Copper-Catalyzed Oxidative Synthesis of Sulfinamides Using Thiols or Disulfides with Amines

Article abstract of DOI:10.1002/ejoc.201600091

Copper-catalyzed coupling of thiols with amines was used to synthesize numerous sulfinamides in excellent yields. Sulfenamides or sulfonamides were also formed as reaction byproducts albeit in trace quantities. The procedure is carried out as a one step a

Full text of DOI:10.1002/ejoc.201600091

DOI: 10.1002/ejoc.201600091
Full Paper
Sulfinamide Synthesis
Copper-Catalyzed Oxidative Synthesis of Sulfinamides Using
Thiols or Disulfides with Amines
Nobukazu Taniguchi*[a]
Abstract: Copper-catalyzed coupling of thiols with amines was of water and NH4PF6 under aerobic conditions. Furthermore,
used to synthesize numerous sulfinamides in excellent yields.
Sulfenamides or sulfonamides were also formed as reaction by-
products albeit in trace quantities. The procedure is carried out
as a one step and was found to be promoted by the addition
the reaction proceeds smoothly when using disulfides. Conse-
quently, it is clear that both thiols and disulfides are useful S-
sources under these reaction conditons.
Introduction
Transition metal-catalyzed synthesis of organosulfur com-
pounds has represented an important area of research in or-
ganic chemistry for some time now and, to date, many efficient
procedures have been developed.[1] Compounds obtained us-
ing such methods have found widespread applications as inter-
mediates or reagents in the fields of organic synthesis and ma-
terial science.[2]
Similarly, sulfur–nitrogen bond generation can be achieved
using a number of methods.[3,4] Indeed, the synthesis of sulfon-
amides by reacting sulfonyl chlorides with amines is well
known. Conversely, synthetic methodologies for sulfonamide
production have been much less widely studied. Sulfinamides
are strongly represented in many reagents used in asymmetric
Scheme 1. General synthesis of sulfinamides.
[5]
synthesis as well as in benzothiazine syntheses.[6] Neverthe-
less, efficient procedures for sulfinamide synthesis remain
largely unknown. The majority of established methods for sulf-
inamide generation involve the use of disulfides.[5,7] For in-
stance, the treatment of sulfinic esters with LiHMDS yields sulf-
inamides and sulfinic esters can be prepared by reacting disulf-
ides with NBS in one′s alcohol of choice (Scheme 1, a).[5b] The
reaction of thiosulfinates with amines has also been reported
(Scheme 1, b).[5a] Sulfinamides can also be prepared from sulf-
onyl chlorides in the presence of PPh3 as a reductant
(Scheme 1, c).[8]
These procedures usually require two or three steps. In addi-
tion, the substrate scope of such approaches is often limited
and reaction conditions may be sensitive to the presence of air
and/or moisture.
We envisioned that a transition metal-catalyzed reaction
might represent a convenient method for the synthesis of sulf-
inamides, since transition metals often enable processes such
as facile single electron transfers and are easily oxidized or re-
duced under certain conditions. The desired capabilities of a
transition metal catalyst in sulfonamide synthesis are to: (1) pro-
mote coupling of thiols or disulfides with amines resulting in
the formation of sulfur–nitrogen bonds, and (2) oxidize the
sulfur atom of intermediate sulfenamides. Moreover, the reac-
tion must occur under mild conditions due to the inherent in-
stability of sulfur–nitrogen bonds.
On the basis of previous reports, it was apparent that cop-
per-catalyzed coupling of thiols or disulfides with amines af-
fords sulfenamides containing sulfur–nitrogen bonds.[9] It was
therefore anticipated that a copper catalyst would be the most
likely candidate for transition metal-catalyzed synthesis of sulf-
inamides.
Unfortunately, the previously reported copper catalyst could
not convert thiols or disulfides to sulfinamides using the estab-
lished methods. To prepare sulfinamides, it was necessary to
use CuI–PdCl2 as the catalyst[9b] although substrate limitations
were very pronounced with this procedure. Therefore, a more
convenient and substrate compatible method was investigated.
Consequently, it was found that, following the addition of water
and NH4PF6, it is possible to obtain sulfonamides via copper-
[a] Department of Chemistry, Fukushima Medical University,
Hikarigaoka 1 Fukushima, Japan
E-mail: taniguti@fmu.ac.jp
http://www.fmu.ac.jp/
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/ejoc.201600091.
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catalyzed chemistry, even in the absence of PdCl2. In this study,
this successful methodology will be described.
In contrast, the use of other additives, ligands or solvents
resulted in lower yields (Table 1, Entries 7–15). When using
PhCh3, (ClCH2)2 or EtOH, the formation of disulfide was ob-
served with a trace amount of sulfinamides (Table 1, Entries 10–
12). The reactivity of other copper catalysts was also evaluated.
Although the use of CuBr2 afforded desired product 3aa in
72 % yield, other salts displayed lower levels of reactivity
(Table 1, Entries 17–21).
Numerous substrates were then screened for their reaction
compatibilities using the optimized reaction conditions. As
shown in Table 2, mixtures of thiols 1 and amines 2 were
treated with CuI/bpy (1:1, 5 mol-%) in the presence of air. Reac-
tions involving secondary amines afforded the best results at
80 °C. On the other hand, the reaction using tert-butylamine
proceeded smoothly at 70 °C. Reactions of 4-chloroaniline and
4-aminothiophenol did not afford expected sulfinamide 3 ow-
ing to the formation of complex mixtures and the lower sub-
strate reactivity (Table 2, Entries 6 and 11). The reaction of n-
butyl thiol gave virtually no product (Table 2, Entry 17).
Results and Discussion
To establish suitable conditions, the reaction between 4-thio-
toluene 1a and diethylamine 2a was initially investigated in the
presence of air (Table 1). No product was obtained when the
reaction was performed in the absence of CuI catalyst or when
the CuI catalyst was used in the absence of bpy (Table 1, Entries
1 and 2). However, the catalyst formed by reaction of CuI with
bpy enabled the generation of sulfinamide 3aa in 6 % yield.
When water was added, the product yield increased to 17 %
[10]
(Table 1, Entries 3 and 4). The addition of NH4PF6
in DMSO
furnished 3aa in 48 % yield (Table 1, Entry 5). Fortunately, the
reaction, in the presence of both NH4PF6 and H2O, afforded 3aa
in 80 % yield; trace amounts of sulfenamides and sulfonamides
(Table 1, Entry 6) were also detected. The procedure effectively
suppressed the formation of sulfonamide, and selectively oxid-
ized the sulfur atom on the sulfenamide.
Table 2. Coupling of thiols with amines.[a]
Table 1. Investigation of suitable reaction conditions.[a]
Entry
1
2
Temp.
[°C]
3
3
[%]
1
2
3
4
5
6
7
8
4-MeC6H4SH
Et2NH
80
80
80
80
70
70
80
80
80
80
80
80
80
80
80
80
70
3aa
3ab
3ac
3ad
3ae
3af
3ba
3ca
3da
3ea
3fa
3ga
3ha
3ia
80
74
88
71
75
pyrrolidine
piperidine
morpholine
tBuNH2
4-ClC6H4NH2
Et2NH
Entry
Cu–L
Additive
Solvent [mL]
3aa [%]
1
2
3
4
none
CuI
CuI-bpy
none
none
none
none
DMSO(0.3)
DMSO(0.3)
DMSO(0.3)
DMSO/H2O
(0.3/0.05)
0
0
6
17
trace
64
C6H5SH
4-MeOC6H4SH
4-ClC6H4SH
4-BrC6H4SH
4-H2NC6H4SH
2-NaphthylSH
2-MeC6H4SH
2-MeOC6H4SH
2-BrC6H4SH
3-MeC6H4SH
nBuSH
80[c]
62[d]
70
9
10
11
12
13
14
15
16
17
5
6
NH4PF6
DMSO(0.3)
DMSO/H2O
(0.3/0.05)
48
80
trace[b]
67
70
7
8
NH4BF4
NH4PF6
60
65
62d
52c
81
DMF/H2O
(0.3/0.05)
DMF(0.3)
3ja
3ka
3la
9
10
NH4PF6
NH4PF6
41
trace
0
PhCH3/H2O
(0.3/0.05)
(ClCH2)2/H2O
(0.3/0.05)
EtOH/H2O
(0.3/0.05)
DMSO/H2O
(0.3/0.05)
[a] Reaction conditions: a mixture of 1 (0.3 mmol), Et2NH (0.33 mmol) and
CuI-bpy (1:1, 5 mol-%) in DMSO (0.3 mL) and H2O (0.05 mL) was treated at
80 or 70 °C in the presence of air provided by a balloon. [b] A complex
mixture was obtained. [c] 36 h. [d] 24 h.
11
12
13
NH4PF6
NH4PF6
NH4PF6
trace
trace
57
CuI-Phen
Disulfides were also successfully used as substrates in the
procedure (Table 3). The reaction between disulfides 4 and
amines 2 afforded desired sulfinamides 3 in excellent yields
with only trace amounts of sulfenamide byproducts. Both sulf-
ide groups on the disulfides reactants were completely con-
sumed. Reactions using of di(n-butyl) disulfide failed to afford
any product (Table 3, Entry 18).
To gain insight into the reaction mechanism, several experi-
ments were performed. At first, the reaction in the absence of
oxygen was evaluated. When a mixture of 4-thiotoluene 1a or
di(4-tolyl) disulfide 4a with diethylamine 2a was treated with
14
15
16
17
18
19
20
21
CuI-Phen·H2O
CuI-TMEDA
CuI-PPh3
CuBr2-bpy
CuCl-bpy
CuCl2-bpy
CuOAc-bpy
Cu(OAc)2-bpy
NH4PF6
NH4PF6
NH4PF6
NH4PF6
NH4PF6
NH4PF6
NH4PF6
NH4PF6
63
trace
trace
72
13
4
trace
trace
[a] Reaction conditions: a mixture of 1a (0.3 mmol), Et2NH 2a (0.33 mmol) and
CuI–L (1:1, 5 mol-%) in solvent was reacted in the presence of air provided
by a balloon.
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Table 3. Coupling of disulfides with amines.[a]
Scheme 4. Reaction in the presence of TEMPO.
Entry
4
2
Temp.
[°C]
3
3
[%]
Subsequently, the origin of the oxygen atom bound to sulfur
was investigated. When H218O was employed instead of water,
both 18O- and 16O-containing sulfinamides were formed as de-
termined by ESI-MS analysis (Scheme 5).[12]
1
2
3
4
5
6
7
8
(4-MeC6H4S)2
Et2NH
80
80
80
80
70
80
70
80
70
70
70
80
70
80
70
80
70
70
3aa
3ab
3ac
3ad
3ae
3ba
3be
3ca
3ce
3ea
3ee
3ga
3ge
3hc
3he
3ic
61
68
86
74
76
73
82
70
69
61
71
73
75
85
75
82
70
0
pyrrolidine
piperidine
morpholine
tBuNH2
Et2NH
tBuNH2
Et2NH
tBuNH2
Et2NH
(C6H5S)2
(4-MeOC6H4S)2
(4-BrC6H4S)2
(2-NaphthylS)2
(2-MeC6H4S)2
(2-MeOC6H4S)2
(nBuS)2
9
10
11
12
13
14
15
16
17
18
tBuNH2
Et2NH
tBuNH2
piperidine
tBuNH2
piperidine
tBuNH2
tBuNH2
Scheme 5. Reaction in the presence of H218O.
3ie
3le
As shown in Scheme 6, the oxidation of sulfenamides was
also surveyed. The reaction gave expected sulfinamides 3 in
good yields. Finally, the necessity of a halide source within the
reaction was investigated (Schemes 7 and 8). Indeed, we found
that addition of KI promoted the reaction when using CuOAc
as catalyst.[13]
[a] Reaction conditions: A mixture of 4 (0.15 mmol), 2 (0.33 mmol) and CuI-
bpy (1:1, 10 mol-%) in DMSO (0.3 mL) and H2O (0.1 mL) was treated at 80 or
70 °C in the presence of air provided by a balloon.
copper under an atmosphere of nitrogen, the production of
3aa proceeded with diminished yield, relative to the aerobic
scenario, and also afforded trace amounts of sulfenamide 5aa
(Scheme 2).
Scheme 6. Oxidation of sulfenamide.
Scheme 2. Reaction in the absence of oxygen.
Similarly, the reactivity of copper(I)–thiolate[11] a possible re-
action intermediate, was investigated. In this case, sulfinamide
3ba was formed in 60 % yield (Scheme 3).
Scheme 7. CuOAc-catalyzed reaction in the presence of added KI.
Scheme 3. Reactivity of copper–thiolate complex.
Scheme 8. Oxidation of sulfenamide using CuOAc catalyst and KI.
The addition of TEMPO (1 equiv.) afforded 3aa in 71 % yield
These results demonstrated that the presence of oxygen was
along with traces of sulfenamide 5aa (Scheme 4). Thus, the necessary for the reaction to occur successfully, and that the
reaction was not completely inhibited by the presence of a radi- sulfur–nitrogen bond was not formed via a free radical pathway.
[10]
cal scavenger.
The presence of NH4PF6 and iodonium ion can promote the
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reaction.[14] Furthermore, the oxygen atom of the sulfinamide
was found to be introduced by the addition of water.[14]
In cycle A of the reaction mechanism, sulfenamide is pro-
duced via reductive elimination of 9 which is formed by the
reaction of complex 8 with thiol (Figure 1). Consequently, cop-
per(I) catalyst 6 is produced in the presence of oxygen. In cycle
B, the complex 10 affords sulfenamides and copper(I)–thiolate
11 via reductive elimination. Sequentially, the oxidation of 11
affords copper(II) complex 12. Following the reaction of 12 with
an amine, sulfenamide is formed via reductive elimination of
9 and concomitant production of 6 (Figure 1).[15] Finally, the
sulfinamide can be produced via oxidation of its sulfenamide
precursor in a halogen-promoted fashion.[16,17]
0.33 mmol), and NH4PF6 (24.9 mg, 0.15 mmol), in DMSO (0.3 mL)
and H2O (0.05 mL) were added CuI (2.9 mg, 0.015 mmol) and bpy
(2.3 mg, 0.015 mmol), and the mixture was stirred at 80 °C for 18 h
in the presence of air provided by a balloon . After the residue was
dissolved in Et2O, the solution was washed with H2O and saturated
sodium chloride and dried with anhydrous magnesium sulfate.
Chromatography on silica gel (50 % diethyl ether/hexane) gave N-
(4-methylphenylsulfinyl)-N,N-diethylamine 3aa (50.6 mg, 80 %).
N-(4-Methylphenylsulfinyl)-N,N-diethylamine (3aa): (50.6 mg,
80 %). Pale yellow oil. 1H NMR (270 MHz, CDCl3): δ = 7.53 (d, J =
8.0 Hz, 2 H), 7.29 (d, J = 8.0 Hz, 2 H), 3.13 (q, J = 7.2 Hz, 4 H), 2.41
(s, 3 H), 1.12 (t, J = 7.2 Hz, 6 H) ppm. 13C{1H} NMR (67.5 MHz, CDCl3):
δ = 141.1 (C), 140.8 (C), 129.4 (CH), 126.2 (CH), 41.8 (NCH2), 21.3
(ArCH3), 14.4 (CH3) ppm. IR (CHCl3) 2973, 2934, 2871, 1462, 1455,
1175, 1065 cm–1. C11H17NOS (211.32): calcd. C 62.52, H 8.11, N 6.63;
found C 62.75, H 8.19, N 6.42.
N-(4-Methylphenylsulfinyl)pyrrolidine (3ab): Pale yellow solid
1
(46.2 mg, 74 %), m.p. 50–52 °C. H NMR (270 MHz, CDCl3): δ = 7.56
(d, J = 8.0 Hz, 2 H), 7.29 (d, J = 8.0 Hz, 2 H), 3.36–3.32 (m, 2 H),
3.02–2.98 (m, 2 H), 2.40 (s, 3 H), 1.87–1.82 (s, 4 H) ppm. 13C{1H} NMR
(67.5 MHz, CDCl3): δ = 141.4 (C), 140.7 (C), 129.4 (CH), 125.7 (CH),
45.9 (NCH2), 25.9 (CH2), 21.3 (ArCH3) ppm. IR (CHCl3) 2999, 2878,
1491, 1051 cm–1. C11H15NOS (209.31): calcd. C 63.12, H 7.22, N 6.69;
found C 63.17, H 7.25, N 6.68.
N-(4-Methylphenylsulfinyl)piperidine (3ac): White solid (58.8 mg,
88 %), m.p. 63–64 °C. 1H NMR (270 MHz, CDCl3): δ = 7.54 (d, J =
8.0 Hz, 2 H), 7.30 (d, J = 8.0 Hz, 2 H), 3.10–3.06 (m, 2 H), 2.98–2.93
(m, 2 H), 2.41 (s, 3 H), 1.62–1.56 (m, 6 H) ppm. 13C{1H} NMR
(67.5 MHz, CDCl3): δ = 140.8 (C), 140.2 (C), 129.4 (CH), 126.1 (CH),
46.7 (NCH2), 26.1 (CH2), 23.8 (CH2), 21.2 (ArCH3) ppm. IR (CHCl3)
2998, 2942, 2853, 1597, 1491, 1452, 1055 cm–1. C12H17NOS (223.33):
calcd. C 64.53, H 7.67, N 6.27; found C 64.14, H 7.78, N 6.40.
Figure 1. Plausible reaction mechanism for sulfenamide production under
aerobic, halide-containing conditions.
N-(4-Methylphenylsulfinyl)morpholine (3ad): White solid
(47.8 mg, 71 %), m.p. 119–121 °C. 1H NMR (270 MHz, CDCl3): δ =
7.56 (d, J = 8.0 Hz, 2 H), 7.32 (d, J = 8.0 Hz, 2 H), 3.77–3.66 (m, 4 H),
3.19–3.11 (m, 2 H), 3.00–2.92 (m, 2 H), 2.42 (s, 3 H) ppm. 13C{1H}
NMR (67.5 MHz, CDCl3): δ = 141.5 (C), 139.1 (C), 129.6 (CH), 126.1
(CH), 66.9 (OCH2), 45.6 (NCH2), 21.3 (ArCH3) ppm. IR (CHCl3) 3019,
1452, 1258, 1112, 1066 cm–1. C11H15NO2S (225.31): calcd. C 58.64,
H 6.71, N 6.22; found C 58.31, H 6.74, N 6.28.
N-(4-Methylphenylsulfinyl)-N-(tert-butyl)amine (3ae)::[9b] White
solid (47.3 mg, 75 %), m.p. 77–79 °C. 1H NMR (270 MHz, CDCl3): δ =
7.57 (d, J = 8.0 Hz, 2 H), 7.28 (d, J = 8.0 Hz, 2 H), 3.82 (br. s, 1 H),
2.40 (s, 3 H), 1.40 (s, 9 H) ppm. 13C{1H} NMR (67.5 MHz, CDCl3): δ =
143.5 (C), 140.9 (C), 129.4 (CH), 125.5 (CH), 54.2 (NC), 31.1 (CH3), 21.3
(ArCH3) ppm. IR (CHCl3) 2976, 1493, 1370, 1052 cm–1. C11H17NOS
(211.32): calcd. C 62.52, H 8.11, N 6.63; found C 62.28, H 8.08, N
6.50.
Conclusions
The copper-catalyzed synthesis of sulfinamides was achieved
using a combination of thiols with amines in the presence of
air. The procedure can be performed in one step and sup-
presses the generation of sulfonamides. Furthermore, the pro-
cedure can employ disulfides, and both sulfide groups on the
disulfide are available for reaction.
Experimental Section
N-(Phenylsulfinyl)-N,N-diethylamine (3ba):[9b,18] Pale yellow oil
(42.1 mg, 64 %). H NMR (270 MHz, CDCl3): δ = 7.69–7.65 (m, 2 H),
7.53–7.45 (m, 3 H), 3.14 (q, J = 7.2 Hz, 4 H), 1.12 (t, J = 7.2 Hz, 6
H) ppm. 13C{1H} NMR (67.5 MHz, CDCl3): δ = 144.2 (C), 130.5 (C),
128.7 (CH), 126.2 (CH), 41.9 (NCH2), 14.3 (CH3) ppm. IR (CHCl3) 2975,
2872, 2731, 1633, 1443, 1174, 1057 cm–1. C10H15NOS (197.29): calcd.
C 60.88, H 7.66, N 7.10; found C 60.56, H 7.78, N 6.59.
General Procedure: All reactions were carried out in the presence
1
of air. NMR spectra were recorded with a JEOL EX-270 spectrometer
1
(270 MHz for H, 67.5 MHz for 13C). Chemical shifts are reported in
1
δ ppm referenced to an internal tetramethylsilane standard for H
NMR and [D]chloroform (δ = 77.0 ppm) for 13C NMR spectroscopy.
IR spectra were measured using a Perkin–Elmer Spectrum One FT-
IR spectrometer. Melting points were measured with a BÜCHI Melt-
ing Point B-540 apparatus. Elemental analyses and ESI-MS analyses
were performed at the Instrumental Analysis Centre for Chemistry,
Tohoku University (Japan).
N-(4-Methoxyphenylsulfinyl)-N,N-diethylamine (3ca): Pale yel-
1
low oil (54.3 mg, 80 %). H NMR (270 MHz, CDCl3): δ = 7.57 (d, J =
9.5 Hz, 2 H), 7.00 (d, J = 9.5 Hz, 2 H), 3.86 (s, 3 H), 3.12 (qd, J = 7.2
and 2.7 Hz, 4 H), 1.12 (t, J = 7.2 Hz, 6 H) ppm. 13C{1H} NMR
(67.5 MHz, CDCl3): δ = 161.4 (OC), 135.5 (C), 127.8 (CH), 114.0 (CH),
Typical Procedure for Copper-catalyzed Synthesis of Sulfin-
amide Using Thiols with Amines: (Table 2, Entry 1). To a mixture
of 4-thiotoluene (37.3 mg, 0.3 mmol), diethylamine (24.1 mg, 55.4 (OCH3), 47.2 (NCH2), 14.4 (CH3) ppm. IR (CHCl3) 2988, 2838,
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2499, 1593, 1493, 1020 cm–1. C11H17NO2S (227.32): calcd. C 58.12,
H 7.54, N 6.16; found C 57.94, H 7.58, N 5.97.
Typical Procedure for Copper-catalyzed Synthesis of Sulfin-
amides Using Disulfides with Amines: (Table 3, Entry 1). To a
mixture of di(4-tolyl) disulfide (37.0 mg, 0.15 mmol), diethylamine
(24.1 mg, 0.33 mmol), and NH4PF6 (4.9 mg, 0.15 mmol), in DMSO
(0.3 mL) and H2O (0.1 mL) were added CuI (2.9 mg, 0.015 mmol)
and bpy (2.3 mg, 0.015 mmol), and the mixture was stirred at 80 °C
for 18 h in the presence of air provided by a balloon. After the
residue was dissolved in Et2O, the solution was washed with H2O
and saturated sodium chloride and dried with anhydrous magne-
sium sulfate. Chromatography on silica gel (50 % diethyl ether/hex-
ane) gave 3aa (38.7 mg, 61 %).
N-(4-Chlorophenylsulfinyl)-N,N-diethylamine (3da): Pale yellow
oil (42.7 mg, 62 %). 1H NMR (270 MHz, CDCl3): δ = 7.61 (d, J = 8.5 Hz,
2 H), 7.47 (d, J = 8.5 Hz, 2 H), 3.13 (q, J = 7.2 Hz, 4 H), 1.13 (t, J =
7.2 Hz, 6 H) ppm. 13C{1H} NMR (67.5 MHz, CDCl3): δ = 142.9 (C),
136.8 (C), 128.9 (CH), 127.8 (CH), 41.9 (NCH2), 14.3 (CH3) ppm. IR
(CHCl3) 2988, 2726, 2496, 1472, 1013 cm–1. C10H14ClNOS (231.74):
calcd. C 51.83, H 6.09, N 6.04; found C 51.45, H 6.41, N 5.72.
N-(4-Bromophenylsulfinyl)-N,N-diethylamine (3ea): Pale yellow
oil (64.8 mg, 70 %). 1H NMR (270 MHz, CDCl3): δ = 7.63 (d, J =
10.8 Hz, 2 H), 7.53 (d, J = 10.8 Hz, 2 H), 3.13 (q, J = 7.2 Hz, 4 H),
1.13 (t, J = 7.2 Hz, 6 H) ppm. 13C{1H} NMR (67.5 MHz, CDCl3): δ =
143.5 (C), 131.9 (CH), 127.9 (CH), 125.2 (C), 41.9 (NCH2), 14.3
N-(4-Methylphenylsulfinyl)pyperidine (3ab): Pale yellow solid
(42.5 mg, 68 %).
N-(4-Methylphenylsulfinyl)piperidine (3ac): White solid (57.6 mg,
86 %).
(CH3) ppm. IR (CHCl3) 2987, 2727, 2496, 1571, 1470, 1010 cm–1
.
C10H14BrNOS (276.19): calcd. C 43.49, H 5.11, Br 28.93, N 5.07; found
C 43.33, H 5.14, N 5.06.
N-(4-Methylphenylsulfinyl)morpholine (3ad): White solid
(50.1 mg, 74 %).
N-(2-Naphthylsulfinyl)-N,N-diethylamine (3ga): Pale yellow oil
(50.0 mg, 67 %). H NMR (270 MHz, CDCl3): δ = 8.30 (s, 1 H), 7.99–
N-(4-Methylphenylsulfinyl)-N-(tert-butyl)amine (3ae): White
solid (48.0 mg, 76 %).
1
7.87 (m, 3 H), 7.59–7.54 (m, 3 H), 3.18 (q, J = 7.2 Hz, 4 H), 1.13 (t,
J = 7.2 Hz, 6 H) ppm. 13C{1H} NMR (67.5 MHz, CDCl3): δ = 141.3 (C),
134.1 (C), 132.8 (C), 128.7 (CH), 128.5 (CH), 127.8 (CH), 127.6 (CH),
127.0 (CH), 126.9 (CH), 122.4 (CH), 41.9 (NCH2), 14.4 (CH3) ppm. IR
(CHCl3) 2988, 2727, 2494, 1624, 1502, 1061 cm–1. C14H17NOS
(247.35): calcd. C 67.98, H 6.93, N 5.66; found C 67.64, H 7.05, N
5.73.
N-(4-Phenylsulfinyl)-N,N-diethylamine (3ba): Pale yellow oil
(42.1 mg, 73 %).
N-(Phenylsulfinyl)-N-(tert-butyl)amine
(3be):
White
solid
(48.6 mg, 82 %), m.p. 68–69 °C. 1H NMR (270 MHz, CDCl3): δ = 7.71–
7.67 (m, 2 H), 7.48–7.46 (m, 3 H), 3.87 (br. s, 1 H), 1.41 (s, 9 H) ppm.
13C{1H} NMR (67.5 MHz, CDCl3): δ = 146.5 (C), 130.5 (CH), 128.7 (CH),
125.6 (CH), 54.2 (NC), 31.1 (CH3) ppm. IR (CHCl3) 2974, 1475, 1368,
1053 cm–1. C10H15NOS (197.29): calcd. C 60.88, H 7.66, N 7.10; found
C 61.01, H 7.86, N . 6.95.
N-(2-Methylphenylsulfinyl)-N,N-diethylamine (3ha): Pale yellow
1
oil (44.2 mg, 70 %). H NMR (270 MHz, CDCl3): δ = 7.99–7.96 (m, 1
H), 7.40–7.34 (m, 2 H), 7.20–7.17 (m, 1 H), 3.28–3.14 (m, 2 H), 3.11–
2.98 (m, 2 H), 2.38 (s, 3 H), 1.03 (t, J = 7.2 Hz, 6 H) ppm. 13C{1H} N-(4-Methoxyphenylsulfinyl)-N,N-diethylamine (3ca): Pale yel-
NMR (67.5 MHz, CDCl3): δ = 141.4 (C), 136.1 (C), 130.8 (CH), 130.6
(CH), 126.2 (CH), 125.3 (CH), 42.0 (NCH2), 18.6 (ArCH3), 14.1
(CH3) ppm. IR (CHCl3) 2973, 1456, 1380, 1176, 1085 cm–1. C11H17NOS
(211.32): calcd. C 62.52, H 8.11, N 6.63; found C 62.28, H 8.38, N
6.55.
low oil (48.0 mg, 70 %).
N-(4-Methoxyphenylsulfinyl)-N-(tert-butyl)amine (3ce):[9b] White
solid (47.1 mg, 69 %), m.p. 90–92 °C. 1H NMR (270 MHz, CDCl3): δ =
7.60 (d, J = 8.9 Hz, 2 H), 6.98 (d, J = 8.9 Hz, 2 H), 3.85 (s, 3 H), 3.81
(br. s, 1 H), 1.40 (s, 9 H) ppm. 13C{1H} NMR (67.5 MHz, CDCl3): δ =
161.5 (OC), 137.8 (C), 127.2 (CH), 114.1 (CH), 55.5 (OCH3), 54.1 (NC),
N-(2-Methoxyphenylsulfinyl)-N,N-diethylamine (3ia): Pale yellow
31.1 (CH3) ppm. IR (CHCl3) 2974, 1596, 1495, 1369, 1051 cm–1
.
1
oil (42.0 mg, 62 %). H NMR (270 MHz, CDCl3): δ = 7.89–7.86 (m, 1
C11H17NO2S (227.32): calcd. C 58.12, H 7.54, N 6.16; found C 57.83,
H 7.60, N 5.95.
H), 7.46–7.40 (m, 1 H), 7.14–7.08 (m, 1 H), 6.90 (d, J = 8.2 Hz, 1 H),
3.86 (s, 3 H), 3.22–3.02 (m, 4 H), 1.03 (t, J = 7.2 Hz, 6 H) ppm. 13C{1H}
NMR (67.5 MHz, CDCl3): δ = 156.6 (OC), 139.4 (C), 132.2 (CH), 126.8
(CH), 120.6 (CH), 110.8 (CH), 55.5 (OCH3), 41.5 (NCH2), 14.4
N-(4-Bromophenylsulfinyl)-N,N-diethylamine (3ea): Pale yellow
oil (50.1 mg, 61 %).
(CH3) ppm. IR (CHCl3) 2976, 1477, 1189, 1071, 1041 cm–1
.
N-(4-Bromophenylsulfinyl)-N-(tert-butyl)amine (3ee): White solid
(58.7 mg, 71 %), m.p. 115–116 °C. 1H NMR (270 MHz, CDCl3): δ =
7.62 (d, J = 8.9 Hz, 2 H), 7.55 (d, J = 8.9 Hz, 2 H), 3.88 (br. s, 1 H),
1.40 (s, 9 H) ppm. 13C{1H} NMR (67.5 MHz, CDCl3): δ = 145.7 (C),
131.9 (CH), 127.4 (CH), 125.3 (C), 54.5 (NC), 31.1 (CH3) ppm. IR
(CHCl3) 2976, 1470, 1370, 1216, 1055 cm–1. C10H14BrNOS (276.19):
calcd. C 43.49, H 5.11, N 5.07; found C 43.36, H 5.18, N 4.62.
C11H17NO2S (227.32): calcd. C 58.12, H 7.54, N 6.16; found C 57.79,
H 7.72, N 5.80.
N-(2-Bromophenylsulfinyl)-N,N-diethylamine (3ja): Pale yellow
1
oil (43.0 mg, 52 %). H NMR (270 MHz, CDCl3): δ = 8.01–7.98 (m, 1
H), 7.60–7.56 (m, 1 H), 7.54–7.48 (m, 1 H), 7.36–7.30 (m, 1 H), 3.35–
3.22 (m, 2 H), 3.14–3.01 (m, 2 H), 1.04 (t, J = 7.2 Hz, 6 H) ppm.
13C{1H} NMR (67.5 MHz, CDCl3): δ = 143.0 (C), 133.4 (CH), 132.0 (CH),
127.8 (CH), 127.6 (CH), 121.3 (C), 41.6 (NCH2), 13.9 (CH3) ppm. IR
(CHCl3) 2976, 1447, 1188, 1092, 1070 cm–1. C10H14BrNOS (276.19):
calcd. C 43.49, H 5.11, N 5.07; found C 43.41, H 5.25, N 4.93.
N-(2-Naphthylsulfinyl)-N,N-diethylamine (3ga): Pale yellow oil
(53.0 mg, 73 %).
N-(2-Naphthylsulfinyl)-N-(tert-butyl)amine (3ge): White solid
(55.6 mg, 75 %), m.p. 108–110 °C. 1H NMR (270 MHz, CDCl3): δ =
8.30 (s, 1 H), 7.96–7.86 (m, 3 H), 7.62–7.55 (m, 3 H), 3.92 (br. s, 1 H),
1.44 (s, 9 H) ppm. 13C{1H} NMR (67.5 MHz, CDCl3): δ = 143.5 (C),
134.2 (C), 132.7 (C), 128.7 (CH), 128.6 (CH), 127.8 (CH), 127.7 (CH),
126.9 (CH), 125.7 (CH), 122.2 (CH), 54.4 (NC), 31.1 (CH3) ppm. IR
(CHCl3) 2976, 1470, 1370, 1216, 1055 cm–1. C14H17NOS (247.35):
calcd. C 67.98, H 6.93, N 5.66; found C 67.67, H 6.91, N 5.65.
N-(3-Methylphenylsulfinyl)-N,N-diethylamine (3ka): Pale yellow
oil (51.1 mg, 81 %). 1H NMR (270 MHz, CDCl3): δ = 7.49 (s, 1 H), 7.26
(d, J = 6.9 Hz, 1 H), 7.45 (dd, J = 7.6 and 6.9 Hz, 1 H), 7.35 (d, J =
7.6 Hz, 1 H), 3.13 (q, J = 7.2 Hz, 4 H), 2.42 (s, 3 H), 1.13 (t, J = 7.2 Hz,
6 H) ppm. 13C{1H} NMR (67.5 MHz, CDCl3): δ = 144.1 (C), 138.7 (C),
131.3 (CH), 128.5 (CH), 126.6 (CH), 123.3 (CH), 41.9 (NCH2), 21.4
(ArCH3), 14.4 (CH3) ppm. IR (CHCl3) 2979, 1463, 1381, 1216,
1087 cm–1. C11H17NOS (211.32): calcd. C 62.52, H 8.11, N 6.63; found
C 62.37, H 8.27, N 6.45.
N-(2-Methylphenylsulfinyl)piperidine (3hc): Pale yellow oil
1
(57.0 mg, 85 %). H NMR (270 MHz, CDCl3): δ = 7.93–7.90 (m, 1 H),
Eur. J. Org. Chem. 2016, 2157–2162
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2161
© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
[4] For selected articles, see: a) F. A. Davis, A. J. Friedman, E. W. Kluger, E. B.
Sleibo, E. R. Fretz, A. P. Milicia, W. C. LeMasters, M. D. Bentley, J. A. Lacadie,
I. B. Douglass, J. Org. Chem. 1977, 42, 967–972; b) A. Correa, I. Tellitu, E.
Domínguez, R. SanMartin, Org. Lett. 2006, 8, 4881–4813; c) S. M. Nair, S.
Devipriya, D. Sethumadhara, Tetrahedron Lett. 2006, 47, 1109–1111; d) X.
Huang, J. Wang, Z. Ni, S. Wang, Y. Pan, Chem. Commun. 2014, 50, 4582–
4584.
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3740; b) T. Billard, A. Greiner, B. R. Langlois, Tetrahedron 1999, 55, 7243–
7250; c) J. L. Ruano, J. Alemán, A. Parra, M. B. Cid, Org. Synth. 2007, 84,
129–136; d) F. A. Davis, Y. Zhang, Y. Andemichael, T. Fang, D. L. Farelli, H.
Zhang, J. Org. Chem. 1999, 64, 1403–1406; e) F. A. Davis, R. E. Reddy,
J. M. Sewecyk, G. V. Reddy, P. S. Portonovo, H. Zhang, D. Fanell, R. T.
Reddy, P. Zhou, P. J. Carroll, J. Org. Chem. 1997, 62, 2555–2563; f) D. L.
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Synth. 2000, 77, 50–63.
[6] a) M. Hamata, M. Kahraman, J. Org. Chem. 1998, 63, 6845–6851; b) M.
Harmata, R. J. Claasenll, C. L. Barnes, J. Org. Chem. 1991, 56, 5059–5062.
[7] a) M. Furukawa, T. Okawara, Synthesis 1976, 339–340; b) F. Yuste, V. M.
Mastranzo, Synthesis 2008, 311–312; c) D. A. Cogan, G. Liu, K. Kim, B. A.
Backes, J. A. Ellman, J. Am. Chem. Soc. 1998, 120, 8011–8019; d) F. A.
Davis, A. J. Friedman, E. Kluger, J. Am. Chem. Soc. 1974, 96, 5000–5001;
e) P. K. Shyam, Y. K. Kim, C. Lee, H.-Y. Jang, Adv. Synth. Catal. 2016, 358,
56–61.
7.39–7.34 (m, 2 H), 7.23–7.19 (m, 1 H), 3.13–3.08 (m, 2 H), 2.98–2.91
(m, 2 H), 2.38 (s, 3 H), 1.61–1.52 (m, 6 H) ppm. 13C{1H} NMR
(67.5 MHz, CDCl3): δ = 140.4 (C), 136.2 (C), 131.0 (CH), 130.6 (CH),
125.9 (CH), 125.6 (CH), 46.6 (NCH2), 26.1 (CH2), 24.0 (CH2), 18.7
(ArCH3) ppm. IR (CHCl3) 2942, 1453, 1273, 1215, 1075 cm–1
.
C12H17NOS (223.33): calcd. C 64.53, H 7.67, N 6.27; found C 64.57, H
7.87, N 6.50.
N-(2-Methylphenylsulfinyl)-N-(tert-butyl)amine (3he):[9b] White
solid (47.4 mg, 75 %), m.p. 125–126 °C. 1H NMR (270 MHz, CDCl3):
δ = 8.02–7.98 (m, 1 H), 7.40–7.36 (m, 2 H), 7.20–7.17 (m, 1 H), 3.60
(br. s, 1 H), 2.40 (s, 3 H), 1.40 (s, 9 H) ppm. 13C{1H} NMR (67.5 MHz,
CDCl3): δ = 144.4 (C), 135.4 (C), 130.7 (CH), 130.6 (CH), 126.6 (CH),
123.1 (CH), 54.4 (NC), 30.9 (CH3), 18.7 (ArCH3) ppm. IR (CHCl3) 2973,
1470, 1368, 1072 cm–1. C11H17NOS (211.32): calcd. C 62.52, H 8.11,
N 6.63; found C 62.66, H 8.22, N 6.49.
N-(2-Methoxyphenylsulfinyl)piperidine (3ic): White solid
(58.7 mg, 82 %), m.p. 120–121 °C. 1H NMR (270 MHz, CDCl3): δ =
7.84–7.81 (m, 1 H, Ar-H), 7.47–7.40 (m, 1 H, Ar-H), 7.14–7.08 (m, 1
H, Ar-H), 6.94 (d, J = 7.9 Hz, 1 H, Ar-H), 3.87 (s, 3 H, OCH3), 3.11–
3.04 (m, 2 H, NCH2), 2.93–2.86 (m, 2 H, CH2), 1.58–1.48 (m, 6 H,
CH2) ppm. 13C{1H} NMR (67.5 MHz, CDCl3): δ = 156.7 (OC), 132.2 (C),
130.4 (CH), 127.0 (CH), 120.5 (CH), 111.1 (CH), 55.8 (OCH3), 46.2
(NCH2), 26.2 (CH2), 24.2 (CH2) ppm. IR (CHCl3) 2939, 2851, 1476,
1272, 1079 cm–1. C12H17NO2S (239.33): calcd. C 60.22, H 7.16, N 5.85;
found C 60.09, H 7.32, N 5.76.
[8] M. Harmata, P. Zheng, C. Huang, M. G. Gomes, W. Ying, K.-O. Ranyamil,
G. Balan, N. L. Calkins, J. Org. Chem. 2007, 72, 683–685.
[9] a) N. Taniguchi, Eur. J. Org. Chem. 2010, 2670–2673; b) N. Taniguchi,
Synlett 2007, 1917–1920; c) C. Lee, Y. N. Lim, H.-Y. Jang, Eur. J. Org. Chem.
2015, 5934–5938.
[10] It is well known that the PF6 anion usually stabilizes a metal cation. This
effect can enhance the efficiency of metal-catalyzed reactions. Numer-
ous reactions have been reported, see: a) J. Srogl, G. D. Allred, L. S.
Liebeskind, J. Am. Chem. Soc. 1997, 119, 12376–12377; b) C. A. Merlic,
M. E. Pauly, J. Am. Chem. Soc. 1996, 118, 11319–11320; c) G. J. Kubas,
Inorg. Synth. 1979, 19, 90–92.
[11] For the preparation of PhSCu see: Adams, R., Reifschneider, W. Ferretti,
A. Organic Synthesis, vol. 5, John Wiley & Sons, New York, 1973, p. 107–
110.
N-(2-Methoxyphenylsulfinyl)-N-(tert-butyl)amine (3ie): Pale yel-
low oil (47.5 mg, 70 %). H NMR (270 MHz, CDCl3): δ = 7.86 (d, J =
1
7.6 Hz, 1 H), 7.43 (dd, J = 7.6 and 8.5 Hz, 1 H), 7.10 (dd, J = 7.6 and
8.5 Hz, 1 H), 6.93 (d, J = 8.5 Hz, 1 H), 3.88 (s, 3 H), 3.88 (br. s, 1 H),
1.38 (s, 9 H) ppm. 13C{1H} NMR (67.5 MHz, CDCl3): δ = 155.8 (OC),
134.4 (CH), 132.3 (C), 124.9 (CH), 120.9 (CH), 111.4 (CH), 55.6 (OCH3),
54.0 (NC), 30.9 (CH3) ppm. IR (CHCl3) 2974, 1478, 1274, 1218,
1042 cm–1. C11H17NO2S (227.32): calcd. C 58.12, H 7.54, N 6.16;
found C 58.10, H 7.70, N 6.02.
[12] On the basis of MS analyses, it appears that sulfinamide 3aa′ bearing
18O isotope is obtained as a major product.
[13] In the present reaction, iodonium or bromium ion is necessary. Reactions
using CuCl, CuCl2, CuOAc and Cu(OAc)2 lead to lower yields or simply
are unable to produce corresponding sulfinamides.
[14] a) W. Takagi, K. Kikukawa, N. Kunieda, S. Oae, Bull. Chem. Soc. Jpn. 1966,
39, 614–617; b) S. Oae, Y. Ohnishi, W. Kozuka, Bull. Chem. Soc. Jpn. 1966,
39, 364–366.
Keywords: Homogeneous catalysis · Copper · Oxidative
coupling · Thiols · Sulfinamides · Amines
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Ed. 2003, 42, 5400–5449; Angew. Chem. 2003, 115, 5558; b) T. Kondo, T.
Mitsudo, Chem. Rev. 2000, 100, 3205–3220.
[2] For selected reviews, see: a) P. Metzner, A. Thuillier, Sulfur Reagents in
Organic Synthesis (Eds.: A. R. Katritzky, O. Meth-Cohn, C. W. Rees), Aca-
demic Press, San Diego, 1994; b) Comprehensive Organic Synthesis, vol.
6 (Eds.: B. M. Trost, I. Fleming), Pergamon Press, New York, 1991; c) Com-
prehensive Organic Synthesis, vol. 4 (Eds.: B. M. Trost, I. Fleming) Perga-
mon Press, New York, 1991.
[15] Organometallic Mechanisms and Catalysis (Ed.: J. K. Kochi), Academic
Press, London, UK, 1978.
[16] G. B. Kauffman, C. Y. Fang, N. Viswanathan, G. Townsend, Inorg. Synth.,
John Wiley & Sons, New York, 1983, vol. 22, p. 101–103.
[17] In the absence of oxygen, the reaction using H218O gave only the 18O-
labelled sulfinamide in 4 % yield.
[18] J.-i. Matsuo, D. Iida, K. Tatani, T. Mukaiyama, Bull. Chem. Soc. Jpn. 2002,
75, 223–234.
[3] For a selected review, see: a) F. A. Davis, J. Org. Chem. 2006, 71, 8993–
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Received: January 24, 2016
Published Online: April 5, 2016
Eur. J. Org. Chem. 2016, 2157–2162
www.eurjoc.org
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© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim