Squaramide-catalysed enantio- and diastereoselective sulfa-Michael addition of thioacetic acid to α,β-disubstituted nitroalkenes

Article abstract of DOI:10.1039/c2ob26068a

A highly enantio- and diastereoselective sulfa-Michael addition of thioacetic acid to α,β-disubstituted nitroalkenes catalysed by a chiral squaramide organocatalyst has been described. This organocatalytic reaction at an extremely low catalyst loading (0.2 mol%) furnished synthetically useful β-nitro sulfides in excellent yields with good diastereoselectivities and high enantioselectivities (up to 94:6 dr, 95% ee). In addition, the catalytic reaction can be performed on a 10 gram scale, and facile transformation into taurine derivative is also presented.

Full text of DOI:10.1039/c2ob26068a

View Article Online / Journal Homepage / Table of Contents for this issue
This article is part of the
Organocatalysis
web themed issue
Guest editors: Professors Keiji Maruoka, Hisashi
Yamamoto, Liu-Zhu Gong and Benjamin List
All articles in this issue will be gathered together online at
www.rsc.org/organocatalysis

Dynamic Article Links
Organic &
Biomolecular
Chemistry
Cite this: Org. Biomol. Chem., 2012, 10, 6876
www.rsc.org/obc
PAPER
Squaramide-catalysed enantio- and diastereoselective sulfa-Michael addition
of thioacetic acid to α,β-disubstituted nitroalkenes†
Wen Yang and Da-Ming Du*
Received 4th June 2012, Accepted 4th July 2012
DOI: 10.1039/c2ob26068a
A highly enantio- and diastereoselective sulfa-Michael addition of thioacetic acid to α,β-disubstituted
nitroalkenes catalysed by a chiral squaramide organocatalyst has been described. This organocatalytic
reaction at an extremely low catalyst loading (0.2 mol%) furnished synthetically useful β-nitro sulfides in
excellent yields with good diastereoselectivities and high enantioselectivities (up to 94 : 6 dr, 95% ee). In
addition, the catalytic reaction can be performed on a 10 gram scale, and facile transformation into taurine
derivative is also presented.
of good hydrogen-bonding organocatalyst, chiral squaramide is
Introduction
increasingly utilized in organocatalysis.6 After the pioneering
The asymmetric sulfa-Michael addition is one of the fundamen-
tal carbon–sulfur bond forming reactions in organic synthesis,
and plays a key role in the synthesis of biologically active sulfur-
containing compounds.1 In recent years, considerable efforts
have been devoted, and various approaches for asymmetric
sulfa-Michael additions have been reported.2,3 To date, these
reports have mainly focused on alkyl or aryl thiols as Michael
donors. However, studies on the asymmetric sulfa-Michael
addition employing thioacetic acid are currently limited.4,5
Among them, the asymmetric sulfa-Michael addition of thio-
acetic acid to nitroalkenes is extremely attractive because it can
provide an easy access to synthetically useful 1,2-aminothiol or
taurine derivatives. To the best of our knowledge, only three
reports have been described.5 Wang first reported the asymmetric
sulfa-Michael addition of thioacetic acid to trans-β-nitrostyrenes
catalysed by Takemoto’s thiourea, but unsatisfactory enantio-
selectivities (20–70% ee) were achieved.5a Subsequently, Ellman
and co-workers developed a sulfinyl urea organocatalyst to
promote this reaction with high enantioselectivities, however,
harsh reaction condition (−78 °C) was required.5b Very recently,
Ellman and co-workers extended the substrate scope to an array
of cyclic α,β-disubstituted nitroalkenes.5c In view of these
limited successes, the development of other new efficient cata-
lytic systems for high enantioselectivity, low catalyst loading,
and mild reaction conditions is in great demand. As a new class
work reported by Rawal, various asymmetric reactions catalysed
by squaramide organocatalysts have been developed.3f,7
In recent years, our group has also done some related research
in this field.8 As a continuation of the research on squaramide-
catalysed asymmetric reactions, in this paper, we wish to
describe the asymmetric sulfa-Michael addition of thioacetic
acid to α,β-disubstituted nitroalkenes catalysed by chiral squar-
amide organocatalysts.
Results and discussion
Initially, we started our investigation with the sulfa-Michael
addition of thioacetic acid 2 to trans-β-methyl-β-nitrostyrene 1a
as a model reaction. To our delight, when the model reaction
was performed in the presence of 5 mol% catalyst I in CH2Cl2 at
room temperature for 2 h, the desired adduct 3a was obtained in
97% yield with 75 : 25 dr and 70% ee. With the promising
result, a series of squaramide catalysts (Fig. 1) was readily pre-
pared and their catalytic capacity to promote the addition was
evaluated. The catalyst screening results are shown in Table 1.
Squaramides II–IV derived from chiral 1,2-diaminocyclohexane
were examined, and squaramide III was found to give a better
result (80 : 20 dr, 84% ee) than squaramide I (entries 1–4).
Cinchona-based squaramides V and VI afforded the corres-
ponding adducts only with moderate diastereoselectivities and
enantioselectivities (entries 5 and 6). When C2-symmetric squar-
amides VII and VIII were tested, the adducts with very low
enantioselectivities (18% ee and 17% ee, respectively) were
obtained (entries 7 and 8). For investigation on the effect of
steric hindrance, structural variations IX and X bearing a piperi-
dinyl group as squaramide III were screened, but no better
results were observed (entries 9–10). In contrast, common
School of Chemical Engineering and Environment, Beijing Institute of
Technology, Beijing 100081, People’s Republic of China.
E-mail: dudm@bit.edu.cn; Tel: +86 10 68914985
†Electronic supplementary information (ESI) available: Copies of 1H
and 13C NMR spectra of new compounds, X-ray crystal structure cif file
of 3e and HPLC chromatograms. CCDC 886084. For ESI and crys-
tallographic data in CIF or other electronic format see DOI:
10.1039/c2ob26068a
6876 | Org. Biomol. Chem., 2012, 10, 6876–6884
This journal is © The Royal Society of Chemistry 2012

The solvent optimization disclosed that various common sol-
vents were well tolerated and CH2Cl2 was the best reaction
medium (entries 1–7). It is noteworthy that the reaction pro-
ceeded smoothly in brine to achieve comparable good diastereo-
selectivity and enantioselectivity (entry 8). When the reaction
was performed at 0 °C, an increase on the stereoselectivity
(85 : 15 dr, 90% ee) was observed (entry 9). Unfortunately,
further lowering the temperature did not improve the enantio-
selectivity (entries 10 and 11). Subsequently, the effect of cata-
lyst loading was investigated. Interestingly, increasing the
catalyst loading (10 mol%) led to a slight decrease in the stereo-
selectivity, while good diastereoselectivity and high enantio-
selectivity were maintained with a reduced catalyst loading
(1 or 0.2 mol%) (entries 12–14). Further reducing the cata-
lyst loading to 0.1 mol % decreased the enantioselectivity
slightly (entry 15). Additionally, the amount of solvent was
simply examined, and only a small impact was observed
(entries 16 and 17).
Having established the optimal reaction conditions, we
explored the scope of the asymmetric sulfa-Michael addition of
thioacetic acid to α,β-disubstituted nitroalkenes. The results are
presented in Table 3. An array of aromatic α,β-disubstituted
nitroalkenes 1a–k bearing electron-neutral, electron-withdrawing
or electron-donating substitutions reacted smoothly with thioace-
tic acid 2 to afford the corresponding adducts in excellent yields
with good diastereoselectivities and high enantioselectivities
(87–95% ee) (entries 1–11). The position of the substitution at
the aromatic ring had an effect on the enantioselectivity. Steric
hindrance benefits the enantioselectivity. These nitroalkenes with
ortho groups on the aromatic ring gave relatively higher enantio-
selectivities. Heteroaromatic nitroalkene 1l derived from furfural
worked well to furnish the corresponding adduct with good yield
and diastereoselectivity albeit with lower enantioselectivity
(entry 12). Aliphatic nitroalkenes 1m–o were also viable sub-
strates, despite lower reactivity (entries 13–15). The α,β-unsatu-
rated nitroalkene 1m afforded the product 3m with comparable
diastereoselectivity but moderate enantioselectivity (69% ee).
Aliphatic nitroalkene 1n gave product 3n with comparable result
at room temperature, and aliphatic nitroalkene 1o proceeded with
2 mol% III to furnish the adduct 3o in 76% yield with 70 : 30 dr
and 78% ee. Unfortunately, aromatic nitroalkenes 1p and 1q
with larger substituted groups at the α-position gave unsatisfac-
tory enantioselectivities (77% ee and 75% ee, respectively)
(entries 16 and 17). The addition of thioacetic acid 2 to nitro-
alkene 1p was selected as a model reaction, and reaction con-
ditions involving solvent, temperature, and catalyst loading
were simply reoptimized. But no satisfactory enantioselectivity
was observed. The β-nitrostyrene 1r was also evaluated, but
only moderate enantioselectivity (51% ee) was obtained
(entry 18). The absolute configuration of enantiopure anti dia-
stereomer of 3e was determined to be (1S,2R) by X-ray analysis
(Fig. 2).9
Fig. 1 Screened organocatalysts.
Table 1 Screening of organocatalysts for the asymmetric sulfa-
Michael addition of thioacetic acid to trans-β-methyl-β-nitrostyrenea
Entry
Catalyst
Yieldb (%)
drc (anti/syn)
eec,d (%)
1
2
3
4
5
6
7
8
I
II
98
96
98
98
89
84
94
92
94
98
97
97
75 : 25
64 : 36
80 : 20
66 : 34
71 : 29
67 : 33
66 : 34
64 : 36
67 : 33
68 : 32
70 : 30
68 : 32
70
54
84
57
52
−47
18
17
50
III
IV
V
VI
VII
VIII
IX
X
9
10
11
12
73
45
40
XI
XII
a Reactions were carried out with trans-β-methyl-β-nitrostyrene 1a
(0.2 mmol) and thioacetic acid 2 (0.2 mmol) in CH2Cl2 (0.5 mL).
b Isolated yield. c Determined by chiral HPLC analysis. d Enantiomeric
excess of the major anti diastereomer.
On the basis of the absolute configuration of the anti-3e, we
propose a possible reaction mechanism for this Michael addition
(Fig. 3). The squaramide III may act in a bifunctional fashion.
In the transition state A, the squaramide moiety activates
nitroalkene 1e through double hydrogen bonding, and thioacetic
acid 2 is deprotonated by the basic nitrogen atom of the tertiary
amine. The thioacetic acid anion attacks the activated nitroalkene
thiourea catalysts XI and XII gave lower enantioselectivities
than the corresponding squaramides I and V (entries 11 and 12).
With squaramide III as the optimal catalyst, several reaction
parameters, such as solvent, temperature, catalyst loading, and
concentration were successively investigated for the optimal
reaction conditions. The results are summarized in Table 2.
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 6876–6884 | 6877

Table 2 Optimization of reaction conditions for the asymmetric sulfa-Michael addition of thioacetic acid to trans-β-methyl-β-nitrostyrenea
Entry
Solvent
Loading (mol%)
T (°C)
t(h)
Yieldb (%)
drc (syn/ anti)
eec,d (%)
1
2
3
4
5
6
7
8
CH2Cl2
CH2ClCH2Cl
CHCl3
THF
Et2O
PhMe
5
5
5
5
5
5
5
5
5
rt
rt
rt
rt
rt
rt
rt
rt
0
−20
−40
0
0
0
0
0
0
2
2
2
2
2
2
2
2
3
5
9
3
3
6
10
6
98
99
98
93
94
98
90
83
98
95
92
94
94
92
95
96
96
80 : 20
79 : 21
80 : 20
73 : 27
77 : 23
72 : 28
81 : 19
77 : 23
85 : 15
86 : 14
89 : 11
83 : 17
86 : 14
85 : 15
85 : 15
86 : 14
85 : 15
84
79
80
63
82
72
79
78
90
89
88
87
90
90
88
90
88
iPrOH
Brine
9
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
10
11
12
13
14
15
16e
17f
5
5
10
1
0.2
0.1
0.2
0.2
10
a Unless noted otherwise, reactions were carried out with trans-β-methyl-β-nitrostyrene 1a (0.2 mmol) and thioacetic acid 2 (0.2 mmol) in the solvent
(0.5 mL). b Isolated yield. c Determined by chiral HPLC analysis. d Enantiomeric excess of the major anti diastereomer. e 0.25 mL of CH2Cl2 was
used. f 1.0 mL of CH2Cl2 was used.
Table 3 Scope of the asymmetric sulfa-Michael addition of thioacetic acid to α,β-disubstituted nitroalkenesa
Entry
R1
R2
t(h)
Product
Yieldb (%)
drc (anti/syn)
eec,d (%)
1
2
3
C6H5
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Me
Et
6
6
6
6
6
6
6
6
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
3r
96
97
97
96
98
93
95
98
97
97
92
85
77
91
76
95
94
94
86 : 14
86 : 14
87 : 13
89 : 11
86 : 14
86 : 14
88 : 12
92 : 8
86 : 14
89 : 11
80 : 20
92 : 8
85 : 15
72 : 28
70 : 30
94 : 6
86 : 14
—
90
90
90
95
90
94
88
95
87
90
94
78
69
84
78
77
75
51
4-FC6H4
4-ClC6H4
2-ClC6H4
4-BrC6H4
2-BrC6H4
4-MeC6H4
2-MeC6H4
4-MeOC6H4
2-MeOC6H4
1-Naphthyl
2-Furanyl
Cinnamyl
iPr
4
5e
6
7
8
9
6
6
10
11
12
13
14f
15g
16
17
18
12
12
12
12
24
6
Cyclohexyl
C6H5
C6H5
Ph
H
6
2
C6H5
a Unless noted otherwise, reactions were carried out with α,β-disubstituted nitroalkenes 1 (0.2 mmol) and thioacetic acid 2 (0.2 mmol) in CH2Cl2
(0.25 mL). b Isolated yield. c Determined by chiral HPLC analysis. d Enantiomeric excess of the major anti diastereomer. e The absolute configuration
of 3e was determined by X-ray analysis. f Reaction was performed at room temperature. g 2 mol% III was used at room temperature.
1e from the Si-face to afford the intermediate C. Since the steric
hindrance of methyl is greater than the planar nitro group, the
proposed Newman projection in the box is favored. Then the
intermediate C abstracts a proton from ammonium via the
transition state B to form the desired anti-3e with the release of
catalyst III. The steric hindrance of phenyl group is greater than
that of AcS group, so the protonation occurs favorably from the
less steric AcS side leading to (1S,2R)-configuration.
6878 | Org. Biomol. Chem., 2012, 10, 6876–6884
This journal is © The Royal Society of Chemistry 2012

Conclusions
In conclusion, we have developed a squaramide-catalysed highly
asymmetric sulfa-Michael addition of thioacetic acid to α,β-
disubstituted nitroalkenes. The reactions proceeded well with
0.2 mol% catalyst, and the desired adducts were obtained in
excellent yields with good diastereoselectivities and high
enantioselectivities. This process provides an easy access to opti-
cally active β-nitro sulfides, which can be readily transformed
into taurine derivatives. Moreover, this catalytic reaction can be
performed on a 10 gram scale. Further studies on squaramide-
catalysed asymmetric reactions are underway in our laboratory.
Fig. 2 X-ray crystal structure of the enantiopure anti diastereomer
of 3e.
Experimental
General methods
Commercially available compounds were used without further
purification, unless otherwise stated. Column chromatography
was carried out with silica gel (200–300 mesh). Melting points
were measured with a XT-4 melting point apparatus without
correction. 1H NMR spectra were recorded with a Varian
Mercury-plus 400 MHz spectrometer. Chemical shifts were
reported in ppm with the internal TMS signal at 0.0 ppm as a
standard. 13C NMR spectra were recorded at 100 MHz. The high
resolution MS spectra were obtained with ESI ionization using a
Bruker APEX IV FTMS. Optical rotations were measured with a
Krüss P8000 polarimeter at the indicated concentration with
units g/100 mL. The enantiomeric excesses were determined by
chiral HPLC using an Agilent 1200 LC instrument with Daicel
Chiralpak IA, AS-H or Chiralcel OJ-H column.
Materials
Fig. 3 Proposed mechanism for the Michael addition.
α,β-Disubstituted nitroalkenes were prepared according to the
literature procedures.11 The squaramide catalysts I–VI,7b,8a,b
VII,12 VIII,8e and thiourea catalysts XI13 and XII14 were pre-
pared following the reported procedures, respectively.
Preparation of squaramide catalyst IX
To a solution of 3,4-dimethoxycyclobut-3-ene-1,2-dione (1.42 g,
10.0 mmol) in MeOH (15 mL) was added 2,6-diisopropylbenzen-
amine (1.77 g, 10.0 mmol). After stirring for 48 h at room temp-
erature, the reaction mixture was concentrated and directly
purified by silica gel column chromatography to afford the
mono-squaramide 6 as a pale yellow solid (1.40 g, 49% yield).
1
M.p. 152–154 °C; H NMR (400 MHz, CDCl3): δ 8.06 (s, 1H,
Scheme 1 The gram-scale preparation and transformation of 3a.
NH), 7.35 (t, J = 7.8 Hz, 1H, ArH), 7.18 (d, J = 7.6 Hz, 2H,
ArH), 4.18 (s, 3H, OCH3), 3.12–3.05 (m, 2H, CH), 1.19 (d,
J = 6.8 Hz, 12 H, CH3) ppm; 13C NMR (100 MHz, CDCl3):
δ 189.4, 184.0, 179.2, 172.1, 146.1, 131.0, 129.2, 123.6, 60.4,
28.6, 23.5; IR (KBr): ν 3207, 3028, 2966, 2869, 1813, 1707,
To further evaluate the synthetic potential of this catalytic
system, the gram-scale preparation and transformation of 3a
were conducted. As shown in Scheme 1, the catalytic reaction on
a 10 gram scale was performed well without any loss of yield
and stereoselectivity, and almost optically pure adduct 3a was
easily obtained by a simple recrystallization from EtOH. Accord-
ing to the recently reported method,10 β-nitro sulfide 3a was
readily transformed to taurine derivative 5 in good yield through
successive oxidation and hydrogenation.
1611, 1584, 1521, 1457, 1369, 1358, 1031, 937, 813, 757 cm−1
;
HRMS (ESI): m/z calcd for C17H22NO3 [M + H]+ 288.15942,
found 288.15957.
To a solution of (1S,2S)-2-(1-piperidinyl)-cyclohexanamine
(547 mg, 3.0 mmol) in CH2Cl2 (5 mL) was added 6 (575 mg,
2.0 mmol). After stirring for 24 h at room temperature, the
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 6876–6884 | 6879

reaction mixture was concentrated and directly purified by silica
gel column chromatography to afford the squaramide catalyst IX
as a pale yellow solid (485 mg, 55% yield). M.p. > 310 °C
enantioselectivity of the reaction (86 : 14 dr, 90% ee for the
major anti diastereomer) by HPLC (IA and AS-H columns in
series, n-hexane-2-propanol 95 : 5, flow rate 0.5 mL min−1
,
1
(Decomp.); [α]2D5 +35.5 (c 0.31, CH2Cl2); H NMR (400 MHz,
detection at 254 nm): anti diastereomer: tmajor = 33.9 min,
tminor = 36.4 min; syn diastereomer: tR = 37.6, 42.0 min. The
anti diastereomer was obtained by recrystallization from ethyl
acetate/petroleum ether as a colorless solid, m.p. 91–93 °C;
CDCl3): δ 8.82 (s, 1H, NH), 7.34 (t, J = 7.6 Hz, 1H, ArH), 7.20
(t, J = 7.6 Hz, 2H, ArH), 4.96 (s, 1H, NH), 3.51 (t, J = 9.6 Hz,
1H, CH), 3.32–3.26 (m, 1H, CH), 3.14–3.08 (m, 1H, CH), 2.54
(d, J = 9.6 Hz, 1H, CH2), 2.41 (d, J = 10.0 Hz, 2H, CH2), 1.98
(t, J = 7.6 Hz, 2H, CH2), 1.74–1.72 (m, 3H, CH2), 1.61 (d, J =
12.8 Hz, 1H, CH2), 1.27–0.94 (m, 22H, CH3 + CH2) ppm; 13C
NMR (100 MHz, CDCl3): δ 183.5, 182.6, 169.5, 166.5, 146.8,
131.5, 129.3, 123.7, 123.2, 68.8, 53.5, 49.2, 34.8, 28.8, 28.4,
26.0, 25.4, 24.6, 24.5, 24.3, 23.7, 23.3, 22.5, 22.2 ppm; IR
(KBr): ν 3145, 2932, 2854, 1800, 1650, 1572, 1537, 1449,
1362, 1333, 1144, 871, 800, 732 cm−1; HRMS (ESI): m/z calcd
for C27H40N3O2 [M + H]+ 438.31150, found 438.31065.
1
[α]2D2 +302.0 (c 1.38, CH2Cl2); H NMR (400 MHz, CDCl3): δ
7.33–7.26 (m, 5H, ArH), 5.14 (d, J = 9.2 Hz, 1H, CH),
5.01–4.93 (m, 1H, CH), 2.36 (s, 3H, COCH3), 1.68 (d, J =
6.4 Hz, 3H, CH3) ppm; 13C NMR (100 MHz, CDCl3): δ 192.3,
136.9, 128.9, 128.5, 127.9, 86.6, 50.3, 30.4, 17.5 ppm; IR
(KBr): ν 2995, 2942, 1695, 1552, 1451, 1388, 1356, 1288,
1127, 1100, 949, 865, 743, 700, 659, 630 cm−1; HRMS (ESI):
m/z calcd for C11H13NNaO3S [M + Na]+ 262.05084, found
262.05060.
(1S,2R)-1-(4-Fluorophenyl)-2-nitropropyl ethanethioate (3b).
The title compound 3b (the mixture of the syn and anti diastereo-
mer) was obtained as a colorless solid according to the general
procedure (50.2 mg, 97% yield), m.p. 60–62 °C. It was analyzed
to determine the diastereoselectivity and enantioselectivity of the
reaction (86 : 14 dr, 90% ee for the major anti diastereomer) by
HPLC (AS-H column, n-hexane-2-propanol 95 : 5, flow rate
Preparation of squaramide catalyst X
To a solution of 3,4-dimethoxycyclobut-3-ene-1,2-dione (1.42 g,
10.0 mmol) in MeOH (10 mL) was added adamantanamine
(1.50 g, 10.0 mmol). The reaction mixture was stirred for 48 h at
room temperature and the white precipitation formed. The mono-
squaramide 7 was obtained by filtration as a white solid (2.20 g,
84% yield).
1.0 mL min−1, detection at 254 nm): anti diastereomer: tmajor
=
11.7 min, tminor = 13.4 min; syn diastereomer: tR = 16.2,
To a solution of (1S,2S)-2-(1-Piperidinyl)-cyclohexanamine
(547 mg, 3.0 mmol) in CH2Cl2 (5 mL) was added mono-squara-
mide 7 (523 mg, 2.0 mmol). After stirring for 24 h at room
temperature, the reaction mixture was concentrated and directly
purified by silica gel column chromatography to afford the squar-
amide catalyst X as a white solid (294 mg, 36% yield). M.p. >
280 °C (Decomp.); [α]2D5 +36.8 (c 0.25, DMSO); 1H NMR
(400 MHz, d6-DMSO): δ 7.44 (s, 1H, NH), 7.20 (d, J = 8.8 Hz,
1H, NH), 3.86–3.79 (m, 1H, CH), 2.60 (t, J = 7.6 Hz, 2H, CH2),
2.27–2.16 (m, 3H, CH + CH2), 2.08 (s, 3H, CH), 2.03–1.82 (m,
8H, CH2), 1.72–1.63 (m, 8H, CH2), 1.37–1.18 (m, 10H, CH2)
ppm; 13C NMR (100 MHz, d6-DMSO): δ 182.2, 180.4, 169.1,
167.2, 68.5, 53.8, 51.8, 49.2, 42.6, 35.3, 34.3, 28.9, 26.2, 24.7,
24.5, 24.4, 23.4; IR (KBr): ν 3243, 2909, 2852, 2791, 1790,
1663, 1574, 1526, 1453, 1438, 1359, 1308, 1127, 1105, 1021,
870, 660 cm−1; HRMS (ESI): m/z calcd for C25H38N3O2
[M + H]+ 412.29585, found 412.29547.
1
19.2 min. [α]2D2 +205.5 (c 0.94, CH2Cl2); H NMR (400 MHz,
CDCl3): δ 7.28–7.24 (m, 2H, ArH), 7.00 (t, J = 8.4 Hz, 2H,
ArH), 5.10 (d, J = 9.2 Hz, 1H, CH), 4.97–4.90 (m, 1H, CH),
2.36 (s, 3H, COCH3), 1.67 (d, J = 6.8 Hz, 3H, CH3) ppm;
1
13C NMR (100 MHz, CDCl3): δ 192.1, 162.4 (d, JC-F = 246.8
4
3
Hz), 132.8 (d, JC-F = 3.2 Hz), 129.8 (d, JC-F = 8.2 Hz),
2
115.8 (d, JC-F = 21.9 Hz), 86.5, 49.6, 30.4, 17.6 ppm; IR
(KBr): ν 2987, 2940, 1702, 1603, 1556, 1511, 1452, 1389,
1359, 1301, 1231, 1127, 1101, 957, 842, 801, 661, 622 cm−1
;
HRMS (ESI): m/z calcd for C11H12FNNaO3S [M + Na]+
280.04141, found 280.04139.
(1S,2R)-1-(4-Chlorophenyl)-2-nitropropyl ethanethioate (3c).
The title compound 3c (the mixture of the syn and anti diastereo-
mer) was obtained as a colorless solid according to the general
procedure (53.0 mg, 97% yield), m.p. 59–61 °C. It was analyzed
to determine the diastereoselectivity and enantioselectivity of the
reaction (87 : 13 dr, 90% ee for the major anti diastereomer) by
HPLC (AS-H column, n-hexane-2-propanol 95 : 5, flow rate
General procedure for the asymmetric sulfa-Michael addition of
thioacetic acid to α,β-disubstituted nitroalkenes
1.0 mL min−1, detection at 254 nm): anti diastereomer: tmajor
=
11.0 min, tminor = 13.7 min; syn diastereomer: tR = 16.6,
1
19.9 min. [α]2D2 +237.8 (c 0.98, CH2Cl2); H NMR (400 MHz,
7.8 mg of organocatalyst III was added to dichloromethane to
afford 10 mL of catalyst solution (c 1.6 mmol L−1). A mixture
of α,β-disubstituted nitroalkene 1 (0.2 mmol) and 0.25 mL of
the above catalyst solution (0.0004 mmol, 0.2 mol%) was stirred
at 0 °C for 30 min. Then thioacetic acid 2 (0.2 mmol) was added
in one portion. After stirring at 0 °C for 6–12 h, the reaction
mixture was concentrated and directly purified by silica gel
column chromatography to afford the desired adduct 3.
CDCl3): δ 7.29 (d, J = 8.0 Hz, 2H, ArH), 7.22 (d, J = 8.4 Hz,
2H, ArH), 5.08 (d, J = 9.2 Hz, 1H, CH), 4.97–4.90 (m, 1H,
CH), 2.36 (s, 3H, COCH3), 1.67 (d, J = 6.4 Hz, 3H, CH3) ppm;
13C NMR (100 MHz, CDCl3): δ 192.0, 135.5, 134.4, 129.3,
129.1, 86.3, 49.6, 30.4, 17.6 ppm; IR (KBr): ν 2993, 2941,
1704, 1556, 1493, 1452, 1411, 1388, 1358, 1291, 1127, 1093,
1015, 956, 866, 826, 657, 622 cm−1; HRMS (ESI): m/z calcd for
C11H12ClNNaO3S [M + Na]+ 296.01186, found 296.01186.
(1S,2R)-2-Nitro-1-phenylpropyl ethanethioate (3a). The title
compound 3a (the mixture of the syn and anti diastereomer) was
obtained according to the general procedure (45.7 mg, 96%
yield). It was analyzed to determine the diastereoselectivity and
(1S,2R)-1-(2-Chlorophenyl)-2-nitropropyl ethanethioate (3d).
The title compound 3d (the mixture of the syn and anti diastereo-
mer) was obtained as colorless oil according to the general
6880 | Org. Biomol. Chem., 2012, 10, 6876–6884
This journal is © The Royal Society of Chemistry 2012

procedure (52.7 mg, 96% yield). It was analyzed to determine
the diastereoselectivity and enantioselectivity of the reaction
(89 : 11 dr, 95% ee for the major anti diastereomer) by HPLC
(OJ-H column, n-hexane-2-propanol 95 : 5, flow rate 0.5 mL min−1,
detection at 254 nm): anti diastereomer: tmajor = 41.4 min,
tminor = 28.7 min; syn diastereomer: tR = 20.0, 24.8 min. [α]D22
+216.1 (c 1.18, CH2Cl2); 1H NMR (400 MHz, CDCl3): δ
7.39–7.37 (m, 1H, ArH), 7.33–7.30 (m, 1H, ArH), 7.26–7.21
(m, 2H, ArH), 5.59 (d, J = 9.2 Hz, 1H, CH), 5.28–5.21 (m, 1H,
CH), 2.37 (s, 3H, COCH3), 1.67 (d, J = 6.8 Hz, 3H, CH3) ppm;
13C NMR (100 MHz, CDCl3): δ 192.2, 134.2, 133.5, 130.4,
130.1, 129.7, 127.2, 84.6, 47.8, 30.2, 17.2 ppm; IR (KBr):
ν 3064, 2993, 2941, 2899, 1705, 1554, 1475, 1447, 1388, 1358,
1289, 1128, 1038, 955, 865, 754, 657, 623 cm−1; HRMS (ESI):
m/z calcd for C11H12ClNNaO3S [M + Na]+ 296.01186, found
296.01210.
to determine the diastereoselectivity and enantioselectivity of the
reaction (88 : 12 dr, 88% ee for the major anti diastereomer) by
HPLC (AS-H column, n-hexane-2-propanol = 98 : 2, flow rate
0.4 mL min−1, detection at 254 nm): anti diastereomer: tmajor
=
24.8 min, tminor = 28.0 min; syn diastereomer: tR = 29.6,
1
35.3 min. [α]2D2 +262.4 (c 1.01, CH2Cl2); H NMR (400 MHz,
CDCl3): δ 7.15 (d, J = 8.0 Hz, 2H, ArH), 7.11 (d, J = 8.0 Hz,
2H, ArH), 5.10 (d, J = 9.2 Hz, 1H, CH), 4.99–4.92 (m, 1H,
CH), 2.34 (s, 3H, COCH3), 2.30 (s, 3H, CH3), 1.66 (d, J =
6.8 Hz, 3H, CH3) ppm; 13C NMR (100 MHz, CDCl3): δ 192.4,
138.3, 133.8, 129.5, 127.8, 86.6, 50.0, 30.3, 21.1, 17.5 ppm;
IR (KBr): ν 2989, 2941, 1698, 1558, 1516, 1446, 1391, 1358,
1294, 1126, 1040, 967, 869, 828, 784, 662, 623 cm−1; HRMS
(ESI): m/z calcd for C12H15NNaO3S [M + Na]+ 276.06649,
found 276.06648.
(1S,2R)-1-(2-Methylphenyl)-2-nitropropyl ethanethioate (3h).
The title compound 3h (the mixture of the syn and anti diastereo-
mer) was obtained as colorless oil according to the general pro-
cedure (53.4 mg, 98% yield). It was analyzed to determine the
diastereoselectivity and enantioselectivity of the reaction (92 : 8
dr, 95% ee for the major anti diastereomer) by HPLC (OJ-H
(1S,2R)-1-(4-Bromophenyl)-2-nitropropyl ethanethioate (3e).
The title compound 3e (the mixture of the syn and anti diastereo-
mer) was obtained as a colorless solid according to the general
procedure (62.1 mg, 98% yield), m.p. 66–68 °C. It was analyzed
to determine the diastereoselectivity and enantioselectivity of the
reaction (86 : 14 dr, 90% ee for the major anti diastereomer) by
HPLC (AS-H column, n-hexane-2-propanol 95 : 5, flow rate
column, n-hexane-2-propanol 95 : 5, flow rate 0.5 mL min−1
,
detection at 254 nm): anti diastereomer: tmajor = 49.6 min,
tminor = 68.5 min; syn diastereomer: tR = 39.2, 47.9 min.
1.0 mL min−1, detection at 254 nm): anti diastereomer: tmajor
=
1
10.9 min, tminor = 13.2 min; syn diastereomer: tR = 15.3,
[α]2D2 +289.2 (c 1.18, CH2Cl2); H NMR (400 MHz, CDCl3): δ
1
18.6 min. [α]2D2 +253.7 (c 1.43, CH2Cl2); H NMR (400 MHz,
7.20–7.14 (m, 4H, ArH), 5.47 (d, J = 9.6 Hz, 1H, CH),
5.07–4.99 (m, 1H, CH), 2.43 (s, 3H, CH3), 2.35 (s, 3H,
COCH3), 1.70 (d, J = 6.8 Hz, 3H, CH3) ppm; 13C NMR
(100 MHz, CDCl3): δ 192.6, 136.1, 135.2, 131.1, 128.3, 127.0,
126.5, 86.0, 46.1, 30.2, 19.4, 17.4 ppm; IR (KBr): ν 3067, 3021,
2970, 2941, 1701, 1555, 1491, 1452, 1387, 1358, 1288, 1127,
1103, 1037, 955, 865, 751, 723, 658, 625 cm−1; HRMS (ESI):
m/z calcd for C12H15NNaO3S [M + Na]+ 276.06649, found
276.06649.
CDCl3): δ 7.48–7.42 (m, 2H, ArH), 7.18–7.12 (m, 2H, ArH),
5.07 (d, J = 9.6 Hz, 1H, CH), 4.97–4.90 (m, 1H, CH), 2.36
(s, 3H, COCH3), 1.67 (d, J = 6.4 Hz, 3H, CH3) ppm; 13C NMR
(100 MHz, CDCl3): δ 192.0, 136.0, 132.0, 129.6, 122.5, 86.2,
49.6, 30.4, 17.6 ppm; IR (KBr): ν 2992, 2940, 1704, 1555,
1489, 1451, 1407, 1388, 1357, 1292, 1127, 1074, 1012, 956,
866, 822, 660, 621 cm−1; HRMS (ESI): m/z calcd for
C11H12BrNNaO3S [M + Na]+ 339.96135, found 339.96121.
(1S,2R)-1-(2-Bromophenyl)-2-nitropropyl ethanethioate (3f).
The title compound 3f (the mixture of the syn and anti diastereo-
mer) was obtained as colorless oil according to the general pro-
cedure (59.1 mg, 93% yield). It was analyzed to determine
the diastereoselectivity and enantioselectivity of the reaction
(86 : 14 dr, 94% ee for the major anti diastereomer) by HPLC
(OJ-H column, n-hexane-2-propanol 90 : 10, flow rate 1.0 mL min−1,
detection at 254 nm): anti diastereomer: tmajor = 41.2 min,
tminor = 28.6 min; syn diastereomer: tR = 18.4, 25.9 min.
[α]2D2 +142.2 (c 1.44, CH2Cl2); 1H NMR (400 MHz,
CDCl3): δ 7.57 (dd, J1 = 8.0 Hz, J2 = 1.2 Hz, 1H, ArH),
7.33–7.25 (m, 2H, ArH), 7.17–7.12 (m, 1H, ArH), 5.64 (d, J =
8.0 Hz, 1H, CH), 5.26–5.23 (m, 1H, CH), 2.37 (s, 3H, COCH3),
1.67 (d, J = 6.4 Hz, 3H, CH3) ppm; 13C NMR (100 MHz,
CDCl3): δ 192.1, 135.8, 133.7, 129.9, 127.8, 84.6, 49.7, 30.2,
16.9; IR (KBr): ν 3060, 2989, 2939, 1702, 1553, 1472, 1441,
(1S,2R)-1-(4-Methoxyphenyl)-2-nitropropyl ethanethioate (3i).
The title compound 3i (the mixture of the syn and anti diastereo-
mer) was obtained as a colorless solid according to the general
procedure (52.1 mg, 97% yield), m.p. 57–59 °C. It was analyzed
to determine the diastereoselectivity and enantioselectivity of the
reaction (86 : 14 dr, 87% ee for the major anti diastereomer) by
HPLC (AS-H column, n-hexane-2-propanol = 99 : 1, flow rate
0.4 mL min−1, detection at 254 nm): anti diastereomer: tmajor
=
64.9 min, tminor = 81.2 min; syn diastereomer: tR = 70.2,
1
107.2 min. [α]2D2 +233.7 (c 1.27, CH2Cl2); H NMR (400 MHz,
CDCl3): δ 7.19 (d, J = 8.4 Hz, 2H, ArH), 6.83 (d, J = 8.8 Hz,
2H, ArH), 5.08 (d, J = 9.2 Hz, 1H, CH), 4.98–4.90 (m, 1H,
CH), 3.76 (s, 3H, OCH3), 2.35 (s, 3H, COCH3), 1.66 (d, J =
6.8 Hz, 3H, CH3) ppm; 13C NMR (100 MHz, CDCl3): δ 192.4,
159.4, 129.1, 128.7, 114.2, 86.7, 55.2, 49.8, 30.4, 17.5 ppm; IR
(KBr): ν 2945, 1692, 1611, 1556, 1516, 1460, 1391, 1356,
1253, 1183, 1127, 1032, 960, 842, 816, 767, 657, 635,
1387, 1357, 1286, 1127, 1026, 954, 865, 751, 656, 621 cm−1
;
HRMS (ESI): m/z calcd for C11H12BrNNaO3S [M + Na]+
625 cm−1
; HRMS (ESI): m/z calcd for C12H15NNaO4S
339.96135, found 339.96121.
[M + Na]+ 292.06140, found 292.06150.
(1S,2R)-1-(4-Methylphenyl)-2-nitropropyl ethanethioate (3g).
The title compound 3g (the mixture of the syn and anti diastereo-
mer) was obtained as a colorless solid according to the general
procedure (48.1 mg, 95% yield), m.p. 44–46 °C. It was analyzed
(1S,2R)-1-(2-Methoxyphenyl)-2-nitropropyl ethanethioate (3j).
The title compound 3j (the mixture of the syn and anti diastereo-
mer) was obtained as colorless oil according to the general pro-
cedure (52.2 mg, 97% yield). It was analyzed to determine the
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 6876–6884 | 6881

diastereoselectivity and enantioselectivity of the reaction (89 : 11
dr, 90% ee for the major anti diastereomer) by HPLC (IA and
AS-H columns in series, n-hexane-2-propanol = 95 : 5, flow rate
diastereoselectivity and enantioselectivity of the reaction
(85 : 15 dr, 69% ee for the major anti diastereomer) by HPLC
(AS-H column, n-hexane-2-propanol 98 : 2, flow rate 0.4 mL
0.5 mL min−1, detection at 254 nm): anti diastereomer: tmajor
=
min−1, detection at 254 nm): anti diastereomer: tmajor
=
29.8 min, tminor = 31.8 min; syn diastereomer: tR = 35.8 min.
35.6 min, tminor = 33.6 min; syn diastereomer: tR = 39.1,
41.5 min. The anti diastereomer was obtained by recrystalliza-
tion from ethyl acetate/petroleum ether as a white solid, m.
p. 77–79 °C; [α]D22 +301.3 (c 0.79, CH2Cl2); 1H NMR
(400 MHz, CDCl3): δ 7.37–7.28 (m, 5H, ArH), 6.68 (d, J = 15.6
Hz, 1H,vCH), 6.15 (dd, J1 = 15.6 Hz, J2 = 9.6 Hz, 1H,vCH),
4.87–4.80 (m, 1H, CH), 4.64 (dd, J1 = 15.6 Hz, J2 = 9.6 Hz, 1H,
CH), 2.38 (s, 3H, COCH3), 1.65 (d, J = 6.8 Hz, 3H, CH3) ppm;
13C NMR (100 MHz, CDCl3): δ 193.0, 135.6, 135.2, 128.6,
128.4, 126.7, 122.3, 85.4, 49.0, 30.7, 17.4 ppm; IR (KBr): ν
2999, 2982, 1693, 1553, 1447, 1387, 1354, 1288, 1120, 968,
950, 866, 742, 690, 658, 628 cm−1; HRMS (ESI): m/z calcd for
C13H15NNaO3S [M + Na]+ 288.06649, found 288.06616.
1
[α]2D2 +262.3 (c 1.13, CH2Cl2); H NMR (400 MHz, CDCl3):
δ 7.28–7.18 (m, 2H, ArH), 6.89–6.84 (m, 2H, ArH), 5.29–5.23
(m, 2H, CH), 3.88 (s, 3H, OCH3), 2.34 (s, 3H, COCH3), 1.64
(d, J = 6.4 Hz, 3H, CH3) ppm; 13C NMR (100 MHz, CDCl3):
δ 193.6, 156.9, 130.2, 129.9, 124.6, 120.8, 111.1, 85.0, 55.5,
47.4, 30.2, 17.6 ppm; IR (KBr): ν 2939, 2835, 1698, 1600,
1553, 1494, 1452, 1387, 1358, 1292, 1250, 1127, 1050, 1023,
954, 865, 755, 626 cm−1; HRMS (ESI): m/z calcd for
C12H15NNaO4S [M + Na]+ 292.06140, found 292.06149.
(1S,2R)-1-(1-Naphthyl)-2-nitropropyl ethanethioate (3k). The
title compound 3k (the mixture of the syn and anti diastereomer)
was obtained according to the general procedure (53.6 mg, 92%
yield). It was analyzed to determine the diastereoselectivity and
enantioselectivity of the reaction (80 : 20 dr, 94% ee for the
major anti diastereomer) by HPLC (AS-H column, n-hexane-
2-propanol = 98 : 2, flow rate 0.5 mL min−1, detection at
254 nm): anti diastereomer: tmajor = 28.3 min, tminor = 32.8 min;
syn diastereomer: tR = 35.5, 44.4 min. The anti diastereomer was
obtained as a colorless solid by silica gel column chromato-
graphy, m.p. 55–57 °C. [α]2D2 +300.2 (c 1.19, CH2Cl2); 1H NMR
(400 MHz, CDCl3): δ 8.18 (br s, 1H, ArH), 7.85 (d, J = 8.0 Hz,
1H, ArH), 7.78 (d, J = 8.0 Hz, 1H, ArH), 7.61 (t, J = 7.6 Hz,
1H, ArH), 7.51 (t, J = 7.2 Hz, 1H, ArH), 7.46 (d, J = 7.2 Hz,
1H, ArH), 7.39 (t, J = 7.6 Hz, 1H, ArH), 6.16 (br s, 1H, CH),
5.28–5.24 (m, 1H, CH), 2.36 (s, 3H, COCH3), 1.72 (d, J =
6.8 Hz, 3H, CH3) ppm; 13C NMR (100 MHz, CDCl3): δ 192.7,
134.0, 132.8, 130.4, 129.3, 129.1, 127.1, 126.2, 125.1, 122.6,
85.5, 30.2, 19.1, 17.1 ppm; IR (KBr): ν 3051, 2989, 2940, 1698,
1553, 1552, 1452, 1387, 1357, 1278, 1127, 954, 866, 791, 775,
(3S,4R)-2-Methyl-4-nitropentan-3-yl ethanethioate (3n). A
mixture of α,β-disubstituted nitroalkene 1n (0.4 mmol, 51.6 mg)
and 0.5 mL of the above catalyst solution (0.2 mol%) was stirred
at room temperature for 30 min. Then thioacetic acid 2
(0.4 mmol) was added in one portion. After stirring for 12 h, the
reaction mixture was concentrated and directly purified by silica
gel column chromatography to afford the desired adduct 3n (the
mixture of the syn and anti diastereomer, 74.4 mg, 91% yield).
It was analyzed to determine the diastereoselectivity and enan-
tioselectivity of the reaction (72 : 28 dr, 84% ee for the major
anti diastereomer) by HPLC (AS-H column, n-hexane-2-propa-
nol 99 : 1, flow rate 0.5 mL min−1, detection at 210 nm): anti
diastereomer: tmajor = 12.9 min, tminor = 11.6 min; syn diastereo-
mer: tR = 16.3, 17.6 min. The anti diastereomer was obtained as
colorless oil by silica gel column chromatography. [α]2D2 +66.4
(c 1.59, CH2Cl2); 1H NMR (400 MHz, CDCl3): δ 4.76–4.68 (m,
1H, CH), 4.08 (dd, J1 = 9.6 Hz, J2 = 4.0 Hz, 1H, CH), 2.41 (s,
3H, COCH3), 1.92–1.85 (m, 1H, CH), 1.58 (d, J = 6.4 Hz, 3H,
CH3), 0.97 (d, J = 6.8 Hz, 3H, CH3), 0.93 (d, J = 6.8 Hz, 3H,
CH3) ppm; 13C NMR (100 MHz, CDCl3): δ 193.3, 84.6, 53.1,
30.7, 28.9, 20.6, 17.8, 17.3 ppm; IR (KBr): ν 2968, 2934, 2877,
1703, 1553, 1454, 1388, 1358, 1293, 1129, 952, 863, 658,
619 cm−1
; HRMS (ESI): m/z calcd for C15H15NNaO3S
[M + Na]+ 312.06649, found 312.06630.
(1R,2R)-1-(2-Furyl)-2-nitropropyl ethanethioate (3l). The title
compound 3l (the mixture of the syn and anti diastereomer) was
obtained as pale yellow oil according to the general procedure
(39.1 mg, 85% yield). It was analyzed to determine the diaster-
eoselectivity and enantioselectivity of the reaction (92 : 8 dr,
78% ee for the major anti diastereomer) by HPLC (OJ-H
627 cm−1
; HRMS (ESI): m/z calcd for C8H15NNaO3S
[M + Na]+ 228.06649, found 228.06647.
column, n-hexane-2-propanol 95 : 5, flow rate 0.5 mL min−1
,
(1S,2R)-1-Cyclohexyl-2-nitropropyl ethanethioate (3o). To a
solution of α,β-disubstituted nitroalkene 1o (0.2 mmol, 33.8 mg)
and oraganocatalyst III (0.004 mmol, 1.9 mg) in CH2Cl2
(0.25 mL) was added thioacetic acid 2 (0.2 mmol, 15 μL) in one
portion. After stirring at room temperature for 24 h, the reaction
mixture was concentrated and directly purified by silica gel
column chromatography to afford the desired adduct 3o (the
mixture of the syn and anti diastereomer, 37.2 mg, 76% yield). It
was analyzed to determine the diastereoselectivity and enantio-
selectivity of the reaction (70 : 30 dr, 78% ee for the major anti
diastereomer) by HPLC (AS-H column, n-hexane-2-propanol
99 : 1, flow rate 0.5 mL min−1, detection at 210 nm): anti diaster-
eomer: tmajor = 14.7 min, tminor = 13.1 min; syn diastereomer:
tR = 16.7, 18.6 min. The anti diastereomer was obtained by
recrystallization from ethyl acetate/petroleum ether as a white
detection at 254 nm): anti diastereomer: tmajor = 30.9 min,
tminor = 37.4 min; syn diastereomer: tR = 24.4, 26.6 min. [α]D22
1
+199.7 (c 1.18, CH2Cl2); H NMR (400 MHz, CDCl3): δ 7.35
(s, 1H, ArH), 6.33–6.29 (m, 2H, ArH), 5.35 (d, J = 8.0 Hz, 1H,
CH), 5.09–4.99 (m, 1H, CH), 2.39 (s, 3H, COCH3), 1.66 (d, J =
6.8 Hz, 3H, CH3) ppm; 13C NMR (100 MHz, CDCl3): δ 192.2,
149.0, 143.0, 110.6, 108.9, 84.2, 43.5, 30.3, 17.0 ppm; IR
(KBr): ν 2988, 2940, 1704, 1555, 1452, 1388, 1358, 1291,
1128, 1013, 956, 864, 748, 622 cm−1; HRMS (ESI): m/z calcd
for C9H11NNaO4S [M + Na]+ 252.03010, found 252.03005.
(E,3S,4R)-4-Nitro-1-phenylpent-1-en-3-yl ethanethioate (3m).
The title compound 3m (the mixture of the syn and anti diaster-
eomer) was obtained according to the general procedure
(40.8 mg, 77% yield). It was analyzed to determine the
1
solid, m.p. 95–97 °C; [α]2D2 +52.7 (c 0.74, CH2Cl2); H NMR
6882 | Org. Biomol. Chem., 2012, 10, 6876–6884
This journal is © The Royal Society of Chemistry 2012

(400 MHz, CDCl3): δ 4.80–4.73 (m, 1H, CH), 4.08 (dd, J1 =
8.8 Hz, J2 = 4.4 Hz, 1H, CH), 2.39 (s, 3H), 1.82–1.60 (m, 5H,
CH + CH2), 1.56 (d, J = 6.4 Hz, 3H, CH3), 1.52–1.45 (m, 1H,
CH2), 1.29–1.09 (m, 4H, CH2), 1.03–0.94 (m, 1H, CH2) ppm;
13C NMR (100 MHz, CDCl3): δ 193.3, 83.9, 52.3, 38.9, 30.7,
30.6, 28.5, 25.9, 25.86, 25.82, 17.0 ppm; IR (KBr): ν 2927,
2854, 1694, 1552, 1450, 1388, 1358, 1299, 1134, 958, 884, 865,
CH2), 2.36 (s, 3H, COCH3) ppm; 13C NMR (100 MHz, CDCl3):
δ 193.3, 135.6, 129.2, 128.8, 127.7, 77.9, 44.4, 30.3 ppm.
The 10 gram scale preparation of 3a and its transformation
A
mixture of trans-β-Methyl-β-nitrostyrene 1a (12.2 g,
75.0 mmol) and catalyst III (0.2 mol%, 73.4 mg, 0.15 mmol) in
CH2Cl2 (100 mL) was stirred at 0 °C for 30 min. Then thioacetic
acid 2 (5.7 g, 75.0 mmol) was added dropwise. After stirring at
0 °C for 6 h until completion of the reaction (monitored by
TLC), the mixture was quenched by addition of saturated NH4Cl
(50 mL). The organic layer was separated, washed with saturated
brine, and dried over anhydrous Na2SO4. The crude adduct 3a
was obtained by concentration in vacuo (17.7 g, 99% yield). It
was analyzed to determine the diastereoselectivity and enantio-
selectivity of the reaction (85 : 15 dr, 90.5% ee for the major anti
diastereomer) by HPLC. The anti diastereomer was obtained by
a simple recrystallization from EtOH as a white solid (10.5 g,
59% yield, 98.8% ee, 99 : 1 dr).
632 cm−1
; HRMS (ESI): m/z calcd for C11H19NNaO3S
[M + Na]+ 268.09779, found 268.09753.
(1S,2R)-2-Nitro-1-phenylbutyl ethanethioate (3p). The title
compound 3p (the mixture of the syn and anti diastereomer) was
obtained according to the general procedure (45.0 mg, 89%
yield). It was analyzed to determine the diastereoselectivity and
enantioselectivity of the reaction (94 : 6 dr, 77% ee for the major
anti diastereomer) by HPLC (AS-H column, n-hexane-2-propa-
nol 95 : 5, flow rate 0.5 mL min−1, detection at 254 nm): anti
diastereomer: tmajor = 16.1 min, tminor = 23.8 min; syn diastereo-
mer: tR = 17.9, 22.4 min. The anti diastereomer was obtained by
recrystallization from ethyl acetate/petroleum ether as a white
solid, m.p. 120–122 °C; [α]2D2 +311.5 (c 0.94, CH2Cl2);
1H NMR (400 MHz, CDCl3): δ 7.33–7.24 (m, 5H, ArH), 5.08
(d, J = 10.0 Hz, 1H, CH), 4.84–4.78 (m, 1H, CH), 2.36 (s, 3H,
COCH3), 2.13–2.04 (m, 2H, CH2), 0.99 (t, J = 7.2 Hz, 3H, CH3)
ppm; 13C NMR (100 MHz, CDCl3): δ 192.3, 136.9, 128.9,
128.5, 127.9, 93.4, 49.4, 30.4, 25.2, 10.3 ppm; IR (KBr): ν
2974, 2932, 1698, 1553, 1456, 1374, 1261, 1133, 963, 956, 811,
746, 696, 651, 628 cm−1; HRMS (ESI): m/z calcd for
C12H15NNaO3S [M + Na]+ 276.06649, found 276.06632.
According to the reported procedure,10 the transformation of
3a into 5 was performed. A mixture of formic acid (98%,
50 mL) and hydrogen peroxide (30%, 20 mL) was stirred at 0 °C
for 2 h (peroxyformic acid solution was prepared in situ), then a
solution of 3a (4.79 g, 20.0 mmol) in THF (15 mL) was added
dropwise. The reaction mixture was stirred at room temperature
for 12 h until completion (monitored by TLC), and water
(150 mL) was added. The mixture was washed with diethyl ether
(80 mL) and dichloromethane (80 mL), respectively. The
aqueous phase was concentrated to afford 2-nitroalkylsulfonic
acid 4 as a yellow solid. The crude product was used directly in
the subsequent hydrogenation without any further purification.
The yellow solid 4 prepared above was dissolved in MeOH
(50 mL), and 10 wt% Pd(OH)2/C (1.40 g, 5 mol%) was added.
The mixture was placed under an atmosphere of H2 in a rubber
balloon and stirred at room temperature for 36 h. After filtration
with celite, the filtrate was concentrated in vacuo to afford the
crude product. The pure 2-aminoalkylsulfonic acid 5 was
obtained by recrystallization from methanol/diethyl ethyl as a
white solid (3.67 g, 85% yield), m.p. >310 °C (Decomp.).
(1S,2R)-2-Nitro-1,2-diphenylethyl ethanethioate (3q). The title
compound 3q (the mixture of the syn and anti diastereomer) was
obtained according to the general procedure (56.4 mg, 94%
yield). It was analyzed to determine the diastereoselectivity and
enantioselectivity of the reaction (86 : 14 dr, 75% ee for the
major anti diastereomer) by HPLC (AS-H column, n-hexane-
2-propanol 95 : 5, flow rate 0.5 mL min−1, detection at 254 nm):
anti diastereomer: tmajor = 19.8 min, tminor = 21.1 min; syn dia-
stereomer: tR = 23.2, 35.1 min. The anti diastereomer was
obtained by recrystallization from ethyl acetate/petroleum ether
as a white solid, m.p. 155–157 °C; [α]2D2 +114.5 (c 0.77,
1
[α]2D0 +122.5 (c 1.58, H2O); H NMR (400 MHz, D2O): δ 7.53
1
(s, 5H, ArH), 4.28 (d, J = 6.0 Hz, 1H, CH), 4.22–4.17 (m, 1H,
CH), 1.52 (d, J = 6.4 Hz, 1H, CH3); 13C NMR (100 MHz, D2O–
HCO2H): δ 132.0, 130.1, 130.0, 68.1, 49.5, 17.7 ppm.
CH2Cl2); H NMR (400 MHz, CDCl3): δ 7.60 (dd, J1 = 8.0 Hz,
J2 = 1.6 Hz, 2H, ArH), 7.44–7.28 (m, 8H, ArH), 5.91 (d, J =
12.0 Hz, 1H, CH), 5.68 (d, J = 12.0 Hz, 1H, CH), 2.11 (s, 3H)
ppm; 13C NMR (100 MHz, CDCl3): δ 191.3, 137.6, 132.0,
130.5, 129.0, 128.9, 128.5, 128.4, 127.9, 94.0, 49.2, 30.2; IR
(KBr): ν 3035, 2951, 1694, 1554, 1497, 1456, 1360, 1266,
1128, 965, 744, 721, 702, 670, 629 cm−1; HRMS (ESI): m/z
calcd for C16H15NNaO3S [M + Na]+ 324.06649, found
324.06662. (NO 1590)
Acknowledgements
We are grateful for financial support from the National Natural
Science Foundation of China (Grant No 21072020), the Science
and Technology Innovation Program of Beijing Institute of
Technology (Grant No 2011CX01008) and the Development
Program for Distinguished Young and Middle-aged Teachers of
Beijing Institute of Technology.
(S)-2-Nitro-1-phenylethyl ethanethioate (3r).5a The title com-
pound 3r was obtained according to the general procedure
(42.2 mg, 94% yield). It was analyzed to determine the enantio-
selectivity of the reaction (51% ee) by HPLC (AS-H column,
n-hexane-2-propanol 95 : 5, flow rate 1.0 mL min−1, detection at
254 nm): major enantiomer tR = 17.1 min, minor enantiomer
tR = 22.0 min. White solid, m.p. 122–124 °C; [α]2D2 +136.4
(c 0.90, CH2Cl2); 1H NMR (400 MHz, CDCl3): δ 7.35–7.30 (m,
5H, ArH), 5.29 (t, J = 8.0 Hz, 1H, CH), 4.84 (d, J = 8.0 Hz, 2H,
Notes and references
1 P. Perlmutter, Conjugate Addition Reactions in Organic Synthesis,
Pergamon, Oxford, 1992.
2 For a review see: D. Enders, K. Lüttgen and A. A. Narine, Synthesis,
2007, 959.
This journal is © The Royal Society of Chemistry 2012
Org. Biomol. Chem., 2012, 10, 6876–6884 | 6883

3 For selected recent examples of asymmetric sulfa-Michael additions:
(a) P. Ricci, A. Carlone, G. Bartoli, M. Bosco, L. Sambri and
P. Melchiorre, Adv. Synth. Catal., 2008, 350, 49; (b) Y. Liu, B. Sun,
B. Wang, M. Wakem and L. Deng, J. Am. Chem. Soc., 2009, 131, 418;
(c) D. Ender and K. Hoffman, Eur. J. Org. Chem., 2009, 1665; (d) Y. Hui,
J. Jiang, W. Wang, W. Chen, Y. Cai, L. Lin, X. Liu and X. Feng, Angew.
Chem., Int. Ed., 2010, 49, 4290; (e) N. K. Rana, S. Selvakumar and V.
K. Singh, J. Org. Chem., 2010, 75, 2089; (f) L. Dai, S.-X. Wang and F.-
E. Chen, Adv. Synth. Catal., 2010, 352, 2137; (g) X.-F. Wang, Q.-L. Hua,
Y. Cheng, X.-L. An, Q.-Q. Yang, J.-R. Chen and W.-J. Xiao, Angew.
Chem., Int. Ed., 2010, 49, 8379; (h) F. L . Z h a o , W. Z h a n g , Y. Y. Ya n g , Y.
H. Pan, W. C. Chen, H. J. Liu, L. Yan, C.-H. Tan and Z. Y. Jiang, Adv.
Synth. Catal., 2011, 353, 2624; (i) Q.-L. Pei, H.-W. Sun, Z.-J. Wu, X.-
L. Du, X.-M. Zhang and W.-C. Yuan, J. Org. Chem., 2011, 76, 7849;
(j) S. Bonollo, D. Lanari, F. Pizzo and L. Vaccaro, Org. Lett., 2011, 13,
2150; (k) X.-Q. Dong, X. Fang and C.-J. Wang, Org. Lett., 2011, 13, 4426;
(l) N. K. Rana and V. K. Singh, Org. Lett., 2011, 13, 6520; (m) X. Tian,
C. Cassani, Y. K. Liu, A. Moran, A. Urakawa, P. Galzerano, E. Arceo and
P. Melchiorre, J. Am. Chem. Soc., 2011, 133, 17934; (n) C. Palacio and S.
J. Connon, Chem. Commun., 2012, 48, 2849.
7 For selected examples of asymmetric reactions using squaramides, see:
(a) J. P. Malerich, K. Hagihara and V. H. Rawal, J. Am. Chem. Soc.,
2008, 130, 14416; (b) Y. Zhu, J. P. Malerich and V. H. Rawal, Angew.
Chem., Int. Ed., 2010, 49, 153; (c) D. Q. Xu, Y.-F. Wang, W. Zhang,
S.-P. Luo, A.-G. Zhong, A.-B. Xia and Z.-Y. Xu, Chem.–Eur. J., 2010,
16, 4177; (d) Y. Qian, G. Ma, A. Lv, H.-L. Zhu, J. Zhao and V. H. Rawal,
Chem. Commun., 2010, 46, 3004; (e) H. Konishi, T. Y. Lam,
J. P. Malerich and V. H. Rawal, Org. Lett., 2010, 12, 2028;
(f) S. V. Pansare and E. K. Paul, Chem. Commun., 2011, 47, 1027;
(g) C. Min, X. Han;, Z. Q. Liao, X. F. Wu, H.-B. Zhou and C. Dong,
Adv. Synth. Catal., 2011, 353, 2715; (h) H. Y. Bae, S. Some, J. H. Lee,
J.-Y. Kim, M. J. Song, S. Lee, Y. J. Zhang and C. E. Song, Adv. Synth.
Catal., 2011, 353, 3196.
8 Asymmetric reactions using squaramides reported by our group:
(a) W. Yang and D.-M. Du, Org. Lett., 2010, 12, 5450; (b) W. Yang and
D.-M. Du, Adv. Synth. Catal., 2011, 353, 1241; (c) W. Yang and
D.-M. Du, Chem. Commun., 2011, 47, 12706; (d) W. Yang, Y. Jia and
D.-M. Du, Org. Biomol. Chem., 2012, 10, 332; (e) W. Yang, J. S. Wang
and D.-M. Du, Tetrahedron: Asymmetry, 2012, DOI: 10.1016/
j.tetasy.2012.06.018.
4 (a) F. Effenberger and H. Isak, Chem. Ber., 1989, 122, 553;
(b) T.-C. Tseng and M.-J. Wu, Tetrahedron: Asymmetry, 1995, 6, 1633;
(c) B. H. Kim, H. B. Lee, J. K. Hwang and Y. G. Kim, Tetrahedron:
Asymmetry, 2005, 16, 1215; (d) H. Li, L. Zu, J. Wang and W. Wang,
Tetrahedron Lett., 2006, 47, 3145.
5 Asymmetric sulfa-Michael addition of thioacetic acid to nitroalkenes:
(a) H. Li, J. Wang, L. S. Zu and W. Wang, Tetrahedron Lett., 2006, 47,
2585; (b) K. L. Kimmel, M. T. Robak and J. A. Ellman, J. Am. Chem.
Soc., 2009, 131, 8754; (c) K. L. Kimmel, M. T. Robak, S. Thomas,
M. Lee and J. A. Ellman, Tetrahedron, 2012, 68, 2704.
9 Crystallographic data for enantiopure anti diastereomer of 3e has been
provided as CIF file in ESI.†
10 N. Chen and J. Xu, Tetrahedron, 2012, 68, 2513.
11 (a) A. Fryszkowska, K. Fisher, J. M. Gardiner and G. M. Stephens,
J. Org. Chem., 2008, 73, 4295; (b) L. Muñoz, A. M. Rodriguez,
G. Rosell, M. P. Bosch and A. Guerrero, Org. Biomol. Chem., 2011, 9,
8171.
12 J. W. Lee, T. H. Ryu, J. S. Oh, H. Y. Bae, H. B. Jang and C. E. Song,
Chem. Commun., 2009, 45, 7224.
13 T. Okino, Y. Hoashi and Y. Takemoto, J. Am. Chem. Soc., 2003, 125,
12672.
14 B. Vakulya, S. Varga, A. Csampai and T. Soós, Org. Lett., 2005, 7,
1967.
6 For reviews of squaramides, see: (a) R. I. Storer, C. Aciro and
L. H. Jones, Chem. Soc. Rev., 2011, 40, 2330; (b) J. Alemán, A. Parra,
H. Jiang and K. A. Jørgensen, Chem.–Eur. J., 2011, 17, 6890.
6884 | Org. Biomol. Chem., 2012, 10, 6876–6884
This journal is © The Royal Society of Chemistry 2012