Organocatalytic asymmetric addition of aliphatic thiols to nitro olefins and nitrodienes

Article abstract of DOI:10.1016/j.tetasy.2013.03.007

The N-3,5-bis(trifluoromethyl)phenyl thiourea derivative of readily available chiral 1-benzyl-3-aminopyrrolidine was an effective organocatalyst for the asymmetric sulfa-Michael reaction. The adducts of aliphatic thiols to nitro olefins and nitrodienes we

Full text of DOI:10.1016/j.tetasy.2013.03.007

Tetrahedron: Asymmetry 24 (2013) 505–514
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Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Organocatalytic asymmetric addition of aliphatic thiols to nitro olefins
and nitrodienes
⇑
_
Rafał Kowalczyk , Anna E. Nowak, Jacek Skarzewski
Department of Organic Chemistry, Faculty of Chemistry, Wrocław University of Technology, 50-370 Wrocław, Poland
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 21 February 2013
Accepted 13 March 2013
The N-3,5-bis(trifluoromethyl)phenyl thiourea derivative of readily available chiral 1-benzyl-3-amino-
pyrrolidine was an effective organocatalyst for the asymmetric sulfa-Michael reaction. The adducts of ali-
phatic thiols to nitro olefins and nitrodienes were formed in good yields and with up to 87% ee in the
presence of 2.5 mol % of the organocatalyst.
Ó 2013 Elsevier Ltd. All rights reserved.
1. Introduction
lability of the C(sp3)–S bond seems to be responsible for the failure
of the previously developed catalytic systems. Consequently, only a
The direct addition of sulfur-centered nucleophiles onto
Michael acceptors is a straightforward approach to C–S bond for-
mation.1 The discovery of Cinchona alkaloid catalyzed sulfa-Mi-
chael reactions is a milestone of organocatalysis.2 Reactions using
both metal- and organocatalysts gave access to the asymmetric
sulfa-Michael adducts of thiols to unsaturated amides,3 alde-
few isolated examples of such sulfa-Michael reactions have been
reported14 and the direct enantioselective addition of aliphatic thi-
ols to nitro alkenes remains a difficult task.15 Recently, a derivative
of a Cinchona alkaloid has been designed and successfully applied to
the enantioselective addition of benzyl type thiols to nitro
alkenes.13 All of these facts encouraged us to report our new results
on the catalyzed enantioselective sulfa-Michael reaction of
demanding aliphatic thiols and nitro alkenes.
hydes,4 cyclic,5 linear6 and branched
a
,b-unsaturated ketones.7
Moreover, asymmetric additions of thiols to highly active Michael
acceptors, such as nitro olefins, give useful intermediates for the
synthesis of 1,2-aminothiols. This synthetic approach exploits the
reaction of thioacetic acid with aromatic or aliphatic nitro olefins.8
As an alternative to this addition, we were interested in the devel-
opment of a new organocatalytic protocol for the sulfa-Michael
reaction of thioalkyl nucleophiles.
The successful enantioselective additions of aromatic thiols to
Michael acceptors have already been accomplished in the presence
of thiourea-type catalysts.3f,g,9 Aliphatic thiols10 are characterized
by reduced acidity in comparison to their aromatic counterparts
(e.g., thiophenol’s pKa is 6.52, for benzyl mercaptan, pKa = 9.43).11
While thiophenols react with nitro olefins without a catalyst,12
analogous reactions of mercaptans require prolonged reaction
times or an additional basic catalyst. Therefore, the activation of a
nucleophile by a basic function together with the binding of an
acceptor by a bifunctional catalyst should facilitate the reaction.
However, organization of the transition state resulting from the
binding of the aliphatic thiol by an amino group in the typically
tested Cinchona derivatives has been suggested to be poor.13 In fact,
relatively weaker interactions between the basic moiety of the
catalyst and the aliphatic thiol, in addition to the conformational
2. Results and discussion
First, quinine 1 (Fig. 1) was examined in the test reaction of
benzyl thiol with trans-b-nitrostyrene and, similar to the reported
result,14 practically no enantioselectivity was observed. The intro-
duction of an extra donor of a hydrogen bond in cupreine 2 or in
the epi-quinine based thiourea 3 also led to a nearly racemic
product. These results were in agreement with the observations
of Connon.13 Changing the chiral core from the Cinchona alkaloid
to trans-1,2-diaminocyclohexane (Takemoto catalyst 4 and bis-
thiourea 5), gave no satisfactory results. Thus, we decided to devise
a new catalyst that activated both the thiol and nitro alkene with a
chiral unit that was structurally different from the classical
(privileged) one. We noted that the simple, commercially available
(R)-(ꢀ)-1-benzyl-3-aminopyrrolidine16 offers a useful scaffold for
the bifunctional thioureas 6 and 7. The opposite enantiomer of
N-3,5-bis(trifluoromethyl)phenyl thiourea derivative 7 has already
been tested in the organocatalytic asymmetric hetero-Diels–Alder
reaction but it was found to be ineffective.17 However, Bolm
et al. have recently described the successful use of bifunctional
catalysts of similar structures in stereoselective quaternary
carbon–carbon bond formations.18 Both compounds 6 and 7 were
easily prepared from (R)-1-benzyl-3-aminopyrrolidine and the cor-
responding isothiocyanates in a simple, one-step procedure. The
⇑
Corresponding author. Tel.: +48 713203302; fax: +48 713202427.
E-mail address: rafal.kowalczyk@pwr.wroc.pl (R. Kowalczyk).
URL: http://www.org.ch.pwr.wroc.pl (R. Kowalczyk).
0957-4166/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetasy.2013.03.007

506
R. Kowalczyk et al. / Tetrahedron: Asymmetry 24 (2013) 505–514
O
CF3
N
O
N
OH
N
S
N
N
NH
N
H
N
H
CF3
N
N
S
NH
OH
OH
4
F3C
CF3
2
1
3
CF3
CF3
S
F3C
F3C
S
S
CF3
CF3
Ph
S
Ph
S
NH HN
N
H
N
H
CF3
N
N
NH
HN
N
N
H
N
H
N
H
N
H
CF3
Ph
5
7
8
6
Figure 1. Structures of catalysts tested.
application of 10 mol % of thiourea 7 in dichloromethane at ꢀ30 °C
gave the desired sulfa-Michael adduct in 81% yield and 70% ee. In
contrast, the closely related catalyst 8, based on another five-mem-
bered nitrogen heterocycle with a proline core, leading to the prod-
uct with only 4% ee (Table 1).
Table 2
Influence of the solvent in reaction of benzyl mercaptan and b-nitrostyrenea
NO2
7 (7.5 mol %)
NO2
+ PhCH2SH
(1.0 equiv)
Ph
Ph
S
Ph
solvent (9 mL)
-30 °C, 48 h
Table 1
Screening of catalysts in the reaction of benzyl mercaptan and b-nitrostyrenea
b
Entry
Solvent
Yield (%)
eec (%)
NO2
1
2
ClCH2CH2Cl
CH2Cl2
CHCl3
CCl4
PhCF3
CH2Cl2/PhCF3 (1:1, v/v)
PhCH3
Et2O
t-BuOMe
DME
CH3CN
76
86
83
86
84
84
81
71
82
63
90
61
67
64
68
75
67
60
38
27
24
16
catalyst (10 mol %)
NO2
+ PhCH2SH
(1.0 equiv)
Ph
DCM (9 mL)
Ph
S
Ph
3
-30 °C
4d
5
48 h
6
7
8
9
10
11
Catalystb
Yieldc (%)
eed (%)
1
2
3
4
5
6
7
8
84
82
71
97
84
78
81
79
7
2
14
17
0
41
70
4
a
Unless otherwise stated, reactions were performed on a 0.33 mmol scale in
9.0 mL of solvent at ꢀ30 °C for 48 h, applying 7.5 mol % of catalyst 7 (2.75 mM).
b
Isolated yield after flash chromatography.
c
Determined by chiral HPLC.
Reaction was performed at ꢀ20 °C.
d
a
Reactions were performed on a 0.33 mmol scale in 9.0 mL of dichloromethane
at ꢀ30 °C for 48 h, applying 10 mol % of catalyst.
b
Structures of the catalysts are shown in Figure 1.
Isolated yield after flash chromatography.
Determined by chiral HPLC.
c
d
catalyst association effects can be excluded. When the transforma-
tion was performed at 0 °C, the adduct was formed in 97% yield and
56% ee after 24 h. Lowering the temperature increased the stere-
oselectivity and at ꢀ30 °C we obtained 72% ee while at ꢀ80 °C,
76% ee was obtained (Table 3).
Next, we examined the influence of the catalyst loading. The
test reaction in the presence of 2.5 and 20 mol % of 7 gave 76
and 77% ee, respectively. The effectiveness of the developed cata-
lyst was rather invariable for a broad range of loadings (Table 3).
In the final step of the optimization process, the influence of the
thiol/b-nitrostyrene ratio was examined (Table 4). Even when 2 or
5 equiv of benzyl thiol was used, the enantioselectivity remained
unchanged (Table 4, entries 2 and 4). The reaction worked well
when the total volume of solvent was decreased six times (entries
2 and 3). Therefore, the efficiency of the catalytic system remained
unaffected by an increase in the thiol concentration.
Similarity in the results between thiourea 7 and Takemoto cat-
alyst 4 suggests that effective hydrogen bonding19 also occurs in
our case. This effect can be fine-tuned by the proper choice of sol-
vent and concentration. Thus, the reactions in different solvents
were tested and the results obtained clearly indicate the superior-
ity of halogenated alkanes over ethers and acetonitrile (Table 2).
When the reaction was performed in trifluorotoluene, it was
more effective than in dichloromethane. However, due to the high
melting point of PhCF3 (ꢀ30 °C) the system turned out to be par-
tially non-homogenous and thus precluded potential optimization
by lowering the temperature. For practical reasons, dichlorometh-
ane was chosen for further examination. Generally, the test reac-
tions were run with equimolar amounts of both b-nitrostyrene
and benzyl mercaptan, using 7.5 mol % of 7 at ꢀ30 °C. In order to
examine the influence of possible self-association of the catalyst,
we diluted the reaction mixture with different volumes of solvent,
running it at 2.75 and 16.5 mM of 7. The product was obtained in
86% yield, 67% ee and 82% yield, 69% ee, respectively. Accordingly,
Bearing in mind that lowering the temperature from ꢀ30 to
ꢀ80 °C did not improve the enantioselectivity by much (76 vs
72% ee), for practical reasons we performed further experiments
at ꢀ30 °C, applying 2.5 mol % of catalyst 7.

R. Kowalczyk et al. / Tetrahedron: Asymmetry 24 (2013) 505–514
507
Table 3
Table 5
Influence of catalyst loading for the yield and ee in the test reactiona
Scope of the nitro olefins in the reaction with benzyl mercaptan catalyzed by 7a
NO2
NO2
7 (x mol %)
7 (2.5 mol %)
NO2
+ PhCH2SH
(1.0 equiv)
+ PhCH2SH
(1.0 equiv)
NO2
Ph
Ph
S
Ph
R
S
Ph
R
DCM (1.5 mL)
temp., 48 h
DCM (1.5 mL)
-30 °C, 48 h
9
Entry
7 (mol %)
Temp (°C)
Yieldb (%)
eec,d (%)
Entry
R
Product
Yieldb (%)
eec (%)
1
2
3
4
5
6
1.0
2.5
2.5
7.5
10
ꢀ30
ꢀ30
ꢀ80
ꢀ80
ꢀ80
ꢀ80
83
82
84
79
93
90
70
72
76
77
78
77
1
Ph
4-F-C6H4
9a
9b
9c
9d
9e
9f
9g
9h
9i
9j
9k
9l
9m
9n
82
95
78
81
92
88
85
83
83
92
92
87
74
50
72
69
70
75
66
68
67
50
69
70
68
63
26
0
2
3d
4
4-Br-C6H4
4-Cl-C6H4
2,6-Cl2-C6H3
2,4-Cl2-C6H3
2-Cl-C6H4
4-NO2-C6H4
4-MeO-C6H4
2-Naphthyl
2-Thienyl
Cyclohexyl
2-OH-C6H4
3-Indolyl
5
20
6e
7
a
Reactions were performed on a 0.33 mmol scale in 1.5 mL of dichloromethane
for 48 h.
8f
b
9
Isolated yield after flash chromatography.
Determined by chiral HPLC.
10e
11
12
13g
14f
c
d
Configuration (S) of the main product was ascribed by analogy to the product of
a known Michael adduct of this type.13
a
Unless otherwise noted, reactions were performed on a 0.33 mmol scale in
Table 4
Influence of the thiol/b-nitrostyrene ratio for yield and eea
1.5 mL of dichloromethane at ꢀ30 °C for 48 h applying 2.5 mol % of catalyst 7.
b
Isolated yield after flash chromatography.
Determined by chiral HPLC.
5 mL of dichloromethane was used.
2 mL of dichloromethane was used.
9 mL of dichloromethane was used.
7 mL of dichloromethane was used.
NO2
S
c
7 (10 mol %)
d
NO2
+ PhCH2SH
(x equiv)
Ph
DCM (9 mL)
-30 °C
e
Ph
Ph
f
time (h)
g
c
Entry
Thiol/nitrostyrene ratio
Time (h)
Yieldb (%)
ee (%)
1
1.2
2.0
2.0
5.0
48
48
24
48
99
99
79
96
69
73
71
73
that NH and OH can specifically interact with the thiourea func-
tionality of 7 and such competitive withdrawal of the catalyst is
responsible for a decrease in the ee.19a
2
3d
4
a
Further studies were focused on the effects caused by the struc-
turally different alkyl thiols in the catalyzed reaction of b-nitrosty-
rene. Hence, benzyl-type, thioglycolic acid methyl ester and
cyclohexyl thiols were screened (Table 6).
Unless otherwise stated, reactions were performed on a 0.33 mmol scale in
9 mL of dichloromethane at ꢀ30 °C applying 10 mol % of 7.
b
Isolated yield after flash chromatography.
Determined by chiral HPLC.
Reaction performed in 1.5 mL of dichloromethane.
c
d
Table 6
The absolute configuration of the sulfa-Michael adducts ob-
tained in the presence of (R)-7 was determined to be (S) by com-
parison the sign of the specific rotation with that for the known
compounds [e.g., (S)-10a].13 Moreover, the order of elution of the
enantiomers from the identical chiral stationary phases was the
same as previously described by Connon.13 For further details,
see Section 4.
Scope of the thiols in the reaction of b-nitrostyrene catalyzed by 7a
NO2
7 (2.5 mol %)
NO2
+ RSH
R
Ph
DCM (1.5 mL)
-30 °C, 48 h
Ph
S
(1.0 equiv)
9a, R = Bn
10
Entry
R
Product
Yieldb (%)
eec (%)
With the optimized protocol in hand, we studied the scope of
the addition of the benzyl mercaptan to different nitro olefins
(Table 5). The amount of solvent used depended on the solubilities
of the reactants and the products.
1
2
3
Bn
9a
82
79
72
72
4-MeO-C6H4CH2
4-t-Bu-C6H4CH2
4-Cl-C6H4CH2
MeOC(O)CH2
Cyclohexyl
10a
10b
10c
10d
10e
10f
85 (76)d
73
76 (87)d
60
4
5e
6
84 (76)d
30
43 (35)d
36
Reactions of various aromatic nitro olefins with benzyl mercap-
tan led to the products with enantiomeric excesses ranging from
50% (entry 8) to 75% (entry 4) in good to excellent yields. These re-
sults showed that the character of the atom or group located at the
para position of the aromatic ring had only a little influence on the
enantioselectivity. Indeed, the application of unsubstituted (entry
1), 4-methoxy- (entry 9), and 4-fluoro- (entry 2) derivatives gave
72, 69, and 69% ee, respectively. Moreover, 2-chloro and 2,6-di-
chloro derivatives did not give very different results (entries 5
and 7), although a diminished enantioselectivity was seen for the
4-nitro derivative (entry 8). Heteroaromatic (entry 11) and alkyl
(entry 12) nitro olefins gave products with good yields and moder-
ate ee values.
7e
HOCH2CH2
55
22
a
Unless otherwise noted, reactions were performed on a 0.33 mmol scale in
1.5 mL of dichloromethane at ꢀ30 °C for 48 h applying 2.5 mol % of catalyst 7.
b
Isolated yield after flash chromatography.
c
Determined by chiral HPLC.
d
Reaction was performed at ꢀ80 °C.
e
Reaction was performed on a 0.5 mmol scale in 2.5 mL of dichloromethane.
The para-substituted benzyl mercaptans showed similar activi-
ties in the test reaction and gave products with small variations in
ee compared to the unsubstituted nucleophile. Better stereoselec-
tivity was achieved for 4-tert-butylbenzyl mercaptan (Table 6, en-
try 3), especially when the reaction was performed at ꢀ80 °C with
2.5 mol % of catalyst. It is worth mentioning that a similar result
(88% ee) was observed in the same reaction in the presence of
5 mol % of the alkaloid catalyst.13 Moderate ee values were ob-
tained in the case of methyl thioglycolate, and only 22% ee for
In order to gain a better understanding of the activation mode
exerted by catalyst 7, substrates with hydrogen bond donor/accep-
tor groups, such as phenolic OH and indolyl NH were tested (en-
tries 13 and 14). The observed ee values were much less than
those obtained with the other nitro olefins (entries 1–12). It seems

508
R. Kowalczyk et al. / Tetrahedron: Asymmetry 24 (2013) 505–514
Cl
Cl
Cl
Cl
7 (5mol %)
SnCl2 (3.7 equiv)
AcOH, MeOH
Ac2O
Et3N
SH
+
Cl
CH2Cl2, 9 mL
Cl
Cl
-80 °C, 72 h
Cl
Cl
71 % ,68 % ee
S
NO2
S
S
AcHN
H2N
11
NO2
13
12
14
Cl
Cl
Cl
Cl
(ref. 8b)
iPr
S
O
NO2
NHAc
Cl
NO2
N
H
N
H
Cl
AcS
HS
N
iPr
iPr
SnCl2 (10 equiv)
S
Cl
Cl
N
HCl (10 equiv), EtOH,
reflux 15 h
AcSH, CPME, -78 °C, 48 h
N
Cl
96% ee
Cl
Cl
Cl
Sulconazole
Scheme 1. Synthetic approaches to Sulconazole.
R
R
R
NO2
NO2
or
NO2
Nu
Nu
1,6-addition
1,4-addition
reactive site
Nu
for further transformations
Figure 2. 1,4- and 1,6-addition to nitrodienes.
2-mercaptoethanol. Such observation can again be rationalized by
the ability of the nucleophile to compete with the nitro group for
the hydrogen bond to the catalyst. If the lower stereocontrol was
caused by the higher reactivity of the thiol, the reaction of methyl
thioglycolate performed at ꢀ80 °C should have assured better
chirality transfer. However, at this temperature the product was
obtained in only 35% ee.
ence of 7, these dienes were reacted with various aliphatic thiols
(Table 7). The reaction was performed under the usual conditions
(ꢀ30 °C) and gave the product 14a with 57% ee. Hence, with the
aim of obtaining better enantioselectivity in the next set of exper-
iments, we lowered the temperature to ꢀ80 °C. Due to the reduced
activity of the nitrodienes in comparison to the nitro olefins,
2 equiv of the respective mercaptan was used. Excess thiol was
The more sterically congested, and thus more demanding,
nucleophiles such as cyclohexanethiol turned out to be non-com-
patible with the catalytic system, generating the product with
36% ee and 30% yield.
Table 7
Addition of thiols to nitrodienes catalyzed by 7a
For an extension of the reaction scope, we carried out the addi-
tion of p-chlorobenzyl mercaptan to the acceptor 11 (Scheme 1,
upper part). The oily sulfa-Michael adduct 12 was obtained in
71% yield and 68% ee. The subsequent reduction of 12 with the
SnCl2 dihydrate20 followed by acylation led to 14 in 41% yield over
two steps. However, the crude amine 13 can be directly trans-
formed into the respective imidazole antifungal drug, Sulconazole.
The reported synthesis of Sulconazole (Scheme 1, lower part) re-
quired additional steps (thiol deprotection, alkylation of the sulfur
atom with p-chlorobenzyl bromide and finally hydrolytic removal
of the acyl function) to give the free amine necessary for the forma-
tion of the imidazole ring.8b The proposed direct methodology of-
fers an alternative and shorter approach to the synthesis of
Sulconazole and its derivatives.
NO2
7 (2.5 mol %)
NO2
+ RSH
R
Ph
Ph
S
DCM (1.5 mL)
-80 °C, 72 h
2.0 equiv
14
Entry
R
Product
Yieldb (%)
eec (%)
1
Bn
Bn
14a
14b
14c
14d
14e
14f
93
—
67
70
70
82
78
58
5
2d
3
4-MeO-C6H4CH2
4-tBu-C6H4CH2
2-furylmethyl
4-Cl-C6H4CH2
MeOC(O)CH2
68
85
64
75
92
4
5
6
7
Finally, we tested the catalytic reaction of aliphatic thiols with
nitrodienes. Although one can speculate as to whether the nucleo-
phile adds at the b- or d-position of the nitrodiene,21 the resulting
adduct would be amenable for further transformations at the
14g
a
Reactions were performed on a 0.33 mmol scale in 1.5 mL of dichloromethane
at ꢀ80 °C for 72 h applying 2.5 mol % of catalyst 7.
b
Isolated yield after flash chromatography.
remaining double bond (either in the reactions of
a,b-conjugated
c
Determined by chiral HPLC.
system or cycloadditions, Fig. 2).22
d
Nitrodiene: 4-MeO–C6H4CH@CH–CH@CH–NO2 was used. An attempt to isolate
pure product by chromatography failed. Ee was determined by HLPC after column
chromatography.
In order to establish the regio- and stereoselectivity of the addi-
tion of the sulfur centered nucleophiles to nitrodienes in the pres-

R. Kowalczyk et al. / Tetrahedron: Asymmetry 24 (2013) 505–514
509
also used in order to force the reaction to completion and to avoid
the problematic separation of the unreacted nitrodiene from the
desired product with nearly identical Rf values. The results are pre-
sented in Table 7.
Both benzyl-type compounds and 2-furylmethanethiol reacted
well, leading exclusively to the respective 1,4-adducts21c,23 in good
yields and enantiomeric excesses ranging from 67% to 82%. The
regioselectivity of the addition was determined by 1H NMR, and
analyzing the chemical shifts of the vinyl protons. Additional struc-
tural evidence for the 1,4-addition was obtained from HMBC corre-
lations of carbon–proton couplings in the adduct of methyl
thioglycolate to the nitrodiene (Fig. 3).
Avance DRX 300 and NMR Bruker Avance™ 600 MHz. 1H NMR
chemical shifts are reported in ppm (d) relative to tetramethylsil-
ane (TMS, d 0.00 ppm) and CHCl3 (d 7.26 ppm). Data are reported
as follows: chemical shift, multiplicity (s = singlet, br s = broad sin-
glet, d = doublet, t = triplet, q = quartet, m = multiplet), coupling
constants (Hz) and integration. 13C NMR chemical shifts are re-
ported in ppm from tetramethylsilane (TMS) and CDCl3 (d
77.0 ppm) or DMSO-d6 (39.52 ppm). FT-IR spectra were recorded
on System 2000 FT-IR Perkin–Elmer spectrometer. ESI HRMS spec-
tra were recorded on WATERS LCT Premier XE apparatus. HPLC
analysis was performed on Thermo Scientific System (SCM 1000,
Spectra System P4000 pump and Spectra System UV 2000 detec-
tor) using Chiralpak AD-H, Chiralcel OD-H and Chiralpak AS-H col-
umns (4.6 mm ꢁ 25 cm). No guard column was used. Each HPLC
analysis was controlled by comparison with the pure sample and
the racemate. Optical rotations were measured on an automatic
polarimeter at k = 589 nm (c g/100 mL).
The absolute configuration of the sulfa-Michael adduct was as-
cribed as (S) by analogy to known compounds for example, 10a,
10b13 and by comparison of the sign of the specific rotation mea-
sured in the same solvent as described for analogues. Moreover,
the order of elution of enantiomers from the chiral stationary
phases was the same as that described for known, analogue com-
pounds for example, 10a.
7.40
6.60
S
CO2Me
NO2
126.7
134.9
135.3
6.02
123.2
Figure 3. Selected HMBC correlations for adduct 14g. Numbers correspond to 1H
and 13C chemical shifts (ppm).
Application of 4-chlorobenzenemethanethiol gave the product
with only 58% ee while the use of methyl thioglycolate furnished
a product with negligible enantioselectivity.
4.2. General procedure 1 for the synthesis of thioureas 6, 7, and 8
3. Conclusion
Amine (1.0 equiv) and isothiocyanate (1.3 equiv) were mixed in
dichloromethane and stirred at rt for 24 h. Then, the solvent was
evaporated and the residue was subjected to column chromatogra-
phy on silica gel (hexanes/EtOAc, 1:1, v/v) that afforded the desired
thiourea.
In conclusion, we have reported a simple organocatalytic sys-
tem for the sulfa-Michael reaction of aliphatic thiols and nitro ole-
fins, leading to the respective adducts in good to excellent yields
and with up to 87% ee. Application of the more demanding nitrodi-
enes led exclusively to 1,4-adducts with up to 82% ee. Catalyst 7
was obtained from a commercially available enantiomeric amine
and isothiocyanate in a one step-procedure as a crystalline, air-sta-
ble product. The catalytic system developed is effective using as lit-
tle as 2.5 mol % of 7 and works well in a broad range of catalyst
concentrations as well as in an excess of the thiols.
4.2.1. Thiourea 6
The reaction was carried out with (R)-(ꢀ)-1-benzyl-3-amino-
pyrrolidine (0.39 mL, 2.3 mmol, and 1.0 equiv) and phenyl isothio-
cyanate (0.7 mL, 3.0 mmol, 1.3 equiv) in 6 mL of CH2Cl2 to give the
desired thiourea as a solid, yield 85%; mp: 63–64 °C (hexanes/
diethyl ether), Rf = 0.18 (hexanes/EtOAc, 1/1, v/v), ½a D20
¼ ꢀ39:3 (c
ꢂ
0.89, CH2Cl2); 1H NMR (600 MHz, CDCl3) d 1.74 (br s, 1H), 2.17–
2.37 (m, 2H), 2.46 (dd, J = 10.0, 6.0 Hz, 1H), 2.72 (br s, 1H), 2.91
(br s, 1H), 3.53 (d, J = 12.9 Hz, 1H), 3.62 (d, J = 12.9 Hz, 1H), 4.91
(br s, 1H), 6.66 (br s, 1H), 7.16–7.32 (m, 8H), 7.40–7.45 (m, 2H),
8.09 (br s, 1H); 13C NMR (151 MHz, CDCl3) d 31.9, 52.2, 54.5,
59.4, 59.7, 124.8, 126.5, 127.0, 128.2, 128.5, 129.7, 136.4, 138.2,
4. Experimental
4.1. General
Commercially available starting materials were used without
further purification. Carbon tetrachloride and a,a,a-triflurotoluene
were used as received. Chloroform and 1,2-dichloroethane were
distilled over P2O5 under argon. Dichloromethane, tert-butyl-
methyl ether, dimethoxyethane, and acetonitrile were distilled
with CaH2 under argon and further stored over 3 Å molecular
sieves. Diethyl ether was distilled over sodium/benzophenone
and stored over 4 Å molecular sieves. Toluene was dried over so-
dium wires.
Nitro olefins were prepared by following literature precedents
and yields were not optimized.24 Nitrodienes were prepared
according to the literature.25 Catalysts 2,26 327 and 528 were
prepared according to the literature. Catalyst 4 was purchased
from a commercial supplier.
Reactions were performed in reaction tubes with the gas inlet.
Tubes were heated to 550 °C for 3–5 min under high vacuum,
cooled down and then flushed with argon.
Flash chromatography (FC) was performed using silica gel 35–
70 lm. Thin layer chromatography was performed using silica
179.2; IR (KBr)
1496, 1452, 1397, 1344, 1313, 1244, 1194, 1181, 1136, 1119,
1072, 746 cmꢀ1 HRMS (ESI): calcd for C18H22N3S ([M+H]+):
v: 3249, 3193, 3173, 3028, 2978, 2808, 1531,
;
312.1529, found 312.1534.
4.2.2. Thiourea 7
The enantiomer of 7 is a known17 compound, however, no spectra
are available. Reaction applying (R)-(ꢀ)-1-benzyl-3-aminopyrrol-
idine (0.49 mL, 2.8 mmol, 1.0 equiv) and 3,5-bis(trifluoromethyl)
phenyl isothiocyanate (0.44 mL, 3.7 mmol, 1.3 equiv) in 8 mL of
CH2Cl2 gave the desired thiourea as colorless crystals, yield 95%;
mp: 127–128 °C, lit.17 129.0–132.0 °C, Rf = 0.15 (hexanes/EtOAc, 1/
1, v/v); ½a 2D0
ꢂ
¼ ꢀ56:5 (c 0.46, CH2Cl2); 1H NMR (600 MHz, DMSO-
d6) d 1.69 (br s, 1H), 2.21–2.27 (m, 1H), 2.36 (br s, 1H), 2.57 (d,
J = 7.2 Hz, 1H), 2.64–2.81 (m, 2H), 3.61 (br s, 2H), 4.69 (br s, 1H),
7.24–7.27 (m, 1H), 7.32–7.33 (m, 4H), 7.71 (br s, 1H), 8.25 (s, 2H),
8.39 (br s, 1H), 9.97 (br s, 1H); 13C NMR (151 MHz, DMSO-d6) d
31.0, 52.2, 53.1, 59.2, 59.6, 115.9, 121.7, 123.2 (q, JCF = 273 Hz),
126.9, 128.2, 128.6, 130.0 (q, JCF = 33 Hz), 138.7, 141.9, 179.9; IR
(KBr) v: 3228, 3121, 3064, 3028, 2986, 2958, 2815, 1613, 1542,
1474, 1457, 1387, 1340, 1282, 1182, 1124, 885, 726, 700,
gel on aluminium foil plates with an indicator. Chromatograms
were visualized using UV-lamp and KMNO4 dip.
1H and 13C NMR (300 and 75 MHz or 600 and 151 MHz, respec-
tively) spectra were recorded in CDCl3 and DMSO-d6 on Bruker

510
R. Kowalczyk et al. / Tetrahedron: Asymmetry 24 (2013) 505–514
682 cmꢀ1. HRMS (ESI): calcd for C20H20F6N3S ([M+H]+): 448.1277,
found 448.1282.
J = 1.3 Hz, 1H), 6.96–7.04 (m, 2H), 7.18–7.28 (m, 6H), 7.30–7.33
(m, 1H). 13C NMR (75 MHz, CDCl3): d 36.0, 45.1, 79.0, 116.0
(JCF = 21.6 Hz), 127.6, 128.7, 128.8, 129.5 (d, JCF = 8.3 Hz), 132.8
4.2.3. Thiourea 8
(d, JCF = 3.3 Hz), 136.7, 162.5 (d, JCF = 248 Hz); IR (neat) v: 3063,
An application of compound 8 was reported,29 no spectroscopic
data were provided. Reaction applying (R)-2-aminomethyl-l-ben-
zyl-pyrrolidine30 (170 mg, 0.9 mmol, and 1.0 equiv) and 3,5-
bis(trifluoromethyl)phenyl isothiocyanate (0.26 mL, 1.1 mmol,
1.2 equiv) in 5 mL of CH2Cl2 gave the desired thiourea as a colorless
3030, 2918, 1603, 1555, 1509, 1454, 1428, 1375, 1227, 1160,
1100, 839, 798, 768, 704 cmꢀ1; HRMS (ESI): calcd for C15H14FNO2S-
Na [M+Na]+: 314.0627, found: 314.0615; HPLC: AD-H, n-hexane/
IPA 97:3; 0.7 mL/min; k = 254 nm; tr = 13.59 min (minor);
tr = 14.79 (major); 69% ee.
liquid, yield 30%; Rf = 0.36 (hexanes/EtOAc, 1/1, v/v); ½a D20
¼ þ7:8 (c
ꢂ
0.32, CH2Cl2); 1H NMR (300 MHz, CDCl3) d 1.45–1.69 (m, 3H), 2.07–
2.26 (m, 2H), 2.62 (d, J = 11.1 Hz, 1H), 2.79 (d, J = 7.7 Hz, 1H), 2.77–
2.80 (m, 1H), 3.33 (d, J = 13.1 Hz, 1H), 3.46 (d, J = 13.1 Hz, 1H), 4.54
(br s, 1H), 6.90 (br s, 2H), 7.10–7.21 (m, 4H), 7.78–7.79 (m, 3H),
8.73 (br s, 1H); 13C NMR (75 MHz, CDCl3) d 21.7, 27.5, 50.6, 53.7,
56.9, 62.7, 119.3, 122.9 (q, JCF = 272 Hz), 123.9, 127.3, 128.2,
128.7, 133.3 (JCF = 35 Hz), 137.5, 138.8, 178.4; HRMS (ESI): calcd
for C21H22F6N3S ([M+H]+) 462.1433, found 462.1432.
4.4.3. (S)-Benzyl (1-(4-bromophenyl)-2-nitroethyl) sulfide 9c
Reaction was performed in 5 mL of CH2Cl2; colorless oil, yield
78%, 70% ee; ½a 2D0
ꢂ
¼ þ170:0 (c 0.5, CHCl3); 1H NMR (300 MHz,
CDCl3): d 3.49 (d, J = 13.7 Hz, 1H), 3.60 (d, J = 13.5 Hz, 1H), 4.26
(dd, J = 8.4, 7.2 Hz, 1H), 4.53 (s, 1H), 4.54 (d, J = 1.3 Hz, 1H), 7.04
(d, J = 8.4 Hz, 2H), 7.13–7.17 (m, 2H), 7.19–7.27 (m, 3H), 7.38 (d,
J = 8.6 Hz, 2H); 13C NMR (75 MHz, CDCl3): d 36.0, 45.2, 78.7,
122.4, 127.6, 128.7, 128.8, 129.4, 132.1, 136.1, 136.6; IR (neat) v:
3029, 2918, 1555, 1489, 1375, 1074, 1011, 705 cmꢀ1; HRMS
(ESI): calcd for C15H14Br79NO2SNa [M+Na]+: 373.9826, found:
373.9818; HPLC: AD-H, n-hexane/IPA 97:3; 0.7 mL/min;
k = 254 nm; tr = 15.36 min (minor); tr = 17.82 (major); 70% ee.
4.3. General procedure 2 for the reaction of nitro olefins and
aliphatic thiols leading to racemates
At first, DABCO (0.10 mmol, 10 mol %, 11 mg) was added to a
solution of thiol (1.5 equiv, 1.5 mmol) in dichloromethane
(2.5 mL) at 20 °C, stirred for 15 min followed by the addition of ni-
tro olefin or nitrodiene (1.0 mmol, 1.0 equiv). The resulting solu-
tion was stirred from 3 to 20 h at 20 °C and filtered through a
plug of silica gel (10 g). The filtrate was concentrated in vacuo
and dried under high vacuum to afford the crude sulfa-Michael ad-
duct. Purification, if needed, was performed using flash chromatog-
raphy on silica-gel (40 g) eluting by hexanes/EtOAc, 25:1, v/v.
4.4.4. (S)-Benzyl (1-(4-chlorophenyl)-2-nitroethyl) sulfide 9d
Colorless oil, yield 81%, 75% ee; ½a D20
ꢂ
¼ þ185:7 (c 0.5, CHCl3); 1H
NMR (300 MHz, CDCl3): d 3.55 (d, J = 13.5 Hz, 1H), 3.65 (d,
J = 13.7 Hz, 1H), 4.33 (dd, J = 8.5, 7.2 Hz, 1H), 4.58 (s, 1H), 4.60 (d,
J = 1.1 Hz, 1H), 7.14–7.23 (m, 4H), 7.24–7.33 (m, 3H), 7.24–7.27
(m, 2H); 13C NMR (75 MHz, CDCl3): d 36.0, 45.1, 78.8, 127.6,
128.7, 128.8, 129.1, 129.2, 134.3, 135.6, 136.6. Spectra are in agree-
ment with the reported ones for a racemic sample;31 IR (neat)
v:
3063, 3030, 1555, 1493, 1454, 1427, 1411, 1375, 1092, 1015,
843, 831, 705 cmꢀ1; HPLC: AD-H, n-hexane/IPA 97:3; 0.7 mL/
min; k = 254 nm; tr = 14.59 min (minor); tr = 16.51 (major); 75% ee.
4.4. General procedure for the catalytic reaction of nitro olefins
and aliphatic thiols
A
reaction tube was charged with catalyst
7
(3.7 mg,
4.4.5. (S)-Benzyl (1-(2,6-dichlorophenyl)-2-nitroethyl) sulfide 9e
0.008 mmol, 2.5 mol %), nitro olefin (1.0 equiv, 0.33 mmol) and
dichloromethane (1.0 mL) under argon at 20 °C. The resulting solu-
tion was stirred at 20 °C for 20 min, and cooled to ꢀ30 °C for
10 min Then, a solution of thiol (1.0 equiv, 0.33 mmol) in dichloro-
methane (0.5 mL) was added slowly over 10 min via syringe. The
resulting solution was stirred for 3 h at ꢀ30 °C, flushed with argon,
sealed and put into a freezer (ꢀ30 °C). After 48 h, the cold reaction
mixture was filtered through a plug of silica (4 ꢁ 4 cm) eluting
with dichloromethane (100 mL). The resulting filtrate was concen-
trated in vacuo and the residue was subjected to flash chromatog-
raphy (silica gel, 20 g, hexanes/EtOAc, 25:1, v/v) to afford the
desired product.
Colorless oil, yield 92%, 66% ee; ½a D20
¼ þ138:0 (c 0.58, CHCl3);
ꢂ
1H NMR (300 MHz, CDCl3): d 3.80 (d, J = 13.4 Hz, 1H), 3.87 (d,
J = 13.4 Hz, 1H), 4.68 (dd, J = 13.2, 7.1 Hz, 1H), 5.02 (dd, J = 13.4,
8.4 Hz, 1H), 5.33 (dd, J = 8.4, 7.1 Hz, 1H), 7.05 (dd, J = 8.6, 7.3 Hz,
1H), 7.16–7.30 (m, 7H); 13C NMR (75 MHz, CDCl3): d 38.6, 42.5,
77.1, 127.6, 128.65, 128.7, 129.0, 129.5, 129.9, 133.8, 135.06,
135.1, 136.9; IR (neat)
1436, 1374, 1179, 1089, 778, 702 cmꢀ1; HRMS (ESI): calcd for
15H13Cl235NO2SNa [M+Na]+: 363.9942; found: 363.9953; HPLC:
v: 3063, 3030, 2967, 1553, 1495, 1454,
C
AD-H, n-hexane/IPA 99:1; 1 mL/min; k = 254 nm; tr = 14.54 min
(minor); tr = 16.25 (major); 66% ee
In the case of the limited solubility of a nitro olefin, an increased
amount of solvent was used. Such information is provided below in
each case, where relevant.
4.4.6. (S)-Benzyl (1-(2,4-dichlorophenyl)-2-nitroethyl) sulfide 9f
Reaction was performed in 2 mL of CH2Cl2; colorless oil, yield
88%, 68% ee; ½a 2D0
ꢂ
¼ þ100:6 (c 0.54, CHCl3); 1H NMR (300 MHz,
CDCl3): d 3.69 (s, 2H), 4.51 (dd, J = 13.2, 7.2 Hz, 1H), 4.67 (dd,
J = 13.2, 8.0 Hz, 1H), 4.85 (t, J = 7.5 Hz, 1H), 7.18–7.28 (m, 6H),
7.31 (d, J = 8.4 Hz, 1H), 7.34 (d, J = 2.0 Hz, 1H); 13C NMR (75 MHz,
CDCl3): d 36.8, 42.2, 77.6, 127.6, 127.7, 128.7, 128.9, 129.5, 129.9,
4.4.1. (S)-Benzyl (2-nitro-1-phenylethyl) sulfide 9a
Pale yellow liquid, yield 90%, 77% ee; ½a D20
¼ þ185:5 (c 1.54,
ꢂ
CHCl3); 1H NMR (300 MHz, CDCl3): d 3.56 (d, J = 13.5 Hz, 1H),
3.65 (d, J = 13.5 Hz, 1H), 4.38 (dd, J = 8.9, 6.8 Hz, 1H), 4.57–4.67
(m, 2H), 7.19–7.7.32 (m, 10H); 13C NMR (75 MHz, CDCl3): d 36.0,
45.9, 79.0, 127.5, 127.7, 128.5, 128.7, 128.9, 129.0, 136.9, 137.0.
Spectra are in agreement with the reported ones for a racemic sam-
ple.31 HPLC: AD-H, n-hexane/IPA 99:1; 1 mL/min; k = 254 nm;
tr = 11.89 min (minor); tr = 12.95 (major); 77% ee.
133.3, 134.4, 134.6, 136.4; IR (neat)
v: 3090, 2919, 1588, 1555,
1490, 1472, 1427, 1375, 1095, 10523, 1016, 871, 826, 778, 722,
674, 652 cmꢀ1
;
HRMS (ESI): calcd for C15H13Cl235NO2SNa
[M+Na]+: 363.9942, found: 363.9951; HPLC: AD-H, n-hexane/IPA
99:1; 1 mL/min; k = 254 nm; tr = 19.11 min (minor); tr = 21.25
(major); 68% ee.
4.4.2. (S)-Benzyl (1-(4-fluorophenyl)-2-nitroethyl) sulfide 9b
4.4.7. (S)-Benzyl (1-(2-chlorophenyl)-2-nitroethyl) sulfide 9g
Colorless oil, yield 95%, 69% ee; ½a D20
ꢂ
¼ þ172:0 (c 0.35, CHCl3);
Colorless oil, yield 85%, 67% ee; ½a D20
ꢂ
¼ þ83:2 (c 0.5, CHCl3); 1H
1H NMR (300 MHz, CDCl3): d 3.50 (d, J = 13.5 Hz, 1H), 3.60 (d,
J = 13.5 Hz, 1H), 4.30 (dd, J = 8.6, 7.1 Hz, 1H), 4.53 (s, 1H), 4.56 (d,
NMR (300 MHz, CDCl3): d 3.76 (s, 2H), 4.59 (dd, J = 13.1, 7.4 Hz,
1H), 4.77 (dd, J = 13.1, 7.9 Hz, 1H), 5.00 (t, J = 7.7 Hz, 1H), 7.21–

R. Kowalczyk et al. / Tetrahedron: Asymmetry 24 (2013) 505–514
511
7.36 (m, 7H), 7.38–7.45 (m, 2H); 13C NMR (75 MHz, CDCl3): d 37.0,
42.9, 78.0, 127.5, 127.6, 128.7, 128.8, 129.0, 129.5, 130.3, 133.8,
1.62–1.77 (m, 4H), 3.15 (td, J = 7.5, 3.8 Hz, 1H), 3.72 (d,
J = 13.4 Hz, 1H), 3.77 (d, J = 13.4 Hz, 1H), 4.36 (dd, J = 12.6, 7.3 Hz,
1H), 4.56 (dd, J = 12.6, 7.6 Hz, 1H), 7.24–7.30 (m, 1H), 7.31–7.37
(m, 4H); 13C NMR (75 MHz, CDCl3): d 26.0, 26.03, 28.4, 30.2, 37.2,
40.1, 48.7, 78.0, 127.4, 128.6, 129.0, 137.5. Spectra are in agree-
134.7, 136.8; IR (neat)
v: 3063, 3030, 2918, 1555, 1495, 1475,
1454, 1431, 1375, 1053, 1071, 1036, 755, 702 cmꢀ1; HRMS (ESI):
calcd for C15H14Cl35NO2SNa [M+Na]+: 330.0331, found: 330.0338;
HPLC: OD-H, n-hexane/IPA 99:1; 1 mL/min; k = 254 nm;
tr = 53.32 min (minor); tr = 60.53 (major); 67% ee.
ment with the reported ones for a racemic sample.31 IR (neat)
v
:
;
3029, 2928, 2854, 2552, 1494, 1451, 1428, 1377, 767, 702 cmꢀ1
HRMS (ESI): calcd for C15H21NO2SNa [M+Na]+: 302.1191, found:
302.1191; HPLC: AD-H, n-hexane/IPA 99:1; 1 mL/min;
k = 254 nm; tr = 8.59 min (major); tr = 9.58 (minor); 63% ee.
4.4.8. (S)-Benzyl (1-(4-nitrophenyl)-2-nitroethyl) sulfide 9h
Racemic product is known,32 however no spectra were avail-
able. Reaction was performed in 9 mL of CH2Cl2; light yellow solid-
ifying oil, yield 83%, 50% ee; ½a D20
ꢂ
¼ þ134:7 (c 0.6, CHCl3); 1H NMR
4.4.13. (S)-2-(1-(Benzylthio)-2-nitroethyl)phenol 9m
(600 MHz, CDCl3): d 3.66 (d, J = 13.6 Hz, 1H), 3.77 (d, J = 13.9 Hz,
1H), 4.49 (t, J = 7.9 Hz, 1H), 4.72 (dd, J = 7.5, 0.8 Hz, 2H), 7.26–
7.27 (m, 2H), 7.31–7.34 (m, 1H), 7.35–7.38 (m, 2H), 7.44 (d,
J = 8.7 Hz, 2H), 8.22 (d, J = 8.7 Hz, 2H); 13C NMR (151 MHz, CDCl3):
d 36.3, 45.0, 78.3, 124.2, 127.9, 128.8, 128.85, 128.9, 136.2, 144.6,
Reaction was performed in 7 mL of CH2Cl2; reddish oil, yield
74%, 26% ee; ½a 2D0
ꢂ
¼ þ72:4 (c 0.38, CHCl3); 1H NMR (600 MHz,
CDCl3): d 3.70 (d, J = 13.2 Hz, 1H), 3.76 (d, J = 13.2 Hz, 1H), 4.70–
4.74 (m, 2H), 4.86 (dd, J = 15.4, 10.5 Hz, 1H), 5.96 (br s, 1H), 6.87
(dd, J = 8.3, 0.8 Hz, 1H), 6.95 (dt, J = 7.5, 0.8 Hz, 1H), 7.13 (dd,
J = 7.5, 1.5 Hz, 1H), 7.25 (td, J = 7.9, 1.5 Hz, 1H), 7.27–7.32 (m,
3H), 7.34–7.37 (m, 2H); 13C NMR (151 MHz, CDCl3): d 36.1, 42.5,
77.4, 117.4, 121.3, 122.3, 127.6, 128.7, 128.9, 129.3, 129.9, 136.6,
147.7; IR (neat)
v: 3082, 3029, 2928, 1605, 1552, 1516, 1346,
1180. 1110, 859, 697 cmꢀ1; HRMS (ESI): calcd for C15H14N2O4SNa
[M+Na]+: 341.0572, found: 341.0562; HPLC: OD-H, n-hexane/IPA
80:20; 1 mL/min; k = 225 nm; tr = 27.19 min (minor); tr = 29.04
(major); 50% ee.
154.0; IR (neat)
v: 3480, 3063, 3031, 1596, 1557, 1495, 1455,
1427, 1377, 1335, 1237, 1103, 841, 756, 704 cmꢀ1; HRMS (ESI):
calcd for C15H15NO3SNa [M+Na]+: 312.0670, found: 312.0658.
HPLC: AD-H, n-hexane/IPA 90:10; 1 mL/min; k = 254 nm;
tr = 13.84 min (minor); tr = 15.11 (major); 26% ee.
4.4.9. (S)-Benzyl (1-(4-methoxyphenyl)-2-nitroethyl) sulfide 9i
Light yellow oil, yield 83%, 69% ee; ½a D20
¼ þ175:5 (c 0.51,
ꢂ
CHCl3); 1H NMR (300 MHz, CDCl3): d 3.60 (d, J = 13.7 Hz, 1H),
3.69 (d, J = 13.5 Hz, 1H), 3.81 (s, 3H), 4.40 (dd, J = 8.9, 6.9 Hz, 1H),
4.59–4.71 (m, 2H), 6.89 (d, J = 8.8 Hz, 2H), 7.21 (d, J = 8.6 Hz, 2H),
7.24–7.33 (m, 4H), 7.34–7.37 (m, 1H); 13C NMR (75 MHz, CDCl3):
d 35.9, 45.4, 55.2, 79.2, 114.3, 127.4, 128.6, 128.7, 128.85, 129.0,
137.0, 159.5. Spectra are in agreement with the reported ones for
racemic sample.12 HPLC: AD-H, n-hexane/IPA 95:5; 1 mL/min;
k = 254 nm; tr = 10.31 min (minor); tr = 11.27 (major); 69% ee.
4.4.14. 3-(1-(Benzylthio)-2-nitroethyl)-1H-indole 9n
Reaction was performed in 9 mL of CH2Cl2; light brown oil, yield
50%, 0% ee; 1H NMR (300 MHz, CDCl3): d 3.66 (d, J = 13.7 Hz, 1H),
3.72 (d, J = 13.7 Hz, 1H), 4.74 (dd, J = 9.3, 4.0 Hz, 1H), 4.80–4.92
(m, 2H), 7.09 (d, J = 2.6 Hz, 1H), 7.16 (dt, J = 8.1, 1.1 Hz, 1H),
7.23–7.39 (m, 7H), 7.61 (dd, J = 8.1, 0.6 Hz, 1H), 8.11 (br s, 1H);
13C NMR (75 MHz, CDCl3): d 36.1, 38.9, 78.8, 111.4, 111.6, 119.3,
120.2, 122.9, 123.0, 125.4, 127.5, 128.7, 129.0, 136.6, 137.5; IR
4.4.10. (S)-Benzyl (1-(naphthlen-2-yl)-2-nitroethyl) sulfide 9j
(neat)
1340, 1249, 1102, 746, 704 cmꢀ1
17H16N2O2SNa [M+Na]+: 335.0830, found: 335.0831. HPLC: AD-
H, n-hexane/IPA 90:10; 1 mL/min; k = 254 nm; tr = 20.59 min;
tr = 24.20; 0% ee.
v
: 3420, 3060. 3029, 2917, 1554, 1494, 1456, 1421, 1378,
Reaction was performed in 2 mL of CH2Cl2; yellow solid, yield
;
HRMS (ESI): calcd for
92%, 70% ee; ½a 2D0
ꢂ
¼ þ191:0 (c 0.52, CHCl3); 1H NMR (300 MHz,
C
CDCl3): d 3.55 (d, J = 13.5 Hz, 1H), 3.65 (d, J = 13.5 Hz, 1H), 4.55
(dd. J = 9.0, 6.6 Hz, 1H), 4.69 (dd, J = 12.9, 6.6 Hz, 1H), 4.77 (dd,
J = 12.9, 9.0 Hz, 1H), 7.20–7.32 (m, 5H), 7.40 (dd, J = 8.6, 1.8 Hz,
1H), 7.44–7.49 (m, 2H), 7.62 (br s, 1H), 7.75–7.84 (m, 3H); 13C
NMR (151 MHz, CDCl3): d 35.9, 46.1, 78.9, 124.9, 126.57, 126.6,
127.2, 127.5, 127.7, 127.9, 128.7, 128.9, 129.2, 133.1, 133.2,
4.4.15. (S)-(4-Methoxybenzyl) (2-nitro-1-phenylethyl) sulfide
10a13
Light yellow oil, yield 79%, 72% ee; ½a D20
¼ þ175:0 (c 1.0, CHCl3),
ꢂ
134.1, 136.9; IR (KBr)
v
: 3054, 3028, 2910, 1548, 1494, 1375,
lit.13 +55 (c 0.4, CHCl3); 1H NMR (600 MHz, CDCl3): d 3.57 (d,
J = 13.6 Hz, 1H), 3.65 (d, J = 13.6 Hz, 1H), 3.82 (s, 3H), 4.42 (dd,
J = 9.0, 6.8 Hz, 1H), 4.66 (dd, J = 13.2, 6.8 Hz, 1H), 4.70 (dd,
J = 12.8, 9.0 Hz, 1H), 6.80 (d, J = 8.7 Hz, 2H), 7.18 (d, J = 8.7 Hz,
2H), 7.27–7.29 (m, 2H), 7.31–7.33 (m, 1H), 7.35–7.38 (m, 2H);
13C NMR (151 MHz, CDCl3): d 35.4, 45.8, 55.3, 79.1, 114.1, 127.7,
128.4, 128.7, 129.0, 130.0, 137.1, 158.9; HRMS (ESI): calcd for
810, 801, 745, 724 cmꢀ1; HRMS (ESI): calcd for C19H17NO2SNa
[M+Na]+: 346.0878, found: 346.0888; HPLC: AD-H, n-hexane/IPA
95:5; 1 mL/min; k = 254 nm; tr = 10.73 min (minor); tr = 12.32
(major); 70% ee. Crystallization from CHCl3/hexanes afforded col-
orless crystals, yield 53%, mp: 71.6–72.2 °C, 68% ee;
½
a 2D0
ꢂ
¼ þ199:2 (c 0.60, CHCl3).
C
16H17NO3SNa [M+Na]+: 326.0827, found: 326.0836; HPLC: AD-H,
4.4.11. (R)-2-(1-(Benzylthio)-2-nitroethyl)thiophene 9k
n-hexane/IPA 99:1; 1 mL/min; k = 254 nm; tr = 26.33 min (minor);
tr = 28.85 (major); 72% ee, lit.13 AD-H, n-hexane/IPA 99:1; 1 mL/
min; k = 220 nm; tr = 26.65 min (minor); tr = 31.50 (major).
Light brown oil, yield 92%, 68% ee; ½a D20
¼ þ175:3 (c 0.50,
ꢂ
CHCl3); 1H NMR (300 MHz, CDCl3): d 3.70 (d, J = 13.5 Hz, 1H),
3.78 (d, J = 13.5 Hz, 1H), 4.62–4.77 (m, 3H), 6.96 (d, J = 3.7 Hz,
2H), 7.25–7.30 (m, 3H), 7.31–7.34 (m, 2H), 7.35–7.38 (m, 1H);
13C NMR (75 MHz, CDCl3): d 36.1, 41.2, 79.5, 126.1, 126.6, 126.9,
4.4.16. (S)-(4-tert-Butylbenzyl) (2-nitro-1-phenylethyl) sulfide
10b13
127.6, 128.7, 128.9, 136.6, 140.9; IR (neat)
v
: 3030, 2927, 2854,
Pale yellow oil, yield 76%, 87% ee; ½a D20
¼ þ243:2 (c 0.27, CHCl3),
ꢂ
1551, 1495, 1452, 1428, 1377, 768, 703 cmꢀ1; HRMS (ESI): calcd
for C13H13NO2S2Na [M+Na]+: 302.0285, found: 302.0304; HPLC:
AD-H, n-hexane/IPA 99:1; 1 mL/min; k = 254 nm; tr = 13.84 min
(minor); tr = 15.11 (major); 68% ee.
lit.13 +135 (c 0.2, CHCl3); 1H NMR (300 MHz, CDCl3): d 1.34 (s, 9H),
3.59 (d, J = 13.4 Hz, 1H), 3.68 (d, J = 13.4 Hz, 1H), 4.45 (dd, J = 9.0,
6.7 Hz, 1H), 4.63–4.76 (m, 2H), 7.19 (d, J = 8.4 Hz, 2H), 7.27–7.39
(m, 7H); 13C NMR (150 MHz, CDCl3): d 31.3, 34.5, 35.6, 45.9, 79.1,
125.6, 127.7, 128.4, 128.5, 128.9, 133.7, 137.1, 150.5; HRMS
4.4.12. Benzyl (1-cyclohexyl-2-nitroethyl) sulfide 9l
(ESI): calcd for C
19H23NO2SNa [M+Na]+: 352.1347, found:
Colorless oil, yield 87%, 63% ee; ½a D20
ꢂ
¼ 0:0 (c 0.54, CHCl3); 1H
352.1339; HPLC: AD-H, n-hexane/IPA 99:1; 0.7 mL/min;
k = 254 nm; tr = 12.30 min (minor); tr = 14.12 (major); 87% ee.
NMR (300 MHz, CDCl3): d 0.95–1.34 (m, 5H), 1.43–1.54 (m, 2H),

512
R. Kowalczyk et al. / Tetrahedron: Asymmetry 24 (2013) 505–514
4.4.17. (S)-(4-Chlorobenzyl) (2-nitro-1-phenylethyl) sulfide 10c
99:1; 1 mL/min; k = 254 nm; tr = 20.40 min (minor); tr = 25.41
(major); 68% ee.
Colorless oil, yield 73%, 60% ee; ½a D20
ꢂ
¼ þ157:5 (c 0.8, CHCl3); 1H
NMR (600 MHz, CDCl3): d 3.55 (d, J = 13.6 Hz, 1H), 3.64 (d,
J = 13.6 Hz, 1H), 4.41 (m, 1H), 4.66–4.73 (m, 2H), 7.18 (d,
J = 8.3 Hz, 2H), 7.27–7.31 (m, 4H), 7.32–7.34 (m, 1H), 7.36–7.39
(m, 2H); 13C NMR (151 MHz, CDCl3): d 35.2, 46.0, 79.0, 127.8,
4.5. General procedure for the catalytic reaction of nitrodienes
and aliphatic thiols
128.6, 128.8, 129.1, 130.2, 133.3, 135.4, 136.8; IR (neat)
3031, 2920, 1555, 1491, 1427, 1376, 1093, 1015, 830, 747,
700 cmꢀ1 HRMS (ESI): calcd for C15H14Cl35NO2SNa [M+Na]+:
330.0331, found: 330.0342; HPLC: AD-H, n-hexane/IPA 99:1;
1 mL/min; k = 254 nm; tr = 21.03 min (minor); tr = 22.87 (major);
60% ee.
v: 3064,
A
reaction tube was charged with catalyst 7 (3.7 mg,
0.008 mmol, 2.5 mol %), nitrodiene (1.0 equiv, 0.33 mmol) and
dichloromethane (1.0 mL) under argon at 20 °C. The resulting solu-
tion was stirred at 20 °C for 20 min, and cooled to ꢀ78 °C for
10 min. Then, a solution of thiol (2.0 equiv, 0.66 mmol) in dichloro-
methane (0.5 mL) was slowly added over 10 min via syringe. The
resulting solution was stirred for 3 h at ꢀ78 °C, flushed with argon,
sealed and maintained at ꢀ80 °C. After 72 h, the cold reaction mix-
ture was filtered through a plug of silica gel (4 ꢁ 4 cm) eluting with
dichloromethane (100 mL). The resulting filtrate was concentrated
in vacuo and the residue was subjected to flash chromatography
(silica gel, 25 g, hexanes/EtOAc, 30:1, v/v) to afford the desired
product.
;
4.4.18. Methyl 2-((2-nitro-1-phenylethyl)thio)acetate 10d
Reaction was performed in 0.5 mmol scale in 2.5 mL of CH2Cl2;
colorless oil, yield 84%, 43% ee; ½a D20
ꢂ
¼ þ90:0 (c 0.49, CHCl3), lit.15b
[a]
D = +20.4 (c 1.031, CHCl3,); 1H NMR (600 MHz, CDCl3): d 3.08 (d,
J = 15.4 Hz, 1H), 3.17 (d, J = 15.4 Hz, 1H), 3.71 (s, 3H), 4.80–4.89 (m,
3H), 7.31–7.36 (m, 4H), 7.37–7.39 (m, 1H); 13C NMR (150 MHz,
CDCl3): d 32.5, 46.5, 52.6, 78.5, 127.8, 128.7, 129.1, 136.0, 170.2;
IR (neat)
v: 3032, 2955, 1736, 1555, 1435, 1377, 1285, 1197,
4.5.1. (S)-(E)-Benzyl(1-nitro-4-phenylbut-3-en-2-yl) sulfide 14a
1136, 1006, 701 cmꢀ1
;
HRMS (ESI): calcd for C11H13NO4SNa
Light brown oil, yield 93%, 67% ee; ½a D20
¼ þ154:8 (c 0.30,
ꢂ
[M+Na]+: 278.0463, found: 278.0475; HPLC: AS-H, n-hexane/IPA
90:10; 1 mL/min; k = 254 nm; tr = 19.11 min (major); tr = 20.61
(minor); 43% ee.
CHCl3); 1H NMR (300 MHz, CDCl3): d 3.78 (d, J = 13.7 Hz, 1H),
3.84 (d, J = 13.7 Hz, 1H), 4.04 (m, 1H), 4.49–4.57 (m, 2H), 6.06
(dd, J = 15.9, 9.0 Hz, 1H), 6.49 (d, J = 15.9 Hz, 1H), 7.32–7.39 (m,
10H); 13C NMR (75 MHz, CDCl3): d 35.3, 44.4, 77.9, 124.4, 126.6,
4.4.19. Cyclohexyl (2-nitro-1-phenylethyl) sulfide 10e
Colorless oil, yield 30%, 36% ee; 1H NMR (600 MHz, CDCl3): d
1.20–1.28 (m, 3H), 1.30–1.39 (m, 2H), 1.57–1.60 (m, 1H), 1.69–
1.77 (m, 2H), 1.86 (d, J = 13.2 Hz, 1H), 1.95 (bd, J = 12.8 Hz, 1H),
2.59 (tt, J = 10.5, 3.7 Hz, 1H), 4.62 (dd, J = 8.7, 6.8 Hz, 1H), 4.70–
4.76 (m, 2H), 7.29–7.32 (m, 1H), 7.34–7.37 (m, 4H); 13C NMR
(150 MHz, CDCl3): d 25.6, 25.7, 25.8, 33.4, 33.5, 44.0, 45.1, 79.9,
127.6, 128.3, 129,0, 138.1. Spectra are in agreement with the re-
ported ones for racemic sample.12 HPLC: AD-H, n-hexane/IPA
99:1; 1 mL/min; k = 225 nm; tr = 7.27 min (minor); tr = 8.58 (ma-
jor); 36% ee.
127.5, 128.3, 128.6, 128.7, 128.9, 134.0, 135.5, 137.0; IR (neat)
3061, 3029, 2918, 1555, 1494, 1375, 966, 746, 695 cmꢀ1; HRMS
(ESI): calcd for
17H17NO2SNa [M+Na]+: 322.0878, found:
322.0860; HPLC: AD-H, n-hexane/IPA 97:3; 0.7 mL/min;
k = 225 nm; tr = 15.86 min (minor); tr = 18.64 (major); 67% ee.
v:
C
4.5.2. (S)-(E)-Benzyl(4-(4-methoxyphenyl)-1-nitrobut-3-en-2-
yl) sulfide 14b
An attempt to isolate the pure compound failed; HPLC: AD-H, n-
hexane/IPA 90:10; 1 mL/min; k = 254 nm; tr = 10.89 min (minor);
tr = 13.60 (major); 70% ee.
4.4.20. 2-((2-Nitro-1-phenylethyl)thio)ethanol 10f
Compound 10f is known, however, no spectra were provided.33
Reaction was performed on a 0.5 mmol scale in 2.5 mL of CH2Cl2.
Compound 10f was purified using flash chromatography using gra-
dient CH2Cl2–hexanes (1:1, v/v) to CH2Cl2 (100%); colorless oil,
4.5.3. (S)-(E)-(4-Methoxybenzyl)(1-nitro-4-phenylbut-3-en-2-yl)
sulfide 14c
Yellow oil, yield 68%, 70% ee; ½a D20
ꢂ
¼ þ166:5 (c 1.2, CHCl3); 1H
NMR (300 MHz, CDCl3): d 3.76 (d, J = 2.6 Hz, 2H), 3.82 (s, 3H),
3.99–4.07 (m, 1H), 4.48–4.57 (m, 2H), 6.04 (dd, J = 15.7, 9.0 Hz,
1H), 6.47 (d, J = 15.7 Hz, 1H), 6.86–6.91 (m, 2H), 7.23–7.28 (m,
2H), 7.29–7.33 (m, 1H), 7.34–7.40 (m, 4H); 13C NMR (75 MHz,
CDCl3): d 34.8, 44.3, 55.2, 77.9, 114.1, 124.5, 126.6, 128.3, 128.6,
yield 55%, 22% ee;
½
a 2D0
ꢂ
¼ þ14:2 (c 0.96, CHCl3); 1H NMR
(300 MHz, CDCl3): d 2.03 (br s, 1H), 2.58–2.73 (m, 2H), 3.70 (br s,
2H), 4.62–4.70 (m, 1H), 4.74–4.84 (m, 2H), 7.32–7.39 (m, 5H);
13C NMR (75 MHz, CDCl3): d 34.5, 46.4, 60.9, 79.2, 127.6, 128.6,
128.9, 130.0, 133.9, 135.6, 158.9; IR (neat) v: 3029, 3004, 2957,
129.1, 137.1; IR (neat)
v: 3392, 3031, 2927, 2879, 1555, 1377,
1048, 701 cmꢀ1; HRMS (ESI): calcd for C10H13NO3SNa [M+Na]+:
250.0514, found: 250.0530; HPLC: AD-H, n-hexane/IPA 90:10;
1 mL/min; k = 254 nm; tr = 14.01 min (major); tr = 14.79 (minor);
22% ee.
2935, 2914, 2837, 1610, 1558, 1512, 1463, 1449, 1427, 1375,
1302, 1250, 1176, 1033, 966, 833, 748, 694 cmꢀ1; HRMS (ESI):
calcd for C18H19NO3SNa [M+Na]+: 352.0983, found: 352.0994;
HPLC: AD-H, n-hexane/IPA 90:10; 1 mL/min; k = 254 nm;
tr = 10.34 min (minor); tr = 11.93 (major); 70% ee.
4.4.21. (S)-(4-Chlorobenzyl) (1-(2,4-dichlorophenyl)-2-
nitroethyl) sulfide 12
4.5.4. (S)-(E)-(4-(tert-Butyl)benzyl)(1-nitro-4-phenylbut-3-en-2-
Reaction was performed using 5 mol % of catalyst 7 in 9 mL of
yl) sulfide 14d
CH2Cl2 at ꢀ80 °C; yellow oil, yield 71%, 68% ee; ½a D20
ꢂ
¼ þ99:5 (c
Pale yellow oil, yield 85%, 82% ee; ½a D20
¼ þ213:6 (c 0.66, CHCl3);
ꢂ
0.27, CHCl3); 1H NMR (300 MHz, CDCl3): d 3.65 (d, J = 13.6 Hz,
1H), 3.72 (d, J = 13.6 Hz, 1H), 4.60 (dd, J = 13.2, 7.8 Hz, 1H), 4.71
(dd, J = 13.2, 7.5 Hz, 1H), 4.89 (t, J = 7.6 Hz, 1H), 7.17 (d, J = 8.4 Hz,
2H), 7.24–7.30 (m, 3H), 7.36–7.40 (m, 2H); 13C NMR (75 MHz,
CDCl3): d 36.0, 42.2, 77.6, 127.8, 128.8, 129.6, 130.0, 130.2, 133.1,
1H NMR (300 MHz, CDCl3): d 1.35 (s, 9H), 3.78 (s, 2H), 4.03–4.11
(m, 1H), 4.49–4.61 (m, 2H), 6.04 (dd, J = 15.7, 9.0 Hz, 1H), 6.49 (d,
J = 15.7 Hz, 1H), 7.26–7.39 (m, 9H); 13C NMR (75 MHz, CDCl3): d
31.3, 34.5, 34.9, 44.4, 77.9, 124.5, 125.6, 126.6, 127.7 (CIV°), 128.3,
128.5, 128.6, 133.9, 135.6, 150.4; IR (neat) v: 3028, 2963, 1624,
133.4, 134.4, 134.8, 135.0; IR (neat)
1555, 1490, 1472, 1427, 1375, 1095, 1016, 871, 826, 778, 750,
674, 652 cmꢀ1 HRMS (ESI): calcd for C15H12Cl335NO2SNa
[M+Na]+: 397.9552, found: 397.9571; HPLC: AD-H, n-hexane/IPA
v: 3090, 3028, 2919, 1588,
1556, 1495, 1375, 1332, 1269, 965, 837, 745, 694 cmꢀ1; HRMS
(ESI): calcd for C21H25NO2SNa [M+Na]+: 378.1504, found:
378.1497; HPLC: AD-H, n-hexane/IPA 99:1; 1 mL/min;
k = 254 nm; tr = 12.83 min (minor); tr = 16.26 (major); 82% ee.
;

R. Kowalczyk et al. / Tetrahedron: Asymmetry 24 (2013) 505–514
513
4.5.5. (S)-(E)-2-(((1-Nitro-4-phenylbut-3-en-2-yl)thio)methyl)
furan 14e
was diluted with CH2Cl2 (10 mL) and treated with water (10 mL).
The phases were separated, and the aqueous layer was washed
with CH2Cl2 (2 ꢁ 10 mL). The combined organic extracts were
washed with NaHCO3 (satd aq 10 mL) and dried (MgSO4). After
evaporation of the solvent, the oily residue was subjected to flash
chromatography (silica gel, 30 g, CHCl3) to afford 154 mg (41%
yield after two steps) of the desired racemic amide 14: light brown
oil; 1H NMR (300 MHz, CDCl3): d 1.88 (s, 3H), 3.47–3.64 (m, 2H),
3.53 (d, J = 13.4 Hz, 1H), 3.68 (d, J = 13.4 Hz, 1H), 4.36 (t,
J = 7.3 Hz, 1H), 5.64–5.68 (m, 1H), 7.14 (d, J = 8.2 Hz, 2H), 7.21–
7.26 (m, 3H), 7.35 (d, J = 2.2 Hz, 1H), 7.46 (d, J = 8.4 Hz, 1H); 13C
NMR (75 MHz, CDCl3): d 23.2, 35.3, 43.4, 44.7, 121.8, 128.7,
129.5, 130.0, 130.3, 133.1, 133.9, 134.7, 136.03, 136.04, 170.0.
Spectra are in agreement with the reported ones.8b
Sandy amorphous solid that turned brown during storage, yield
64%, 78% ee; ½a 2D0
ꢂ
¼ þ261:0 (c 0.40, CHCl3); 1H NMR (300 MHz,
CDCl3): d 3.80 (s, 2H), 4.13–4.22 (m, 1H), 4.51–4.60 (m, 2H), 6.04
(dd, J = 15.6, 9.0 Hz, 1H), 6.24 (dd, J = 3.2, 0.7 Hz, 1H), 6.36 (dd,
J = 3.2, 1.8 Hz, 1H), 6.56 (d, J = 15.6 Hz, 1H), 7.29–7.42 (m, 6H);
13C NMR (75 MHz, CDCl3): d 27.3, 44.6, 77.8, 108.1, 110.6, 124.0,
126.7, 128.4, 128.7, 134.4, 135.5, 142.5, 150.6; IR (neat) v: 3028,
1556, 1376, 1150, 1012, 967, 744, 694 cmꢀ1; HRMS (ESI): calcd
for C15H15NO3SNa [M+Na]+: 312.0670, found: 312.0664; HPLC:
AD-H, n-hexane/IPA 99:1; 1 mL/min; k = 254 nm; tr = 28.04 min
(minor); tr = 32.03 (major); 78% ee.
4.5.6. (S)-(E)-(4-Chlorobenzyl)(1-nitro-4-phenylbut-3-en-2-yl)
sulfide 14f
Acknowledgement
Pale yellow oil, yield 75%, 58% ee; ½a D20
¼ þ169:9 (c 0.98, CHCl3);
ꢂ
1H NMR (300 MHz, CDCl3): d 3.76 (d, J = 1.5 Hz, 2H), 4.02 (dd,
J = 16.4, 7.8 Hz, 1H), 4.55 (d, J = 7.7 Hz, 2H), 6.01 (dd, J = 15.7,
9.0 Hz, 1H), 6.45 (d, J = 15.7 Hz, 1H), 7.25–7.29 (m, 2H), 7.30–7.37
(m, 7H); 13C NMR (75 MHz, CDCl3): d 34.6, 44.5, 77.9, 124.2,
126.6, 128.4, 128.7, 128.9, 130.2, 133.3, 134.2, 135.4, 135.6; IR
This project was funded by the National Science Centre, Cracow,
Poland (Grant 03/D/ST5/05766).
References
(neat)
v: 3028, 2919, 1555, 1490, 1375, 1093, 1015, 966, 834,
747, 693 cmꢀ1; HRMS (ESI): calcd for C17H16Cl35NO2SNa [M+Na]+:
356.0488, found 356.0483; HPLC: AD-H, n-hexane/IPA 90:10;
1 mL/min; k = 254 nm; tr = 8.81 min (minor); tr = 10.46 (major);
58% ee.
1. (a) Koval’, I. V. Russ. J. Org. Chem. 2007, 43, 319; (b) Enders, D.; Luttgen, K.;
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Lett. 2011, 13, 2150; (c) Zhao, F.; Zhang, W.; Yang, Y.; Pan, Y.; Chen, W.; Liu, H.;
Yan, L.; Tan, C.-H.; Jiang, Z. Adv. Synth. Catal. 2011, 353, 2624; for the cascade
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4.5.7. (S)-(E)-Methyl-2-((1-nitro-4-phenylbut-3-en-2-
yl)thio)acetate 14g
Compound 13f was purified using flash chromatography using
gradient CH2Cl2–hexanes (1:1, v/v) to CH2Cl2 (100%); light yellow
oil, yield 92%, 5% ee; ½a D20
ꢂ
¼ þ12:2 (c 0.59, CHCl3); 1H NMR
(600 MHz, CDCl3): d 3.29 (d, J = 1.9 Hz, 2H), 3.72 (s, 3H), 4.37 (td,
J = 8.7, 6.4 Hz, 1H), 4.63 (dd, J = 12.8, 8.7 Hz, 1H), 4.71 (dd,
J = 12.8, 6.4 Hz, 1H), 6.02 (dd, J = 15.8, 9.0 Hz, 1H), 6.60 (d,
J = 15.8 Hz, 1H), 7.27–7.30 (m, 1H), 7.33–7.35 (m, 2H), 7.38–7.40
(m, 2H); 13C NMR (150 MHz, CDCl3): d 31.9, 45.2, 52.6, 77.6,
123.2, 126.7, 128.5, 128.6, 134.9, 135.3, 170.3; IR (neat)
2954, 1734, 1555, 1436, 1376, 1295, 1154, 1006, 968, 749,
695 cmꢀ1 HRMS (ESI): calcd for C13H15NO4SNa [M+Na]+:
v: 3028,
;
304.062, found 304.0628; HPLC: AD-H, n-hexane/IPA 90:10;
1 mL/min; k = 254 nm; tr = 12.02 min (minor); tr = 13.31 (major);
5% ee.
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The reduction was performed by adopting a literature proce-
dure.19 Tin(II) chloride dihydrate (790 mg, 3.52 mmol 3.66 equiv)
was added to a solution of racemic 12 (360 mg, 0.96 mmol,
1.0 equiv) in methanol (2.0 mL) and acetic acid (1.0 mL). The
resulting solution was stirred at reflux for 3 h and then cooled. Vol-
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