Enantioselective Sulfa-Michael Addition of Aromatic Thiols to β-Substituted Nitroalkenes Promoted by a Chiral Multifunctional Catalyst

Article abstract of DOI:10.1002/adsc.201700109

An efficient enantioselective Michael addition of a series of aromatic thiols acting as nucleophiles for β-monosubstituted, α,β- and β,β-disubstituted nitroalkenes promoted by a multi-functional chiral catalyst has been developed. The methodology accommodates a wide variety of aryl thiols and nitroalkene substrates, and affords the 2-nitro-1-arylethyl sulfides in excellent yields (up to 99%) and enantioselectivities (up to 99% ee). This reaction could be scaled up to gram even with a dramatically reduced catalyst loading of 0.05 mol%. (Figure presented.).

Full text of DOI:10.1002/adsc.201700109

Title: Enantioselective Sulfa-Michael Addition of Aromatic Thiols to β-
Substituted Nitroalkenes Promoted by a Chiral Multi-functional
Catalyst
Authors: Qi Wei, Wenduan Hou, Na Liao, and Yungui Peng
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10.1002/adsc.201700109
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Enantioselective Sulfa-Michael Addition of Aromatic Thiols to
β-Substituted Nitroalkenes Promoted by a Chiral
Multifunctional Catalyst
Qi Wei,a Wenduan Hou,a Na Liaoa and Yungui Penga,*
a
Key Laboratory of Applied Chemistry of Chongqing Municipality, School of Chemistry and Chemical Engineering,
Southwest University, Chongqing 400715, P.R. China.
Fax: (+86)-023-68253157; e-mail: pengyungui@hotmail.com or pyg@swu.edu.cn
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
thiols with β-substituted nitroalkenes gave very low
a series of aromatic thiols acting as nucleophiles for β- enantioselectivities;[12] this can probably be ascribed
Abstract: An efficient enantioselective Michael addition of
monosubstituted, α,β- and β,β-disubstituted nitroalkenes
promoted by a multi-functional chiral catalyst has been
developed. The methodology accommodates a wide variety
of aryl thiols and nitroalkene substrates, and affords the 2-
nitro-1-arylethyl sulfides in excellent yields (up to 99%)
and enantioselectivities (up to 99% ee). This reaction could
be scaled up to gram even with a dramatically reduced
catalyst loading of 0.05 mol %.
to the reversibility of the reaction under the basic
catalytic conditions.[2a,13] In view of the commercial
availability of a wide variety of aromatic thiols and
the synthetic value of the resulting chiral sulfides, the
development of efficient methods for the
enantioselective SMA of aromatic thiols with β-
substituted nitroalkenes is an important challenge for
organic chemists.
Our ongoing interest is in the development of an
efficient approach to the construction of chiral sulfur-
containing molecules that is triggered by sulfur
nucleophiles.[14] Here, we show that the
enantioselective SMA of various aromatic thiols with
β-substituted nitroalkenes can be achieved in
excellent yields and enantioselectivities using a
multi-functional organocatalyst.
Keywords: enantioselective; Michael addition; aromatic
thiol; nitroalkene; multi-functional catalyst
Chiral sulfur-containing motifs are widespread in
biologically
active
natural
products
and
pharmaceutical agents.[1] As one of the most efficient
methodologies for accessing optically active chiral
sulfur compounds, the catalytic enantioselective
Michael addition of sulfur-centered nucleophiles to
α,β-unsaturated compounds has attracted the attention
of many groups, and great achievements have been
made in recent decades.[2] Various types of electron-
The reaction of thiophenol 1a with β-phenyl
substituted nitroalkene 2a was chosen as a model
reaction. The enantioselective variant of this reaction
has
been
documented
only
with
low
enantioselectivities.[12] In initial screenings, quinine-
derived Lu’s catalyst 3a showed good catalytic
performance; an almost quantitative yield of product
4aa was obtained with good enantioselectivity (80%
ee) after reaction in the presence of 10 mol % 3a at
−40 °C for 1 h (Table 1, entry 1). Sulfa-Michael
adducts racemize at room temperature, but this
process is suppressed at low temperature to improve
the enantioselectivity of the reaction.[2a,13,15] We
therefore used cryogenic column chromatography to
purify the product, which dramatically improved the
enantioselectivity to 91% ee (Table 1, entry 2). Based
on these results and the chiral framework of catalyst
3a, we further synthesized catalysts 3b–3e, and used
them to investigate the effects of steric hindrance and
the π-electron interactions of the substituents on the
reaction (Table 1, entries 3–6). When the R
substituent in the catalyst was changed from Me (3a)
deficient
olefins,
including
α,β-unsaturated
aldehydes,[3] ketones,[4] esters,[5] nitroalkenes[6] and
others,[7] have been shown to be applicable as the
sulfur-centered
Michael
acceptor
in
this
transformation. In particular, the use of β-substituted
nitroalkenes in the enantioselective sulfa-Michael
addition (SMA) represents an appealing approach to
the synthesis of chiral 2-nitroethyl sulfide analogues,
which are potential intermediates in the synthesis of
bioactive compounds.[8] The use of thioacetic acid[9]
and benzyl mercaptan[10] as sulfur donors was highly
successful and gave the corresponding adducts in
good yields and enantioselectivties. However, there is
only one report of satisfactory results when aromatic
thiols were employed as nucleophiles for β-
substituted nitroalkenes, and this success was limited
to compounds with Michael-donor-bearing electron-
donating substituents on the aromatic ring, such as
3,4-dimethoxythiophenol.[11] Other reports have
mentioned that the enantioselective SMA of aromatic
i
t
to Pr (3b) and Bu (3c), the enantioselectivity of the
product increased slightly from 91% to 95% and 95%
1
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10.1002/adsc.201700109
Advanced Synthesis & Catalysis
Table 1. Effect of catalyst substituents and reaction
were screened. All of these solvents were suitable for
the reaction, but the best results in terms of both yield
and enantioselectivity were achieved in MTBE
(Table 1, entries 4, 7–15). Changing the reaction
temperature from −40 °C to −30 °C and −50 °C
caused the enantioselectivity to decrease slightly
from 97% ee to 95% ee and 96% ee (Table 1, entries
9, 16 and 17). The effect of catalyst loading on the
reaction was also optimized, and these experiments
revealed that satisfactory results could be obtained
with 1 mol % catalyst (Table 1, entries 9 and 18–21).
conditions on enantioselective sulfa-Michael additions.[a]
Table 2. Enantioselective sulfa-Michael reaction of
various thiophenols 1 in the presence of catalyst 3c.[a]
Time Yield ee
(h)
Entry
Cat.
Solvent
[%][b] [%][c]
1[d]
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16[e]
17[f]
18[g]
19[h]
20[i]
21[j]
DCM
DCM
DCM
DCM
DCM
DCM
THF
2-Me-THF
MTBE
Et2O
PhF
PhCl
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
2
2
4
4
99
99
99
99
99
99
99
99
99
99
99
99
99
99
99
99
99
99
99
99
99
80
91
95
95
95
91
97
86
97
97
97
96
93
92
95
95
96
95
95
95
93
3a
3a
3b
3c
3d
3e
3c
3c
3c
3c
3c
3c
3c
3c
3c
3c
3c
3c
3c
3c
3c
Entry
R1
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
p-tBuC6H4
o-MeC6H4
m-MeC6H4
p-MeC6H4
p-MeOC6H4
o-FC6H4
m-FC6H4
p-FC6H4
o-ClC6H4
4ba, 97
4ca, 95
4da, 95
4ea, 99
4fa, 98
4ga, 83
4ha, 91
4ia, 92
4ja, 96
4ka, 96
4la, 99
4ma, 88
4na, 72
97
96
96
95
97
89
78
89
87
77
92
96
99
97
99
76
70
PhMe
PhEt
9
m-xylene
MTBE
MTBE
MTBE
MTBE
MTBE
MTBE
10
11
12
13
14
15
16[d]
17[e]
o-BrC6H4
1-Naphthyl
2-Naphthyl
p-ClC6H4CH2
p-tBuC6H4CH2 4oa, 91
C6H4CH2
Bu
4pa, 86
4qa, 89
4ra, 77
[a] Reactions were carried out with 1a (0.12 mmol), 2a (0.1
mmol) and the catalyst (10 mol %) in 0.5 mL of solvent
at −40 °C.
tBu
[a] Reactions were carried out with 1 (0.12 mmol), 2a (0.1
mmol) and 3c (1 mol %) in 0.5 mL MTBE at −40 °C for
4 h.
[b] Isolated yield.
[c]
Determined by HPLC analysis on a chiral stationary
[b] Isolated yield.
phase.
[c]
Determined by HPLC analysis on a chiral stationary
[d] Purified by column chromatography at rt.
[e] Performed at −30 °C.
phase.
[d] Reaction time was 10 h.
[e] Performed at 0 °C for 24 h.
[f] Performed at −50 °C.
[g] 5 mol % of 3c was used.
[h] 2.5 mol % of 3c was used.
[I] 1 mol % of 3c was used.
[j] 0.5 mol % of 3c was used.
After establishing the optimized reaction
conditions, we turned our attention to the
applicability of this reaction to various substrates.
First, various aromatic thiols were used in the
enantioselective SMA with β-phenylnitroalkene 2a;
the results are summarized in Table 2. Aromatic
thiols bearing electron-donating and electron-
withdrawing substituents on the aromatic ring were
suitable for this reaction and gave the corresponding
products in good to excellent yields and
enantioselectivities (Table 2, entries 1–10). However,
aromatic thiols containing electron-donating groups
resulted in comparatively better yields and
enantioselectivities than those with electron-
withdrawing groups (Table 2, entries 1–5 vs 6–10).
The substituent pattern had little influence on the
reaction (Table 2, entries 2–4 and 6–8), and 1-
ee. The yields were excellent in all three cases (up to
99%) (Table 1, entries 2–4). Good catalytic
performance was also observed with R = Ph (3d) and
Bn (3e) (Table 1, entries 5 and 6). Other bifunctional
and multifunctional catalysts were also screened in
this reaction, no better catalytic performance was
observed than that of 3c (see ESI). From these results,
we concluded that 3c was the best catalyst for
promoting the enantioselective SMA of thiophenol
with β-substituted nitroalkenes. With the best catalyst
in hand, we next investigated the reaction conditions.
First, a series of solvents, DCM, THF, 2-Me-THF,
MTBE, Et2O, PhF, PhCl, PhMe, PhEt and m-xylene,
2
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10.1002/adsc.201700109
Advanced Synthesis & Catalysis
naphthyl and 2-naphthyl thiols furnished products 4la
(99% yield, 92% ee) and 4ma (88% yield, 96% ee).
Pleasingly, benzyl mercaptans also displayed good
reactivity and provided chiral adducts 4na–4pa in
good yields and excellent enantioselectivities (Table
2, entries 13–15). Alkanethiols were applicable for
the reaction and led good yields and
enantioselectivities (Table 2, entries 16, 17).
enantioselectivities (95%–96% ee) (Table 3, entries
16 and 17). β,β-Disubstituted nitroalkenes were also
suitable for the reaction (Table 3, entries 18 and 19).
However, when one of the β substituents was CF3, the
product was obtained in only 61% yield and 65% ee
(Table 3, entry 19). α,β-Disubstituted nitroalkenes
were amenable to the reaction and afforded the
corresponding products with excellent yields, good
diastereoselectivities and enantioselectivities (Table 3,
entries 20 and 21).
Table 3. Enantioselective sulfa-Michael reactions of
various nitroalkenes 2 in the presence of catalyst 3c.[a]
To evaluate the potential utility of this
methodology in organic synthesis, reactions with a
dramatically reduced catalyst loading (0.05 mol %)
were investigated on a gram scale. The reaction was
successful and gave the product in 98% yield with
slightly lower enantioselectivity (90% ee) (Scheme
1a). The product of the SMA reaction of 4-
chlorobenzyl thiol (1n) with 2,4-dichloro-1-(2-
nitrovinyl)benzene (2u) is an intermediate in the
synthesis of the antifungal agent sulconazole.[10a,16]
We thus aimed to promote the enantioselective
version of this reaction using our catalytic system and
obtained the product 4nw in 93% yield with 89% ee
(Scheme 1b). To demonstrate the synthetic utility of
available products 4, we further transformed them
into chiral amino sulfone derivatives. A one-pot
strategy has been exploited for this reaction to avoid
the possible racemization of 4aa at room temperature.
Treatment of the final reaction mixture of 1a and 2a
with Zn/MeOH/HCl, followed by protection of the
resulting amine with Boc2O gave intermediate 5 in
82% yield and did not affect the enantiopurity of the
product (97% ee). Subsequent oxidation of the sulfide
with m-CPBA afforded sulfone 6 in 91% yield and
97% ee (Scheme 1c).
Yield
[%][b]
ee
Entry
R1
R2, R3
[%][c]
1
2
3
4
5
6
7
8
o-MeC6H4
m-MeC6H4
p-MeC6H4
o-FC6H4
m-FC6H4
p-FC6H4
m-ClC6H4
m-BrC6H4
m-MeOC6H4 H, H
H, H
H, H
H, H
H, H
H, H
H, H
H, H
H, H
4bb, 92
4bc, 99
4bd, 99
4be, 98
4bf, 99
4bg, 97
4bh, 98
4bi, 96
4bj, 96
4bk, 99
4bl, 99
4bm, 98
4bn, 99
4bo, 92
4bp, 98
4bq, 94
4br, 91
4bs, 88
96
97
96
96
95
96
93
94
97
95
94
96
94
90
93
96
95
98
65
83
82
9
10
11
12
13
14
15
16
17
18
19
20[d]
21[e]
p-ClC6H4
p-BrC6H4
p-MeOC6H4 H, H
H, H
H, H
2-Naphthyl
H, H
H, H
H, H
H, H
H, H
Me, H
2-Furyl
2-Thienyl
Pr
iBu
Ph
Ph
Ph
CF3, H 4bt, 61
H, Ph
1-Cyclohexenyl
4bu, 98
4bv, 96
[a]
Reactions were carried out with 1b (0.12 mmol), 2 (0.1
mmol) and 3c (1 mol %) in 0.5 mL MTBE at −40 °C for
4 h.
[b] Isolated yield.
[c]
Determined by HPLC analysis on a chiral stationary
phase.
[d] The dr value was determined by HPLC and up to 91:9.
[e] The dr value was determined by HPLC and up to >99:1.
We then employed 4-(tert-butyl)phenylthiol 1b as
a nucleophile in reactions with various nitrostyrenes
(Table 3). High yields (92%–99%) with excellent
enantioselectivities (93%–97% ee) were achieved
irrespective of whether the substituent on the phenyl
ring of the β-nitroalkene was electron donating or
withdrawing (Table 3, entries 1–12). The substituent
pattern had almost no effect on the reactivity and
stereocontrol results (Table 3, entries 1–6). Reactions
of nitrostyrenes with a β-naphthyl or heteroaromatic
ring also proceeded smoothly to furnish the
corresponding products in 92%–99% yields and
90%–94% ee (Table 3, entries 13–15). Less reactive
aliphatic nitroalkenes also reacted well and gave the
products in good yields (91%–94%) and
Scheme 1. Gram-scale sulfa-Michael addition and
subsequent derivatization
The absolute configuration of product 4oa was
determined as S by comparing its specific rotation [α]
20
= + 187° (c = 0.5, DCM, 97% ee) with literature
D
data [α]2D0 = + 177° (c = 0.428, DCM, 93% ee),[12b]
and the configuration of the other products was
deduced according to this. A transition-state model
that accounts for the stereochemical outcome is
3
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10.1002/adsc.201700109
Advanced Synthesis & Catalysis
proposed in Figure 1. The protons of the thiourea
interact with the nitro group through two hydrogen
bonds; this activates the nitroalkene. The thiophenol
is deprotonated by the tertiary amine moiety of the
catalyst and the resulting thiolate anion forms
hydrogen bonds with the amide group. This
orientation allows the sulfa-Michael addition to
proceed from the Si-face of the nitrostyrene, which
results in the observed product.
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Figure 1. Proposed transition-state model
In summary, an efficient enantioselective sulfa-
Michael reaction of aromatic thiols with β-
nitroalkenes has been established in the presence of a
multifunctional chiral organocatalyst. This reaction
accommodates an unprecedented range of sulfur-
containing nucleophiles; aromatic and alkyl thiols
reacted smoothly and afforded the corresponding
products in excellent yields and enantioselectivities.
The catalyst loading could be dramatically reduced to
0.05 mol %, and also exhibited good catalytic
performance when the reaction was performed on the
gram scale.
Experimental Section
General Experimental Procedure for the Sulfa-Michael
Reactions
Nitrostyrenes 2 (0.1 mmol, 1.0 equiv.) and 3c (1 mol %)
were dissolved in 0.5 mL of THF at –40 °C and stirred for
5 min. Thiophenols 1 (0.12 mmol, 1.2 equiv.) was added at
–40 °C and stir for 4 h, monitored by TLC until the
nitrostyrenes 2 have been completely consumed. The
reaction was then treated with CH3CO2H, which was added
in a dropwise manner to quench the catalyst. The mixture
was then purified directly by flash chromatography over
silica gel (0.5–2% EtOAc/PE) to give the product 4.
Acknowledgements
We are grateful to the National Natural Science Foundation of
China (21172180 and 21472151)
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4
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10.1002/adsc.201700109
Advanced Synthesis & Catalysis
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10.1002/adsc.201700109
Advanced Synthesis & Catalysis
COMMUNICATION
Enantioselective Sulfa-Michael Addition of
Aromatic Thiols to β-Substituted Nitroalkenes
Promoted by a Chiral Multi-functional Catalyst
Adv. Synth. Catal. Year, Volume, Page – Page
Qi Wei, Wenduan Hou, Na Liao and Yungui Peng*
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