Organocatalytic enantioselective sulfur-michael addition of thioacetic acid to arylmethylidenemalonates

Article abstract of DOI:10.1002/adsc.201400664

An organocatalytic enantioselective sulfur-Michael addition of thioacetic acid to arylmethyli-denemalonates was developed with high yields and up to 97% enantiomeric excess. Both enantiomers of the products were accessible with two different organocatalys

Full text of DOI:10.1002/adsc.201400664

FULL PAPERS
DOI: 10.1002/adsc.201400664
Organocatalytic Enantioselective Sulfur-Michael Addition of
Thioacetic Acid to Arylmethylidenemalonates
a
a
a,
Renchao Wang, Jing Liu, and Jiaxi Xu *
a
State Key Laboratory of Chemical Resource Engineering, Department of Organic Chemistry, Faculty of Science, Beijing
University of Chemical Technology, Beijing 100029, Peopleꢀs Republic of China
Fax : (+86)-10-6443-5565; phone: (+86)-10-6443-5565; e-mail: jxxu@mail.buct.edu.cn
Received: July 10, 2014; Revised: September 7, 2014; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201400664.
Abstract: An organocatalytic enantioselective sulfur- practical, and convenient preparation of enantiomer-
Michael addition of thioacetic acid to arylmethyli- ically enriched acetylthiomethylmalonate derivatives.
ACHTUNGTRENNUNGd enemalonates was developed with high yields and
up to 97% enantiomeric excess. Both enantiomers of
the products were accessible with two different orga- Keywords: alkylidenemalonates; Michael addition;
nocatalysts. The current method provides the first, organocatalysis; thioacetic acid
[
8]
Introduction
actions with several nucleophiles, such as ketones,
[
9]
[10]
indoles, and nitroalkanes etc. However, the asym-
Optically active chiral organic sulfur-containing com- metric SMA of thiocarboxylic acids to arylmethyli-
pounds play an important role in biochemistry and denemalonates has not been explored to date. Herein,
pharmaceutical chemistry. The asymmetric sulfur- we present the first and highly enantioselective SMA
Michael addition (SMA) represents a fundamental of thioacetic acid to arylmethylidenemalonates cata-
method for creating the carbon-sulfur bond in an lyzed by bifunctional amine thioureas with high yields
AHCTUNGTRENNUNG
[
1]
[
2]
asymmetric fashion.
Although various catalytic and up to 97% ee.
asymmetric SMAs employing alkyl or aryl thiols as
sulfur nucleophiles have been developed over the
[
3]
past few decades, reactions using thiocarboxylic Results and Discussion
acids have been less explored. The asymmetric addi-
tions of thiocarboxylic acids to a,b-unsaturated ke- Bifunctional amine thioureas have proved to be pow-
tones catalyzed by Cinchona alkaloid, chiral amine erful catalysts in asymmetric SMAs, thus three types
thiourea or urea have been reported during the past of amine thiourea catalysts bearing different chiral
[
4]
few years with moderate enantioselectivities. Wang skeletons were synthesized and tested in the enantio-
and co-workers disclosed an efficient method for selective SMA of thioacetic acid to diethyl 2-benzyli-
enantioselective SMA of thioacetic acid with b-nitro- denemalonate (1a). As the results in Table 1 show, or-
styrenes with high yields and moderate enantioselec- ganocatalysts 3–5 effectively catalyzed the reaction
[5]
tivities in 2006. Ellmanꢀs group applied the N-sulfi- with high yields and good enantioselectivities. Cata-
nylurea-catalyzed enantio- and diastereoselective lyst 3a based on quinine was found to be the best
SMA of thioacetic acid to nitroalkenes with high ste- choice with 76% ee (Table 1, entry 1), while catalysts
[6]
reocontrol. Chiral squaramides were also effective 4 derived from l-amino acids afforded slightly lower
organocatalysts in the SMA of thioacetic acid to a,b- enantioselectivities than 3 (Table 1, entries 1–6). The
disubstituted nitroalkenes with good to excellent dia- opposite enantiomer was obtained with catalysts 5,
[
7]
stereo- and enantioselectivities. Currently, the sub- derived from (R,R)-cyclohexane-1,2-diamine (Table 1,
strate scope of asymmetric SMAs using thiocarboxylic entries 7–9), and good enantioselectivity is maintained
acids is limited to a,b-unsaturated ketones and nitro- with catalyst 5b compared with catalyst 3a (Table 1,
alkenes.
entry 8). Thus, both enantiomers of products 2a and
Arylmethylidenemalonates, as good Michael addi- ent-2a were accessible by using either catalyst 3a or
tion acceptors, have been involved in asymmetric re- 5b.
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Table 1. Asymmetric Michael addition of thioacetic acid to nate (1c) gave slightly lower ee compared with 1a.
diethyl 2-benzylidenemalonate (1a) catalyzed by different
organocatalysts.
Substrate concentration had almost no influence on
[a]
the reaction (Table 2, entries 14 and 15), and use of
ꢂ molecule sieve had a negative effect on the enan-
4
tioselectivity in the reaction. Next we undertook
a screening of the solvent effect and found that the
solvent has a great impact on the asymmetric SMA
(
Table 2, entries 17–23). The reaction became sluggish
when performed in dichloromethane or chloroform,
meanwhile ee values decreased. Toluene is a good re-
action medium, and ether was found to be superior
for the reaction. Diisopropyl ether was finally selected
as the reaction solvent with the highest ee of 78%.
Lowering the reaction temperature resulted in an im-
provement on the product ee although at the expense
of longer reaction time, and the reaction at À408C af-
forded the desired product 2a in 97% yield with 82%
ee (Table 2, entries 24 and 25).
Under the optimal reaction conditions, a series of
arylmethylidenemalonates 1 was reacted with thioace-
tic acid as shown in Table 3. Firstly we were pleased
to find that ortho-substitution on the aromatic ring re-
[b]
[c]
Entry
Catalyst
Yield [%]
ee [%] sulted in a remarkable increase in the enantioselectiv-
ity (Table 3, entries 2–4). The benefit of ortho-substi-
tution was further demonstrated via various ortho-
substituted arylmethylidenemalonates with excellent
1
2
3
4
5
6
7
8
9
3a
3b
4a
4b
4c
4d
5a
5b
5c
98
97
95
92
96
95
90
94
93
76
75
66
62
64
67
À34
À74
À68
stereocontrol compared with their para-substituted
counterparts (Table 3, entries 5–12). Except for me-
thoxy-substituted substrate 1m with moderate enan-
tioselectivity possibly due to the electronic effect and
formation of hydrogen bonding between the catalyst
and the methoxy group, the substrates with electron-
withdrawing groups at the ortho-position afforded ex-
cellent ee values. Diethyl 2-(naphthalen-1-ylmethyl-
[
[
[
d]
d]
d]
[
a]
Reactions were carried out with 1a (24.8 mg, 0.10 mmol)
and AcSH (14 mL, 15.2 mg, 0.2 mmol) in the presence of
0 mol% organocatalyst in Et O (1 mL) at 08C.
1
ACHTUNGTRENNUNG
2
[
[
b]
c]
Isolated yield.
Determined by HPLC analysis using an AS-H chiral entry 13). However, 2,6-dichlorophenylmethylidene-
column and hexane-2-propanol (90:10, v/v) as eluent.
The product is ent-2a.
malonate (1r), a double ortho-substituted substrate,
gave rise to the desired adduct 2r in excellent yield
[
d]
but poor enantioselectivity (Table 3, entry 14). Fur-
thermore, the opposite enantiomers with high yields
After identifying the catalysts 3a and 5b as the best and moderate to excellent ee values were obtained as
catalysts for each of the enantiomers, we turned our the major products with catalyst 5b (Table 3, en-
attention to optimizing the reaction conditions and tries 15–21). Similar to the results obtained with cata-
the results are shown in Table 2. The catalyst loading lyst 3a, ortho-substitution was also critical for obtain-
had little effect on enantioselectivity and 5 mol% cat- ing high stereoselectivity with 5b as a catalyst. To
alyst loading provided the best result (Table 2, en- extend the substrate scope, an aliphatic substrate di-
tries 1–5). To check the effect of the ester group on ethyl cyclohexylmethylidenemalonate (1s) was pre-
the reactivity and enantioselectivity in the asymmetric pared and attempted. However, moderate yield and
SMA reaction, substrates bearing different ester poor enantioselectivity were observed (Table 3,
groups were probed (Table 2, entries 6–13). The reac- entry 22). The results reveal that our catalytic system
tivity of the substrate dropped significantly as the shows good performance for ortho-substituted aro-
steric hindrance of the substrate increased, and the matic substrates with high yields and excellent enan-
enantioselectivity varied to a certain extent. Among tioselectivity.
the five substrates bearing different ester groups, di-
To determine the absolute configuration of the
ethyl substrate 1a gave the best result with both cata- products 2, 2a was selected and converted to 3-mer-
lysts 3a and 5b, and diisopropyl 2-benzylidenemalo- capto-3-phenylpropanoic acid via acidic hydrolysis.
2
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Organocatalytic Enantioselective Sulfur-Michael Addition of Thioacetic Acid
Table 2. Optimization of the reaction conditions for the asymmetric Michael addition of thioacetic acid to different arylme-
[a]
thylidenemalonates.
[b]
[c]
Entry
R
Catalyst (mol%)
Solvent
Time [h]
Product
Yield [%]
ee [%]
1
2
3
4
5
6
7
8
9
Et
Et
Et
Et
3a (20)
3a (10)
3a (5)
3a (2.5)
3a (1.3)
3a (5)
3a (5)
3a (5)
3a (5)
5b (5)
5b (5)
5b (5)
5b (5)
3a (5)
3a (5)
3a (5)
3a (5)
3a (5)
3a (5)
3a (5)
3a (5)
3a (5)
3a (5)
3a (5)
3a (5)
Et O
0.5
1
1.5
3
4
1
14
20
1.5
1
12
24
1.5
1
3
2
5.5
5.5
3.5
5
4
4
6
7
2a
2a
2a
2a
2a
2b
2c
2d
95
96
94
93
94
98
94
55
94
96
95
70
92
98
97
99
20
15
93
60
99
96
89
96
97
74
76
76
74
74
56
75
67
2
Et O
2
Et O
2
Et O
2
Et
Et O
2
Me
i-Pr
t-Bu
Bn
Me
i-Pr
t-Bu
Bn
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et O
2
Et O
2
Et O
2
Et O
2e
53
2
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
Et O
ent-2b
ent-2c
ent-2d
ent-2e
2a
2a
2a
2a
2a
2a
2a
À68
À70
À60
À61
76
76
67
44
29
73
34
78
75
29
81
82
2
Et O
2
Et O
2
Et O
2
[
[
[
d]
e]
f]
Et O
2
Et O
2
Et O
2
CH Cl
2
2
CHCl3
PhMe
THF
(i-Pr) O
t-BuOMe
PhOMe
(i-Pr) O
(i-Pr) O
2a
2a
2a
2a
2
[
[
g]
h]
2
22
2a
2
[
a]
Reactions were conducted with 1 (0.10 mmol) and AcSH (14 mL, 15.2 mg, 0.2 mmol) in the presence of organocatalyst 3a
or 5b in solvent (1 mL).
Isolated yield.
Determined by HPLC analysis using an AS-H or AD-H chiral column.
[
[
[
[
[
[
[
b]
c]
d]
e]
f]
With Et O (0.5 mL) as solvent.
2
With Et O (2 mL) as solvent.
2
With 4 ꢂ molecular sieve.
g]
h]
Reaction was performed at À208C.
Reaction was carried out at À408C.
The acid was further esterified to afford the corre- nate (7), was obtained in high yield and without loss
[
11]
sponding known ester 6, which shows the opposite of enantioselectivity in acidic ethanol solution (12M
[
13]
direction of optical rotation compared with the re- HCl/EtOH) (Scheme 1).
ported methyl (S)-3-mercapto-3-phenylpropanoate.
The results indicate that
both thioacetate and malonate were hydrolyzed in the
Thus, the absolute configuration of both esters 6 and relatively diluted hydrochloric acid (6M HCl aqueous
a should be R (Scheme 1). Certain decrease in the solution), while only acetyl was removed in the con-
[
12]
2
enantiomeric excess was observed in this transforma- centrated solution of hydrochloric acid in ethanol
tion, which was possibly due to the enolization of the (12M HCl/EtOH), revealing that the thioacetate
carboxylic acid group and the double bond rearrange- group is less stable than the carboxylates in the acidic
ment to the conjugated position with the phenyl hydrolysis because deacetylation occurred in each of
group under reflux at high temperature.
cases (Scheme 1). Here, diethyl (R)-acetylthio(phe-
To extend the application of products 2, product 2a nyl)methylmalonate (2a) was successfully converted
was also subjected to selective hydrolysis. The free to diethyl (R)-mercapto(phenyl)methylmalonate (7),
mercaptan, diethyl (R)-mercapto(phenyl)methylmalo- (R)-3-mercapto-3-phenylpropanoic acid, and methyl
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Table 3. Asymmetric Michael addition of thioacetic acid to
[a]
arylmethylidenemalonates 1.
[
b]
[c]
Entry
R
Catalyst Product Yield
%]
ee
[
[%]
1
2
3
4
5
6
7
8
9
Ph
2-ClC H4
3-ClC H4
4-ClC H4
2-FC H4
2-BrC H4
2-F CC H
2-MeC H4
2-MeOC H
4-FC H4
4-BrC H4
4-MeOC H
1-naphthyl
2,6-Cl C H
3
2-ClC H4
4-ClC H4
2-MeC H4
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
3a
5b
5b
5b
5b
5b
5b
5b
3a
2a
2f
2g
2h
2i
2j
2k
2l
2m
2n
2o
2p
2q
3r
ent-2f
ent-2h
ent-2l
ent-2m
ent-2o
ent-2p
ent-2q
2s
97
95
96
98
99
99
94
92
90
94
97
99
96
92
97
95
93
94
95
96
97
85
82
97
82
81
91
97
97
90
68
79
79
60
97
26
6
6
6
6
6
3
6
4
6
6
4
10
11
12
13
14
15
16
17
18
19
20
21
22
6
6
6
4
2
6
Scheme 2. Plausible transition state models.
À96
À77
À92
À72
À79
6
6
6
2-MeOC H
4-BrC H4
4-MeOC H
1-naphthyl
cyclohexyl
6
4
Based on the experimental results, both plausible
6
À62 transition state models for the two complementary
6
4
À97 catalyst systems were proposed to account for the
12
major
(Scheme 2).
productsꢀ
absolute
stereochemistry
[
14]
[
a]
Arylmethylidenemalonate 1f interacts
Reactions were carried out with 1 (0.10 mmol) and
AcSH (14 mL, 15.2 mg, 0.2 mmol) in the presence of
with the thiourea moiety of the catalyst 3a via double
H-bonds, while thioacetic acid is deprotonated by the
tertiary amine group and attacks the pro-chiral
5
mol% catalyst in (i-Pr) O (1 mL) at À408C.
2
[
[
b]
Isolated yield.
c]
Determined by HPLC analysis using an AS-H or AD-H carbon center of 1f from its Re face, thus generating
chiral column.
the desired product 2f with R configuration. In addi-
tion, the ortho-substitution on the aromatic ring in-
creases the steric hindrance near the pro-chiral
center, inhibiting the free rotation of the CÀC bond
between the aryl group and the C=C bond, predomi-
nant formation of the p-stacking interaction between
the aryl group and thioacetate. The p-stacking inter-
action is favorable to the proposed transition state, re-
sulting in improvement of the enantioselectivity
(
Table 3, entries 1 and 16). Thioacetate is an electron-
rich conjugative species. The electron-deficient ortho-
substituted substrates 1f and 1i–k show stronger p-
stacking interaction with it, resulting in higher ee
values than the substrates 1l and 1m with electron-
rich ortho-substituents. For aliphatic substrate 1s, poor
enantioselectivity was observed possibly due to the
lack of p-stacking interaction. These results support
the p-stacking interaction. Similar phenomena were
also observed in other asymmetric catalytic reac-
Scheme 1. Transformations of product 2a.
[
15]
(
R)-3-mercapto-3-phenylpropanoate (6). Different op- tions. When catalyzed by 5b, thioacetic acid attacks
tically active sulfur-containing compounds were ob- the Si face of the pro-chiral carbon center of 1f due
tained from our products 2 via simple conversion. to the opposite configuration of the thiourea and ter-
4
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Organocatalytic Enantioselective Sulfur-Michael Addition of Thioacetic Acid
tiary amine groups in the catalysts 5, and (S)-2f was 2.28 (s, 3H), 4.02 (q, J=7.2 Hz, 2H), 4.01 (d, J=10.0 Hz,
1
7
7
1
1
1
H), 4.20 (dq, J=10.8, 7.2 Hz, 1H), 4.21 (dq, J=10.8,
.2 Hz, 1H), 5.34 (d, J=10.0 Hz, 1H), 7.21–7.30 (m, 3H),
obtained as the major product.
1
3
.35–7.38 (m, 2H); C NMR (100 MHz, CDCl ): d=13.7,
3
4.0, 30.3, 46.0, 57.3, 61.8, 61.9, 127.8, 128.1, 128.5, 139.4,
Conclusions
66.4, 166.8, 192.8; IR (KBr): v=2962, 2922, 1734, 1696,
À1
384, 1258, 1096, 1031, 801, 698, 629 cm ; HR-MS (ESI): m/
In summary, we have successfully developed the first
organocatalytic and highly stereoselective sulfur Mi-
chael addition of thioacetic acid to arylmethylidene-
+
+
z=325.1109, calcd. for C H O S [M+H] : 325.1110. The
ee was determined to be 82% by chiral HPLC analysis (AS-
H
1
6
21
5
À1
column, hexane-2-propanol 90:10, 1.0 mLmin , l=
malonates. High yields and moderate to excellent 220 nm): t (major, R)=7.4 min, tR (minor, S)=6.7 min;
enantioselectivities are observed with a wide substrate [a] : 104.4 (c, 1.08, CHCl ).
R
2
0
D
3
scope, especially with ortho-substituted arylmethylide-
Dimethyl (R)-acetylthio(phenyl)methylmalonate (2b):
nemalonates, and both enantiomers of the products Colorless oil; yield of 2b: 29.1 mg (98%); yield of ent-2b:
1
2
3
8.5 mg (96%). H NMR (400 MHz, CDCl ): d=2.29 (s,
are accessible. This approach expands the scope of
the asymmetric sulfur-Michael addition with thiocar-
boxylic acids and provides a practical method for the
preparation of enantiomerically enriched sulfur-con-
taining malonate derivatives.
3
H), 3.57 (s, 3H), 3.74 (s, 3H), 4.05 (d, J=9.6 Hz, 1H), 5.33
d, J=9.6 Hz, 1H), 7.21–7.32 (m, 3H), 7.34–7.37 (m, 2H);
(
1
3
C NMR (100 MHz, CDCl ): d=30.3, 46.1, 52.7, 52.8, 57.1,
3
1
2
6
27.9, 128.0, 128.6, 139.1, 166.8, 167.2, 192.7; IR (KBr): v=
953, 2923, 1740, 1696, 1453, 1354, 1255, 1142, 1022, 952,
À1
99, 624 cm ; HR-MS (ESI): m/z=297.0800, calcd. for
+
+
C H O S [M+H] : 297.0797. The ee was determined to
1
4
17
5
Experimental Section
be 56% with catalyst 3a and À68% with catalyst 5b by
chiral HPLC analysis (AS-H column, hexane-2-propanol
À1
0
General Information
90:10, 1.0 mLmin , l=220 nm): t (R)=8.2 min, tR (S)=
R
2
20
7
.8 min; 2b: [a] : +65.8 (c, 0.96, CHCl ); ent-2b: [a] :
D
3
D
Melting points were measured on a Yanaco MP-500 melting
À79.6 (c, 0.98, CHCl ).
1
3
point apparatus and are uncorrected. H NMR spectra were
Diisopropyl (R)-acetylthio(phenyl)methylmalonate (2c):
recorded on a Bruker 400 MHz spectrometer. Chemical
shifts are reported in ppm with TMS signal at 0.0 ppm as an
Colorless crystals; yield of 2c: 33.0 mg (94%); yield of ent-
1
2
c: 33.6 mg (95%); mp 66–688C. H NMR (400 MHz,
1
3
internal standard. C NMR spectra were recorded at
CDCl ): d=1.03 (d, J=6.4 Hz, 3H), 1.07 (d, J=6.4 Hz, 3H),
À1
3
1
00 MHz. The IR spectra (KBr pellets, v [cm ]) were taken
1
3
5
7
.22 (d, J=6.0 Hz, 3H), 1.23 (d, J=6.0 Hz, 3H), 2.28 (s,
H), 3.96 (d, J=10.0 Hz, 1H), 4.85 (hept, J=6.4 Hz, 1H),
.06 (hept, J=6.4 Hz, 1H), 5.33 (d, J=10.0 Hz, 1H), 7.19–
.24 (m, 1H), 7.25–7.30 (m, 2H), 7.35–7.38 (m, 2H);
on a Nicolet 370 MCT FTIR spectrometer. The high resolu-
tion mass spectra were obtained with ESI ionization using
a Waters Xevo G2 Q-Tof MS. Optical rotations were mea-
sured with an Anton Paar MCP 200 polarimeter at the indi-
cated concentration with units g/100 mL. The enantiomeric
excesses were determined by chiral HPLC analysis using an
Agilent 1260 LC instrument with Daicel Chiralpak AS-H or
AD-H column. Column chromatography was carried out
with silica gel (200–300 mesh). Commercially available com-
pounds were used as received without further purification,
1
3
C NMR (100 MHz, CDCl ): d=21.3, 21.4, 21.6, 30.3, 45.9,
3
5
7.5, 69.5, 69.5, 127.7, 128.1, 128.4, 139.6, 165.9, 166.4, 192.8;
IR (KBr): v=2981, 2933, 1732, 1699, 1454, 1375, 1261, 1102,
À1
9
09, 698, 630 cm ; HR-MS (ESI): m/z=353.1426, calcd. for
+
+
C H O S [M+H] : 353.1423. The ee was determined to
1
8
25
5
be 75% with catalyst 3a and À70% with catalyst 5b by
[
16]
[17]
[18]
chiral HPLC analysis (AS-H column, hexane-2-propanol
unless otherwise stated. Catalysts 3, 4, and 5 and aryl-
À1
[19]
90:10, 1.0 mLmin , l=220 nm): t
R
(R)=5.0 min, t
R
20
(S)=
methylidenemalonates were prepared according to the lit-
erature procedures and their analytic data are identical as
those reported.
2
0
4
(
.5 min; 2c: [a] : +90.4 (c, 1.01, CHCl ), ent-2c: [a] : À83.4
D
3
D
c, 1.06, CHCl ).
3
Di-tert-butyl (R)-acetylthio(phenyl)methylmalonate (2d):
Colorless crystals; yield of 2d: 21.0 mg (55%), yield of ent-
1
2
d: 26.5 mg (70%); mp 98–998C. H NMR (400 MHz,
General Procedure for the Organocatalytic Enantio-
selective Michael Addition of Thioacetic Acid to
Arylmethylidenemalonates 1
CDCl ): d=1.26 (s, 9H), 1.44 (s, 9H), 2.28 (s, 3H), 3.83 (d,
3
J=10.0 Hz, 1H), 5.27 (d, J=9.6 Hz, 1H), 7.19–7.29 (m,
13
3
H), 7.35–7.38 (m, 2H); C NMR (100 MHz, CDCl ): d=
3
To
a
stirred solution of arylmethylidenemalonate
27.5, 27.8, 30.3, 46.0, 58.8, 82.2, 82.3, 127.5, 128.2, 128.3,
1
(0.1 mmol), catalyst 3a or 5b (5 mol%) in (i-Pr) O (1 mL)
139.9, 165.6, 166.1, 193.0; IR (KBr): v=2978, 2932, 1733,
2
À1
at À408C was added thioacetic acid (14 mL, 15.2 mg,
1699, 1393, 1369, 1290, 1256, 1139, 849, 747, 698, 631 cm ;
+
0.2 mmol). The reaction mixture was stirred until the disap-
HR-MS (ESI): m/z=381.1735, calcd. for C20
H
29
O
5
S
[M+
+
pearance of the starting material as detected by TLC. The
solution was directly subject to column chromatography on
silica gel (petroleum ether/ethyl acetate=20:1 v/v as eluent)
to afford the desired product 2.
Diethyl (R)-acetylthio(phenyl)methylmalonate (2a): Col-
orless oil; yield: 31.4 mg (97%). H NMR (400 MHz,
H] : 381.1736. The ee was determined to be 67% with cata-
lyst 3a and À60% with catalyst 5b by chiral HPLC analysis
À1
(AD-H column, hexane-2-propanol 90:10, 1.0 mLmin , l=
20
220 nm): t
(R)=5.3 min, t (S)=7.4 min; 2d: [a] : +75.2
R
D
20
R
(c, 1.01, CHCl
), ent-2d: [a] : À67.5 (c, 1.13, CHCl
).
3
3
D
1
Dibenzyl (R)-acetylthio(phenyl)methylmalonate (2e):
Colorless crystals; yield of 2e: 42.3 mg (94%), yield of ent-
CDCl ): d=1.06 (t, J=7.2 Hz, 3H), 1.25 (t, J=7.2 Hz, 3H),
3
Adv. Synth. Catal. 0000, 000, 0 – 0
ꢁ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
5
ÞÞ
These are not the final page numbers!

Renchao Wang et al.
FULL PAPERS
1
À1
2
e: 41.3 mg (92%); mp 119–1218C. H NMR (400 MHz,
nol 98:2, 1.0 mLmin , l=220 nm): t (R)=16.1 min, t
R R
2
0
20
CDCl ): d=2.16 (s, 3H), 4.14 (d, J=10.0 Hz, 1H), 4.95 (s,
(S)=15.1 min. 2h: [a] : 64.4 (c, 1.02, CHCl ), ent-2h: [a] :
3
D
3
D
2
5
1
6
1
3
1
H), 5.12 (d, J=12.4 Hz, 1H), 5.16 (d, J=12.4 Hz, 1H),
À61.5 (c, 0.98, CHCl ).
3
.36 (d, J=9.6 Hz, 1H), 7.07–7.10 (m, 2H), 7.21–7.32 (m,
Diethyl
(R)-acetylthio(2-fluorophenyl)methylmalonate
1
13
3H); C NMR (100 MHz, CDCl ): d=30.2, 46.0, 57.2, 67.4,
(2i): Colorless oil; yield: 34.0 mg (99%). H NMR
3
7.5, 127.8, 128.0, 128.2, 128.3, 128.3, 128.4, 128.4, 128.5,
28.5, 134.8, 135.0, 139.1, 166.1, 166.5, 192.6; IR (KBr): v=
064, 3033, 2958, 1737, 1698, 1455, 1377, 1258, 1215, 1133,
(400 MHz, CDCl ): d=1.05 (t, J=7.2 Hz, 3H), 1.25 (t, J=
3
7.2 Hz, 3H), 2.29 (s, 3H), 4.01 (q, J=7.2 Hz, 2H), 4.16 (d,
J=10.4 Hz, 1H), 4.19 (dq, J=10.8, 7.2 Hz, 1H), 4.22 (dq,
J=10.8, 7.2 Hz, 1H), 5.49 (d, J=10.8 Hz, 1H), 7.00–7.08 (m,
+
029, 951, 750, 698, 626. HRMS (ESI) calcd for C H O S
2
6
25
5
+
À1
13
[M+H] =m/z: 449.1423; found: 449.1423 cm . The ee was
2H), 7.21–7.27 (m, 1H), 7.42–7.46 (m, 1H); C NMR
3
determined to be 53% with catalyst 3a and À61% with cata-
(100 MHz, CDCl ): d=13.7, 13.9, 30.2, 41.3, 55.7 (d, J
=
=
3
C,F
2
4
lyst 5b by chiral HPLC analysis (AS-H column, hexane-2-
3 Hz), 61.8, 61.9, 115.7 (d, JC,F =22 Hz), 124.0 (d, JC,F
À1
2
3
propanol 90:10, 1.0 mLmin , l=220 nm): t (R)=10.9 min,
tR (S)=12.6 min; 2e: [a] : +41.9 (c, 1.09, CHCl ), ent-2e:
3 Hz), 126.2 (d, J =13 Hz), 129.7 (d, J =8 Hz), 130.7 (d,
R
CF C,F
2
D
0
3
1
JC,F =4 Hz), 160.5 (d, J =247 Hz), 166.3, 166.6, 192.5; IR
C,F
3
2
D
0
[a] : À47.9 (c, 1.00, CHCl ).
(KBr): v=2984, 2925, 1735, 1696, 1492, 1369, 1309, 1236,
1142, 1106, 954, 757, 625 cm ; HR-MS (ESI): m/z=
3
À1
Diethyl
(R)-acetylthio(2-chlorophenyl)methylmalonate
+
+
(
2f): Yellowish oil; yield of 2f: 34.0 mg (95%), yield of ent-
343.1012, calcd. for C H FO S [M+H] : 343.1015. The ee
16 20 5
1
2
f: 34.9 mg (97%). H NMR (400 MHz, CDCl ): d=1.09 (t,
was determined to be 91% by chiral HPLC analysis (AS-H
column, hexane-2-propanol 90:10, 1.0 mLmin , l=
3
À1
J=7.2 Hz, 3H), 1.24 (t, J=7.2 Hz, 3H), 2.29 (s, 3H), 4.06
q, J=7.2 Hz, 2H), 4.17 (dq, J=10.8, 7.2 Hz, 1H), 4.20 (dq,
J=10.8, 7.2 Hz, 1H), 4.32 (d, J=9.2 Hz, 1H), 5.70 (d, J=
(
220 nm): t (major, R)=7.8 min, tR (minor, S)=6.9 min.
R
2
D
0
[a] : 100.0 (c, 0.99, CHCl ).
3
9
7
3
1
1
.2 Hz, 1H), 7.18–7.21 (m, 2H), 7.34–7.36 (m, 1H), 7.48–
Diethyl
(R)-acetylthio(2-bromophenyl)methylmalonate
13
1
.51 (m, 1H); C NMR (100 MHz, CDCl ): d=13.8, 13.9,
(2j): Yellowish oil; yield: 40.0 mg (99%). H NMR
(400 MHz, CDCl ): d=1.12 (t, J=7.2 Hz, 3H), 1.23 (t, J=
3
0.1, 44.0, 55.5, 61.8, 126.8, 129.1, 130.0, 131.0, 133.6, 136.3,
3
66.5, 166.8, 192.8; IR (KBr): v=2980, 2928, 1733, 1699,
7.2 Hz, 3H), 2.30 (s, 3H), 4.07 (dq, J=10.8, 7.2 Hz, 1H),
4.09 (dq, J=10.8, 7.2 Hz, 1H), 4.16 (dq, J=10.8, 7.2 Hz,
1H), 4.19 (dq, J=10.8, 7.2 Hz, 1H), 4.33 (d, J=8.4 Hz, 1H),
5.71 (d, J=8.4 Hz, 1H), 7.11 (ddd, J=1.2, 7.6, 7.6 Hz, 1H),
7.24 (ddd, J=1.2, 7.6 7.6 Hz, 1H), 7.51 (dd, J=1.2, 7.6 Hz,
À1
475, 1391, 1245, 1132, 1038, 954, 755, 630 cm ; HR-MS
+
+
(
ESI): m/z=359.0719, calcd. for C H ClO S [M+H] :
16 20 5
359.0720. The ee was determined to be 97% with catalyst 3a
and À96% with catalyst 5b by chiral HPLC analysis (AS-H
À1
13
column, hexane-2-propanol 90:10, 1.0 mLmin , l=
1H), 7.55 (dd, J=1.2, 7.6 Hz, 1H); C NMR (100 MHz,
2
D
0
2
1
20 nm): tR (R)=6.6 min, t (S)=6.2 min. 2f: [a] : 68.5 (c,
.06, CHCl ), ent-2f: [a] : À65.8 (c, 1.01, CHCl ).
CDCl ): d=13.8, 13.9, 30.1, 46.0, 55.6, 61.8, 61.8, 123.8,
R
3
2
D
0
127.4, 129.3, 131.0, 133.3, 137.9, 166.5, 166.8, 192.9; IR
(KBr): v=2980, 2928, 1732, 1699, 1469, 1369, 1259, 1097,
953, 752, 626 cm ; HR-MS (ESI): m/z=403.0219, calcd. for
3
3
Diethyl
(R)-acetylthio(3-chlorophenyl)methylmalonate
1
À1
(
2g): Yellowish oil; yield: 34.4 mg (96%). H NMR
+
+
(400 MHz, CDCl ): d=1.10 (t, J=7.2 Hz, 3H), 1.26 (t, J=
C H BrO S [M+H] : 403.0215. The ee was determined to
16 20 5
3
7
.2 Hz, 3H), 2.30 (s, 3H), 3.97 (d, J=9.6 Hz, 1H), 4.05 (q,
J=7.2 Hz, 2H), 4.20 (dq, J=10.8, 7.2 Hz, 1H), 4.22 (dq, J=
be 97% by chiral HPLC analysis (AS-H column, hexane-2-
À1
propanol 96:4, 1.0 mLmin , l=220 nm): t (major, R)=
R
2
0
1
2
0.8, 7.2 Hz, 1H), 5.29 (d, J=9.6 Hz, 1H), 7.20–7.23 (m,
11.9 min, tR (minor, S)=11.0 min. [a] : 40.2 (c, 1.06,
D
1
3
H), 7.25–7.27 (m, 1H), 7.36–7.37 (m, 1H); C NMR
CHCl ).
3
(
1
100 MHz, CDCl ): d=13.8, 13.9, 30.3, 45.5, 56.9, 61.9, 62.0,
26.4, 128.0, 128.4, 129.7, 134.2, 141.4, 166.2, 166.6, 192.5; IR
Diethyl (R)-acetylthio(2-trifluorophenyl)methylmalonate
(2k): Colorless oil; yield: 37.0 mg (94%). H NMR
3
1
(
1
KBr): v=2982, 1735, 1700, 1476, 1369, 1301, 1249, 1131,
(400 MHz, CDCl ): d=1.14 (t, J=7.2 Hz, 3H), 1.22 (t, J=
3
À1
098, 953, 692, 626 cm ; HR-MS (ESI): m/z=359.0716,
7.2 Hz, 3H), 2.28 (s, 3H), 4.09 (dq, J=10.8, 7.2 Hz, 1H),
4.12 (dq, J=10.8, 7.2 Hz, 1H), 4.16 (d, J=6.8 Hz, 1H), 4.16
(dq, J=10.8, 7.2 Hz, 1H), 4.19 (dq, J=10.8, 7.2 Hz, 1H),
+
+
calcd. for C H ClO S [M+H] : 359.0720. The ee was de-
termined to be 82% by chiral HPLC analysis (AD-H
column, hexane-2-propanol 99:1, 1.0 mLmin , l=220 nm):
tR (major, R)=32.8 min, tR (minor, S)=30.3 min. [a] : 84.7
16
20
5
À1
5.76 (d, J=6.8 Hz, 1H), 7.34–7.39 (m, 1H), 7.47–7.51 (m,
2
0
13
1H), 7.65–7.67 (m, 2H); C NMR (100 MHz, CDCl ): d=
D
3
(
c, 0.94, CHCl ).
13.7, 13.9, 30.0, 42.1, 57.3, 61.8, 61.9, 124.1 (q, JC,F =
3
Diethyl
(R)-acetylthio(4-chlorophenyl)methylmalonate
272.6 Hz), 126.6 (q, JC,F =5.8 Hz), 127.8 (q, JC,F =29.8 Hz),
127.9, 130.6, 132.0, 137.9, 166.4, 167.0, 192.4; IR (KBr): v=
(
2
2h): Yellowish oil; yield of 2h: 35.3 mg (98%), yield of ent-
h: 34.0 mg (95%). H NMR (400 MHz, CDCl ): d=1.09 (t,
J=7.2 Hz, 3H), 1.26 (t, J=7.2 Hz, 3H), 2.29 (s, 3H), 3.97
1
À1
2982, 1737, 1704, 1312, 1156, 1127, 1037 cm ; HR-MS
3
+
+
(ESI): m/z=393.0988, calcd. for C H F O S [M+H] :
17 20 3 5
(
d, J=10.0 Hz, 1H), 4.04 (q, J=7.2 Hz, 2H), 4.19 (dq, J=
393.0984. The ee was determined to be 97% by chiral HPLC
1
9
2
5
0.8, 7.2 Hz, 1H), 4.22 (dq, J=10.8, 7.2 Hz, 1H), 5.29 (d, J=
analysis (AD-H column, hexane-2-propanol 90:10,
À1
.6 Hz, 1H), 7.25 (d, J=8.4 Hz, 2H), 7.32 (d, J=8.4 Hz,
1.0 mLmin , l=220 nm): t (major, R)=7.3 min, t (minor,
R
R
13
20
D
H); C NMR (100 MHz, CDCl ): d=13.8, 14.0, 30.3, 45.4,
S)=7.7 min. [a] : 84.9 (c, 1.0, CHCl ).
3
3
7.0, 61.9, 62.0, 128.6, 129.6, 133,6, 138.0, 166.2, 166.6, 192.6;
Diethyl
(R)-acetylthio(2-methylphenyl)methylmalonate
IR (KBr): v=2962, 2920, 1733, 1699, 1490, 1384, 1259, 1127,
(2l): Colorless oil; yield of 2l: 31.3 (92%), yield of ent-2l:
À1
1
1
015, 799, 625 cm ; HR-MS (ESI): m/z=381.0539, calcd.
31.6 mg (93%). H NMR (400 MHz, CDCl ): d=1.02 (t, J=
3
+
+
for C H ClO SNa [M+Na] : 381.0539. The ee was deter-
7.2 Hz, 3H), 1.26 (t, J=7.2 Hz, 3H), 2.27 (s, 3H), 2.53 (s,
3H), 3.98 (q, J=7.2 Hz, 2H), 4.03 (d, J=10.0 Hz, 1H), 4.19
(dq, J=9.2, 7.2 Hz, 1H), 4.21 (dq, J=9.2, 7.2 Hz, 1H), 5.59
16
19
5
mined to be 81% with catalyst 3a and À77% with catalyst
5b by chiral HPLC analysis (AS-H column, hexane-2-propa-
6
asc.wiley-vch.de
ꢁ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 0000, 000, 0 – 0
ÝÝ
These are not the final page numbers!

FULL PAPERS
Organocatalytic Enantioselective Sulfur-Michael Addition of Thioacetic Acid
(
d, J=10.4 Hz, 1H), 7.12–7.15 (m, 3H), 7.25–7.28 (m, 1H);
Diethyl (R)-acetylthio(4-methoxyphenyl)methylmalonate
13
C NMR (100 MHz, CDCl ): d=13.7, 13.9, 19.6, 30.1, 42.4,
(2p): Colorless oil; yield of 2p: 35.0 mg (99%), yield of ent-
3
1
5
1
1
7.3, 61.7, 61.8, 126.2, 127.7, 127.9, 130.7, 136.2, 137.5, 166.5,
2p: 34.0 mg (96%). H NMR (400 MHz, CDCl
): d=1.08 (t,
3
66.9, 192.9; IR (KBr): v=2974, 2929, 1735, 1696, 1464,
J=7.2 Hz, 3H), 1.26 (t, J=7.2 Hz, 3H), 2.28 (s, 3H), 3.77 (s,
3H), 3.98 (d, J=9.6 Hz, 1H), 4.03 (q, J=7.2 Hz, 2H), 4.19
(dq, J=10.8, 7.2 Hz, 1H), 4.22 (dq, J=10.8, 7.2 Hz, 1H),
5.30 (d, J=10.0 Hz, 1H), 6.81 (d, J=8.8 Hz, 2H), 7.29 (d,
À1
369, 1306, 1253, 1128, 1094, 1049, 626 cm ; HR-MS (ESI):
+
+
m/z=339.1265, calcd. for C H O S [M+H] : 339.1266.
1
7
23
5
The ee was determined to be 90% with catalyst 3a and
À92% with catalyst 5b by chiral HPLC analysis (AS-H
1
3
J=8.8 Hz, 2H); C NMR (100 MHz, CDCl
30.4, 45.6, 55.2, 57.4, 61.8, 61.8, 113.8, 129.3, 131.4, 159.0,
): d=13.8, 14.0,
3
À1
column, hexane-2-propanol 94:6, 1.0 mLmin , l=220 nm):
2
0
1
1
(
66.4, 166.9, 192.9; IR (KBr): v=2961, 2924, 1735, 1696,
tR (R)=6.8 min, tR (S)=6.2 min. 2l: [a] : 107.5 (c, 1.00,
CHCl ), ent-2l: [a] : À112.1 (c, 1.06, CHCl ).
D
À1
2
D
0
513, 1463, 1368, 1259, 1141, 1028, 799, 626 cm ); HR-MS
3
3
+
+
ESI): m/z=355.1211, calcd. for C H O S [M+H] :
Diethyl (R)-acetylthio(2-methoxyphenyl)methylmalonate
17 23 6
3
55.1215. The ee was determined to be 60% with catalyst 3a
(
2
2m): Colorless oil; yield of 2m: 32.0 mg (90%), yield of ent-
1
and À62% with catalyst 5b by chiral HPLC analysis (AD-H
m: 33.4 mg (94%). H NMR (400 MHz, CDCl ): d=1.01 (t,
3
À1
column, hexane-2-propanol 80:20, 1.0 mLmin , l=
J=7.2 Hz, 3H), 1.24 (t, J=7.2 Hz, 3H), 2.27 (s, 3H), 3.89 (s,
2
0
2
1
20 nm): t (R)=9.3 min, t (S)=10.6 min. 2p: [a] : 31.8 (c,
R R
D
20
3
4
5
1
1
1
1
3
H), 3.96 (q, J=7.2 Hz, 2H), 4.17 (dq, J=10.8, 7.2 Hz, 1H),
.21 (dq, J=10.8, 7.2 Hz, 1H), 4.36 (d, J=10.4 Hz, 1H),
.48 (d, J=10.8 Hz, 1H), 6.83–6.89 (m, 2H), 7.20–7.25 (m,
.00, CHCl ), ent-2p: [a] : À30.3 (c, 1.01, CHCl ).
3
D
3
Diethyl (R)-acetylthio(naphthalen-1-yl)methylmalonate
(2q): Colorless oil; yield of 2q: 36.0 mg (96%); yield of ent-
1
3
H), 7.36–7.39 (m, 1H); C NMR (100 MHz, CDCl ): d=
3
1
2
q: 36.4 mg (97%). H NMR (400 MHz, CDCl ): d=0.90 (t,
3
3.7, 14.0, 30.2, 43.2, 55.4, 55.5, 61.4, 61.6, 110.9, 120.4, 126.8,
J=7.2 Hz, 3H), 1.25 (t, J=7.2 Hz, 3H), 2.28 (s, 3H), 3.93
(q, J=7.2 Hz, 2H), 4.19 (dq, J=10.8, 7.2 Hz, 1H), 4.21 (dq,
J=10.8, 7.2 Hz, 1H), 4.30 (d, J=9.6 Hz, 1H), 6.21 (d, J=
.2 Hz, 1H), 7.39 (dd, J=7.6, 7.6 Hz, 1H), 7.50 (dd, J=7.2,
.6 Hz, 1H), 7.56 (d, J=7.2 Hz, 1H), 7.60 (dd, J=8.0,
29.2, 130.5, 157.1, 166.8, 167.2, 193.4; IR (KBr): v=2924,
À1
734, 1696, 1251, 1118, 1026 cm ; HR-MS (ESI): m/z=
+
+
55.1212, calcd. for C H O S [M+H] : 355.1215. The ee
1
7
23
6
9
7
was determined to be 68% with catalyst 3a and À72% with
catalyst 5b by chiral HPLC analysis (AS-H column, hexane-
À1
7.2 Hz, 1H), 7.75 (d, J=8.0 Hz, 1H), 7.84 (d, J=8.4 Hz,
2
7
2
-propanol 90:10, 1.0 mLmin , l=220 nm): tR (R)=
13
2
D
0
1H), 8.32 (d, J=7.6 Hz, 1H). C NMR (100 MHz, CDCl
d=13.6, 13.9, 30.1, 57.5, 61.7, 61.9, 123.4, 125.1, 125.9, 126.7,
28.6, 128.9, 130.5, 133.9, 135.2, 166.5, 167.0, 193.0; IR
3
):
.4 min, t (S)=6.6 min. 2m: [a] : 90.8 (c, 0.98, CHCl ), ent-
R
3
20
m: [a] : À98.0 (c, 1.02, CHCl ).
D
3
1
Diethyl
(R)-acetylthio(4-fluorophenyl)methylmalonate
1
(KBr): v=2960, 2930, 1731, 1693, 1259, 1111, 1031,
(
2n): Colorless oil; yield: 32.3 mg (94%). H NMR
À1
7
97 cm ; HR-MS (ESI): m/z=375.1260, calcd. for
(400 MHz, CDCl ): d=1.08 (t, J=7.2 Hz, 3H), 1.25 (t, J=
3
+
+
C H O S [M+H] : 375.1266. The ee was determined to
2
0
23
5
7
.2 Hz, 3H), 2.29 (s, 3H), 3.97 (d, J=9.6 Hz, 1H), 4.04 (q,
be 97% with catalyst 3a and À97% with catalyst 5b by
J=7.2 Hz, 2H), 4.19 (dq, J=10.8, 7.2 Hz, 1H), 4.22 (dq, J=
1
8
chiral HPLC analysis (AS-H column, hexane-2-propanol
0.8, 7.2 Hz, 1H), 5.30 (d, J=10.0 Hz, 1H), 6.97 (dd, J=8.4,
À1
20
9
9
(
4:6, 1.0 mLmin , l=220 nm): t (R)=9.9 min, t (S)=
1
3
R
R
20
.8 Hz, 2H), 7.36 (dd, J=5.2, 8.4 Hz, 2H); C NMR
.2 min. 2q: [a] : 67.8 (c, 1.11, CHCl ), ent-2q: [a] : À61.7
D
3
D
(100 MHz, CDCl ): d=13.8, 13.9, 30.3, 45.4, 57.2, 61.9, 61.9,
3
c, 1.01, CHCl ).
3
2
3
1
15.3 (d, JC,F =22 Hz), 129.9 (d, JC,F =8 Hz), 135.2 (d,
Diethyl
nate (2r): Colorless oil; yield: 36.3 mg (92%). H NMR
400 MHz, CDCl ): d=1.02 (t, J=7.2 Hz, 3H), 1.28 (t, J=
(R)-acetylthio(2,6-dichlorophenyl)methylmalo-
4
1
JC,F =3 Hz), 162.1 (d, J =246 Hz), 166.3, 166.7, 192.7; IR
1
C,F
(
9
KBr): v=2961, 2923, 1735, 1696, 1509, 1368, 1098, 1023,
(
À1
3
56, 799, 624 cm ; HR-MS (ESI): m/z=365.0834, calcd. for
7
2
7
.2 Hz, 3H), 2.31 (s, 3H), 3.92–4.00 (m, 2H), 4.19–4.28 (m,
H), 4.61 (d, J=11.6 Hz, 1H), 6.38 (d, J=11.6 Hz, 1H),
.10–7.14 (m, 1H), 7.26–7.28 (m, 1H), 7.31–7.33 (m, 1H);
+
+
C H FO SNa [M+Na] : 365.0835. The ee was determined
to be 79% by chiral HPLC analysis (AS-H column, hexane-
2
8
16
19
5
À1
-propanol 90:10, 1.0 mLmin , l=220 nm): t (major, R)=
13
R
C NMR (100 MHz, CDCl ): d=13.6, 13.9, 29.8, 41.3, 55.0,
3
2
0
.2 min, tR (minor, S)=7.6 min. [a] : 82.8 (c, 1.21, CHCl ).
D
3
61.7, 61.9, 128.8, 129.3, 129.3, 134.8, 135.7, 136.2, 166.1,
Diethyl
(R)-acetylthio(4-bromophenyl)methylmalonate
1
1
66.4, 191.9; IR (KBr): v=2980, 2928, 1733, 1699, 1475,
(
2
2o): Yellowish oil; yield of 2o: 39.0 mg (97%), yield of ent-
À1
391, 1245, 1132, 1038, 954, 755, 630 cm ; HR-MS (ESI): m/
1
o: 37.8 mg (95%). H NMR (400 MHz, CDCl ): d=1.10 (t,
+
+
3
z=392.0253, calcd. for C H Cl O S [M+H] : 392.0252.
16 18 2 5
J=7.2 Hz, 3H), 1.26 (t, J=7.2 Hz, 3H), 2.28 (s, 3H), 3.97
d, J=10.0 Hz, 1H), 4.04 (q, J=7.2 Hz, 2H), 4.19 (dq, J=
The ee was determined to be 26% by chiral HPLC analysis
À1
(
(
2
[
AS-H column, hexane-2-propanol 90:10, 1.0 mLmin , l=
1
1
2
5
0.8, 7.2 Hz, 1H), 4.22 (dq, J=10.8, 7.2 Hz, 1H), 5.27 (d, J=
20 nm): t (major, R)=7.5 min, tR (minor, S)=6.7 min.
R
2
D
0
0.0 Hz, 1H), 7.26 (d, J=8.0 Hz, 2H), 7.41 (d, J=8.0 Hz,
a] : 18.8 (c, 1.03, CHCl )
3
13
H); C NMR (100 MHz, CDCl ): d=13.8, 14.0, 30.3, 45.5,
3
Diethyl (S)-acetylthio(cyclohexyl)methylmalonate (2s):
1
6.9, 62.0, 62.0, 121.8, 129.9,131.6, 138.5, 166.2, 166.6, 192.6;
Colorless oil; yield: 28.0 mg (85%). H NMR (400 MHz,
IR (KBr): v=2980, 1736, 1698, 1488, 1369, 1309, 1249, 1132,
1
for C H BrO S [M+H] : 403.0215. The ee was deter-
CDCl ): d=0.95–1.20 (m, 5H), 1.24 (t, J=7.2 Hz, 3H), 1.27
3
À1
029, 1011, 624 cm ; HR-MS (ESI): m/z=403.0214, calcd.
(t, J=7.2 Hz, 3H), 1.55–1.75 (m, 5H), 1.80–1.85 (m, 1H),
2.32 (s, 3H), 3.86 (d, J=6.8 Hz, 1H), 4.10–4.26 (m, 5H);
+
+
16
20
5
1
3
mined to be 79% with catalyst 3a and À79% with catalyst
C NMR (100 MHz, CDCl ): d=13.9, 14.0, 26.0, 26.0, 29.4,
3
5
b by chiral HPLC analysis (AD-H column, hexane-2-prop-
30.3, 30.7, 40.4, 47.7, 54.0, 61.5, 61.7, 167.6, 167.8, 194.5; IR
À1
anol 80:20, 1.0 mLmin , l=220 nm): t (R)=7.5 min, tR
(
À81.0 (c, 0.96, CHCl ).
(KBr): v=2927, 2853, 1736, 1692, 1384, 1180, 1142, 1075,
R
2
D
0
20
D
À1
S)=8.9 min. 2o: [a] : 83.4 (c, 1.05, CHCl ), ent-2o: [a] :
629 cm ;. HR-MS (ESI): m/z=331.1582, calcd. for
3
+
+
C H O S [M+H] : 331.1579. The ee was determined to
3
16 27 5
Adv. Synth. Catal. 0000, 000, 0 – 0
ꢁ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Renchao Wang et al.
FULL PAPERS
be 12% by chiral HPLC analysis (AD-H column, hexane-2- Acknowledgements
À1
propanol 90:10, 1.0 mLmin , l=220 nm): t (major, S)=
R
2
0
5
.0 min, tR (minor, R)=4.8 min. [a] : À7.19 (c, 1.21,
This work was supported in part by the National Basic Re-
search Program of China (No. 2013CB328905) and the Na-
tional Natural Science Foundation of China (Nos. 21172017
and 21372025).
D
CHCl ).
3
Transformation of Product 2a to Methyl (R)-3-Mer-
capto-3-phenylpropanoate (6)
Under an N2 atmosphere
a mixture of 2a (130 mg,
0
.4 mmol) and 6M aqueous HCl (2 mL) was refluxed for 6 h
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product methyl (R)-3-mercapto-3-phenylpropanoate (6) as
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a colorless oil: ; yield: 36 mg (46%). H NMR (400 MHz,
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3
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4
sure the crude product was purified by column chromatogra-
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1
nate (7) as a colorless oil; yield: 76 mg (90%). H NMR
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3
7
2
.2 Hz, 3H), 2.42 (d, J=6.8 Hz, 1H), 3.92 (q, J=7.2 Hz,
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1
3
(
(
1
dd, J=6.8, 11.2 Hz, 1H), 7.27–7.34 (m, 5H); C NMR
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3
2
5
27.3, 127.9, 128.7, 140.3, 166.4, 167.4. [a] : 56.0 (c, 0.95,
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10 Organocatalytic Enantioselective Sulfur-Michael Addition
of Thioacetic Acid to Arylmethylidenemalonates
Adv. Synth. Catal. 2014, 356, 1 – 10
Renchao Wang, Jing Liu, Jiaxi Xu*
10
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ÝÝ
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