Synthesis of amino thiols and isocysteines via regioselective ring opening of sulfamidates with tetrathiomolybdate

Article abstract of DOI:10.1016/j.tet.2011.02.074

Herein we present a simple and highly efficient method for the synthesis of β and γ-amino thiols via regioselective ring opening of sulfamidates with tetrathiomolybdate 1. The generality of this methodology has been shown by synthesizing carbohydrate deri

Full text of DOI:10.1016/j.tet.2011.02.074

Tetrahedron 67 (2011) 3111e3118
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Synthesis of amino thiols and isocysteines via regioselective ring opening of
sulfamidates with tetrathiomolybdate
,b,
R.B. Nasir Baig a, N.Y. Phani Kumar a, Jamsad Mannuthodikayil a, Srinivasan Chandrasekaran a
*
a Department of Organic Chemistry, Indian Institute of Science, Bangalore 560012, Karnataka, India
b Jawaharlal Nehru Centre for Advanced Scientific Research, Bangalore, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Herein we present a simple and highly efficient method for the synthesis of
b and g-amino thiols via
Received 19 December 2010
Received in revised form 19 February 2011
Accepted 24 February 2011
Available online 2 March 2011
regioselective ring opening of sulfamidates with tetrathiomolybdate 1. The generality of this method-
ology has been shown by synthesizing carbohydrate derived -amino thiol. The scope and versatility of
this methodology has been demonstrated by synthesizing biologically important unnatural amino acids
like isocysteines in optically pure form.
b
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Tetrathiomolybdate
Sulfamidates
Burgess reagent
Amino thiols
1. Introduction
for the synthesis of
to -amino thiols involves the acid catalyzed ring opening reaction
b
-aminothiols.12 The most straightforward route
b
In the last few decades, there has been a significant interest in the
synthesis and reactions of sulfamidates because of their very high
reactivity and ability to function as carbon electrophiles. Sulfami-
dates and their derivatives are versatile synthetic intermediates for
the synthesis of biologically important compounds.1 Procedures for
the synthesis of sulfamidates have beenwell developed and theyare
as readily available as aziridines.2 Amino sulfides are compounds of
synthetic interest in organic synthesis because of pharmaceutical
of aziridines with hydrogen sulfide or sodium or potassium salt of
thioacetic acid followed by deprotection of thioacetates to corre-
sponding thiols.12b In addition, there are a number of methods
available for the synthesis of b-amino sulfides via Lewis acid cata-
lyzed aziridine ring opening with alkyl thiols.13 Since the depro-
tection of S-alkyl or S-aryl group is non trivial, it makes these
methods not very attractive for the synthesis of b-aminothiols.
Our investigation to understand the reactivity of benzyl-
triethylammonium tetrathiomolybdate, (BnNEt3MoS4) 1 as a reagent
in organic synthesis led to the development of a number of useful
importance.3 Roques et al. found that
b-amino thiols are selective
inhibitors of aminopeptidase A (APA)4 and would be an interesting
probe to explore the physiological involvement of APA in the me-
methodologies.14 Recently, we reported the synthesis of
b-amino
tabolism of neuropeptides.
lopeptidase activity of tetanus toxin5 and of botulinum neurotoxin
type B.6 In addition,
-amino thiol functionality is present in some
HIV protease inhibitors.7 Catalytic quantities of
and -amino thiols
have also been used for asymmetric addition of dialkylzinc to alde-
hydes8 and have been shown to be effective ligands and catalysts in
enantioselective conjugate addition of organocuprates to enones.9
b
-Amino thiols inhibit the zinc metal-
disulfides via ring opening of sulfamidates mediated by tetrathio-
molybdate 1.15 During the course of our investigation we observed an
unusual reactivity of tetrathiomolybdate 1 with sulfamidates derived
from the corresponding diols using Burgess reagent 2 (Et3NSO2N-
COOMe). In this report, we present a novel and versatile method for
b
b
g
the synthesis b-amino thiols by utilizing the unusual reactivity of
tetrathiomolybdate 1 with sulfamidates derived from the corre-
b
-Amino thiols have also been used as a chiral auxiliaries for
sponding diols.
boron-mediated asymmetric aldol reactions10 and the utility of
b
-amino thiols for the synthesis of polythiols and mercapto thio
ethers has been demonstrated.11 In spite of the importance of this
class of compounds very few methods are reported in the literature
2. Results and discussion
Our ongoing study towards the ring opening reaction of sulfa-
midates with tetrathiomolybdate 1 led to the development of a very
* Corresponding author. Tel.: þ91 80 2293 2404; fax: þ91 80 2360 2423; e-mail
address: scn@orgchem.iisc.ernet.in (S. Chandrasekaran).
0040-4020/$ e see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2011.02.074

3112
R.B. Nasir Baig et al. / Tetrahedron 67 (2011) 3111e3118
simple and efficient method for the synthesis of N-alkyl
disulfides (Scheme 1).15
b
-amino
2.2. Synthesis of isocysteine derivatives
In order to demonstrate the utility of this methodology for the
synthesis of isocysteine derivatives, we converted the a,b-unsaturated
O
O
1) [BnNEt3]2MoS4,
CH3CN, rt, 0.5 -18 h
2) H+/H2O, rt, 2- 12 h
3) NH4OH, rt. 10 min
NHR
R2
S
ester 9 to the corresponding diol 10.16 The reaction of 10aec with
excess of 2 (2.5 equiv) under reflux in THF:CH2Cl2 (4:1) gave sulfa-
midates 11aec, respectively, in very good yield (Scheme 4). Treatment
of sulfamidates 11aec with tetrathiomolybdate 1 (1.2 equiv, CH3CN,
28 ꢀC, 45 min) led to the formation of the corresponding isocysteine
derivatives 12aec in excellent yield (Table 2).
O
S
R1
RN
R1
S
R2
NHR
R2
R1
Scheme 1.
In order to demonstrate it as a modular method for the synthesis
b-amino disulfides we synthesized the chiral diol 4a starting from
2.3. Synthesis of chiral isocysteine derivative 12d
of
phenylalanine 3a. The diol 4a was refluxed with Burgess reagent 2 in
THF:CH2Cl2 (4:1) to give sulfamidate 5a in 90% yield. Treatment of
sulfamidate 5a with tetrathiomolybdate 1 (1.2 equiv, CH3CN, 28 ꢀC,
In order to explore this methodology for the synthesis of
enantiomerically pure isocysteine derivative, we synthesized the
sulfamidate 11d from chiral diol (2R, 3S)-ethyl 2,3-dihydroxy-
3-phenylpropanoate, 10d. The reaction of 11d with tetrathiomo-
lybdate 1 gave the optically pure isocysteine derivative 12d in 89%
yield (Scheme 5). The synthesis of 12d in enantiomerically pure
1 h) resulted in a hitherto unreported reactivity of 1. It gave
b-amino
thiol 6a as the only product in very good yield instead of the antic-
ipated
b-amino disulfide 6a2 (Scheme 2).
O
O
Ph
OH
OH
1) CH3COOH, NaNO2
Burgess Reagent, 2
S
N
O
THF: CH2Cl2 (4:1)
rt, 24 h
OH
Ph
Ph
COOMe
H2N
6 h, reflux
90%
2) LiAlH4, THF
0°C-reflux, 10 h
5a
O
3a
4a
1) [BnEt3N]2MoS4
CH3CN, rt, 1 h
2) Sat.Citric acid, rt, 2 h
MeOOCHN
S
Ph
SH
S
NHCOOMe
Ph
Ph
6a2 0%
6a 88%
NHCOOMe
Scheme 2. Reaction of sulfamidate 5a with tetrathiomolybdate 1.
In order to examine the unusual reactivity of tetrathiomolybdate
1 with sulfamidates derived from 1,2 diols and Burgess reagent, we
prepared a number of chiral and achiral sulfamidates 5ael by the
reaction of the corresponding 1,2 diols with 2 employing the pro-
cedure described in Scheme 2. Treatment of sulfamidates 5aej with
tetrathiomolybdate 1 (1.2 equiv, CH3CN, 28 ꢀC, 1 h) gave the corre-
form illustrates that this methodology is general and can be
extended easily for the synthesis of a variety of chiral isocysteine
derivatives.
2.4. Synthesis of carbohydrate derived b-amino thiol 16
sponding b-amino thiols 6aej (Table 1) in good to excellent yields
In continuation of our investigation to examine the efficacy of
this methodology for the synthesis of -amino thiols, we synthe-
sized the diol 14 starting from
-glucose 13.17 The reaction of diol
(78e96%). Results summarized in Table 1 illustrate that this method
is general and is applicable to a variety of sulfamidates 5aej. Sulfa-
midate 5e derived from methionine is the only exception as it gave
b
a-D
14 with 2 gave sulfamidate 15 in 73% of yield.
a mixture of b-aminothiol 6e1 and b-amino disulfide 6e2 (3:7) in 83%
The sulfamidate 15 was then treated with tetrathiomolybdate 1
yield. Sulfamidates 5k and 5l derived from achiral cycloheptane and
cyclooctane 1,2 diols were found to be inert to the reaction with
tetrathiomolybdate 1.
(1.2 equiv, CH3CN, 28 ꢀC, 24 h) to give
b
-amino thiol derivative 16 as
the only product in 78% yield (Scheme 6).
2.5. Synthesis of g-amino thiols via regioselective ring
opening of sulfamidates derived form (2R,4R) pentane diol
2.1. Tentative mechanism for the formation of b-amino thiols
To explore this methodology further we treated (2R,4R) 2,4
pentane diol 17 with 2 to give sulfamidate 18 in 84% yield. The re-
action of sulfamidate 18 with tetrathiomolybdate 1 (1.2 equiv,
It is reasonable to visualize nucleophilic attack of 1 exclusively at
the CeO bond of 5 in a highly stereospecific (SN2) manner to give
intermediate 7. Elimination of MoS3 followed by protonation gives
CH3CN, 28 ꢀC, 1 h) gave
g
-amino thiol 19 in excellent yield (Scheme
7). This result indicates the potential utility of this method for the
synthesis of a number of substituted -amino thiols.
intermediate 8, which on hydrolysis leads to
b-amino thiols 6
(Scheme 3).
g

R.B. Nasir Baig et al. / Tetrahedron 67 (2011) 3111e3118
3113
Table 1
Synthesis of b-amino thiols by reaction sulfamidates with tetrathiomolybdate 1
Entry
1a
Sulfamidates
Time (h)
Productc
Yield (%)
O
S
N
SH
O
O
1
88
87
92
5a
5b
5c
6a
Ph
NHCOOMe
Ph
COOMe
O
SH
O
S
N
2a
1
1
O
6b
NHCOOMe
SH
COOMe
O
S
N
O
3a
O
6c
NHCOOMe
COOMe
O
S
N
SH
O
O
4a
1
95
O
5d
6d
NHCOOMe
SH
COOMe
6e1
NHCOOMe
S
O
S
N
+
S
O
5a
1
83
MeOOCHN
S
5e
(3:7)
COOMe
6e2
S
S
NHCOOMe
S
O
S
N
SH
O
O
6b
1
78
5f
6f
NHCOOMe
SH
COOMe
Ph
Ph
O
S
N
O
7b
8a
9b
O
1
1
1
92
79
95
5g
6g
NHCOOMe
COOMe
O
SH
NH
O
S
O
5h
6h
N
COOMe
COOMe
O
N
O
O
SH
S
5i
6i
NHCOOMe
COOMe
O
N
O
O
SH
S
10b
1
96
5j
6j
NHCOOMe
COOMe
O
O
O
S
11b
1
1
d
d
d
d
5k
N
COOMe
O
O
O
S
12b
5l
N
COOMe
a
Sulfamidates derived from chiral diols.
b
c
Sulfamidates derived from racemic(ꢁ)diols.
Reaction conditions: (i) [BnEt3N]2MoS4 (1.2 equiv, CH3CN, 28 ꢀC, 1 h). (ii) Satd citric acid solution. 28 ꢀC, 2 h.

3114
R.B. Nasir Baig et al. / Tetrahedron 67 (2011) 3111e3118
exemplified by synthesizing a carbohydrate derived
derivative. The reaction of sulfamidates derived form
saturated esters leads to an efficient and modular method for the
synthesis of isocysteine derivatives in optically pure form.
b
-amino thiol
-un-
O
S
O
SH
a,b
[BnNEt3]2MoS4, 1
O
NCOOMe
NHCOOMe
Hydrolysis
R
CH3CN, 28°C,
R
5
6
4. Experimental section
4.1. General methods
S
S
S
SO3
NCOOMe
All the reactions were performed in oven dry apparatus and
were stirred magnetically. Melting points and optical rotation
values (recorded at 25 ꢀC) reported are uncorrected. Infrared
spectra were recorded using an FTIR instrument and the fre-
quencies are reported in wave number (cmꢂ1) and intensities of
the peak are denoted as s (strong), w (weak), m (medium), br
(broad). 1H and 13C spectra were recorded at 300/400 MHz and at
75/100 MHz, respectively. Chemical shifts are reported in parts
Mo
+ MoS3
O3S
R
S
NCOOMe
S
7
8
R
Scheme 3.
O
O
OsO4, NMO
R1
O
O
O
O
R1
OH
OH
O
CH3COCH3:H2O
Burgess reagent, 2
O
S
R1
R
O
N
(1:1)
0°C-rt, 24 h
THF:CH2Cl2 ( 4:1)
reflux, 3 h
R
R
COOMe
9
R = Ph, R1 = Et, 10a
R = Ph, R1 = Et, 11a
R = 2-Nap, R1 = Me, 10b
R = 2-Nap, R1 = Me, 11b
R = 1-Nap, R1 = Et, 10c
R = 1-Nap, R1 = Et, 11c
Scheme 4. Synthesis of sulfamidates from a, b-unsaturated esters.
Table 2
Synthesis of isocysteine derivatives
Entry
Sulfamidates
Timea (h)
Productb
Yield (%)
O
MeOOC
O
O
N
NH O
O
S
1
0.75
93
11a
12a
O
O
O
SH
COOMe
O
MeOOC
O
O
N
NH
O
S
2
3
0.75
88
87
11b
12b
O
O
SH
COOMe
O
COOMe
NH
O
S O
O
O
O
N
11c
12c
MeOOC
0.75
O
SH
a
Time required for the reaction of sulfamidate with 1.
b
Reaction conditions: (i) [BnEt3N]2MoS4 (1.2 equiv, CH3CN, 28 ꢀC, 0.75 h). (ii) Satd citric acid solution. 28 ꢀC, 2 h.
3. Conclusion
per million downfield from the internal reference, tetramethylsi-
lane (TMS). Multiplicity is indicated using the following abbrevi-
ations: s (singlet), d (doublet), dd (double doublet) t (triplet), m
(multiplet), br s (broad singlet). Mass spectra were recorded on
Q-TOF electro-spray instrument. References for the compound
reported previously are indicated against each of them along with
the characterization data.
In summary, the unusual reactivity of tetrathiomolybdate leads
to a simple and highly efficient method for the synthesis of
b and
g-amino thiols via regioselective ring opening of sulfamidates de-
rived from corresponding diols and Burgess reagent (Et3NSO2N-
COOMe). The scope and generality of this methodology has been

R.B. Nasir Baig et al. / Tetrahedron 67 (2011) 3111e3118
3115
COOMe
NH
O
O
O
1) [BnEt3N]2MoS4
CH3CN, rt, 0.75 h
O
OH
OH
O
N
Burgess reagent, 2
O
O
S
O
O
SH
2) Sat.citric acid, rt, 2h
THF, reflux, 2 h
COOMe
10d
11d 95%
12d 89%
Scheme 5. Synthesis of chiral isocysteine derivative 12d.
OBn
OH
OBn
COOMe
Burgess reagent, 2
O
OH
OH
O
OH
OH
O
N
O
3 equiv
S
THF:CH2Cl2(4:1)
reflux, 10 h
73%
O
O
BnO
HO
BnO
OBn
OH
OBn
(ref 17)
13
14
15
1) [BnNEt3]2MoS4
CH3CN, 24 h, rt
2) citric acid, 1 h
78%
OBn
O
NHCOOMe
SH
BnO
OBn
16
Scheme 6. Synthesis of carbohydrate derived b-amino thiol 16.
O
O
1) [BnEt3N]2MoS4
CH3CN, rt, 1 h
N COOMe
OH OH
SH NHCOOMe
S
Burgess Reagent
O
THF: CH2Cl2 (4:1)
8 h, reflux
2) Sat.Citric acid, rt, 2 h
17
84% 18
87% 19
Scheme 7. Synthesis of
g
-amino thiol 19.
4.2. General procedure for the synthesis of sulfamidates from
diols
3.89 (1H, t, J¼9.6 Hz), 2.75e2.67 9 (2H, m), 2.38e2.29 (1H, m), 2.19
(3H, s), 2.13e2.04 (1H, m); 13C NMR (100 MHz, CDCl3),
d 150.3, 78.5,
54.6, 50.4, 31.9, 29.0, 15.6; HRMS calcd for C7H13NO5S2 [MþNa]þ
The appropriate diol (0.5 mmol, 1.0 equiv) was dissolved in
THF/CH2Cl2 (4:1, 5 mL) and the Burgess reagent (1.25 mmol,
2.5 equiv) was added at 25 ꢀC in a single portion. The resultant
solution was immediately warmed to reflux (using a preheated oil
bath) and stirred for 3e6 h. Upon completion, the reaction con-
tents were cooled to 25 ꢀC, poured into saturated aqueous NH4Cl
(25 mL), and extracted with CH2Cl2 (3ꢃ25 mL). The combined
organic layers were then washed with water (50 mL), dried over
(Na2SO4), and concentrated. The resultant yellow residue was
purified by flash column chromatography (silica gel) in an ap-
propriate solvent system to give the desired product in high
purity.
278.0133 found 278.0143.
D25
4.2.2. Compound 5h. Gummy solid; [
(Neat); 2961 (w), 1740 (s), 1442 (m), 1373 (s), 1324 (s), 1189 (s),
1057 (w), 1032 (w), 869 (m), 831 (m), 761 (m), 637 (m) cmꢂ1
a]
ꢂ11.95 (c 1, CHCl3); IR
;
1H NMR (400 MHz, CDCl3),
d 5.12e5.06 (1H, m), 4.40e4.35 (1H,
m), 3.91 (3H, s), 1.47(3H, d, J¼8 Hz), 1.39 (3H, d, J¼8 Hz); 13C
NMR (100 MHz, CDCl3),
d 150.0, 79.8, 58.1, 54.3, 14.0, 12.9; HRMS
calcd for C6H11NO5S [MþNa]þ 232.0256 found 232.0266.
4.2.3. Compound 5k (ꢁ). Gummy solid; IR (Neat); 2947 (w), 2873
(w), 1738 (s), 1376 (s), 1333 (s), 1296 (s), 1185 (s), 1145 (w), 959 (s),
904 (m), 834 (m), 759 (m), 645 (m) cmꢂ1 1H NMR (300 MHz,
;
D25
4.2.1. Compound 5e. Gummy solid; [
a
]
ꢂ8.18 (c 1, CHCl3); IR
(Neat); 2960 (w), 2920 (w), 1744 (s), 1442 (s), 1375 (s), 1332 (s), 1192
CDCl3),
2.70e2.60 (1H, m), 2.43e2.33 (1H, m), 1.89e1.43 (8H, m); 13C NMR
(100 MHz, CDCl3), 151.1, 83.6, 63.8, 54.8, 30.6, 30.0, 25.6, 25.0,
d 4.66e4.58 (1H, m), 4.17e4.69 (1H, m), 3.90 (3H, s),
(s), 1153 (w), 1018 (w), 835 (m), 760 (m), cmꢂ1; 1H NMR (400 MHz,
CDCl3),
d
5.16e5.10 (1H, m), 4.25 (1H, dd, J¼5.6, 8 Hz), 3.97 (3H, s),
d

3116
R.B. Nasir Baig et al. / Tetrahedron 67 (2011) 3111e3118
24.2; HRMS calcd for C9H15NO5S [MþNa]þ 272.0569 found
(3H, s), 3.56e3.50 (1H, m), 3.23e3.11 (2H, m), 2.99 (1H, dd, J¼6,
14 Hz), 2.77 (1H, dd, J¼8, 12 Hz), 1.40 (1H, d, J¼6.8 Hz); 13C NMR
272.0561.
(100 MHz, CDCl3), d 156.9, 138.0, 129.1, 128.4, 126.7, 62.2, 52.2, 47.5,
4.2.4. Compound 5l (ꢁ). White solid; mp 130 ꢀC; IR (Neat); 2932
42.4; HRMS calcd for C11H15NO2S [MþNa]þ 248.0721 found
(s), 2868 (m), 1744 (s), 1593 (w), 1443 (m), 1382 (s), 1325 (s), 1302
248.0711.
(s), 1191 (s), 922 (m), 869(m), 762 (w), 646 (m) cmꢂ1 1H NMR
;
(300 MHz, CDCl3),
d
4.82e4.74 (1H, m), 4.34e4.26 (1H, m), 3.90
4.3.2. Compound 6b. Gummy solid; [
(Neat); 3332 (br), 2961 (m), 2565 (w), 1704 (w), 1528 (m), 1462
(w), 1260 (m), 1191 (w), 1021 (w), 775 (w) cmꢂ1 1H NMR
(400 MHz, CDCl3), 5.18 (1H, br s), 3.68 (3H, s), 3.59e3.49 (1H,
a
]
ꢂ9.34 (c 1, CHCl3); IR
D25
(3H, s), 2.53e2.46 (1H, m), 2.30e2.12 (1H, m), 1.90e1.35 (10H, m);
13C NMR (75 MHz, CDCl3),
d
150.3, 83.0, 62.0, 54.2, 33.0, 26.3, 21.4,
;
20.9; HRMS calcd for C10H17NO5S [MþNa]þ 286.0725 found
d
286.0721.
m), 3.10e3.03 (1H, m), 2.86e2.80 (1H, m), 1.97e1.85 (1H, m), 1.69
(1H, d, J¼16 Hz), 1.02 (3H, d, J¼8 Hz), 0.95 (3H, d, J¼8 Hz); 13C
4.2.5. Compound 11b (ꢁ). White solid; mp 148 ꢀC; IR (Neat); 3060
(w), 2960 (m), 1753 (s), 1440 (s), 1318 (s), 1196 (s), 1044 (s), 946 (s),
848 (s), 830 (s), 750 (m), 737 (m) cmꢂ1; 1H NMR (400 MHz, CDCl3),
NMR (100 MHz, CDCl3), d 156.9, 52.1, 48.1, 46.5, 31.4, 17.7, 17.6;
HRMS calcd for C7H16NO2S [MþNa]þ 200.0721 found 200.0710.
d
7.89e7.82 (4H, m), 7.53e7.48 (3H, m), 5.70 (1H, d, J¼6.4 Hz), 5.64
4.3.3. Compound 6c. Gummy solid; [
(Neat); 3339 (w), 2955 (w), 2560 (w), 1701 (m) 1522 (w), 1219 (m),
772 (s), 668 (s) cmꢂ1 1H NMR (400 MHz, CDCl3),
5.19 (1H, br s),
a
]
ꢂ48.41 (c 1, CHCl3); IR
D25
(1H, d, J¼6.4 Hz), 3.88 (3H, s), 3.36 (3H,s); 13C NMR (100 MHz,
CDCl3),
d
162.6, 149.5, 133.5, 132.7, 130.2, 128.8, 128.2, 127.6, 127.0,
;
d
126.6, 123.9, 77.5, 63.1, 60.2, 54.8, 52.7; HRMS calcd for C16H15NO7S
3.68 (3H, s), 3.50e3.48 (1H, m), 3.09e3.04 (1H, m), 2.97e2.94 (1H,
m), 1.92e1.85 (1H, m), 1.44e1.35 (2H, m), 1.30 (1H, d, J¼8 Hz), 0.93
(3H, d, J¼8 Hz), 0.88 (3H, d, J¼8 Hz); 13C NMR (100 MHz, CDCl3),
[MþNa]þ 388.0467 found 388.0464.
4.2.6. Compound 11c (ꢁ). White solid; mp 143 ꢀC; IR (Neat); 3054
d 156.9, 52.1, 48.6, 44.9, 39.5, 25.4, 22.9, 21.5; HRMS calcd for
(w), 2963 (w), 1752 (s), 1442 (m), 1387 (s), 1320 (s), 1197 (s), 1035
C8H17NO2S [MþNa]þ 214.0878 found 214.0861.
(s), 952 (m), 927 (w), 839 (w) cmꢂ1 1H NMR (400 MHz, CDCl3),
;
d
8.67 (1H, d, J¼8 Hz), 7.88e7.86 (3H, m), 7.61e7.50 (3H, m), 6.56
4.3.4. Compound 6d. Gummy solid; [
(Neat); 3332 (br), 2962 (m), 2930 (w), 2575 (w), 1704 (s), 1530 (s),
1460 (w), 1260 (s), 1191 (w), 1015 (w), 773 (w) cmꢂ1 1H NMR
(400 MHz, CDCl3), 5.17 (1H, br s), 3.68 (3H, s), 3.53e3.49 (1H, m),
3.12e3.06 (1H, m), 3.01e2.95 (1H, m), 1.71e1.61 (1H, m),
a
]
þ28.94 (c 1, CHCl3); IR
D25
(1H, d, J¼6.4 Hz), 5.7 (1H, d, J¼6.4 Hz), 3.80 (3H, s), 3.63e3.59 (1H,
m), 3.39e3.34 (1H, m), 0.46 (3H, J¼7.2 Hz); 13C NMR (100 MHz,
;
CDCl3),
d
162.0, 149.6, 133.4, 130.7, 130.2, 129.0, 128.9, 126.7, 126.0,
d
125.5, 125.4, 122.1, 77.2, 62.4, 57.6, 54.9, 12.8; HRMS calcd for
C17H17NO7S [MþNa]þ 402.0623 found 402.0616.
0.91e0.087 (6H, m); 13C NMR (100 MHz, CDCl3),
d 156.9, 52.1, 46.9,
45.9, 37.5, 27.4, 14.0, 11.5; HRMS calcd for C8H17NO2S [MþNa]þ
D25
4.2.7. Compound 11d. Gummy solid; [
a]
þ23.50 (c 1, CHCl3); IR
214.0878 found 214.0861.
(Neat); 2969 (w), 2930 (w), 1749 (s), 1442 (m), 1388 (s), 1315 (s),
1194 (s), 1043 (s), 836 (s), 701 (s) cmꢂ1; 1H NMR (300 MHz, CDCl3),
4.3.5. Compound 6e1. Gummy solid; [
a
]
þ38.75 (c 1, CHCl3); IR
D25
d
7.46e7.36 (5H, m), 5.56 (1H, d, J¼6.3 Hz), 5.53 (1H, d, J¼6.3 Hz),
(Neat); 3330 (br), 2918 (m), 2852 (w), 2542 (w), 1704 (s), 1520 (m),
1434 (w), 1366 (w), 1222 (s), 1145 (w), 1015 (w), 847 (w), 776 (w)
3.97e3.83 (5H, m), 0.93 (3H, t, J¼7.2 Hz); 13C NMR (75 MHz, CDCl3),
cmꢂ1 1H NMR (400 MHz, CDCl3),
; d 5.14(1H, br s), 3.68 (3H, s),
d
162.1, 149.5, 132.9, 129.6, 128.7, 127.6, 77.4, 63.0, 62.5, 54.7, 13.4;
HRMS calcd for C13H15NO7S [MþNa]þ 352.0467 found 352.0461.
3.50e3.42 (1H, m), 3.22e2.15 (1H, m), 3.08e3.04 (1H, m),
2.76e2.61 (2H, m), 2.10 (3H, s), 2.02e1.93 (1H, m), 1.72e1.65 (1H,
m), 1.35 (1H, d, J¼8 Hz); 13C NMR (100 MHz, CDCl3),
d
157.7, 52.7,
D25
4.2.8. Compound 18. Gummy solid; [
a]
ꢂ21.7 (c 1, CHCl3); IR
48.6, 40.7, 35.4, 31.9, 15.9; HRMS calcd for C7H15NO2S2 [MþNa]þ
(Neat); 2985 (m), 2962 (m), 2942 (m), 1738 (s), 1443 (m), 1380 (m),
1309 (m), 1187 (m), 1117 (m), 923 (m), 897 (m), 797 (m), 714 (w),
232.0442 found 232.0450.
668 (w) cmꢂ1 1H NMR (300 MHz, CDCl3),
; d 5.06e4.98 (1H, m),
4.84e4.73 (1H, m), 3.91 (3H, s), 2.62e2.53 (1H, m), 1.81e1.73 (1H,
4.3.6. Compound 6e2. Gummy solid; [
a
]
þ103.82 (c 1, CHCl3); IR
D25
m), 1.57 (3H, d, J¼6.6 Hz), 1.49 (3H, d, J¼6.9 Hz); 13C NMR (75 MHz,
(Neat); 3328 (br), 2940 (w), 2915 (w), 2842 (w), 1703 (s), 1529
(m), 1434 (w), 1257 (s), 1191 (w), 1021 (w), 775 (w) cmꢂ1; 1H NMR
CDCl3),
d 152.5, 80.2, 54.5, 53.4, 35.2, 22.0, 21.7; HRMS calcd for
C7H13NO5S [MþNa]þ 246.0412 found 246.0393.
(400 MHz, CDCl3),
d 5.46 (1H, br s), 3.69 (3H, s), 3.42e3.36 (2H,
m), 3.02 (1H, m), 2.71e2.60 (2H, m), 2.10 (3H, s), 1.92e1.77 (2H,
m); 13C NMR (100 MHz, CDCl3),
d 157.2, 52.2, 50.2, 44.3, 31.3, 30.4,
4.3. Synthesis of b-amino thiols
15.3; HRMS calcd for C14H28N2O4S4 [MþNa]þ 439.0830 found
General procedure for the synthesis amino thiols: To a well-stirred
solution of appropriate sulfamidate (0.50 mmol) in CH3CN (6 mL)
was added benzyltriethylammonium tetrathiomolybdate 1 (0.365 g,
0.6 mmol) in portions over a period of 5 min. The reaction mixture
was stirred for further 55 min at room temperature. To this saturated
citric acid solution (3 mL) was added and the stirring was continued
for further 2 h at room temperature. Finally the reaction mixture was
extracted with diethyl ether (20 mLꢃ4). The combined organic ex-
tract was washed with brine, dried over anhydrous sodium sulfate,
and concentrated under vacuum. The crude product was purified by
column chromatography on silica gel (100e200 mesh).
439.0826.
4.3.7. Compound 6f (ꢁ). Gummy solid; IR (Neat); 3329 (br), 3023
(w), 2945 (w), 2561 (w), 1705 (s), 1524 (s), 1254 (s), 1147 (w), 1070
(w), 997 (w), 770 (m), 753 (m) cmꢂ1 1H NMR (300 MHz, CDCl3),
;
d
7.31e7.10 (5H, m), 5.15 (1H, br s), 3.67 (3H, s), 3.20e3.11 (1H, m),
2.93e2.68 (3H, m), 2.09e1.91 (1H, m), 1.78e1.66 (1H, m), 1.36 (1H,
d, J¼6 Hz); 13C NMR (100 MHz, CDCl3),
d 156.9, 136.4, 129.5, 128.5,
125.7, 52.1, 48.2, 40.8, 37.5, 33.0; HRMS calcd for C12H17NO2S
[MþNa]þ 262.0878 found 262.0880.
4.3.8. Compound 6g (ꢁ). Gummy solid; IR (Neat); 3342 (br), 2929
D25
4.3.1. Compound 6a. Gummy solid; [
(Neat); 3329 (br), 3023 (w), 2945 (w), 2560 (w), 1705 (s), 1524 (s),
1254 (s), 1147 (w), 1070 (w), 997 (w), 770 (m), 753 (m) cmꢂ1 1H
NMR (400 MHz, CDCl3), 7.33e7.19 (5H, m), 5.14 (1H, br s), 3.67
a
]
ꢂ45.78 (c 1, CHCl3); IR
(s), 2857(m), 2552 (w), 1711 (s), 1533 (m), 1463 (w), 1378 (w),
1288 (m), 1075 (w), 778 (w) cmꢂ1 1H NMR (300 MHz, CDCl3),
;
;
d
5.19 (1H, br s), 3.68 (3H, s), 3.54e3.44 (1H, m), 3.13e3.04 (1H,
d

R.B. Nasir Baig et al. / Tetrahedron 67 (2011) 3111e3118
3117
m), 2.94e2.83 (1H, m), 1.70e1.28 (1H, m), 0.88 (3H, t, J¼6 Hz); 13
C
J¼9 Hz), 5.28 (1H, t, J¼7.8 Hz), 5.59e5.25 (7H, m), 4.08 (1H, m),
3.84e3.73(3H, m), 3.69 (3H, s), 3.27e3.21 (1H, m), 1.97 (1H, d,
NMR (75 MHz, CDCl3),
d 156.9, 52.1, 48.3, 41.4, 35.8, 31.6, 28.8,
26.8, 22.5, 13.9; HRMS calcd for C10H21NO2S [MþNa]þ 242.1190
J¼9.6 Hz); 13C NMR (75 MHz, CDCl3),
d 156.0, 138.1, 137.6, 137.1,
found 242.1198.
128.5, 128.4, 128.3, 128.0, 127.9, 127.6, 127.5, 78.6, 74.7, 73.4, 72.7,
72.6, 72.1, 68.1, 52.4, 41.5; HRMS calcd for C29H33NO6S [MþNa]þ
546.1926 found 546.1907.
D25
4.3.9. Compound 6h. Gummy solid; [
a
]
ꢂ12.0 (c 1, CHCl3); IR
(Neat); 3329 (br), 2973 (m), 2931 (w), 2560 (w), 1702 (s), 1524 (s),
1454 (m), 1249 (m), 1194 (w), 1077 (w), 1018 (w), 777 (w) cmꢂ1; 1H
D25
4.3.16. Compound 19. Gummy solid; [
a
]
ꢂ3.21 (c 1, CHCl3); IR
(Neat); 3334 (br), 2929 (s), 2856 (m), 2558 (w), 1713 (s), 1699 (s),
1537 (m), 1455 (m), 1261 (s), 1103 (s), 1036 (s), 864 (w), 800 (s)
NMR (400 MHz, CDCl3),
d 4.91 (1H, br s), 3.86 (1H, br m), 3.67 (3H,
s), 3.08e3.06 (1H, br m), 1.35 (1H, d, J¼8 Hz), 1.31 (3H, d, J¼6.8 Hz),
cmꢂ1 1H NMR (300 MHz, CDCl3),
; d 4.90 (1H, br s), 3.97 (1H, br s),
1.17 (3H, d, J¼6.4 Hz); 13C NMR (100 MHz, CDCl3),
d 156.6, 52.0, 51.4,
40.7, 21.6, 19.2; HRMS calcd for C6H13NO2S [MþNa]þ 186.0565
3.66 (3H, s), 3.05e2.93(1H, m), 1.68(1H, d, J¼12 Hz), 1.60e1.56 (2H,
m), 1.33 (3H, d, J¼6.9 Hz), 1.17 (3H, d, J¼6.6 Hz); 13C NMR (75 MHz,
found 186.0557.
CDCl3),
d 156.5, 51.9, 48.6, 45.4, 32.2, 25.4, 21.6; HRMS calcd for
C7H15NO2S [MþNa]þ 200.0721 found 200.0723.
4.3.10. Compound 6i (ꢁ). Gummy solid; IR (Neat); 3332 (br),
2965 (m), 2935 (m), 2877 (w), 2561 (w), 1709 (s), 1515 (s), 1460
(m), 1379 (w), 1355 (w), 1238 (m), 1105 (w), 776 (w) cmꢂ1 1H
;
Acknowledgements
NMR (300 MHz, CDCl3),
d
4.88 (1H, d, J¼8.7 Hz), 3.81e3.73 (1H,
m), 3.67 (3H, s), 2.90e2.82 (1H, m), 1.78e1.42 (4H, m), 1.15 (1H,
d, J¼6.9 Hz), 1.04 (3H, t, J¼7.5 Hz), 0.93 (3H, t, J¼7.5 Hz); 13C
N.B.R.B. thanks CSIR, New Delhi for a research fellowship and
SCN thanks DST, New Delhi for the JC Bose National Fellowship.
NMR (75 MHz, CDCl3),
d 157.0, 55.4, 52.0, 46.9, 29.1, 27.2, 12.2,
10.5; HRMS calcd for C8H17NO2S [MþNa]þ 214.0878 found
Supplementary data
214.0877.
Supplementary data associated with this article can be found in
the online version at doi:10.1016/j.tet.2011.02.074.
4.3.11. Compound 6j (ꢁ). Gummy solid; IR (Neat); 3333 (br), 2959
(s), 2872 (s), 2559 (w),1710 (s),1512 (s),1463 (m),1253 (s),1193 (w),
1109 (m), 1067 (m), 1022 (w), 776 (w) cmꢂ1 1H NMR (300 MHz,
;
References and notes
CDCl3),
2.93e2.90 (1H, m), 1.86e1.25 (8H, m), 1.16 (1H, d, J¼6.9 Hz),
0.95e0.88(6H, m); 13C NMR (75 MHz, CDCl3),
156.9, 53.9, 52.0,
d
4.88 (1H, d, J¼9.6 Hz), 3.85e3.80 (1H, m), 3.67 (3H, s),
1. (a) Cohen, S. C.; Halcomb, R. L. J. Am. Chem. Soc. 2002, 124, 2534e2543; (b)
Bower, J. F.; Szeto, P.; Gallagher, T. Org. Biomol. Chem. 2007, 5, 143e150; (c)
Bower, J. F.; Szeto, P.; Gallagher, T. Org. Lett. 2007, 9, 4901e4912; (d) Avenoza, A.;
Busto, J. H.; Jimenez-Oses, G.; Peregrina, J. M. Org. Lett. 2006, 8, 2855e2858; (e)
Bower, J. F.; Chakthong, S.; Svenda, J.; Williams, A. J.; Lawrence, R. M.; Szeto, P.;
Gallagher, T. Org. Biomol. Chem. 2006, 4, 1868e1877; (f) Bower, J. F.; Svenda, J.;
Williams, A. J.; Charmant, J. P. H.; Lawrence, R. M.; Szeto, P.; Gallagher, T. Org.
Lett. 2004, 6, 4727e4730; (g) Avenoza, A.; Busto, J. H.; Corzana, F.; Jimenez-Oses,
G.; Peregrina, J. M. Chem. Commun. 2004, 980e981; (h) Attani, M.; Wei, L.;
Lubell, W. D. Org. Lett. 2001, 3, 2965e2968.
2. (a) Menendez, R. E.; Lubell, W. D. Tetrahedron 2003, 59, 2581e2616; (b) Hu, X. E.
Tetrahedron 2004, 60, 2701e2743.
3. (a) Ingenitio, R.; Bianchi, E.; Fattori, D.; Pessi, A. J. Am. Chem. Soc. 1999, 121,
11369e11374; (b) Adams, B.; Beresford, K. J. M.; Whyte, S. M.; Young, D. W.
Chem. Commun. 2000, 619e620 and references cited therein.
d
45.0, 37.9, 36.4, 20.5, 19.2, 13.8, 13.6; HRMS calcd for C10H21NO2S
[MþNa]þ 242.1191 found 242.1190.
4.3.12. Compound 12b (ꢁ). Gummy solid; IR (Neat); 3342 (br), 3059
(w), 2852 (w), 2563 (w),1733 (s),1701 (s),1511 (s),1511 (s),1260 (w),
1046 (m), 827 (w), 758 (w) cmꢂ1 1H NMR (400 MHz, CDCl3),
;
d
7.84e7.75 (4H, m), 7.05e7.46 (3H, m), 5.75 (1H, d, J¼9.2 Hz), 5.49
(1H, br s), 4.05 (1H, t, J¼8 Hz), 3.70 (3H, s), 3.68 (3H, s), 1.95 (1H, d,
J¼8 Hz); 13C NMR (100 MHz, CDCl3),
d 170.6,156.3,133.0,132.9,128.7,
128.0, 127.6, 126.4, 126.3, 15.7, 124.1, 116.0, 57.1, 53.0, 52.5, 48.4;
HRMS calcd for C16H17NO4S [MþNa]þ 342.0776 found 342.0787.
4. Chauvel, E. N.; Llorens-Cartes, C.; Coric, P.; Wilk, S.; Roques, B. P.; Fournie-Za-
luski, M. C. J. Med. Chem. 1994, 37, 2950e2957.
5. Anne, C.; Turcaud, S.; Quancard, J.; Teffo, F.; Meudal, H.; Fournie-Zaluski, M. C.;
Roques, B. P. J. Med. Chem. 2003, 46, 4648e4656.
6. Martin, L.; Cornille, F.; Coric, P.; Roques, B. P.; Fournie-Zaluski, M. C. J. Med.
Chem. 1998, 41, 3450e3460.
7. (a) Deroose, F. D.; Declercq, P. J. J. Org. Chem.1995, 60, 321e330; (b) Mooknaar, M. J.;
Speckamp, W. N.; Hiemstra, H.; Poetsch, E.; Casutt, M. Angew. Chem., Int. Ed. 1995,
34, 2391e2393; (c) Corey, E. J.; Mehrotra, M. M. Tetrahedron Lett. 1988, 29, 57e60;
(d) Wipf, P.; Venkatraman, S.; Miller, C. P. J. Org. Chem. 1995, 60, 7224e7229.
8. (a) Rijnberg, E.; Jastrzebski, J. T. B. H.; Janssen, M. D.; Boersma, J.; van Koten, G.
Tetrahedron Lett. 1994, 35, 6521e6524; (b) Tseng, S. L.; Yang, T. K. Tetrahedron:
Asymmetry 2005, 16, 773e782.
4.3.13. Compound 12c (ꢁ). Gummy solid; IR (Neat); 1H NMR
(300 MHz, CDCl3),
d
8.10 (1H, d, J¼8.1 Hz), 7.81e7.20 (2H, m),
7.55e7.34 (4H, m), 6.15 (1H, dd, J¼4.8, 9 Hz), 5.72 (1H, d, J¼9 Hz),
4.15e4.09 (3H, m), 3.67 (3H, s), 1.77 (1H, d, J¼5.7 Hz), 1.17 (3H, t,
J¼7.2 Hz); 13C NMR (100 MHz, CDCl3),
d 170.0, 156.2, 134.6, 133.9,
133.0, 129.1, 128.8, 126.9, 125.9, 124.9, 123.6, 122.4, 62.3, 52.7, 52.4,
48.4, 13.9; HRMS calcd for C17H19NO4S [MþNa]þ 356.0932 found
356.0923.
9. (a) Lambert, F.; Knotter, D. M.; Janssen, M. D.; Van Klaveren, M.; Boersma, J.;
Van Koten, G. Tetrahedron: Asymmetry 1991, 2, 1097e1100; (b) Zhou, Q. L.; Pfalz,
A. Tetrahedron Lett. 1993, 34, 7725e7728.
10. Fanjul, S.; Hulme, A. N.; White, J. W. Org. Lett. 2006, 8, 4219e4222.
11. Dix, J. S.; Bresson, C. R. J. Org. Chem. 1967, 32, 282e285.
D25
4.3.14. Compound 12d. Gummy solid; [
a
]
ꢂ3.21 (c 1, CHCl3); IR
(Neat); 3327 (br), 3059 (w), 2955 (w), 2874 (w), 2563 (w), 1371 (s),
1695 (s), 1537 (m), 1455 (w), 1370 (w), 1291 (w), 1253 (w), 1160 (w),
1046 (m), 1023 (m), 758 (w), 701 (m) cmꢂ1 1H NMR (300 MHz,
;
12. (a) Cran, G. A.; Gibson, C. L.; Handa, S. Tetrahedron: Asymmetry 1995, 6,
1553e1556; (b) Bae, J. H.; Shin, S. H.; Park, C. S.; Lee, W. K. Tetrahedron 1999,
55, 10041e10046; (c) Myllymaki, V. T.; Lindvall, M. K.; Koskinen, A. M. Tetra-
hedron 2001, 57, 4629e4635; (d) Harfouche, J.; Herault, D.; Tommasino, M. L.;
Pellet-Rostaing, S.; Lemaire, M. Tetrahedron: Asymmetry 2004, 15, 3413e3418;
(e) Anderson, J. C.; Cubbon, R.; Harding, M.; James, D. J. Tetrahedron: Asym-
CDCl3),
d
7.37e7.25 (5H, m), 5.63 (1H, d, J¼9 Hz), 5.30(1H, dd, J¼6,
8.7 Hz), 4.13 (2H, q, J¼6 Hz), 3.91(1H, t, J¼6 Hz), 3.66 (3H, s), 1.94
(1H, d, J¼9 Hz), 1.19 (3H, t, J¼6 Hz); 13C NMR (75 MHz, CDCl3),
d
170.0, 156.2, 138.9, 128.6, 128.0, 126.6, 62.1, 57.1, 52.4, 48.6, 13.8;
ꢀ
metry 1998, 9, 3461e3490; (f) Mercey, G.; Bregeon, D.; Gaumont, A.-C.; Lev-
HRMS calcd for C13H17NO4S [MþNa]þ 306.0776 found 306.0781.
illain, J.; Gulea, M. Tetrahedron Lett. 2008, 49, 6553e6555; (g) Mercey, G.;
Lohier, J.-F.; Gaumont, A.-C.; Levillain, J.; Gulea, M. Eur. J. Org. Chem. 2009,
4357e4364; (h) Sureshbabu, V. V.; Vishwanatha, T. M.; Vasantha, B. Synlett
2010, 1037e1042.
D25
4.3.15. Compound 16. Gummy solid; [
a
]
þ28.70 (c 1, CHCl3);
3332 (br), 3028 (w), 2928 (m), 2568 (w), 1732 (s), 1714 (s), 1518 (m),
1454 (s), 1359 (m), 1260 (m), 1092 (s), 1023 (s), 748 (m), 698 (s)
13. Wu, J.; Hou, X. L.; Dai, L. X. J. Chem. Soc., Perkin Trans. 1 2001, 1314e1317 and
references therein.
14. (a) Nasir Baig, R. B.; Chandrakala, R. N.; Sai Sudhir, V.; Chandrasekaran, S. J. Org.
Chem. 2010, 75, 2910e2921; (b) Sureshkumar, D.; Koutha, S.; Chandrasekaran,
cmꢂ1; 1H NMR (300 MHz, CDCl3),
d 7.30e7.25 (1H, m), 5.38 (1H, d,

3118
R.B. Nasir Baig et al. / Tetrahedron 67 (2011) 3111e3118
S. J. Am. Chem. Soc. 2005, 127, 12760e12761; (c) Sureshkumar, D.; Gunasundari,
15. Nasir Baig, R. B.; Catherine Kanimozhi, K.; Sai Sudhir, V.; Chandrasekaran, S.
Synlett 2009, 1227e1232.
16. Sharpless, K. B.; Amberg, W.; Bennani, Y. L.; Crispino, G. A.; Hortung, J.; Jeong,
K. S.; Known, H. L.; Morikawa, K.; Wang, Z. M.; Xu, D.; Zhang, X. ,L. J. Org. Chem.
1992, 57, 2768e2771.
T.; Ganesh, V.; Chandrasekaran, S. J. Org. Chem. 2007, 72, 2106e2117; (d) Prabhu,
K. R.; Devan, N.; Chandrasekaran, S. Synlett 2002, 1762e1778; (e) Bhat, R. G.;
Porhiel, E.; Saravanan, V.; Chandrasekaran, S. Tetrahedron Lett. 2003, 44,
5251e5253; (f) Nasir Baig, R. B.; Sai Sudhir, V.; Chandrasekaran, S. Synlett 2008,
2684e2688; (g) Nasir Baig, R. B.; Sai Sudhir, V.; Chandrasekaran, S. Tetrahedron:
Asymmetry 2008, 19, 1424e1428.
17. Nicolaou, K. C.; Snyder, S. A.; Longbottom, D. A.; Nalbandian, A. Z.; Huang, X.
Chem.dEur. J. 2004, 10, 5581e5606.