4SH
(PhS)2
45
74
62
60
6[d]
7[e]
8[e]
0
0
0
Copper-catalyzed sulfur–nitrogen bond formation was
achieved by dehydrocoupling of thiols with amines. The
present procedure can afford sulfenamides or sulfonamides
in good yields. Addition of palladium can selectively pro-
duce sulfinamides.
(4-MeC6H4S)2
[a] The mixture of ArSH (0.3 mmol), tBuNH2 (0.3 mmol), PdCl2
(3 mol-%), CuI (5 mol-%), and bpy (8 mol-%) in DMSO (0.2 mL)
was treated at 60 °C in air. [b] Isolated yields after silica gel
chromatography. [c] CuI was not added. [d] This reaction was per-
formed by using PdCl2 (10 mol-%), CuI (5 mol-%), and bpy
(15 mol-%) for 42 h under an oxygen atmosphere. [e] NH4PF6
(10 mol-%) was added under oxygen.
Experimental Section
Copper-Catalyzed Synthesis of Sulfenamides: To a mixture of CuI
(2.9 mg, 0.015 mmol), bpy (2.3 mg, 0.015 mmol), and DMSO
(0.2 mL) were added PhSH (33.1 mg, 0.3 mmol) and tert-but-
ylamine (33.4 mg, 0.33 mmol), and the mixture was stirred at 60 °C
for 18 h in air. After the residue was dissolved in Et2O, the solution
was washed with H2O and saturated sodium chloride and dried
with anhydrous magnesium sulfate. The crude product was distilled
sponding sulfenamide 3ba was not detected at all. On the
other hand, the reaction of PhSCuI (8)[14] with tBuNH2 (2a)
produced 3ba in 47% yield in air (Scheme 4). These results
suggest that oxygen is necessary for the present procedure
and that the oxidation of PhSCuI proceeds in air. Therefore,
the reaction mechanism is proposed as follows (Figure 1).
Cycle A: After PhSCuI is formed from PhSH with CuII, the
oxidation of PhSCuI gives PhSCuII(I)Ln.[15] Consequently,
reactions of PhSCuII(I)Ln with amines produce sulfen-
(150 °C/30 Pa)
to
give
N-(phenylthio)-N-(tert-butyl)amine
(48.1 mg, 88%).[3f] 1H NMR (270 MHz, CDCl3, 24 °C): δ = 7.34
[d, 3J(H,H) = 7.6 Hz, 2 H, Ar-H], 7.26 (t, 3JH,H = 7.6 Hz, 2 H, Ar-
3
H), 7.05 (t, JH,H = 7.6 Hz, 1 H, Ar-H), 2.78 (br., 1 H, NH), 1.17
amides, and CuII regenerates in the presence of oxygen. Cy- (s, 9 H, tBu) ppm. 13C NMR (67.5 MHz, CDCl3, 24 °C): δ = 144.4
(C), 128.4 (CH), 124.4 (CH), 122.4 (CH), 54.7 (C), 29.2 (CH3) ppm.
IR (neat): 1/λ = 3327, 2969, 1582, 1476, 1361 cm–1. C10H15NS
(181.30): C 66.25, H 8.34, N 7.73; found C 66.01, H 8.21, N 7.64.
Copper-Catalyzed Synthesis of Sulfonamides: To a mixture of CuI
(2.9 mg, 0.015 mmol), bpy (2.3 mg, 0.015 mmol), and DMSO
(0.2 mL) were added PhSH (33.1 mg, 0.3 mmol) and tert-bu-
tylamine (33.4 mg, 0.33 mmol), and the mixture was stirred at
60 °C for 24 h under oxygen by using a balloon. After the residue
was dissolved in Et2O, the solution was washed with H2O and satu-
rated sodium chloride and dried with anhydrous magnesium sul-
fate. Chromatography on silica gel (80% Et2O in hexane) gave N-
(phenylsulfonyl)-N-(tert-butyl)amine (57.8 mg, 90%). 1H NMR
(270 MHz, CDCl3, 24 °C): δ = 7.93–7.89 (m, 2 H, Ar-H), 7.54–
7.45, (m, 3 H, Ar-H), 4.84 (br., 1 H, NH), 1.22 (s, 9 H, tBu) ppm.
13C NMR (67.5 MHz, CDCl3, 24 °C): δ = 143.4 (C), 132.1 (CH),
128.8 (CH), 126.9 (CH), 54.7 (C), 30.1 (CH3) ppm. IR (CHCl3):
1/λ = 3279, 2976, 1447, 1318, 1151 cm–1. C10H15NO2S (213.30): C
56.31, H 7.09, N 6.57; found C 56.14, H 7.15, N 6.61.
Scheme 3. The reaction of PhSH with an amine in the absence of
oxygen.
Scheme 4. The reaction of PhSCu with an amine.
Copper-Catalyzed Synthesis of Sulfinamides: To a mixture of CuI
(2.9 mg, 0.015 mmol), PdCl2 (1.6 mg, 0.009 mmol), bpy (3.7 mg,
0.024 mmol), and DMSO (0.2 mL) were added PhSH (33.1 mg,
0.3 mmol) and tert-butylamine (24.1 mg, 0.33 mmol), and the mix-
ture was stirred at 60 °C for 18 h in air by using a balloon. After
the residue was dissolved in Et2O, the solution was washed with
H2O and saturated sodium chloride and dried with anhydrous mag-
nesium sulfate. Chromatography on silica gel (60% Et2O in hexane)
gave N-(phenylsulfinyl)-N-(tert-butyl)amine (40.2 mg, 68%). 1H
NMR (270 MHz, CDCl3, 24 °C): δ = 7.71–7.68 (m, 2 H, Ar-H),
Figure 1. A plausible mechanism.
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Copper-Catalyzed Formation of Sulfur–Nitrogen Bonds
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7.50–7.46, (m, 3 H, Ar-H), 3.86 (br., 1 H, NH), 1.41 (s, 9 H, tBu)
ppm. 13C NMR (67.5 MHz, CDCl3, 24 °C): δ = 146.6 (C), 130.6
(CH), 128.7 (CH), 125.6 (CH), 54.3 (C), 31.1 (CH3) ppm. IR
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1
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Received: February 5, 2010
Published Online: March 26, 2010
Eur. J. Org. Chem. 2010, 2670–2673
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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