One-pot multicomponent asymmetric synthesis of α-amidosulfides from thiophenol and N-acylimines generated in situ from α-amidosulfones

Article abstract of DOI:10.1007/s00706-016-1744-4

Abstract: A novel one-pot, multicomponent asymmetric synthesis of α-amidosulfides was described. By employing chiral phosphoric acid as Br?nsted acid and catalyst, α-amidosulfides were obtained in excellent yields with high to excellent enantioselectivities via reaction of thiophenol and N-acylimines generated in situ from α-amidosulfones. Graphical abstract: [Figure not available: see fulltext.]

Full text of DOI:10.1007/s00706-016-1744-4

Monatsh Chem
DOI 10.1007/s00706-016-1744-4
ORIGINAL PAPER
One-pot multicomponent asymmetric synthesis of a-amidosulfides
from thiophenol and N-acylimines generated in situ from a-
amidosulfones
Lanxiang Shi1 Baohua Zhang1 Jinan Zhang2 Xiuxiao Shi3 Ruixia Guo1
•
•
•
•
Received: 27 January 2016 / Accepted: 15 March 2016
Ó Springer-Verlag Wien 2016
Abstract A novel one-pot, multicomponent asymmetric
synthesis of a-amidosulfides was described. By employing
chiral phosphoric acid as Brønsted acid and catalyst, a-
amidosulfides were obtained in excellent yields with high
to excellent enantioselectivities via reaction of thiophenol
and N-acylimines generated in situ from a-amidosulfones.
Graphical abstract
Introduction
a-Amidosulfides are an important class of structural
motifs found in a large of pharmaceutical agents and
heterocycles [1, 2]. In particular, because a-amidosulfides
and a-amidosulfones can generate intermediate imine in
the presence of Brønsted acid [3] or Lewis acid [4], they
are widely used in the synthesis of important compounds.
For example, 2-indolylmethanamines can be obtained
from indoles by nucleophilic addition of imine generated
from a-amidosulfides catalyzed by phosphoric acid [3].
For another example, 1,3-diamine derivatives can be
prepared from enecarbamates and imine generated
from hemiaminal ethers in presence of chiral phosphoric
acid [5].
However, few methods are known for the preparation of
a-amidosulfides and most of them involve multistep pro-
cesses that have limited application scope [6]. Therefore,
the development of simple and convenient methods for
preparing the a-amidosulfides, especially for the optically
active ones, is particularly important. Recently, George
reported a method for obtaining a-amidosulfides in high
yields by nucleophilic addition of thiols to a-amidosulfones
in basic media [3]. Fang demonstrated asymmetric addition
of thiols to trifluoromethylaldimine catalyzed by a
bifunctional squaramide-based organocatalyst for the con-
struction of chiral trifluoromethylated a-amidosulfides [7].
Wang also described the synthesis of chiral a-amidosul-
fides from thiols and a-amidosulfones by using amino acid-
based bifunctional thiourea-ammonium salt as catalysts [8].
Herein, we reported an effective asymmetric synthesis of a-
amidosulfides from thiophenol and N-acylimines generated
in situ from a-amidosulfones in presence of chiral phos-
phoric acid.
Keywords a-Amidosulfide Á a-Amidosulfone Á
Chiral phosphoric acid Á Thiophenol
& Lanxiang Shi
kedashilanxiang@126.com
1
College of Chemical Engineering, Shijiazhuang University,
050035 Shijiazhuang, China
2
China State Construction Engrg. Corp. (Middle East)
(L.L.C.), Dubai, UAE
3
Hebei Veyong Bio-Chemical Co. Ltd, 050000 Shijiazhuang,
China
123

L. Shi et al.
Results and discussion
X
X = SiPh3 (3a)
O
O
O
Initially, we examined the reaction of 4-cholorothiophenol
(1a, 1.2 mmol), chiral phosphoric acid 3a (5 mol%) and a-
amidosulfone 2a (1 mmol) [4, 9] in toluene at -40 °C
(Scheme 1). To our satisfaction, the reaction was complete
in 24 h and yielded 90 % of a-amidosulfide 4a with 14 %
ee. The result indicated that the chiral phosphoric acid is
used as a catalyst for both enantioselective addition reac-
tion and formation of N-acylimines from a-amidosulfone in
quantitative yield [10]. To search for more optimal reaction
conditions, we screened a number of structurally related
chiral phosphoric acids (Fig. 1), solvents and reaction
temperature. Table 1 summarizes these results. 3a was the
most effective catalyst in terms of stereochemical control,
providing an excellent enantioselection. Among the chosen
solvents toluene was the best one for the synthesis of a-
amidosulfide. Upon cooling the reaction, the addition
product was obtained with higher enantioselectivity.
To develop a general, simple, and convenient method
for construction of a-amidosulfide, we sought to the new
technology for the synthesis of a-amidosulfide in one-pot
by using 3a as catalyst and Brønsted acid, benzaldehyde,
benzamide, phenylsulfinic acid, and thiophenol as materi-
als. Thus, in the presence of MgSO4, a toluene solution of
benzaldehyde (5a), benzamide (6), and phenylsulfinic acid
(7) was vigorously stirred at room temperature for 12 h
[11]. Upon complete consumption of the benzaldehyde, the
mixture was cooled to -78 °C, 3a and 4-chlorothiophenol
was added. The resulting mixture was vigorous stirred for
additional 24 h, and the corresponding product 4a was
obtained in 90 % yield with 86 % ee.
X = 2-naphthyl (3b)
P
X = 3,5-(CF3)2C5H3 (3c)
X = Ph (3d)
OH
X
Fig. 1 The structures of catalysts 3
Conclusion
We have described a new one-pot, sequential multicom-
ponent synthesis of optically active a-amidosulfides from
readily accessible starting materials. The method was
general, simple, and convenient, the a-amidosulfides were
obtained in excellent yields with high to excellent
enantioselectivities.
Experimental
1H and 13C spectra were recorded on a 400 MHz instru-
ment at 400 MHz (1H) and 100 MHz (13C) with TMS as
internal standard. Melting points were measured with
micromelting point apparatus. High-performance liquid
chromatography (HPLC) was conducted on an Agilent
1100 liquid chromatograph; HPLC analysis using Diacel
chiralcel OD-H column (eluent: hexane/2-propanol); IR
spectra were performed as KBr pellets on a Bruker VER-
TEX 70 spectrophotometer; MS spectra were recorded on
a. ZAB-HS and ESQUIRE 6000 mass spectrometer.
General procedure for the preparation of a-amidosulfides
4
We next examined a series of aromatic aldehydes and
thiophenols to establish the scope of the novel one-pot
sequential multicomponent synthesis of a-amidosulfides
(Scheme 2, Table 2). Under our optimized reaction con-
ditions, benzaldehyde bearing electron withdrawing
substituents such as chloro, fluoro, and bromo produced
excellent yields and enantioselectivities. Similar result was
obtained with 2-naphthaldehyde. 3-Methylbenzaldehyde
and 4-methylbenzaldehyde were converted into corre-
sponding products in excellent yields with high
enantioselectivities. Thiophenol bearing halogen sub-
stituent has better yield and enantioselectivity than itself.
To a solution of benzamide (6, 1.2 mmol) and phenyl-
sulfinic acid (7, 1.2 mmol) in 4 cm3 toluene, anhydrous
magnesium sulfate (0.9 mmol) was added and the mixture
was vigorously stirred at room temperature, and the flask
was purged with argon. The aldehydes 5 (1 mmol) was
dissolved in 1 cm3 toluene and the solution was added
dropwise, the resulting reaction mixture was vigorous
stirred overnight. Then the resulting mixture was cooled to
-78 °C, 3a (0.05 mmol) and thiophenols 1 (1.5 mmol)
were then added, and the solution was vigorously stirred
for additional 24 h. After warming to room temperature,
Scheme 1
123

One-pot multicomponent asymmetric synthesis of a-amidosulfides from thiophenol and N-…
Table 1 Optimization of the reaction conditions
Entry
Catalyst
Solvent
Temp/°C
Yield/%a
Ee/%b
1
2
3
4
5
6
7
8
a
3a
3a
3a
3b
3c
3d
3a
3a
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
DCM
-40
-60
-78
-78
-78
-78
-78
-78
90
91
90
89
93
91
87
85
14
58
86
12
82
78
53
49
THF
Isolated yield after column purification
b
Determined by HPLC analysis using Diacel chiralcel OD column (eluent: hexane/2-propanol)
Scheme 2
Table 2 Asymmetric synthesis of a-amidosulfides
Entry
R1
R2
Product
Yield/
a
%
Ee/
b
%
1
2
3
4
5
6
7
8
9
10
a
C6H5
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl
4-Cl
4-Br
H
4a
4b
4c
4d
4e
4f
90
93
92
95
93
87
88
90
87
84
86
91
89
88
90
83
81
80
78
70
4-FC6H4
3-ClC6H4
4-ClC6H4
4-BrC6H4
2-C10H7
3-MeC6H4
4-MeC6H4
C6H5
4g
4h
4i
C6H5
4j
Isolated yield
b
Determined by HPLC analysis using Diacel chiralcel OD column (eluent: hexane/2-propanol)
the solid in the reaction mixture was removed by filtration
and the filtrate was concentrated in vacuo. The residues
was purified by column chromatography on neutral
aluminum oxide (hexane/EtOAc = 10:1) to give a-amido-
sulfides 4.
1.0 cm3/min, 228 nm), tminor = 10.6 min, tmajor = 17.7 -
min; 1H NMR (400 MHz, CDCl3): d = 7.66 (d,
J = 7.2 Hz, 2H), 7.52–7.47 (m, 3H), 7.42–7.24 (m, 7H),
7.30–7.22 (m, 2H), 6.77–6.73 (m, 2H) ppm; 13C NMR
(100 MHz, CDCl3): d = 166.2, 138.3, 134.2, 133.8, 133.6,
131.9, 131.4, 129.2, 128.9, 128.7, 128.6, 126.8, 126.6,
59.8 ppm; ESI–MS: m/z = 376.0 ([M ? Na]?); IR (KBr):
N-[(4-Chlorophenylthio)(phenyl)methyl]benzamide
(4a, C20H16ClNOS)
m: = 3303, 2966, 1682, 1579, 1434, 1305, 753 cm-1
;
HRMS (ESI): m/z calcd for C20H16ClNOS ([M?Na]?)
White solid; m.p.: 181–183 °C; 86 % ee determined by
HPLC analysis (chiralpak OD-H, hexane/i-PrOH = 90:10,
376.0533, found 376.0528.
123

L. Shi et al.
N-[(4-Chlorophenylthio)(4-fluorophenyl)methyl]benza-
mide (4b, C20H15ClFNOS)
N-[(4-Chlorophenylthio)(2-naphthalenyl)methyl]benza-
mide (4f, C24H18ClNOS)
White solid; m.p.: 186–189 °C; 91 % ee determined by
HPLC analysis (chiralpak OD-H, hexane/i-PrOH = 90:10,
1.0 cm3/min, 228 nm), tminor = 8.7 min, tmajor = 14.4 min;
1H NMR (400 MHz, CDCl3): d = 7.65 (d, J = 7.6 Hz, 2H),
7.53–7.36 (m, 7H), 7.26–7.20 (m, 2H), 7.08–7.04 (m, 2H),
6.73–6.66 (m, 2H) ppm; 13C NMR (100 MHz, CDCl3): d =
166.3, 163.8, 116.4, 134.5, 134.3, 134.2, 133.8, 133.5,
132.0, 131.2, 129.3, 128.7, 128.5, 128.4, 126.9, 115.9,
115.7, 59.2 ppm; ESI–MS: m/z = 394.8 ([M?Na]?); IR
(KBr): m = 3306, 2970, 1525, 1490, 1150, 801, 747, 514,
White solid; m.p.: 190–193 °C; 83 % ee determined by
HPLC analysis (chiralpak OD-H, hexane/i-PrOH = 90:10,
1.0 cm3/min, 228 nm), tminor = 22.1 min, tmajor = 27.0 min;
1H NMR (400 MHz, CDCl3): d = 7.87–7.70 (m, 4H), 7.67–
7.60 (m, 2H), 7.54–7.50 (m, 1H), 7.45–7.41 (m, 7H), 7.26–
7.22 (m, 2H), 6.90 (d, J = 9.2 Hz, 1H), 6.79 (d, J = 9.2 Hz,
1H) ppm; 13C NMR (100 MHz, CDCl3): d = 166.3, 135.6,
134.4, 133.9, 133.7, 133.2, 133.1, 132.0, 131.4, 129.3,
128.9, 128.7, 128.1, 127.7, 126.9, 126.6, 125.5, 124.5,
60.1 ppm; ESI–MS: m/z = 426.1 ([M?Na]?); IR (KBr): m
= 3310, 3049, 3001, 1669, 1561, 1384, 840, 743, 615,
494, 396 cm-1
.
471 cm-1
.
N-[(4-Chlorophenylthio)(3-chlorophenyl)methyl]benza-
mide (4c, C20H15Cl2NOS)
N-[(4-Chlorophenylthio)(m-tolyl)methyl]benzamide
(4g, C21H18ClNOS)
White solid; m.p.: 165–167 °C; 89 % ee determined by
HPLC analysis (chiralpak OD-H, hexane/i-PrOH =
White solid; m.p.: 173–176 °C; 81 % ee determined by
HPLC analysis (chiralpak OD-H, hexane/i-PrOH = 90:10,
1.0 cm3/min, 228 nm), tminor = 7.5 min, tmajor = 14.2 min;
1H NMR (400 MHz, CDCl3): d = 7.65 (d, J = 7.6 Hz, 2H),
7.50–7.48 (m, 1H), 7.41–7.37 (m, 4H), 7.27–7.21 (m, 5H),
7.13 (d, J = 6.4 Hz, 1H), 6.76–6.70 (m, 2H), 2.35 (s, 3H)
ppm; 13C NMR (100 MHz, CDCl3): d = 166.2, 138.7,
138.2, 134.0, 133.6, 131.8, 129.2, 128.8, 128.6, 127.3,
126.9, 123.6, 21.5 ppm; ESI–MS: m/z = 390.1 ([M?Na]?);
IR (KBr): m = 3309, 3079, 3050, 3022, 1680, 1575, 1492,
1027, 801, 728, 693, 465 cm-1; HRMS (ESI): m/z calcd for
C21H18ClNOS ([M?Na]?) 390.0690, found 390.0681.
90:10, 1.0 cm3/min, 228 nm), tminor = 9.0 min, tmajor
=
1
15.0 min; H NMR (400 MHz, CDCl3): d = 7.66 (d, J =
7.2 Hz, 2H), 7.65–7.50 (m, 2H), 7.249–7.29 (m, 5H),
7.26–7.20 (m, 4H), 6.73–6.68 (m, 2H) ppm; 13C NMR
(100 MHz, CDCl3): d = 166.3, 140.3, 134.8, 134.6,
133.9, 133.3, 132.1, 130.9, 130.1, 126.9, 126.8, 124.9,
59.3 ppm; ESI–MS: m/z = 410.0 ([M?Na]?); IR (KBr):
m = 3326, 3063, 1668, 1601, 1573, 1432, 1303, 1094,
824, 759 cm-1
.
N-[(4-Chlorophenylthio)(4-chlorophenyl)methyl]benza-
mide (4d, C20H15Cl2NOS)
White solid; m.p.: 195–197 °C; 88 % ee determined by
HPLC analysis (chiralpak OD-H, hexane/i-PrOH = 90:10,
1.0 cm3/min, 228 nm), tminor = 9.6 min, tmajor = 13.6 min;
1H NMR (400 MHz, CDCl3): d = 7.65 (d, J = 7.2 Hz, 2H),
7.64–7.50 (m, 1H), 7.44–7.33 (m, 7H), 7.26–7.24 (m, 3H),
6.70–6.63 (m, 2H) ppm; 13C NMR (100 MHz, CDCl3): d =
166.3, 163.8, 116.4, 134.5, 134.3, 134.2, 137.8, 133.5,
132.0, 131.1, 129.3, 128.7, 128.5, 128.4, 126.9, 155.9,
155.7, 59.2 ppm; ESI–MS: m/z = 410.0 ([M?Na]?); IR
(KBr): m = 3308, 3064, 1660, 1570, 1435, 1010, 960, 775,
N-[(4-Chlorophenylthio)(p-tolyl)methyl]benzamide
(4h, C21H18ClNOS)
White solid; m.p.: 198–199 °C; 80 % ee determined by
HPLC analysis (chiralpak OD-H, hexane/i-PrOH = 90:10,
1.0 cm3/min, 228 nm), tminor = 8.5 min, tmajor = 11.9 min;
1H NMR (400 MHz, CDCl3): d = 7.65 (d, J = 6.8 Hz, 2H),
7.64–7.50 (m, 1H), 7.47–7.36 (m, 6H), 7.26–7.17 (m, 4H),
6.73–6.66 (m, 2H), 2.35 (s, 1H) ppm; 13C NMR (100 MHz,
CDCl3): d = 166.2, 138.5, 135.3, 134.1, 133.6, 131.9,
131.6, 129.5, 129.2, 128.8, 128.7, 126.5, 126.0, 59.6,
21.3 ppm; ESI–MS: m/z = 390.1 ([M?Na]?); IR (KBr): m
= 3311, 3054, 1676, 1580, 1500, 1030, 806, 730, 691,
701 cm-1
.
N-[(4-Chlorophenylthio)(4-bromophenyl)methyl]benza-
mide (4e, C20H15BrClNOS)
463 cm-1
.
White solid; m.p.: 202–205 °C; 90 % ee determined by
HPLC analysis (chiralpak OD-H, hexane/i-PrOH = 90:10,
1.0 cm3/min, 228 nm), tminor = 11.1 min, tmajor = 14.2 min;
1H NMR (400 MHz, CDCl3): d = 7.65 (d, J = 7.6 Hz, 2H),
7.54–7.49 (m, 3H), 7.44–7.36 (m, 6H), 7.25–7.21 (m, 2H),
6.68–6.61 (m, 2H) ppm; 13C NMR (100 MHz, CDCl3): d =
166.3, 134.4, 134.6, 133.9, 133.4, 132.0, 130.9, 129.4,
128.8, 128.3, 126.9, 122.6, 59.3 ppm; ESI–MS: m/z =
453.9 ([M?Na]?); IR (KBr): m = 3303, 3055, 1665, 1578,
N-[(4-Bromophenylthio)(phenyl)methyl]benzamide
(4i, C20H16BrNOS)
White solid; m.p.: 187–189 °C; 78 % ee determined by
HPLC analysis (chiralpak OD-H, hexane/i-PrOH = 90:10,
1.0 cm3/min, 228 nm), tminor = 9.5 min, tmajor = 15.0 min;
1H NMR (400 MHz, CDCl3): d = 7.66 (d, J = 6.8 Hz, 2H),
7.65–7.47 (m, 3H), 7.43–7.30 (m, 9H), 7.77–7.71 (m, 2H)
ppm; 13C NMR (CDCl3): d = 166.3, 138.3, 133.9, 132.6,
132.1, 132.0, 128.9, 128.9, 128.7, 128.6, 126.6, 122.2,
59.5 ppm; ESI–MS: m/z = 420.0 ([M?Na]?); IR (KBr): m
1473, 1067, 803, 732, 683, 671, 459 cm-1
.
123

One-pot multicomponent asymmetric synthesis of a-amidosulfides from thiophenol and N-…
= 3304, 2966, 1680, 1579, 1436, 1307, 801, 732, 671,
459 cm-1
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White solid; m.p.: 166–169 °C; 70 % ee determined by
HPLC analysis (chiralpak OD-H, hexane/i-PrOH = 90:10,
1.0 cm3/min, 228 nm), tminor = 9.1 min, tmajor = 10.7 min;
1H NMR (400 MHz, CDCl3): d = 7.63 (d, J = 6.8 Hz, 2H),
7.50–7.45 (m, 5H), 7.40–7.30 (m, 5H), 7.29–7.25 (m, 5H),
6.77 (s, 2H) ppm; 13C NMR (100 MHz, CDCl3): d = 166.3,
138.6, 133.7, 133.0, 132.5, 131.8, 129.0, 128.8, 128.6,
128.4, 128.0, 126.9, 126.5, 59.6 ppm; ESI–MS: m/z =
342.1 ([M?Na]?); IR (KBr): m = 3311, 2960, 1681, 1585,
1450, 688, 672 cm-1; HRMS (ESI): m/z calcd for C20H17-
NOS ([M?Na]?) 342.0923, found 342.0925.
11. Marcantoni E, Petrini M, Profeta R (2004) Tetrahedron Lett
45:2133
Acknowledgments We thank the Hebei province of china science
and technology support programs (Grant No. 15226601D).
123