Prolinal dithioacetals: Highly efficient organocatalysts for the direct nitro-Michael additions in both organic and aqueous media

Article abstract of DOI:10.1016/j.tet.2017.10.008

Some novel prolinal dithioacetal derivatives have been synthesized and applied as the organocatalysts for the direct Michael addition of ketones and aldehydes to nitroalkenes. High enantioselectivities and diastereoselectivities have been obtained in both

Full text of DOI:10.1016/j.tet.2017.10.008

Accepted Manuscript
Prolinal dithioacetals: Highly efficient organocatalysts for the direct nitro-Michael
additions in both organic and aqueous media
Tanmay Mandal, Wen Kuo, Matthew Su, Kartick Bhowmick, John C.-G. Zhao
PII:
S0040-4020(17)31023-2
10.1016/j.tet.2017.10.008
TET 29011
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 18 September 2017
Revised Date: 2 October 2017
Accepted Date: 5 October 2017
Please cite this article as: Mandal T, Kuo W, Su M, Bhowmick K, Zhao JC-G, Prolinal dithioacetals:
Highly efficient organocatalysts for the direct nitro-Michael additions in both organic and aqueous media,
Tetrahedron (2017), doi: 10.1016/j.tet.2017.10.008.
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ACCEPTED MANUSCRIPT
Graphical Abstract
Prolinal dithioacetals: Highly efficient
Leave this area blank for abstract info.
organocatalysts for the direct nitro-Michael
additions in both organic and aqueous Media
Tanmay Mandal, Wen Kuo, Matthew Su, Kartick Bhowmick, and John C.-G. Zhao*
Department of Chemistry, University of Texas at San Antonio, One UTSA Circle, San Antonio, Texas 78249-
0698, USA

1
ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
Prolinal dithioacetals: Highly efficient organocatalysts for the direct nitro-Michael
additions in both organic and aqueous media
Tanmay Mandal, Wen Kuo, Matthew Su, Kartick Bhowmick, and John C.-G. Zhao*
Department of Chemistry, University of Texas at San Antonio, One UTSA Circle, San Antonio, Texas78249-0698, USA
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Some novel prolinal dithioacetal derivatives have been synthesized and applied as the
organocatalysts for the direct Michael addition of ketones and aldehydes to nitroalkenes. High
enantioselectivities and diastereoselectivities have been obtained in both organic and aqueous
media (dichloromethane, water, or brine).
Available online
2017 Elsevier Ltd. All rights reserved
.
Keywords:
Proline
Organocatalysis
Nitro-Michael
Thioacetal
Water
Brine
1. Introduction
2. Results and Discussion
The Michael addition reaction is arguably one of the most
convenient and powerful methods for building new carbon-
carbon bonds.1 Since List2 and Barbas3 reported the first
examples of the amine-catalyzed intermolecular Michael addition
of ketones and aldehydes to nitroalkenes (the nitro-Michael
reaction), numerous organocatalysts have been reported in the
last sixteen years for the enantioselective nitro-Michael reactions
and excellent stereoselectivities have been achieved in many
cases.4,5 In recent years, conducting traditional organic reactions
in aqueous media has been an important topic in organic research
due to the green nature of water as a solvent and its dramatic
solvent effects on organic reactions.6 Not surprisingly, some
organocatalytic reactions have also been realized either in water
or on water.6c,e Nevertheless, despite the fact that numerous
organocatalysts have been developed for the asymmetric nitro-
Michael reaction between aldehydes and ketones to nitroalkenes,
catalytic systems that can operate in aqueous media are relatively
few.7,8 Apparently, finding novel catalysts that can operate in
aqueous media is still warranted. Our group is interested in
developing novel catalysts for the nitro-Michael reaction.9 In this
regard, a few years ago we briefly reported that prolinal
dithioacetal derivatives10 are highly stereoselective catalysts for
the nitro-Michael reaction of aldehydes and ketones in organic
solvents.9a Recently we found that these catalysts could also
catalyze the nitro-Michael reaction in water and brine with high
enantio- and diastereoselectivities. Herein we wish to report a
detailed study of the nitro-Michael reaction using these
derivatives as the catalysts in both organic and aqueous media.
We are interested in using prolinal dithioacetals (3, Scheme 1)
as potential organocatalysts for the direct nitro-Michael reaction
because the formation of the dithioacetal functional group is
much easier than that of C-C bonds and there are many different
thiol structures available.11 These features make the modification
and fine-tuning the catalyst structure much easier. Indeed, most
of the prolinal dithioacetal catalysts used in the current study
were easily synthesized in high yields using a one-pot two-step
reaction between the commercially available (S)-N-Boc-prolinal
(1) and the corresponding thiols (2) using indium(III) chloride as
the catalyst (Scheme 1).9a,10 Nonetheless, catalyst 3d derived
from 4-chlorobenzenethiol (2d) needed boron trifluoride diethyl
etherate as an additional catalyst for the synthesis, and it was
obtained also in a much lower yield (68%, Scheme 1). All of
these catalysts were found to be very stable under our reaction
conditions.
With these catalysts in hand, we initially screened them in the
direct nitro-Michael reaction in CH2Cl2 at rt with benzoic acid as
the cocatalyt, using cyclohexanone (4a) and trans-β-nitrostyrene
(5a) as the model substrates. The results are collected in Table 1.
As the results in Table 1 show, with a 10 mol % loading of the
benzenethiol-derived catalyst 3a, the desired syn nitro-Michael
adduct 6a was obtained in 81% yield, 97:3 dr, and 97% ee in 29 h
(entry 1). With the 4-methylbenzenethiol-derived catalyst 3b, a
slightly improved yield (88%), dr (99:1), and ee value (>99%) of
6a was obtained (entry 2). Excellent results were also obtained
with catalysts 3c and 3d, derived from 4-methoxybenzenethiol,
and 4-chlorobenzenethiol, respectively (entries 3 and 4). When

2
Tetrahedron
the thioacetal moiety in the catalyst contains two sterically
beneficial effects on both the reactivity and stereoselectivity of
ACCEPTED MANUSCRIPT
demanding
the reaction, but it is not essential. Next, using the best catalyst
3b, some common
Table 2. Asymmetric Michael addition ketones and aldehydes
a
to trans-β-nitrostyrenes in CH2Cl2
Entry Product
Time
(h)
Yield
(%)b
drc
(syn/anti) (%)d
ee
1
2
3
6a
6b
6c
28
33
36
88
90
79
99:1
>99
99
99:1
Scheme 1. Synthesis of the prolinal dithioacetal catalysts
>99:1
97
Table 1. Catalyst screening and reaction condition
optimizationsa
4
6d
6e
6f
20
20
38
25
30
27
29
86
90
77
81
85
79
76
99:1
99:1
>99:1
99:1
97:3
99:1
98:2
99
99
97
97
95
96
95
5
6e
7
Entry
Catalyst Solvent
Time
(h)
Yield drc
ee
(%)b
81
88
81
82
85
75
76
80
75
81
78
79
90
(syn/anti)
(%)d
1
3a
3b
3c
3d
3e
3f
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CHCl3
DMF
29
28
28
30
30
40
40
30
33
30
29
31
26
97:3
99:1
98:2
98:2
97:3
95:5
96:4
98:2
94:6
96:4
97:3
98:2
97:3
97
>99
97
98
95
80
96
95
96
97
97
98
98
6g
6h
6i
2
3
8
4
5
6
9
7e
3b
3b
3b
3b
3b
3b
3b
8
10
6j
9
11
6k
6l
26
40
80
78
70
90:10f
---
98
50
99
10
11
12f
13f,g
hexane
toluene
brine
12g
13h
water
6m 46
99:1
aUnless otherwise specified, all the reactions were carried out with
cyclohexanone (4a, 0.30 mmol), trans-β-nitrostyrene (5a, 0.10 mmol),
catalyst 3 (0.01 mmol, 10 mol %), and benzoic acid (0.01 mmol, 10 mol %)
14h,i
15h,i
6n
6o
59
72
70
60
96:4
---
85
76
b
in the specified solvent (0.5 mL) at room temperature. Yield of the isolated
c
1
product after column chromatography. Determined by H NMR analysis of
the crude product. dValue of the major diastereomer was determined by
HPLC analysis on a Chiralpak AD-H column. Absolute configuration was
determined by comparison of the measured optical rotation with the reported
aUnless otherwise specified, all the reactions were carried out with 4 (0.30
mmol), trans-β-nitrostyrene 5 (0.10 mmol), catalyst 3b (0.01 mmol, 10 mol
%), and benzoic acid (0.01 mmol) in CH2Cl2 (0.5 mL) at room temperature.
f
data.12 eWithout benzoic acid. Reaction was conducted in 1.0 mL of solvent.
gReaction was carried out at 5 °C.
bYield of the isolated product after column chromatography. Determined by
c
1H NMR analysis of the crude product. Value of the major diastereomer;
d
2,6-dimethylphenyl groups (3e), the stereoselectivities of the
reaction dropped slightly (entry 5). In contrast, an alkylthiol-
derived catalyst 3f gave a much lower ee value of the product
(80%), although the diastereoselectivity was only slightly lower
than the other arylthiol derivatives (entry 6). With the best
catalyst 3b (entry 2), we found that slightly lower yield, dr, and
ee value of 6a were obtained without adding benzoic acid as the
cocatalyst (entry 7 vs. entry 2). Thus, benzoic acid has some
unless otherwise indicated, the ee value was determined by HPLC analysis on
a ChiralPak AD-H column. Absolute configuration was determined by
comparison of the measured optical rotation with the reported data.3b,12,14 eOn
f
a ChiralPak AS column. The ee value of the minor diastereomer was >99%
ee. gThe reaction was carried out at -25 °C. hThe reaction was carried out at 0
°C without adding benzoic acid. iThe reaction was conducted with 0.02 mmol
(20 mol %) catalyst.

3
organic solvents were screened, and it were found slightly worse
results were obtained in CHCl3 (entry 8), DMF (entry 9), hexane
(entry 10), and toluene (entry 11). Therefore, CH2Cl2 was
identified as the best organic solvent for this reaction.
conditions (cf. Table 1). As the results in Tables 3 and 4 show,
ACCEPTED MANUSCRIPT
with a few exceptions, catalyst 3b yields very similar results in
terms of yields, diastereoselectivities, and ee values in these two
green solvents as compared with those obtained in CH2Cl2.
Recently there has been substantial interest in conducting the
direct nitro-Michael reactions in water and brine,7,8 since these
two solvents are both cheap, green, and renewable.6 We also
evaluated catalyst 3b in these two solvents. As the results in
Table 1 show, when the reaction of 4a and 5a was conducted in
brine (saturated NaCl solution in water) at rt, the desired product
6a was obtained in 79% yield with an ee value of 98% and a dr
of 98:2 (entry 12). A slightly lower ee value (92% ee) of 6a was
obtained when water was used as the solvent under similar
conditions; Nonetheless, when the reaction was carried out at 5
°C, 6a was obtained in 90% yield with an ee value of 98% and a
dr of 97:3 (entry 13). We speculate that these observations are
due to the slight differences of the catalyst conformation in these
two solvents. Thus, both water and brine are almost equally good
solvents as CH2Cl2 for this reaction, except that the reaction
using water as solvent has to be carried out at subambient
temperature.
Table 3. Asymmetric Michael addition of ketones and
aldehydes to trans-β-nitrostyrenes in watera
Entry Product
Time
(h)
Yield drc
ee
(syn/anti) (%)d
(%)b
1
2
3
6a
6b
6c
26
30
33
90
97:3
97:3
97:3
98
97
95
89
82
88
79
The scope of this reaction were initially studied in the best
organic solvent (CH2Cl2). The results are presented in Table 2.
As the data in Table 2 show, besides trans-β-nitrostyrene (5a,
entry 1), substituted trans-β-nitrostyrenes also reacted with
cyclohexanone under the optimized conditions to yield the
desired syn nitro-Michael adducts in high yields and excellent
diastereo- and enantioselectivities (6b-h, entries 2-8). Neither the
electronic nature of the para-substituent (entries 1-5) nor the
position of the substituent on the phenyl ring (entries 6-8) has
any meaningful effects on the reactivity or the stereoselectivities
of the reaction. Nevertheless, our attempt to react an aliphatic
nitroalkene (trans-1-nitroprop-1-ene) with cyclohexanone failed
to produce any desired product under the optimized conditions
(data not shown). Good product yields and high
stereoselectivities were obtained for the products of other cyclic
ketones, such as 4-oxacyclohexanone (6i, entry 9), 4-
thiacyclohexanone (6j, entry 10), and cyclopentanone (6k, entry
11). In contrast, acetone appears to be a more challenging
substrate for this reaction in terms of stereoselectivity. After
careful optimizations, an ee value of only 50% was obtained for
the product 6l at -25 °C (entry 12). In addition to ketones,
aldehydes may also be applied in this reaction. Nonetheless, in
the case of aldehyde substrates, it was found that adding benzoic
acid actually slowed down the reaction and, therefore, these
reactions were carried out without benzoic acid. Under these new
conditions, the Michael addition product of butanal could be
obtained in 99% ee with a dr of 99:1 for the major syn product
6m (entry 13). However, with the increase of the steric hindrance
next to the aldehyde group, the product ee value decreases. For
examples, the best results of the Michael addition of 3-
methylbutanal and 2-methylpropanal to trans-β-nitrostyrene were
achieved only when the reactions were carried out 0 °C. Under
these optimized conditions, the ee value of the Michael adduct of
3-methylbutanal 6n was only 85% (entry 14) and that of the even
more sterically demanding 2-methylpropanal (6o) was only 76%
(entry 15). In addition, these aldehydes are also much less
reactive and the catalyst loading has to be increased (entry 15). It
should be pointed out that, with the same catalyst, opposite
enantiomers of the syn diastereomers were obtained for cyclic
ketones and aldehydes. Similar phenomenon has been observed
before.13
4
5
6e
7
8
9
6d
6e
6f
24
27
34
26
25
32
98:2
94:6
98:2
95:5
98:2
97:3
97
97
96
95
97
93
82
81
83
80
6g
6h
6i
10
11
12
6j
34
27
36
78
78
65
97:3
95
96
97
6k
6p
84:16
90:10
13
14
6q
6r
38
31
60
69
89:11
88:12
95
98
15
6l
16
40
75
80
---
47
81
16f,g
6s
88:12
17g
6m 42
75
71
90:10
92:8
80
82
18g,h
6n
60
Next the same nitro-Michael reactions were conducted using
water or brine as the solvent under their respective optimized

4
Tetrahedron
aUnless otherwise specified, all the reactions were carried out with 4 (0.30
Table 4. Asymmetric Michael addition of ketones and
ACCEPTED MANUSCRIPT
aldehydes to trans-β-nitrostyrenes in brinea
mmol), trans-β-nitrostyrenes 5 (0.10 mmol), catalyst 3b (0.01 mmol, 10 mol
b
%), and benzoic acid (0.01 mmol) in water (1.0 mL) at 5 °C. Yield of the
isolated product after column chromatography. cDetermined by 1H NMR
analysis of the crude product. dValue of the major diastereomer, unless
otherwise indicated, was determined by HPLC analysis on a ChiralPak AD-H
O
O
Ar
*
3b/PhCO2H
NO2
R2
R2
NO2
*
R1
+
Ar
brine, rt
e
f
g
R1
column. On a ChiralPak AS column. On a ChiralCel OD-H column. The
reaction was carried out without adding benzoic acid. hThe reaction was
conducted with 0.02 mmol (20 mol %) catalyst.
4
5
6
Entry Product
Time
(h)
Yield drc
ee
(syn/anti) (%)d
(%)b
The formation of opposite enantiomers of the syn
diastereomers in the nitro-Michael addition of ketones vs.
aldehydes to trans-β-nitrostyrenes may be explained by the
different conformations of the enamine intermediates13 in the
favored acyclic synclinal transition states.15 As shown in Scheme
2, for cyclohexanone (top equation), in the favored transition
state, the enamine double bond is next to the thioacetal group,
and attacking of the enamine onto Re face of nitrostyrene leads to
the observed major syn enantiomer. In contrast, for aldehyde
substrate (bottom equation), in the favored transition state, the
trans-enamine double bond is away from the thioacetal group
and the attack of this enamine onto the Si face of the nitrostyrene
leads to the formation of the observed opposite enantiomer of the
syn diastereomer. Acetone and sterically demanding aldehydes
yield much lower product ee values most likely because, for these
substrates, the energy gap between these two possible enamine
conformations is less, such that both approaches are possible for
these substrates.
1
2
3
6a
31
32
39
79
98:2
97:3
96:4
98
97
97
6b
6c
6d
6e
82
80
83
85
4
5
6e
7
8
9
30
25
40
28
27
31
97:3
95:5
97:3
96:4
97:3
97:3
96
98
93
94
95
91
6f
6g
6h
6i
74
81
76
75
10
11
12
6j
30
31
35
77
63
62
96:4
94
94
93
6k
6p
80:20
88:12
Scheme 2. Proposed transition state models
3. Conclusion
We have synthesized some readily accessible and highly
tunable prolinal dithioacetal catalysts for the direct Michael
addition of both ketones and aldehydes to β-nitrostyrenes. These
catalysts cannot only catalyze the nitro-Michael reaction in
organic solvents, but also in aqueous media, such as water and
brine. With the exception of acetone and sterically demanding
aldehydes, high diastereoselectivities and enantioselectivities
have been uniformly obtained for both ketone and aldehyde
substrates in all of these three reaction media.
13
14
6q
6r
36
31
59
63
86:14
86:14
92
94
15
6l
25
27
73
79
---
46
80
16f,g
6s
87:13
17g
6m 28
76
70
92:8
92:8
82
85
18g,h
6n
45
aUnless otherwise specified, all the reactions were carried out with 4 (0.30
mmol), trans-β-nitrostyrenes 5 (0.10 mmol), catalyst 3b (0.01 mmol, 10 mol
%), and benzoic acid (0.01 mmol) in brine (1.0 mL) at room temperature.
c
bYield of the isolated product after column chromatography. Determined by
d
1H NMR analysis of the crude product. Value of the major diastereomer;
unless otherwise indicated, was determined by HPLC analysis on a ChiralPak
e
f
AD-H column. On a ChiralPak AS column. On a ChiralCel OD-H column.

5
gThe reaction was carried out without adding benzoic acid. hThe reaction was
conducted with 0.02 mmol (20 mol%) catalyst.
4.2.4.
(S)-2-[Bis(2,6-dimethylphenylthio)methyl]pyrrolidine
ACCEPTED MANUSCRIPT
24
(3e). Yellowish viscous liquid, yield 325.8 mg (91%); [α]D = -
25.7 (c 1.0, CHCl3); IR (KBr) 3053, 2952, 2921, 2869, 1458 cm-
1; 1H NMR (500 MHz, CDCl3): δ 7.14-7.05 (m, 6H), 4.10 (d, J =
4.0 Hz, 1H), 3.33-3.29 (m, 1H), 3.19-3.15 (m, 1H), 2.89-2.84 (m,
1H), 2.44 (s, 6H), 2.35 (s, 6H), 2.02-1.75 (m, 5H). 13C NMR (125
MHz, CDCl3): δ 138.0, 137.9, 133.4, 133.3, 131.2, 131.1, 130.0,
129.9, 66.3, 61.9, 47.0, 29.8, 25.9, 21.4. Anal. Calcd. for
C21H27NS2: C, 70.54; H, 7.61; N, 3.92. Found C, 70.27; H, 7.79;
N, 3.84.
4. Experimental Section
4.1. General
All reactions were carried out in oven-dried glass vials.
1
Solvents were dried using standard protocols. H NMR (300 or
500 MHz) and 13C NMR (75 or 125 MHz, respectively) spectra
were recorded at 25 ºC using CDCl3 as solvent. TLC was
conducted on aluminum-backed TLC plates and the spots were
visualized with UV. Column chromatography was performed on
silica gel. HPLC were conducted with a ChiralCel OD-H, a
ChiralPak AS, or a ChiralPak AD-H column using a mixture of
hexanes/i-PrOH as the eluent.
4.2.5. (S)-2-[Bis(tert-butylthio)methyl]pyrrolidine (3f). Pale
23
yellow viscous liquid, yield 230.0 mg (88%); [α]D = -82.6 (c
1.0, CHCl3); IR (KBr) 3108, 2963, 2865, 1463 cm-1; H NMR
1
(500 MHz, CDCl3): δ 4.19 (d, J = 4.0 Hz, 1H), 3.53-3.49 (m,
1H), 3.17-3.12 (m, 1H), 2.86-2.82 (m, 1H), 2.22 (br s, 1H), 1.95-
1.91 (m, 1H), 1.79-1.73 (m, 2H), 1.62-1.58 (m, 1H), 1.41 (m,
18H). 13C NMR (125 MHz, CDCl3): δ 64.6, 49.9, 47.6, 45.0,
44.8, 32.0, 31.8, 28.4, 26.0. HRMS Calcd. for C13H28NS2
([M+H]+): 262.1658. Found: 262.1657.
4.2. General experimental procedure for the synthesis of the
catalysts (3a-c, e and f)
To a solution of (S)-N-Boc-prolinal (1, 199.0 mg, 1.0 mmol)
and the thiol (2.2 mol) in CH2Cl2 (5.0 mL) was added indium(III)
chloride (44.2 mg, 0.20 mmol, 20 mol %) at room temperature
with stirring. The reaction mixture was then refluxed for 1 h.
After the reaction mixture was cooled down to room temperature,
trifluoroacetic acid (0.25 mL) was then added and stirring was
continued for another 3 h. Then the reaction mixture was made
alkaline (pH ≈ 9) by adding 1.0 M aqueous NaOH solution and
extracted with CH2Cl2 (3 × 10 mL). The combined extracts were
washed with brine (2 × 10 mL) and dried over Na2SO4.
Evaporation of the organic solvent provided the crude product,
which was purified by column chromatography over silica gel
with ethyl acetate/hexane (50:50) as the eluent to furnish the
desired product.
4.3. Synthesis
pyrrolidine (3d)
of
(S)-2-[bis(4-chlorophenylthio)methyl]-
To a solution of (S)-N-Boc-prolinal (1, 199.0 mg, 1.0 mmol)
and 4-chlorobenzenethiol (317.0 mg, 2.2 mol) in CH2Cl2 (5.0
mL) were added indium(III) chloride (44.2 mg, 0.2 mmol) and
BF3.OEt2 (13 ꢀL, 0.10 mmol) at room temperature with stirring.
The reaction mixture was then refluxed for 2 h. After the reaction
mixture was cooled down to room temperature, trifluoroacetic
acid (0.25 mL) was then added and stirring was continued for
another 3 h. The reaction mixture was made alkaline (pH ≈ 9) by
adding 1.0 M aqueous NaOH solution and extracted with CH2Cl2
(3 × 10 mL). The combined extracts were washed with brine (2 ×
10 mL) and dried over Na2SO4. Evaporation of the organic
solvent provided the crude product, which was purified by
column chromatography over silica gel with ethyl acetate/hexane
(50:50) as the eluent to furnish the desired product as a colorless
viscous liquid (252.8 mg, 68% yield). [α]D23 -25.6 (c 1.0, CHCl3);
4.2.1. (S)-2-[(Diphenylthio)methyl]pyrrolidine (3a). Yellowish
viscous liquid, yield 283.3 mg (94%). [α]D24 -29.5 (c 1.0, CHCl3);
1
IR (KBr): 3054, 3017, 2962, 2865, 1580, 1477 cm-1; H NMR
(500 MHz, CDCl3): δ 7.48-7.43 (m, 4H), 7.30-7.25 (m, 6H), 4.50
(d, J = 5.0 Hz, 1H), 3.50-3.46 (m, 1H), 3.13-3.08 (m, 1H), 2.93-
2.88 (m, 1H), 2.28 (br s, 1H), 1.99-1.73 (m, 4H); 13C NMR (125
MHz, CDCl3): δ 134.9, 134.8, 132.8, 132.7, 129.2, 129.1, 127.9,
127.8, 65.4, 62.1, 47.1, 29.8, 25.9; Anal. Calcd. for C17H19NS2:
C, 67.73; H, 6.53; N, 4.65. Found: C, 67.91; H, 6.47; N, 4.65.
IR (KBr) 3049, 2962, 2865, 1572, 1473 cm-1; H NMR (500
1
MHz, CDCl3): δ 7.41-7.32 (m, 4H), 7.28-7.24 (m, 4H), 4.39 (d, J
= 5.5 Hz, 1H), 3.46-3.42 (m, 1H), 3.11-3.07 (m, 1H), 2.94-2.89
(m, 1H), 2.01-1.96 (m, 1H), 1.94-1.85 (m, 2H), 1.82-1.74 (m,
1H); 13C NMR (125 MHz, CDCl3): δ 134.3, 134.2, 133.1, 132.9,
129.4, 129.3, 66.4, 61.9, 47.1, 30.0, 25.9; HRMS Calcd. for
C17H18Cl2NS2 ([M+H]+): 370.0252, found: 370.0252.
4.2.2. (S)-2-[Bis(4-methylphenylthio)methyl]pyrrolidine (3b).
Pale yellow viscous liquid, yield 306.2 mg (93%). [α]D23 -86.8 (c
1.0, CHCl3); IR (KBr): 3017, 2947, 2918, 2864, 1564, 1490 cm-1;
1H NMR (500 MHz, CDCl3): δ 7.39-7.27 (m, 4H), 7.11-7.09 (m,
4H), 4.38 (d, J = 5.0 Hz, 1H), 3.44-3.40 (m, 1H), 3.11-3.07 (m,
1H), 2.90-2.86 (m, 1H), 2.34 (s, 6H), 2.26 (br s, 1H), 1.99-1.73
(m, 4H); 13C NMR (125 MHz, CDCl3): δ 138.0, 137.9, 133.4,
133.3, 131.2, 131.1, 130.0, 129.9, 66.3, 61.9, 47.0, 29.8, 25.9,
21.4; Anal. Calcd. for C19H23NS2: C, 69.25; H, 7.04; N, 4.25.
Found: C, 69.41; H, 7.05; N, 4.16.
4.4. General experimental procedure for the Michael addition
of ketones to trans-β-nitrostyrenes in CH2Cl2
To a mixture of catalyst 3b (3.3 mg, 0.010 mmol, 10 mol %)
and ketone 4 (0.30 mmol) in CH2Cl2 (0.5 mL) was added benzoic
acid (1.2 mg, 0.010 mmol, 10 mol %) at room temperature. The
reaction mixture was stirred for 4 min, then trans-β-nitrostyrene
5 (0.10 mmol) was added. The reaction mixture was further
stirred for the desired time (monitored by TLC). After that the
reaction mixture was extracted with ethyl acetate (3 x 1 mL). The
combined extracts were washed with water (1 x 1 mL) and brine
(1 x 1 mL) and then dried over Na2SO4. Evaporation of the
organic solvent provided the crude product, which was purified
by column chromatography over silica gel with ethyl
acetate/hexane (15:85) as an eluent to afford the desired product.
4.2.3. (S)-2-[Bis(4-methoxyphenylthio)methyl]pyrrolidine (3c).
23
Colourless viscous liquid, yield 296.9 mg (82%). [α]D -39.3 (c
1.0, CHCl3); IR (KBr): 2999, 2938, 2865, 2833, 1589, 1569,
1
1490 cm-1; H NMR (500 MHz, CDCl3): δ 7.42-7.37 (m, 4H),
6.84-6.82 (m, 4H), 4.19 (d, J = 5.5 Hz, 1H), 3.81 (s, 6H), 3.39-
3.35 (m, 1H), 3.11-3.07 (m, 1H), 2.90-2.86 (m, 1H), 2.08 (br s,
1H), 1.99-1.92 (m, 1H), 1.88-1.73 (m, 3H); 13C NMR (125 MHz,
CDCl3): δ 159.9, 135.9, 135.8, 125.2, 125.1, 114.7, 114.6, 68.2,
62.0, 55.6, 46.9, 29.8, 25.8; Anal. Calcd. for C19H23NO2S2: C,
63.12; H, 6.41; N, 3.87. Found C, 62.97; H, 6.38; N, 3.84.
1
Diastereoselectivity was determined by H NMR analysis of the
crude reaction mixture. All the nitro-Michael addition products
are known compounds and have identical spectroscopic data as
those reported.
4.5. General experimental procedure for the Michael addition
of aldehydes to trans-β-nitrostyrene in CH2Cl2

6
Tetrahedron
ACCEPTED MANUSCRIPT
To a solution of trans-β-nitrostyrene (5a, 14.9 mg, 0.1
References
mmol) and catalyst 3b (3.3 mg, 0.010 mmol, 01 mol %) in
CH2Cl2 (0.5 mL) was added aldehyde 4 (0.40 mmol) at 0 °C.
Then the reaction mixture was allowed to stir for the desired time
(monitored by TLC). After that the reaction mixture was
quenched by adding aq. 1N HCl (0.1 mL). Organic materials
were then extracted with ethyl acetate (3 x 1 mL) and washed
with water (1 x 1 mL) and brine (1 x 1 mL). The combined
extracts were dried over Na2SO4. The solvent was evaporated to
provide the crude product, which was purified by column
chromatography over silica gel with ethyl acetate/hexane (15:85)
as an eluent to afford the desired product. Diastereoselectivity
was determined by 1H NMR analysis of the crude reaction
mixture. All the nitro-Michael addition products are known
compounds and have identical spectroscopic data as those
reported.
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Chem. Int. Ed. 2008, 47, 545-548; (f) Belot, S.; Massaro, A.;
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Lett. 2006, 8, 3077-3079; (i) Luo, S.; Mi, X.; Liu, S.; Xu, H.;
Cheng, J.-P. Chem. Commun. 2006, 3687-3689; (j) Chuan, Y.;
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Syu, S.-e.; Kao, T.-T.; Lin, W. Tetrahedron 2010, 66, 891-897; (l)
Wang, B. G.; Ma, B. C.; Wang, Q.; Wang, W. Adv. Synth. Catal.
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Zhang, W.-J.; Tao, Y.; Zhu, Y.; Tao, J.-C.; Tang, M.-S. Eur. J.
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4.6. General experimental procedure for the Michael addition
in water
To a mixture of catalyst 3b (3.3 mg, 0.010 mmol, 10 mol %),
trans-β-nitrostyrene 5 (0.10 mmol) in water (1.0 mL) was added
benzoic acid (1.2 mg, 0.010 mmol, 10 mol %) at 5 °C. The
reaction mixture was stirred for 5 min, then ketone 4 (0.30 mmol)
was added. The reaction mixture was further stirred for the
desired time (monitored by TLC). After that the reaction mixture
was extracted with ethyl acetate (3 x 1 mL) and the combined
extracts were washed with brine (1 x 1 mL). The organic layer
was dried over Na2SO4. Evaporation of the solvent provided the
crude product, which was purified by column chromatography
over silica gel with ethyl acetate/hexane (15:85) as an eluent to
afford the desired product. Diastereoselectivity was determined
by 1H NMR analysis of the crude reaction mixture. For aldehyde
substrates, benzoic acid was not added.
4.7. General experimental procedure for the Michael addition
in brine
To a mixture of catalyst 3b (3.3 mg, 0.01 mmol, 10 mol %),
trans-β-nitrostyrene 5 (0.10 mmol) in brine (1.0 mL) was added
benzoic acid (1.2 mg, 0.01 mmol, 10 mol %) at room
temperature. The reaction mixture was stirred for 4 min, then
ketone 4 (0.30 mmol) was added. The reaction mixture was
further stirred for the desired time (monitored by TLC). After that
the reaction mixture was extracted with ethyl acetate (3 x 1 mL)
and the combined organic extracts were dried over Na2SO4.
Evaporation of the solvent provided the crude product, which
was purified by column chromatography over silica gel with
ethyl acetate/hexane (15:85) as an eluent to afford the desired
product. Diastereoselectivity was determined by 1H NMR
analysis of the crude reaction mixture. For aldehyde substrates,
benzoic acid was not added.
Acknowledgements
The authors thank the generous financial support of this
research by the Welch Foundation (Grant No. AX-1593). Some
of the NMR data reported in this paper were collected on a NMR
spectrometer acquired with the funding from the NSF (Grant No.
CHE-1625963). KB thanks the University Grants Commission,
Ministry of Human Resource Development, India, for a Raman
Fellowship.
8. For examples using brine as the solvent in the nitro-Michael
reactions, see: (a) Kaplaneris, N.; Koutoulogenis, G.; Raftopoulou,
M.; Kokotos, C. G. J. Org. Chem. 2015, 80, 5464-5473; (b) Wang,
C. A.; Zhang, Z. K.; Yue, T.; Sun, Y. L.; Wang, L.; Wang, W. D.;
Zhang, Y.; Liu, C.; Wang, W. Chem. Eur. J. 2012, 18, 6718-6723;
(c) Lin, J.; Tian, H.; Jiang, Y.-J.; Huang, W.-B.; Zheng, L.-Y.;
Zhang, S.-Q. Tetrahedron: Asymmetry 2011, 22, 1434-1440; (d)
See also refs. 7a and 7p.
9. (a) Mandal, T.; Zhao, C.-G. Tetrahedron Lett. 2007, 48, 5803-
5806; (b) Mandal, T.; Zhao, C.-G. Angew. Chem. Int. Ed. 2008,
47, 7714-7717; (c) Rana, N. K.; Huang, H.; Zhao, J. C. G. Angew.
Chem. Int. Ed. 2014, 53, 7619-7623.
Supplementary data
Supplementary data related to this article can be found at

7
10. Samanta, S.; Krause, J.; Mandal, T.; Zhao, C.-G. Org. Lett. 2007,
ACCEPTED MANUSCRIPT
9, 2745-2748.
11. For a closely related study, see: Chuan, Y.-M.; Yin, L.-Y.; Zhang,
Y.-M.; Peng, Y.-G. Eur. J. Org. Chem. 2011, 578-583.
12. Pansare, S. V.; Pandya, K. J. Am. Chem. Soc. 2006, 128, 9624–
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13. Alexakis, A.; Andrey, O. Org. Lett. 2002, 4, 3611-3614.
14. Gu, L.; Wu, Y.; Zhang, Y.; Zhao, G. J. Mol. Catal. A: Chem.
2007, 263, 186-194.
15. Seebach, D.; Golinski, J. Helv. Chim. Acta 1981, 64, 1413-1423.