Synthesis of α-sulfanyl-β-amino acid derivatives by using nanocrystalline magnesium oxide

Article abstract of DOI:10.1016/j.tet.2010.05.002

The Mannich-type reaction between alkyl, aryl and heterocyclic aldimines and sulfonium salts for the synthesis of α-sulfanyl-β-amino acid derivatives by using nanocrystalline magnesium oxide (NAP-MgO) is described. These products are obtained in moderate to high yields with moderate diastereoselectivities. The configuration of ethyl-3-{[(4-methylphenyl)sulfonyl] amino}-2-(methylsulfanyl)-3-(4-nitrophenyl)propanoate (major isomer) has been confirmed by X-ray diffraction technique to be anti, and consistent with the assignment based on ¹H NMR spectroscopy. These α-sulfanyl- β-amino acid derivatives are important building blocks for pharmaceuticals with potent biological activity.

Full text of DOI:10.1016/j.tet.2010.05.002

Tetrahedron 66 (2010) 5042e5052
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis of a-sulfanyl-b-amino acid derivatives by using nanocrystalline
magnesium oxide
,
a
a
b
M. Lakshmi Kantam a , Koosam Mahendar , Bojja Sreedhar , Boyapati. M. Choudary ,
*
Suresh K. Bhargava c, Steven H. Priver c
a Inorganic and Physical Chemistry Division, Indian Institute of Chemical Technology, Hyderabad 500 007, India
b Ogene Systems (I) Pvt. Ltd, Hyderabad 500 037, India
c School of Applied Sciences, RMIT University, Melbourne 3001, Australia
a r t i c l e i n f o
a b s t r a c t
Article history:
The Mannich-type reaction between alkyl, aryl and heterocyclic aldimines and sulfonium salts for the
Received 20 December 2009
Received in revised form 11 April 2010
Accepted 1 May 2010
synthesis of a-sulfanyl-b-amino acid derivatives by using nanocrystalline magnesium oxide (NAP-MgO)
is described. These products are obtained in moderate to high yields with moderate diaster-
eoselectivities. The configuration of ethyl-3-{[(4-methylphenyl)sulfonyl]amino}-2-(methylsulfanyl)-3-(4-
nitrophenyl)propanoate (major isomer) has been confirmed by X-ray diffraction technique to be anti, and
Available online 7 May 2010
consistent with the assignment based on 1H NMR spectroscopy. These
a
-sulfanyl-
rivatives are important building blocks for pharmaceuticals with potent biological activity.
Ó 2010 Elsevier Ltd. All rights reserved.
b-amino acid de-
1. Introduction
promising route for the synthesis of b-amino esters is the one-pot
Ni, Rh or Zn catalyzed Reformatsky-type reaction of an aldehyde,
b
-Amino acids and their derivatives, although far less abundant
in nature than their -analogues, are pharmacologically important
compounds.1a They can be used as precursors for medicinally
important
-lactam antibiotics,1b antifungal cyclic -amino acids1c,
amine and ester.7
In addition, the synthesis of sulfur containing amino acid
derivatives has received considerable attention due to the unique
biological properties imparted by the sulfur atom.8 For example,
a
b
b
and as constituents of biologically active unnatural peptides.1e,f
The Mannich reaction is one of the direct approaches for the
preparation of these useful class of compounds, and has been ac-
tively investigated for many years.2 The Mannich reaction produces
two adjacent stereogenic centres, constructed simultaneously with
concomitant CeC bond formation. This provides a unique oppor-
tunity for directly and selectively introducing substituents at both
pseudotripeptides containing a-mercapto-b-amino acid residues
d
have been shown to be potent inhibitors of aminopeptidase A,9a
tetanus neurotoxin9b and botolinum neurotoxin type B,9cef while
azetidinones derived from
a-mercapto-b-amino acids display
potent inhibition of cholesterol absorption.9g Some amino acid
drugs containing the thiol moiety, such as captopril, are well-
known angiotensin-converting enzyme inhibitors.10 As a result of
the
a
and
b
-positions through the choice of electrophile and
the biological activity associated with these a-mercapto-b-amino
nucleophile employed.3
acid derivatives, the synthesis of these derivatives has evoked
Based on these considerations, numerous reports for the
a lot of interest.11e14
synthesis of
b-amino acids (esters) have been investigated to date.
The procedures used for the synthesis of b-amino acid
For example, Lewis acid and Lewis base promoted addition of silyl
derivatives often involve the use of undesirable toxic and hazard-
ous metal salts. The development of suitable ecofriendly reagents is
of great significance and the use of relatively benign heterogeneous
catalysts has been reported recently.15
Nanocrystalline metal oxides have found excellent applications as
active adsorbents for gases, for the destruction of hazardous chem-
icals,16 and as catalysts for various organic transformations.17 These
high reactivities are due to high surface areas combined with
unusually reactive morphologies. In continuation of our work on the
application of nanomaterials in organic methodologies, we report an
effective Mannich-type reaction between N-sulfonyl aldimines18 and
enol ethers to aldimines4 and addition of Li and Ti ester enolates to
aldimines5 are widely used for the synthesis of
b-amino esters. The
most prevalent methods for asymmetric Mannich reactions rely on
Shibasaki’s (S,S)-linked-binol complexes,6a,b Jacobsen’s urea deriv-
atives,6c Trost’s dinuclear zinc complexes6d and List’s proline
organo catalysis6e for the synthesis of chiral
b-amino acids. Another
* Corresponding author. Fax: þ91 40 27160921; e-mail addresses: mlakshmi@iict.
res.in, lkmannepalli@yahoo.com (M.L. Kantam).
0040-4020/$ e see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2010.05.002

M.L. Kantam et al. / Tetrahedron 66 (2010) 5042e5052
5043
various sulfonium salts to afford
in moderate to high yields with moderate diastereoselectivities us-
ing nanocrystalline magnesium oxide (NAP-MgO).
a
-sulfanyl-
b
-amino acid derivatives
(Table 2, entry 8). Conversely, using an excess sulfonium salt (Table 2,
entries 9 and 10) gave higher yields; there was also a slight im-
provement in diastereoselectivity, which led us to adopt these con-
ditions as optimal for this reaction (Table 2, entry 10). Using dried
solvent and performing the reaction under an inert atmosphere did
not significantly alter the yield or diastereoselectivity (Table 2, entry
11). Subsequently, when we used 0.5, 1.0, 2.0 equiv of water in
combination with acetonitrile did not significantly effect the yield or
diastereoselectivity (Table 2, entries 12e14). When 50.0 equiv of
water in acetonitrile and water without any organic solvent were
used, it showed no reaction because more water content de-
composes the catalyst and sulfonium salt (Table 2, entries 15 and 16).
2. Results and discussion
N-Sulfonyl aldimines 1 react with sulfonium salts 2 in a Man-
nich-type reaction in the presence of a nanocrystalline MgO
catalyst to afford
These results are in contrast to many reports in which aziridine,
aziridinyl carboxamide or
-amino alkenes are the final products.19
a-sulfanyl-b-amino acid derivatives (Scheme 1).
b
In order to understand the relationship between structure and
PG
PG
PG
HN
HN
N
Br-
NAP-MgO
COOR2
COOR2
+
+
+
R
COOR2
2A-D
1S
R
R
acetonitrile, rt
R
H
SR1
(syn)
SR1
(anti)
1a-p
R = aromatic,
heterocylic,
aliphatic
PG = Ts, Bzs, Ms,
Tris, Bus
R1 = Me, R2 = Et 2A
R1 = Me, R2 = tBu 2B
R1 = Me, R2 = Me 2C
R1 = Et, R2 = Et 2D
R1 = Me, Et
R2 = Me, Et, tBu
Scheme 1. NAP-MgO catalyzed Mannich-type reaction between N-sulfonyl aldimines 1 and ester sulfonium salts 2AeD.
reactivity, various forms of magnesium oxide crystals [CM-MgO
Table 2
(commercial MgO, SSA: 30 m2/g), NA-MgO (NanoActive MgO,
conventionally prepared MgO, SSA: 250 m2/g), NAP-MgO
(NanoActive Plus MgO, aerogel prepared MgO, SSA: 590 m2/g) and
silylated MgO, Sil-NAP-MgO] were initially evaluated in the
reaction between N-tosyl benzaldimine 1a (PG¼Ts, R¼Ph) and
(ethoxycarbonylmethyl)dimethylsulfonium bromide 2A (Scheme
1). It was found that all forms of MgO catalyze the reaction in
high yields, however, the high surface area NAP-MgO was found to
be superior to that of NA-MgO and CM-MgO (Table 1).
Optimization of the Mannich-type reaction of N-tosyl benzaldimine 1a with
(ethoxycarbonylmethyl)dimethylsulfonium bromide 2A catalyzed by NAP-MgOa
Entry
Solvent
Time (h)
Yieldb (%)
anti/sync
1
2
3
4
5
6
7
8
THF
DCM
DMF
CHCl3
Methanol
Toluene
Acetonitrile
Acetonitriled
Acetonitrilee
Acetonitrilef
Dry acetonitrilef,g
Acetonitrilei
Acetonitrilej
Acetonitrilek
Acetonitrilel
Water
24
24
12
24
6
24
24
24
16
12
12
12
16
24
24
24
64
65
56
61
62:38
66:34
60:40
56:44
d
Traceh
36
50:50
72:28
68:32
72:28
76:24
75:25
72:28
70:30
72:28
d
72
61
84
91
89
90
89
Table 1
9
Mannich-type reaction between N-tosyl benzaldimine 1a and (ethoxy-
10
11
12
13
14
15
16
carbonylmethyl)dimethylsulfonium bromide 2A with various catalystsa
Entry
Catalyst
Time (h)
Yieldb (%)
anti/sync
1
2
3
4
5
NAP-MgO
NA-MgO
CM-MgO
Sil-NAP-MgO
None
12, 15d
21
32
22
48
91, 89d
90
87
76:24
72:28
62:38
71:29
d
84
NRm
NRm
d
85
a
N.Re
Reaction conditions: N-tosyl benzaldimine 1a (1 mmol), (ethoxy-
carbonylmethyl)dimethylsulfonium bromide 2A (1 mmol), NAP-MgO catalyst
(0.1 g), solvent (5 mL) at room temperature.
a
Reaction conditions: N-tosyl benzaldimine 1a (1 mmol), (ethoxy-
carbonylmethyl)dimethylsulfonium bromide 2A (2 mmol), catalyst (0.1 g), aceto-
nitrile (5 mL) at room temperature.
b
Isolated yield of both diastereomers.
c
The ratio of anti/syn isomers was determined by 1H NMR spectroscopy of the
b
Isolated yield of both diastereomers.
crude reaction mixture.
c
The ratio of anti/syn isomers was determined by 1H NMR spectroscopy of the
d
Reaction conducted at 0 ꢀC.
Reaction using 1.5 mmol sulfonium salt.
Reaction using 2 mmol sulfonium salt.
Under N2 atmosphere.
Tosyl amine was isolated almost quantitatively.
Water (0.5 equiv)was added.
Water (1.0 equiv) was added.
Water (2.0 equiv) was added.
e
crude reaction mixture.
d
f
Fourth cycle.
No Reaction.
e
g
h
i
Based on these initial results, the effect of various solvents on the
reaction between 1a and 2A was investigated using NAP-MgO as
catalyst. The nature of the solvent had a striking effect on the yields
as well as diastereoselectvity of the reaction product. The use of
a non-coordinating solvent like toluene led to lower yields with
lower diastereoselectivity when compared to polar solvents. Using
the highly polar, protic solvent methanol, the starting imine was
converted to p-tosyl amine and only traces of the product were
isolated (Table 2, entry 5). In polar, aprotic solvents (THF, DCM, DMF
and CHCl3), the products were obtained in moderate yields with
moderate diastereoselectivities. However, in acetonitrile, a reason-
able yield was obtained with good selectivity (Table 2, entry 7),
which was therefore selected for future reactions. At low tempera-
ture, a decrease in the diastereoselectivity and yield was observed
j
k
l
Water (50.0 equiv) was added (excess).
Due to more water content, catalyst and sulfonium salt were decomposed.
m
Using the optimized conditions above, the reaction between
various aldimines 1 and sulfonium salts 2 was investigated and the
results are summarized in Table 3. In all cases, the reaction
proceeded smoothly to provide the desired
a-sulfanyl-b-amino
esters in high yields with moderate diastereoselectivity. As expec-
ted, the rate of the reaction was faster for electron-poor imines (1c,
1d, 1i and 1m) than for electron-rich imines (1b, 1j and 1n). Het-
erocyclic aldimines (1p and 1f) reacted with the sulfonium salts 2A
and 2B, respectively, to afford the products with poor

5044
M.L. Kantam et al. / Tetrahedron 66 (2010) 5042e5052
Table 3
the assignments was obtained by a single crystal X-ray analysis of
compound ethyl-3-{[(4-methylphenyl)sulfonyl]amino}-2-(methyl-
sulfanyl)-3-(4-nitrophenyl)propanoate (major isomer) (Table 3,
rntry 3). Crystal was grown from CHCl3 and was shown to be the
anti configuration (Fig. 1),20 and consistent with the NMR spec-
troscopic assignments.
NAP-MgO catalyzed Mannich-type reaction between N-sulfonyl aldimines 1 and
ester sulfonium salts 2AeDa
Sl. no. Aldimine 1
Sulfonium Time Products
salt 2
(h)
R
PG
Yieldb (%) anti/sync
1
2
3
4
5
6
7
8
Ph
4-OMePh
4-NO2Ph
Ts
Ts
Ts
1a 2A
12
24
15
12
20
18
12
6
6
10
7
8
6
18
14
8
24
12
8
12
8
10
7
91
86
82
92
73
94
88
82
94
89
85
84
86
83
77
89
90
91
92
88
87
94
91
82
89
79
76:24
78:22
79:71
81:19
76:24
69:31
67:33
75:25
78:22
71:29
78:22
75:25
68:32
70:30
90:10
52:48
92:8
55:45
90:10
86:14
58:42
55:45
52:48
89:11
85:15
83:17
1b 2A
1c 2A
1d 2A
1e 2A
2A
1g 2A
1h 2A
2A
2A
1k 2A
1l 2A
1m 2A
1n 2A
4-Cl,3-NO2Ph Ts
Cinnamyl
2-Furyl
Cyclohexyl
Ph
4-ClPh
4-MePh
2-Napthyl
Ph
4-ClPh
4-OMePh
4-NO2Ph
2-Pyridyl
4-OMePh
2-Furyl
4-ClPh
Ph
Ts
Ts
Ts
Bzs
Bzs
Bzs
Bzs
Ms
Ms
Ms
1f
9
1i
1j
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
TIP Bzs 1o 2A
Bus
Ts
Ts
Bzs
Ms
Ts
Bzs
Ms
Ts
1p 2A
1b 2B
1f
1i
1l
2B
2B
2B
Ph
4-MePh
Ph
Ph
4-ClPh
Ph
1a 2C
1j
1l
2C
2C
1a 2D
16
10
12
Bzs
Ms
1i
1l
2D
2D
a
Reaction conditions: aldimine 1 (1 mmol), sulfonium salt 2AeD (2 mmol), NAP-
MgO catalyst (0.1 g), acetonitrile (5 mL) at room temperature.
b
Isolated yield of both diastereomers.
c
The ratio of anti/syn isomers was determined by 1H NMR spectroscopy of the
crude reaction mixture.
Figure 1. Thermal ellipsoidal plot of compound ethyl-3-{[(4-methylphenyl)sulfonyl]
amino}-2-(methylsulfanyl)-3-(4-nitrophenyl)propanoate (major isomer) (Table 3, en-
try 3). Displacement ellipsoids are drawn at the 25% probability level except for the
hydrogen atoms, which are shown as circles of arbitrary radius.
diastereoselectivity (syn/anti ratio 52:48 and 55:45, respectively)
(Table 3, entries 16 and 18). The furfural-derived imine 1f reacted
with 2A (Table 3, entry 6) to afford the corresponding product in
high yield with moderate diastereoselectivity. This reaction is of
particular interest as the furan moiety can be readily derivatized
into several useful functional groups. The reaction of the cyclohexyl
The results of the structural studies gave us great confidence in
assigning the anti configuration to the major isomers and syn
configuration to the minor isomers on the basis of chemical shift,
coupling constant trends and response factors (Rf) of isomers.21
Most of the syn and anti diastereomers were easily separated by
means of column chromatography; but those compounds obtained
from heterocyclic and aliphatic imines, and those with tert-butyl
ester sulfonium salts could not be separated.
The results from these reactions prompted us to expand our
investigation using other sulfonium salts as nucleophiles. Using the
optimized reaction conditions, other sulfonium salts (2E, 2F, 2G,
2H) reacted with N-sulfonyl aldimines to give the corresponding
aldimine 1g with 2A gave the b-amino ester in high yield with
moderate selectivity (Table 3, entry 7), indicating that the reaction
is not only restricted to aromatic aldimines and the scope of the
transformation may be further extended to include alkyl aldimines.
The protecting group on the aldimine was varied to determine if
this has any influence on the reaction outcome. A variety of struc-
turally different aldimines containing N-p-toluene sulfonyl (Ts),
N-benzene sulfonyl (Bzs), N-methane sulfonyl (Ms), N-2,4,6-tri-
isopropylbenzene sulfonyl (Tris) and N-tert-butyl sulfonyl (Bus)
groups were reacted with the sulfonium salts 2AeD, afforded the
expected products in high yields and moderate diaster-
eoselectivities. Replacement of the Ts group by the much bulkier
Tris group (Table 3, entries 3 and 15) gave a higher proportion of the
anti configuration, suggesting the diastereoselectivity is influenced
by the steric bulk of the imine protecting group.
Greater diastereoselectivity was also observed when sulfonium
salts containing bulkier substituents were used. Changing the ester
functionality from ethyl to tert-butyl resulted in a significant in-
crease in the proportion of the anti configuration (Table 3, entries 2
and 17). A similar effect was observed by increasing the alkyl chain
length at the sulfonium centre from methyl to ethyl (Table 3, entries
1 and 24).
a-sulfanyl-b-amino nitriles, ketones and amides, respectively
(Scheme 2) and the results are summarized in Table 4. It is worth
noting that relatively few systems have been developed for the
preparation of these b
-amino nitriles, ketones and amides.22
Moderate yields of the coupled products were obtained using
cyanomethyl dimethylsulfonium bromide 2E, however the dia-
stereoselectivity was poor, which might be due to the lower
steric requirements of the linear cyanogroup. Good diaster-
eoselectivity was obtained from the reactions of the ketonic
sulfonium salts [Me2SCH2C(O)R0]Br (R0¼Ph (2F), Naphthyl (2G))
and from the amido sulfonium salt (R0¼NEt2 (2H)). Uniquely,
the syn isomer was the major diastereomer formed from the
later reaction, however the reasons for this are not clear. The
diastereomers containing the nitrile functional group could be
readily separated by column chromatography, while those
containing the ketone and amide groups were obtained as in-
separable mixtures.
The syn and anti diastereomers were generally distinguishable
3
by 1H NMR spectroscopy. The JHeH coupling in the (PG-NH)
CHReCH(SR1)(COOR2) unit were typically larger for the anti di-
astereomer compared to its syn analogue. Similar observations
have been observed in the literature.12a Additional confirmation for

M.L. Kantam et al. / Tetrahedron 66 (2010) 5042e5052
5045
PG
PG
PG
H
HN
HN
Br-
Me2S
N
NAP-MgO
R'
R'
R'
R
R
acetonitrile, rt
R
SMe
(anti)
SMe
(syn)
2
1
R = aromatic
PG = Ts, Bzs, Ms
R' = CN
2E
R' = CN, COPh,
CONaphthyl,
CONEt2
COPh 2F
CONaphthyl 2G
CONEt2 2H
Scheme 2. NAP-MgO catalyzed Mannich-type reaction between N-sulfonyl aldimines 1 and nitrile/ketone/amide sulfonium salts 2EeH.
Tounderstandtherelationshipbetweenstructureandreactivityof
the NAP-MgO catalyst in the Mannich-type reaction, it is important to
know the structure and nature of the reactive sites. NAP-MgO has
a single-crystallite, three-dimensional polyhedral structure, with
high surface concentrations of edge/corner and various exposed
crystal planes (such as 002, 001,111). This leads to an inherently high
surface reactivity per unit area. In addition, the NAP-MgO contains
Lewis acid sites (Mg2þ), Lewis base sites (O2ꢁ and Oꢁ), lattice-bound
and isolated Bronsted hydroxyls and anionic and cationic vacancies.26
Generally, Mannich-type reactions are known to be driven by basic
catalysts,4a,d,5a,b,e and accordingly, the surface eOH, and O2ꢁ sites of
these oxide crystals are expected to trigger these reactions. To
examine the role of hydroxyl groups in the coupling reaction, the
silylated catalyst, Sil-NAP-MgO,26e devoid of free eOH groups, was
tested using the optimized reaction conditions. In this case, the rate of
the reaction was slow and a longer reaction time was required (Table
1, entry 4). Although both NAP-MgO and NA-MgO possess defined
shapes and the same average concentrations of surface eOH groups,
apossiblerationaleforthedisplayofhigherreactivityintheMannich-
type reaction of NAP-MgO is the presenceof more surface Mg2þ Lewis
acid sites (20%) and eOH groups present on the edge and corner sites
ontheNAP-MgO.Thesearestretchedinthree-dimensionalspace, and
are thus more isolated and accessible to the reactants. Indeed, NAP-
MgO displayed the highest activity compared to NA-MgO and
CM-MgO. In the Mannich-type reaction, O2ꢁ/Oꢁ (Lewis base) of NAP-
MgO activates the sulfonium salts 2, to form sulfur ylides, which may
coordinate to the unsaturated Mg2þ/Mgþ (Lewis acid) of the NAP-
MgO. The Mannich-type reaction proceeds via dual activation of both
substrates (electrophiles and nucleophiles) by NAP-MgO. Thus, the
Lewis base moieties (O2ꢁ/Oꢁ) of the catalyst activate the sulfonium
salt and the Lewis acid moieties (Mg2þ/Mgþ) activate the aldimine.27
The NAP-MgO was reused for four cycles with consistent activity
(Table 1, entry 1). After completion of the reaction, the catalyst was
centrifuged and washed with ethyl acetate several times. The
recovered catalyst was activated at 250 ꢀC for 1 h under a nitrogen
atmosphere before reuse.
Table 4
NAP-MgO catalyzed Mannich-type reaction between N-sulfonyl aldimines 1 and
nitrilo/ketonic/amido sulfonium salts 2EeHa
Sl. No. Aldimine 1
Sulfonium salt 2 Time (h) Products
Yieldb (%) anti/sync
R
PG
Ts
1
2
3
4
5
6
7
8
9
Ph
1a 2E
1c 2E
36
36
40
36
36
40
48
36
36
64
69
53
55
52
73
62
64
74
53:47
55:45
50:50
76:24
65:35
77:23
61:39
66:34
37:63
4-NO2Ph Ts
4-MePh Bzs 1j 2E
Ph
4-ClPh
4-ClPh
Ts
1a 2F
Bzs 1i 2F
Bzs 1i 2G
4-MePh Bzs 1j 2G
Ph Ms 1l 2G
4-NO2Ph Ts 1c 2H
a
Reaction conditions: aldimine 1 (1 mmol), sulfonium salt 2EeH (2 mmol), NAP-
MgO catalyst (0.1 g), acetonitrile (5 mL) at room temperature.
b
Isolated yield of both diastereomers.
c
The ratio of anti/syn isomers was determined by 1H NMR spectroscopy of the
crude reaction mixtures.
On treatment with NAP-MgO, sulfonium salts 2 were converted
into sulfur ylides, similar to phosphorous ylides.17d Meanwhile,
imine 1 was activated by Mg2þ/Mgþ (Lewis acid) of NAP-MgO, then
the carbanionoid carbon of sulfur ylide attacks the electrophilic
carbon of the imine and forms the intermediate betaine.19a,23 We
assume that the betaine forms a complex with NAP-MgO as imine
and the carbonyl oxygen of the ylide is coordinated to the
unsaturated Mg2þ/Mgþ (Lewis acid).17d,24 Sulfur of the ylide was
coordinated to O2ꢁ/Oꢁ (Lewis base) of NAP-MgO, resulting in the
polarization of one of the alkyl subtituents on sulfur, and the
O2ꢁ/Oꢁ (Lewis base) of NAP-MgO directs dealkylation to form
a
-sulfanyl-b-amino acid derivative as Mannich product. This type
of CeS bond cleavage with demethylation was earlier observed in
the synthesis of methylthio-substituted heterocycles from hetero
aryl(dimethyl)sulfonium salts in the presence of triethylamine as
a base (Scheme 3).25
.. PG
N
MgO
PG
.. PG
N
GP
HN
Br-
+SMe2
H+
N - +SMe
R
H
MgO
-CH
COOEt
CH2
-MeBr
NAP-MgO
+SMe2
R
H
COOEt
Me
R
CH CH
COOEt
SMe
R
COOEt
Mg
O
Mg
OH
O
HO
=
MgO
Mg
O
Mg
O
Scheme 3. The plausible mechanism for the Mannich-type reaction between N-sulfonyl aldimines 1 and sulfonium salts 2 catalyzed by NAP-MgO.

5046
M.L. Kantam et al. / Tetrahedron 66 (2010) 5042e5052
3. Conclusion
centrifuged to obtain silylated NAP-MgO, which was washed sev-
eral times with n-pentane.
Nanocrystalline MgO has been shown to be an effective catalyst
for the Mannich-type reaction of various alkyl, aryl and heterocyclic
N-sulfonyl aldimines with a variety of sulfonium salts to afford the
4.3. Preparation of aldimines18
corresponding a-sulfanyl-b-amino acid derivatives in moderate to
The imines 1aef,18a,b 1g,18c 1heo18a,b and 1p18d,e were prepared
according to literature methods.
high yields with moderate diastereoselectivities. NMR spectro-
scopic data suggest the anti diastereomer is the major isomer
product, and is consistent with that found by a single crystal X-ray
diffraction study on one example.
Typical procedure. Under a nitrogen atmosphere, the sulfon-
amide (25 mmol) and Si(OEt)4 (25 mmol) were added to a flask
equipped with a reflux condenser and downward distillation con-
denser attached to a receiving flask. The aldehyde (25 mmol) was
slowly added and the reaction mixture was stirred at 160 ꢀC under
nitrogen for 6 h, during which time ethanol was collected in the
receiving flask. After cooling to room temperature, the reaction
mixture was suspended in diethyl ether and filtered. The pre-
cipitate was washed with diethyl ether and the crude product was
recrystallized from ethyl acetate/hexane (6:4).
4. Experimental section
4.1. General remarks
Nanocrystalline MgO samples were obtained from NanoScale
Materials Inc. (formally Nantek, Inc.) Manhattan, Kansas, USA. All
catalysts were calcined at 400 ꢀC for 4 h before use. Other chemicals
were purchased from Aldrich Chemicals and S.D Fine Chemicals,
Pvt. Ltd. India and used as received. All solvents used were LR grade
and used as received from S.D Fine Chemicals Pvt. Ltd. India. ACME
silica gel (100e200 mesh) was used for column chromatography
and thin layer chromatography was performed on Merck precoated
silica gel 60-F254 plates. Melting points were measured in open
glass capillary tubes and are uncorrected. The IR spectra of all
compounds were recorded on a NEXUS 670 FTIR spectrometer
(Necolet Corporation Ltd, USA) as KBr discs and values are reported
in reciprocal centimetres (cmꢁ1). The 1H and 13C NMR spectra were
recorded on a Varian Gemini 200 MHz or Bruker Avance 300 MHz
4.4. Typical procedure for the preparation of sulfonium salts
2AeH19f
To a dry flask, the bromo derivative (a-bromo acetate/nitrile/
ketone/amide) (25 mmol) and dimethyl sulfide (25 mmol) were
added at 0 ꢀC under a nitrogen atmosphere and stirred for 30 min.
The reaction mixture was warmed to room temperature and fur-
ther stirred for 6e12 h until the mixture solidified. In the case of the
diethyl sulfide analogues, the mixture was stirred for 18 h to give
a viscous liquid (sometimes it is difficult to reproduce 2D). The
resulting sulfonium salts 2AeH were dried under high vacuum at
0 ꢀC for 2 h and stored at sub-zero temperatures.
spectrometer. Chemical shifts (d) are reported in parts per million,
using TMS (
d
¼0) as an internal standard in CDCl3. Mass spectra
were recorded on a QSTAR XL high resolution mass spectrometer
(Applied Biosystems, Foster City, USA).
4.5. Typical procedure for the Mannich-type reaction
between N-sulfonyl aldimines and sulfonium salts
4.2. Preparation of nanocrystalline MgO catalysts26cee
4.2.1. Preparation of NA-MgO26c,d. Several grams of commercially
available MgO was refluxed in 500 mL of distilled water overnight.
After cooling, the slurry was filtered and the filter cake was dried in
an oven at 120 ꢀC. The dried powder was broken into pieces and
dried at 500 ꢀC under vacuum in a Pyrex reaction tube placed in
a cylindrical furnace. Heating took about 12 h, and the sample was
maintained at 500 ꢀC for several hours, usually overnight. The
vacuum reached about 1ꢂ10ꢁ3 Torr.
To a stirred solution of sulfonium salt 2AeH (2 mmol) in ace-
tonitrile (5 mL) was added NAP-MgO (0.1 g). After 5e10 min, the
aldimine 1 (1 mmol) was added and the reaction mixture stirred at
room temperature. After completion of the reaction (as monitored
by TLC), the catalyst was centrifuged, and washed with ethyl ace-
tate (3ꢂ5 mL). The combined organic solvent was removed under
reduced pressure. The crude product was purified by column
chromatography on silica gel (100e200 mesh) using ethyl acetate/
hexane in varying proportions as an eluent to afford the pure
products. All products were characterized by 1H NMR, 13C NMR, IR
and high resolution mass spectroscopies.
4.2.2. Preparation of NAP-MgO26c,d. In a three-necked 2 L round
bottom flask equipped with a mechanical stirrer, water cooled
condenser and argon inlet with a three-way stopcock was placed
300 mL of toluene. In another flask, 2.4 g (0.1 mol) of Mg turnings
was allowed to react with 100 mL of CH3OH under argon. The
resulting 1 M solution of Mg(OCH3)2 was added dropwise to the
toluene with vigorous stirring under argon. Distilled water (4 mL,
0.22 mol) was added dropwise from a syringe over a 30 min period.
This solution was stirred at room temperature under argon over-
night. The resulting slightly turbid mixture was placed in an au-
toclave and slowly heated to 265 ꢀC to give a Mg(OH)2 aerogel.26c
After cooling, the slurry was filtered, and the filter cake was dried
in an oven at 120 ꢀC. The dried powder was broken into pieces and
heat treated to 500 ꢀC under vacuum in a Pyrex reaction tube
placed in a cylindrical furnace. Heating took about 12 h, and the
sample was maintained at 500 ꢀC for several hours, usually over-
night. The vacuum reached about 1ꢂ10ꢁ3 Torr.
4.5.1. Ethyl-3-{[(4-methylphenyl)sulfonyl]amino}-2-(methyl-
sulfanyl)-3-phenylpropanoate12a (Table 3, entry 1). anti: Rf 0.4
(hexane/EtOAc 7:3); white solid; mp 127e128 ꢀC; IR: 3259, 2924,
1729, 1332, 1156 cmꢁ1; 1H NMR (200 MHz):
d
1.01 (t, 3H, J¼7.2 Hz),
2.05 (s, 3H), 2.35 (s, 3H), 3.3 (d, 1H, J¼10.6 Hz), 3.93 (q, 2H,
J¼7.2 Hz), 4.55 (dd, 1H, J¼10.6, 3.0 Hz), 5.68 (d, 1H, J¼3.0 Hz), 7.04
(d, 2H, J¼8.3 Hz), 7.1 (m, 5H), 7.43 (d, 2H, J¼8.3 Hz); 13C NMR
(50 MHz): d 12.1, 13.7, 21.3, 52.5, 55.9, 61.2, 127.2, 127.9, 128.1, 129.1,
136.9, 137.1, 143.0, 168.6; ESI-MS: m/z 416 [MþNa]þ, HRMS (ESI)
calcd for C19H23NO4NaS2: 416.0966, found: 416.0970.
syn: Rf 0.36 (hexane/EtOAc 7:3); white solid; mp 136e137 ꢀC; IR:
3194, 2924, 1713, 1335, 1162 cmꢁ1; 1H NMR (300 MHz):
d 1.17 (t, 3H,
J¼7.2 Hz), 2.06 (s, 3H), 2.34 (s, 3H), 3.44 (d, 1H, J¼6.0 Hz), 4.03e4.13
(m, 2H), 4.79 (dd, 1H, J¼6.0, 9.1 Hz), 6.13 (d, 1H, J¼9.1 Hz), 7.05e7.15
(m, 7H), 7.53 (d, 2H, J¼8.3 Hz); 13C NMR (75 MHz):
d 13.9, 15.3, 21.3,
4.2.3. Preparation of Sil-NAP-MgO26e. A mixture of 0.5 g of NAP-
MgO and 0.3 g of methoxytrimethylsilane in 20 mL of toluene was
refluxed for 7 h and the reaction mixture was allowed to cool and
53.9, 59.0, 61.6, 126.7, 127.0, 127.8, 128.3, 129.0, 137.6, 137.8, 142.8,
170.6; ESI-MS: m/z 416 [MþNa]þ, HRMS (ESI) calcd for
C19H23NO4NaS2: 416.0966, found: 416.0965.

M.L. Kantam et al. / Tetrahedron 66 (2010) 5042e5052
5047
4.5.2. Ethyl-3-(4-methoxyphenyl)-3-{[(4-methylphenyl)sulfonyl]
amino}-2-(methylsulfanyl)propanoate (Table 3, entry 2). anti: Rf 0.38
(hexane/EtOAc 6:4); colourless solid; mp 123e125 ꢀC; IR: 3307,
[MþNa]þ, HRMS (ESI) calcd for C21H25NO4NaS2: 442.1122, found:
442.1127.
syn: Rf 0.36 (hexane/EtOAc 7:3); colourlessꢁ1 solid; mp
2956,1705,1332,1157 cmꢁ1; 1H NMR (200 MHz):
d
1.04 (t, J¼7.2 Hz,
121e123 ꢀC; IR: 3289, 2925, 1720, 1331, 1160 cm
;
1H NMR
3H), 2.05 (s, 3H), 2.36 (s, 3H), 3.25 (d, J¼10.6 Hz, 1H), 3.73 (s, 3H),
3.94 (q, J¼7.2 Hz, 2H), 4.48 (dd, J¼10.6, 3.0 Hz, 1H), 5.53 (d,
J¼3.0 Hz, 1H), 6.59 (d, J¼8.3 Hz, 2H), 6.99 (d, J¼9.1 Hz, 2H), 7.06 (d,
(200 MHz):
d
1.28 (t, J¼7.2 Hz, 3H), 2.18 (s, 3H), 2.27 (s, 3H), 3.33 (d,
J¼5.5 Hz, 1H), 4.19 (m, 2H), 4.4 (m, 1H), 5.63 (d, J¼9.6 Hz, 1H), 5.8
(dd, J¼15.8, 7.2 Hz, 1H), 6.26 (d, J¼15.8 Hz, 1H), 7.05e7.22 (m, 7H),
7.71 (d, J¼8.2 Hz, 1H); ESI-MS: m/z 442 [MþNa]þ, HRMS (ESI) calcd
for C21H25NO4NaS2: 442.1122, found: 442.1118.
J¼8.3 Hz, 2H), 7.4 (d, J¼9.1 Hz, 2H); 13C NMR (50 MHz):
d 12.1, 13.8,
21.3, 52.5, 55.1, 55.3, 61.2, 113.5, 127.3, 128.9, 129.1, 129.2, 136.9,
143.0, 159.3, 168.7; ESI-MS: m/z 446 [MþNa]þ, HRMS (ESI) calcd for
C20H25NO5NaS2: 446.1071, found: 446.1057.
4.5.6. Ethyl-3-(2-furyl)-3-{[(4-methylphenyl)sulfonyl]amino}-2-
(methylsulfanyl)propanoate (Table 3, entry 6). synand anti (in-
separable isomers): Rf 0.33 (hexane/EtOAc 7:3); colourless solid; mp
syn: Rf 0.33 (hexane/EtOAc 6:4); colourless solid; mp
131e133 ꢀC; IR: 3289, 2963, 1721, 1342, 1156 cmꢁ1
;
1H NMR
(300 MHz):
d
1.17 (t, J¼7.2 Hz, 3H), 2.08 (s, 3H), 2.34 (s, 3H), 3.46 (d,
118e120 ꢀC; IR: 3254, 3183, 2925, 1722, 1372, 1334, 1159 cmꢁ1 1H
;
J¼6.0 Hz, 1H), 3.74 (s, 3H), 4.08 (m, 2H), 4.78 (dd, J¼6.0, 9.1 Hz, 1H),
6.04 (d, J¼9.1 Hz, 1H), 6.68 (d, J¼8.7 Hz, 2H), 7.01 (d, J¼8.7 Hz, 2H),
7.11 (d, J¼8.0 Hz, 2H), 7.54 (d, J¼8.0 Hz, 2H); ESI-MS: m/z 446
[MþNa]þ, HRMS (ESI) calcd for C20H25NO5NaS2: 446.1071, found:
446.1066.
NMR (300 MHz):
d
1.16 (t, J¼7.2 Hz, 3H)anti, 1.25 (t, J¼7.2 Hz, 3H)syn
,
2.05 (s, 3H)anti, 2.07 (s, 3H)syn, 2.38 (s, 3H)anti, 2.39 (s, 3H)syn, 3.55 (d,
J¼9.5 Hz, 1H)anti, 3.57 (d, J¼6.8 Hz, 1H)syn, 4.05 (q, J¼7.2 Hz, 2H)anti
,
4.14 (q, J¼7.2 Hz, 2H)syn, 4.77 (dd, J¼9.44, 6.6 Hz, 1H)anti, 4.87 (dd,
J¼6.8, 9.8 Hz, 1H)syn, 5.42 (s, br, 1H)anti, 5.73 (d, J¼9.8 Hz, 1H)syn
,
6.02e6.14 (m, 4H), 7.1e7.18 (m, 6H), 7.57 (d, J¼8.3 Hz, 2H), 7.62 (d,
4.5.3. Ethyl-3-{[(4-methylphenyl)sulfonyl]amino}-2-(methyl-
sulfanyl)-3-(4-nitrophenyl)propanoate (Table 3, entry 3). anti: Rf 0.4
(hexane/EtOAc 6:4); yellow solid; mp 133e135 ꢀC; IR: 3253, 2923,
J¼8.3 Hz, 2H); 13C NMR (75 MHz):
d 12.8, 13.9, 14.0, 15.1, 21.4, 50.4,
50.8, 51.4, 53.0, 61.4, 61.6,108.4,109.2,110.1,110.2,126.9,127.0,129.2,
137.0, 137.5, 142.0, 142.3, 143.0, 143.1, 149.6, 150.3, 168.8, 170.1; ESI-
MS: m/z 406 [MþNa]þ, HRMS (ESI) calcd for C17H21NO5NaS2:
406.0758, found: 406.0754.
1721, 1521, 1340, 1155 cmꢁ1; 1H NMR (300 MHz):
d
1.07 (t, J¼7.2 Hz,
3H), 2.01 (s, 3H), 2.37 (s, 3H), 3.28 (d, J¼10.6 Hz, 1H), 3.89e4.02 (m,
2H), 4.6 (dd, J¼10.6, 3.0 Hz, 1H), 5.79 (d, J¼3.0 Hz, 1H), 7.1 (d,
J¼8.3 Hz, 2H), 7.33 (d, J¼9.1 Hz, 2H), 7.46 (d, J¼8.3 Hz, 2H), 7.97 (d,
4.5.7. Ethyl-3-cyclohexyl-3-{[(4-methylphenyl)sulfonyl]amino}-2-
(methylsulfanyl)propanoate (Table 3, entry 7). syn and anti (in-
separable isomers): Rf 0.3 (hexane/EtOAc 8:2); colourless solid; mp
J¼9.1 Hz, 2H); 13C NMR (75 MHz):
d 11.9, 13.7, 21.3, 51.8, 55.0, 61.6,
123.2, 127.2, 129.0, 129.4, 136.1, 143.9, 144.8, 147.4, 168.1; ESI-MS:
m/z 461 [MþNa]þ, HRMS (ESI) calcd for C19H22N2O6NaS2: 461.0817,
found: 461.0809.
113e114 ꢀC; IR: 3276, 2924, 2851, 1727, 1372, 1313, 1151 cmꢁ1 1H
;
NMR (300 MHz):
d
0.82e1.2 (m, 12H), 1.25 (t, J¼7.2 Hz, 3H)syn, 1.28
syn: Rf 0.35 (hexane/EtOAc 6:4); yellow solid; mp 136e138 ꢀC;
(t, J¼7.2 Hz, 3H)anti, 1.43e1.8 (m, 10H), 1.96 (s, 3H)anti, 2.03 (s, 3H)syn
,
IR: 3233, 2924, 1711, 1520, 1345, 1162 cmꢁ1
;
1H NMR (300 MHz):
2.42 (s, 3H)syn, 2.43 (s, 3H)anti, 3.23 (d, J¼6.8 Hz, 1H)anti, 3.25 (d,
d
1.25 (t, J¼7.2 Hz, 3H), 2.03 (s, 3H), 2.34 (s, 3H), 3.48 (d, J¼7.6 Hz,
J¼4.5 Hz, 1H)syn, 3.57e3.63 (m, 2H)syn,anti, 4.04e4.09 (m, 2H)syn
,
1H), 4.07e4.22 (m, 2H), 4.86 (dd, J¼7.6, 9.1 Hz, 1H), 6.61 (d,
J¼9.1 Hz, 1H), 7.07 (d, J¼8.3 Hz, 2H), 7.32 (d, J¼9.1 Hz, 2H), 7.51 (d,
J¼8.3 Hz, 2H), 7.99 (d, J¼9.1 Hz, 2H); ESI-MS: m/z 461 [MþNa]þ,
HRMS (ESI) calcd for C19H22N2O6NaS2: 461.0817, found: 461.0815.
4.13 (q, J¼7.2 Hz, 2H)anti, 4.86 (d, J¼8.3 Hz, 1H)anti, 5.36 (d, J¼9.8 Hz,
1H)syn, 7.22e7.27 (m, 4H), 7.72e7.76 (m, 4H); 13C NMR (75 MHz):
d
14.0, 14.4, 15.7, 21.4, 26.0, 26.1, 26.2, 27.7, 29.2, 29.6, 29.9, 30.4,
40.9, 41.7, 50.5, 51.5, 58.4, 60.3, 61.4, 61.5, 127.0, 127.2, 129.1, 129.3,
138.4, 138.5, 142.8, 143.1, 170.1, 171.4; ESI-MS: m/z 422 [MþNa]þ,
HRMS (ESI) calcd for C19H29NO4NaS2: 422.1435, found: 422.1428.
4.5.4. Ethyl-3-(3-chloro-4-nitrophenyl)-3-{[(4-methylphenyl)sulfo-
nyl]amino}-2-(methylsulfanyl)propanoate (Table 3, entry 4). anti: Rf
0.37 (hexane/EtOAc 7:3); white solid; mp 121e122 ꢀC; IR: 3318,
4.5.8. Ethyl-2-(methylsulfanyl)-3-phenyl-3-[(phenylsulfonyl)amino]
2921, 1703, 1536, 1340, 1159 cmꢁ1
;
1H NMR (300 MHz):
d
1.11 (t,
propanoate (Table 3, entry 8). anti: Rf 0.4 (hexane/EtOAc 7:3); white
J¼7.2 Hz, 3H), 2.09 (s, 3H), 2.39 (s, 3H), 3.26 (d, J¼10.6 Hz, 1H),
3.92e4.1 (m, 2H), 4.61 (dd, J¼10.6, 2.7 Hz,1H), 5.78 (d, J¼2.7 Hz,1H),
7.09 (d, J¼8.3 Hz, 2H), 7.31 (d, J¼8.3 Hz, 1H), 7.36 (d, J¼2.1 Hz, 1H),
7.42 (d, J¼8.3 Hz, 2H), 7.46 (d, J¼2.1 Hz, 1H); 13C NMR (75 MHz):
solid; mp 107e108 ꢀC; IR: 3271, 2926, 1724, 1322, 1161 cmꢁ1 1H
;
NMR (300 MHz):
d
1.0 (t, J¼7.2 Hz, 3H), 2.06 (s, 3H), 3.29 (d,
J¼10.4 Hz, 1H), 3.92 (q, J¼7.2 Hz, 2H), 4.58 (dd, J¼10.4, 3.0 Hz, 1H),
5.67 (d, J¼3.0 Hz, 1H), 7.07e7.09 (m, 5H), 7.25 (t, J¼7.7 Hz, 2H), 7.37
d
12.1,13.8, 21.4, 51.7, 54.7, 61.8,125.2,127.2,129.5,131.6,133.1,136.2,
(t, J¼7.6 Hz, 1H), 7.53 (d, J¼8.5 Hz, 2H); 13C NMR (75 MHz):
d 12.1,
138.0, 144.2, 147.3, 168.2; ESI-MS: m/z 495 [MþNa]þ, HRMS (ESI)
calcd for C19H21N2O6NaS2Cl: 495.0427, found: 495.0425.
13.7, 52.5, 56.0, 61.2, 127.1, 127.8, 128.0, 128.1, 128.5, 132.2, 136.9,
139.9, 168.6; ESI-MS: m/z 397 [MþNH4]þ, HRMS (ESI) calcd for
C18H25N2O4S2: 397.1255, found: 397.1269.
syn: Rf 0.33 (hexane/EtOAc 7:3); white solid; mp 137e139 ꢀC; IR:
3174, 2920, 1703, 1537, 1341, 1160 cmꢁ1; 1H NMR (300 MHz):
d
1.26
syn: Rf 0.35 (hexane/EtOAc 7:3); white solid; mp104e105 ꢀC; IR:
(t, J¼7.2 Hz, 3H), 2.11 (s, 3H), 2.38 (s, 3H), 3.45 (d, J¼6.8 Hz, 1H),
4.08e4.27 (m, 2H), 4.8 (dd, J¼6.8, 9.1 Hz, 1H), 6.36 (d, J¼9.1 Hz, 1H),
7.1 (d, J¼8.3 Hz, 2H), 7.33e7.49 (m, 5H); ESI-MS: m/z 495 [MþNa]þ,
HRMS (ESI) calcd for C19H21N2O6NaS2Cl: 495.0427, found: 495.0427.
3274, 2925, 1727, 1332, 1162 cmꢁ1 1H NMR (300 MHz):
; d 1.23 (t,
J¼7.2 Hz, 3H), 1.98 (s, 3H), 3.48 (d, J¼7.7 Hz, 1H), 4.05e4.23 (m, 2H),
4.79 (dd, J¼7.7, 9.8 Hz, 1H), 6.62 (d, J¼9.8 Hz, 1H), 7.08e7.1 (m, 5H),
7.22 (t, J¼7.7 Hz, 2H), 7.32 (t, J¼7.6 Hz, 1H), 7.61 (d, J¼8.5 Hz, 2H);
ESI-MS: m/z 397 [MþNH4]þ, HRMS (ESI) calcd for C18H25N2O4S2:
397.1255, found: 397.1251.
4.5.5. Ethyl-(E)-3-{[(4-methylphenyl)sulfonyl]amino}-2-(methyl-
sulfanyl)-5-phenyl-4-pentenoate (Table 3, entry 5). anti: Rf 0.43
(hexane/EtOAc 7:3); colourless solid; mp 129e131 ꢀC; IR: 3244,
4.5.9. Ethyl-3-(4-chlorophenyl)-2-(methylsulfanyl)-3-[(phenyl-
sulfonyl)amino]propanoate (Table 3, entry 9). anti: Rf 0.44 (hexane/
EtOAc 7:3); white solid; mp 120e122 ꢀC; IR: 3322, 2924, 1705, 1337,
2923,1725,1329,1153 cmꢁ1; 1H NMR (200 MHz):
d
1.22 (t, J¼7.2 Hz,
3H), 2.11 (s, 3H), 2.3 (s, 3H), 3.31 (d, J¼7.6 Hz, 1H), 4.13 (q, J¼7.2 Hz,
2H), 5.35 (d, J¼5.1 Hz, 1H), 5.78 (dd, J¼16.1, 8.5 Hz, 1H), 6.25 (d,
J¼16.1 Hz, 1H), 7.04e7.22 (m, 7H), 7.69 (d, J¼8.5 Hz, 2H); 13C NMR
1161 cmꢁ1; 1H NMR (300 MHz):
d
1.05 (t, J¼7.2 Hz, 3H), 2.04 (s, 3H),
3.27 (d, J¼10.6 Hz, 1H), 3.87e4.02 (m, 2H), 4.55 (dd, J¼10.6, 3.8 Hz,
1H), 5.85 (d, J¼3.8 Hz, 1H), 7.01e7.04 (m, 4H), 7.25e7.32 (m, 2H),
7.44 (t, J¼7.6 Hz, 1H), 7.56 (d, J¼7.6 Hz, 2H); 13C NMR (75 MHz):
(50 MHz): d 13.7, 14.1, 21.3, 51.6, 55.6, 61.5, 124.4, 126.5, 127.5, 128.0,
128.4, 129.5, 134.5, 135.8, 137.3, 143.5, 169.6; ESI-MS: m/z 442

5048
M.L. Kantam et al. / Tetrahedron 66 (2010) 5042e5052
d
12.0, 13.7, 52.1, 55.2, 61.4, 127.1, 128.3, 128.6, 129.3, 132.5, 134.0,
EtOAc 7:3); white solid; mp 120e122 ꢀC; IR: 3313, 2928, 1723, 1329,
1160 cmꢁ1; 1H NMR (300 MHz):
135.6, 139.6, 168.4; ESI-MS: m/z 436 [MþNa]þ, HRMS (ESI) calcd for
C18H20NO4NaS2Cl: 436.0419, found: 436.0420.
d
1.14 (t, J¼7.2 Hz, 3H), 2.23 (s, 3H),
2.55 (s, 3H), 3.38 (d, J¼10.6 Hz, 1H), 3.99e4.1 (m, 2H), 4.75 (dd,
syn: Rf 0.41 (hexane/EtOAc 7:3); white solid; mp133e134 ꢀC; IR:
J¼10.6, 3.8 Hz, 1H), 5.62 (d, J¼3.8 Hz, 1H), 7.34e7.38 (m, 4H); 13C
3295, 2926, 1716, 1341, 1163 cmꢁ1
;
1H NMR (200 MHz):
d
1.24 (t,
NMR (75 MHz): d 12.4, 13.8, 42.1, 52.0, 55.3, 61.5, 129.0, 129.3, 134.6,
J¼7.2 Hz, 3H), 2.01 (s, 3H), 3.44 (d, J¼7.8 Hz, 1H), 4.03e4.22 (m, 2H),
4.76 (dd, J¼7.8, 9.6 Hz, 1H), 6.58 (d, J¼9.6 Hz, 1H), 7.06e7.09 (m,
4H), 7.24e7.32 (m, 2H), 7.41 (t, J¼7.8 Hz, 1H), 7.63 (d, J¼7.8 Hz, 2H);
ESI-MS: m/z 436 [MþNa]þ, HRMS (ESI): calcd for C18H20NO4NaS2Cl:
436.0419, found: 436.0413.
136.5, 168.6; ESI-MS: m/z 374 [MþNa]þ, HRMS (ESI) calcd for
C13H18NO4NaS2Cl: 374.0263, found: 374.0258.
syn: Rf 0.29 (hexane/EtOAc 7:3); white solid; mp 106e108 ꢀC; IR:
3274, 2928, 1725, 1329, 1153 cmꢁ1 1H NMR (300 MHz):
; d 1.27 (t,
J¼7.2 Hz, 3H), 2.1 (s, 3H), 2.72 (s, 3H), 3.47 (d, J¼7.9 Hz, 1H),
4.11e4.26 (m, 2H), 4.81 (dd, J¼7.9, 9.6 Hz, 1H), 6.34 (d, J¼9.6 Hz,
1H), 7.31e7.35 (m, 4H); ESI-MS: m/z 374 [MþNa]þ, HRMS (ESI) calcd
for C13H18NO4NaS2Cl: 374.0263, found: 374.0268.
4.5.10. Ethyl-3-(4-methylphenyl)-2-(methylsulfanyl)-3-[(phenyl-
sulfonyl)amino]propanoate (Table 3, entry 10). anti: Rf 0.4 (hexane/
EtOAc 7:3); white solid; mp 106e107 ꢀC; IR: 3323, 2924,1709,1333,
1159 cmꢁ1; 1H NMR (300 MHz):
d
1.05 (t, J¼7.2 Hz, 3H), 2.06 (s, 3H),
4.5.14. Ethyl-3-(4-methoxyphenyl)-2-(methylsulfanyl)-3-[(methyl-
sulfonyl)amino]propanoate (Table 3, entry 14). anti: Rf 0.42 (hexane/
EtOAc 1:1); white solid; mp 123e124 ꢀC; IR: 3303, 2928, 1719, 1384,
2.26 (s, 3H), 3.33 (d, J¼10.4 Hz, 1H), 3.95 (q, J¼7.2 Hz, 2H), 4.56 (dd,
J¼10.4, 4.2 Hz, 1H), 5.84 (d, J¼4.2 Hz, 1H), 6.88 (d, J¼8.1 Hz, 2H),
6.99 (d, J¼8.1 Hz, 2H), 7.25e7.3 (m, 2H), 7.4 (t, J¼7.6 Hz, 1H), 7.58
1252, 1158 cmꢁ1; 1H NMR (300 MHz):
d
1.09 (t, J¼7.2 Hz, 3H), 2.2 (s,
(d, J¼8.1 Hz, 2H); 13C NMR (75 MHz):
d
12.2, 13.7, 20.9, 52.5, 55.7,
3H), 2.44 (s, 3H), 3.36 (d, J¼10.6 Hz, 1H), 3.79 (s, 3H), 3.99 (q,
J¼7.2 Hz, 2H), 4.67 (dd, J¼10.6, 2.2 Hz, 1H), 5.48 (d, J¼2.2 Hz, 1H),
6.85 (d, J¼8.3 Hz, 2H), 7.29 (d, J¼8.3 Hz, 2H); 13C NMR (75 MHz):
61.2, 127.2, 127.7, 128.4, 128.8, 132.1, 133.9, 137.8, 139.9, 168.6;
ESI-MS: m/z 416 [MþNa]þ, HRMS (ESI) calcd for C19H23NO4NaS2:
416.0966, found: 416.0966.
d
12.1, 13.8, 42.0, 52.0, 55.2, 61.3, 114.2, 129.3, 159.7, 168.8; ESI-MS:
syn: Rf 0.36 (hexane/EtOAc 7:3); white solid; mp 117e118 ꢀC; IR:
m/z 370 [MþNa]þ, HRMS (ESI) calcd for C14H21NO5NaS2: 370.0758,
3278, 2920, 1732, 1325, 1162 cmꢁ1 1H NMR (300 MHz):
; d 1.22 (t,
found: 370.0741.
J¼7.2 Hz, 3H), 2.0 (s, 3H), 2.24 (s, 3H), 3.45 (d, J¼7.6 Hz, 1H),
4.03e4.21 (m, 2H), 4.74 (dd, J¼7.6, 9.8 Hz,1H), 6.45 (d, J¼9.8 Hz,1H),
6.89 (d, J¼8.3 Hz, 2H), 6.96 (d, J¼8.3 Hz, 2H), 7.21e7.27 (m, 2H), 7.36
(t, J¼7.6 Hz, 1H), 7.62 (d, J¼9.1 Hz, 2H); ESI-MS: m/z 416 [MþNa]þ,
HRMS (ESI) calcd for C19H23NO4NaS2: 416.0966, found: 416.0969.
syn: Rf 0.36 (hexane/EtOAc 1:1); colourless ꢁs1olid; mp
118e120 ꢀC; IR:.3214, 2926, 1705, 1333, 1259, 1154 cm
;
1H NMR
(300 MHz):
d
1.28 (t, J¼7.2 Hz, 3H), 2.08 (s, 3H), 2.63 (s, 3H), 3.46 (d,
J¼8.3 Hz, 1H), 3.78 (s, 3H), 4.13e4.26 (m, 2H), 4.76 (t, J¼8.7 Hz, 1H),
6.24 (d, J¼9.8 Hz, 1H), 6.85 (d, J¼8.7 Hz, 2H), 7.27 (d, J¼8.7 Hz, 2H);
ESI-MS: m/z 370 [MþNa]þ, HRMS (ESI) calcd for C14H21NO5NaS2:
370.0758, found: 370.0752.
4.5.11. Ethyl-3-{[(4-methylphenyl)sulfonyl]amino}-2-(methyl-
sulfanyl)-3-(2-naphthyl)propanoate (Table 3, entry 11). anti: Rf 0.37
(hexane/EtOAc 7:3); white solid; mp 124e126 ꢀC; IR: 3305, 2922,
4.5.15. Ethyl-2-(methylsulfanyl)-3-(4-nitrophenyl)-3-{[(2,4,6-triiso-
propylphenyl)sulfonyl]amino]propanoate (Table 3, entry 15). anti: Rf
0.4 (hexane/EtOAc 8:2); pale yellow solid; mp 140e143 ꢀC; IR:
1759, 1315, 1173 cmꢁ1; 1H NMR (300 MHz):
d
0.91 (t, J¼7.2 Hz, 3H),
2.11 (s, 3H), 3.47 (d, J¼10.6 Hz, 1H), 3.78e3.93 (m, 2H), 4.77 (dd,
J¼10.6, 4.3 Hz, 1H), 6.04 (d, J¼4.3 Hz, 1H), 7.03 (t, J¼7.6 Hz, 2H), 7.16
3224, 2967, 1727, 1520, 1385, 1158 cmꢁ1; 1H NMR (300 MHz):
d 1.06
(t, J¼7.6 Hz, 2H), 7.37e7.65 (m, 8H); 13C NMR (75 MHz):
d
12.2, 13.7,
(t, J¼7.2 Hz, 3H), 1.12 (d, J¼6.8 Hz, 6H), 1.2 (d, J¼7.6 Hz, 6H), 1.26 (d,
J¼6.8 Hz, 6H), 2.07 (s, 3H), 2.78e2.87 (m, 1H), 3.29 (d, J¼10.6 Hz,
1H), 3.9e4.02 (m, 4H), 4.83 (dd, J¼10.6, 2.3 Hz, 1H), 5.83 (d,
J¼2.3 Hz, 1H), 6.99 (s, 2H), 7.33 (d, J¼9.1 Hz, 2H), 7.92 (d, J¼9.1 Hz,
52.3, 56.1, 61.3, 124.8, 126.0, 126.2, 127.1, 127.4, 127.9, 128.1, 128.3,
132.1, 132.7, 132.9, 134.1, 139.8, 168.6; ESI-MS: m/z 452 [MþNa]þ,
HRMS (ESI): calcd for C22H23NO4NaS2: 452.0966, found: 452.0979.
syn: Rf 0.32 (hexane/EtOAc 7:3); white solid; mp 138e139 ꢀC; IR:
2H); 13C NMR (75 MHz):
d 11.7, 13.8, 23.5, 23.6, 24.5, 25.0, 29.8, 34.1,
3313, 2909, 1742, 1327, 1158 cmꢁ1
;
1H NMR (300 MHz):
d
1.11 (t,
52.0, 54.7, 61.6, 123.0, 123.4, 129.0, 132.9, 145.0, 147.5, 150.0, 153.4,
168.1; ESI-MS: m/z 551 [MþH]þ, HRMS (ESI) calcd for
C27H39N2O6S2: 551.2249, found: 551.2251.
J¼7.2 Hz, 3H), 2.12 (s, 3H), 3.6 (d, J¼5.8 Hz, 1H), 3.97e4.15 (m, 2H),
5.02 (dd, J¼5.8, 9.1 Hz, 1H), 6.31 (d, J¼9.1 Hz, 1H), 7.14e7.24 (m, 4H),
7.42e7.45 (m, 2H), 7.51 (s, 1H), 7.62e7.75 (m, 5H); ESI-MS: m/z 452
[MþNa]þ, HRMS (ESI) calcd for C22H23NO4NaS2: 452.0966, found:
452.0966.
syn: Rf 0.32 (hexane/EtOAc 8:2); pale yellowꢁ1solid; mp
109e111 ꢀC; IR: 3283, 2962, 1721, 1525, 1345, 1160 cm
;
1H NMR
(300 MHz):
d
1.18 (t, J¼9.1 Hz, 3H), 1.19 (d, J¼9.1 Hz, 6H), 1.24 (d,
J¼6.8 Hz, 6H), 1.29 (d, J¼6.8 Hz, 6H), 2.11 (s, 3H), 2.79e2.94 (m, 1H),
3.56 (d, J¼6.0 Hz, 1H), 3.92e4.0 (m, 2H), 4.05e4.1 (m, 2H), 5.03 (dd,
J¼6.0, 8.3 Hz, 1H), 6.34 (d, J¼8.3 Hz, 1H), 7.13 (s, 2H), 7.34 (d,
J¼9.1 Hz, 2H), 8.02 (d, J¼9.1 Hz, 2H); ESI-MS: m/z 551 [MþH]þ,
HRMS (ESI) calcd for C27H39N2O6S2: 551.2249, found: 551.2241.
4.5.12. Ethyl-2-(methylsulfanyl)-3-[(methylsulfonyl)amino]-3-phe-
nylpropanoate (Table 3, entry 12). anti: Rf 0.37 (hexane/EtOAc 6:4);
white solid; mp 143e145 ꢀC; IR: 3306, 2926, 1728, 1384, 1157 cmꢁ1
;
1H NMR (300 MHz):
d
1.06 (t, J¼7.2 Hz, 3H), 2.21 (s, 3H), 2.45 (s, 3H),
3.39 (d, J¼10.6 Hz, 1H), 3.99 (q, J¼7.2 Hz, 2H), 4.73 (dd, J¼10.6,
3.0 Hz, 1H), 5.44 (d, J¼3.0 Hz, 1H), 7.3e7.5 (m, 5H); 13C NMR
(75 MHz): 12.4, 13.9, 42.1, 52.3, 56.0, 61.4, 128.0, 128.8, 128.9, 137.9,
168.8; ESI-MS: m/z 340 [MþNa]þ, HRMS (ESI) calcd for
C13H19NO4NaS2: 340.0653, found: 340.0648.
4.5.16. Ethyl-3-[(tert-butylsulfonyl)amino]-2-(methylsulfanyl)-3-(3-
pyridyl)propanoate (Table 3, entry 16). syn and anti (inseparable
isomers): Rf 0.45 (hexane/EtOAc 6:4); white solid; mp 102e104 ꢀC;
IR: 3346, 3248, 2985, 2928, 1726, 1308, 1129, 1124 cmꢁ1 1H NMR
;
syn: Rf 0.33 (hexane/EtOAc 6:4); colourless solid; mp
(300 MHz):
d
1.12 (t, J¼7.2 Hz, 3H)anti, 1.25 (t, J¼7.2 Hz, 3H)syn, 1.28
131e132 ꢀC; IR: 3255, 2923, 1729, 1319, 1147 cmꢁ1
;
1H NMR
(s, 9H)syn, 1.37 (s, 9H)anti, 2.12 (s, 3H)syn, 2.16 (s, 3H)anti, 3.76 (d,
J¼9.1 Hz,1H)anti, 3.79 (d, J¼7.4 Hz,1H)syn, 3.95e4.05 (m, 2H)anti, 4.15
(q, J¼7.2 Hz, 2H)syn, 4.84 (dd, J¼9.1, 8.7 Hz, 1H)anti, 4.89 (dd, J¼7.4,
(300 MHz):
d
1.22 (t, J¼7.2 Hz, 3H), 2.16 (s, 3H), 2.72 (s, 3H), 3.51 (d,
J¼6.8 Hz, 1H), 4.08e4.21 (m, 2H), 4.86 (t, J¼8.7 Hz, 1H), 6.1 (d,
J¼9.1 Hz, 1H), 7.29e7.39 (m, 5H); ESI-MS: m/z 340 [MþNa]þ, HRMS
(ESI) calcd for C13H19NO4NaS2: 340.0653, found: 340.0656.
10.2 Hz, 1H)syn, 5.25 (d, J¼8.7 Hz, 1H)anti, 5.56 (d, J¼10.2 Hz, 1H)syn
,
7.18e7.22 (m, 2H), 7.35 (d, J¼7.7 Hz, 1H), 7.48 (d, J¼7.9 Hz, 1H),
7.61e7.72 (m, 2H), 8.54e8.58 (m, 2H); 13C NMR (75 MHz):
d 13.9,
4.5.13. Ethyl-3-(4-chlorophenyl)-2-(methylsulfanyl)-3-[(methyl-
sulfonyl)amino]propanoate (Table 3, entry 13). anti: Rf 0.33 (hexane/
14.0, 14.2, 15.2, 24.0, 24.1, 29.6, 52.0, 53.5, 57.6, 59.3, 60.2, 60.6, 61.4,
61.7, 123.8, 124.2, 124.7, 138.7, 139.4, 146.7, 147.6, 157.3, 157.4, 169.4,

M.L. Kantam et al. / Tetrahedron 66 (2010) 5042e5052
5049
170.6; ESI-MS: m/z 361 [MþH]þ, HRMS (ESI) calcd for
1H), 5.55 (d, J¼3.0 Hz,1H), 7.04 (d, J¼8.3 Hz, 2H), 6.98e7.22 (m, 5H),
C15H25N2O4S2: 361.1255, found: 361.1266.
7.4 (d, J¼8.3 Hz, 2H); 13C NMR (75 MHz):
d 12.2, 21.4, 52.1, 52.5,
55.9, 127.3, 127.9, 128.0, 128.2, 129.1, 137.2, 142.9, 169.1; ESI-MS: m/z
402 [MþNa]þ, HRMS (ESI) calcd for C18H21NO4NaS2: 402.0809,
found: 402.0794.
4.5.17. tert-Butyl-3-(4-methoxyphenyl)-3-{[(4-methylphenyl)sulfo-
nyl]amino}-2-(methylsulfanyl)propanoate (Table 3, entry 17). syn
and anti (inseparable isomers): Rf 0.31 (hexane/EtOAc 7:3); white
solid; mp 165e167 ꢀC; IR: 3324, 2922, 1697, 1384, 1362, 1297, 1254,
syn: Rf 0.34 (hexane/EtOAc 7:3); colourlessꢁ1 solid; mp
136e139 ꢀC; IR: 3251, 2924, 1740, 1326, 1163 cm
;
1H NMR
1158 cmꢁ1; 1H NMR (300 MHz):
d
1.21 (s, 9H)anti,1.22 (s, 9H)syn, 2.03
(300 MHz):
d
2.03 (s, 3H), 2.33 (s, 3H), 3.48 (d, J¼6.8 Hz, 1H), 3.64 (s,
(s, 3H)anti, 2.06 (s, 3H)syn, 2.35(s, 3H)syn, 2.36 (s, 3H)anti, 3.15 (d,
J¼10.6 Hz, 1H)anti, 3.29 (d, J¼6.0 Hz, 1H)syn, 3.73 (s, 3H)anti, 3.74 (s,
3H)syn, 4.41 (dd, J¼10.6, 3.0 Hz, 1H)anti, 4.68 (dd, J¼6.0, 9.1 Hz,
1H)syn, 5.52 (d, J¼3.0 Hz, 1H)anti, 6.08 (d, J¼9.1 Hz, 1H)syn, 6.59 (d,
J¼8.3 Hz, 2H), 6.63 (d, J¼8.3 Hz, 2H), 7.0 (d, J¼8.3 Hz, 4H), 7.06 (d,
J¼8.3 Hz, 4H), 7.41 (d, J¼8.3 Hz, 2H), 7.51 (d, J¼8.3 Hz, 2H); 13C NMR
(75 MHz): 11.9, 15.3, 21.4, 27.6, 27.8, 29.6, 53.2, 54.7, 55.2, 55.4, 58.6,
82.0, 113.4, 113.6, 127.1, 127.3, 128.0, 129.0, 129.1, 129.4, 136.9, 143.0,
159.1, 159.3, 167.8; ESI-MS: m/z 474 [MþNa]þ, HRMS (ESI) calcd for
C22H29NO5NaS2: 474.1384, found: 474.1403.
3H), 4.77 (dd, J¼6.8, 9.1 Hz, 1H), 6.3 (d, J¼9.1 Hz, 1H), 7.03e7.13 (m,
7H), 7.52 (d, J¼8.3 Hz, 2H); ESI-MS: m/z 402 [MþNa]þ, HRMS (ESI)
calcd for C18H21NO4NaS2: 402.0809, found: 402.07816.
4.5.22. Methyl-3-(4-methylphenyl)-2-(methylsulfanyl)-3-[(phenyl-
sulfonyl)amino]propanoate (Table 3, entry 22). anti: Rf 0.4 (hexane/
EtOAc 7:3); colourless solid; mp 152e154 ꢀC; IR: 3270, 2924,
1730, 1316, 1158 cmꢁ1 1H NMR (300 MHz):
; d 2.03 (s, 3H), 2.24 (s,
3H), 3.31 (d, J¼9.8 Hz, 1H), 3.49 (s, 3H), 4.54 (dd, J¼9.8, 3.0 Hz,
1H), 5.59 (d, J¼3.0 Hz, 1H), 6.87 (d, J¼8.3 Hz, 2H), 6.96 (d,
J¼8.3 Hz, 2H), 7.25 (t, J¼7.6 Hz, 2H), 7.39 (t, J¼7.6 Hz, 1H), 7.53 (d,
4.5.18. tert-Butyl-3-(2-furyl)-3-{[(4-methylphenyl)sulfonyl]amino}-
2-(methylsulfanyl)propanoate (Table 3, entry 18). syn and anti (in-
separable isomers): Rf 0.41 (hexane/EtOAc 7:3); colourless solid;
mp 132e135 ꢀC; IR: 3245, 3173, 2928, 1725, 1696, 1598, 1384,
J¼7.6 Hz, 2H); 13C NMR (75 MHz):
d 12.3, 21.0, 52.2, 52.5, 55.7,
127.1, 127.6, 128.5, 128.9, 132.1, 133.9, 137.8, 139.9, 169.1; ESI-MS:
m/z 402 [MþNa]þ, HRMS (ESI) calcd for C18H21NO4NaS2:
402.0809, found: 402.0800.
1158 cmꢁ1
;
1H NMR (200 MHz):
d
1.33 (s, 9H)anti, 1.44 (s, 9H)syn
,
syn: Rf 0.32 (hexane/EtOAc 7:3); white solid; mp 126e129 ꢀC; IR:
2.05 (s, 3H)anti, 2.06 (s, 3H)syn, 2.38(s, 6H)syn,anti, 3.45 (d, J¼9.6 Hz,
1H)anti, 3.46 (d, J¼6.9 Hz, 1H)syn, 4.7 (dd, J¼9.6, 6.1 Hz, 1H)anti, 4.8
(dd, J¼6.9, 9.6 Hz, 1H)syn, 5.39 (d, J¼6.1 Hz, 1H)anti, 5.79 (d, J¼9.6 Hz,
1H)syn, 6.01e6.11 (m, 4H), 7.1e7.17 (m, 6H), 7.54e7.62 (m, 4H); 13C
3252, 2922, 1730, 1326, 1160 cmꢁ1 1H NMR (200 MHz):
; d 2.08 (s,
3H), 2.27 (s, 3H), 3.45 (d, J¼6.3 Hz, 1H), 3.61 (s, 3H), 4.77 (dd, J¼6.3,
9.4 Hz, 1H), 6.08 (d, J¼9.4 Hz, 1H), 6.93e6.96 (m, 4H), 7.29e7.32 (m,
3H), 7.66 (d, J¼7.8 Hz, 2H); ESI-MS: m/z 402 [MþNa]þ, HRMS (ESI)
calcd for C18H21NO4NaS2: 402.0809, found: 402.0816.
NMR (50 MHz):
d 12.6, 15.1, 21.4, 27.7, 27.8, 50.4, 51.6, 52.3, 53.2,
82.3, 82.7, 108.3, 109.3, 110.1, 110.2, 127.0, 127.1, 129.2, 129.3, 141.9,
142.2, 143.0, 143.1, 149.8, 150.7, 167.9, 169.4; ESI-MS: m/z 434
[MþNa]þ, HRMS (ESI) calcd for C19H25NO5NaS2: 434.1071, found:
434.1070.
4.5.23. Methyl-2-(methylsulfanyl)-3-[(methylsulfonyl)amino]-3-phe-
nylpropanoate (Table 3, entry 23). anti: Rf 0.39 (hexane/EtOAc 1:1);
white solid; mp 150e151 ꢀC; IR: 3309, 2927, 1729, 1322, 1155 cmꢁ1
;
1H NMR (300 MHz):
1H), 3.55 (s, 3H), 4.74 (dd, J¼10.6, 3.0 Hz, 1H), 5.46 (d, J¼3.0 Hz, 1H),
d
2.21 (s, 3H), 2.44 (s, 3H), 3.42 (d, J¼10.6 Hz,
4.5.19. tert-Butyl-3-(4-chlorophenyl)-2-(methylsulfanyl)-3-[(phenyl-
sulfonyl)amino]propanoate (Table 3, entry 19). syn and anti (in-
separable isomers): Rf 0.3 (hexane/EtOAc 8:2); white solid; mp
7.29e7.4 (m, 5H); 13C NMR (75 MHz):
d 12.3, 42.0, 52.1, 52.3, 55.8,
127.9, 128.8, 128.9, 137.7, 169.2; ESI-MS: m/z 326 [MþNa]þ, HRMS
(ESI) calcd for C12H17NO4NaS2: 326.0496, found: 326.0497.
syn: Rf 0.34 (hexane/EtOAc 1:1); colourless solid; mp
152e155 ꢀC; IR: 3311, 2925, 1699, 1365, 1159 cmꢁ1
(300 MHz):
;
1H NMR
d
1.22 (s, 9H)anti, 1.39 (s, 9H)syn, 2.02 (s, 3H)anti, 2.06 (s,
3H)syn, 3.14 (d, J¼10.6 Hz, 1H)anti, 3.29 (d, J¼6.0 Hz, 1H)syn, 4.48 (dd,
J¼10.6, 2.3 Hz, 1H)anti, 4.72 (dd, J¼6.0, 9.1 Hz, 1H)syn, 5.67 (d,
J¼2.3 Hz, 1H)anti, 6.31 (d, J¼9.1 Hz, 1H)syn, 7.04e7.12 (m, 8H),
7.25e7.65 (m, 10H); 13C NMR (75 MHz): 11.9, 15.4, 27.6, 27.7, 27.9,
53.0, 54.3, 55.4, 58.7, 82.4, 83.2, 127.0, 127.2, 128.2, 128.3, 128.4,
128.6, 128.7, 128.8, 129.6, 132.3, 132.5, 134.0, 135.8, 136.4, 139.7,
167.7; ESI-MS: m/z 464 [MþNa]þ, HRMS (ESI) calcd for
C20H24NO4NaS2Cl: 464.0732, found: 464.0732.
120e122 ꢀC; IR: 3228, 2921, 1729, 1313, 1145 cmꢁ1 1H NMR
;
(300 MHz):
d
2.11 (s, 3H), 2.69 (s, 3H), 3.53 (d, J¼6.8 Hz, 1H), 3.71 (s,
3H), 4.84 (dd, J¼6.8, 9.1 Hz,1H), 6.24 (d, J¼9.1 Hz,1H), 7.29e7.36 (m,
5H); ESI-MS: m/z 326 [MþNa]þ, HRMS (ESI) calcd for C12H17NO4
-
NaS2: 326.0496, found: 326.0488.
4.5.24. Ethyl-2-(ethylsulfanyl)-3-{[(4-methylphenyl)sulfonyl]
amino}-3-phenylpropanoate (Table 3, entry 24). anti: Rf 0.39 (hex-
ane/EtOAc 7:3); white solid; mp 116e118 ꢀC; IR: 3252, 2927, 1731,
4.5.20. tert-Butyl-2-(methylsulfanyl)-3-[(methylsulfonyl)amino]-3-
phenylpropanoate (Table 3, entry 20). syn and anti (inseparable iso-
mers): Rf 0.31 (hexane/EtOAc 7:3); colourless solid; mp 104e106 ꢀC;
IR: 3300, 3211, 2929,1721,1693,1327,1156 cmꢁ1; 1H NMR (300 MHz):
1328,1157 cmꢁ1; 1H NMR (300 MHz):
d
1.03 (t, J¼7.3 Hz, 3H),1.24 (t,
J¼7.3 Hz, 3H), 2.37 (s, 3H), 2.47e2.63 (m, 2H), 3.35 (d, J¼9.7 Hz, 1H),
3.94 (q, J¼7.3 Hz, 2H), 4.55 (dd, J¼9.7, 2.8 Hz, 1H), 5.59 (d, J¼2.8 Hz,
1H), 7.07 (d, J¼8.3 Hz, 2H), 7.11e7.15 (m, 5H), 7.43 (d, J¼8.3 Hz, 2H);
d
1.21 (s, 9H)anti, 1.47 (s, 9H)syn, 2.01 (s, 3H)syn, 2.23(s, 3H)anti, 2.5(s,
13C NMR (75 MHz):
d 13.7, 13.9, 21.3, 24.4, 52.9, 56.9, 61.2, 127.2,
3H)anti, 2.57(s, 3H)syn, 3.36 (d, J¼10.6 Hz, 1H)anti, 3.39 (d, J¼6.4 Hz,
127.9, 128.1, 129.1, 136.9, 137.2, 143.1, 169.2; ESI-MS: m/z 430
[MþNa]þ, HRMS (ESI) calcd for C20H25NO4NaS2: 430.1122, found:
430.1114.
1H)syn, 4.67 (dd, J¼10.6, 5.3 Hz, 1H)anti, 4.73 (dd, J¼6.4, 9.8 Hz, 1H)syn
,
5.94 (d, J¼5.3 Hz, 1H)anti, 6.46 (d, J¼9.8 Hz, 1H)syn, 7.27e7.4 (m, 10H);
13C NMR (CDCl3þDMSO-d6, 75 MHz): 12.0, 13.8, 27.0, 27.3, 41.1, 41.3,
52.4, 53.7, 55.9, 58.6, 81.0, 81.5, 126.8, 127.4, 127.7, 127.8, 128.0, 128.1,
138.3,138.6,167.8,168.9;ESI-MS: m/z 368[MþNa]þ, HRMS (ESI) calcd
for C15H23NO4NaS2: 368.0966, found: 368.0972.
syn: Rf 0.35 (hexane/EtOAc 7:3); white solid; mp 109e110 ꢀC; IR:
3211, 2922, 1719, 1337, 1161 cmꢁ1 1H NMR (300 MHz):
; d 1.12 (t,
J¼7.2 Hz, 3H), 1.2 (t, J¼7.2 Hz, 3H), 2.32 (s, 3H), 2.39e2.47 (m, 2H),
3.52 (d, J¼6.8 Hz, 1H), 4.04e4.16 (m, 2H), 4.73 (dd, J¼6.8, 9.8 Hz,
1H), 6.39 (d, J¼9.8 Hz, 1H), 7.03 (d, J¼8.3 Hz, 2H), 7.07e7.12 (m, 5H),
7.51 (d, J¼8.3 Hz, 2H); ESI-MS: m/z 430 [MþNa]þ, HRMS (ESI) calcd
for C20H25NO4NaS2: 430.1122, found: 430.1129.
4.5.21. Methyl-3-{[(4-methylphenyl)sulfonyl]amino}-2-(methyl-
sulfanyl)-3-phenylpropanoate (Table 3, entry 21). anti: Rf 0.41
(hexane/EtOAc 7:3); white solid; mp 139e141 ꢀC; IR: 3277, 2925,
1730, 1326, 1158 cmꢁ1
;
1H NMR (300 MHz):
d
2.05 (s, 3H), 2.34 (s,
4.5.25. Ethyl-3-(4-chlorophenyl)-2-(ethylsulfanyl)-3-[(phenyl-
3H), 3.32 (d, J¼10.6 Hz, 1H), 3.48 (s, 3H), 4.56 (dd, J¼10.6, 3.0 Hz,
sulfonyl)amino]propanoate (Table 3, entry 25). anti: Rf 0.4 (hexane/

5050
M.L. Kantam et al. / Tetrahedron 66 (2010) 5042e5052
EtOAc 7:3); pale yellow solid; mp 94e95 ꢀC; IR: 3251, 2931, 1721,
1329,1157 cmꢁ1; 1H NMR (300 MHz):
m/z 414 [MþNa]þ, HRMS (ESI) calcd for C17H17N3O4NaS2: 414.0558,
d
1.07 (t, J¼7.3 Hz, 3H),1.23 (t,
found: 414.0563.
J¼7.3 Hz, 3H), 2.45e2.64 (m, 2H), 3.3 (d, J¼7.3 Hz, 1H), 3.96 (q,
J¼10.3 Hz, 2H), 4.54 (dd, J¼10.3, 3.0 Hz, 1H), 5.75 (d, J¼3.0 Hz, 1H),
7.02e7.07 (m, 4H), 7.3 (t, J¼8.5 Hz, 2H), 7.41e7.46 (m, 1H), 7.53 (d,
4.5.29. N-[2-Cyano-1-(4-methylphenyl)-2-(methylsulfanyl)ethyl]-1-
benzenesulfonamide (Table 4, entry 3). anti: Rf 0.33 (hexane/EtOAc
7:3); colourless solid; mp 105e107 ꢀC; IR: 3237, 2922, 2244, 1515,
J¼8.5 Hz, 2H); 13C NMR (75 MHz):
d 13.7, 13.9, 24.5, 52.5, 56.3, 61.5,
127.2, 128.3, 128.6, 129.4, 132.4, 134.0, 135.7, 139.8, 169.0; ESI-MS:
m/z 450 [MþNa]þ, HRMS (ESI) calcd for C19H22NO4NaS2Cl:
450.0576, found: 450.0571.
1445,1350,1152 cmꢁ1; 1H NMR (300 MHz):
d 2.02 (s, 3H), 2.29(s, 3H),
3.95(d, J¼7.6 Hz,1H), 4.42(t, J¼6.8 Hz,1H), 6.06 (d, J¼6.0 Hz,1H), 6.99
(d, J¼8.3 Hz, 2H), 7.06 (d, J¼8.3 Hz, 2H), 7.36 (t, J¼7.6 Hz, 2H), 7.46 (t,,
J¼7.6 Hz,1H), 7.71 (d, J¼7.6 Hz, 2H); ESI-MS:m/z 369 [MþNa]þ, HRMS
(ESI) calcd for C17H18N2O2NaS2: 369.0707, found: 369.0695.
syn: Rf 0.36 (hexane/EtOAc 7:3); pale yellow solid; mp 92e94 ꢀC;
IR: 3184, 2926, 1704, 1340, 1164 cmꢁ1; 1H NMR (300 MHz):
d 1.16 (t,
J¼7.3 Hz, 3H), 1.21 (t, J¼7.3 Hz, 3H), 2.53 (q, J¼7.3 Hz, 2H), 3.47 (d,
J¼5.1 Hz, 1H), 4.0e4.15 (m, 2H), 4.76 (dd, J¼5.1, 8.8 Hz, 1H), 6.21 (d,
J¼8.8 Hz, 1H), 7.04 (d, J¼8.8 Hz, 2H), 7.13 (d, J¼8.8 Hz, 2H), 7.33 (t,
J¼8.1 Hz, 2H), 7.41e7.48 (m, 1H), 7.67 (d, J¼8.1 Hz, 2H); ESI-MS: m/z
450 [MþNa]þ, HRMS (ESI) calcd for C19H22NO4NaS2Cl: 450.0576,
found: 450.0582.
syn: Rf 0.3 (hexane/EtOAc 7:3); colourless solid; mp 131e133 ꢀC;
IR: 3257, 2922, 2241, 1520, 1456, 1346, 1159 cmꢁ1
;
1H NMR
(300 MHz):
d
2.15 (s, 3H), 2.29 (s, 3H), 3.82 (d, J¼5.3 Hz, 1H), 4.74
(dd, J¼5.3, 9.1 Hz, 1H), 5.64 (d, J¼9.1 Hz, 1H), 6.99e7.05 (m, 4H),
7.31e7.54 (m, 3H), 7.7 (d, J¼7.6 Hz, 2H); ESI-MS: m/z 369 [MþNa]þ,
HRMS (ESI) calcd for C17H18N2O2NaS2: 369.0707, found: 369.0701.
4.5.26. Ethyl-2-(ethylsulfanyl)-3-[(methylsulfonyl)amino]-3-phenyl-
propanoate (Table 3, entry 26). anti: Rf 0.45 (hexane/EtOAc 6:4);
4.5.30. N-[2-(Methylsulfanyl)-3-oxo-1,3diphenylpropyl]-4-methyl-1-
benzenesulfonamide (Table 4, entry 4). syn and anti (inseparable
isomers): Rf 0.31 (hexane/EtOAc 7:3); colourless solidꢁ;1 mp
white solid; mp 115e117 ꢀC; IR: 3305, 2930, 1727, 1323, 1156 cmꢁ1
;
1H NMR (300 MHz):
d
1.07 (t, J¼7.3 Hz, 3H), 1.3 (t, J¼7.3 Hz, 3H),
170e171 ꢀC; IR: 3316, 2922, 1662, 1596, 1450, 1330, 1157 cm
;
1H
2.48 (s, 3H), 2.64e2.78 (m, 2H), 3.45 (d, J¼10.2 Hz, 1H), 3.99 (q,
NMR (300 MHz):
d
1.85 (s, 3H)anti, 2.02 (s, 3H)syn, 2.33 (s, 3H)syn
,
,
J¼7.3 Hz, 2H), 4.74 (dd, J¼10.2, 3.9 Hz, 1H), 5.55 (d, J¼3.9 Hz, 1H),
2.35 (s, 3H)anti, 4.31 (d, J¼10.6 Hz, 1H)anti, 4.46 (d, J¼6.0 Hz, 1H)syn
7.3e7.39 (m, 5H); 13C NMR (75 MHz):
d
13.8, 14.1, 24.6, 42.0, 52.6,
4.78 (dd, J¼10.6, 3.0 Hz, 1H)anti, 5.0 (dd, J¼6.0, 9.1 Hz, 1H)syn, 5.74 (d,
J¼3.0 Hz, 1H)anti, 6.37 (d, J¼9.1 Hz, 1H)syn, 7.01e7.15 (m, 14H),
56.9, 61.4, 128.0, 128.7, 137.8, 169.3; ESI-MS: m/z 354 [MþNa]þ,
HRMS (ESI) calcd for C14H21NO4NaS2: 354.0809, found: 354.0802.
syn: Rf 0.39 (hexane/EtOAc 6:4); colourless solid; mp 83e85 ꢀC;
7.28e7.77 (m, 14H); 13C NMR (75 MHz):
d 10.3, 14.0, 21.4, 29.6, 51.6,
51.8, 54.2, 59.9, 127.0, 127.3, 127.6, 127.7, 128.0, 128.1, 128.2, 128.3,
128.4, 128.5, 129.0, 129.2, 133.2, 133.5, 135.6, 136.8, 137.9, 143.1,
190.9, 195.1; ESI-MS: m/z 448 [MþNa]þ, HRMS (ESI) calcd for
C23H23NO3NaS2: 448.1017, found: 448.1016.
IR: 3254, 2925, 1723, 1324,1149 cmꢁ1; 1H NMR (300 MHz):
d 1.21 (t,
J¼7.3 Hz, 3H), 1.25 (t, J¼7.3 Hz, 3H), 2.58 (q, J¼7.3 Hz, 2H), 2.72 (s,
3H), 3.57 (d, J¼6.6 Hz, 1H), 4.07e4.19 (m, 2H), 4.82 (dd, J¼6.6,
9.6 Hz, 1H), 6.18 (d, J¼9.6 Hz, 1H), 7.31e7.36 (m, 5H); ESI-MS: m/z
354 [MþNa]þ, HRMS (ESI) calcd for C14H21NO4NaS2: 354.0809,
found: 354.0798.
4.5.31. N-[1-(4-Chlorophenyl)-2-(methylsulfanyl)-3-oxo-3-phenyl-
propyl]-1-benzenesulfonamide (Table 4, entry 5). syn and anti (in-
separable isomers): Rf 0.31 (hexane/EtOAc 7:3); colourless solid;
4.5.27. N-[2-Cyano-2-(methylsulfanyl)-1-phenylethyl]-4-methyl-1-
benzenesulfonamide (Table 4, entry 1). anti: Rf 0.47 (hexane/EtOAc
6:4); white solid; mp 136e138 ꢀC; IR: 3236, 2920, 2231, 1319,
mp 184e186 ꢀC; IR: 3311, 2922, 1664, 1589, 1446, 1330, 1158 cmꢁ1
;
1H NMR (300 MHz):
d
1.83 (s, 3H)anti, 1.97 (s, 3H)syn, 4.29 (d,
J¼10.6 Hz, 1H)anti, 4.44 (d, J¼6.0 Hz, 1H)syn, 4.79 (dd, J¼10.6, 3.0 Hz,
1151 cmꢁ1; 1H NMR (300 MHz):
d 2.01 (s, 3H), 2.39 (s, 3H), 3.93 (d,
1H)anti, 4.99 (dd, J¼6.0, 9.1 Hz, 1H)syn, 5.91 (d, J¼3.0 Hz, 1H)anti, 6.53
J¼7.6 Hz, 1H), 4.44 (t, J¼6.8 Hz, 1H), 5.59 (d, J¼6.0 Hz, 1H), 7.16 (d,
(d, J¼9.1 Hz, 1H)syn, 6.95e7.79 (m, 28H); 13C NMR (75 MHz):
d 10.2,
J¼8.3 Hz, 2H), 7.2e7.25 (m, 5H), 7.57 (d, J¼8.3 Hz, 2H); 13C NMR
14.1, 29.6, 31.9, 51.3, 53.6, 59.5, 127.0, 127.3, 128.1, 128.3, 128.4, 128.5,
128.6, 128.7, 128.8, 129.6, 132.2, 132.5, 133.5, 133.8, 135.3, 136.4,
138.6, 139.6, 190.5; ESI-MS: m/z 468 [MþNa]þ, HRMS (ESI) calcd for
C22H20NO3NaS2Cl: 468.0470, found: 468.0448.
(75 MHz):
d 13.9, 21.5, 41.1, 58.3, 115.9, 127.1, 127.4, 128.8, 129.2,
129.6, 135.1, 136.4, 143.9; ESI-MS: m/z 369 [MþNa]þ, HRMS (ESI)
calcd for C17H18N2O2NaS2: 369.0707, found: 369.0698.
syn: Rf 0.41 (hexane/EtOAc 6:4); colourlessꢁ1solid; mp
160e162 ꢀC; IR: 3213, 2915, 2234, 1321, 1150 cm
;
1H NMR
4.5.32. N-[1-(4-Chlorophenyl)-2-(methylsulfanyl)-3-(2-naphthyl)-3-
oxo-propyl]-1-benzenesulfonamide (Table 4, entry 6). syn and anti
(inseparable isomers): Rf 0.33 (hexane/EtOAc 7:3); white solid; mp
(300 MHz):
d
2.02 (s, 3H), 2.45 (s, 3H), 3.84 (d, J¼4.5 Hz, 1H), 4.77
(dd, J¼4.5, 9.1 Hz, 1H), 5.53 (d, J¼9.1 Hz, 1H), 7.12e7.31 (m, 7H), 7.8
(d, J¼8.3 Hz, 2H); ESI-MS: m/z 369 [MþNa]þ, HRMS (ESI) calcd for
C17H18N2O2NaS2: 369.0707, found: 369.0703.
170e172 ꢀC; IR: 3311, 2923, 2363, 1658, 1335, 1161 cmꢁ1 1H NMR
;
(200 MHz):
d
1.88 (s, 3H)anti, 2.05 (s, 3H)syn, 4.44 (d, J¼10.6 Hz, 1H)anti
,
4.6(d, J¼5.5 Hz,1H)syn, 4.86(dd, J¼10.6, 2.3 Hz, 1H)anti, 5.06(dd,J¼5.5,
4.5.28. N-[2-Cyano-2-(methylsulfanyl)-1-(4-nitrophenyl)ethyl]-4-
methyl-1-benzenesulfonamide (Table 4, entry 2). anti: Rf 0.42 (hex-
ane/EtOAc 6:4); colourless solid; mp 130e131 ꢀC; IR: 3237, 2923,
9.4 Hz, 1H)syn, 5.82 (d, J¼2.3 Hz, 1H)anti, 6.52 (d, J¼9.3 Hz, 1H)syn
,
6.94e7.86 (m, 30H), 8.18 (s,1H)anti, 8.28 (s,1H)syn 13C NMR (50 MHz):
;
d
10.3,14.1, 26.9, 51.4, 53.7, 59.5, 123.6, 123.8, 126.9, 127.3, 127.6, 128.4,
2244, 1350, 1153 cmꢁ1
;
1H NMR (300 MHz):
d
2.21(s, 3H), 2.39 (s,
128.6, 128.7, 129.0, 129.5, 129.6, 129.8, 130.2, 132.3, 132.5, 133.7, 135.6,
135.7, 136.4, 139.6, 190.5, 194.3; ESI-MS: m/z518 [MþNa]þ, HRMS(ESI)
calcd for C26H22NO3NaS2Cl: 518.0627, found: 518.0636.
3H), 3.91 (d, J¼7.6 Hz, 1H), 4.57 (t, J¼6.8 Hz, 1H), 6.16 (d, J¼6.0 Hz,
1H), 7.16 (d, J¼7.6 Hz, 2H), 7.39 (d,, J¼9.1 Hz, 2H), 7.55 (d, J¼7.6 Hz,
2H), 8.08 (d,, J¼9.1 Hz, 2H); 13C NMR (75 MHz):
d 13.9, 21.5, 40.7,
57.3, 115.3, 123.8, 127.2, 128.7, 129.7, 136.1, 142.2, 144.6, 148.3; ESI-
MS: m/z 414 [MþNa]þ, HRMS (ESI) calcd for C17H17N3O4NaS2:
414.0558, found: 414.0547.
4.5.33. N-[1-(4-Methylphenyl)-2-(methyl sulfanyl)-3-(2-naphthyl)-
3-oxo-propyl]-1-benzenesulfonamide (Table 4, entry 7). syn and anti
(inseparable isomers): Rf 0.33 (hexane/EtOAc 7:3); colourless solid;
syn: Rf 0.36 (hexane/EtOAc 6:4); colourlessꢁ1solid; mp
mp 155e157 ꢀC; IR: 3308, 2922, 2362, 1659, 1329, 1159 cmꢁ1 1H
;
159e162 ꢀC; IR: 3257, 2922, 2241, 1355, 1160 cm
;
1H NMR
NMR (200 MHz):
d
1.88 (s, 3H)anti, 2.04 (s, 3H)syn, 2.15 (s, 3H)anti
,
,
(300 MHz):
d
2.21 (s, 3H), 2.37 (s, 3H), 3.85 (d, J¼5.3 Hz, 1H), 4.86 (t,
2.21 (s, 3H)syn, 4.51 (d, J¼10.2 Hz, 1H)anti, 4.63 (d, J¼5.5 Hz, 1H)syn
J¼6.8 Hz, 1H), 5.84 (d, J¼8.3 Hz, 1H), 7.16 (d, J¼8.3 Hz, 2H), 7.38 (d,
J¼9.1 Hz, 2H), 7.57 (d, J¼8.3 Hz, 2H), 8.09 (d, J¼9.1 Hz, 2H); ESI-MS:
4.84 (dd, J¼10.2, 2.3 Hz, 1H)anti, 5.06 (dd, J¼5.5, 8.6 Hz, 1H)syn, 5.84
(d, J¼2.3 Hz, 1H)anti, 6.52 (d, J¼8.6 Hz, 1H)syn, 6.79e7.89 (m, 30H),

M.L. Kantam et al. / Tetrahedron 66 (2010) 5042e5052
5051
8.18 (s, 1H)anti, 8.27 (s, 1H)syn 13C NMR (50 MHz):
; d 10.4, 13.9, 20.9,
3. (a) Kobayashi, S.; Ueno, M. In Comprehensive Asymmetric Catalysis; Jacobsen, E.
N., Pfaltz, A., Yamamoto, H., Eds.; Springer: Berlin, 2003; p 143; Supplement 1,
Chapter 29.5; (b) Kobayashi, S.; Ishitani, H. Chem. Rev. 1999, 99, 1069; (c) Abele,
S.; Seebach, D. Eur. J. Org. Chem. 2000, 1.
51.5, 51.7, 54.1, 59.8, 123.8, 123.9, 126.8, 126.9, 127.0, 127.3, 128.0,
128.4, 128.5, 128.6, 128.7, 128.9, 129.1, 129.5, 129.7, 130.1, 131.9,
132.2, 132.3, 132.8, 133.3, 134.7, 135.2, 135.5, 135.7, 137.5, 139.9,
140.7, 190.8, 195.1; ESI-MS: m/z 498 [MþNa]þ, HRMS (ESI) calcd for
C27H25NO3NaS2: 498.1173, found: 498.1172.
4. (a) Fujisawa, H.; Takahashi, E.; Mukaiyama, T. Chem.dEur. J. 2006, 12, 5082; (b)
González, A. S.; Arrayás, R. G.; Carretero, J. C. Org. Lett. 2006, 8, 2977; (c) Ranu,
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Takahashi, E.; Nakagawa, T.; Mukaiyama, T. Chem. Lett. 2003, 32, 1036; (e)
Hernández-Toribio, J.; Arrayás, R. G.; Carretero, J. C. J. Am. Chem. Soc. 2008, 130,
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125, 4712; (b) Harada, S.; Handa, S.; Matsunaga, S.; Shibasaki, M. Angew. Chem.,
Int. Ed. 2005, 44, 4365; (c) Wenzel, A. G.; Jacobsen, E. N. J. Am. Chem. Soc. 2002,
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4.5.34. N-[2-(Methylsulfanyl)-3-(2-naphthyl)-3-oxo-1-phenylpropyl]
methanesulfonamide (Table 4, entry 8). syn and anti (inseparable
isomers): Rf 0.47 (hexane/EtOAc 1:1); white solid; mp 149e150 ꢀC;
IR: 3291, 2924, 2362, 1658, 1318, 1158 cmꢁ1 1H NMR (200 MHz):
;
d
2.0 (s, 3H)syn, 2.07 (s, 3H)anti, 2.45 (s, 3H)anti, 2.64 (s, 3H)syn, 4.66 (d,
J¼10.6 Hz, 1H)anti, 4.72 (d, J¼5.5 Hz, 1H)syn, 5.06 (dd, J¼10.6, 4.3 Hz,
1H)anti, 5.11 (dd, J¼5.5, 9.2 Hz, 1H)syn, 5.94 (d, J¼4.3 Hz, 1H)anti, 6.4
(d, J¼9.2 Hz, 1H)syn, 7.15e7.95 (m, 22H), 8.26 (s, 1H)anti, 8.42 (s,
1H)syn 13C NMR (50 MHz):
; d 10.7, 13.7, 41.8, 42.1, 51.2, 51.3, 54.4,
59.3,123.8,123.9,126.8,126.9,127.2,127.6,128.2,128.3,128.5,128.6,
128.9,129.5,129.7,130.1,132.3,132.7,133.3,135.5,135.7,138.5,139.1,
190.8, 194.9; ESI-MS: m/z 422 [MþNa]þ, HRMS (ESI) calcd for
C21H21NO3NaS2: 422.0860, found: 422.0852.
4.5.35. N,N-Diethyl-3-{[(4-methylphenyl)sulfonyl]amino}-2-(meth-
ylsulfanyl)-3-(4-nitrophenyl)propanamide (Table 4, entry 9). syn and
anti (inseparable isomers): Rf 0.38 (hexane/EtOAc 1:1); yellow
solid; mp 143e145 ꢀC; IR: 3246, 2924, 1616, 1552, 1347, 1158 cmꢁ1
;
1H NMR (300 MHz):
d
0.83 (t, J¼6.8 Hz, 3H)syn, 0.89 (t, J¼6.8 Hz,
3H)anti, 1.0 (t, J¼6.8 Hz, 3H)syn, 1.8 (s, 3H)anti, 2.16 (s, 3H)syn, 2.35 (s,
3H)syn, 2.39 (s, 3H)anti, 2.85e3.35 (m, 8H)anti,syn, 3.39 (d, J¼10.6 Hz,
1H)anti, 3.6 (d, J¼4.5 Hz, 1H)syn, 4.68 (dd, J¼10.6, 2.3 Hz, 1H)anti, 4.89
(dd, J¼3.7, 8.3 Hz, 1H)syn, 5.88 (d, J¼2.3 Hz, 1H, NH)anti, 7.08(d,
J¼8.3 Hz, 2H), 7.16 (d, J¼8.3 Hz, 2H), 7.31 (d, J¼8.3 Hz, 2H), 7.43 (d,
J¼8.3 Hz, 2H), 7.53 (d, J¼8.3 Hz, 4H), 7.53 (d, J¼8.3 Hz, 1H, NH)syn
,
7.98 (d, J¼8.3 Hz, 4H); 13C NMR (75 MHz):
d 10.2, 12.6, 12.7, 14.2,
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14.4, 21.3, 21.4, 40.8, 40.9, 42.1, 42.4, 47.6, 47.8, 54.9, 59.9, 123.0,
123.3, 126.8, 127.3, 128.0, 129.1, 129.3, 129.5, 135.9, 138.0, 143.1,
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[MþNa]þ, HRMS (ESI) calcd for C21H27N3O5NaS2: 488.1289, found:
488.1281.
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Supplementary data
X-ray crystallographic data of compound ethyl-3-{[(4-methyl-
phenyl)sulfonyl]amino}-2-(methylsulfanyl)-3-(4-nitrophenyl)pro-
panoate (major isomer) (Table 3, entry 3). Supplementary data
associated with this article can be found in the online version, at
doi:10.1016/j.tet.2010.05.002. This data include MOL files and
InChiKey of the most important compound described in this article.
References and notes
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5052
M.L. Kantam et al. / Tetrahedron 66 (2010) 5042e5052
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