Copper-catalyzed synthesis of sulfenamides utilizing diaryl disulfides with alkyl amines

Article abstract of DOI:10.1055/s-2007-984539

The copper-catalyzed coupling of diaryl disulfides with alkyl amines can afford various sulfenamides in good yields. Furthermore, the present reaction is efficient and can be used for both of the aryl sulfide groups on disulfide. Georg Thieme Verlag Stutt

Full text of DOI:10.1055/s-2007-984539

LETTER
1917
Copper-Catalyzed Synthesis of Sulfenamides Utilizing Diaryl Disulfides with
Alkyl Amines
C
opper-Catalyzed
o
Synthesis of
b
Sulfenamide
u
s
kazu Taniguchi*
Department of Chemistry, Fukushima Medical University, Fukushima 960-1295, Japan
Fax +81(24)5471369; E-mail: taniguti@fmu.ac.jp
Received 18 April 2007
cat. [M]
(R1S)2
R22NH
R1S NR2
2
Abstract: The copper-catalyzed coupling of diaryl disulfides with
alkyl amines can afford various sulfenamides in good yields. Fur-
thermore, the present reaction is efficient and can be used for both
of the aryl sulfide groups on disulfide.
+
+
R1S-[M]
oxidation
R22NH
X
[M]
R1S
Key words: sulfenamide, copper catalyst, diaryl disulfide, alkyl-
amine
Scheme 2 Strategy of metal-catalyzed synthesis of sulfenamides
from disulfides with amines
Sulfenamides, with a sulfur–nitrogen bond, have found
widespread utilization as reagents or intermediates in or-
ganic synthesis.1 For instance, these compounds are em-
ployed in oxidation of alcohol as a catalyst in the presence
of N-chlorosuccinimide2 or in an introduction of sulfur
atom or nitrogen atom into an unsaturated carbon–carbon
bond.3
diphenyl disulfide 1 with diethylamine 2a in the presence
of CuI–TMEDA (1:1, 10 mol%) was performed in toluene
(0.3 mL) at 65 °C, disulfide 1 was transformed to the cor-
responding sulfenamide 3a in 55% yield (67% conversion
of 1) with recovery of 1 (Table 1, entry 1).9 Fortunately,
when other solvents such as DMF or DMSO were em-
ployed, the yield of 3a increased to 73% and 74% (98%
and 100% conversion of 1), respectively (Table 1, entries
3 and 4). However, the conditions at 100 °C decreased the
yield to 65% (Table 1, entry 5).
As a general rule, to synthesize sulfenamide, a reaction of
sulfenyl chloride with amine4 or a coupling of disulfide
with amine by silver nitrate5 has been developed to date
(Scheme 1).6 Regrettably, these reactions require employ-
ments of toxic chlorine gas in order to prepare for sulfenyl
chloride or a stoichiometric silver salt. Therefore, the
development of a transition-metal-catalyzed procedure
has been desired.
Table 1 Copper-Catalyzed Coupling of Bis(4-tolyl) Disulfide with
Diethylamine
[Cu]-L
(10 mol%)
(PhS)2
2 Et2NH
2 PhS-NEt2
+
65 °C, air
18 h
AgNO3
1
2a
3a
(ArS)2
Cl2
R2NH
+
+
ArS NR2
+
ArS-Ag
HCl
Entry [Cu]
L
Solvent
Conv. of 1 Yield of 3a
(%)a
(%)b
55
58
73
74
65
69
71
69
72
70
R2NH
ArSCl
ArS NR2
+
1
2
3
4
5c
6
7
8
9
CuI
TMEDA PhMe
67
Scheme 1 Synthesis of sulfenaimides
Dioxane
DMF
71
98
To accelerate the metal-catalyzed coupling of disulfide
with amine, oxidation of a generated metal–monosulfide
complex as an intermediate is necessary (Scheme 2).7
DMSO
100
74
As an approach to solve this problem, we researched con-
ditions whereby disulfide or R1S–[M]X was formed by
oxidation of R1S–[M]8 and found that a copper-catalyzed
reaction can be carried out in air. In this paper, we wish to
describe the methodology of the copper-catalyzed synthe-
sis of sulfenamides using disulfides with alkylamines.
bpy
95
Ph3P
95
CuCl
CuBr
CuCl2
TMEDA
94
98
Initially, to optimize the reaction conditions, various sol-
vents were examined (Table 1). When the reaction of
10
94
a Determined by 1H NMR.
b Isolated yields after distillation.
SYNLETT 2007, No. 12, pp 1917–1920
Advanced online publication: 27.06.2007
2
4
.0
7
.2
0
0
7
c This reaction was carried out at 100 °C.
DOI: 10.1055/s-2007-984539; Art ID: U03507ST
© Georg Thieme Verlag Stuttgart · New York

1918
N. Taniguchi
LETTER
Table 3 Copper-Catalyzed Coupling of Various Diaryl Disulfides
Table 2 Copper-Catalyzed Coupling of Diphenyl Disulfide with
with Amine
Various Amines
CuI-TMEDA
(10 mol%)
CuI-TMEDA
(10 mol%)
(R1S)2
+
2 PhS-NR1R2
2 R1S-NR2R3
(PhS)2
+
2 R1R2NH
2 R2R3NH
DMSO, air,
60–6% °c
DMSO, air,
60–65 °C
1
2
3
4
2
5
R2R3NH = Et2NH 2a
t-BuNH2 2b
Entry 3
Time Conv. of 1 Yield of 3
(h)
18
24
18
(%)c
100
95
(%)d
Entry 5
Time Conv. of 4 Yieldof5
1
2
3
PhS–N(Et)2
Aa
Aa
Aa
74
(h)
(%)c
(%)d
PhS–N(i-Pr)2
74
1
2
Aa 18
Aa 18
Aa 18
Aa 24
Aa 22
Bb 24
Bb 24
Bb 24
Bb 36
Aa 48
100
87
S
NEt2
S
100
80
PhS
PhS
PhS
PhS
N
N
N
N
Me
100
100
100
100
100
100
100
100
5
73
67
70
64
60
68
71
51
–
4
5
Aa
Aa
18
18
100
100
88
82
NEt2
Me
3
S
O
NEt2
6
7
Aa
Bb
18
18
95
90
71
74
MeO
Cl
OH
4
S
Me
NEt2
PhS
PhS
N
H
5
S
NEt2
8
9
Bb
Bb
24
18
82
0
77
–
N
H
O2N
PhS–NHPh
6
S
NHt-Bu
a Conditions A: The mixture of 1 (0.5 mmol), 2 (1.05 mmol), and CuI–
TMEDA (1:1, 10 mol%) in DMSO (0.3 mL) was treated at 65 °C.
b Conditions B: NH4PF6 (10 mol%) was also added, and the reaction
was carried out in DMSO (0.8 mL) at 60 °C.
Me
7
S
NHt-Bu
c Determined by 1H NMR.
Me
MeO
Cl
d Isolated yields after distillation.
8
S
NHt-Bu
Other ligands (bpy and PPh3) or other copper catalysts
(CuCl, CuBr and CuCl2) could give excellent results
(Table 2, entries 6–10).
9
S
NHt-Bu
The coupling of diphenyl disulfide 1 with different alkyl-
amines 2 was then investigated. As shown in Table 2,
when a mixture of diphenyl disulfide 1 with secondary
alkyl amines 2 were treated by CuI–TMEDA (1:1, 10
mol%) in DMSO (0.3 mL) at 65 °C, expected sulfen-
amides were obtained in good yields (Table 2, entries 1–
6).11
10
S
NEt2
a Conditions A: The mixture of 4 (0.5 mmol), 2 (1.05 mmol), CuI–
TMEDA (1:1, 10 mol%) in DMSO (0.3 mL) was treated at 65 °C.
b Conditions B: NH4PF6 (10 mol%) was also added, and the reaction
was carried out in DMSO (0.8 mL) at 60 °C.
c Determined by 1H NMR.
d Isolated yields after distillation.
On the other hand, in the reaction of primary alkyl amines,
the addition of NH4PF6 (10 mol%) and the use of DMSO
(0.8 mL) at 60 °C were required so as to obtain the good
results (Table 2, entries 7 and 8). Unfortunately, aniline
could not be converted into the corresponding product and
starting materials were recovered (Table 2, entry 9).
CuI-TMEDA (10 mol%)
NH4PF6
(PhS)2
+ 2 t-BuNH2
1
2 PhS-NHt-Bu
+
DMSO, 60 °C
under N2
1
2b
3b
40%
45%
Thus, the copper-catalyzed preparation of sulfenamides
using disulfides could take advantage of both primary and
secondary alkyl amines.
Scheme 3 Reaction of (PhS)2 with t-BuNH2 in the absence of
oxygen
On the basis of the above-described result, we also in-
vestigated the coupling of various diaryl disulfides with (Table 3, entries 1–9). However, when bis(n-butyl) di-
diethylamine or tert-butylamine. As expected, the corre- sulfide was employed, the reactivity was significantly de-
sponding products could be obtained in excellent yields creased (Table 3, entry 10).
Synlett 2007, No. 12, 1917–1920 © Thieme Stuttgart · New York

LETTER
Copper-Catalyzed Synthesis of Sulfenamides
1919
TMEDA,
NH4PF6
Acknowledgment
(PhS)2
+
t-BuNH2
PhS-NHt-Bu
+
This work was supported by Meiji Seika Co. Ltd.
PhSCu
DMSO, 60 °C,
in air
6
2b
3b
1
59%
trace
References and Notes
(1) (a) Davis, F. A. J. Org. Chem. 2006, 71, 8993. (b) Craine,
L.; Raban, M. Chem. Rev. 1989, 89, 689.
Scheme 4 Reaction of PhSCu with t-BuNH2
(2) (a) Matsuo, J.-i.; Iida, D.; Tatani, K.; Mukaiyama, T. Bull.
Chem. Soc. Jpn. 2002, 75, 223. (b) Matsuo, J.-i.; Iida, D.;
Yamanaka, H.; Mukaiyama, T. Tetrahedron 2003, 59, 6739.
(3) (a) Kuniyasu, H.; Kato, T.; Asano, S.; Ye, J.-H.; Ohmori, T.;
Morita, M.; Hiraike, H.; Fujiwara, S.-i.; Terao, J.; Kurosawa,
H.; Kambe, N. Tetrahedron Lett. 2006, 47, 1141.
(b) Kondo, T.; Baba, A.; Nishi, Y.; Mitsudo, T.-a.
Tetrahedron Lett. 2004, 45, 1469. (c) Zyk, N. V.;
Beloglzkina, E. K.; Gazzaeva, R.; Tyurin, V. S.; Titanyuk, I.
D. Phosphorus, Sulfur Silicon Relat. Elem. 1999, 155, 33.
(4) (a) Miura, Y.; Asada, H.; Kinoshita, M. Bull. Chem. Soc.
Jpn. 1977, 50, 1855. (b) Heimer, N. E.; Field, L. J. Org.
Chem. 1970, 35, 3012.
(5) (a) Davis, F. A.; Friedman, A. J.; Kluger, E. W.; Skibo, E.
B.; Fretz, E. R.; Milicia, A. P.; LeMasters, W. C.; Bentley,
M. D.; Lacadie, J. A.; Douglass, I. B. J. Org. Chem. 1977,
42, 967. (b) Davis, F. A.; Slgeir, W. A. R.; Evans, S.;
Schwartz, A.; Goff, D. L.; Palmer, R. J. Org. Chem. 1973,
38, 2809.
(6) Intramolecular S–N bond formation is also reported:
(a) Correa, A.; Tellitu, I.; Domínguez, E.; SanMartin, R.
Org. Lett. 2006, 8, 4811. (b) Jin, C. K.; Moon, J.-K.; Lee,
W. S.; Nam, K. S. Synlett 2003, 1967.
(7) Taniguchi, N. J. Org. Chem. 2004, 69, 915.
(8) (a) Taniguchi, N. Synlett 2006, 1351. (b) Taniguchi, N.
J. Org. Chem. 2007, 72, 1241. (c) Taniguchi, N. J. Org.
Chem. 2006, 71, 7874.
To clarify the reaction pathway for this sulfenamide syn-
thesis, we next performed some experiments. When the
reaction of diphenyl disulfide with tert-butylamine was
carried out in the absence of oxygen, sulfenamide 3b was
obtained in only 40% yield and disulfide 1 was recovered
in 45% yield (Scheme 3).
Moreover, the reactivity of PhSCu considered as an inter-
mediate was also examined. The reaction with tert-butyl-
amine gave sulfenamide 3b in 59% yield (Scheme 4).10
Consequently, the coupling of disulfide with amine re-
quires oxygen, and it seems that the copper catalyst works
as a Lewis acid or co-oxidant in air.
From these results, a plausible reaction mechanism is con-
sidered as follows (Figure 1). After a reaction of R2N–
Cu(I)Ln 8 with disulfide, the corresponding PhS–NR2 3
and PhS–Cu(I)Ln 6 are obtained. Sequentially, herein pro-
duced 6 gives disulfide 1 or PhS–Cu(II)ILn 9 via the oxi-
dation. Finally, after the intermediate 10 is formed from 9,
it affords the corresponding sulfenamide by the oxidation.
+ 1/2 H2O
PhS-NR2
3
R2NH
2
Cu(I)ILn
(9) Typical Procedure
HI + 1/2 O2
HI
To a mixture of CuI (9.5 mg, 0.05 mmol), TMEDA (5.8 mg,
0.05 mmol), and DMSO (0.3 mL) were added (PhS)2 (109.2
mg, 0.5 mmol) and Et2NH (76.8 mg, 1.05 mmol), and the
mixture was stirred at 65 °C for 18 h in air. After the residue
was dissolved in Et2O, the solution was washed with H2O
and sat. NaCl and dried over anhyd MgSO4. The crude
product was distilled (140 °C/30 Pa) to give N-(phenylthio)-
N,N-diethylamine (134.8 mg, 74%).5a
PhS
R2N
7
Cu(II)Ln
10
R2N-Cu(I)Ln
HI
8
R2NH
PhS
Cu(II)Ln
I
(PhS)2
9
1
N-(Phenylthio)-N,N-diethylamine
1/2 H2O
IR (neat): 2970, 2847, 1582, 1475, 1438, 1374 cm–1. 1H
NMR (270 MHz, CDCl3): d = 7.34–7.25 (m, 4 H), 7.15–7.08
(m, 1 H), 3.00 (q, J = 7.1 Hz, 4 H), 1.18 (t, J = 7.1 Hz, 6 H).
13C NMR (67.5 MHz, CDCl3): d = 141.2, 128.4, 125.3,
125.0, 52.1, 13.7. Anal. Calcd for C10H15NS: C, 66.25; H,
8.34; N, 7.73. Found: C, 65.92; H, 8.02; N, 7.80.
N-(Phenylthio)pyrrolidine
PhSCu(I)Ln
PhS-NR2
6
HI + 1/2 O2
3
1/2 H2O
1/2 (PhS)2
+ 7
HI + 1/2 O2
1
Figure 1 Plausible reaction mechanism
IR (neat): 2967, 2845, 1582, 1475, 1438 cm–1. 1H NMR (270
MHz, CDCl3): d = 7.31–7.27 (m, 4 H), 7.18–7.14 (m, 1 H),
3.13–3.09 (m, 4 H), 1.87–1.82 (m, 4 H). 13C NMR (67.5
MHz, CDCl3): d = 139.4, 128.6, 126.3, 125.9, 55.2, 25.6.
Anal. Calcd for C10H13NS: C, 66.99; H, 7.31; N, 7.81.
Found: C, 66.70; H, 7.24; N, 7.84.
Further investigations on the exact details of the reaction
mechanism are now in progress.
In conclusion, we could achieve the copper-catalyzed syn-
thesis of sulfenamides having sulfur–nitrogen bond using
diaryl disulfides with alkyl amines.
N-(Phenylthio)-N-(methyl)aminoethanol
IR (neat) 3391, 2940, 2880, 1582, 1476, 1438 cm–1. 1H NMR
(270 MHz, CDCl3): d = 7.40–7.23 (m, 5 H), 3.77 (t, J = 5.1
Hz, 2 H), 3.02 (t, J = 5.1 Hz, 2 H), 2.87 (s, 3 H), 2.00 (br, 1
H). 13C NMR (67.5 MHz, CDCl3): d = 136.3, 129.4, 128.8,
127.5, 60.8, 59.9, 47.3. Anal. Calcd for C9H13NS: C, 58.98;
H, 7.15; N, 7.64. Found: C, 59.17; H, 7.11; N, 7.24.
N-(Phenylthio)-N-butylamine
IR (neat): 3338, 2957, 2929, 1582, 1476, 1438 cm–1. 1H
NMR (270 MHz, CDCl3): d = 7.34–7.24 (m, 4 H), 7.15–7.10
Synlett 2007, No. 12, 1917–1920 © Thieme Stuttgart · New York

1920
N. Taniguchi
LETTER
(m, 1 H), 2.93 (q, J = 6.9 Hz, 2 H), 2.80 (br, 1 H), 1.56–1.50
C11H17NS: C, 67.64; H, 8.77; N, 7.17. Found: C, 67.51; H,
8.79; N, 7.22.
(m, 2 H), 1.48–1.31 (m, 2 H), 0.90 (t, J = 7.2 Hz, 3 H). 13
C
NMR (67.5 MHz, CDCl3): d = 141.9, 128.7, 125.2, 123.8,
51.9, 32.5, 20.0, 13.9. Anal. Calcd for C10H15NS: C, 66.25;
H, 8.34; N, 7.73. Found: C, 66.46; H, 8.05; N, 7.70.
N-(Phenylthio)-N-(tert-butyl)amine4a,5a
N-(4-Methoxylphenylthio)-N,N-diethylamine
IR (neat): 2971, 2835, 1590, 1492 cm–1. 1H NMR (270 MHz,
CDCl3): d = 7.36 (d, J = 8.7 Hz, 2 H), 6.87 (d, J = 8.7 Hz, 2
H), 3.80 (s, 3 H), 2.81 (q, J = 7.0 Hz, 4 H), 1.21 (t, J = 7.0
Hz, 6 H). 13C NMR (67.5 MHz, CDCl3): d = 159.5, 132.8,
126.9, 114.1, 55.3, 51.4, 13.7. Anal. Calcd for C11H17NOS:
C, 62.52; H, 8.11; N, 6.63. Found: C, 62.47; H, 8.03; N, 6.42.
N-(2-Methylphenylthio)-N-(tert-butyl)amine
IR (neat): 3327, 2969, 1582, 1476, 1361 cm–1. 1H NMR (270
MHz, CDCl3): d = 7.34 (d, J = 7.6 Hz, 2 H), 7.26 (t, J = 7.6
Hz, 2 H), 7.05 (t, J = 7.6 Hz, 1 H), 2.78 (br, 1 H), 1.17 (s, 9
H). 13C NMR (67.5 MHz, CDCl3): d = 144.4, 128.4, 124.4,
122.4, 54.7, 29.2. Anal. Calcd for C10H15NS: C, 66.25; H,
8.34; N, 7.73. Found: C, 65.98; H, 8.20; N, 7.54.
IR (neat): 3322, 2969, 1589, 1463, 1361 cm–1. 1H NMR (270
MHz, CDCl3): d = 7.65 (d, J = 7.9 Hz, 1 H), 7.18, (t, J = 7.9
Hz, 1 H), 7.05–6.95 (m, 2 H), 2.60 (br, 1 H), 2.23 (s, 3 H),
1.19 (s, 9 H). 13C NMR (67.5 MHz, CDCl3): d = 142.5,
131.5, 129.5, 125.9, 123.9, 122.4, 54.6, 29.2, 18.5. Anal.
Calcd for C11H17NS: C, 67.64; H, 8.77; N, 7.17. Found: C,
67.54; H, 8.79; N, 6.97.
(10) N-(2-Methylphenylthio)-N,N-diethylamine
IR (neat): 2970, 2849, 1589, 1463, 1378 cm–1. 1H NMR (270
MHz, CDCl3): d = 7.50 (d, J = 7.9 Hz, 1 H), 7.15 (t, J = 7.9
Hz, 1 H), 7.07–6.97 (m, 2 H), 3.05 (q, J = 7.0 Hz, 4 H), 2.20
(s, 3 H), 1.17 (t, J = 7.0 Hz, 6 H). 13C NMR (67.5 MHz,
CDCl3): d = 141.2, 131.6, 129.7, 125.8, 124.0, 122.8, 52.1,
18.5, 13.5. Anal. Calcd for C11H17NS: C, 67.64; H, 8.77; N,
7.17. Found: C, 67.34; H, 8.71; N, 7.02.
N-(4-Methylphenylthio)-N-(tert-butyl)amine
IR (neat): 3325, 2969, 1598, 1490, 1361 cm–1. 1H NMR (270
MHz, CDCl3): d = 7.25 (d, J = 8.2 Hz, 2 H), 7.08 (d, J = 8.2
Hz, 2 H), 2.80 (br, 1 H), 2.30 (s, 3 H), 1.17 (s, 9 H). 13C NMR
(67.5 MHz, CDCl3): d = 140.8, 134.3, 129.2, 122.9, 54.8,
29.2, 20.9. Anal. Calcd for C11H17NS: C, 67.64; H, 8.77; N,
7.17. Found: C, 67.35; H, 8.71; N, 6.92.
N-(4-Methylphenylthio)-N,N-diethylamine
IR (neat): 2970, 2830, 1597, 1489, 1374 cm–1. 1H NMR (270
MHz, CDCl3): d = 7.25 (d, J = 7.9 Hz, 2 H), 7.10 (d, J = 7.9
Hz, 2 H), 2.93, (q, J = 7.0 Hz, 4 H), 2.32 (s, 3 H), 1.19 (t,
J = 7.0 Hz, 6 H). 13C NMR (67.5 MHz, CDCl3): d = 136.0,
135.8, 129.3, 127.3, 51.9, 21.0, 13.7. Anal. Calcd for
(11) Adams, R.; Reifschneider, W.; Ferretti, A. Org. Synth., Coll.
Vol. V; John Wiley & Sons: New York, 1973, 107–110.
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