Diastereoselectivity in the triethylamine-catalyzed sulfa-Michael addition of thiols to nitroalkenes: Kinetic and thermodynamic control

Article abstract of DOI:10.1016/j.tet.2015.04.053

The diastereoselectivity in the triethylamine-catalyzed sulfa-Michael addition of nitroalkenes and thiols was investigated. The sulfa-Michael addition is kinetic control at the beginning and thermodynamic control at the end for less bulky reactants. Thus,

Full text of DOI:10.1016/j.tet.2015.04.053

Tetrahedron xxx (2015) 1e8
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Diastereoselectivity in the triethylamine-catalyzed sulfa-Michael
addition of thiols to nitroalkenes: kinetic and thermodynamic
control
*
*
Jiandong Wang, Ning Chen , Jiaxi Xu
State Key Laboratory of Chemical Resource Engineering, Beijing Key Laboratory of Functional Organic and Pharmaceutical Intermediate Synthesis,
Department of Organic Chemistry, Faculty of Science, Beijing University of Chemical Technology, China
a r t i c l e i n f o
a b s t r a c t
Article history:
The diastereoselectivity in the triethylamine-catalyzed sulfa-Michael addition of nitroalkenes and thiols
was investigated. The sulfa-Michael addition is kinetic control at the beginning and thermodynamic
control at the end for less bulky reactants. Thus, kinetic and thermodynamic-controlled adducts can be
obtained as major products by controlling the reaction time in those cases. Linear nitroalkenes generally
produce anti-adducts as major kinetic products due to favorable steric and stereoelectronic effects, but
the diastereoselectivity decreases obviously with steric increase of the substituent located in the vicinal
olefinic carbon to the nitro group, even leading to syn-adducts as major kinetic products. 1-
Nitrocyclohexene gives rise stereospecifically to kinetic cis-adduct, which epimerizes into more stable
trans-adduct as major product through the thermodynamic equilibrium. However, the Michael additions
involving bulky reactants are generally slow, resulting in the direct generation of thermodynamic
adducts.
Received 16 February 2015
Received in revised form 14 April 2015
Accepted 18 April 2015
Available online xxx
Keywords:
Diastereoselectivity
Sulfa-Michael addition
Nitroalkenes
Thiophenol
Kinetic control
Thermodynamic control
Ó 2015 Elsevier Ltd. All rights reserved.
1. Introduction
the catalysis of triethylamine at room temperature. Several reports
have been published later until recent years for discussing the
Sulfa-Michael additions have a profound importance in the
construction of the sulfurecarbon bond in both synthetic and
medicinal chemistry.1 Conjugated nitroolefins serve as excellent
Michael acceptors ascribing to the strong electron-withdrawing
capacity of the nitro group.2 Meanwhile, the nitro group can be
easily converted into various useful function groups, such as ke-
tone, nitrile, nitrile oxide, and amino groups.3 The diaster-
various diastereoselectivity under different catalytic systems.6 In
most cases, however, the diastereoselectivity was pretty low in the
absence of chiral catalysts. In our recent study, we found that ter-
tiary amine can catalyze the sulfa-Michael addition of
a,b-di-
substituted nitroolefins and thiolacetic acid in perfect yields with
moderate to good diastereoselectivities.7 Consequently, we are still
interested in controlling the diastereoselectivity in the sulfa-
Michael reaction of nitroolefins and thiols. Herein, we report the
kinetic and thermodynamic control in the sulfa-Michael addition of
eoselective sulfa-Michael addition of a,b-disubstituted nitroolefins
and thiols has been studied for many years. Although good dia-
stereo- and even enantioselective sulfa-Michael additions of
nitroolefins with thiols and thiolacetic acid were devoted under the
catalysis of various organic chiral catalysts such as thiourea cata-
lysts in recent years,4 the diastereoselective control in the sulfa-
Michael addition is still one of important issues and not clear
completely. In 1990, Kamimura et al. reported the synthesis of anti-
thiols to
a,b-disubstituted nitroalkenes under the catalysis of
triethylamine.
2. Results and discussion
We initially commenced the reaction of (E)-2-nitro-2-butene
(1a), the simplest 1,2-disubstituted nitroalkene, with thiophenol
under the catalysis of triethylamine (10 mol %) (Table 1). The sub-
strate was conducted on 1 mmol scale in all reactions. Very poor
diastereoselectivity (anti:syn¼40:60) was obtained when the re-
action was conducted in acetonitrile (Table 1, entry 5), which was
similar with the reported result.5 Subsequently, we hoped to op-
timize the reaction conditions by carefully tracing the reaction
b
-nitro sulfides from the corresponding nitroalkenes with thiolate
anion followed by a harsh protonation conditions at ꢀ78 ꢁC.5 In
their report, very lower diastereoselectivities were obtained under
* Corresponding authors. Tel.: þ86 10 64435565; e-mail addresses: chenning@
mail.buct.edu.cn (N. Chen), jxxu@mail.buct.edu.cn (J. Xu).
http://dx.doi.org/10.1016/j.tet.2015.04.053
0040-4020/Ó 2015 Elsevier Ltd. All rights reserved.
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J. Wang et al. / Tetrahedron xxx (2015) 1e8
Table 1
was too fast, other solvents, like tetrahydrofuran (THF), diethyl
ether (Et2O), benzene (PhH), ethanol (EtOH), and dichloromethane
(DCM), were further investigated (Table 1, entries 7e24). The epi-
merization rate decreased with the change of solvents. However,
only CH2Cl2 kept the dr value (Table 1, entry 19e24). Extending the
time to 48 h in CH2Cl2 (Table 1, entry 24), the reaction also reached
to the thermodynamic equilibrium as the similar ratio in CH3CN at
1 h (Table 1, entry 5). Hence, dichloromethane was chosen as the
model solvent for the further research. Detailed tendency of dia-
stereoselectivity with the increase of reaction time in the reaction
of (E)-2-nitro-2-butene (1a) and thiophenol is shown in Fig. 1. We
next studied the effect of the amount of the catalyst loading (Table
1, entries 25e33). High dr values were kept when 1 mol % amount
of Et3N was investigated, but the yield is only 36% after purifying
from column chromatography. Only extending to 5 min could the
nitroolefin 1a be totally transferred according to the trace of thin-
layer chromatography (TLC). Moreover, the epimerization was ex-
tremely slow even prolonging to 1 h (Table 1, entry 27). Similar
result was obtained with 5 mol % amount of Et3N (Table 1, entries
28e30). In addition, increasing the amount of Et3N to 20 mol % did
not have the obvious change (Table 1, entry 33). Therefore, to obtain
the both kinetic and thermodynamic stable products, 10 mol % of
catalyst loading is more suitable to control. Finally, different tem-
perature were attempted from ꢀ78 ꢁC to 35 ꢁC (Table 1, entries
34e41), but all results did not have obvious improvement in the dr
value.
Diastereoselective sulfa-Michael addition of thiolphenol to (E)-2-nitro-2-butene
(1a)
Entry
Reaction conditions
Drb (anti/syn)
Solv.
Cat.a (mol %)
Temp(ꢁC)
Time
1
2
3
4
5
6
7
8
CH3CN
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
1
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
rt
10 s
5 min
10 min
30 min
1 h
20 h
10 s
1 h
20 h
10 s
1 h
20 h
10 s
1 h
20 h
10 s
1 h
20 h
10 s
10 min
30 min
1 h
20 h
48 h
10 s
10 min
1 h
10 s
10 min
1 h
93:7
87:13
69:31
51:49
40:60
40:60
91:9
90:10
66:34
91:9
THF
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
Et2O
PhH
EtOH
DCM
90:10
76:24
91:9
91:9
50:50
85:15
78:22
42:58
93:7
80:20
75:25
71:29
60:40
43:57
90:10c
91:9
89:11
90:10d
88:12
84:16
87:13
76:24
66:34
93:7
DCM
DCM
DCM
1
1
5
5
5
20
20
20
10
10
10
10
10
10
10
10
10 s
10 min
1 h
10 s
1 h
10 s
1 h
10 s
1 h
rt
DCM
DCM
DCM
DCM
ꢀ78
ꢀ78
ꢀ30
ꢀ30
0
0
35
35
89:11
92:8
86:14
90:10
76:24
86:14
64:36
Fig. 1. Tendency of diastereoselectivity with the increase of reaction time in the re-
action of (E)-2-nitro-2-butene (1a) and thiophenol.
10 s
1 h
a
The molar percentage amount of catalyst.
Dr values were determined by 1H NMR.
The isolated yield is 36%.
b
c
Inspired by the above results, the substrate scope of various
nitroolefins 1 was examined with thiophenol on the 1 mmol scale
in CH2Cl2 in the presence of Et3N (10 mol %). The results are listed in
Table 2. Gratifyingly, all addition reactions showed high conversion
and moderate to good diastereoselectivities (except for 1e with low
diastereoselectivity) when the reactions were quenched in 10 s. 2-
Nitro-2-alkenes 1aef decrease generally the diastereoselectivity
along with the increasing steric hindrance on the vicinal carbon to
the nitro group (Table 2, entries 1e6). Nitroolefins 1gei with
geminal ethyl and vicinal alkyl groups to the nitro group show
similar diastereoselectivity (Table 2, entries 7e9). For aryl
substituted nitroolefins 1f, j, k, 1,2-diphenylnitroethene (1k) shows
the highest diastereoselectivity (Table 2, entry 11), while 1-aryl-2-
nitro-1-butene (1j) displays higher diastereoselectivity than 2-
nitro-1-phenyl-1-propene (1f) (Table 2, entries 6 and 10). The re-
sults indicate that the steric hindrance of the vicinal substituents to
the nitro group in 2-nitro-2-alkenes 1aef shows obvious influence
on the diastereoselectivity. The thermodynamically stable ratios of
the diastereomeric products 2 are also provided herein (Table 2,
d
The isolated yield is 54%.
progress with 1H NMR analysis. After the addition of Et3N and
stirring for 10 s (s for short), excess AcOH was added to quench the
reaction. Gratifyingly, nitroalkene 1a was consumed completely
and adducts 2a were obtained in 90% isolated yield with an anti/syn
ratio of 93:7. Further prolonging the reaction time clearly showed
the tendency that the proportion of anti-2a was gradually de-
creased (Table 1, entries 1e6). Eventually, the reaction was ac-
complished to the thermodynamic equilibrium after 1 h with the
anti/syn ratio at 40:60, because the dr ratio (diastereoselective ra-
tio) did not change any more even extending the time to 20 h (Table
1, entry 6). The results indicate that the diastereoselectivity in the
current sulfa-Michael addition is a kinetic control at the beginning
and thermodynamic control at the end. The epimerization occurred
in the presence of base triethylamine during reaction process. Thus,
the reaction time is the key factor to control the diaster-
eoselectivity. Moreover, considering that the epimerization process
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J. Wang et al. / Tetrahedron xxx (2015) 1e8
3
Table 2
slightly higher field than those in the corresponding anti-ones
(Fig. 2 and Table 3).9 The major
-gauche effect affects the terminal
Diastereoselective sulfa-Michael addition of various nitroolefins and thiophenol
g
carbons (C3) when the C1 atom is in the bulky substituents like
isopropyl (2d) and tert-butyl (2e) groups (Table 3, entries 3 and 4).
Parenthetically, an interesting fragmentation in the HRMS
(high-resolution mass spectroscopy) is worth to mention herein.
When all of new b-nitro phenylsulfides 2 were subjected to HRMS
Entry
Nitroolefins
Dr (anti/syn)a
Yield (%)b
determination under the electrospray ionization (ESI), the in-
tensities of their protonated molecular ion peaks [MþH]þ are very
low and hardly detected with the relative abundance less than 1%.
The major ion peaks (most of base peaks) are the [MþH-47u]þ,
which demonstrated that a molecule of nitrous acid (HONO) is lost
from the protonated molecular ions through an intramolecular
nucleophilic substitution by the vicinal sulfur atom in the thioether
group. Hence, the major peaks are the corresponding S-phenyl-
thiiranium fragments (Table 4). Though Ono and Kamimura re-
(After 10 s)
(After 20 h)
40:60
1
2
3
4
93:7
90
86
1a
85:15
89:11
75:25
66:34c
65:35
68:32
1b
ported that
b-nitro thioethers could lose the nitro group in the
presence of Lewis acid catalyst,8b this fragmentation under ESI
83
1c
conditions is first reported herein.
83d
1d
1e
5
6
7
45:55
72:28
87:13
55:45
42:58
86:14c
86d
82
1f
Fig. 2.
g-Gauche effects in anti- and syn-products 2.
92
1g
1h
Table 3
Partial13C chemical shifts in the syn- and anti-products 2
8
9
88:12
90:10
87:13
89:11
90
87
Entry
Products
C
1 (or C3) (ppm)
C2 (ppm)
anti-2
syn-2
anti-2
syn-2
1
2
3
4
5
6
7
2b
2c
2d
2e
2g
2h
2i
16.6
32.1
13.9
31.3
25.3
31.2
30.3
28.4
25.5
25.2
31.2
22.2
28.7
29.1
28.3
22.6
22.9
29.5
21.3 (17.7, 17.5)a
36.8 (17.6)a
18.2
21.7 (17.5, 17.1)a
36.7 (16.5)a
16.7
1i
1j
24.5
31.2
22.8
31.3
10
11
80:20
93:7
75:25
91:9
85
80
a
The major g-gauche effect affects the terminal carbons (C3) when C1 is in the
bulky substituents isopropyl (2d) and tert-butyl (2e).
Some alkanethiols, including primary, secondary, and tertiary
thiols, were also screened with the nitroalkene 1a (Table 5, entries
1e14). Benzyl thiol (BnSH) produced the desired adducts 2l in good
yield (95%) at 10 s with the dr value of 78:22 (Table 5, entry 1).
1k
Dr values were determined by both 1H NMR and 13C NMR.
Isolated yield for 20 h by column chromatography.
a
b
c
The thermodynamic stable dr ratios of 2b and 2g are 48:52 and 37:63, re-
spectively, in Kamimura’s report.5
Table 4
The conversions of 1d and 1e were 92% and 95% by 1H NMR after 10 s.
d
Fragmentation of 2-nitroalkyl phenylthioethers 2 under HRMS-ESI conditions
column 4). Comparing with the nitroolefins 1b, c, f with the gem-
inal methyl group (Table 2, entries 2e6), the corresponding nitro-
olefins 1hej with the geminal ethyl group show much higher anti-
diastereoselectivities (Table 2, entries 8e11). The results indicate
that the geminal substitutent (R2) of nitroolefins would retard the
epimerization with the increase of its steric hindrance.
Comp.
m/z: [MþH]þ
m/z: Thiiranium
The configurations of the syn- and anti-products 2 were de-
Found (calcd)
Found (calcd)
termined by the 13C NMR spectra via the -gauche effect or the 1H
g
2c
2e
2h
2i
2j
2k
268.1355 (268.1366)
254.1204 (254.1209)
240.1052 (240.1053)
282.1518 (282.1522)
322.0655 (322.0663)
336.1049 (336.1053)
221.1355 (221.1358)
207.1198 (207.1202)
193.1044 (193.1045)
235.1512 (235.1515)
275.0652 (275.0656)
289.1041 (289.1045)
NMR coupling constants of the vicinal protons (see Electronic
Supplementary data), and some of the known products were con-
firmed by the reported data in the literature.5,8 The
g-gauche effect
demonstrates that the chemical shifts of the 13C atoms in the
methylene (or methyl) group in the syn-products syn-2 are in the
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Table 5
Diastereoselective sulfa-Michael addition of nitroolefins 1 and alkanethiols
Entry
1
Nitroolefin
Thiols
BnSH
Time (h)
10 s
2
Dra (anti/syn) Yieldb (%)
2l 78:22
95c
2
3
4
5
6
7
8
9
10
11
12
13
BnSH
BnSH
n-BuSH 10 s
n-BuSH
n-BuSH
i-PrSH
i-PrSH
i-PrSH
i-PrSH
1
20
2l 47:53
2l 45:55
2m 76:24
2m 66:34
2m 59:41
100c
98
55c
96c
75
1
20
10 s
1
20
48
1a
2n
d
d
2n 66:34
2n 56:44
2n 42:58
68c
86c
89
Fig. 3. Tendency of diastereoselectivity with the increase of reaction time in the re-
action of 1-nitrocyclohexene and thiophenol in acetonitrile.
t-BuSH 10 s
t-BuSH
t-BuSH
2o
d
d
1
48
2o 75:25
2o 40:60
41c
70
It is well known that nitronate anions were first generated
during the addition of thiols to nitroolefins in the presence of base.
The diastereoselectivity of adducts was controlled by the sub-
sequent protonation rather than the first Michael addition step.
Mohrig et al. have proved that it was the stability of the transition
state, rather than that of enolate intermediates, which determined
the diastereoselectivity in the protonation of the enolate anion
when they investigated the Michael addition of alkyl 2-alkenoates
with ethanol.10 Similar to the enolate protonation, a Curtin-
Hammett schematic diagram of the nitronate protonation is pro-
vided herein (Fig. 4). According to the Curtin-Hammett principle,11
the conformation of the new forming chiral center, with a phenyl-
14
i-PrSH
10 s
2p
d
d
15
16
17
18
19
i-PrSH
i-PrSH
t-BuSH 10 s
t-BuSH
t-BuSH
1
48
2p 65:35
2p 60:40
2q
2q
80c
83
1d
d
d
1
48
d
d
2q 65:35
31
a
Dr values were determined by both 1H NMR and 13C NMR.
Isolated yield for 20 h by column chromatography.
b
c
The conversion was determined by 1H NMR spectrum of the reaction mixture at
the time indicated in Table 5.
thio group at C(1) relative to the delocalized C]N
p system, was
considered to determine the electrophilic direction (Fig. 4a). The
kinetic control product compositions are determined by the dif-
ference in the standard Gibbs energies (DDG*) of the respective
transition states Ts-A and Ts-a (Figs. 4b and 6). In the current case,
Similar to thiophenol, the anti/syn value decrease with prolonging
the reaction time (Table 5, entries 1e3). Finally, syn-adduct syn-2l
was obtained as major thermodynamic product (Table 5, entry 3).
Primary n-butanethiol gave rise to the corresponding adducts 2m
in 55% yield at 10 s with the dr value of 76:24 (Table 5, entry 4).
Similarly the dr value decreased extending the reaction time (Table
5, entries 4e6). However, both secondary isopropylthiol and ter-
tiary tert-butylthiol showed lower reactivity with nitroalkene 1a
due to their steric hindrance (Table 5, entries 7e13). No corre-
sponding adducts 2n and 2o was observed at 10 s in each of cases
(Table 5, entries 7 and 11). They yielded adducts 2n and 2o in 68%
and 41% yields, respectively, at 1 h with low diastereoselectivity
(Table 5, entries 8 and 12). When they reacted with more bulky
nitroolefin 1d, isopropylthiol can give the desired adducts 2p in 80%
yield at 1 h with 65:35 anti/syn-ratio (Table 5, entry 15). However,
no reaction was observed for tert-butylthiol at 1 h. The results in-
dicate that the steric hindrance plays a crucial role on the reaction
rate.
DDG* is approximately ꢀ1.53 kcal/mol
(DDG*¼ꢀRTln[anti-
Finally, cyclic 1-nitrocyclohexene (1r) was also conducted with
thiophenol. 1H NMR tracing experiments during specific time
intervals inclined to show the process for thermodynamic equi-
librium clearly (Fig. 3). The reaction completed at 10 s in 85%
isolated yield with cis-2r as sole adduct. The configuration was
assigned by the vicinal HeH coupling constant. Subsequent pro-
longing the reaction time, thermodynamically stable anti-2r
appeared and increased rapidly. The thermodynamic equilibrium
achieved at 1 h with an 88:12 trans-/cis-2r ratio (Fig. 3).5 It should
be mentioned that CH3CN was used in the current case to instead
of CH2Cl2 as solvent because the epimerization was too low in
CH2Cl2.
Fig. 4. Curtin-Hammett schematic diagram in the triethylamine-catalyzed sulfa-Mi-
chael addition of thiophenol to nitroalkene 1a.
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5
Ts-A to Ts-C are responsible for the formation of anti-2, while the
corresponding Ts-a to Ts-c for that of syn-2. On the basis of both
stereoelectronic and steric effects, Ts-A is unhesitatingly the most
stable transition state when R1 and/or R2 are/is not more steric
substitutent(s), resulting in anti-2 as major products kinetically. On
one hand, the antiperiplanar
s* orbital of the CeS bond in Ts-A can
stabilize the upcoming orbital of the forming CeH bond via the
s
stereoelectronic interaction.17 On the other hand, R1 occupies at
‘outside’ position in the allylic chiral center to avoid destabilizing
the allylic 1,3-interaction (Figs. 5 and 6).18 Ts-a favors formation of
syn-2 stereoelectronically, but with the allylic 1,3-interaction, ste-
rically unfavorable. Ts-b loses stabilizing stereoelectronic effect and
possesses a gauche interaction between R2 and R3S groups in spite
of the absence of the allylic 1,3-interaction. That is the reason why
anti-products anti-2 are kinetic products generally except for 2e,
which shows an anti/syn at 45:55 (Table 2, entry 5). However, with
the steric increase of the R1 group, such as becoming isopropyl and
tert-butyl groups (Table 2, entries four and 5), their Ts-A loses the
priority eventually with the competition of the corresponding Ts-
a and Ts-b, especially Ts-b, in which less bulky R2 group locates in
the gauche position with less R3S group, while more steric R1 group
adopts nearly perpendicular position with both R2 and nitronate
groups, resulting in increase of syn-products syn-2, even as major
product when R1 is the tert-butyl group (Table 2, entry 5).
Fig. 5. Transition state models for electrophilic attack on enolate anions.
In cyclic system (Fig. 7), the conformational restriction forces R1
and R2 groups, herein, both of them are the methylene group lo-
cated in the gauche position, in the same side as Ts-A, and the
protonation process is depicted in Fig. 7. In the protonation tran-
sition state, the extra stabilizing interaction is generated from the
Fig. 6. Transition state models in the protonation of nitronates.
stereoelectronic effect between the
s* orbital in the CeS bond and
partially formed -bond between the C and H atoms. Therefore, cis-
s
2a(10s)]/[syn-2a(10s)]¼ꢀRTln[93/7]), revealing that the transition
product cis-2r was obtained kinetically as a sole product in 10 s.
However, the trans-product trans-2r is much more thermody-
namically stable. Thus, trans-2r was generated thermodynamically
through the deprotonation-protonation process in the presence of
triethylamine, finally reached the thermodynamic equilibrium at
the cis/trans ratio of 16:84.
state energy of Ts-a is at least higher than that of Ts-A 1.53 kcal/mol.
Subsequently, the adducts 2a underwent
a deprotonation-
protonation process, even a reverse Michael reaction, in the pres-
ence of Et3N at room temperature, eventually achieving into the
thermodynamic equilibrium (anti:syn¼40:60). The anti:syn value is
determined by the difference in the standard Gibbs energies (DDG)
of the respective products anti-2a and syn-2a (Fig. 4b). In the cur-
rent case, DDG is approximately 0.24 kcal/mol (DDG¼ꢀRTln[anti-
2a(20h)]/[syn-2a(20h)]¼ꢀRTln[40/60]). The results indicate that
syn-2a is 0.24 kcal/mol more stable than anti-2a.
Similar to the nucleophilic attack on the carbonyl group, which
well-known as the Cram’s rule12 and further refined by Karabatsos,
Finkin, and Anh, and Cieplak,13 the electrophilic addition to the
enolate bearing an adjacent stereogenic center was also meticu-
lously studied by Fleming14 and Mohrig.15 The transition state
models for the electrophilic attack on the enolate anions of ketones
and esters are shown in Fig. 5. Generally, in the Fleming’s Model,
Stereoelectronic effect stabilizes the transition state
H
HOMO
O
H
N
NO2
SPh
kinetic
control
H
O
O
O-
N
H
C-S
(
SPh
SPh
cis-2r
Fig. 7. Transition state model in the protonation of the cyclic nitronate.
the trajectory of the electrophile on the face of the
p
-bond should
3. Conclusions
be opposite to the largest group (L) due to the steric hindrance or
the electron-donating group due to the stereoelectronic effect with
the smallest group (S) at the chiral center gauche to the p-system to
In conclusion, the diastereoselectivity in the triethylamine-
catalyzed sulfa-Michael addition between nitroalkenes and thiols
was investigated. The sulfa-Michael addition involving thiophenol
and primary alkanethiols is kinetic control at the beginning and
thermodynamic control at the end. Thus, kinetic and
thermodynamic-controlled adducts can be obtained as major
products, respectively, by controlling the reaction time. Linear
nitroolefins generally produce anti-adducts as major kinetic prod-
ucts due to favorable steric and stereoelectronic effects, but the
diastereoselectivity decreases obviously with steric increase of the
substituent located in the vicinal olefinic carbon to the nitro group,
even leading to syn-adducts as major kinetic products. Cyclic
nitrocyclohexene gives rise stereospecifically to kinetic cis-adduct,
which epimerizes into more stable trans-adduct as major product
through the thermodynamic equilibrium in the presence of
avoid the allylic 1,3-interaction.14 The further calculation evidences
provided by Houk support the argument that the trajectory of
electrophile would take a antiperiplanar position to the electron-
donating group because of the hyperconjugative effect in the fa-
vored transition state.16 Mohrig further applied this model in the
electrophilic deuteration of the enolate anions, which were derived
from the stereoselective 1,4-conjugative addition of ethanol-D to
a,b
-unsaturated esters.10,16 In the current system, nitronate anions,
similar to enolate analogs, should have similar results during the
protonation process.
To explain the kinetic stereocontrol in the protonation of
nitroate anions, six possible transition state Newman perpendicu-
lar projection models are presented in Fig. 6. The transition states
Please cite this article in press as: Wang, J.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.04.053

6
J. Wang et al. / Tetrahedron xxx (2015) 1e8
triethylamine as base. However, the Michael additions of secondary
and tertiary alkanethiols are apt to the formation of thermody-
namic products because their reaction rates are low due to steric
hindrance. The configurations of syn- and anti-adducts were de-
termined by the HeH coupling constants of vicinal hydrogens and
11.5. Syn-2b: 1H NMR (400 MHz, CDCl3)
d: 7.48e7.42 (m, 2H),
7.36e7.28 (m, 3H), 4.58 (dq, J¼5.5, 6.8 Hz, 1H), 3.58 (ddd, J¼3.6, 5.5,
10.1 Hz, 1H), 1.72 (ddq, J¼10.1, 14.3, 7.3 Hz, 1H), 1.59 (d, J¼6.8 Hz,
3H), 1.47 (ddq, J¼3.6, 14.3, 7.3 Hz, 1H), 1.14 (t, J¼7.3 Hz, 3H). 13C NMR
(101 MHz, CDCl3)
11.7.
d: 133.3, 133.1, 129.3, 128.0, 86.1, 53.7, 22.2, 13.9,
the 13C chemical shifts via the
g-gauche effect. Additionally, an
intramolecular fragmentation of vicinal nitrothioethers with loss of
nitrous acid was also observed under the electrospray ionizations.
4.3.3. 2-Nitro-3-phenylthiooctane (2c). Yellowish oil, 222 mg, 83%,
Rf¼0.43, 0.45 (PE:EA¼40:1, v/v). Anti-2c: 1H NMR (400 MHz, CDCl3)
4. Experimental section
4.1. General
d
: 7.46e7.42 (m, 2H), 7.36e7.28 (m, 3H), 4.58 (dq, J¼7.2, 6.8 Hz, 1H),
3.67 (ddd, J¼4.4, 7.2, 8.8 Hz, 1H), 1.76e1.66 (m, 2H), 1.64 (d,
J¼6.8 Hz, 3H), 1.55e1.42 (m, 2H), 1.33e1.26 (m, 4H), 0.89 (t,
J¼6.8 Hz, 3H). 13C NMR (101 MHz, CDCl3)
d: 133.3, 133.1, 129.2,
Dichloromethane was refluxed with CaH2 and freshly distilled
prior to use. Diethyl ether, THF, and benzene were refluxed over
sodium with benzophenone as indicator and freshly distilled prior
to use. Melting points were obtained on a Yanaco MP-500 melting
point apparatus and are uncorrected. 1H and 13C NMR spectra were
recorded on a Bruker AV 400 (400 MHz) in CDCl3 with TMS as the
128.0, 86.4, 53.4, 32.1, 31.2, 26.5, 22.4, 16.5, 13.9. Syn-2c: 1H NMR
(400 MHz, CDCl3) d: 7.46e7.42 (m, 2H), 7.36e7.28 (m, 3H), 4.54 (dq,
J¼5.6, 6.8 Hz, 1H), 3.67 (ddd, J¼3.6, 5.6 10.0 Hz, 1H), 1.63e1.56 (m,
2H), 1.59 (d, J¼6.8 Hz, 3H), 1.55e1.42 (m, 2H), 1.33e1.26 (m, 4H),
0.88 (t, J¼6.8 Hz, 3H). 13C NMR (101 MHz, CDCl3)
d: 133.4, 132.2,
129.3, 127.8, 85.1, 51.8, 31.3, 28.7, 26.6, 22.4, 16.5, 13.6. IR (CH2Cl2), v
(cmꢀ1): 1552 (NO2). HRMS (ESI) calcd for C14H22NO2Sþ [MþH]þ m/
z: 268.1366, found 268.1355.
internal standard and the chemical shifts (d) are reported in ppm. IR
spectra were taken directly on a Nicolet AVATAR 330 FT-IR spec-
trometer with KBr. HRMS spectra were obtained with an Agilent LC/
MSD TOF mass spectrometer. TLC analysis was performed on silica
gel GF254 plates. Spots were visualized with UV light or iodine.
Column chromatography was performed on silica gel zcx II
4.3.4. 4-Methyl-2-nitro-3-phenylthiopentane (2d).5,8 Colorless oil,
205 mg, 83%, Rf¼0.23, 0.28. Anti-2d: 1H NMR (400 MHz, CDCl3)
d:
7.45e7.42 (m, 2H), 7.36e7.27 (m, 2H), 7.27e7.20 (m, 1H), 4.80 (dq,
J¼9.6, 6.8 Hz, 1H), 3.46 (dd, J¼4.4, 9.6 Hz, 1H), 1.91 (dhept, J¼4.4,
6.8 Hz, 1H), 1.63 (d, J¼6.8 Hz, 3H), 1.16 (d, J¼6.8 Hz, 3H), 1.04 (d,
(200e300 mesh) with
a mixture of petroleum ether (PE)
(60e90 ꢁC) and ethyl acetate (EA) as an eluent with gradient
elution.
J¼6.8 Hz, 3H). 13C NMR (101 MHz, CDCl3)
d: 135.8, 131.3, 129.2,
127.3, 86.14, 61.2, 30.3, 21.3, 17.7, 17.5. Syn-2d: 1H NMR (400 MHz,
4.2. General procedure for the synthesis of nitroolefins 1
CDCl3) d: 7.45e7.42 (m, 2H), 7.36e7.27 (m, 2H), 7.27e7.20 (m, 1H),
4.70 (dq, J¼8.4, 6.8 Hz, 1H), 3.48 (dd, J¼4.4, 8.4, 1H), 2.13 (dhept,
Liner nitroolefins (1ae1k) were prepared by dehydration of the
corresponding vicinal nitro alcohols according to literature proce-
dure2c and 1-nitrocyclohexene (1r) was prepared by referring the
Corey’s method3a and their analytical data are identical to those
reported previously.
J¼4.4, 6.8 Hz, 1H), 1.16 (d, J¼6.8 Hz, 3H), 1.11 (d, J¼6.8 Hz, 3H), 0.99
(d, J¼6.8 Hz, 3H). 13C NMR (101 MHz, CDCl3)
d: 135.5, 131.1, 129.0,
127.4, 86.7, 59.9, 29.1, 21.7, 17.5, 17.1.
4.3.5. 4,4-Dimethyl-2-nitro-3-phenylthiopentane (2e). Colorless oil,
218 mg, 86%, Rf¼0.23 (PE:EA¼40:1, v/v). Anti-2e: 1H NMR
4.3. General procedure for the synthesis of
b
-nitro sulfides 2
(400 MHz, CDCl3) d: 7.41e7.38 (m, 2H), 7.33e7.21 (m, 3H), 4.87 (dq,
J¼3.8, 6.7 Hz, 1H), 3.83 (d, J¼3.8 Hz, 1H), 1.70 (d, J¼6.7 Hz, 3H), 1.14
(s, 9H). 13C NMR (101 MHz, CDCl3)
: 136.2, 131.3, 129.1, 127.2, 83.8,
64.7, 36.7, 28.4, 17.6. Syn-2e: 1H NMR (400 MHz, CDCl3)
: 7.48e7.45
To a solution of thiophenol or alkanethiol (1.2 mmol) in 10 mL of
dry dichloromethane (DCM) (or other solvents) was added trie-
d
d
thylamine (14
m
L, 10.1 mg, 0.1 mmol) and the resultant mixture
(m, 2H), 7.33e7.21 (m, 3H), 4.91 (dq, J¼3.3, 6.8 Hz, 1H), 3.4 (d,
continued to be stirred for 10 min at room temperature under ni-
trogen atmosphere. Nitroalkene 1 (1.0 mmol) was added via a sy-
ringe in one portion. For quenching the reaction, excess AcOH was
added to neutralize the base in the resulting solution at the time
indicated in Tables 1, 2 and 5). After removal of the solvent in
vaccum, the residue was detected by 1H NMR to provide the dr
value (anti/syn). Finally, subjecting the mixture directly to purifi-
cation on silica gel chromatography afforded the desired products
2.
J¼3.3 Hz, 1H), 1.74 (d, J¼6.8 Hz, 3H), 1.21 (s, 9H). 13C NMR (101 MHz,
CDCl3) d: 136.9, 130.9, 129.3, 127.0, 83.7, 63.6, 36.8, 28.3, 16.5. IR
(CH2Cl2), v (cmꢀ1): 1549 (NO2). HRMS (ESI) calcd for C13H20NO2Sþ
[MþHþ] m/z: 254.1209, found 254.1204.
4.3.6. 2-Nitro-3-phenyl-3-phenylthiopropane (2f).5,8 Yellowish oil,
222 mg, 81%, Rf¼0.48, 0.50 (PE:EA¼20:1, v/v). Anti-2f: 1H NMR
(400 MHz, CDCl3) d: 7.29e7.10 (m, 8H), 7.19e7.08 (m, 2H), 4.95 (dq,
J¼9.39, 6.6 Hz,1H), 4.56 (d, J¼9.39 Hz,1H),1.82 (d, J¼6.6 Hz, 3H). 13
C
NMR (101 MHz, CDCl3) d: 136.5, 133.7, 132.4, 129.0, 126.6, 128.4,
4.3.1. 2-Nitro-3-phenylthiobutane (2a).5,8 Colorless oil, 202 mg,
95%, Rf¼0.47 (PE:EA¼20:1, v/v). Anti-2a: 1H NMR (400 MHz, CDCl3)
128.2, 128.1, 86.9, 57.3, 18.1. Syn-2f: 1H NMR (400 MHz, CDCl3)
d:
7.29e7.10 (m, 8H), 7.19e7.08 (m, 2H), 4.95 (dq, J¼9.38, 6.7 Hz, 1H),
d
: 7.48e7.45 (m, 2H), 7.37e7.31 (m, 3H), 4.50 (dq, J¼7.6, 6.7 Hz, 1H),
4.57 (d, J¼9.38 Hz, 1H), 1.41 (d, J¼6.7 Hz, 3H). 13C NMR (101 MHz,
3.52 (dq, J¼7.6, 6.9 Hz, 1H), 1.68 (d, J¼6.7 Hz, 3H), 1.34 (d, J¼6.9 Hz,
CDCl3) d: 136.5, 134.0, 132.1, 129.0, 128.7, 128.5, 128.3, 127.9, 86.3,
3H). Syn-2a: 1H NMR (400 MHz, CDCl3)
d: 7.48e7.45 (m, 2H),
56.7, 17.5.
7.37e7.31 (m, 3H), 4.55 (dq, J¼5.7, 6.7 Hz), 3.82 (dq, J¼5.7, 7.0 Hz,
1H), 1.57 (d, J¼6.7 Hz, 3H), 1.29 (d, J¼7.0 Hz, 3H).
4.3.7. 3-Nitro-2-phenylthiopentane (2g).5,8 Yellowish oil, 208 mg,
92%, Rf¼0.37, 0.39 (PE:EA¼40:1, v/v). Anti-2g: 1H NMR (400 MHz,
4.3.2. 2-Nitro-3-phenylthiopentane (2b).5,8 Yellowish oil, 194 mg,
86%, Rf¼0.52 (PE:EA¼40:1, v/v). Anti-2b: 1H NMR (400 MHz, CDCl3)
CDCl3)
d
: 7.47e7.44 (m, 2H), 7.34e7.30 (m, 3H), 4.31 (ddd, J¼3.2, 8.6,
10.6 Hz, 1H), 3.42 (dq, J¼8.6, 6.9 Hz, 1H), 2.23 (ddq, J¼3.2, 14.7,
d
: 7.48e7.42 (m, 2H), 7.36e7.28 (m, 3H), 4.60 (dq, J¼7.5, 6.8 Hz, 1H),
7.3 Hz,1H), 2.02 (ddq, J¼10.6,14.7, 7.3 Hz,1H),1.32 (d, J¼6.9 Hz, 3H),
3.40 (ddd, J¼7.5, 4.4, 9.0 Hz, 1H), 1.70 (ddq, J¼4.4, 14.7, 7.3, 1H), 1.66
0.95 (t, J¼7.3 Hz, 3H). 13C NMR (101 MHz, CDCl3)
d: 133.8, 132.1,
(d, J¼6.8 Hz, 3H), 1.57e1.50 (m, 1H), 1.14 (t, J¼7.3 Hz, 3H). 13C NMR
129.2, 128.4, 94.3, 45.6, 25.5, 18.2, 10.4. Syn-2g: 1H NMR (400 MHz,
(101 MHz, CDCl3)
d: 133.4, 132.3, 129.2, 127.8, 86.2, 55.1, 25.3, 16.6,
CDCl3)
d: 7.47e7.44 (m, 2H), 7.34e7.30 (m, 3H), 4.36 (ddd, J¼3.6, 7.0,
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J. Wang et al. / Tetrahedron xxx (2015) 1e8
7
10.4 Hz, 1H), 3.60 (dq, J¼7.0, 7.0 Hz, 1H), 2.23 (ddq, J¼3.6, 14.7,
7.3 Hz, 1H), 2.02e1.91 (m, 1H), 1.31 (d, J¼7.0 Hz, 3H), 0.96 (t,
(cmꢀ1): 1549 (NO2). HRMS (ESI) calcd for C20H18NO2Sþ [MþH]þ m/
z: 336.1053, found 336.1049.
J¼7.3 Hz, 3H). 13C NMR (101 MHz, CDCl3)
d: 133.6,132.1,129.2,128.3,
92.9, 45.5, 22.6, 16.7, 10.6.
4.3.12. 3-Benzylthio-2-nitrobutane (2l). Colorless oil, 220 mg, 98%,
Rf¼0.25 (PE:diethyl ether¼40:1, v/v). Anti-2l: 1H NMR (400 MHz,
4.3.8. 3-Nitro-4-phenylthiohexane (2h). Colorless oil, 217 mg, 90%,
Rf¼0.40, 0.40 (PE:EA¼40:1, v/v). Anti-2h: 1H NMR (400 MHz, CDCl3)
CDCl3)
d
: 7.35e7.25 (m, 5H), 4.46 (dq, J¼7.1, 6.7 Hz, 1H), 3.76 (s, 2H),
3.14 (dq, J¼7.1, 7.0 Hz, 1H), 1.58 (d, J¼6.7 Hz, 3H), 1.29 (d, J¼7.0 Hz,
3H). 13C NMR (101 MHz, CDCl3)
: 137.4, 128.9, 128.6, 127.4, 87.1,
42.9, 35.6, 18.9, 16.4. Syn-2l, 1H NMR (400 MHz, CDCl3)
: 7.38e7.25
d
: 7.45e7.42 (m, 2H), 7.35e7.29 (m, 3H), 4.39 (ddd, J¼3.2, 9.2,
d
10.8 Hz, 1H), 3.28 (ddd, J¼3.6, 9.2, 9.2 Hz, 1H), 2.27 (ddq, J¼3.2, 14.4,
7.2 Hz, 1H), 1.99 (ddq, J¼10.8, 14.4, 7.2 Hz, 1H), 1.68 (ddq, J¼3.6, 14.6,
7.2 Hz, 1H), 1.49 (ddq, J¼9.2, 14.6, 7.2 Hz, 1H), 1.15 (t, J¼7.2 Hz, 3H),
d
(m, 5H), 4.55 (dq, J¼5.8, 6.8 Hz, 1H), 3.79 (d, J¼14.0 Hz, 1H), 3.75 (d,
J¼14.0 Hz, 1H), 3.26 (dq, J¼5.8, 7.1 Hz, 1H), 1.52 (d, J¼6.8 Hz, 3H),
0.93 (t, J¼7.2 Hz, 3H). 13C NMR (101 MHz, CDCl3)
d: 133.2, 133.0,
1.21 (d, J¼7.1 Hz, 3H). 13C NMR (101 MHz, CDCl3)
d:
13C NMR
129.2, 128.0, 93.7, 53.8, 25.2, 24.5, 11.2, 10.4. Syn-2h: 1H NMR
(101 MHz, CDCl3) d: 137.4, 128.8, 128.7, 127.4, 86.1, 42.1, 36.2, 16.1,
(400 MHz, CDCl3)
d: 7.45e7.42 (m, 2H), 7.35e7.29 (m, 3H), 4.45
14.1. IR (CH2Cl2), v (cmꢀ1): 1552 (NO2). HRMS (ESI) calcd for
(ddd, J¼4.0, 7.2, 10.8 Hz, 1H), 3.39 (ddd, J¼3.6, 7.2, 10.0 Hz, 1H),
2.13e2.02 (m, 1H), 1.68 (ddq, J¼3.6, 14.0, 7.2 Hz, 1H), 1.89e1.71 (m,
2H), 1.12 (t, J¼7.2 Hz, 3H), 0.96 (t, J¼7.2 Hz, 3H). 13C NMR (101 MHz,
C
11H15NNaO2Sþ, [MþNa]þ m/z: 248.0716, found 248.0718.
4.3.13. 3-Butylthio-2-nitrobutane (2m). Colorless oil, 144 mg, 75%,
Rf¼0.30 (PE:diethyl ether¼40:1, v/v). Anti-2m: 1H NMR (400 MHz,
CDCl3) d: 133.2,132.8,129.2, 127.9, 92.5, 53.7, 22.9, 22.8,11.5, 10.8. IR
(CH2Cl2), v (cmꢀ1): 1549 (NO2). HRMS (ESI) calcd for C12H18NO2Sþ
[MþH]þ m/z: 240.1053, found 240.1052.
CDCl3)
d
: 4.63 (dq, J¼6.2, 6.7 Hz, 1H), 3.36 (dq, J¼6.2, 7.0 Hz, 1H),
2.63e2.52 (m, 2H), 1.62e1.52 (m, 2H), 1.57 (d, J¼6.7 Hz, 3H),
1.46e1.36 (m, 2H), 1.28 (d, J¼7.0 Hz, 3H), 0.92 (t, J¼7.3 Hz, 3H). 13
C
4.3.9. 3-Nitro-4-phenylthiononane (2i). Yellowish oil, 248 mg, 87%,
Rf¼0.56, 0.58 (PE:EA¼40:1, v/v). Anti-2i: 1H NMR (400 MHz,
NMR (101 MHz, CDCl3) d: 86.4, 42.8, 31.5, 31.3, 21.9, 16.2, 14.1, 13.6.
Syn-2m, 1H NMR (400 MHz, CDCl3)
d: 4.55 (dq, J¼7.5, 6.6 Hz, 1H),
CDCl3)
d
: 7.44e7.42 (m, 2H), 7.32e7.31 (m, 3H), 4.37 (ddd, J¼3.2,
3.21 (dq, J¼7.4, 7.0 Hz,1H), 2.63e2.52 (m, 2H),1.66 (d, J¼6.7 Hz, 3H),
1.62e1.52 (m, 2H), 1.46e1.36 (m, 2H), 1.35 (d, J¼7.0 Hz, 3H), 0.91 (t,
9.2, 10.8 Hz, 1H), 3.31 (ddd, J¼3.6, 7.2, 9.2 Hz, 1H), 2.24 (ddq,
J¼3.2, 14.8, 7.2 Hz, 1H), 1.98 (ddq, J¼10.8, 14.4, 7.2 Hz, 1H),
1.77e1.68 (m, 1H), 1.60e1.57 (m, 1H), 1.53e1.44 (m, 2H), 1.34e1.25
(m, 4H), 0.93 (t, J¼7.2 Hz, 3H), 0.89 (t, J¼7.2 Hz, 3H). 13C NMR
J¼7.3 Hz, 3H). 13C NMR (101 MHz, CDCl3)
d:
13C NMR (101 MHz,
CDCl3) d: 87.6, 43.6, 31.7, 30.9, 21.9, 19.2, 16.7, 13.6. IR (CH2Cl2), v
(cmꢀ1): 1550 (NO2). HRMS (ESI) calcd for C8H17NNaO2Sþ, [MþNa]þ
m/z: 214.0872, found 214.0878.
(101 MHz, CDCl3) d: 133.3, 133.1, 129.2, 128.4, 93.6, 52.2, 31.3, 31.2,
26.3, 25.2, 22.4, 13.9, 10.5. Syn-2i: 1H NMR (400 MHz, CDCl3)
d:
7.46e7.42 (m, 2H), 7.35e7.27 (m, 3H), 4.43 (ddd, J¼4.0, 6.8,
10.0 Hz, 1H), 3.46 (ddd, J¼3.2, 6.8, 10.4 Hz, 1H), 2.12e1.80 (m, 2H),
1.77e1.68 (m, 1H), 1.60e1.57 (m, 1H), 1.53e1.44 (m, 2H), 1.34e1.25
(m, 4H), 0.95 (t, J¼7.2 Hz, 3H), 0.90 (t, J¼7.2 Hz, 3H). 13C NMR
4.3.14. 3-Isopropylthio-2-nitrobutane (2n). Colorless oil, 158 mg,
89%, Rf¼0.28 (PE:diethyl ether¼40:1, v/v). Syn-2n: 1H NMR
(400 MHz, CDCl3)
d
: 4.50 (dq, J¼7.0, 6.7 Hz, 1H), 3.29 (dq, J¼7.0,
6.9 Hz,1H), 2.987 (hept, J¼6.7 Hz, 1H),1.64 (d, J¼6.7 Hz, 3H), 1.35 (d,
(101 MHz, CDCl3) d: 133.1, 132.8, 128.9, 127.9, 92.6, 51.9, 31.3, 29.5,
J¼6.7 Hz, 3H), 1.30 (d, J¼7.0 Hz, 3H), 1.25 (d, J¼6.9 Hz, 3H). 13C NMR
26.4, 25.2, 22.6, 13.8, 10.8. IR (CH2Cl2), v (cmꢀ1): 1549 (NO2).
HRMS (ESI) calcd for C15H24NO2Sþ [MþH]þ m/z: 282.1522, found
282.1518.
(101 MHz, CDCl3)
NMR (400 MHz, CDCl3)
d
: 87.6, 42.5, 35.5, 23.8, 23.5, 20.1, 16.3. Syn-2n: 1H
d: 4.63 (dq, J¼5.8, 6.7 Hz, 1H), 3.42 (dq,
J¼5.8, 7.0 Hz, 1H), 2.994 (hept, J¼6.7 Hz 1H), 1.57 (d, J¼6.7 Hz, 3H),
1.32 (d, J¼6.7 Hz, 3H), 1.27 (d, J¼7.0 Hz, 3H), 1.26 (d, J¼6.7 Hz, 3H).
4.3.10. 4-(4-Chlorophenyl)-3-nitro-4-phenylthiobutane
13C NMR (101 MHz, CDCl3)
d: 86.7, 41.4, 35.4, 23.6, 23.3, 16.7, 13.9. IR
(2j). Yellowish oil, 273 mg, 85%, Rf¼0.28 (PE:EA¼40:1, v/v). Anti-2j:
(CH2Cl2),
v
(cmꢀ1): 1551 (NO2). HRMS (ESI) calcd for
1H NMR (400 MHz, CDCl3)
d
: 7.28‒7.17 (m, 7H), 7.05e7.02 (d,
C7H15NNaO2Sþ, [MþNa]þ m/z: 200.0716, found 200.0719.
J¼8.4 Hz, 2H), 4.78 (ddd, J¼3.0, 10.5, 10.5 Hz, 1H), 4.42 (d, J¼10.5 Hz,
1H), 2.51 (ddq, J¼3.0, 14.8, 7.2 Hz,1H), 2.12 (ddq, J¼10.5,14.8, 7.2 Hz,
4.3.15. 3-tert-Butylthio-2-nitrobutane (2o). Colorless oil, 135 mg,
70%, Rf¼0.36 (PE:diethyl ether¼40:1, v/v). Anti-2o: 1H NMR
1H), 1.04 (t, J¼7.2 Hz, 3H). 13C NMR (101 MHz, CDCl3)
d: 136.0, 134.6,
134.0, 131.5, 129.2, 129.1, 128.8, 128.7, 93.15, 55.4, 26.1, 10.2. Syn-2j:
(400 MHz, CDCl3)
d
: 4.45 (dq, J¼7.2, 7.2 Hz, 1H), 3.21 (dq, J¼7.2,
1H NMR (400 MHz, CDCl3)
d: 7.28e7.17 (m, 7H), 7.05e7.02 (d,
6.8 Hz, 1H), 1.63 (d, J¼6.8 Hz, 3H), 1.33 (s, 9H), 1.40 (d, J¼7.2 Hz, 3H).
13C NMR (101 MHz, CDCl3)
: 87.9, 44.0, 40.9, 31.2, 22.5, 16.4. Syn-
2o, 1H NMR (400 MHz, CDCl3)
: 4.66 (dq, J¼5.2, 6.7 Hz, 1H), 3.40
J¼8.4 Hz, 2H), 4.73 (ddd, J¼3.1, 10.3, 10.3 Hz, 1H), 4.41 (d, J¼10.3 Hz,
d
1H), 1.77 (ddq, J¼10.3, 14.5, 7.2 Hz, 1H), 1.56 (ddq, J¼3.1, 14.5, 7.2 Hz,
d
1H), 0.88 (t, J¼7.2 Hz, 3H). 13C NMR (101 MHz, CDCl3)
d
: 135.7, 134.2,
(dq, J¼5.2, 7.1 Hz, 1H), 1.54 (d, J¼6.7 Hz, 3H), 1.36 (s, 9H), 1.28 (d,
133.9, 131.4, 129.7, 129.5, 128.9, 128.6, 92.8, 55.7, 25.7, 10.3. IR
(CH2Cl2), v (cmꢀ1): 1551 (NO2). HRMS (ESI) calcd for C16H17ClNO2Sþ
[MþH]þ m/z: 322.0663, found 322.0665.
J¼7.1 Hz, 3H) 13C NMR (101 MHz, CDCl3)
d: 87.5, 44.3, 39.9, 31.0,
18.2, 13.4. IR (CH2Cl2), v (cmꢀ1): 1549 (NO2). HRMS (ESI) calcd for
C8H17NaNO2Sþ [MþNa]þ m/z: 214.0872, found 214.0882.
4.3.11. 1-Nitro-1,2-diphenyl-2-phenylthioethane
(2k). Colorless
4.3.16. 3-Isopropylthio-2-methyl-4-nitropentane (2p). Colorless oil,
171 mg, 83%, Rf¼0.31, 0.37 (PE: diethyl ether¼40:1, v/v). Anti-2p: 1H
crystals, 269 mg, 80%, m.p. (for anti-2k) 160e162 ꢁC, Rf¼0.24, 0.26
(PE:EA¼40:1, v/v). Anti-2k: 1H NMR (400 MHz, CDCl3)
d: 7.62e7.60
NMR (400 MHz, CDCl3)
d
: 4.65 (dq, J¼9.5, 6.7 Hz, 1H), 2.98 (dd,
(d, J¼6.8 Hz, 2H), 7.44e7.36 (m, 3H), 7.28e7.25 (m, 5H), 7.17 (t,
J¼7.2 Hz, 1H), 7.10e7.07 (t, J¼7.2 Hz, 2H), 6.99e6.97 (d, J¼7.2 Hz,
2H), 5.89 (d, J¼11.7 Hz, 1H), 5.03 (d, J¼11.7 Hz, 1H). 13C NMR
J¼3.4, 9.5 Hz, 1H), 2.81 (hept, J¼6.7 Hz, 1H), 2.06 (dhept, J¼3.4,
6.7 Hz, 1H), 1.60 (d, J¼6.7 Hz, 3H), 1.25 (d, J¼6.6 Hz, 3H), 1.20 (d,
J¼6.7 Hz, 3H), 1.11 (d, J¼6.6 Hz, 3H), 0.85 (d, J¼6.7 Hz, 3H). 13C NMR
(101 MHz, CDCl3)
d
: 137.4, 134.4, 132.3, 132.1, 130.4, 128.9, 128.7,
(101 MHz, CDCl3) d: 86.3, 55.8, 37.5, 30.1, 23.9, 23.6, 21.1, 17.6, 17.2.
128.6, 128.3, 128.2, 127.8, 94.7, 56.4. Syn-2k: 1H NMR (400 MHz,
CDCl3)
: 7.49 (d, J¼6.8 Hz, 2H), 7.44e7.35 (m, 3H), 7.30e7.23 (m,
5H), 7.17e6.97 (m, 5H), 5.86 (d, J¼12.2 Hz, 1H), 5.03 (d, J¼12.2 Hz,
1H). 13C NMR (101 MHz, CDCl3)
: 137.3, 135.2, 131.1, 130.5, 129.8,
129.1, 128.9, 128.6, 128.3, 128.2, 127.6, 94.2, 56.2. IR (CH2Cl2), v
Syn-2p: 1H NMR (400 MHz, CDCl3)
d
: 4.68 (dq, J¼8.9, 6.6 Hz, 1H),
d
2.94 (dd, J¼4.5, 8.9 Hz, 1H), 2.87 (hept, J¼6.6 Hz, 1H), 1.75 (dhept,
J¼4.5, 6.6 Hz, 1H), 1.70 (d, J¼6.6 Hz, 3H), 1.30 (d, J¼6.6 Hz, 3H), 1.26
d
(d, J¼6.8 Hz, 3H), 1.06 (d, J¼6.6 Hz, 3H), 0.96 (d, J¼6.8 Hz, 3H). 13
C
NMR (101 MHz, CDCl3) d: 88.2, 54.5, 37.4, 28.4, 23.9, 23.4, 21.5, 17.8,
Please cite this article in press as: Wang, J.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.04.053

8
J. Wang et al. / Tetrahedron xxx (2015) 1e8
16.84. IR (CH2Cl2), v (cmꢀ1): 1551 (NO2). HRMS (ESI) calcd for
C9H20NO2Sþ [MþHþ] m/z: 206.1209, found 206.1207.
ꢀ
ꢀ
2. (a) Ballini, R.; Araujo, N.; Gil, M. V.; Roman, E.; Serrano, J. A. Chem. Rev. 2013, 113,
3493e3515; (b) Barrett, A. G. M.; Graboski, G. G. Chem. Rev. 1986, 86, 751e762;
ꢁ
(c) Dumez, E.; Faure, R.; Dulcere, J.-P. Eur. J. Org. Chem. 2001, 2577e2588; (d)
Berner, O. M.; Tedeschi, L.; Enders, D. Eur. J. Org. Chem. 2002, 1877e1894.
3. (a) Corey, E. J.; Estreicher, H. J. Am. Chem. Soc. 1978, 100, 6294e6295; (b) Ca-
pecchi, T.; de Koning, C. B.; Michael, J. P. J. Chem. Soc., Perkin Trans. 1 2000,
2681e2688; (c) Mineno, T.; Miller, M. J. J. Org. Chem. 2003, 68, 6591e6596; (d)
Kozikowski, A. P. Acc. Chem. Res. 1984, 17, 410e416; (e) Eyer, M.; Seebach, D. J.
Am. Chem. Soc. 1985, 107, 3601e3606; (f) Xu, C. X.; Xu, J. X. Amino Acids 2011, 41,
195e203.
4.3.17. 3-tert-Butylthio-2-methyl-4-nitropentane (2q). Colorless oil,
68 mg, 31%, Rf¼0.31 (PE: diethyl ether¼40:1, v/v). Anti-2q: 1H NMR
(400 MHz, CDCl3)
d
: 4.65 (dq, J¼8.8, 6.8, Hz, 1H), 3.03 (dd, J¼4.4,
8.8 Hz, 1H), 1.81 (dhept, J¼4.4, 7.2 Hz, 1H), 1.69 (d, J¼6.8 Hz, 3H),
1.32 (s, 9H), 1.05 (d, J¼7.2 Hz, 3H), 0.96 (d, J¼7.2 Hz, 3H). 13C NMR
4. For selected examples of the diastereo- and enantioselective sulfa-Michael
(101 MHz, CDCl3) d: 86.0, 52.6, 43.6, 32.0, 30.9, 21.1, 18.0, 17.9. Syn-
additions of
a,b-disubstituted nitroolefins and thiols, see: (a) Wang, X. F.;
2q: 1H NMR (400 MHz, CDCl3)
d
: 4.67 (dq, J¼6.4, 6.8 Hz, 1H), 3.16
Hua, Q. L.; Chen, Y.; An, X. L.; Yang, Q. Q.; Chen, J. R.; Xiao, W. J. Angew. Chem.,
Int. Ed. 2010, 49, 8379e8383; (b) Wang, X. F.; Peng, L.; An, J.; Li, C.; Yang, Q. Q.;
Lu, L. Q.; Gu, F. L.; Xiao, W. J. Chem.dEur. J. 2011, 17, 6484e6491; (c) Kimmel, K.
L.; Robak, M. T.; Thomas, S.; Lee, M.; Ellman, J. A. Tetrahedron 2012, 68,
2704e2712; (d) Pei, Q. L.; Han, W. Y.; Wu, Z. J.; Zhang, X. M.; Yuan, W. C. Tet-
rahedron 2013, 69, 5367e5373; (e) Yang, W.; Yang, Y.; Du, D. M. Org. Lett. 2013,
15, 1190e1193; (f) Zhang, Y.; Vongvilai, P.; Sakulsombat, M.; Fischer, A.;
Ramstrc¸ m, O. Adv. Synth. Catal. 2014, 356, 987e992; (g) Chauhan, P.; Mahajan,
S.; Enders, D. Chem. Rev. 2014, 114, 8807e8864; (h) Wang, R. C.; Xu, J. X. Helv.
Chim. Acta 2014, 97, 1700e1707.
(dd, J¼4.4, 6.4 Hz, 1H), 1.97 (dhept, J¼4.4, 6.8 Hz, 1H), 1.62 (d,
J¼6.8 Hz, 3H), 1.33 (s, 9H), 1.01 (d, J¼6.8 Hz, 3H), 0.95 (d, J¼6.8 Hz,
3H). 13C NMR (101 MHz, CDCl3)
d: 88.3, 51.7, 43.7, 31.4, 28.1, 21.7,
19.0, 15.1. IR (CH2Cl2), v (cmꢀ1): 1549 (NO2). HRMS (ESI) calcd for
C
10H21NaNO2Sþ [MþNa]þ m/z: 242.1185, found 242.1187.
4.3.18. 1-Nitro-2-phenylthiocyclohexane
(2r).5,8 Colorless
oil,
5. Kamimura, A.; Sasatani, H.; Hashimoto, T.; Kawai, T.; Hori, K.; Ono, N. J. Org.
Chem. 1990, 55, 2437e2442.
203 mg, 85%, Rf¼0.43, 0.31 (PE:EA¼20:1, v/v). Cis-2r: 1H NMR
(400 MHz, CDCl3) d: 7.44e7.42 (m, 2H), 7.30e7.26 (m, 3H), 4.59 (ddd,
6. (a) Da Silva, F. M.; Jones, J. J. J. Braz. Chem. Soc. 2001, 12, 135e137; (b) Ranu, B. C.;
Dey, S. S.; Hajra, A. Tetrahedron 2003, 59, 2417e2421; (c) Lewandowska, E.
Tetrahedron 2006, 62, 4879e4883; (d) Almeida, Q. A. R.; Pereira, M. L. O.;
Coelho, R. B.; Carvalho, E. M.; Kaiser, C. R.; Jones, J. J.; Silva, F. M. J. Braz. Chem.
Soc. 2008, 19, 894e902; (e) Chu, C. M.; Tu, Z.; Wu, P.; Wang, C. C.; Liu, J. T.; Kuo,
C. W.; Shin, Y. H.; Yao, C. F. Tetrahedron 2009, 65, 3878e3885.
J¼4.1, 4.1, 9.5 Hz, 1H), 3.82 (m, 1H), 2.21e2.12 (m, 2H), 2.09e2.02 (m,
1H),1.92e1.86(m,1H),1.83e1.75(m, 2H),1.57e1.49 (m,1H),1.42e1.31
(m, 1H). Trans-2r: 1H NMR (400 MHz, CDCl3)
d: 7.50e7.47 (m, 2H),
7.34e7.33 (m, 3H), 4.38 (ddd, J¼4.1,10.9,10.9 Hz,1H), 3.34 (ddd, J¼4.1,
10.9,10.9 Hz,1H), 2.34e2.30 (m,1H), 2.19e2.16 (m,1H),1.97e1.87 (m,
1H), 1.81e1.73 (m, 2H), 1.40e1.33 (m, 2H), 1.28e1.19 (m, 1H).
7. Chen, N.; Xu, J. X. Tetrahedron 2012, 68, 2513e2522.
8. (a) Ono, N.; Kamimura, A.; Sasatani, H.; Kaji, A. J. Org. Chem. 1987, 52,
4133e4135; (b) Kamimura, A.; Sasatani, H.; Hashimoto, T.; Ono, N. J. Org. Chem.
1989, 54, 4998e5003.
9. (a) Heathcock, C. H.; Pirrung, M. C.; Sohn, J. E. J. Org. Chem. 1979, 44,
4294e4299; (b) Hoffmann, R. W.; Froech, S. Tetrahedron Lett. 1985, 26,
1643e1646; (c) Rychnovsky, S. D.; Skalitzky, D. J. Tetrahedron Lett. 1990, 31,
945e948; (d) Peter, A.; Vaughan-Williams, G. F.; Rosser, R. M. Tetrahedron 1993,
49, 3007e3034.
Acknowledgements
This work was supported in part by the National Basic Research
Program of China (No. 2013CB328905) and the National Natural
Science Foundation of China (Nos. 21372025 and 21172017).
10. Mohrig, J. R.; Rosenberg, R. E.; Apostol, J. W.; Bastienaansen, M.; Evans, J. W. J.
Am. Chem. Soc. 1997, 119, 479e486.
11. Seeman, J. I. Chem. Rev. 1983, 83, 83e134.
12. Cram, D. J.; Elhafez, F. A. A. J. Am. Chem. Soc. 1952, 74, 5828e5835.
13. (a) Mengel, A.; Reiser, O. Chem. Rev. 1999, 99, 1191e1224; (b) Cieplak, A. S. Chem.
Rev. 1999, 99, 1265e1336; (c) Carey, F. A.; Sundberg, R. J. Advanced Organic
Chemistry Part A: Structure and Mechanisms, 5th ed.; Springer, 2007;
pp 177e182; (d) Anslyn, E. V.; Dougherty, D. A. Modern Physical Organic
Chemistry; University Science Books, 2005; pp 562e563.
14. (a) Crump, R. A. N. C.; Fleming, I.; Hill, J. H. M.; Parker, D.; Reddy, N. L.; Wa-
terson, D. J. Chem. Soc., Perkin Trans. 1 1992, 3277e3294; (b) Fleming, I.; Lewis, J.
J. Chem. Soc., Perkin Trans. 1 1992, 3257e3266.
Supplementary data
Supplementary data (copies of 1H and 13C NMR spectra of
products 2, copies of 1H NMR spectra of all reaction mixtures for
determination of their diastereoselectivities, and list of the vicinal
HeH coupling constants in anti- and syn-products 2ae2q and cis-
and trans-2r) associated with this article can be found in the online
version at http://dx.doi.org/10.1016/j.tet.2015.04.053. These data
include MOL files and InChIKeys of the most important compounds
described in this article.
15. (a) Rosenberg, R. E.; Mohrig, J. R. J. Am. Chem. Soc. 1997, 119, 487e492; (b)
Mohrig, J. R. Acc. Chem. Res. 2013, 46, 1407e1416.
16. (a) Houk, K. N.; Paddon-Row, M. N.; Rondan, N. G.; Wu, Y. D.; Brown, F. K.;
Spellmeyer, D. C.; Metz, J. T.; Li, Y.; Loncharich, R. J. Science 1986, 231,
1108e1117; (b) Houk, K. N.; Rondan, N. G.; Wu, Y.-D.; Metz, J. T.; Paddon-Row,
M. N. Tetrahedron 1984, 40, 2257e2274; (c) Paddon-Row, M. N.; Rondan, N. G.;
Houk, K. N. J. Am. Chem. Soc. 1982, 104, 7162e7166; (d) Houk, K. N.; Paddon-
Row, M. N. J. Am. Chem. Soc. 1986, 108, 2659e2662.
17. Alabugin, I. V.; Zeidan, T. A. J. Am. Chem. Soc. 2002, 124, 3175e3185.
18. (a) Johnson, F. Chem. Rev. 1968, 68, 375e413; (b) Hoffmann, R. W. Chem. Rev.
1989, 89, 1841e1860.
References and notes
~ꢀ
1. (a) Aydillo, C.; Companon, I.; Avenoza, A.; Busto, J. H.; Corzana, F.; Peregrina, J.
M.; Zurbano, M. M. J. Am. Chem. Soc. 2014, 136, 789e800; (b) White, J. D.; Shaw,
S. Chem. Sci. 2014, 5, 2200e2204; (c) Enders, D.; Luttgen, K.; Narine, A. A.
Synthesis 2007, 959e980.
€
Please cite this article in press as: Wang, J.; et al., Tetrahedron (2015), http://dx.doi.org/10.1016/j.tet.2015.04.053