Expeditious synthesis of 1-substituted taurines with diverse functionalized side-chains

Article abstract of DOI:10.1016/j.tet.2012.10.029

A radical addition reaction and subsequent performic acid oxidation were used for the synthesis of 1-substituted taurines with diverse functionalized side-chains from N-allylphthalimide and various xanthates. The current approach shows high yields and short synthetic route and reaction time. Moreover, the current method is a convenient and practical method for the synthesis of 1-substituted taurines with different functionalized side-chains.

Full text of DOI:10.1016/j.tet.2012.10.029

Tetrahedron 69 (2013) 302e309
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Tetrahedron
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Expeditious synthesis of 1-substituted taurines with diverse
functionalized side-chains
,b,
Saeed Kakaei a, Ning Chen a, Jiaxi Xu a
*
a State Key Laboratory of Chemical Resource Engineering, Department of Organic Chemistry, Faculty of Science, Beijing University of Chemical Technology, Beijing 100029, China
b State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100191, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 31 July 2012
Received in revised form 27 September 2012
Accepted 9 October 2012
Available online 16 October 2012
A radical addition reaction and subsequent performic acid oxidation were used for the synthesis of 1-
substituted taurines with diverse functionalized side-chains from N-allylphthalimide and various xan-
thates. The current approach shows high yields and short synthetic route and reaction time. Moreover,
the current method is a convenient and practical method for the synthesis of 1-substituted taurines with
different functionalized side-chains.
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
Amino acid
Aminoalkanesulfonic acid
Taurine
Functionalized side-chain
Radical reaction
1. Introduction
thiolacetic acid, and nitroolefins and subsequent (oxidation and)
catalytic hydrogenation.10
The good biological compatibility is a reason for the increasing
interest in the preparation of amino acids. Among these compounds,
2-aminoethanesulfonic acid, known as taurine, and its derivatives
have been found in many mammals, marine algaes, fishes, and
shellfishes.1,2 They are closely related to the many biological pro-
cesses in living organisms. Taurine and its cyclic analogs have been
reported to show different effects on ATP-dependent calcium ion
uptake and protein phosphorylation in rat retina.3 Taurine and
substituted taurines are building blocks for synthesis of sulfono-
peptides, important mimetics of naturally occurring peptides.4
Due to the importance, much attention has been devoted to the
synthesis of substituted taurines.4,5 1-Substituted and 1,1-
disubstituted taurines have been prepared via the Mitsunobu
Because important protein encoded amino acids possess various
functionalized side-chains, 1-substituted taurines with different
functionalized side-chains are significant sulfur analogs of naturally
occurring amino acids and also a class of important natural prod-
ucts, such as cysteic acid, 3-amino-2-sulfopropoinic acid,11 which is
a well-known nontoxic, nonallergenic, and physiological com-
pound, and was prepared from L-cysteine via the bromine oxida-
tion,12 hydrogen peroxide oxidation,13 I2eHCl oxidation,14 or
chlorine oxidation.15 Its enantiomer was synthesized from the
corresponding aziridine5b and thiazolidine-2-thione derivative as
well.9 Some 1-subsituted taurines with functionalized side-chains,
such as alkoxy, aminoalkyl, and chloromethyl, have been prepared
from the corresponding amino secondary alcohols6b or from the
ring-opening of substituted thiiranes.7c Similarly, racemic and
enantiopure 1-benzyloxymethyl and 1-hydroxymethyl taurines
were synthesized from alkyloxymethylthiiranes via a ring-opening
with dibenzylamine and further oxidation and deprotection.7a Boc-
substitution from
b-amino secondary and tertiary alcohols and
oxidation with performic acid;6 via a ring-opening with ammonia/
amines from aliphatic thiiranes and oxidation with performic acid;7
via the bisulfite ring-opening process from aromatic 2,2-
disubstituted aziridines;8 via the oxidation of 5-substituted thia-
zolidine-2-thiones;9 and via the Michael addition from sulfur nu-
cleophiles, such as sodium sulfite, potassium O-ethyl xanthate, and
Arg(Cbz2)-j[CH2SO2]eNH2, a 1-substituted taurinamide with
a side chain containing a guanidine group, was prepared from the
deprotected ornithine derivative.16 Additionally, 5-hydroxy-2-
aminopentane-1-sulfonic acid, a taurine derivative containing
a hydroxypropyl side-chain, was afforded from the corresponding
olefin via an amino-sulfonation process.17 However, the side-chains
of the synthesized 1-substituted taurines are limited. An efficient
* Corresponding author. Tel./fax: þ86 10 64435565; e-mail address: jxxu@
mail.buct.edu.cn (J. Xu).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.10.029

S. Kakaei et al. / Tetrahedron 69 (2013) 302e309
303
Table 1
and versatile synthetic method for 1-substituted taurines with di-
Synthesis of various xanthates 3
verse functionalized side-chains is still scarce and in demand.
Thiazolidine-2-thiones9 and O-ethyl S-2-nitroalkyl dithiocarbo-
nates10b have been used as the key intermediates for the preparation
of various substituted taurines. As the linear analogs of thiazolidine-
2-thiones and analogs of O-ethyl S-2-nitroalkyl di-thiocarbonates,
S-2-aminoalkyl O-ethyl dithiocarbonates can be considered as an-
other class of useful precursors for the preparation of 1-substituted
taurines with diverse functionalized side-chains. Various 2-N-
phthalimidoalkylxanthates can be synthesized from N-allylph-
thalimide and different xanthates via a radical addition process
according to Zard and co-workers’ method (Fig. 1).18 Herein, we
describe an expeditious and versatile route for the preparation of
N-protected 1-substituted taurines with diverse functionalized
side-chains.
S
S
Acetone
0
oC - rt
R
X
O
SR
O
SK
1
2
3
Entry
R
3
Isolated yield (%)
1
2
3
4
5
6
7
8
Bn
AcCH2
3a
3b
3c
3d
3e
3f
3g
3h
3i
82
77
83
83
72
84
88
61
88
94
91
PhCOCH2
PhthNCH2
(EtO2C)2CH
MeO2CCH2
EtO2CCH2
a
C4H6O2
NCCH2
Me
9
10
11
3j
3k
n-Bu
a
2-Oxotetrahydrofuran-3-yl.
S
S
S
S
NH
EtO
R
S
Table 2
R
H
N
Optimization of reaction conditions in the preparation of dithiocarbonate 5a
PG
Ph
PhthN
EtO
R
S
O
DLP, DCE
PG: protecting group
PhthN
+
S
OEt
NO2
EtO
SBn
Temp. Time
S
5a
3a
4
Fig. 1. Design on the synthesis of taurine precursors.
Entry
3a:4a
DLP (mol %/h)
Temp (ꢀC)
Time (h)
Isolated yield (%)
2. Results and discussion
1
2
3
4
5
6
1:1
1:1
1:1
2:1
2:1
2:1
3
3
3
3
5
8
rt
7
7
7
7
7
7
0
8
15
35
88
25
50
84
84
84
84
In our studies, different xanthates 3 were prepared via the dis-
placement of potassium O-ethyl xanthate 2 with various halo de-
rivatives 1. They reacted with N-allylphthalimide (4) to afford S-2-
phthalimidoethyl xanthate derivatives 5, which were oxidized to N-
phthalimido-1-substituted taurine derivatives with performic acid
(Scheme 1).
a sudden decrease of the yield from 88 to 25% (Table 2, entry 6)
possibly because DLP generated lauroyl radical, which further
lossed CO2 to yield dodecyl radical. The dodecyl radical combined to
generate a linear alkane under a high concentration conditions.
Thus, the optimal conditions are xanthate 3: N-allylphthalimide (4)
in a molar ratio of 2:1 with addition of DLP at 5 mol% per hour in
refluxing DCE for 7 h (Table 2, entry 5).
S
PhthN
S
2
EtO
SK
4
R
X
EtO
SR
3
1
Acetone
H2O2, HCO2H
OEt 0 oC - rt
PhthN
R
PhthN
R
SO3H
S
6
A series of xanthates 5 was synthesized under the optimized
conditions. The results are listed in Table 3. In most cases, S-2-
5
S
R = aliphatic or functionized aliphatic substituents
Scheme 1. Synthesis of 1-substituted taurine derivatives.
Table 3
Radical addition of xanthates 3 with olefin 4
PhthN
R
OEt
O
DLP, DCE
reflux
Various xanthates 3 were synthesized in high yields from po-
tassium O-ethyl dithiocarbonate 2 and different haloalkane de-
rivatives 1. The results are listed in Table 1. N-Allylphthalimide (4)
was prepared from allylamine in acetic acid and phthalic
anhydride.
PhthN
+
S
EtO
SR
S
5
3
4
Entry
3
R
5
Isolated yield (%)
To prepare S-2-phthalimidoethyl xanthate derivatives 5, we first
selected the reaction of xanthate 3a with N-allylphthalimide (4) as
a model reaction with dilauroyl peroxide (DLP) as a radical initiator
to optimize the reaction conditions. The results are presented in
Table 2. No desired product 5a was observed after 7 h under the
total 21% loading of DLP (3 mol % DLP was added portionwise per
hour) in 1,2-dichloroethane (DCE) at room temperature (Table 2,
entry 1). However, the product 5a was obtained in 8% yield at 50 ꢀC
(Table 2, entry 2), and the yield increased to 15% at 84 ꢀC in
refluxing DCE. The yield was improved to 35% by changing the ratio
of 3a:4 to 2:1 (Table 2, entries 3 and 4). When the loading amount
of DLP was increased from 3 to 5 mol % per hour, the yield was
further improved remarkably from 35 to 88% (Table 2, entries 4 and
5). However, further increasing to 8 mol % DLP per hour resulted in
1
2
3
4
5
6
7
8
3a
3b
3b
3c
3d
3e
3e
3f
3g
3h
3i
3j
3k
BnCH2
AcCH2
AcCH2
PhCOCH2
PhthNCH2
(EtO2C)2CH
(EtO2C)2CH
MeO2CCH2
EtO2CCH2
C4H6O2
NCCH2
Me
5a
5b
5b
5c
5d
5e
5e
5f
5g
5h
5i
5j
5k
88
56
81a
93
84
27
94a
98
92
94c
79
0
9
b
10
11
12
13
n-Bu
0
a
Xanthate 3:4¼4:1.
b
c
2-Oxotetrahydrofuran-3-yl.
Dr value is 1.1:1.0.

304
S. Kakaei et al. / Tetrahedron 69 (2013) 302e309
Ph 80%H2NNH2. H2O
phthalimidoalkyl xanthates 5 were obtained in moderate to good
yields. However, for S-alkyl O-ethyl dithiocarbonates 3j and 3k, no
desired reaction occurred (Table 3, entries 12 and 13). According to
Zard’s proposed mechanism,19 the carbonesulfur single bond in
xanthates 3 firstly underwent a homolytic cleavage to give two
radicals (Rꢁ and ethoxythiocarbonylthio radical EtOCSS$) under the
initiation of DLP. The formation and stability of the Rꢁ are the key
factors for the reactions. When the radical carbon is attached with
conjugative systems, such as phenyl (3a), acyl (keto) (3b,c),
phthalimido (3d), esters (alkoxycarbonyl) (3eeg) and 2-
oxotetrahydrofuran-3-yl (lacton-2-yl) (3h), and cyano (3i) groups,
the radical Rꢁ groups are more stable and favorable formation due
to the conjugative effect, leading to the corresponding S-2-
phthalimidoalkyl xanthates 5 in higher yields (Table 3, entries
1e11). On the other hand, when S-substituents in xanthates 3 are
simple aliphatic alkyl groups, neither 5j nor 5k was obtained be-
cause the corresponding radicals Rꢁ are highly unstable with higher
energy, possibly difficult generation under the reaction conditions
and favorable dimerization in the reaction system even if they
generated (Table 3, entries 12 and 13). Additionally, the steric
hindrance also affected the radical reactions. Compared with 5g
(Table 3, entry 9), the yield of 5e decreased to 27% due to the bulky
substituent of xanthate 3e (Table 3, entry 6). However, the yield of
5e was remarkably improved to 94% when the ratio of 3e:4 was
increased to 4:1 (Table 3, entry 7).
Ph
H2N
PhthN
SO3H
7a
SO3H
6a
EtOH, reflux, 2 hrs
77%
Scheme 2. Removal of the N-phthoyl protecting group via hydrazinolysis.
Besides S-2-phthalimidoalkyl xanthate 5a with a phenylethyl
substituent, side-chain functionalized substrates 5bee were also
oxidized readily to the corresponding taurine derivatives 6bee in
good yields (Table 4, entries 2e5). However, xanthates 5f,g with
esters and 5i with cyano group in their side-chains produced 5-
phthalimido-4-sulfonopentanoic acid (6j) under the same reaction
conditions due toacidic hydrolysis of the estersorcyanogroups. S-2-
Phthalimidoalkyl xanthates 5fei gave rise to the corresponding 1-
substituted taurines 6fei with the original side-chains when they
were oxidized at room temperature with a controlled amount of
water (hydrogen peroxide) in formic acid and were worked up at
room temperature (Table 4, entries 6e9)(vide post).
It is well-known that ester and cyano groups are easily hydro-
lyzed to the corresponding carboxylic acids in a diluted acidic
aqueous solution. Actually, only hydrolyzed product taurine 6j was
obtained when 5f was oxidized with H2O2 (2 mL)/HCO2H (10 mL) for
1 mmol of substrate 5f by referring to our previously reported
method, that is, the solvent was removed under reduced pressure at
50e60 ꢀC6b,10b (Table 5, entry 6). It demonstrates that the ester was
hydrolyzed to the corresponding carboxylic acid during the oxida-
tion process or workup. The oxidation mechanism of xanthates to
sulfonic acids has been studied previously.10b We attempted to
control the temperature and the amount of water in the performic
acid oxidation to prepare the taurines with both original esters or
cyano groups and the corresponding carboxylic acid group.
In our previously reported method,10b 2-nitroalkyl xanthates were
oxidized by performic acid to generate the corresponding 2-
nitroalkanesulfonic acids, which were further converted to the cor-
responding substituted taurines under the catalytic hydrogenation.
Referring to the previous oxidation conditions, S-2-phthalimidoalkyl
xanthate 5a was oxidized with performic acid for 12 h to afford the
corresponding 4-phenyl-1-phthalimidobutane-2-sulfonic acid (6a)
in 85% yield (Table 4, entry 1). It is well-known that the phthalimido
group can be converted into the corresponding free amino group via
acidic or basic hydrolysis or hydrazinolysis. Thus, the method can be
used as a novel route to the preparation of N-phthoyl-protected or N-
free 1-substituted taurines. Various substituted xanthates 5 were
oxidized to the corresponding N-phthoyl-protected 1-substituted
taurines 6 in moderate to good yields (Table 4). The N-protected
taurines 6 can be used as building blocks for synthesis of sulfono-
peptides. The N-protected taurine 6a was selected as an example to
remove the protecting group. It was refluxed in ethanol in the pres-
ence of 80% hydrazine hydrate to give rise to N-free taurine 7a in
a good yield (77%) (Scheme 2). Hydrazinolysis is a good choice for
removal of the protecting group because it is very convenient for
separation of substituted taurines from crystalline byproduct
phthalhydrazide.
Table 5
Optional hydrolyzes during oxidation of 5 to taurines 6a
30%H2O2, HCO2H
PhthN
R
PhthN
R
S
OEt
0C to rt
SO3H
0
6
S
5
CO2H
PhthN
or
SO3H
6j
Entry
5a
Oxidation conditions
6
Isolated
yield (%)
H2O2/HCO2H
(mL:mL)
Temp
(ꢀ C)
1
2
3
4
5
6
7
8
5f
0.5:10
1:10
2:10
0.5:10
1:10
rt
rt
rt
6f
75
75
77
76
77
69
98
97
79
80
87
78
78
81
89
88
87
65
5f
5f
5f
5f
5f
6f
6f
5e
5e
5e
5g
5g
6fþ6j (42:58)
Table 4
6fþ6j (37:63)
Oxidation of aminoalkyl xanthates 5 to taurines 6
60
60
60
rt
60
rt
60
80
rt
60
rt
6fþ6j (16:84)
30%H2O2, HCO2H
PhthN
R
OEt
6fþ6j (12:88)
PhthN
R
SO3H
2:10
6j
6j
6j
S
2b:10
2b:10
0.5:10
2:10
0
0C to rt
6
S
5
9
6e
6e
6e
6g
6j
6h
6h
6h
6i
10
11
12
13
14
15
16
17
18
Entry
5
R
6
Isolated yield (%)
4:10
0.5:10
2:10
0.5:10
2:10
4:10
1
2
3
4
5
6
7
8
9
5a
5b
5c
5d
5e
5f
5g
5h
5i
BnCH2
AcCH2
6a
6b
6c
6d
6e
6f
6g
6h
6i
85
92
54
90
87
77
78
89
91
PhCOCH2
PhthNCH2
(EtO2C)2CH
MeO2CCH2
EtO2CCH2
C4H6O2
5h
5h
5h
5i
60
80
rt
0.5:10
2:10
5i
60
6j
a
All reactions were run in 1 mmol scale of xanthates 5.
2 mL of water was added instead of 30% H2O2.
NCCH2
b

S. Kakaei et al. / Tetrahedron 69 (2013) 302e309
305
To control the hydrolysis, 5f was selected as an example to in-
3. Conclusion
vestigate the oxidation conditions. The xanthate 5f (1 mmol) was
oxidized in formic acid (10 mL) with different amount of H2O2 at
different temperature (Table 5, entries 1e6). The results illustrate
that the xanthate 5f was oxidized to taurine 6f without the hy-
drolysis of the ester in its side-chain with 0.5 mL of H2O2 during the
oxidation process for 1 day and workup at rt (Table 5, entry 1).
However, it was hydrolyzed partly when H2O2 was increased to
1e2 mL, or the solvent was removed at 50e60 ꢀC during workup
(Table 5, entries 2e5). The ester group was completely hydrolyzed
when 2 mL of H2O2 was added and the solvent was removed at
50e60 ꢀC and the hydrolyzed product 6j was obtained as sole
product (Table 5, entry 6). To verify whether the hydrolysis is acidic
hydrolysis or performic acid-catalyzed hydrolysis, taurine 6f was
stirred in a mixture of water (2 mL) and formic acid (10 mL) to
afford taurine 6j at both rt and 60 ꢀC, indicating that the hydrolysis
is acidic hydrolysis (Table 5, entries 7 and 8). To avoid the hydrolysis
at higher temperature when removal of solvent, the reaction mix-
ture was mixed with silica gel and allowed to evaporate to dry at
room temperature during workup. Other xanthates 5g and 5i were
converted to the corresponding taurines 6g and 6i or the corre-
sponding carboxylic acid 6j, respectively, in good yields under
different oxidation conditions (0.5 mL of H2O2 at rt or 2 mL of H2O2
and removal of solvent at 50e60 ꢀC) (Table 5, entries 12, 13, 17, and
18). To our surprise, xanthate 5e with malonate in its side-chain
cannot be hydrolyzed to the corresponding carboxylic acid under
the oxidation (Table 5, entry 10), even with the more excessive
amount of H2O2 (4 mL) at higher reaction temperature (at 80 ꢀC)
(Table 5, entry 11). Apparently, the malonate group is more stable
than the other esters during the oxidation process possibly due to
its steric hindrance. Additionally, 6h also cannot be hydrolyzed,
even after 1 day with addition of 4 mL of H2O2 at reflux tempera-
ture (Table 5, entries 14e16). The stability may be a consequence of
In summary, we have developed a novel and practical protocol
for the preparation of 1-substituted taurines with diverse func-
tionalized side-chains from N-allylphthalimide and various xan-
thates with different functionalized groups via a radical addition
process and subsequent performic acid oxidation. Compared with
previous methods, the current approach shows higher overall
yields and a short synthetic route. Additionally, the esters and cy-
ano group in the side-chain can be hydrolyzed with diluted formic
acid or at higher temperature. Controlling the amount of water in
the reaction mixture and the reaction temperature can selectively
realize the synthesis of 1-substituted taurines with different func-
tionalized groups in their substituents.
4. Experimental section
4.1. General
Melting points were determined with a melting point apparatus
and are uncorrected. 1H NMR spectra were recorded at 400 MHz in
CDCl3 or D2O with TMS or DOH as the internal standards. 13C NMR
spectra were recorded at 100.6 MHz in CDCl3 or D2O (with HCO2H
as an internal standard at 163.3 ppm). IR spectra were determined
directly. HRMS spectra were recorded with an LC/MSD TOF mass
spectrometer. TLC analysis was performed on glass pre-coated silica
gel YT257-85 (10e40
mm) plate. Spots were visualized with UV
light or iodine. Column chromatography was performed on silica
gel zcx II (200e300 mesh) with silica gel (200e300 mesh) with
petroleum ether and ethyl acetate as the eluent.
4.2. General procedure for synthesis of xanthates 3
the favorable formation of the five-membered ring g-lactone. The
results reveal that the use of excessive hydrogen peroxide and the
increase of temperature have no significant effect on the hydrolysis
of the side-chain malonate and g-lactone groups in 5e and 5h.
To a solution of a haloalkane derivative 1 (25.0 mmol) in acetone
(12 mL) precooled at 0 ꢀC was added a solution of potassium O-ethyl
dithiocarbonate 2 (4.00 g, 25.0 mmol) in acetone (25 mL) slowly
under stirring at 0 ꢀC. After the addition, the mixture was allowed to
warm to rt under stirring. After acetone was evaporated, water
(50 mL) was added to the residue and the mixture was extracted
with CHCl3 (3ꢂ50 mL). The combined organic phase was dried over
MgSO4. After removal of solvents with a rotary evaporator, the res-
idue was purified on a silica gel column with petroleum ether and
ethyl acetate (from 20:1 to 10:1, v/v) as eluent to afford the desired
xanthate 3. Their analytical data are identical to those reported
previously (for details, see SD).
Compared with previous method for the synthesis of taurine
derivatives, the current method is a novel route for the preparation
of 1-substituted taurines with ketone, ester, cyano, or carboxylic
acid as functionalized side-chains. This process is quite practical
and versatile for only two steps. In addition, the whole process is
salt-free, which is beneficial for the purification of water soluble
and strong polar taurine derivatives.
Having synthesized the desired functionalized and non-
functionalized N-phthoyl-1-substituted taurines, the process was
extended to the radical addition to other olefins. Benzyl N-allyl-
carbamate (8), generated from allylamine and benzyl chlor-
oformate, reacted with xanthate 3i to give rise to the corresponding
S-2-Cbz-aminoalkyl xanthate 9 in 70% yield. Subsequent performic
acid oxidation furnished the corresponding taurine derivative 7i in
93% yield. The protecting group (Cbz) was removed, while the cy-
ano group was remained during the oxidation process at room
temperature (Scheme 3).
4.3. General procedure for synthesis of O-ethyl S-2-
phthalimidoalkyl xanthates 5
A
magnetically stirred solution of N-allylphthalimide 4
(1 equiv) and a xanthate 3 (2e4 equiv) in 1,2-dichloroethane
(2e4 mL/mmol of N-allylphthalimide) was heated at reflux for
15 min. DLP (3e5 mol %) was added and additional DLP
(5 mol %) was added per hour until complete consumption of 4.
The mixture was allowed to cool to room temperature and the
solvent was evaporated under reduced pressure. The residue was
purified by flash chromatography on silica gel to yield the de-
sired product 5.
S
CbzCl, K2CO3
90%
NC
S
OEt
CbzHN
H2N
35 mol% DLP
70%
8
CN
CN
4.3.1. O-Ethyl S-3-phenyl-1-phthalimidomethylpropyl dithiocar-
H2O2, HCO2H
93%
H2N
CbzHN
bonate (5a). Yellow oil, yield: 88%. 1H NMR (CDCl3, 400 MHz) (
d,
SO3H
S
OEt
ppm) 7.84 (dd, J¼5.6, 3.0 Hz, 2H, ArH), 7.72 (dd, J¼5.6, 3.0 Hz, 2H,
ArH), 7.27e7.18 (m, 5H, ArH), 4.60 (dq, J¼10.7, 7.2 Hz, 1H in OCH2),
4.65 (dq, J¼10.7, 7.2 Hz, 1H in OCH2), 4.17 (dddd, J¼8.6, 7.2, 7.1,
5.1 Hz, 1H, CHS), 4.01 (dd, J¼14.0, 7.2 Hz, 1H in CH2N), 3.96 (dd,
S
7i
9
Scheme 3. Synthesis of 1-substituted taurine 9.

306
S. Kakaei et al. / Tetrahedron 69 (2013) 302e309
J¼14.0, 7.1 Hz, 1H in CH2N), 2.92 (ddd, J¼13.8, 10.2, 5.1 Hz, 1H in
CH2), 2.74 (ddd, J¼13.8, 10.4, 6.4 Hz, 1H in CH2), 2.06 (dddd, J¼14.3,
10.2, 6.4, 5.1 Hz, 1H in CH2), 1.95 (dddd, J¼14.3, 10.4, 8.6, 5.1 Hz, 1H
30.5, 13.9 (2C overlaps), 13.6. IR (nmax, cmꢃ1) 2981.1, 2928.8, 1719.5,
1615.9,1467.3,1046.3, 715.9. HRMS (ESI) calcd for C21H26NO7S2 m/z:
468.1151 [MþH]þ; found 468.1119.
in CH2), 1.39 (t, J¼7.2 Hz, 3H, CH3). 13C NMR (CDCl3, 100 MHz) (
d,
ppm) 212.5, 168.1, 140.9, 134.1, 131.8, 128.4, 128.3, 126.1, 123.4, 70.1,
48.9, 41.0, 33.5, 32.9, 14.1. IR (nmax, cmꢃ1) 3023.7, 2927.4, 1716.3,
1608.3, 1467.3, 1047.3, 722.1. HRMS (ESI) calcd for C21H21NO3S2Na
m/z: 422.0855 [MþNa]þ; found 422.0855.
4.3.6. O-Ethyl S-4-methoxy-4-oxo-1-phthalimidomethylbutyl dithio-
carbonate (5f).21 Yellow oil; yield: 98%. 1H NMR (CDCl3, 400 MHz)
(
d
, ppm) 7.86 (dd, J¼5.4, 3.1 Hz, 2H, ArH), 7.73 (dd, J¼5.4, 3.1 Hz, 2H,
ArH), 4.61 (dq, J¼10.7, 7.1 Hz, 1H in OCH2), 4.58 (dq, J¼10.7, 7.1 Hz,
1H in OCH2), 4.18 (dddd, J¼9.4, 7.6, 7.2, 4.6 Hz, 1H, SCH), 4.01 (dd,
J¼14.0, 7.6 Hz, 1H in NCH2), 3.94 (dd, J¼14.0, 7.2 Hz, 1H in NCH2),
3.66 (s, 3H, OCH3), 2.60 (ddd, J¼16.4, 9.1, 5.7 Hz, 1H in CH2), 2.51
(ddd, J¼16.4, 9.0, 6.8 Hz, 1H in CH2), 2.15 (dddd, J¼14.6, 9.1, 6.8,
4.6 Hz, 1H in CH2), 1.93 (dddd, J¼14.6, 9.4, 9.0, 5.7 Hz, 1H in CH2),
4.3.2. O-Ethyl S-4-oxo-1-phthalimidomethylpentyl dithiocarbonate
(5b). Yellow oil; yield: 81%. 1H NMR (CDCl3, 400 MHz) (
d, ppm)
7.85 (dd, J¼5.4, 3.0 Hz, 2H, ArH), 7.73 (dd, J¼5.4, 3.0 Hz, 2H, ArH),
4.59 (dq, J¼10.7, 7.1 Hz, 2H, CH2), 4.62 (dq, J¼10.7, 7.1 Hz, 2H, CH2),
4.14 (dddd, J¼8.9, 7.6, 7.2, 5.1 Hz, 1H, CHS), 3.99 (dd, J¼13.9, 7.6 Hz,
1H in NCH2), 3.92 (dd, J¼13.9, 7.2 Hz, 1H in NCH2), 2.72 (ddd,
J¼18.0, 8.8, 5.7 Hz, 1H in CH2), 2.64 (ddd, J¼18.0, 8.6, 6.6 Hz, 1H in
CH2), 2.15 (s, 3H, CH3), 2.09 (dddd, J¼14.6, 8.9, 8.6, 5.7 Hz, 1H in
CH2), 1.84 (dddd, J¼14.6, 8.8, 6.6, 5.1 Hz, 1H in CH2), 1.40 (t,
1.42 (t, J¼7.1 Hz, 3H, CH3). 13C NMR (CDCl3,100 MHz) (
d, ppm) 212.2,
172.9, 168.0, 134.1, 131.8, 123.4, 70.3, 51.7, 48.8, 40.9, 31.2, 26.8, 13.6.
IR (nmax, cmꢃ1) 3049.3, 2965.2, 1773.6, 1613.9, 1467.3, 1047.2, 714.6.
4.3.7. O-Ethyl S-4-ethoxy-4-oxo-1-phthalimidomethylbutyl dithio-
carbonate (5g). Yellow oil; yield: 92%. 1H NMR (CDCl3, 400 MHz) (
d,
J¼7.1 Hz, 3H, CH3). 13C NMR (CDCl3, 100 MHz) (
d, ppm) 212.3, 207.1,
168.0, 134.1, 131.8, 123.4, 70.3, 48.8, 40.9, 40.3, 29.9, 25.1, 13.6. IR
ppm) 7.87 (dd, J¼5.5, 3.1 Hz, 2H, ArH), 7.73 (dd, J¼5.5, 3.1 Hz, 2H,
ArH), 4.61 (dq, J¼10.8, 7.2 Hz,1H in CH2O), 4.58 (dq, J¼10.8, 7.2 Hz,1H
in CH2O), 4.20 (dddd, J¼9.6, 7.6, 7.2, 4.6 Hz,1H, SCH), 4.12 (q, J¼7.2 Hz,
2H, CH2O), 3.98 (dd, J¼14.0, 7.6 Hz, 1H in NCH2), 3.93 (dd, J¼14.0,
7.2 Hz,1H in NCH2), 2.58 (ddd, J¼16.0, 9.2, 5.6 Hz,1H in CH2CO), 2.49
(ddd, J¼16.0, 9.0, 6.9 Hz, 1H in CH2CO), 2.16 (dddd, J¼14.5, 9.2, 6.9,
4.6 Hz,1H in CH2),1.92 (dddd, J¼14.5, 9.6, 9.0, 5.6 Hz,1H in CH2),1.41
(t, J¼7.2 Hz, 3H, CH3), 1.24 (t, J¼7.2 Hz, 3H, CH3). 13C NMR (CDCl3,
(
nmax, cmꢃ1) 3010.1, 2930.3, 1774.0, 1715.7, 1607.5, 1469.8, 1045.7,
713.5. HRMS (ESI) calcd for C17H19NO4S2Na m/z: 388.0648
[MþNa]þ; found 388.0560.
4.3.3. O-Ethyl S-4-oxo-4-phenyl-1-phthalimidomethylbutyl dithio-
carbonate (5c).20 Yellowish solids; mp: 93e97 ꢀC; yield: 93%. 1H
NMR (CDCl3, 400 MHz) (d, ppm) 7.94 (d, J¼7.6 Hz, 2H, ArHortho),
100 MHz) (d, ppm) 212.2, 172.5, 168.0, 134.1, 131.8, 123.4, 70.5, 60.6,
7.86 (dd, J¼5.4, 3.1 Hz, 2H, ArH), 7.73 (dd, J¼5.4, 3.1 Hz, 2H, ArH),
7.55 (dd, J¼7.5, 7.5 Hz, 1H, ArHpara), 7.45 (dd, J¼7.6, 7.5 Hz, 2H,
ArHmeta), 4.58 (q, J¼7.1 Hz, 2H, CH2O), 4.26 (dddd, J¼9.2, 7.5, 7.3,
4.6 Hz, 1H, SCH), 4.06 (dd, J¼14.0, 7.5 Hz, 1H in NCH2), 3.99 (dd,
J¼14.0, 7.3 Hz, 1H in NCH2), 3.26 (ddd, J¼17.6, 9.0, 5.4 Hz, 1H in
CH2), 3.18 (ddd, J¼17.6, 8.3, 6.8 Hz, 1H in CH2), 2.29 (dddd, J¼14.6,
9.0, 6.8, 4.6 Hz, 1H in CH2), 2.02 (dddd, J¼14.6, 9.2, 8.3, 5.4 Hz, 1H
48.8, 40.9, 31.4, 26.8,14.1,13.6. IR (nmax, cmꢃ1) 3028.1, 2933.8,1773.6,
1613.9, 1467.3, 1047.2, 714.6. HRMS (ESI) calcd for C18H22NO5S2 m/z:
396.0939 [MþH]þ; found 396.0916.
4.3.8. O-Ethyl S-3-(2-oxotetrahydrofuran-3-yl)-1-phthalimido-
methylethyl dithiocarbonate (5h). Yellow oil; yield: 94%.
Dr¼1.1:1.0. 1H NMR (CDCl3, 400 MHz) (
, ppm) 7.86 (dd, J¼5.4,
d
in CH2), 1.39 (t, J¼7.1 Hz, 3H, CH3). 13C NMR (CDCl3, 100 MHz) (
d,
3.1 Hz, 2H, ArH), 7.74 (dd, J¼5.4, 3.1 Hz, 2H, ArH), 4.66e4.54 (m, 2H,
OCH2), 4.40e3.94 (m, 5H, OCH2, SCH, & NCH2), 2.89 (dddd, J¼11.3,
11.2, 8.7, 3.8 Hz, 1H, CHCO), 2.49 (dddd, J¼12.3, 8.3, 6.3, 1.8 Hz, 1H in
CH2CO), 2.31 (ddd, J¼14.8, 11.0, 3.8 Hz, 1H in CH2CS), 1.98 (dddd,
J¼12.3, 11.3, 11.0, 8.7 Hz, 1H in CH2CO), 1.83 (ddd, J¼14.8, 11.2,
4.0 Hz, 1H in CH2CS), 1.40 (t, J¼7.1 Hz, 3H, CH3). 13C NMR
ppm) 212.3, 198.6, 168.0, 136.6, 134.1, 133.1, 131.8, 128.6, 128.0,
123.4, 70.3, 48.9, 41.1, 35.4, 25.7, 13.6. IR (nmax, cmꢃ1) 3028.1,
2933.8, 1773.6, 1613.9, 1467.3, 1047.2, 714.6.
4.3.4. O-Ethyl S-3-phthalimido-1-phthalimidomethylpropyl dithio-
carbonate (5d). White solid, mp: 154e155 ꢀC; yield: 84%. 1H NMR
(100.6 MHz, CDCl3) (d, ppm) 212.1, 178.4, 168.0, 134.2, 131.7, 123.4,
70.6, 66.4, 48.2, 41.5, 37.3, 32.2, 29.2, 13.6. IR (nmax, cmꢃ1) 3049.3,
2965.2, 1773.6, 1613.9, 1467.3, 1047.2, 714.6. HRMS (ESI) calcd for
C18H20NO5S2 m/z: 394.0783 [MþH]þ; found 394.0650.
(CDCl3, 400 MHz) (
d, ppm) 7.84 (dd, J¼5.2, 3.2 Hz, 2H, ArH), 7.83 (dd,
J¼5.2, 3.2 Hz, 2H, ArH), 7.73 (dd, J¼5.2, 3.2 Hz, 2H, ArH), 7.73 (dd,
J¼5.2, 3.2 Hz, 2H, ArH), 4.59 (dq, J¼10.8, 7.2 Hz,1H in OCH2), 4.56 (dq,
J¼10.8, 7.2 Hz, 1H in OCH2), 4.15 (dddd, J¼8.8, 7.0, 7.0, 6.7 Hz, 1H,
CHS), 4.08 (dd, J¼14.0, 7.0 Hz, 1H in CH2N), 4.01 (dd, J¼14.0, 6.7 Hz,
1H in CH2N), 3.95 (ddd, J¼13.9, 8.1, 6.5 Hz, 1H in CH2N), 3.87 (ddd,
J¼13.9, 8.5, 6.0 Hz,1H in CH2N), 2.15 (dddd, J¼14.6, 8.8, 8.1, 6.0 Hz,1H
in CH2), 2.06 (dddd, J¼14.6, 8.5, 7.0, 6.5 Hz, 1H in CH2), 1.39 (t,
Its diastereoisomer. 1H NMR (CDCl3, 400 MHz) (
d, ppm) 7.85 (dd,
J¼5.4, 3.1 Hz, 2H, ArH), 7.73 (dd, J¼5.4, 3.1 Hz, 2H, ArH), 4.66e4.54
(m, 2H, OCH2), 4.40e3.94 (m, 5H, OCH2, SCH, & NCH2), 2.83 (dddd,
J¼11.3, 8.8, 8.7, 5.8 Hz,1H, CHCO), 2.61 (dddd, J¼12.6, 8.4, 6.3,1.9 Hz,
1H in CH2CO), 2.33 (ddd, J¼14.8, 6.5, 6.2 Hz, 1H in CH2CS), 2.13
(dddd, J¼12.6, 11.0, 11.0, 8.6 Hz, 1H in CH2CO), 1.86 (ddd, J¼14.8, 8.2,
8.0 Hz, 1H in CH2CS), 1.40 (t, J¼7.1 Hz, 3H, CH3). 13C NMR (CDCl3,
J¼7.2 Hz, 3H, CH3). 13C NMR (CDCl3, 100 MHz) (
d, ppm) 212.1,168.12,
168.10, 134.1, 133.9, 132.1, 131.8, 123.5, 123.3, 70.3, 47.1, 40.7, 35.6,
30.5, 13.6. IR (nmax, cmꢃ1) 3110.1, 2925.3, 1712.8, 1610.7, 1431.6,
1047.0, 719.7. HRMS (ESI) calcd for C23H20N2O5S2Na. m/z: 491.0706
[MþNa]þ; found 491.0718.
100 MHz) (d, ppm) 212.3, 178.3, 168.0, 134.1, 131.7, 123.5, 70.4, 66.5,
48.1, 40.2, 37.4, 33.0, 29.4, 13.6. HRMS (ESI) calcd for C18H20NO5S2
m/z: 394.0783 [MþH]þ; found 394.0650.
4.3.5. O-Ethyl S-4-ethoxy-3-ethoxycarbonyl-4-oxo-1-phthalimido-
4.3.9. O-Ethyl S-3-cyano-1-phthalimidomethylethyl dithiocarbonate
methylbutyl dithiocarbonate (5e). Yellow oil; yield: 94%. 1H NMR
(5i). Yellow solid; mp: 96e99 ꢀC; yield: 79%. 1H NMR (CDCl3,
(CDCl3, 400 MHz) (
d
, ppm) 7.86 (dd, J¼5.6, 3.0 Hz, 2H, ArH), 7.73 (dd,
400 MHz) (
d
, ppm) 7.87 (dd, J¼5.5, 3.1 Hz, 2H, ArH), 7.75 (dd, J¼5.5,
J¼5.6, 3.0 Hz, 2H, ArH), 4.59 (q, J¼7.1 Hz, 2H, CH2), 4.20e4.17 (m,
5H, SCH2 & SCH), 4.02 (dd, J¼14.0, 6.9 Hz, 1H in NCH2), 3.97 (dd,
J¼14.0, 7.4 Hz, 1H in NCH2), 3.68 (dd, J¼9.6, 4.8 Hz, 1H, CHCO), 2.43
(ddd, J¼14.8, 9.6, 4.4 Hz, 1H in CH2), 2.14 (ddd, J¼14.8, 10.6, 4.8 Hz,
1H in CH2), 1.42 (t, J¼7.1 Hz, 3H, CH3), 1.26 (t, J¼7.1 Hz, 3H, CH3), 1.25
3.1 Hz, 2H, ArH), 4.63 (q, J¼7.1 Hz, 2H, CH2), 4.24 (dddd, J¼9.5, 7.1,
7.1, 4.8 Hz, 1H, CHS), 4.03 (dd, J¼14.1, 7.1 Hz, 1H in CH2N), 3.96 (dd,
J¼14.1, 7.1 Hz, 1H in CH2N), 2.76 (ddd, J¼16.9, 8.8, 5.6 Hz, 1H in
CH2CN), 2.56 (ddd, J¼16.9, 8.8, 7.1 Hz, 1H in CH2CN), 2.19 (dddd,
J¼14.6, 8.8, 7.1, 4.8 Hz, 1H in CH2), 2.00 (dddd, J¼14.6, 9.5, 8.8,
5.6 Hz, 1H in CH2), 1.43 (t, J¼7.1 Hz, 3H, CH3). 13C NMR (CDCl3,
(t, J¼7.1 Hz, 3H, CH3). 13C NMR (CDCl3, 100 MHz) (
d, ppm) 212.7,
168.8, 168.5, 167.9, 134.1, 131.8, 123.4, 70.4, 61.8, 61.7, 49.6, 47.5, 41.2,
100 MHz) (d, ppm) 211.0, 167.9, 134.3, 131.7, 123.6, 118.6, 70.7, 48.4,

S. Kakaei et al. / Tetrahedron 69 (2013) 302e309
307
40.4, 27.9, 14.9, 13.6. IR (nmax, cmꢃ1) 3009.4, 2927.4, 2244.8, 1715.6,
1613.9, 1467.2, 1045.5, 713.8. HRMS (ESI) calcd for C16H17N2O3S2 m/
z: 349.0681 [MþH]þ; found 349.0650.
ppm) 7.28e7.23 (m, 4H, ArH), 7.10 (dd, J¼5.1, 3.1 Hz, 2H, ArH), 6.95
(dd, J¼5.1, 3.1 Hz, 2H, ArH), 3.52 (dd, J¼13.8, 3.4 Hz, 1H in NCH2),
3.42e3.33 (m, 2H, NCH2), 3.20 (d, J¼13.8 Hz,1H in NCH2), 2.83e2.74
(m, 1H, CHS), 1.92e1.87 (m, 1H in CH2), 1.50e1.44 (m, 1H in CH2). 13
C
4.4. General procedure for synthesis of vicinal amino-
alkanesulfonic acids 6
NMR (D2O, 100 MHz) (d, ppm) 169.9, 169.5, 135.1, 134.9, 130.2, 130.1,
123.2, 123.0, 55.4, 38.8, 37.2, 26.9. IR (nmax, cmꢃ1) 3529.1, 2383.1,
1712.1, 1, 1228.7. HRMS (ESI) calcd for C20H16N2NaO7S m/z: 451.0576
[MþNa]þ; found 451.0535.
Procedure A without hydrolysis of side-chains: To a performic acid
solution, prepared by mixing and stirring 30% H2O2 (0.5 mL) and
98% HCO2H (10 mL) at room temperature for 1 h and cooled in an
ice bath, was added dropwise a solution of a dithiocarbonate de-
rivative 5 (1 mmol) in 98% formic acid (2 mL), keeping the tem-
perature at 0 ꢀC. After the mixture was stirred at 0 ꢀC for 2 h and at
room temperature for 20 h, the resulting mixture was mixed with
silica gel and allowed to evaporate to dry at room temperature. The
residue was separated on a silica gel column with a mixture of
chloroform and methanol in 20:1e10:1 (v/v), and methanol as el-
uents to give the pure product 6.
Procedure B with hydrolysis of side-chains in 5f,g,i: To a performic
acid solution, prepared by mixing and stirring 30% H2O2 (2 mL) and
98% HCO2H (10 mL) at room temperature for 1 h and cooled in an
ice bath, was added dropwise a solution of a dithiocarbonate de-
rivative 5 (1 mmol) in 98% formic acid (2 mL), the resulting mixture
was stirred overnight at rt. After removal of solvent under reduce
pressure at 50e60 ꢀC and washing with chloroform, the residue
was crystallized from methanol to afford pure product 6j.
4.4.5. Diethyl 3-phthalimido-2-sulfopropylmalonate (6e). Colorless
crystals, mp: 168e172 ꢀC; yield: 87%. 1H NMR (CDCl3, 400 MHz) (
d,
ppm) 7.67e7.62 (m, 4H, ArH), 4.02 (dq, J¼10.8, 7.1 Hz, 1H in CH2O),
3.98 (dq, J¼10.8, 7.1 Hz, 1H in CH2O), 3.94 (dd, J¼14.2, 8.8 Hz, 1H in
NCH2), 3.91 (dq, J¼10.8, 7.1 Hz, 1H in CH2O), 3.89 (dq, J¼10.8, 7.1 Hz,
1H in CH2O), 3.78 (dd, J¼9.4, 5.8 Hz, 1H, CH), 3.65 (dd, J¼14.2,
8.8 Hz, 1H in NCH2), 3.14e3.05 (m, 1H, CHS), 2.24 (ddd, J¼14.3, 6.8,
5.8 Hz, 1H in CH2), 1.95 (ddd, J¼14.3, 9.4, 4.2 Hz, 1H in CH2), 1.03 (t,
J¼7.1 Hz, 3H, CH3), 0.94 (t, J¼7.1 Hz, 3H, CH3). 13C NMR (D2O,
100 MHz) (
d, ppm) 170.34,170.29,169.77, 169.72,134.9, 130.9, 123.4,
62.89, 62.84, 55.0, 50.2, 38.3, 27.2, 13.13, 13.09. IR (nmax, cmꢃ1
)
3401.6, 2939.9, 1772.7, 1712.7, 1439.4, 1402.7, 1224.3, 722.2. HRMS
(ESI) calcd for C18H21DNO9S m/z: 429.1073 [MþD]þ; found
429.1052.
4.4.6. Methyl 5-phthalimido-4-sulfopentanoate (6f). Colorless crys-
tals, mp: 109e112 ꢀC; yield: 77%. 1H NMR (CDCl3, 400 MHz) (
d,
ppm) 7.42e7.37 (m, 4H, ArH), 3.70 (dd, J¼14.4, 6.0 Hz, 1H in NCH2),
3.39 (dd, J¼14.4, 8.0 Hz, 1H in NCH2), 3.05 (s, 3H, CH3), 2.94 (dddd,
J¼8.0, 7.2, 6.8, 6.0 Hz, 1H, SCH), 2.31 (t, J¼7.2 Hz, 2H, CH2), 1.73
(dddd, J¼14.0, 7.2, 7.2, 6.8 Hz, 1H in CH2), 1.54 (dddd, J¼14.0, 7.2, 7.2,
4.4.1. 4-Phenyl-1-phthalimidobutane-2-sulfonic acid (6a). Colorless
oil; yield: 85%. 1H NMR (D2O, 400 MHz) (
d, ppm) 7.44 (dd, J¼5.2,
3.0 Hz, 2H, ArH), 7.35 (dd, J¼5.2, 3.0 Hz, 2H, ArH), 6.64e6.50 (m, 5H,
ArH), 3.58 (dd, J¼14.1, 4.8 Hz, 1H in NCH2), 3.39 (dd, J¼14.1, 4.7 Hz,
1H in NCH2), 2.81 (dddd, J¼8.4, 4.8, 4.7, 4.7 Hz, 1H, SCH), 2.43 (ddd,
J¼13.9, 6.0, 6.0 Hz, 1H in CH2), 2.28 (ddd, J¼13.9, 9.3, 5.8 Hz, 1H in
CH2), 1.94 (dddd, J¼14.9, 6.0, 6.0, 4.7 Hz, 1H in CH2), 1.40 (dddd,
6.8 Hz, 1H in CH2). 13C NMR (D2O, 100 MHz) (
d, ppm) 176.9, 169.5,
134.7, 130.8, 123.2, 56.3, 48.8, 37.8, 30.8, 23.1. IR (nmax, cmꢃ1) 3441.2,
2923.8, 1770.8, 1710.0, 1401.8, 717.1. HRMS (ESI) calcd for
C14H15NO7S m/z: 342.0642 [MþH]þ; found 342.0649.
J¼14.9, 9.3, 8.4, 5.8 Hz,1H in CH2). 13C NMR (D2O,100 MHz) (
d, ppm)
169.4, 140.8, 134.6, 130.7, 128.3, 125.8, 123.3, 56.0, 38.4, 32.8, 29.6. IR
4.4.7. Ethyl 5-phthalimido-4-sulfopentanoate (6g). Colorless crys-
(
nmax, cmꢃ1) 3344.4, 2347.3, 1704.8, 1219.3. HRMS (ESI) calcd for
tals, mp: 189e193 ꢀC; yield: 78%. 1H NMR (CDCl3, 400 MHz) (
d,
C18H18NO5S m/z: 360.0900 [MþH]þ; found 360.0874.
ppm) 7.78e7.69 (m, 4H, ArH), 4.03e3.89 (m, 2H, CH2O), 3.96 (dd,
J¼14.4, 7.3 Hz, 1H in NCH2), 3.70 (dd, J¼14.4, 7.5 Hz, 1H in NCH2),
3.25e3.16 (m, 1H, CHS), 2.58 (ddd, J¼16.9, 8.8, 7.1 Hz, 1H in CH2),
2.50 (ddd, J¼16.9, 7.1, 6.2 Hz, 1H in CH2), 2.02 (dddd, J¼14.1, 7.1, 7.1,
5.9 Hz, 1H in CH2), 1.80 (dddd, J¼14.1, 6.8, 6.8, 6.2 Hz, 1H in CH2),
4.4.2. 5-Oxo-1-phthalimidohexane-2-sulfonic acid (6b). Colorless
crystals, mp: 179e183 ꢀC; yield: 92%. 1H NMR (CDCl3, 400 MHz) (
d,
ppm) 7.58e7.56 (m, 4H, ArH), 3.83 (dd, J¼14.4, 6.6 Hz, 1H in NCH2)
3.60 (dd, J¼14.4, 7.6 Hz, 1H in NCH2), 3.01 (dddd, J¼8.8, 7.6, 6.6,
6.4 Hz, 1H, CHS), 2.69e2.58 (m, 1H, SCH), 1.94 (s, 3H, COCH3), 1.92
(m, 1H, CH2, Overlapped with COMe), 1.78e1.72 (m, 1H in CH2), 1.61
(m, 1H in CH2). 13C NMR (D2O: HCOOH as the internal standard,
1.05 (t, J¼7.0 Hz, 3H, CH3). 13C NMR (D2O, 100 MHz) (
d, ppm) 175.5,
170.1, 134.8, 131.1, 123.4, 61.7, 56.3, 38.0, 31.3, 23.3, 13.2. IR (nmax
,
cmꢃ1) 3410.7, 2930.3, 1777.2, 1712.7, 1400.4, 1400.4, 1189.5, 717.1.
HRMS (ESI) calcd for C15H18NO7S m/z: 356.0798 [MþH]þ; found
356.0787.
100 MHz) (d, ppm) 215.4, 170.7, 135.5, 131.8, 124.1, 57.1, 40.7, 38.6,
30.0, 22.5. IR (nmax, cmꢃ1) 3344.8, 2518.4, 1709.5, 1222.9. HRMS
(ESI) calcd for C14H16NO6S m/z: 326.0698 [MþH]þ; found 326.0936.
4.4.8. 3-(2-Oxo-3-oxacyclopentyl)-1-phthalimidopropane-2-sulfonic
acid (6h). Colorless crystals, mp: 199e203 ꢀC; yield: 89%
4.4.3. 5-Oxo-1-phthalimidopentane-2-sulfonic acid (6c). Colorless
(dr¼1.1:1.0). 1H NMR (CDCl3, 400 MHz) (
d, ppm) 7.14e7.06 (m, 4H,
crystals; mp 72e76 ꢀC, yield: 54%. 1H NMR (CDCl3, 400 MHz) (
d
,
ArH), 3.82e3.62 (m, 2H, OCH2), 3.48 (dd, J¼14.3, 5.1 Hz, 1H in
CH2N), 3.11 (dd, J¼14.3, 6.6 Hz, 1H in CH2N), 2.89e2.77 (m, 1H,
CHS), 2.56 (dddd, J¼10.0, 9.8, 9.6, 5.1 Hz, 1H, CHCO), 2.00e1.90 (m,
1H in CH2CO), 1.73 (ddd, J¼14.3, 8.3, 5.1 Hz, 1H in CH2CS), 1.45e1.37
(m, 1H in CH2CO), 1.36e1.27 (m, 1H in CH2CS). 13C NMR (D2O,
ppm) 7.54 (d, J¼8.0 Hz, 2H, ArHortho), 7.62 (dd, J¼5.4, 3.1 Hz, 2H,
ArH), 7.56 (dd, J¼5.4, 3.1 Hz, 2H, ArH), 7.20 (dd, J¼7.6, 7.2 Hz, 1H,
ArHpara), 7.06 (dd, J¼8.0, 7.6 Hz, 2H, ArHmeta), 3.78 (dd, J¼14.4,
5.2 Hz, 1H in NCH2), 3.51 (dd, J¼14.4, 8.8 Hz, 1H in NCH2), 3.11e2.99
(m, 1H, SCH), 3.97 (ddd, J¼15.2, 7.1, 7.1 Hz, 1H in CH2), 2.89 (ddd,
J¼15.2, 7.2, 6.8 Hz, 1H in CH2), 1.95 (dddd, J¼13.6, 7.1, 7.1, 6.8 Hz, 1H
in CH2), 1.67 (dddd, J¼13.6, 7.9, 7.2, 6.8 Hz, 1H in CH2). 13C NMR
100 MHz) (d, ppm) 181.84, 169.10, 134.6, 130.62, 123.04, 67.74, 54.9,
38.3, 37.4, 28.7, 28.3.
Its diastereoisomer: 1H NMR (CDCl3, 400 MHz) (
d, ppm) 7.14e7.06
(D2O, 100 MHz) (
d
, ppm) 203.2, 169.6, 135.4, 134.7, 133.8, 130.7,
(m, 4H, ArH), 3.82e3.62 (m, 2H, OCH2), 3.50 (dd, J¼14.4, 5.8 Hz, 1H
in CH2N), 3.14 (dd, J¼14.4, 8.0 Hz, 1H in CH2N), 2.89e2.77 (m, 1H,
CHS), 2.43 (dddd, J¼10.8, 8.7, 8.1, 7.7 Hz, 1H, CHCO), 2.00e1.90 (m,
1H in CH2CO), 1.47 (ddd, J¼14.3, 8.0, 5.8 Hz, 1H in CH2CS), 1.39e1.27
128.6, 127.8, 123.3, 56.4, 38.1, 35.7, 22.8. IR (nmax, cmꢃ1) 3028.1,
2933.8, 1773.6, 1613.9, 1467.3, 1047.2, 714.6. HRMS (ESI) calcd for
C19H18NO6S m/z: 388.0849 [MþH]þ; found 388.0841.
(m, 1H in CH2CO), 1.09 (ddd, J¼14.5, 9.9, 4.4 Hz, 1H in CH2CS). 13
C
4.4.4. 1,4-Diphthalimidobutane-2-sulfonic acid (6d). Colorless crys-
NMR (D2O, 100 MHz) (d, ppm) 181.88, 169.12, 134.5, 130.65, 123.02,
tals, mp: 216e217 ꢀC; yield: 90%. 1H NMR (CDCl3, 400 MHz) (
d
,
67.67, 55.0, 37.6, 37.0, 28.8, 27.9. IR (nmax, cmꢃ1) 3429.8, 2914.2,

308
S. Kakaei et al. / Tetrahedron 69 (2013) 302e309
1767.5, 1711.6, 1434.5, 1170.5, 726.7. HRMS (ESI) calcd for
(CDCl3, 100 MHz) (
66.7, 43.4.
d, ppm) 156.2, 136.5, 134.4, 128.4, 128.0, 115.9,
C15H16NO7S m/z: 354.0642 [MþH]þ; found 354.0644.
4.4.9. 4-Cyano-1-phthalimidobutane-3-sulfonic acid (6i). Colorless
4.7. Synthesis of benzyl 4-cyano-2-(ethoxycarbonothioylthio)
butyl-carbamate (9)
crystals, mp: 187e190 ꢀC; yield: 91%. 1H NMR (CDCl3, 400 MHz) (
d,
ppm) 7.61e7.57 (m, 4H, ArH), 3.86 (dd, J¼14.4, 6.8 Hz, 1H in NCH2),
3.20 (dd, J¼14.4, 7.5 Hz, 1H in NCH2), 3.01 (dddd, J¼8.0, 7.5, 6.8,
6.8 Hz, 1H, CHS), 2.33 (t, J¼7.6 Hz, 2H, CH2), 1.89 (dddd, J¼14.4, 7.5,
7.1, 6.8 Hz, 1H in CH2), 1.69 (dddd, J¼14.4, 8.0, 7.5, 5.6 Hz, 1H in CH2).
Benzyl 4-cyano-2-(ethoxycarbonothioylthio)butylcarbamate (9)
was obtained according to the general synthetic procedure of 5.
Yellow oil; yield: 70%. 1H NMR (CDCl3, 400 MHz) (
d, ppm) 7.38e7.32
13C NMR (D2O, 100 MHz) (
d, ppm) 177.0, 134.8, 131.1, 123.5, 120.9,
(m, 5H, ArH), 5.13 (br s, NH), 5.10 (s, 2H, OCH2), 4.64 (q, J¼7.2 Hz, 2H,
OCH2), 3.94 (dddd, J¼9.0, 7.7, 6.5, 5.7 Hz,1H, SCH), 3.56 (ddd, J¼14.4,
8.0, 6.2 Hz, 1H in CH2N), 3.50 (ddd, J¼14.4, 8.0, 6.2 Hz, 1H in CH2N),
2.52 (ddd, J¼16.8, 8.8, 7.6 Hz, 1H in CH2), 2.48 (ddd, J¼16.8, 8.8,
8.8 Hz,1H in CH2), 2.15 (dddd, J¼14.0, 9.2, 8.8, 7.6 Hz,1H in CH2),1.93
56.1, 37.8, 24.2, 14.8. IR (nmax, cmꢃ1) 3436.5, 2939.9, 2244.8 (nCN),
1767.6, 1711.6, 1431.3, 1189.5, 716.9. HRMS (ESI) calcd for
C13H12NaN2O5S m/z: 331.0359 [MþNa]þ; found 331.0363.
(dddd, J¼14.0, 8.8, 8.8, 5.7 Hz,1H, CH2),1.42 (t, J¼7.1 Hz, 3H, CH3).13
C
4.4.10. 5-Phthalimido-4-sulfopentanoic acid (6j). Colorless crystals,
mp: 228e231 ꢀC; yield: 65%. 1H NMR (CDCl3, 400 MHz) (
d, ppm)
NMR (CDCl3,100 MHz) (d, ppm) 211.8,156.5,136.1,128.5,128.2,128.1,
118.7, 70.7, 67.1, 50.4, 43.7, 27.3, 14.9, 13.7. IR (ymax, cmꢃ1) 3348.1,
2932.1, 2244.8, 1721.2, 1519.7, 1231.4. HRMS (ESI) calcd for
C16H21N2O3S2 m/z: 353.0994 [MþH]þ; found 353.0960.
7.75e7.63 (m, 4H, ArH), 3.94 (dd, J¼14.5, 6.8 Hz, 1H in NCH2), 3.64
(dd, J¼14.5, 7.5 Hz, 1H in NCH2), 3.14 (dddd, J¼7.5, 7.0, 6.8, 5.9 Hz,
1H, SCH), 2.41 (t, J¼7.5 Hz, 2H, CH2), 1.98 (dddd, J¼14.0, 7.5, 7.5,
7.0 Hz, 1H in CH2), 1.77 (dddd, J¼14.0, 7.5, 7.5, 5.9 Hz, 1H in CH2). 13
C
NMR (D2O, 100 MHz) (d, ppm) 177.2, 169.9, 134.7, 131.0, 123.4, 56.4,
4.8. Synthesis of 1-amino-4-cyanobutane-2-sulfonic acid (7i)
37.9, 30.9, 23.2. IR (nmax, cmꢃ1) 3218.8e2635.5 (nOH), 1771.9, 1713.2,
1402.7, 1031.9, 720.9. HRMS (ESI) calcd for C13H13NNaO7S m/z:
350.0310 [MþNa]þ; found 350.0293.
1-Amino-4-cyanobutane-2-sulfonic acid (7i) was obtained
according to the general synthetic procedure of 6 (Procedure A).
Colorless crystals, mp: 221e223 ꢀC; yield: 93%. 1H NMR (CDCl3,
4.5. Synthesis of 1-amino-4-phenylbutane-2-sulfonic acid (7a)
400 MHz) (
d
, ppm) 3.24 (d, J¼6.3 Hz, 2H, NCH2), 3.12 (dddd, J¼6.9,
6.3, 6.3, 6.2 Hz, 1H, SCH2), 2.69 (ddd, J¼17.3, 7.6, 7.5 Hz, 1H in
CH2CN), 2.64 (ddd, J¼17.3, 7.5, 6.6 Hz, 1H in CH2CN), 2.11 (dddd,
J¼14.6, 7.6, 6.9, 6.6 Hz, 1H, CH2), 1.89 (dddd, J¼14.6, 7.6, 7.5, 6.2 Hz,
A solution of 1-phthalimido-4-phenylbutane-2-sulfonic acid
(6a) (718 mg, 2 mmol) and 80% hydrazine hydrate (0.42 mL,
6 mmol) in ethanol (5 mL) was refluxed for 2 h. After cooling to
room temperature the solution was diluted with dichloromethane
(30 mL) to precipitate phthalhydrazide. After filtration and washing
with dichloromethane and ethyl acetate. The combined filtrate was
evaporated to dryness. The residue was crystallized from methanol
to give 1-amino-4-phenylbutane-2-sulfonic acid (7a) as colorless
1H, CH2). 13C NMR (CDCl3, 100 MHz) (
d, ppm) 120.5, 55.4, 39.4, 24.1,
14.5. IR (nmax, cmꢃ1) 3151.4, 3101.3, 2361.2 (nCN), 1718.6, 1701.9,
1400.2, 1033.7. HRMS (ESI) calcd forC5H11N2O3S m/z: 179.0485
[MþH]þ; found 179.0483.
Acknowledgements
crystals 353 mg, yield: 77%; mp>300 ꢀC 1H NMR (D2O, 400 MHz) (
d,
ppm) 7.19e7.05 (m, 5H, ArH) 3.19e3.15 (m, 1H in NCH2), 3.11e3.05
(m, 1H in NCH2), 2.89e2.83 (m, 1H, SCH), 2.66 (ddd, J¼14.2, 7.1,
6.5 Hz, 1H in CH2), 2.58 (ddd, J¼14.2, 7.5, 7.1 Hz, 1H in CH2), 2.02
(dddd, J¼14.6, 7. 6, 6.9, 6.6 Hz, 1H in CH2), 1.46 (dddd, J¼14.6, 8.5,
This work was supported in part by the National Natural Science
Foundation of China (Project No 20973013), Beijing Natural Science
Foundation (No 2092022), and the Fundamental Research Funds for
the Central Universities (No ZY1216).
7.5, 7.4 Hz, 1H in CH2). 1H NMR (DMSO-d6, 400 MHz) (
d, ppm)
7.90e7.31 (m, 3H, SO3H, NH2), 7.30e7.12 (m, 5H, ArH), 3.15e3.03
(m, 1H in CH2N), 3.02e2.90 (m, 1H in CH2N), 2.83e2.73 (m, 1H,
CHS), 2.72e2.55 (m, 2H, CH2), 2.15e1.96 (m, 1H in CH2), 1.71e1.54
Supplementary data
Analytical data of xanthates 3, Copies of the 1H NMR and 13C
NMR spectra of all key intermediates and final products. Supple-
mentary data associated with this article can be found in the online
version, at http://dx.doi.org/10.1016/j.tet.2012.10.029. These data
include MOL files and InChiKeys of the most important compounds
described in this article.
(m, 1H in CH2). 13C NMR (DMSO-d6, 100 MHz) (
d, ppm) 141.6, 128.3,
128.2, 125.7, 55.0, 39.5, 32.1, 29.9. IR (nmax, cmꢃ1) 3247.3, 3012.5,
2728.5, 2549.1, 1563.9, 1494.2, 1081.4, 968.8. HRMS (ESI) calcd for
C10H16NO3S m/z: 230.0845 [MþH]þ; found 230.0842.
4.6. Synthesis of benzyl N-allylcarbamate (8)22
References and notes
A round-bottomed flask equipped with a magnetic stir bar was
charged with allylamine (0.57 g, 10 mmol), 15 mL of water, potas-
sium carbonate (0.35 g, 25 mmol), and 15 mL of ethyl acetate. The
flask was cooled in an ice bath and 95% of benzyl chloroformate
(1.79 g, 10.5 mmol) was added during 30 min by using a syringe
pump. After stirring at room temperature for 2 h, the organic layer
was separated and washed twice with 10 mL portions of 1 mol/L
HCl, once with 10 mL of saturated aqueous NaCl. The combined
organic phase was dried over MgSO4. After removal of solvents with
a rotary evaporator, the residue was purified by flash chromatog-
raphy on silica gel to give the desired colorless oil 7. Colorless oil;
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