Insights into the diastereoselective control in the sulfa-Michael addition of thiols to nitroalkenes: Stereoelectronic effect in the cyclic chelated transition state

Article abstract of DOI:10.1016/j.tet.2015.11.030

The diastereoselective control in the sulfa-Michael addition of nitroalkenes and lithium thiolates followed by protonation was investigated. Lithium thiolates first added to nitroalkenes to afford cyclic lithium-chelated nitronates. The subsequent kinetic protonation of nitronates was proved to be the stereochemical determinant through the chelate-controlled six-membered half-chair transition state bearing two approximately 1,2-diaxial substituents due to stereoelectronic effect control. The stereoelectronic effect in the cyclic chelated transition state was probed and verified by tuning the steric bulkiness of the corresponding substituents. The reaction involving 1-nitrocyclohexene provided perfect support for the proposed diastereoselective control model. The current investigation provided not only comprehensive insights into the diastereoselective control in the sulfa-Michael addition of nitroalkenes and thiolates, but also an important role of the stereoelectronic effect in certain organic reactions involving cyclic chelate transition states.

Full text of DOI:10.1016/j.tet.2015.11.030

Accepted Manuscript
Insights into the diastereoselective control in the sulfa-Michael addition of thiols to
nitroalkenes: Stereoelectronic effect in the cyclic chelated transition state
Jiandong Wang, Pingfan Li, Zhanhui Yang, Ning Chen, Jiaxi Xu
PII:
S0040-4020(15)30215-5
10.1016/j.tet.2015.11.030
TET 27287
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 22 August 2015
Revised Date: 7 November 2015
Accepted Date: 16 November 2015
Please cite this article as: Wang J, Li P, Yang Z, Chen N, Xu J, Insights into the diastereoselective
control in the sulfa-Michael addition of thiols to nitroalkenes: Stereoelectronic effect in the cyclic chelated
transition state, Tetrahedron (2015), doi: 10.1016/j.tet.2015.11.030.
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Insights into the diastereoselective control in the sulfa-
Micheal addition of thiols to nitroalkenes: Stereo-
electronic effect in the cyclic chelated transition state
Jiandong Wang, Pingfan Li, Zhanhui Yang, Ning Chen, Jiaxi Xu*

1
ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
Insights into the diastereoselective control in the sulfa-Michael addition of thiols to
nitroalkenes: Stereoelectronic effect in the cyclic chelated transition state
Jiandong Wang, PingfanLi, Zhanhui Yang, Ning Chen, and Jiaxi Xu
State Key Laboratory of Chemical Resource Engineering, Department of Organic Chemistry, Faculty of Science, Beijing University of Chemical Technology,
Beijing 100029, China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
The diastereoselective control in the sulfa-Michael addition of nitroalkenes and lithium
thiolates followed by protonation was investigated. Lithium thiolates first added to
nitroalkenes to afford cyclic lithium-chelated nitronates. The subsequent kinetic protonation
of nitronates was proved to be the stereochemical determinant through the chelate-controlled
six-membered half-chair transition state bearing two approximately 1,2-diaxial substituents
due to stereoelectronic effect control. The stereoelectronic effect in the cyclic chelated
transition state was probed and verified by tuning the steric bulkiness of the corresponding
substituents. The reaction involving 1-nitrocyclohexene provided perfect support for the
proposed diastereoselective control model. The current investigation provided not only
comprehensive insights into the diastereoselective control in the sulfa-Michael addition of
nitroalkenes and thiolates, but also an important role of the stereoelectronic effect in certain
organic reactions involving cyclic chelate transition states.
Available online
Keywords:
Diastereoselectivity
Sulfa-Michael addition
Nitroalkene
Thiol
Stereoelectronic effect
Cyclic chelated transition state
Half-chair conformation
2015 Elsevier Ltd. All rights reserved
.
1. Introduction
In our recent study on the preparation of various disubstituted
taurines, moderate to good diastereoselectivities were observed in
the tertiary amine-catalyzed SMA of thiolacetic acid to α,β-
disubstituted nitroalkenes with perfect yields.8 Subsequently, we
found that controlling the reaction time exerted remarkable
impact on the diastereoselectivity in the triethylamine-catalyzed
SMA between nitroalkenes and thiols. The SMA involving
thiophenol and primary alkanethiols has been proven to be
kinetic control at the beginning and thermodynamic control at the
end and linear nitroalkenes generally produce anti-adducts as
major kinetic products due to favorable steric and
stereoelectronic effects.9 In our continuous interest on the
diastereoselective control in the SMA of nitroalkenes without any
chiral auxiliary or catalysts, we have investigated the
diastereoselective formation of anti-β-nitro sulfides in reactions
of nitroalkenes with sulfur nucleophiles, lithium thiolates R3S Li,
The sulfa-Michael addition (SMA), which is considered as
the reaction of a sulfur nucleophile and carbon-carbon multiple
bond electrophile activated by an conjugated electron-deficient
group, has proven to be one of the most powerful strategies in
constructing the sulfur-carbon bond,1 and always plays a crucial
role in the formation of key structural motifs of biologically
active sulfur-containing compounds.2 Meanwhile, when
appropriately disubstituted activated π-systems serve as Michael
acceptors, the SMA has the potential to introduce two vicinal
stereogenic centers via only one transformation. Thus, extensive
and intensive studies have been directed toward the development
of the diastereoselective control of this transformation for quite a
long time.3 As we all know, conjugated nitroalkenes act as
excellent Michael acceptors ascribing to their strongly electron-
withdrawing capacity of the nitro group.4 Furthermore, the nitro
group is usually considered as masked functionality to be further
converted to various useful functional groups, such as ketone,
nitrile, nitrile oxide, and amino groups.5 Additionally, the SMA
adducts β-nitro sulfides are particularly versatile in synthetic
o
followed by protonation at -78 C according to literature report
due to their synthetic applicability.10 Although Hori et al assumed
a concept of “the endo alkoxy effect” which insisted that the
substituent R3 on the sulfur atom should take the cis position to
the nitro fragment to cover one side of the nitronate plane to
minimize the repulsion between S-lone electron pairs and the
anion orbital in terms of computational consideration, their
arguments were proposed on the basis of certain unconvincing
hypothesis involving regardless of the chelating ability of lithium
and the steric impact of substituent group R3 on the sulfur atom
(Scheme 1).11 Furthermore, Apeloig et al reported that low
rotation barriers for adjacent σ-bonds in carbanions stabilized by
the nitro group via ab initio calculations.12 Thus, interconversion
of the conformations at the stereogenic center of carbanions in
nitronate anion intermediates could take place by rotating about
chemistry since they can undergo
a series of attractive
transformations to provide diverse functionality.6 Therefore, the
diastereoselective sulfa-Michael addition of α,β-disubstituted
nitroalkenes and thiols has been studied for many years.
Although impressive advances have been made in
organocatalyzed asymmetric SMA of nitroalkenes with thiols and
thiolacetic acid in recent years,1b,7 the diastereoselective control
in the sulfa-Michael addition is still one of important issues and
not clear completely.
———
Corresponding author. Tel.: +8610-6443-5565; fax: +8610-6443-5565; e-mail: jxxu@mail.buct.edu.cn

2
Tetrahedron
the Cα-Cβ σ-bond of the nitronate anion intermediates.
esters13 and the geometry of the enolate anion intemediates
ACCEPTED MANUSCRIPT
Therefore, the origin of the stereocontrol in the conjugate
addition reactions of sulfur nucleophiles R3SLi to α,β-unsaturated
acyclic nitroalkenes followed by protonation at -78 is still a
riddle.
should be relatively unaffcted the stereocontrol.14
To discern the stereochemical determinant in the sulfa-
Michael addition of thiols to nitroalkenes, we should apply both
(E)- and (Z)-nitroalkenes as Michael acceptors. Most of the
available procedures for the synthesis of nitroalkenes, such as
Henry reactions involving base mediated condensation of
nitroalkanes with aldehydes followed by subsequent dehydration,
are known to provide thermodynamically more stable E isomers,
independently of the nitro compound precursors.15 However, Z
isomers can be prepared indirectly from the corresponding E
derivatives. Treatment of (E)-2-nitro-2-butene (1a) and (E)-2-
nitro-3-phenyl-2-propene (1b) with sodium benzeneselenolate
followed by kinetically protonation with acetic acid afforded
anti-nitroselenides. After H2O2-promoted syn-elimination of
benzeneselenenic acid, E-1a and E-1b were converted into Z/E
mixtures (4:1) and (2:3) of isomeric nitroalkenes,
respectively.4c,16
H+
(a) Kamimura and Hori's proposal:
R2
NO2
R1
R1
-O
O-
R2
NO2
R1
R2 NO2
N
H
H+
-78 o
R2
R3S- Li+
H+
S
R3
C
C
SR3
SR3
R2
C
R1
H
S
N
R1
-O
O-
R3 covered one side of the nitronate plane
anti-products
R3
(1) Ignoring the chelating ability of lithium comletely;
(2) The stereocontrol should be independent to the steric hindrance of R3;
(3) Regardless of the relative low rotation barrier of the C -C
bond.
(b) Our cyclic chelated model:
R3
axial
S
H+
R3
S
H+
-O
O
NO2
R2
SR3
H
R2 NO2
N
Li
S
R3S- Li+
R1
H+
R3 -78 o
H
R2
C
N
O
O
N
O
O
R2
R2
R1
pseudoaxial
Li
C
R1
Li
R1
anti-products
R1
TS-A
The stereoelectronic effect (equatorial S-lone pair
conformation.
The stereoelectronic effect-controlled diastereoselectivity
of the Li-O bond) plays a crucial role in half-chair
The problem: how to probe stereoelectronic effect in the chelate-controlled nitronate anion
protonation?
Table
1 Diastereoselective sulfa-Michael addition of thiophenol to
Scheme 1. Proposed transition state models for diastereoselective sulfa-
Michael additions of lithium thiolates and nitroalkenes followed by
protonation.
nitroalkenes 1a,b
In order to reveal the origin of the anti-selectivity and to find
out the dominated elements in the stereocontrolled process, we
proposed a cyclic transition state TS-A (Scheme 1) for the
protonation of nitronate anions, which will be proved to be the
stereochemical determinant in this transformation, incorporating
with the consideration of chelation control of lithium and
stereoelectronic effect control. Although TS-A would be
expected to be stabilized by the stereoelectronic effect,
stereoelectronic and steric requirements imposed an approximate
1,2-diaxial substituted half-chair conformational bias to TS-A
(Scheme 1). Especially, one of two S-lone pair orbitals has to
occupy the equatorial direction in TS-A to share an
antiperiplanar relationship with the σ* antibonding orbital of the
Li-O bond. Nevertheless, all the experimental evidences provided
by literature10,11 seem to support the prediction made by TS-A.
However, the problem is that how to further probe the
stereoelectronic effect in the protonation reaction of the
chelate-controlled nitronate anions experimentally? We
successfully tackled the problem by extrapolating from the
diastereoselective change through tuning the steric hindrance of
substituent groups R1 and R3. Herein, we present our results and
hope that the results provide a potentially valuable guide to
analyze the stereoelectronic factors that control the
diastereoselectivity in chelate-controlled addition reactions.
Entry
1
R1
R2
R3
Z/E
2
Dr a
(anti:syn)
Yield b
(%)
E-1a
Z/E-1a
E-1b
2a
2a
2b
2b
1
2
3
Me Me
Me Me
Ph Me
Ph Me
Ph
Ph
Ph
Ph
0/1
4/1
0/1
2/3
91:9 c
92:8
75
67 d
70
75:25 c
76:24
Z/E-1b
4
77 d
a
b
Dr values were determined by 1H NMR.
Isolated yield by column
chromatography. c The dr ratios were completely in accord with Kamimura’s report
[ref 10]. d 0.22 mmol scale for the starting nitroalkenes in 2 mL dry THF.
Subsequently, the sulfa-Michael additions were performed
with (E)-isomers and Z/E mixtures of nitroalkenes 1a and 1b as
substrates. Not surprisingly, the E/Z mixtures provided almost the
same diastereoselectivities comparing with their corresponding
pure E isomers (Table 1, entries 1 vs 2, 3 vs 4). The experimental
evidences clearly indicated that the same nitronate anion
intermediates should be generated as a pair of enantiomers in
each of reactions. The subsequent protonation is responsible for
the generation of the diastereoselectivity. In other words, kinetic
protonation of nitronate anions is the stereochemical determinant
in the Michael addition of thiolates R3SLi to α,β-disubstituted
nitroalkenes. That is, the diastereoselectivity is controlled by the
subsequent protonation process rather than the first Michael
addition step.
2. Results and Discussion
2.1 The stereochemical determinant step.
The original motivation of our study was to understand the
diastereoselectivity of conjugate addition reactions of sulfur
nucleophiles R3SLi to α,β-unsaturated acyclic nitroalkenes. The
stepwise addition reactions consisted of two processes. Initial
conjugate addition of nucleophiles to Michael acceptors gave rise
to nitronate anion intermediates, which were protonated or
further trapped with other electrophiles. Inagaki et al. argued that
the stereospecific conjugate addition of lithium thiophenoxides to
α,β-unsaturated carboxylic acid derivatives could be achieved via
rapid protonation prior to conformational change in the
corresponding intermediates.3a However, Morig et al maintained
that the stereoselection of enolate protonation was responsible for
the diastereoselective 1,4-conjugate addition to α,β-unsaturated
2.2 Cyclic chelated TS models for kinetic protonation
It is noteworthy that we are not considering about the stability
of nitronate anions themselves but instead of the corresponding
transition states for kinetic protonation process, which is quite
consistent with the Curtin-Hammett principle.17 On one hand, an
asymmetric center including a heteroatom-containing substituent
is introduced into the substrates in the first conjugate addition
step; on the other hand, an effective transfer of the chiral
information of this stereogenic center to the diastereoface may be

3
achieved by chelation control in the presence of equal amount of
oxocarbenium ion which exhibits a pseudoaxial conformation
bias for the nucleophilic attack.26
ACCEPTED MANUSCRIPT
lithium. In contrast, the conjugate addition of alkyl groups to
simple nitroalkenes proceeds in a nonstereoselective way.10 In
other words, the general poor magnitudes of diastereofacial
selectivities in nitronate anions devoid of additional heteroatoms
suggest that the potential chelation control in the 1,2-
stereochemical control for protonation of β-sulfur substituted
nitronate anions. Additionally, even catalytic amounts of Lewis
acids such as LiClO4 have been demonstrated to induce excellent
degree of chelation control in the Adol reaction of an enolsilane
and an α-alkoxy aldehyde.18 However, incorporating chelation
control factor for rationalizing the diastereoselectivity in the
conjugate addition reactions of sulfur nucleophiles R3SLi to
α,β-unsaturated acyclic nitroalkenes has not been investigated.
Furthermore, the diastereoselection investigation into the
chelated-controlled reaction might not be attributed solely to
steric elements, stereoelectronic consideration also cannot be
ignored. Thus, the survey of literature for chelation adition
reactions is necessary and the chelation control in protonation
process of nitronate anions could be extrapolated from the
diastereoselectively nucleophilic addition of β-alkoxy carbonyl
ketones or aldehydes through six-membered-ring chelated
transition states.
Scheme 3. Transition state models in the protonation of nitronates
Cram-Reetz chelate model
Nu
H
H
Nu
Bn
O
R
TiLn
H
R
O
O
TiLn
Bn
H
H
O
H
Scheme 2. Cram-Reetz Chelate model
The analysis of chelation control in the nucleophilic attack on
the carbonyl group is of particular interest since Cram’s seminal
research on the diastereoselective addition of organometallic
reagents to acyclic carbonyl substrates bearing heteroatom-
containing substituents.19 The chelation controlled transition state
model of α-chelation (the five-membered chelate ring) was
proposed to rationalize the carbonyl π-facial diastereoselectivity
(1,2-stereochemical control) via reacting selectively from the
sterically less hindered π-face.20 For 1,3-stereochemical control
of β-chelation (the six-membered chelate ring), Narasaka
reported the synthesis of syn-1,3-diols from β-hydroxyketones by
the treatment with tributylborane and the successive reduction
with hydride through chelated pseudo boat or chelated pseudo
chair conformation.21 Still and Schneider firstly reported that β-
alkoxy aldehydes reacted with Gilman reagents via β-chelation to
provide the chelation controlled products with high levels of
Scheme 4. Newman projections for transition state models in the protonation
of nitronates
Inspired by the understanding of the chelation control in
diastereoselective nucleophilic attack at the carbonyl compounds,
especially Cram-Reetz chelate model which exhibits a half chair
conformation from an experimental viewpoint, four possible
cyclic chelated transition states which would convert to the
corresponding chair-like intermediates have been presented in
scheme 3 in order to explain the diastereofacial differentiation in
the protonation of nitroate anions. Meanwhile, four possible
transition state Newman perpendicular projection models are also
presented in Scheme 4. Presumably, the observed
diastereoselectivity of the sulfa-Michael addition is determined
by the competing four transition states, in which heteroatoms in
nitronate anions linked together through chelation to lithium. The
half-chair chelated transition states Ts-A and Ts-B are
responsible for the formation of anti-2, while the corresponding
Ts-a to Ts-b for that of syn-2. On the basis of the principle of
least conformational change,27 the optimal trajectory for
electrophilic attack of proton is considered as on the upper
surface relative to the delocalized C=N π system in Ts-A/Ts-B
and on the lower surface of the same π plane in Ts-a/Ts-b
because the opposite attack can give rise to the corresponding
intermediates bearing a twist-boat conformation, which is too
high in energy in kinetic control process. Although Ts-A is
almost 1,2-diaxially substituted, it is still considered as the
favored even most stable transition state for nitronate anion
protonation under chelation control of lithium due to strong
stereoelectronic effect, resulting in anti-2 as major products
kinetically. In the six-membered chelation TS-A, the substituted
group R3 occupies axial direction and R1 locates pseudoaxial
stereocontrol.22 Thus,
a conformationally constrained six-
membered ring bearing sterically differentiated diastereofaces
could be conceivable via metal ion chelation between the
carbonyl group and the corresponding β-heteroatom substituents.
In 1983, Reetz and Jung reported the reaction of chiral β-alkoxy
aldehydes, unsubstituted at the α-position, with the very Lewis
acidic compound CH3TiCl3 to form Cram-type chelates, which
then converted to chelation-controlled products.23 Then Reetz
proposed a half-chair chelated transition state model (Cram-
Reetz chelate model), which would lead to a chair-like
intermediate, to account for the diastereoselectivity (Scheme 2).24
Keck and Castellino provided spectroscopic evidence that the
favored TiCl4 chelate half-chair conformation positions β-alkyl
substituent in the pseudoequatorial position when the O-
substituent was sterically more demanding than the methyl group
due to disfavored gauche interaction.25 Additionally,
stereoelectronic factors can be extrapolated from nucleophilic
addition to heteroatom-substituted six-membered ring

4
Tetrahedron
ACCEPTED MANUSCRIPT
orientation of the half-chair conformation. In spite of
the delocalized C=N π plane and is nearly vertical to Cβ-R1 σ
unfavorably steric elements, the stereoelectronic effect, which
provides the stabilization for the diaxial conformer and overrides
the inherent steric bias of the axial substituent R1 and R3, may
serve as a critical factor in determining the anti-selective
stereocontrol. When substituent R3 takes the axial orientation, the
sulfur lone pair orbital would stay in the equatorial position in
TS-A, leading to the antiperiplanar relationship between S-lone
pair orbital and lithium-oxygen σ* acceptor orbital. Subsequently
the donor-acceptor interaction (the effective orbital overlap
between S-lone pair and antibonding σ* Li-O) will decrease the
energy of TS-A and compensate for destabilized energy causing
by the steric bias. Meanwhile TS-A could convert to TS-a via
ring flipping. To avoid a large swing to final tetrahedral
geometry, the approach angle for protonation is expected to be
abuse. Although TS-a seems to be more stable from the
viewpoint of steric effect because of the equatorial substituent R3
and pseudoequatorial R1, on the other hand, R1 and R3 are in
gauche position in TS-a rather than anti in TS-A, the steric
hindrance of pseudoequatorial R1 would obstruct the approaching
of proton, resulting in the increasing repulsive energy to
destabilize TS-a. Meanwhile, TS-b also bears the same
disfavored repulsive interaction. Therefore, the priority for TS-A
could ascribe to two factors: 1). stereoelectronic effect; 2).
devoid of repulsive interaction between the pseudo-equatorial R1
and upcoming attack of proton.
Thus, the proposed stereoelectronic effect appears to exhibit
significant role in determining diastereofacial selectivity in the
sulfa-Michael addition to nitroalkenes followed protonation at -
78 oC. However, the problem provided above is that how to
probe the stereoelectronic effect in this chelation control
protonation reaction from experimental investigations? The
stereoelectronic effect which exerts a conformational bias, 1,2-
diaxial substituted half-chair conformation, for protonation
process of nitronate anions can be extrapolated from the change
of diastereomeric ratio triggering by tuning the steric hindrance
in both nitroalkenes and thiols. Especially, we have to provide
experimental evidence to prove that the substituent R3 was
constrained to occupy the axial position in the half-chair chelated
TS-A to meet the requirements for orbital overlap consideration
of the equatorial S-lone pair orbital and σ*Li-O. Thus, the anti-
selectivity would be expected to decrease along with the increase
the size of axial substituent R3. Meanwhile, the
diastereoselectivity affected by the increasing of steric bulkiness
of R3 can also rule out the open-chain non-chelation transition
state model in which R3 was regarded as irrelevant factor.10,11
Additionally, the destabilized energy would be also increased
along with the increase steric hindrance of pseudoaxial
substituent R1, resulting in the dr value decrease as well. Thus,
the competitive relationship between steric effect and
stereoelectronic effect would be demonstrated by the decreasing
anti-selectivity caused by the increasing steric effect of R1. The
poorly diastereoselective outcome, ultimately, would suggest that
the stereoelectronic effect and steric effect are closely balanced.
Herein, we shall present our results and hope that the results
provide an important guide to the understanding stereoelectronic
elements in controlling the diastereoselectivity in the sulfa-
Michal addition of thiols to nitroalkenes under chelation
conditions and to discern the relative importance of
stereoelectronic effect and steric effect.
bond, seeming to play a minimal role in stereocontrol of kinetic
protonation for nitronates. And the experimental evidences from
literature10 have supported this assumption. In Table 2, when
keeping vicinal alkyl group (R1) to nitro group and the
substituent (R3) on sulfur unchanged, the appropriate substituents
in the R2 position, such as methyl, ethyl, 1-cyclohexenyl, 1-
cycloheptenyl,
and
phenyl
groups,
show
similar
diastereoselectivities (anti:syn = 91:9 in average) except for
isopropyl (which possibly followed both half-chair and twist-boat
conformations as shown in Schemes 3 and 5 due to its bulkiness,
vida post). However, the importance of R1 and R3, especially the
substituent group R3, in TS-A has not been systematically
investigated.
Table 2 Relationship between substituent R2 and the diastereoselectivitya
Yield
(%)
Dr
(anti:syn)
Entry
R1
R2
R3
1
2
3
4
5
6
Me
Me
Me
Me
Me
Me
Me
Ph
Ph
Ph
Ph
Ph
Ph
75
63
67
58
56
79
91:9
91:9
Et
1-cyclohexenyl
1-cycloheptenyl
i-Pr
96:4
92:8
57:43
90:10
Ph
a Cited from Kamimura’s paper [10].
When keeping vicinal substituent R1 and germinal alkyl R2
relative to nitro group unchanged, the dr (anti/syn) value
generally decrease with increasing the steric bulkiness of R3
(Table 3). For instance, when R1= R2 = Me, the dr values
(anti/syn) decrease from 92:8 to 86:14 to 84:16 along with
increasing R3 from phenyl to isopropyl to tert-butyl substituents
(Table 3, entries 1−3). Subsequently when changing R1 and R2 to
the ethyl group, the same phenomenon was observed. The dr
value reduced gradually from 85:15 to 78:22 along with
increasing R3 from phenyl to tert-butyl substituents (Table 3,
entries 4−6). Furthermore, the obvious decreased tendency in the
dr value from 73:27 to 55:45 along with increasing R3 from
phenyl to isopropyl substituent was exhibited (Table 3, entries 8
and 9) when keeping R1 = i-Pr and R2 = Me. For aryl substituted
nitroalkenes, the paradigm between the dr value change and the
steric hindrance of R3 was still obvious. For instance, 1,2-
diphenylnitroethene (1l) showed the highest diastereoselectivity
(dr 89:11) (Table 3, entry 11) when it reacted with thiophenol,
while the reaction of 1-methyl-2-phenylnitroethene (1b) and
thiophenol displays much higher diastereoselectivity than the
reaction of 1b and isopropanethiol (Table 2, entries 12 and 13, dr
76:24 vs 65:35). The results clearly indicate that the steric
hindrances of R3 show obvious influence on the
diastereoselectivity. Consequently, the hypothesis above about
the R3 group preferring to occupying the axial position of TS-A
had been proved by the experimental results in Table 3 (entries 1
vs 2 and 3, 4 vs 5 and 6, 8 vs 9, 12 vs 13). In other words, the
importance of the stereoelectronic effect seems inescapable in the
diastereoselective chelation control addition reaction.
Additionally, the steric bulkiness of R1 could also exert
significant influence on the stereochemistry because R1 takes the
pseudo-axial position in TS-A as well (Schemes 3 and 4).
Keeping geminal methyl or ethyl (R2) unchanged, the
diastereoselectivity in the sulfa-Michael addition of thiophenol to
2.3 To probe the stereoelectronic effect in TS-A
In the most stable chelated transition state model TS-A
(Schemes 3 and 4) which incorporates the stereoelectronic effect
to control the stereochemistry, substituent R2, which locates in

5
nitroalkenes obviously decreased along with the increasing steric
hindrance of R1 on the vicinal carbon to the nitro group. For
instance, the dr values (anti:syn) were generally in the range of
92:8 to 85:15 when R1 is methyl, ethyl, or other primary straight
chain alkyl group (Table 3, entries 1, 4, and 7). However, when
isopropyl and phenyl occupied the position of R1, the
diastereoselective ratio falled to 73:27 (Table 3, entry 8) and
76:24 (Table 3, entry 12), respectively. With the continuous
steric increase of the R1 group, such as becoming tert-butyl
substituent, the diastereoselectivity dramatically decrease to
53:47 (Table 3, entry 10). Subsequently, the sulfa-Michael
addition of isopropanethiol to various α,β-disubstituted
nitroalkenes also exhibited the same tendency (Table 3, entries 2,
5, 9, and 13), the dr value decrease from 86:14 when R1 is the
methyl group to 55:45 when R1 is the isopropyl group. These
poor diastereoselective outcomes (Table 3, entries 9 and 10)
indicate that the stabilized energy provided by the
stereoelectronic effect and the destabilized energy generated by
steric factors are closely balanced. Thus, the experimental results
are strongly in favor of our argument about the stereoelectronic
effect in TS-A and we can probe the stereoelectronic effect from
the dr value change by tuning steric effect.
electronic effect reinforces or weakens the cyclic transition state.
ACCEPTED MANUSCRIPT
The configurations of the syn- and anti-products 2 were
determined by the coupling constants of the vicinal protons and
the 13C NMR spectra via the γ-gauche effect and some of the
known products were confirmed by the reported data in the
literature.8-10 The γ-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 slightly higher field than those in
the corresponding anti-ones.9,28
We wonder whether syn-2 could serve as major products,
while inherent steric hindrance overrides the stereoelectronic
effect. When R1 and R3 still remained steric increasing, the steric
effect may be dominated the stereocontrol process and 1,2-
diaxial substituted TS-A may incline to flip to steric favored Ts-a
(Schemes 3 and 4), which were expected to offer reversal
stereoselectivity. Thus, several special nitroalkenes bearing a
bulky group on R1 position were screened to react with bulky
secondary or tertiary thiols in order to verify our assumption.
However, the turnover in diastereoselectivity had not been
observed. And it is really puzzled that the similar moderate dr
value (approximately anti:syn = 80:20) had been provided when
very bulky substituents occupy the positions of R1 and R3 (Table
4, entries 1−3). Additionally, in the sulfa-Michael addition of
tert-butanethiol to tert-butyl substituted nitroalkene, (E)-4,4-
dimethyl-2-nitropent-2-ene (1f), no desired product could be
monitored by the analysis of TLC and 1H-NMR from really
complex reaction mixture. And how to rationalize the interesting
results in these bulky steric cases?
Table 3 Substituent effect of R3 and R1 on diastereoselectivity
1
Yield,
(%) anti:syn
Dr, b
Entry
R1
R2
R3
Product
Table 4 Bulky substituent effect of R3 and R1 on the diastereoselectivity
Me c
Me
Me
Et
Me c
Me
Me
Et
Ph
i-Pr
t-Bu
Ph
2a
2c
2d
2e
2f
77
27
12
50
66
54
41
37
7
92:8
1a
1a
1a
1c
1c
1c
1d
1e
1e
1f
1
2
86:14
84:16
85:15
77:23
78:22
85:15
73:27
55:45
53:47
89:11
76:24
65:35
88:12
95:5
3
4
1
Yield,a
(%)
Dr b
Entry
R1
R2
R3
Product
5
Et
Et
i-Pr
t-Bu
Ph
anti:syn
1e
1f
6
Et
Et
2g
2h
2i
1
2
3
4
i-Pr
t-Bu
Ph
Me
Me
Me
Me
t-Bu
i-Pr
2p
2q
2r
2s
10
11
69
---
80:20
77:23
79:21
N.D. c
7
n-hex
i-Pr
i-Pr
t-Bu
Ph
Et
1b
1f
8
Me
Me
Me
Ph
Ph
t-Bu
9
i-Pr
Ph
2j
t-Bu
t-Bu
a Dr values were determined by both 1H NMR and 13C NMR.
b Isolated yield by column chromatography. c. Not detected
10
11
12
13
14
2k
2l
10
78
77
70
67
31
.
1g
1b
1b
1a
1a
Ph
Ph c
Me c
Ph
2b
2m
2n
2o
In the investigation of chelation control in Lewis acid
promoted Mukaiyama aldol rections of chiral β-hydroxy
aldehydes and achiral unsubstituted enolsilanes, Evans argued
that boat chelates were responsible for the stereocontrol based on
the semiempirical calculations (PM3).29 Thus, it is logical to
hypothesize that 1,2-diaxial TS-A would be potential to flip to
the corresponding lower energy twist boat geometry, rather than
standard boat conformation because the standard boat
conformation locates in relatively higher potential energy than
the twist boat one,30 due to steric factors reinforced by bulky
substituents (Scheme 5). Although the twist boat conformation of
TS-A was deemed to be lack of the stereoelectronic effect, it is
favored solely from the viewpoint of steric factor. Especially,
substituents R2 and R3 occupied the bowsprit and stern positions
in the twist-boat conformation, respectively, while hydrogen and
lone-pair orbital of oxygen atom tend to take up the flagstaff
positions. And proton would attack from unhindered approach
(exo side)(as shown in Scheme 5) to afford anti-2 mainly. It is
reasonable to conclude that the steric factors may act as dominate
element in the twist-boat chelae transition state for kinetic
protonation of nitronate anions when the stereoelectronic effect
could not balance the destabilizing energy provided by opposing
Ph
Me
i-Pr
Me
Me
Me 4-MeOC6H5
Me 4-O2NC6H5
15
a
b
Dr values were determined by both 1H NMR and 13C NMR. Isolated yield by
column chromatography. c Z/E = 4:1 for 2-nitro-2-butene (1a) and Z/E = 2:3 for 2-
nitro-3-phenyl-2-propene (1b)
It would be interesting to look into influence of different
substituents on the aromatic ring in ArSLi on the
diastereoselectivity. Arenethiols with para electron-donating
MeO and electron- withdrawing NO2 groups were evaluated with
(E)-2-nitro-2-butene (1a) (Table 3, entries 14 and 15). The results
reveal that the electron-deficient 4-nitrothiophenol shows better
diastereoselectivity than the electron-rich 4-methoxythiophenol
possibly because the sulfur atom in 4-nitrothiophenol is harder
acid than that in 4-methoxythiophenol, favorably coordinating
with hard base lithium cation. The electronic effect of
substituents on the aromatic ring of thiophenols do affect the
stereocontrol, attributing to the stereoelectronic interaction
between S-lone pair orbital and lithium-oxygen σ* acceptor
orbital in the proposed cyclic transition state because the

6
Tetrahedron
ACCEPTED MANUSCRIPT
steric factors in the half-chair TS-A. When R1 and R3 are both
Firstly, the experimental results clearly indicate that nitronate
tert-butyl group, no target β-nitro sulfide could be monitored
because too much angle and torsional strain would be imposed
even in twist-boat conformation and prevent the protonation
process, even sulfa-Michael addition due to heavy bulkiness.
protonation serves as the stereochemical determinant in this
chelation control reaction. Subsequently, half-chair six-
membered chelate ring transition state bearing a nearly 1,2-
diaxial substituents was proposed for nitronate protonation on the
basis of the stereoelectronic effect control (the equatorial S-lone
pair orbital shares an antiperiplanar relationship with the
antibonding orbital of the Li-O bond). The stereoelectronic effect
was verified through the change of diastereoselectivity by tuning
the steric bulkiness of R1 and R3. Especially, R3 occupying the
axial position or S-lone pair taking the equatorial direction has
been proved to be rational by the decreasing diastereoselectivity
along with the steric increasing of R3. Meanwhile, the
diastereoselectivity also decreases obviously with steric increase
of the substituent located in the vicinal olefinic carbon to the
nitro group because it possesses a pseudoaxial position in the
half-chair conformation. The poor diastereoselective outcomes
indicate that the stereoelectronic effect and opposing steric effect
are closely balanced. When the steric hindrance of substituent R3
and R1 increases continuously, TS-A inclines to flip to the
corresponding twist boat conformation which generates moderate
anti-selectivity dominated by steric effect exclusively. The
reaction of nitrocyclohexene and thiophenol supports the
proposed cyclic chelate transition state model perfectly. As a
consequence, stereoelectronic control elements cannot be ignored
in diastereoselective chelate-controlled addition reactions.
Scheme 5. Twist boat conformation of TS-A for protonation of nitronates
with two heavily bulky substituents.
Our stereoelectronic controlled transition state model TS-A
also could be applied to cyclic system with conformational
restriction. In literature reports, exposure of 1-nitrocyclohex-1-
ene to thiophenol under standard procedure resulted in the
formation
of
cis-1-nitro-2-(phenylthio)cyclohexane
exclusively.10,31 However, no convincing explanation was
provided for the priority of formation cis-product which was
always considered to be less thermodynamically stable. In this
case, the most stable transition state TS-A, which would convert
to cis-decalin-like intermediate followed transformation to the
corresponding product in cis-configuration, inclined to adopt a
chair/half-chair conformation which is favored by the
stereoelectronic effect. However, it is unfavorable enormously
for protonation when TS-A flips to its conformer TS-a which
would be responsible for trans-product because of steric
hindrance (Scheme 6). The preference for approach of proton
from the lower surface of C=N π plane is strongly blocked by the
cyclohexane ring.
4. Experimental section
4.1 General
Dry tetrahydrofuran (THF) was refluxed under nitrogen with
sodium wire and benzophenone as an indicator, and freshly
distilled prior to use. Melting points were obtained on a Yanaco
MP-500 melting point apparatus and are uncorrected. H and 13C
1
NMR spectra were recorded on a Bruker AV 400 (400 MHz) in
CDCl3 with TMS as the internal standard and the chemical shifts
(δ) are reported in ppm. IR spectra were taken directly on a
Nicolet AVATAR 330 FT-IR spectrometer 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 (200–300
mesh) with a mixture of petroleum ether (PE) (60–90o) and ethyl
acetate (EA) as an eluent with gradient elution.
Scheme 6. Transition state model in the protonation of the cyclic nitronate.
Our stereoelectronic controlled cyclic chelate transition state
model TS-A can be applied to rationalize the
diastereoselectivities in sulfa-Michael additions involving both
linear and cyclic nitroalkenes, even other Michael additions, in
which both donors and acceptors possess coordinating atoms in
appropriate positions in the presence of metal ions in the reaction
system. However, the Kamimura and Hori's model completely
ignored the stereoelectronic effect and chelation in the sulfa-
Michael additions. They considered repellency between S-lone
pair orbitals and p orbital in C=N bond only in their model. They
mentioned that R3 did not impact the diastereoselectivity on the
basis of their model. In fact, R3 does affect the
diastereoselectivity according to our experimental results. Our
proposed stereoelectronic controlled cyclic chelate transition
state model was verified by tuning the steric bulkiness of the
corresponding substituents.
4.2 General procedure for the synthesis of nitroalkenes 1
Nitroalkenes 1 in Table 3−4 were prepared by dehydration of
the corresponding vicinal nitro alcohols according to literature
procedure15 and 1-nitrohexane was prepared by referring the
Corey’s method5a and their analytical data are identical to those
reported previously.
4.3 General procedure for the synthesis of β-nitro sulfides 210
To a solution of thiophenol or alkanethiol (1.2 mmol) in 2.0
mL of dry THF was added n-butyllithium (2.4 M, 450ꢀL, 1.1
o
mmol) at below 0 C, and the resultant mixture was continued to
be stirred for 30 min at the same temperature under nitrogen
atmosphere. Subsequently, α,β-disubstituted nitroalkene 1 (1.0
o
mmol) was added via a syringe in one portion at 0 C, and the
3. Conclusions
mixture was stirred for 1 h at room temperature. For kinetic
protonation process of nitronate anion intermediate, the resulting
The stereoelectronic effect plays an extremely important role
in the diastereoselective sulfa-Michael addition between
nitroalkenes and thiols under chelation conditions of lithium.
o
solution was required to cool at -78 C, excess AcOH (0.3 mL)
was added and the resulting solution was stirred for 1 h at -78 oC.

7
After warming to room temperature, the solution was poured into
water (10 mL) and extracted with EA (10 mL × 3). The
combined extracts were washed with brine (15 mL) and dried
over Na2SO4 and concentrated in vacuo to afford crude β-nitro
sulfide. Finally, subjecting the mixture directly to purification on
silica gel chromatography (PE/EA) afforded the desired product
2.
m, 1H), 1.68 (ddq, J = 3.6, 14.0, 7.2 Hz, 1H), 1.89–1.71 (m,
ACCEPTED MANUSCRIPT
2H), 1.12 (t, J = 7.2 Hz, 3H), 0.96 (t, J = 7.2 Hz, 3H). 13C NMR
(101 MHz, CDCl3) δ: 133.2, 132.8, 129.2, 127.9, 92.5, 53.7,
22.9, 22.8, 11.5, 10.8.
4.3.6 4-Isopropylthio-3-nitrohexane (2f)
Colorless oil, 135mg, 66%, Rf = 0.46 (PE:EA = 40:1, v/v),
mixture of anti- and syn-2f. Anti-2f: 1H NMR (400 MHz, CDCl3)
δ: 4.37 (ddd, J = 2.8, 9.2, 10.8 Hz, 1H), 2.94 (ddd, J = 3.4, 9.2,
8.8 Hz, 1H), 2.93 (hept, J = 6.8 Hz, 1H), 2.25 (ddq, J = 14.8, 2.8,
7.3 Hz, 1H), 2.06 (ddq, J = 14.8, 10.8, 7.3 Hz 1H), 1.66 (ddq, J =
14.4, 3.4, 7.2 Hz, 1H), 1.47 (ddq, J = 14.4, 8.8, 7.2 Hz,1H), 1.30
(d, J = 6.8 Hz, 3H), 1.26 (d, J = 6.8 Hz, 3H), 1.06 (t, J = 7.3Hz,
3H), 0.97 (t, J = 7.2 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ:
4.3.1 2-Nitro-3-phenylthiobutane (2a) 9,10
Colorless oil, 163 mg, 77%, Rf = 0.47 (PE:EA = 20:1, v/v) ,
mixture of anti- and syn-2a. Anti-2a: 1H NMR (400 MHz,
CDCl3) δ: 7.48–7.45 (m, 2H), 7.37–7.31 (m, 3H), 4.50 (dq, J =
7.6, 6.7 Hz, 1H), 3.52 (dq, J = 7.6, 6.9 Hz, 1H), 1.68 (d, J = 6.7
1
Hz, 3H), 1.34 (d, J = 6.9 Hz, 3H). Syn-2a: H NMR (400 MHz,
1
94.2, 49.3, 36.3, 25.9, 24.8, 24.0, 23.5, 10.7, 10.6. Syn-2f: H
CDCl3) δ: 7.48–7.45 (m, 2H), 7.37–7.31 (m, 3H), 4.55 (dq, J =
5.7, 6.7 Hz), 3.82 (dq, J = 5.7, 7.0 Hz, 1H), 1.57 (d, J = 6.7 Hz,
3H), 1.29 (d, J = 7.0 Hz, 3H).
NMR (400 MHz, CDCl3) δ: 4.47 (ddd, J = 10.2, 6.6, 3.3 Hz, 1H),
2.98 (ddd, J = 9.7, 6.6, 3.6 Hz, 1H), 2.96–2.87 (m, 1H), 2.03–
1.98 (m, 1H), 1.91 (ddq, J = 14.8, 3.2, 7.2 Hz, 1H), 1.77 (ddq, J =
14.4, 3.6, 7.2 Hz, 1H), 1.52–1.40 (m, 1H), 1.30 (d, J = 6.8 Hz,
3H), 1.25 (d, J = 6.8 Hz, 3H), 1.04 (t, J = 7.2 Hz, 3H), 1.01 (t, J =
7.2 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ: 94.1, 49.0, 36.3,
24.1, 23.8, 23.4, 23.0, 11.0, 10.8. IR (CH2Cl2) v (cm-1): 2970,
1550, 1398, 1368. HRMS (ESI) calcd. for fragment C9H19S+
[M+H-47u]+ or [M+H-HONO]+ m/z: 159.1202, found 159.1200.
4.3.2 2-Nitro-3-phenyl-3-phenylthiopropane (2b) 9,10
Yellowish oil, 211 mg, 77%, Rf = 0.48, 0.50 (PE:EA = 20:1, v/v),
mixture of anti- and syn-2b. Anti-2b: 1H NMR (400 MHz,
CDCl3) δ: 7.29–7.10 (m, 8H), 7.19–7.08 (m, 2H), 4.95 (dq, J =
9.39, 6.6 Hz, 1H), 4.56 (d, J = 9.39 Hz, 1H), 1.82 (d, J = 6.6 Hz,
3H). 13C NMR (101 MHz, CDCl3) δ: 136.5, 133.7, 132.4, 129.0,
1
126.6, 128.4, 128.2, 128.1, 86.9, 57.3, 18.1. Syn-2b: H NMR
4.3.7 4-tert-Butylthio-3-nitrohexane (2g)
(400 MHz, CDCl3) δ: 7.29–7.10 (m, 8H), 7.19–7.08 (m, 2H),
4.95 (dq, J = 9.38, 6.7 Hz, 1H), 4.57 (d, J = 9.38 Hz, 1H), 1.41
(d, J = 6.7 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ: 136.5, 134.0,
132.1, 129.0, 128.7, 128.5, 128.3, 127.9, 86.3, 56.7, 17.5.
Colorless oil, 118mg, 54%, Rf = 0.35 (PE:EA = 40:1, v/v),
mixture of anti- and syn-2g. 1H NMR (400 MHz, CDCl3) δ: 4.36
(ddd, J = 11.3, 8.8, 2.9 Hz, 1H), 2.99 (ddd, J = 8.8, 7.2, 4.4 Hz,
1H), 2.26 (ddq, J = 14.8, 2.9, 7.3 Hz, 1H), 1.98 (ddq, J = 14.8,
11.3, 7.3 Hz, 1H), 1.72 (ddq, J = 14.7, 4.4, 7.2 Hz, 1H), 1.58
(ddq, J = 14.7, 7.2, 7.2 Hz, 1H), 1.33 (s, 9H), 1.04 (t, J = 7.3 Hz,
3H), 0.96 (t, J = 7.2 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ:
93.6, 46.7, 44.1, 31.5, 27.4, 25.0, 10.8, 10.2. 1H NMR (400 MHz,
CDCl3) δ: 4.52 (ddd, J = 10.6, 5.2, 3.0 Hz, 1H), 3.03–2.97 (m,
1H), 2.50 (ddq, J = 14.8, 10.6, 7.2 Hz, 1H), 1.89 (ddq, J = 14.8,
3.0, 7.2 Hz, 1H), 1.79 (ddq, J = 14.4, 3.6, 7.2 Hz, 1H), 1.65–1.54
(m, 1H), 1.36 (s, 9H), 1.04 (t, J = 7.2 Hz, 3H), 0.98 (t, J = 7.2 Hz,
3H). 13C NMR (101 MHz, CDCl3) δ: 94.8, 47.5, 44.1, 31.2, 23.9,
21.4, 11.3, 11.2. IR (CH2Cl2) v (cm-1): 2970, 1551, 1400, 1366.
HRMS (ESI) calcd. for fragment C10H21S+ [M+H-47u]+ or
[M+H-HONO]+ m/z: 173.1358, found 173.1352.
4.3.3 3-Isopropylthio-2-nitrobutane (2c) 9
Colorless oil, 48 mg, 27%, Rf = 0.28 (PE:diethyl ether = 40:1,
1
v/v), mixture of anti- and syn-2c. Anti-2c: H NMR (400 MHz,
CDCl3) δ: 4.50 (dq, J = 7.0, 6.7 Hz, 1H), 3.29 (dq, J = 7.0, 6.9
Hz, 1H), 2.987 (hept, J = 6.7 Hz, 1H), 1.64 (d, J = 6.7 Hz, 3H),
1.35 (d, J = 6.7 Hz, 3H), 1.30 (d, J = 7.0 Hz, 3H), 1.25 (d, J = 6.9
Hz, 3H). 13C NMR (101 MHz, CDCl3) δ: 87.6, 42.5, 35.5, 23.8,
23.5, 20.1, 16.3. Syn-2c: 1H NMR (400 MHz, CDCl3) δ: 4.63 (dq,
J = 5.8, 6.7 Hz, 1H), 3.42 (dq, J = 5.8, 7.0 Hz, 1H), 2.994 (hept, J
= 6.7 Hz 1H), 1.57 (d, J = 6.7 Hz, 3H), 1.32 (d, J = 6.7 Hz, 3H),
1.27 (d, J = 7.0 Hz, 3H), 1.26 (d, J = 6.7 Hz, 3H). 13C NMR (101
MHz, CDCl3) δ: 86.7, 41.4, 35.4, 23.6, 23.3, 16.7, 13.9.
4.3.8 3-Nitro-4-phenylthiononane (2h) 9
4.3.4 3-tert-Butylthio-2-nitrobutane (2d)9
Yellowish oil, 117 mg, 41%, Rf = 0.56, 0.58 (PE:EA = 40:1, v/v),
mixture of anti- and syn-2h. Anti-2h: 1H NMR (400 MHz,
CDCl3) δ: 7.44–7.42 (m, 2H), 7.32–7.31 (m, 3H), 4.37 (ddd, J =
3.2, 9.2, 10.8 Hz, 1H), 3.31 (ddd, J = 3.6, 7.2, 9.2 Hz, 1H), 2.24
(ddq, J = 3.2, 14.8, 7.2 Hz, 1H), 1.98 (ddq, J = 10.8, 14.4, 7.2 Hz,
1H), 1.77–1.68 (m, 1H), 1.60–1.57 ( m, 1H), 1.53–1.44 (m, 2H),
1.34–1.25 (m, 4H), 0.93 (t, J = 7.2 Hz, 3H), 0.89 (t, J = 7.2 Hz,
3H). 13C NMR (101 MHz, CDCl3) δ: 133.3, 133.1, 129.2, 128.4,
Colorless oil, 24 mg, 12%, Rf = 0.36 (PE:diethyl ether = 40:1,
v/v), mixture of anti- and syn-2d. Anti-2d: H NMR (400 MHz,
1
CDCl3) δ: 4.45 (dq, J = 7.2, 7.2 Hz, 1H), 3.21 (dq, J = 7.2, 6.8
Hz, 1H), 1.63 (d, J = 6.8 Hz, 3H), 1.33 (s, 9H), 1.40 (d, J = 7.2
Hz, 3H). 13C NMR (101 MHz, CDCl3) δ: 87.9, 44.0, 40.9, 31.2,
1
22.5, 16.4. Syn-2d: H NMR (400 MHz, CDCl3) δ: 4.66 (dq, J =
5.2, 6.7 Hz, 1H), 3.40 (dq, J = 5.2, 7.1 Hz, 1H), 1.54 (d, J = 6.7
Hz, 3H), 1.36 (s, 9H), 1.28 (d, J = 7.1 Hz, 3H) 13C NMR (101
MHz, CDCl3) δ: 87.5, 44.3, 39.9, 31.0, 18.2, 13.4.
1
93.6, 52.2, 31.3, 31.2, 26.3, 25.2, 22.4, 13.9, 10.5. Syn-2h: H
NMR (400 MHz, CDCl3) δ: 7.46–7.42 (m, 2H), 7.35–7.27 (m,
3H), 4.43 (ddd, J = 4.0, 6.8, 10.0 Hz, 1H), 3.46 (ddd, J = 3.2, 6.8,
10.4 Hz, 1H), 2.12–1.80 (m, 2H), 1.77–1.68 (m, 1H), 1.60−1.57
(m, 1H), 1.53–1.44 (m, 2H), 1.34–1.25 (m, 4H), 0.95 (t, J = 7.2
Hz, 3H), 0.90 (t, J = 7.2 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ:
133.1, 132.8, 128.9, 127.9, 92.6, 51.9, 31.3, 29.5, 26.4, 25.2,
22.6, 13.8, 10.8.
4.3.5 3-Nitro-4-phenylthiohexane (2e) 9
Colorless oil, 121mg, 50%, Rf = 0.40 (PE:EA = 40:1, v/v),
mixture of anti- and syn-2e. Anti-2e: 1H NMR (400 MHz, CDCl3)
δ: 7.45–7.42 (m, 2H), 7.35–7.29 (m, 3H), 4.39 (ddd, J = 3.2, 9.2,
10.8 Hz, 1H), 3.28 (ddd, J = 3.6, 9.2, 9.2 Hz, 1H), 2.27 (ddq, J =
3.2, 14.4, 7.2 Hz, 1H), 1.99 (ddq, J = 10.8, 14.4, 7.2 Hz, 1H),
1.68 (ddq, J = 3.6, 14.6, 7.2 Hz, 1H), 1.49 (ddq, J = 9.2, 14.6, 7.2
Hz, 1H), 1.15 (t, J = 7.2 Hz, 3H), 0.93 (t, J = 7.2 Hz, 3H). 13C
NMR (101 MHz, CDCl3) δ: 133.2, 133.0, 129.2, 128.0, 93.7,
53.8, 25.2, 24.5, 11.2, 10.4. Syn-2e: 1H NMR (400 MHz, CDCl3)
δ: 7.45–7.42 (m, 2H), 7.35–7.29 (m, 3H), 4.45 (ddd, J = 4.0, 7.2,
10.8 Hz, 1H), 3.39 (ddd, J = 3.6, 7.2, 10.0 Hz, 1H), 2.13–2.02 (
4.3.9 4-Methyl-2-nitro-3-phenylthiopentane (2i) 9,10
Colorless oil, 90 mg, 37%, Rf = 0.23, 0.28, mixture of anti- and
1
syn-2i. Anti-2i: H NMR (400 MHz, CDCl3) δ: 7.45–7.42 (m,
2H), 7.36–7.27 (m, 2H), 7.27–7.20 (m, 1H), 4.80 (dq, J = 9.6, 6.8
Hz, 1H), 3.46 (dd, J = 4.4, 9.6 Hz, 1H), 1.91 (dhept, J = 4.4, 6.8

8
Tetrahedron
Hz, 1H), 1.63 (d, J = 6.8 Hz, 3H), 1.16 (d, J = 6.8 Hz, 3H), 1.04
35.7, 23.13, 23.06, 17.8. IR (CH2Cl2) v (cm-1): 2960, 2925, 1552,
ACCEPTED MANUSCRIPT
(d, J = 6.8 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ: 135.8, 131.3,
129.2, 127.3, 86.14, 61.2, 30.3, 21.3, 17.7, 17.5. Syn-2i: 1H NMR
(400 MHz, CDCl3) δ: 7.45–7.42 (m, 2H), 7.36–7.27 (m, 2H),
7.27–7.20 (m, 1H), 4.70 (dq, J = 8.4, 6.8 Hz, 1H), 3.48 (dd, J =
4.4, 8.4, 1H), 2.13 (dhept, J = 4.4, 6.8 Hz, 1H), 1.16 (d, J = 6.8
Hz, 3H), 1.11 (d, J = 6.8 Hz, 3H), 0.99 (d, J = 6.8 Hz, 3H). 13C
NMR (101 MHz, CDCl3) δ: 135.5, 131.1, 129.0, 127.4, 86.7,
59.9, 29.1, 21.7, 17.5, 17.1.
1451, 1385, 1357. HRMS (ESI) calcd. for C12H18NO2S+ [M+H]+
m/z: 240.1053, found 240.1054.
4.3.14 anti-2-(4-Methoxyphenylthio)-3-nitrobutane (anti-2n)
The reaction was performed on a 0.5-mmol scale. Colorless oil,
81 mg, 67%, Rf = 0.45 (PE:EA = 20:1, v/v). H NMR (400 MHz,
CDCl3) δ: 7.41 (d, J = 8.8 Hz, 2H), 6.87 (d, J = 8.8 Hz, 2H), 4.45
(dq, J = 6.7, 6.7 Hz, 1H), 3.81 (s, 3H), 3.33 (dq, J = 6.9, 6.9 Hz,
1H), 1.70 (d, J = 6.7 Hz, 3H), 1.29 (d, J = 6.9 Hz, 3H). 13C NMR
(100 MHz, CDCl3) δ: 160.3, 136.8, 132.6, 114.7, 87.2, 55.3,
47.5, 18.3, 17.4. IR (film, KBr) v cm-1 1549, 1493, 1388, 1286,
1248, 1173, 1030. HRMS (ESI) calcd. for fragment C11H15OS
[M+H-47u] or [M+H-HONO]+ m/z: 195.0838, found 195.0836.
1
4.3.10 3-Isopropylthio-2-methyl-4-nitropentane (2j) 9
Colorless oil, 16 mg, 7%, Rf = 0.31, 0.37 (PE: diethyl ether =
40:1, v/v), mixture of anti- and syn-2j. Anti-2j: H NMR (400
MHz, CDCl3) δ: 4.65 (dq, J = 9.5, 6.7 Hz, 1H), 2.98 (dd, J = 3.4,
9.5 Hz, 1H), 2.81 (hept, J = 6.7 Hz, 1H), 2.06 (dhept, J = 3.4, 6.7
Hz, 1H), 1.60 (d, J = 6.7 Hz, 3H), 1.25 (d, J = 6.6 Hz, 3H), 1.20
(d, J = 6.7 Hz, 3H), 1.11 (d, J = 6.6 Hz, 3H), 0.85 (d, J = 6.7 Hz,
3H). 13C NMR (101 MHz, CDCl3) δ: 86.3, 55.8, 37.5, 30.1, 23.9,
1
4.3.15 anti-2-Nitro-3-(4-nitrophenylthio)butane (2o)
The reaction was performed on a 0.5-mmol scale. Brown oil, 40
mg, 31%, Rf = 0.42 (PE:EA = 20:1, v/v). H NMR (400 MHz,
CDCl3) δ: 8.17 (d, J = 8.9 Hz, 2H), 7.51 (d, J = 8.9 Hz, 2H), 4.62
(dq, J = 6.8, 6.8 Hz, 1H), 3.91 (dq, J = 6.9, 6.9 Hz, 1H), 1.67 (d,
J = 6.8 Hz, 3H), 1.47 (d, J = 7.0 Hz, 3H). 13C NMR (100 MHz,
CDCl3) δ: 146.6, 143.3, 130.3, 124.2, 86.5, 45.9, 18.7, 16.3. IR
(film, KBr) v cm-1 1551, 1508, 1339, 1315, 1106, 1077. HRMS
(ESI) calcd. for fragment C10H12NO2S [M+H-47u] or [M+H-
HONO]+ m/z: 210.0583, found 210.0574.
1
1
23.6, 21.1, 17.6, 17.2. Syn-2j: H NMR (400 MHz, CDCl3) δ:
4.68 (dq, J = 8.9, 6.6 Hz, 1H), 2.94 (dd, J = 4.5, 8.9 Hz, 1H),
2.87 (hept, J = 6.6 Hz, 1H), 1.75 (dhept, J = 4.5, 6.6 Hz, 1H),
1.70 (d, J = 6.6 Hz, 3H), 1.30 (d, J = 6.6 Hz, 3H), 1.26 (d, J = 6.8
Hz, 3H), 1.06 (d, J = 6.6 Hz, 3H), 0.96 (d, J = 6.8 Hz, 3H). 13C
NMR (101 MHz, CDCl3) δ: 88.2, 54.5, 37.4, 28.4, 23.9, 23.4,
21.5, 17.8, 16.84.
4.3.11 4,4-Dimethyl-2-nitro-3-phenylthiopentane (2k) 9
4.3.16 3-tert-Butylthio-2-methyl-4-nitropentane (2p)9
Colorless oil, 26 mg, 10%, Rf = 0.23 (PE:EA = 40:1, v/v),
mixture of anti- and syn-2k. Anti-2k: 1H NMR (400 MHz,
CDCl3) δ: 7.41–7.38 (m, 2H), 7.33–7.21 (m, 3H), 4.87 (dq, J =
3.8, 6.7 Hz, 1H), 3.83 (d, J = 3.8 Hz, 1H), 1.70 (d, J = 6.7 Hz,
3H), 1.14 (s, 9H). 13C NMR (101 MHz, CDCl3) δ: 136.2, 131.3,
Colorless oil, 22 mg, 10%, Rf = 0.31 (PE: diethyl ether = 40:1,
v/v), mixture of anti- and syn-2p. Anti-2p: H NMR (400 MHz,
1
CDCl3) δ: 4.65 (dq, J = 8.8, 6.8, Hz, 1H), 3.03 (dd, J = 4.4, 8.8
Hz, 1H), 1.81 (dhept, J = 4.4, 7.2 Hz, 1H), 1.69 (d, J = 6.8 Hz,
3H), 1.32 (s, 9H), 1.05 (d, J = 7.2 Hz, 3H), 0.96 (d, J = 7.2 Hz,
3H). 13C NMR (101 MHz, CDCl3) δ: 86.0, 52.6, 43.6, 32.0, 30.9,
1
129.1, 127.2, 83.8, 64.7, 36.7, 28.4, 17.6. Syn-2k: H NMR (400
1
MHz, CDCl3) δ: 7.48–7.45 (m, 2H), 7.33–7.21 (m, 3H), 4.91 (dq,
J = 3.3, 6.8 Hz, 1H), 3.4 (d, J = 3.3 Hz, 1H), 1.74 (d, J = 6.8 Hz,
3H), 1.21 (s, 9H). 13C NMR (101 MHz, CDCl3) δ: 136.9, 130.9,
129.3, 127.0, 83.7, 63.6, 36.8, 28.3, 16.5.
21.1, 18.0, 17.9. Syn-2n: H NMR (400 MHz, CDCl3) δ: 4.67
(dq, J = 6.4, 6.8 Hz, 1H), 3.16 (dd, J = 4.4, 6.4 Hz, 1H), 1.97
(dhept, J = 4.4, 6.8 Hz, 1H), 1.62 (d, J = 6.8 Hz, 3H), 1.33 (s,
9H), 1.01 (d, J = 6.8 Hz, 3H), 0.95 (d, J = 6.8 Hz, 3H). 13C NMR
(101 MHz, CDCl3) δ: 88.3, 51.7, 43.7, 31.4, 28.1, 21.7, 19.0,
15.1.
4.3.12 1-Nitro-1,2-diphenyl-2-phenylthioethane (2l) 9
Colorless crystals, 262 mg, 78%, m.p. (for anti-2l) 160–162 C,
o
Rf = 0.24, 0.26 (PE:EA = 40:1, v/v), mixture of anti- and syn-2l.
Anti-2l: 1H NMR (400 MHz, CDCl3) δ: 7.62–7.60 (d, J = 6.8 Hz,
2H), 7.44–7.36 (m, 3H), 7.28–7.25 (m, 5H), 7.17 (t, J = 7.2Hz,
1H), 7.10–7.07 (t, J = 7.2 Hz, 2H), 6.99–6.97 (d, J = 7.2 Hz, 2H),
5.89 (d, J = 11.7 Hz, 1H), 5.03 (d, J = 11.7 Hz, 1H). 13C NMR
(101 MHz, CDCl3) δ: 137.4, 134.4, 132.3, 132.1, 130.4, 128.9,
4.3.17 anti-3-Isopropylthio-4,4-dimethyl-2-nitropentane (anti-2q)
Colorless oil, 19 mg, 8.5%, Rf = 0.35 (PE: diethyl ether = 40:1,
1
v/v). H NMR (400 MHz, CDCl3) δ: 4.89 (dq, J = 3.6, 6.8 Hz,
1H), 2.90 (hept, J = 7.0 Hz 1H), 2.78 (d, J = 3.6 Hz, 1H), 1.71 (d,
J = 6.8 Hz, 3H), 1.31 (d, J = 7.0 Hz, 3H), 1.29 (d, J = 7.0 Hz,
3H), 1.07 (s, 9H). 13C NMR (101 MHz, CDCl3) δ: 84.9, 58.7,
38.0, 36.4, 28.2, 23.7, 23.3, 18.3. IR (CH2Cl2) v (cm-1): 2964,
2951, 1552, 1453, 1386, 1364. HRMS (ESI) calcd. for fragment
C10H21S+ [M+H-47u]+ or [M+H-HONO]+ m/z: 173.1358, found
173.1357.
1
128.7, 128.6, 128.3, 128.2, 127.8, 94.7, 56.4. Syn-2l: H NMR
(400 MHz, CDCl3) δ: 7.49 (d, J = 6.8 Hz, 2H), 7.44–7.35 (m,
3H), 7.30–7.23 (m, 5H), 7.17–6.97 (m, 5H), 5.86 (d, J = 12.2 Hz,
1H), 5.03 (d, J = 12.2 Hz, 1H). 13C NMR (101 MHz, CDCl3) δ:
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.
4.3.18 syn-3-Isopropylthio-4,4-dimethyl-2-nitropentane (syn-2q)
Colorless oil, 6 mg, 2.5%, Rf = 0.41 (PE: diethyl ether = 40:1,
1
4.3.13 2-nitro-3-isopropylthio-3-phenylpropane (2m)
v/v). H NMR (400 MHz, CDCl3) δ: 4.88 (dq, J = 3.5, 6.6 Hz,
Colorless oil, 168 mg, 70%, Rf = 0.51 (PE:EA = 10:1, v/v),
mixture of anti- and syn-2m. Anti-2m: 1H NMR (400 MHz,
CDCl3) δ: 7.36–7.34 (m, 2H), 7.33–7.29 (m, 2H), 7.28–7.23 (m,
1H), 4.82 (dq, J = 9.2, 6.6 Hz, 1H), 4.36 (d, J = 9.2 Hz, 1H), 2.63
(hept, J = 6.8, 1H), 1.73 (d, J = 6.6 Hz, 3H), 1.24 (d, J = 6.8 Hz,
3H), 1.14 (d, J = 6.8 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ:
138.4, 128.7, 128.4, 128.1, 87.8, 52.3, 35.3, 23.4, 22.9, 17.6. Syn-
1H), 3.31 (d, J = 3.5 Hz, 1H), 2.75 (hept, J = 6.7 Hz 1H), 1.63 (d,
J = 6.6 Hz, 3H), 1.25 (d, J = 6.6 Hz, 3H), 1.18 (d, J = 6.7 Hz,
3H), 1.09 (s, 9H). 13C NMR (101 MHz, CDCl3) δ: 84.0, 59.6,
37.5, 36.0, 30.9, 28.3, 23.6, 16.0. IR (CH2Cl2) v (cm-1): 2965,
2950, 1551, 1452, 1385, 1366. HRMS (ESI) calcd. for fragment
C10H21S+ [M+H-47u]+ or [M+H-HONO]+ m/z: 173.1358, found
173.1359.
1
2m: H NMR (400 MHz, CDCl3) δ: 7.37-7.34(m, 2H), 7.32–7.29
(m, 2H), 7.28–7.23 (m, 1H), 4.82 (dq, J = 9.5, 6.7 Hz, 1H), 4.30
(d, J = 9.5 Hz, 1H), 2.71 (hept, J = 6.8, 1H), 1.35 (d, J = 6.7 Hz,
3H), 1.22 (d, J = 6.8 Hz, 3H), 1.14 (d, J = 6.8 Hz, 3H). 13C NMR
(101 MHz, CDCl3) δ: 137.8, 128.9, 128.2, 128.1, 87.3, 51.8,
4.3.19 3-tert-Butylthio-2-nitro-3-phenylpropane (2r)
Colorless oil, 175 mg, 69%, Rf = 0.43 (PE:EA = 10:1, v/v),
mixture of anti- and syn-2r. Anti-2r: 1H NMR (400 MHz, CDCl3)
δ: 7.40 (d, J = 7.6 Hz, 2H), 7.31 (t, J = 7.4 Hz, 2H), 7.27–7.20

9
Miller, M. J. J. Org. Chem 2003, 68, 6591–6596; (d)
Kozikowski, A. P. Acc. Chem. Res. 1984, 17, 410–416; (e) Eyer,
(m, 1H), 4.71 (dq, J = 8.1, 6.6 Hz, 1H), 4.40 (d, J = 8.1 Hz, 1H),
1.67 (d, J = 6.6 Hz, 3H), 1.22 (s, 9H). 13C NMR (101 MHz,
CDCl3) δ: 140.4, 128.6, 128.3, 127.8, 88.1, 51.1, 44.6, 31.1, 16.6.
13C NMR (101 MHz, CDCl3) δ: 140.4, 128.6, 128.3, 127.8, 88.1,
ACCEPTED MANUSCRIPT
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1
51.1, 44.6, 31.1, 16.6. Syn-2r: H NMR (400 MHz, CDCl3) δ:
7.40 (d, J = 7.4 Hz, 2H), 7.35–7.29 (m, 2H), 7.27–7.22 (m, 1H),
4.74 (dq, J = 9.3, 6.6 Hz, 1H), 4.33 (d, J = 9.3 Hz, 1H), 1.32 (d, J
= 6.6 Hz, 3H), 1.21 (s, 9H). 13C NMR (101 MHz, CDCl3) δ:
139.4, 128.7, 128.6, 127.9, 87.6, 50.3, 44.8, 31.0, 17.5. IR
(CH2Cl2) v (cm-1): 2960, 1552, 1494, 1452, 1386, 1357, 750, 701.
HRMS (ESI) calcd. for C13H20NO2S+ [M+H]+ m/z: 254.1209,
found 254.1202.
4.3.20 anti-3-tert-Butylthio-2-nitro-3-phenylpropane (2r)
Colorless oil, 138 mg, 55%, Rf = 0.43 (PE:EA = 10:1, v/v) H
1
NMR (400 MHz, CDCl3) δ: 7.40 (d, J = 7.6 Hz, 2H), 7.31 (t, J =
7.4 Hz, 2H), 7.27–7.20 (m, 1H), 4.71 (dq, J = 8.1, 6.6 Hz, 1H),
4.40 (d, J = 8.1 Hz, 1H), 1.67 (d, J = 6.6 Hz, 3H), 1.22 (s, 9H).
13C NMR (101 MHz, CDCl3) δ: 140.4, 128.6, 128.3, 127.8, 88.1,
51.1, 44.6, 31.1, 16.6. 13C NMR (101 MHz, CDCl3) δ: 140.4,
128.6, 128.3, 127.8, 88.1, 51.1, 44.6, 31.1, 16.6. IR (CH2Cl2) v
(cm-1): 2961, 1553, 1495, 1451, 1387, 1359, 751, 702. HRMS
(ESI) calcd. for C13H20NO2S+ [M+H]+ m/z: 254.1209, found
254.1205.
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Acknowledgement
This work was supported in part by the National Basic
Research Program of China (No. 2013CB328905), the National
Natrual Science Foundation of China (Nos. 21372025 and
21172017) and specialized Research Fund for the Doctoral
Program of Higher Education, Ministry of Education of China
(No. 20110010110011).
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Supplementary data
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1
The copies of H NMR and 13C NMR spectra of the unknown
1
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