Convenient synthesis of various substituted homotaurines from alk-2-enamides

Article abstract of DOI:10.1002/hlca.201200547

Various substituted homotaurines (=3-aminopropane-1-sulfonic acids) 6 were readily synthesized in satisfactory to good yields via the Michael addition of thioacetic acid to alk-2-enamides 3 (→4), followed by LiAlH₄ reduction (→5) and performic acid oxidation (Scheme 1). The configuration of 'anti'-disubstituted homotaurine 'anti'-6h was deduced from the 3-(acetylthio)alkanamide (=S-(3-amino-1,2-dimethyl-3-oxopropyl) ethanethioate)'anti'-4h formed in the Michael addition, which was identified via the Karplus equation analysis, and confirmed by X-ray diffraction analysis. The current route is an efficient method to synthesize diverse substituted homotaurines, including 1-, 2-, and N-monosubstituted, as well as 1,2-, 1,N-, 2,N-, and N,N-disubstituted homotaurines (Table). Copyright

Full text of DOI:10.1002/hlca.201200547

Helvetica Chimica Acta – Vol. 96 (2013)
1355
Convenient Synthesis of Various Substituted Homotaurines from
Alk-2-enamides
by Youfeng Naia) and Jiaxi Xu*a)b)
a) State Key Laboratory of Chemical Resource Engineering, Department of Organic Chemistry, Faculty
of Science, Beijing University of Chemical Technology, Beijing 100029, P. R. China
(phone/fax: þ 86-10-64435565; e-mail: jxxu@mail.buct.edu.cn)
b) State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing100191, P. R. China
Various substituted homotaurines (¼ 3-aminopropane-1-sulfonic acids) 6 were readily synthesized in
satisfactory to good yields via the Michael addition of thioacetic acid to alk-2-enamides 3 (!4), followed
by LiAlH4 reduction (! 5) and performic acid oxidation (Scheme 1). The configuration of ꢀantiꢀ-
disubstituted homotaurine ꢀantiꢁ-6h was deduced from the 3-(acetylthio)alkanamide (¼ S-(3-amino-1,2-
dimethyl-3-oxopropyl) ethanethioate)ꢀantiꢁ-4h formed in the Michael addition, which was identified via
the Karplus equation analysis, and confirmed by X-ray diffraction analysis. The current route is an
efficient method to synthesize diverse substituted homotaurines, including 1-, 2-, and N-monosubstituted,
as well as 1,2-, 1,N-, 2,N-, and N,N-disubstituted homotaurines (Table).
Introduction. – Homotaurine, i.e., 3-amino-1-propanesulfonic acid (3APS), also
called tramiprosate, shows biological activities as a neuroprotective compound and
amyloid antagonist and was a candidate drug for treating Alzheimerꢁs disease [1].
Moreover, calcium 3-(acetamido)propanesulfonate (acamprosate) is one of the few
medications for the prevention of alcohol relapse in detoxified alcohol-dependent
patients in several countries [2]. Both homotaurine and substituted homotaurine
derivatives are considered as bioisosteres of g-aminobutyric acid (GABA ¼ 3-amino-
butanoic acid) [3], which is of great importance as a specific inhibitor of impulse
transmission in the central nervous system [4]. Therefore, several methods for the
synthesis of substituted homotaurines have been developed.
The 1-carboxyhomotaurine was prepared from methyl 2,4-dibromobutanoate via
displacement of Br-C(2) with thioacetic acid (¼ethanethioic S-acid) in the presence of
diisopropylethylamine and oxidation with H2O2 in AcOH, and subsequent substitution
of Br-C(4) with NaN3, acidic hydrolysis, and hydrogenation [5]. Various 1-substituted
homotaurines were synthesized from a,b-unsaturated nitriles by the Michael addition
with thioacetic acid, reduction with LiAlH4, and oxidation with performic acid [6], or
from S-(N-phthalimidomethyl) xanthate and different olefins via radical addition and
subsequent oxidation with performic acid [7]. The 2-methylhomotaurine was first
synthesized as a competitive antagonists of the GABA receptor via addition of
methacrolein (¼2-methylprop-2-enal) with NaHSO3 and subsequent reductive ami-
nation under hydrogenation conditions [8]. The 2-phenylhomotaurine was prepared
from phenyl styrenesulfonate via addition of nitromethane in the presence of MeONa
ꢂ 2013 Verlag Helvetica Chimica Acta AG, Zꢃrich

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and subsequent catalytic hydrogenation and hydrolysis [9][10]. The 2-(4-chlorophen-
yl)homotaurine was considered as important antagonist of GABA and synthesized
from 2-(4-chlorophenyl)acrylonitrile (¼2-(4-chlorophenyl)prop-2-enenitrile) via ad-
dition with NaHSO3 and subsequent reduction [11], via the O2-catalyzed radical
addition of NaHSO3 to 2-(4-chlorophenyl)allylamine or their N-phthalyl derivatives
[12 – 14]. The 3-carboxyhomotaurine was prepared via hydrolysis of 2-(2,5-dioxoimi-
dazolidin-4-yl)ethanesulfonic acid [15] or via oxidation of homocysteine with peroxy
acid [16]. The 3-substituted homotaurines were synthesized via the HornerꢀWads-
worthꢀEmmons reaction of N-protected a-aminoalkanals and ethyl (diethoxyphos-
phoryl)methanesulfonate in the presence of BuLi and subsequent hydrogenation and
deprotection [17][18]. Ring-opening reactions of substituted propane-1,3-sultones with
NH3 or with NaN3 followed by reduction were applied for the synthesis of variously
substituted homotaurines [19]. Reduction of 4-oximino/imino-substituted 1,2,3,4-
tetrahydronaphthalene-2-sulfonic acids gave rise to 4-(alkyl)amino-1,2,3,4-tetrahydro-
naphthalene-2-sulfonic acids, which are regarded as 1,3-disubstituted homotaurines
[20]. The 3-nitroalkanesulfonic acids, the precursors of 1,3-disubstituted homotaurines,
were obtained via addition of aryl methanesulfonates to nitroolefins in the presence of
BuLi [21]. In addition, a cyclic substituted homotaurine, considered as a 1,3-
disubstituted homotaurine, was synthesized via DielsꢀAlder reaction of cyclopenta-
diene and N-sulfinylcarbamate and subsequent basic hydrolysis and performic acid
oxidation [22]. Recently, cis- and trans-2-(aminomethyl)cyclopropane-1-sulfonic acids
were synthesized via diazo ester addition to olefins as key step as conformationally
restricted GABA analogues serving as pharmacological tools to study GABA receptor
subtypes [4][23]. Despite of these synthetic methods for substituted homotaurines, no
general and versatile method has been developed.
Recently, we focused on the synthesis of various aminoalkanesulfonic acids.
Structurally diverse substituted taurines were prepared from nitroalkenes via Michael
addition with sodium O-ethyl xanthate or thioacetic acid and subsequent oxidation and
reduction [24][25]. We hope to extend our method to the synthesis of substituted
homotaurines from alk-2-enamides as starting materials, which are commercially
available or can be prepared readily from various commercially available alk-2-enoic
acids. Although a,b-unsaturated nitriles have been applied in the synthesis of
substituted homotaurines, they can only be used in the preparation of 1-substituted
homotaurines. Herein, we present a general synthesis of substituted homotaurines from
alk-2-enamides via Michael reaction with thioacetic acid, reduction, and performic acid
(¼ methaneperoxoic acid) oxidation.
Results and Discussion. – Alk-2-enamides 3b – 3d, 3f, 3h, and 3i were prepared from
the corresponding alk-2-enoic acids 1b – 1d, 1f, 1h, and 1i (Scheme 1, Table), whereas
prop-2-enamide (3a) and 2-methylprop-2-enamide (3e) were commercially available.
Thus, alk-2-enoic acids 1 were treated with SOCl2 to afford alk-2-enoyl chlorides 2,
which were directly treated with aqueous NH3 solution to give rise to the corresponding
alk-2-enamides 3 in satisfactory to good yields (Table). The 2-phenylprop-2-enoic acid
(1f) polymerized favorably when it was refluxed with SOCl2. The polymerization was
inhibited when 0.5 equiv. of benzoquinone was added to the reaction mixture (Table,
Entry 6). Alk-2-enoic chlorides 2a, 2b, and 2e reacted with benzylamine in the presence

Helvetica Chimica Acta – Vol. 96 (2013)
1357
of Et3N to produce N-benzylalk-2-enamides 3g, 3j, and 3k, respectively, in excellent
yields (Entries 7, 10, and 11). N,N-Dibenzylprop-2-enamide (3l) was obtained in good
yield via aminolysis of prop-2-enyl chloride (2a) with dibenzylamine in the presence of
Et3N (Entry 12). Alk-2-enamides 3a – 3g were selected as the representatives of
aliphatic and aromatic 2-, 3-, and N-monosubstituted prop-2-enamides, while alk-2-
enamides 3h – 3l were designed as examples of 2,3-, 3,3-, 2,N-, 3,N-, and N,N-
disubstituted prop-2-enamides.
Scheme 1. Synthesis of Substituted Homotaurines 6
Table. Synthesis of Substituted Homotaurines 6 from Alk-2-enamides 3
Entry
R1
R2
R3
R4
R5
1
3
Yield [%]
3
4
6a)
1
2
3
4
5
6
7
8
9
H
H
H
H
H
Me
Ph
H
Me
H
H
Me
H
H
H
H
H
H
H
H
H
Me
H
H
H
H
H
H
H
H
H
Bn
H
H
H
H
H
H
H
H
H
H
H
H
H
Bn
1a
1b
1c
1d
1e
1f
1a
1h
1i
3a
3b
3c
3d
3e
3f
3g
3h
3i
–
50
89
70
–
94
78
83
–
95
70
94
75d)
–
22b)
67
84
Me
Pr
Ph
H
H
H
Me
Me
Me
H
70
74
64c)
94
77
43
96
98
75
63
51e)
10
11
12
Bn
Bn
Bn
1b
1e
1a
3j
3k
3l
88
95
77
91
94
76
H
a) Overall yield from thioacetate 4. b) Overall yield was obtained from 4a via N-Cbz protected 3-
aminopropane-1-thiol (7) after the reduction. c) 0.5% Equiv. of benzoquinone was added to the mixture.
d) ꢀAntiꢁ/ꢀsynꢁ ¼ 10 : 1. e) Yield of ꢀsynꢁ-6h from ꢀsynꢁ-4h.
Although both thioacetic acid and sodium O-ethyl xanthate can serve as good
nucleophiles in the Michael addition with electron-deficient nitroolefins and can be
converted to aminoalkanesulfonic acids, thioacetic acid shows higher efficiency in the
Michael addition with nitroolefins in the synthesis of substituted taurines [24][25].
Thus, thioacetic acid was selected as a sulfur-containing nucleophile in our synthesis of
substituted homotaurines. The Michael addition of thioacetic acid and alk-2-enamides 3
has been explored previously [26]. Considering the solubility of alk-2-enamides 3, the

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Helvetica Chimica Acta – Vol. 96 (2013)
instability of thioacetic acid in air, and the reversibility of the Michael addition reaction
at higher temperature, the Michael addition of thioacetic acid and 3 was conducted in
refluxing CH2Cl2 in the presence of a catalytic amount of Et3N under N2 for 12 h,
affording the corresponding 2-(acetylthio)alkanamides (¼ S-(3-amino-1,2-dimethyl-3-
oxopropyl) ethanethioates) 4 in good to excellent yields (Table), except for
cinnamamide (¼(2E)-3-phenylprop-2-enamide; 3d) and 3-methylbut-2-enamide (3i),
which did not undergo the Michael addition due to favorable E1cb elimination and
steric hindrance, respectively (Table, Entries 4 and 9). It is supported by the fact that 3-
unsubstituted prop-2-enamides 3a, 3e, 3g, and 3k afforded the adducts in higher yields
than the corresponding 3-substituted prop-2-enamides 3b, 3c, 3h, and 3j (Entries 1 vs. 2
and 3, 5 vs. 8, and 6 vs. 4). For 2-methylbut-2-enamide (3h), a mixture of ꢀantiꢁ- and
ꢀsynꢁ-4h was obtained in a ratio 10 :1 (1H-NMR) (Scheme 2). The relative config-
urations of the adducts 4h were assigned on the basis of the reaction mechanism and
their 1H-NMR data. Thioacetate undergoes the Michael addition with 3h to generate an
intermediate A, which is protonated to afford ꢀantiꢁ-4h as major product and ꢀsynꢁ-4h as
minor isomer due to their stability (Scheme 2).
Scheme 2. Diastereoselectivity in the Michael Addition of (2E)-2-Methylbut-2-enamide (3h) and
Thioacetic Acid in the Presence of Et3N
The two H-atoms at C(2) and C(3) in ꢀantiꢁ-4h are in the ꢀantiꢁ (antiperiplanar)
position, while they are in the gauche (syndinal) position in ꢀsynꢁ-4h. According to the
Karplus equation, the coupling constant between these two H-atoms in ꢀantiꢁ-4h should
1
be larger than that in ꢀsynꢁ-4h. H-NMR Spectroscopic analysis indicates that the
coupling constants are 6.8 Hz for the major isomer ꢀantiꢁ-4h and 4.4 Hz for the minor
isomer ꢀsynꢁ-4h. To verify the assignment of the relative configuration, the major
product was recrystallized from AcOEt/hexanes and subjected to single-crystal X-ray
diffraction analysis1). The results revealed that the major product is ꢀantiꢁ-4h (Fig.).
To realize the Michael addition of thioacetic acid and cinnamamide (3d), the
reaction was carried out in THF, a slightly higher boiling solvent, for a longer time
(18 h), but no product was observed. The more electron-rich sulfur-containing
1
)
CCDC-920579 contains the supplementary crystallographic data for this article. These data can be
obtained free of charge via http://www.ccdc.cam.ac.uk/data_request/cif.

Helvetica Chimica Acta – Vol. 96 (2013)
1359
Fig. 1. ORTEP Representation of the molecular structure of ꢁantiꢁ-4h
nucleophile sodium O-ethyl xanthate was also attempted in the Michael addition with
3d in both refluxing THF and in AcOH at 608. No reaction occurred in both cases. The
results indicate that 3d, a 3-arylprop-2-enamide, is inert in the Michael addition.
The 3-(acetylthio)alkanamides 4 were then reduced with LiAlH4 in dry THF to give
the corresponding 3-aminoalkane-1-thiols 5. For complete reduction, 10 equiv. of
LiAlH4 were required. Insufficient reduction resulted in the formation of 3-
mercaptoalkanamides, revealing that the acetylthio group was reduced predominately.
After usual workup, the crude thiols 5 were oxidized to afford substituted
homotaurines 6 in acceptable to excellent overall yields, except for 6a, because it
could not be extracted from the aqueous solution (Scheme 1, Table).
Analogously to a previous report [6], 3-(acetylthio)prop-2-enamide (4a) was
reduced to 5a, which was converted to the less hydrophilic benzyl N-(3-mercaptopro-
pyl)carbamate (7) in 16% overall yield (Scheme 3). If the crude 7 was directly oxidized
with performic acid, 6a was obtained in 22% overall yield from 4a. Oxidation of pure 7
with performic acid gave rise to N-[(benzyloxy)carbonyl]homotaurine (8) in 55% yield
and 6a in 8% yield if the solvent was removed at a temperature below 458, while it gave
6a in 64% yield if the solvent was evaporated above 458 (Scheme 3), as observed in the
synthesis of substituted taurines [27].
Scheme 3. Synthesis of Homotaurine (6a) and N-Cbz-Protected Homotaurine 8
The above method cannot be used to prepare 3-aryl-3-(acetylthio)propanamides.
Considering that alk-2-enoic acids should be better Michael acceptors than the
corresponding alk-2-enamides, we hoped to introduce the sulfur moiety first via the
Michael addition of alk-2-enoic acids and thioacetic acid and then to convert the 3-
(acetylthio)alkanoic acids to 3-(acetylthio)alkanamides. As expected, cinnamic acid
(1d) reacted with thioacetic acid in benzene to give 3-(acetylthio)-3-phenylpropanoic

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acid (9d) in 76% yield (Scheme 4). However, 3-methylbut-2-enoic acid (1i) did not
undergo the Michael addition with thioacetic acid either. To convert 9d to 3-
(acetylthio)-3-phenylpropanamide (4d) under mild conditions, it was treated with ethyl
carbonochloridate in the presence of Et3N to give the mixed anhydride 10d. The latter
was in situ treated with NH3. Unfortunately, cinnamamide (3d) was obtained in 87%
yield instead of 4d (Scheme 4). It is believed that a reverse Michael addition reaction,
an E1cb elimination, occurred during ammonolysis.
Scheme 4. Attempt to Synthesize 3-(Acetylthio)cinnamamide (4d) from Cinnamic Acid (1d)
Conclusion. – A new protocol was developed successfully for the synthesis of
substituted homotaurines from alk-2-enoic acids. Substituted homotaurines were
prepared from alk-2-enamides via Michael addition with thioacetic acid, reduction with
LiAlH4, and oxidation with performic acid. The relative configuration of ꢀantiꢁ-1,2-
disubstituted homotaurine was deduced from the 3-(acetylthio)alkanamide formed in
the Michael addition, which was assigned on the basis of the Karplus equation analysis
and confirmed by X-ray diffraction determination. The presented method can be used
to synthesize 1-alkyl-, 2-alkyl-, 2-aryl-, N-substituted, 1,2-, 1,N-, 2,N-, and N,N-
disubstituted homotaurines from readily available alk-2-enamides or alk-2-enoic acids
as starting materials.
The project was supported partly by the National Basic Research Program of China (No.
2013CB328900), the National Natural Science Foundation of China (No. 20092013) and the Beijing
Natural Science Foundation (No. 2092022).
Experimental Part
General. Thioacetic acid, prop-2-enamide (3a), and 2-methylprop-2-enamide (3e) were commer-
cially available. THF was heated to reflux over Na and diphenyl ketone until the color of the mixture
became blue, and was freshly distilled prior to use; CH2Cl2 was heated to reflux over CaH2 and freshly
distilled prior to use. TLC: glass plates pre-coated with silica gel YT257 – 85 (10 – 40 mm); visualization
with UV light or I2. Column chromatography (CC): silica gel zcx II (SiO2; 200 – 300 mesh) petroleum
ether/AcOEt (v/v) eluent. M.p.: Yanaco-MP-500 melting-point apparatus; uncorrected. IR Spectra:
1
Nicolet-Avatar-330-FT-IR spectrometer; in KBr; ˜n in cmꢀ1. H- and 13C-NMR Spectra: Varian-300-plus
(300 MHz) or Bruker-AV-400 (400 MHz) spectrometer; in CDCl3 with Me4Si as internal standard or in
D2O for homotaurines (with HCOOH as an internal standard at d(C) 166.3; d in ppm, coupling constants
J in Hz. HR-MS: Agilent-LC/MSD-TOF mass spectrometer; in m/z.
1. Alk-2-enamides 3b – 3d, 3f, 3h, and 3i: General Procedure. A soln. of alk-2-enoic acid (40 mmol) in
SOCl2 (3.6 ml, 5.95 g, 50 mmol) was stirred at r.t. for 4 h. After evaporation of the excess SOCl2, the
residue was added dropwise to 25% aq. NH3 soln. (30 ml) under stirring at 08, and the mixture was stirred

Helvetica Chimica Acta – Vol. 96 (2013)
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at r.t. for 30 min. Then, the soln. was extracted with AcOEt (3 ꢁ 30 ml), the combined org. phases dried
(Na2SO4) and concentrated and the colorless crystalline product recrystallized from AcOEt/petroleum
ether: alk-2-enamide as colorless crystals. The anal. data of 3b – 3d and 3f – 3l were identical to those
earlier reported (3b [28], 3c [29], 3d [30], 3f [31], 3h [32] and 3i [32]).
2. N-Benzylalk-2-enamides 3g and 3j – 3l: General Procedure. A soln. of alk-2-enoic acid (100 mmol)
in SOCl2 (8.5 ml, 13.89 g, 110 mmol) was stirred at r.t. for 12 h. The mixture was distilled to collect the
alk-2-enoyl chloride. To a soln. of benzylamine (5.5 g, 51.3 mmol) or dibenzylamine (10.12 g, 51.3 mmol)
and Et3N (7.5 ml, 5.20 g, 51.3 mmol) in dried CH2Cl2 (30 ml) was added dropwise alk-2-enoyl chloride
(34.2 mmol) under stirring at 08. The resulting soln. was stirred at r.t. for 2 h, then washed with sat. NaCl
soln. (3 ꢁ 10 ml), and dried (Na2SO4). After evaporation of the solvent, the residue was subjected to CC:
N-benzylalk-2-enamide as colorless crystals. The anal. data of N-benzylxalk-2-enamides 3g and 3j – 3l
were identical to those earlier reported (3g and 3j [33], 3k [34], and 3l [35]).
3. S-(3-Amino-3-oxopropyl) Ethanethioates 4: General Procedure. To a boiling soln. of Et3N (10
drops) and alk-2-enamide (20 mmol) in dried CH2Cl2 (30 ml) was added thioacetic acid (1.8 ml, 1.90 g,
25 mmol), dropwise under N2. The resulting soln. was heated under reflux for 12 h. After evaporation of
the solvent, the residue was subjected to CC or recrystallization to afford the desired product.
S-(3-Amino-3-oxopropyl) Ethanethioate (4a): CC (petroleum ether/AcOEt 1:2). Colorless crystals.
Yield 2.76 g (94%). M.p. 968 ([36]: 82 – 838). 1H-NMR (300 MHz): 5.90 (br. s, 1 H of NH2); 5.71 (br. m,
1 H of NH2); 3.13 (t, J ¼ 6.9, CH2S); 2.55 (t, J ¼ 6.9, COCH2); 2.34 (s, Me).
S-(3-Amino-1-methyl-3-oxopropyl) Ethanethioate (4b): CC (petroleum ether/AcOEt 1:2): White
wax. Yield 2.51 g (78%). IR: 3349 (NH), 3195 (NH), 1670 (CO). 1H-NMR (400 MHz): 6.16 (br. s, 1 H of
NH2); 6.00 (br. s, 1 H of NH2); 3.87 (ddq, J ¼ 6.0, 8.0, 6.8, CH); 2.61 (dd, J ¼ 6.0, 14.4, 1 H of CH2); 2.44
(dd, J ¼ 8.0, 14.4, 1 H of CH2); 2.32 (s, COMe); 1.39 (d, J ¼ 6.8, Me). 13C-NMR (100 MHz): 195.8; 173.0;
42.5; 36.0; 30.5; 20.4. HR-MS-ESI: 162.0578 ([M þ H]þ, C6H11NO2Sþ; calc. 162.0583).
S-(3-Amino-3-oxo-1-propylpropyl) Ethanethioate (4c): CC (petroleum ether/AcOEt 1:2). Colorless
crystals. Yield 3.50 g (83%). M.p. 73 – 74.58. IR: 3391 (NH), 3197 (NH), 1686 (CO), 1651 (CO).
1H-NMR (400 MHz): 5.80 (br. s, 1 H of NH2); 5.66 (br. s, 1 H of NH2); 3.81 – 3.74 (m, CH); 2.59 (dd, J ¼
6.4, 15.2, 1 H of COCH2); 2.52 (dd, J ¼ 7.2, 15.2, 1 H of COCH2); 2.33 (s, COMe); 1.76 – 1.58 (m, CH2);
1.51 – 1.32 (m, CH2); 0.91 (t, J ¼ 7.2, Me). 13C-NMR (100 MHz): 196.2; 172.9; 41.8; 41.1; 36.1; 30.7; 20.2;
13.6. HR-MS-ESI: 212.0719 ([M þ H]þ, C8H15NO2Sþ; calc. 212.0721).
S-(3-Amino-2-methyl-3-oxopropyl) Ethanethioate (4e) [37]: Recrystallized from EtOH/Et2O.
Colorless crystals. Yield 3.06 g (95%). M.p. 84 – 868. IR: 3381 (NH), 3190 (NH), 1687 (CO), 1656
(CO). 1H-NMR (400 MHz): 6.19 (br. s, 1 H of NH2); 5.96 (br. s, 1 H of NH2); 3.11 (dd, J ¼ 6.8, 13.6, 1 H
of CH2); 2.95 (dd, J ¼ 6.8, 13.6, 1 H of CH2); 2.53 (ddq, J ¼ 6.8, 6.8, 6.8, CH); 2.34 (s, COMe); 1.24 (d, J ¼
6.8, Me). 13C-NMR (100 MHz): 196.1; 177.0; 40.7; 32.4; 30.5; 17.3.
S-(3-Amino-3-oxo-2-phenylpropyl) Ethanethioate (4f): CC (petroleum ether/AcOEt 1:1). Colorless
crystals. Yield 3.09 g (70%). M.p. 116 – 1178. IR: 3389 (NH), 3184 (NH), 1691 (CO), 1655 (CO).
1H-NMR (400 MHz): 7.36 – 7.27 (m, 5 arom. H); 5.91 (br. s, 1 H of NH2); 5.62 (br. s, 1 H of NH2); 3.67
(dd, J ¼ 6.4, 8.4, CH); 3.44 (dd, J ¼ 8.4, 13.6, 1 H of CH2); 3.27 (dd, J ¼ 6.4, 13.6, 1 H of CH2); 2.30 (s, Me).
13C-NMR (100 MHz): 196.1; 174.0; 138.2; 128.9; 127.9; 127.8; 52.1; 32.0; 30.5. HR-MS-ESI: 224.0736
([M þ H]þ, C11H13NO2Sþ; calc. 224.0740).
S-{3-Oxo-3-[(phenylmethyl)amino]propyl} Ethanethioate (4g): Recrystallized from Et2O. Colorless
crystals. Yield 4.46 g (94%). M.p. 80 – 80.58. IR: 3290 (NH), 1692 (CO), 1637 (CO). 1H-NMR
(400 MHz): 7.36 – 7.26 (m, 5 arom. H); 5.87 (br. s, NH); 4.44 (d, J ¼ 5.6, CH2); 3.16 (t, J ¼ 6.8, CH2S); 2.52
(t, J ¼ 6.8, COCH2); 2.31 (s, Me). 13C-NMR (100 MHz): 196.1; 170.4; 138.0; 128.6; 127.7; 127.5; 43.6; 36.1;
30.5; 24.9. HR-MS-ESI: 238.0888 ([M þ H]þ, C12H15NO2Sþ; calc. 238.0896).
S-[(1RS,2RS)-3-Amino-1,2-dimethyl-3-oxopropyl] Ethanethioate (ꢀantiꢁ-4h): Recrystallized from
AcOEt/petroleum ether. Colorless crystals. Yield 2.63 g (75%). M.p. 136 – 1388. IR: 3356 (NH), 3111
(NH), 1685 (CO), 1655 (CO). 1H-NMR (400 MHz): 5.69 (br. s, NH2); 3.76 (dq, J ¼ 6.8, 6.8, CHS); 2.52
(dq, J ¼ 6.8, 6.8, CHCO); 2.33 (s, MeCO); 1.37 (d, J ¼ 6.8, Me); 1.24 (d, J ¼ 6.8, Me). 13C-NMR
(100 MHz): 195.2; 176.3; 45.5; 42.0; 30.7; 19.0; 15.6. HR-MS-ESI: 176.0733 ([M þ H]þ, C7H13NO2Sþ;
calc. 176.0740).

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S-[(1RS,2RS)-3-Amino-1,2-dimethyl-3-oxopropyl] Ethanethioate (ꢀsynꢁ-4h): Data from ꢀsynꢁ/ꢀantiꢁ-
4h after the recrystallization of ꢀantiꢁ-4h (see above). Colorless oil. Yield 0.26 g (7.5%). IR: 3356 (NH),
3111 (NH), 1685 (CO), 1655 (CO). 1H-NMR (400 MHz): 5.82 (br. s, NH2); 3.82 (dq, J ¼ 4.4, 6.8, CHS);
2.63 (dq, J ¼ 4.4, 6.8, CHCO); 2.33 (s, MeCO); 1.30 (d, J ¼ 6.8, Me); 1.17 (d, J ¼ 6.8, Me). 13C-NMR
(100 MHz): 196.5; 176.2; 44.7; 41.9; 30.6; 16.7; 12.9. HR-MS-ESI: 176.0735 ([M þ H]þ, C7H13NO2Sþ;
calc. 176.0740).
S-{1-Methyl-3-oxo-3-[(phenylmethyl)amino]propyl} Ethanethioate (4j): CC (petroleum ether/
AcOEt 2 :1). White crystals. Yield 4.42 g (88%). M.p. 60 – 618 ([38]: 65 – 668). IR: 3276 (NH), 1682
1
(CO), 1644 (CO). H-NMR (400 MHz): 7.35 – 7.27 (m, 5 arom. H); 5.99 (br. s, NH); 4.44 (d, J ¼ 5.6,
ArCH2); 3.87 (ddq, J ¼ 6.4, 7.6, 6.8, CH); 2.58 (dd, J ¼ 6.4, 14.4, 1 H of CH2); 2.45 (dd, J ¼ 7.6, 14.4, 1 H of
CH2); 2.27 (s, COMe); 1.39 (d, J ¼ 6.8, Me). 13C-NMR (100 MHz): 195.8; 169.8; 138.1; 128.6; 127.8; 127.5;
43.5; 43.3; 36.5; 30.6; 20.6.
S-{2-Methyl-3-oxo-3-[(phenylmethyl)amino]propyl} Ethanethioate (4k): CC (petroleum ether/
AcOEt 2 :1). Yellow oil ([38]: M.p. 608). Yield 4.77 g (95%). IR: 3296 (NH), 1692 (CO), 1650 (CO).
1H-NMR (400 MHz): 7.35 – 7.27 (m, 5 arom. H); 6.09 (br. s, NH); 4.43 (d, J ¼ 5.6, ArCH2); 3.11 (dd, J ¼
8.0, 13.6, 1 H of CH2); 2.96 (dd, J ¼ 6.0, 13.6, 1 H of CH2); 2.46 (ddq, J ¼ 6.0, 8.0, 7.2, CH); 2.29 (s,
COMe); 1.23 (d, J ¼ 7.2, Me). 13C-NMR (100 MHz): 196.1; 174.1; 138.2; 128.6; 127.7; 127.4; 43.5; 41.5;
32.7; 30.5; 17.4.
S-{3-[Bis(phenylmethyl)amino]-3-oxopropyl} Ethanethioate (4l): CC (petroleum ether/AcOEt
1
5 :1). Yellow oil. Yield: 5.04 g (77%). IR: 1688 (CO), 1650 (CO). H-NMR (400 MHz): 7.37 – 7.12 (m,
10 arom. H); 4.60 (s, CH2); 4.42 (s, CH2); 3.22 (t, J ¼ 6.8, CH2S); 2.74 (t, J ¼ 6.8, COCH2); 2.29 (s, Me).
13C-NMR (100 MHz): 195.9; 171.2; 137.0; 136.0; 128.8; 128.5; 128.2; 127.5; 127.3; 126.2; 49.6; 48.2; 33.2;
30.4; 24.8. HR-MS-ESI: 328.1362 ([M þ H]þ, C19H21NO2Sþ; calc. 328.1366).
4. Substituted Homotaurines 6: General Procedure. To a suspension of LiAlH4 (1.52 g, 40 mmol) in
dried THF (30 ml) was added a soln. of 4 (4 mmol) in dried THF (5 ml), dropwise under stirring at 08.
The resulting mixture was heated under reflux for 24 h and then cooled to 08. The excess LiAlH4 was
carefully quenched with H2O (10 ml) under stirring at r.t. After filtration, the filtrate was extracted with
CH2Cl2 (3 ꢁ 10 ml), the combined org. phase dried (Na2SO4) and concentrated, and the residual yellow
oil dissolved in HCOOH (10 ml). To the soln. was added a mixture of HCOOH (10 ml) and 30% H2O2
soln. (5 ml), dropwise under stirring at r.t. After stirring for 12 h and removal of the solvent, the residue
was crystallized from MeOH/Et2O to give the substituted homotaurine.
4-Aminobutane-2-sulfonic Acid (6b): Colorless solid. Yield 410 mg (67%). M.p. 281 – 2838 ([39]:
288 – 2898). IR: 3448 (br., NH, OH), 1257 (SO), 1167 (SO). 1H-NMR (400 MHz, D2O): 3.16 – 3.04 (m,
CH2N); 2.94 (ddq, J ¼ 6.4, 6.4, 6.9, CH); 2.12 (ddt, J ¼ 6.9, 14.8, 6.4, 1 H of CH2); 1.82 (ddt, J ¼ 6.8, 14.8,
6.4, 1 H of CH2); 1.25 (d, J ¼ 6.9, Me). 13C-NMR (100 MHz, D2O): 53.0; 37.3; 29.2; 14.6.
1-Aminohexane-3-sulfonic Acid (6c): Colorless crystals. Yield 608 mg (84%). M.p. 230 – 2348. IR:
3407 (br., NH, OH), 1255 (SO), 1163 (SO). 1H-NMR (400 MHz, D2O): 3.13 (t, J ¼ 8.0, CH2N); 2.82 (tt,
J ¼ 4.8, 7.6, CH); 2.08 – 1.92 (m, CH2); 1.82 – 1.73 (m, 1 H of CH2); 1.53 – 1.39 (m, CH2); 1.37 – 1.28 (m,
1 H of CH2); 0.85 (t, J ¼ 7.2, Me). 13C-NMR (100 MHz, D2O): 57.5; 37.5; 31.5; 27.2; 19.5; 13.2. HR-MS-
ESI: 182.0849 ([M þ H]þ, C6H15NO3Sþ; calc. 182.0581).
3-Amino-2-methylpropane-1-sulfonic Acid (6e): Colorless crystals. Yield 428 mg (70%). M.p. 234 –
1
2388 ([8]: 260 – 2658). IR: 3451 (br. NH, OH), 1280 (SO), 1176 (SO). H-NMR (400 MHz, D2O): 3.15
(dd, J ¼ 6.0, 13.2, 1 H of CH2S); 2.93 (dd, J ¼ 6.8, 14.4, 1 H of CH2N); 2.90 (dd, J ¼ 6.8, 13.2, 1 H of CH2S);
2.87 (dd, J ¼ 6.0, 14.4, 1 H of CH2N); 2.37 – 2.26 (m, CH); 1.10 (d, J ¼ 6.8, Me). 13C-NMR (100 MHz,
D2O): 54.7; 44.2; 28.7; 17.0.
3-Amino-2-phenylpropane-1-sulfonic Acid (6f) [10]: Colorless crystals. Yield 636 mg (74%). M.p.
220 – 2258 (dec.). IR: 2960 (br., NH, OH), 1180 (SO), 1142 (SO). 1H-NMR (400 MHz, D2O): 7.40 – 7.30
(m, 5 arom. H); 3.53 (dd, J ¼ 5.2, 12.8, 1 H of CH2S); 3.46 – 3.38 (m, CH); 3.28 (dd, J ¼ 6.4, 14.4, 1 H of
CH2N); 3.24 (m, 1 H of CH2S); 3.22 (dd, J ¼ 6.4, 14.4, 1 H of CH2N). 13C-NMR (100 MHz, D2O): 134.7;
129.4; 128.9; 58.6; 30.3; 16.8.
3-[(Phenylmethyl)amino]propane-1-sulfonic Acid (6g): Colorless crystals. Yield 577 mg (63%). M.p.
241 – 2438 ([40]: 302 – 3038). IR: 3452 (br., NH, OH), 1245 (SO), 1184 (SO). 1H-NMR (400 MHz, D2O):

Helvetica Chimica Acta – Vol. 96 (2013)
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7.42 (s, 5 arom. H); 4.17 (s, PhCH2); 3.15 (t, J ¼ 7.2, CH2S); 2.91 (t, J ¼ 7.2, CH2N); 2.06 (quint., J ¼ 7.2,
CH2). 13C-NMR (100 MHz, D2O): 130.6; 129.8; 129.7; 129.3; 51.1; 47.9; 45.7; 21.3.
(2RS,3RS)-4-Amino-3-methylbutane-2-sulfonic Acid (ꢀantiꢁ-6h): Yellow oil. Yield 341 mg (51%).
IR: 2976 (br., NH, OH), 1205 (SO), 1030 (SO). 1H-NMR (400 MHz, D2O): 3.27 (dd, J ¼ 5.6, 13.2, 1 H of
CH2N); 2.96 (dq, J ¼ 2.8, 7.2, CHS); 2.82 (dd, J ¼ 8.4, 13.2, 1 H of CH2N); 2.42 (dddq, J ¼ 2.8, 5.6, 8.4, 7.2,
CH); 1.21 (d, J ¼ 7.2, Me); 1.05 (d, J ¼ 7.2, Me). 13C-NMR (100 MHz, D2O): 58.5; 41.2; 32.3; 15.4; 9.8.
HR-MS-ESI: 168.0682 ([M þ H]þ, C5H13NO3Sþ; calc. 168.0689).
4-[(Phenylmethyl)amino]butane-2-sulfonic Acid (6j) [19]: Colorless crystals. Yield 885 mg (91%).
M.p. 251 – 2538. IR: 3431 (br., NH, OH), 1210 (SO), 1161, (SO). 1H-NMR (400 MHz, D2O): 7.44 – 7.39
(m, 5 arom. H); 4.17 (s, PhCH2); 3.16 (t, J ¼ 8.0, CH2N); 2.91 (ddq, J ¼ 6.8, 6.8, 6.8, CH); 2.18 – 2.09 (m,
1 H of CH2); 1.90 – 1.80 (m, 1 H of CH2); 1.22 (d, J ¼ 6.8, Me). 13C-NMR (100 MHz, D2O): 130.6; 129.8;
129.7; 129.3; 53.1; 51.1; 44.8; 27.9; 14.6.
2-Methyl-3-[(phenylmethyl)amino]propane-1-sulfonic Acid (6k): Colorless crystals. Yield 914 mg
(94%). M.p. 265 – 2678. IR: 3435 (br., NH, OH), 1209 (SO), 1179 (SO). 1H-NMR (400 MHz, D2O): 7.42
(s, 5 arom. H); 4.18 (d, J ¼ 2.4, PhCH2); 3.20 (dd, J ¼ 6.8, 12.8, 1 H of CH2S); 2.97 (dd, J ¼ 6.8, 12.8, 1 H of
CH2S); 2.91 (dd, J ¼ 6.8, 14.4, 1 H of CH2N); 2.86 (dd, J ¼ 5.6, 14.4, 1 H of CH2N); 2.37 (ddddq, J ¼ 5.6,
6.8, 6.8, 6.8, 6.8, CH); 1.07 (d, J ¼ 6.8, Me). 13C-NMR (100 MHz, D2O): 130.5; 129.9; 129.7; 129.3; 55.0;
51.9; 51.5; 27.8; 17.6. HR-MS-ESI: 244.1005 ([M þ H]þ, C11H17NO3Sþ; calc. 244.1007).
3-[Bis(phenylmethyl)amino]propane-1-sulfonic Acid (6l): Yellow oil. Yield 970 mg (76%). IR: 3424
(br., OH), 1215 (SO), 1151 (SO). 1H-NMR (400 MHz, D2O): 7.45 – 7.32 (m, 10 arom. H); 4.22 (s, 2 CH2);
3.16 (t, J ¼ 8.1, CH2N); 2.75 (t, J ¼ 7.2, CH2N); 2.11 (tt, J ¼ 7.2, 8.1, CH2). 13C-NMR (100 MHz, D2O):
131.0; 130.2; 129.4; 128.9; 57.1; 51.1; 47.9; 19.2. HR-MS-ESI: 320.1313 ([M þ H]þ, C17H21NO3Sþ; calc.
320.1315).
5. N-Cbz-Protected Homotaurine 8 and Homotaurine 6a. Method A: To a suspension of LiAlH4
(1.52 g, 40 mmol) in dried THF (30 ml) was added a soln. of 4a (588 mg, 4 mmol) in dried THF (5 ml),
dropwise under stirring at 08. The resulting soln. was heated to reflux for 24 h and then cooled to 08. The
excess LiAlH4 was carefully quenched with H2O (10 ml) under stirring at r.t. After filtration, benzyl
carbonochloridate (1.36 g, 8 mmol) and Et3N (2.20 g, 20 mmol) were added to the filtrate. The resulting
mixture was stirred at r.t. for 12 h. After evaporation of the solvent, the residue was subjected to CC: 7
(144 mg, 16%). To a soln. of 7 (338 mg, 1.5 mmol) in HCOOH (10 ml) was added a mixture of HCOOH
(10 ml) and 30% H2O2 soln. (5 ml), dropwise under stirring at r.t. After stirring for 12 h and evaporation
of the solvent below 458, the residue was crystallized from MeOH/H2O to give 8 (224 mg, 55%); from the
mother liquor, 6a (17 mg, 8%) was obtained. If the solvent was evaporated above 458 after the reaction,
6a was obtained in 64% yield (134 mg).
Method B: Thioacetate 4a (588 mg, 4 mmol) was reduced with LiAlH4 and treated with benzyl
carbonochloridate as described above. After evaporated of the solvent, the residue, crude 7, was oxidized
directly to afford 6a (123 mg, 22% overall yield from 4a).
Phenylmethyl N-(3-Sulfanylpropyl)carbamate (7): Colorless crystals. M.p. 91 – 928 ([6]: 91 – 928).
1H-NMR (400 MHz): 7.34 – 7.26 (m, 5 arom. H); 5.08 (s, PhCH2); 3.29 (q, J ¼ 6.8, CH2N); 2.70 (t, J ¼ 6.8,
CH2S); 1.90 (quint., J ¼ 6.8, CH2). 13C-NMR (100 MHz, CDCl3): 156.4; 136.5; 128.4; 128.1; 66.6; 39.6;
35.8; 29.3.
3-{[(Phenylmethoxy)carbonyl]amino}propane-1-sulfonic Acid (8) [41]: Colorless crystals. M.p. 90 –
918. IR: 3427 (br., NH, OH), 1732 (CO), 1325 (SO), 1167 (SO). 1H-NMR (400 MHz): 7.43 – 7.30 (m, 5
arom. H); 5.30 (s, PhCH2); 3.82 (t, J ¼ 6.8, CH2S); 3.34 (t, J ¼ 6.8, CH2N); 2.39 (quint., J ¼ 6.8, CH2).
13C-NMR (100 MHz): 150.8; 135.0; 128.5; 128.4; 127.9; 68.6; 49.4; 45.2; 18.6.
3-Aminopropane-1-sulfonic Acid (¼ Homotaurine; 6a): Colorless crystals. M.p. 292 – 2948 ([39]:
294 – 2958). 1H-NMR (400 MHz, D2O): 3.08 (t, J ¼ 7.6, CH2S), 2.94 (t, J ¼ 7.6, CH2N), 2.04 (quint., J ¼ 7.6,
CH2).
6. 3-(Acetylsulfanyl)-3-phenylpropanoic Acid (9d): To a refluxing soln. of cinnamic acid (1d; 2.964 g,
20 mmol) in benzene (40 ml) was added thioacetic acid (2.1 ml, 2.28 g, 30 mmol), dropwise under
stirring. The resulting soln. was heated to reflux for 4 h. After evaporation of the solvent, the residue was
subjected to CC: 9d (3.40 g, 76%). Colorless oil ([42]: M.p. 95 – 968). 1H-NMR (400 MHz): 7.32 – 7.24 (m,

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Helvetica Chimica Acta – Vol. 96 (2013)
5 arom. H); 5.03 (dd, J ¼ 6.8, 8.4, CH); 3.29 (d, J ¼ 6.8, 1 H of CH2); 3.27 (d, J ¼ 8.4, 1 H of CH2); 2.30 (s,
Me).
7. Mixed Anhydride of 9d and Subsequent Ammonolysis. To a soln. of 9d (3.392 g, 15 mmol) and
Et3N (2.2 ml, 1.52 g, 15 mmol) in dried CH2Cl2 (30 ml) was added ethyl carbonochloridate (1.5 ml, 1.63 g,
15 mmol), dropwise under stirring at 08. The resulting soln. was stirred for 30 min to generate the mixed
anhydride 10d, which was directly treated with 25% aq. NH3 soln. (4 ml). The mixture was stirred for 2 h.
The org. phase was separated, the aq. phase extracted with AcOEt (3 ꢁ 25 ml), the combined org. phase
washed with sat. NaCl soln. (3 ꢁ 25 ml) and dried (Na2SO4), the solvent evaporated, and the residue
subjected to CC: cinnamamide (¼(2E)-3-phenylprop-2-enamide (3d; 1.92 g, 87%). Colorless crystals.
M.p. 152 – 1538 ([28]: 148 – 1518). 1H-NMR (400 MHz): 7.65 (d, J ¼ 15.6, CH); 7.52 – 7.36 (m, 5 arom. H);
6.47 (d, J ¼ 15.6, COCH); 5.84 (br. s, NH2).
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Received September 27, 2012