Synthesis of homotaurine and 1-substituted homotaurines from α,β-unsaturated nitriles

Article abstract of DOI:10.1055/s-0031-1289773

Homotaurine and a series of 1-substituted homotaurines were readily synthesized in satisfactory to good yields via the Michael addition of thioacetic acid to aliphatic and aromatic α,β-unsaturated nitriles followed by lithium aluminum hydride mediated reduction and performic acid oxidation. The synthesis of 1,1-disubstituted homotaurines was attempted with β,β-disubstituted acrylonitriles as starting materials but failed due to steric hindrance. The current process is an efficient method for the synthesis of 1-substituted homotaurines. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0031-1289773

PAPER
▌2225
paper
Synthesis of Homotaurine and 1-Substituted Homotaurines from
α,β-Unsaturated Nitriles
Synthesis of 1-Substituted Homotaurines
Yunhai Ma, Jiaxi Xu*
State Key Laboratory of Chemical Resource Engineering, Department of Organic Chemistry, Faculty of Science,
Beijing University of Chemical Technology, Beijing 100029, P. R. of China
Fax +86(10)64435565; E-mail: jxxu@mail.buct.edu.cn
Received: 03.04.2012; Accepted after revision: 02.05.2012
ring-opening reactions of 2-alkylpropane-1,3-sultones
with ammonia or with sodium azide followed by reduc-
tion.12 3-Substituted homotaurines were synthesized
through oxidation of homocysteine,13 via reduction of
Abstract: Homotaurine and a series of 1-substituted homotaurines
were readily synthesized in satisfactory to good yields via the
Michael addition of thioacetic acid to aliphatic and aromatic α,β-un-
saturated nitriles followed by lithium aluminum hydride mediated
reduction and performic acid oxidation. The synthesis of 1,1-disub- amino esters to amino aldehydes, which underwent the
stituted homotaurines was attempted with β,β-disubstituted acrylo-
nitriles as starting materials but failed due to steric hindrance. The
current process is an efficient method for the synthesis of 1-substi-
butyllithium and subsequent hydrogenation and deprotec-
tuted homotaurines.
Horner–Wadsworth–Emmons reaction with ethyl
(diethoxyphosphoryl)methanesulfonate in the presence of
tion.14 3-Nitroalkanesulfonic acids are precursors of 1,3-
disubstituted homotaurines and were obtained through ad-
Key words: acrylonitrile, amino thiols, Michael addition, nucleo-
phile, reduction, oxidation, thioacetic acid
dition of arylmethanesulfonates to nitroolefins in the pres-
ence of n-butyllithium.15 Recently, cis- and trans-2-
aminomethylcyclopropane-1-sulfonic acids were synthe-
Homotaurine (3-aminopropanesulfonic acid) and taurine
sized as conformationally restricted GABA analogues as
(2-aminoethanesulfonic acid) are two powerful inhibitory
pharmacological tools to study GABA receptor sub-
types.16 However, there is no general reported method for
the synthesis of 1-substituted homotaurines. Recently, we
prepared substituted taurines through Michael addition of
thioacetic acid and sodium O-ethyl xanthate to nitroole-
fins and subsequent oxidation and reduction.17 As a part of
our continuing interest in the synthesis and biological ap-
plications of aminoalkanesulfonic acids, we became inter-
ested in the preparation of 1-substituted homotaurines,
especially salt-free preparations. Herein, we present the
synthesis of 1-substituted homotaurines from α,β-unsatu-
rated nitriles.
amino acids with anticonvulsant properties against vari-
ous experimental models of focal epilepsy.1 Homotaurine,
as a sulfur-containing amino acid, has attracted much at-
tention in recent years as a drug candidate for the treat-
ment of Alzheimer’s disease and haemorrhagic stroke.2
Recent studies indicate that it binds to soluble amyloid β-
peptide (Aβ) and decreases Aβ42-induced cell death in
neuronal cell culture.3 It is believed that the reduction or
inhibition of amyloid deposition in the brain and cerebral
vasculature is responsible for the beneficial effects ob-
served in vivo studies.2 Moreover, calcium 3-acetylami-
nopropanesulfonate (acamprosate) is one of the few
medications currently approved for the prevention of al-
cohol relapse in detoxified alcohol dependent patients
both in Europe and USA.4 Both homotaurine and substi-
tuted homotaurine derivatives are considered as bioiso-
steres of γ-aminobutyric acid (GABA).5
α,β-Unsaturated nitriles 1c–j were prepared conveniently
in satisfactory to good yields through condensation of al-
dehydes or ketones and acetonitrile, respectively, in the
presence of potassium hydroxide by referring to the re-
ported method (Scheme 1);18 acrylonitrile (1a) and croto-
nitrile (1b) are commercially available. In most cases, (E)-
α,β-unsaturated nitriles were obtained. However, a mix-
ture of Z- and E-isomers was obtained for α,β-unsaturated
nitriles cinamonitrile (1c) and (3-chlorophenyl)acryloni-
trile (1e) in Z/E ratios of 1:3 and 1:6, respectively.
Homotaurine was synthesized from 3-aminopropanol via
bromination with hydrogen bromide and subsequent dis-
placement with sodium bisulfite or sulfite,6,7 and via addi-
tion of acrylonitrile with sodium bisulfite and subsequent
reduction.8 2-Substituted homotaurines were prepared as
competitive antagonists of the GABA receptor through
addition of isobutenal with sodium bisulfite and subse-
quent reductive amination,9 via addition of 1-arylacrylo-
nitriles with sodium bisulfate and subsequent reduction,10
via the oxygen-catalyzed radical addition of bisulfite to 2-
arylallylamines or their N-phthalyl derivatives,11 and via
R1
O
KOH
NC
MeCN
+
R1
R2
R2
1
Scheme 1 Preparation of α,β-unsaturated nitriles 1
The Michael addition of acrylonitrile and 1-arylacryloni-
triles with sodium bisulfite has been applied in the synthe-
sis of homotaurine and 2-arylhomotaurines.8,10 However,
separation and purification of intermediate 2-cyanoal-
SYNTHESIS 2012, 44, 2225–2230
Advanced online publication: 13.06.2012
DOI: 10.1055/s-0031-1289773; Art ID: SS-2012-H0334-OP
© Georg Thieme Verlag Stuttgart · New York
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X

2226
Y. Ma, J. Xu
PAPER
kanesulfonic acids from the inorganic salts during the 1–7). However, for α,β-unsaturated nitriles 1h–j, which
workup is difficult and tedious due to their large polarity are β,β-disubstituted acrylonitriles, no reaction occurred
and good solubility in water, especially for low molecular under the same reaction conditions (Table 2, entries 8–
weight derivatives. To simplify the purification proce- 10), revealing that the Michael addition is very sensitive
dure, we hoped to develop a salt-free route to the synthesis towards steric hindrance. This is consistent with the ob-
of 1-substituted homotaurines from α,β-unsaturated ni- servation that the sterically hindered nucleophile piperi-
triles. Thus, Michael additions of α,β-unsaturated nitriles dine-1-xanthate cannot undergo the Michael addition with
1 with different sulfur nucleophiles, such as potassium bulky cinamonitrile (1c) due to steric hindrance. The ob-
isothiocyanate, potassium thioacetate, thioacetic acid, and tained S-1-substituted 2-cyanoethyl thioacetates 2a–g
xanthate derivatives, were investigated with acrylonitrile were reduced with lithium aluminum hydride to give rise
(1a) and cinamonitrile (1c) as representatives; the results to the corresponding 1-aminoalkane-3-thiols 3a–g, which
are summarized in Table 1. When simple sulfur-contain- were directly oxidized with peroxyformic acid without
ing salts potassium isothiocyanate and potassium thioace- purification. The residues were recrystallized from a mix-
tate were used as nucleophiles in the reactions with ture of ethanol and diethyl ether to afford 1-substituted
acrylonitrile (1a), no desired product was observed (Table homotaurines 4b–g as colorless crystals in acceptable to
1, entries 1 and 2). Thioacetic acid reacted with acryloni- good yields (Table 2, entries 2–7). However, homotaurine
trile (1a) to afford the adduct S-2-cyanoethyl thioacetate (4a) was not obtained following the same procedure.
(2a) in good yield (72%) in the presence of triethylamine
Table 1 Michael Addition of α,β-Unsaturated Nitriles 1a and 1c
with Sulfur Nucleophiles
(Table 1, entry 3). Xanthate derivatives sodium O-ethyl
xanthate and piperidine-1-xanthate, generated in situ from
SNu
piperidine and carbon disulfide, reacted with acrylonitrile
CN
NuSH/M
+
R1
(1a) to produce the corresponding products in 52% yield
in acetic acid and in 62% yield in water, respectively (Ta-
ble 1, entries 4 and 5). The reaction of piperidine-1-xan-
thate and acrylonitrile (1a) realized 91% yield under
solvent-free conditions (Table 1, entry 6). However, sodi-
um O-ethyl xanthate reacted with cinamonitrile (1c) to
give the corresponding product in less than 10% yield. For
piperidine-1-xanthate and cinamonitrile (1c), no reaction
occurred. Thus, we focused on the reaction with thioacetic
acid as the sulfur nucleophile. To monitor the reaction
progress conveniently with TLC and to explore the influ-
ence of substituents on the yield, the reaction of thioacetic
acid and cinamonitrile (1c) was selected as a model reac-
tion to optimize reaction conditions. The reaction pro-
duced the desired product S-2-cyano-1-phenylethyl
thioacetate (2c) in 33% yield in refluxing toluene, an
aprotic solvent, under the catalysis of triethylamine. How-
ever, it gave rise to only trace amounts of the product in
refluxing methanol, a protic solvent. Considering that the
Michael addition is a reversible reaction and that the reac-
tion is generally favorable to the adduct at lower temper-
atures. To reduce the refluxing temperature and to screen
different solvents, the reaction was conducted in refluxing
tetrahydrofuran (bp 66 °C) and carbon tetrachloride (bp
77 °C), respectively, affording the adduct in 36 and 40%
yields. To evaluate the efficiency of different catalysts,
the reaction was also performed in refluxing carbon tetra-
chloride under the catalysis of tributylamine, giving rise
to the adduct in 40% yield. Carbon tetrachloride is not an
environment-friendly solvent, therefore, the reaction was
finally carried out in toluene at 80 °C under the catalysis
of tributylamine. Under these optimal reaction conditions,
the desired adduct was obtained in 42% yield.
CN
solvent
R1
1a,c
2
Entry 1
NuSH/M
Base Solvent Time Temp Yield
(h) (°C)
(%)
1
2
1a KSCN
–
–
MeOH
MeOH
6
6
6
6
6
6
6
reflux
reflux
0
0
1a KSAc
3
1a AcSH
Et3N toluene
reflux 72
4
1a EtOCS2Na
1a piperidine + CS2
1a piperidine + CS2
1c EtOCS2Na
1c piperidine + CS2
1c AcSH
–
AcOH
H2O
–
0
52
62
5
r.t.
r.t.
0
6
91
7
–
AcOH
–
<10
0
8
72 r.t.
9
Et3N toluene 12 reflux 33
Et3N MeOH 12 reflux trace
10
11
12
13
14
15
1c AcSH
1c AcSH
Et3N toluene 12 r.t.
0
1c AcSH
Et3N THF
Et3N CCl4
Bu3N CCl4
Bu3N toluene
12 reflux 33
1c AcSH
5
5
5
reflux 36
reflux 40
reflux 42
1c AcSH
1c AcSH
It can be seen from Table 2 that 1-arylhomotaurines 4c–g
were obtained in higher yields than 1-methylhomotaurine
(4b). Homotaurine (4a) was not obtained by following the
same procedure. We assumed that 3-aminopropane-1-thi-
ol (3a) and 1-aminobutane-3-thiol (3b) may be more hy-
drophilic than 3-amino-1-arylpropane-1-thiols 3c–g.
Because of their high water-solubility it was only possible
to extract 3b in a lower yield, and 3a could not be extract-
ed at all. However, when 1-substituted taurines were syn-
α,β-Unsaturated nitriles 1a–g underwent the Michael ad-
dition with thioacetic acid to produced 1-substituted 2-cy-
anoethyl thioacetates 2a–g in satisfactory to good yields
under the optimized reaction conditions (Table 2, entries
Synthesis 2012, 44, 2225–2230
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of 1-Substituted Homotaurines
2227
thesized from thiiranes via the silver nitrate-catalyzed Alternatively, we also attempted to oxidize 2-cyanoethyl
nucleophilic ring opening with ammonia, 1-aminoalkane- thioacetates 2 and then reduce the corresponding cyano-
2-thiols could be extracted from aqueous solution without ethanesulfonic acid. However, S-2-cyanoethyl thioacetate
any problem to afford 1-substituted taurines in satisfacto- (2a) generated 3-sulfonopropanoic acid (6) in an excellent
ry to good yields.19 To verify the assumption, after the re- yield (98%) rather than cyanoethanesulfonic acid (7;
duction of 2-cyanoethyl thioacetate (2a) with lithium Scheme 3).
aluminum hydride and usual workup, the generated 3-
aminopropane-1-thiol (3a) in the resulting aqueous solu-
tion was directly reacted with benzyl chloroformate in the
H2O2, HCOOH
COOH
HO3S
CN
6
AcS
presence of triethylamine to increase the hydrophobicity
and aid in the extraction (Scheme 2). After usual workup,
benzyl N-(3-mercaptopropyl)carbamate (5) was obtained
in 25% yield, illustrating that the efficiency of the extrac-
tion was clearly improved. Compound 5 was further oxi-
dized with performic acid to afford homotaurine (4a) in an
excellent yield (97%; overall yield 24% from thioacetate
2a). The results indicate lower molecular weight 1-amino-
alkane-3-thiols are indeed hydrophilic and more difficult
to extract from the aqueous solution than the correspond-
ing 1-aminoalkane-2-thiols.
H2O2, HCOOH
CN
2a
HO3S
7
Scheme 3 Oxidation of S-2-cyanoethyl thioacetate (2a) with perfor-
mic acid
In summary, homotaurine and a series of 1-substituted ho-
motaurines were conveniently synthesized through the
Michael addition of thioacetic acid to α,β-unsaturated ni-
triles and subsequent reduction with lithium aluminum
hydride and oxidation with peroxyformic acid. The cur-
rent method is a general and convenient synthetic route to
1-substituted homotaurines. Compared with the previous-
ly reported methods, the current method is a general and
convenient approach to the synthesis of 1-substituted ho-
motaurines.
Table 2 Synthesis of Homotaurine (4a) and 1-Substituted Homotau-
rines 4b–g
SAc
R2
SO3H
R1
R2
1. LiAlH4
R1
R2
AcSH
Bu3N
CN
CN
R1
NH2
2. H2O2, HCOOH
1
2
4
Melting points were measured with a Yanaco MP-500 melting point
R1
R2
Yield (%)
1
apparatus and are uncorrected. H and 13C NMR spectra were re-
Entry
Nitrile 1
corded with a Varian 300 plus (300 MHz) or a Bruker AV 400 (400
MHz) spectrometer either in CDCl3 with TMS as an internal stan-
dard or in D2O (with HCO2H as an internal standard for 13C NMR
spectra). HRMS were carried out with an Agilent LC/MSD TOF
mass spectrometer. IR spectra were determined with a Nicolet
AVATAR 330 FT-IR spectrometer.
2
4
1
2
1a
1b
1c
1d
1e
1f
H
H
72.6
45.5
41.5
68.3
67.5
66.0
31.2
0
24.3a
54.0
62.5
85.6
75.2
74.8
82.3
–
Me
Ph
H
3
H
Thioacetic acid, acrylonitrile, and crotonitrile were purchased com-
mercially. Et2O was heated at reflux with sodium and diphenyl ke-
tone until the color of system was blue, and freshly distilled prior to
use. TLC analysis was performed on glass pre-coated silica gel
YT257–85 (10–40 μm) plates; spots were visualized with UV light
or iodine. Column chromatography was performed on silica gel zcx
II (200–300 mesh). Petroleum ether (PE), where used, had a boiling
range 60–90 °C.
4
2-ClC6H4
3-ClC6H4
4-ClC6H4
4-MeC6H4
Et
H
5
H
6
H
7
1g
1h
1i
H
8
Et
Me
Ph
Synthesis of α,β-Unsaturated Nitriles 1c–j from Aldehydes and
Ketones; General Procedure
9
Ph
0
–
A 100-mL, three-necked, round-bottomed flask, equipped with a
pressure equalizing addition funnel, reflux condenser, N2 purge, and
magnetic stirring bar, was charged with KOH (2.8 g, 50 mmol) and
anhydrous MeCN (40 mL). The mixture was heated to reflux and a
solution of an aldehyde or ketone (50 mmol) in MeCN (20 mL) was
added in a stream. After the addition was complete, stirring was
continued for the specified time (20 s–24 h; reaction monitored by
TLC analysis) and then the hot solution was poured onto cracked
ice. The mixture was extracted with CH2Cl2 (3 × 75 mL), dried over
anhydrous Na2SO4, and evaporated under reduced pressure (during
evaporation, the bath temperature was maintained at ca 30 °C in or-
der to minimize decomposition). The crude product thus obtained
was purified by flash column chromatography on silica gel (PE–
EtOAc, 10:1) to afford the corresponding α,β-unsaturated nitrile.
The analytical data of 1c–j are identical to those reported in litera-
ture.18,20
10
1j
Ph
0
–
a Overall yield from 2a and after N-protection of 3-aminopropanethiol
(3a) with benzyl chloroformate and subsequent oxidation with perfor-
mic acid.
LiAlH4
Et2O
CbzCl
CN
HS
NH2
AcS
Et3N, CH2Cl2
3a
2a
H2O2, HCOOH
Cbz
HS
N
HO3S
NH2
H
4a
5
Scheme 2 Preparation of homotaurine (4a) from 2-cyanoethyl thio-
acetate (2a)
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 2225–2230

2228
Y. Ma, J. Xu
PAPER
Synthesis of S-2-Cyanoethyl Thioacetates 2 from α,β-Unsatu-
rated Nitriles 1 and Thioacetic Acid; General Procedure
A 50 mL, three-necked, round-bottomed flask, equipped with a
pressure equalizing addition funnel, reflux condenser, N2 purge, and
magnetic stirring bar, was charged with α,β-unsaturated nitrile 1 (5
mmol) and Bu3N (3 drops) in anhydrous toluene (20 mL). The mix-
ture was heated to 75–85 °C, and AcSH (0.5 mL, 0.46 g, 6 mmol)
was slowly added dropwise. After the addition, the resulting solu-
tion was stirred for 5 h and then the mixture was evaporated in
vacuo to remove the excess AcSH and solvent. The residue was pu-
rified by flash column chromatography on silica gel (PE–EtOAc,
8:1), affording S-2-cyanoethyl thioacetate [Rf = 0.50–0.65 (PE–
EtOAc, 8:1)].
1H NMR (400 MHz, CDCl3): δ = 2.38 (s, 3 H, CH3CO), 3.00 (dd,
J = 7.4, 17.0 Hz, 1 H, CH2CN), 3.04 (dd, J = 6.2, 17.0 Hz, 1 H,
CH2CN), 4.80 (dd, J = 6.2, 7.4 Hz, 1 H, CHS), 7.28–7.37 (m, 4 H,
ArH).
13C NMR (100 MHz, CDCl3): δ = 25.4, 30.5, 43.0, 116.7, 128.9,
129.4, 134.7, 136.1, 193.6.
HRMS (ESI): m/z [M + K]+ calcd for C11H10ClKNOS: 277.9809;
found: 277.9795.
S-2-Cyano-1-(4-methylphenyl)cyanoethyl Thioacetate (2g)
Yield: 342 mg (31.2%); yellow crystals; mp 68–69 °C; Rf = 0.60
(PE–EtOAc, 8:1).
IR (KBr): 2254 (CN), 1693 (C=O) cm–1.
1H NMR (400 MHz, CDCl3): δ = 2.37 (s, 3 H, CH3), 2.39 (s, 3 H,
CH3), 3.00 (dd, J = 7.2, 17.0 Hz, 1 H, CH2CN), 3.05 (dd, J = 6.5,
17.0 Hz, 1 H, CH2CN), 4.83 (dd, J = 6.5, 7.2 Hz, 1 H, CHS), 7.20
(d, J = 8.1 Hz, 2 H, ArH), 7.25 (d, J = 8.1 Hz, 2 H, ArH).
13C NMR (100 MHz, CDCl3): δ = 21.1, 25.6, 30.4, 43.5, 117.0,
127.3, 129.8, 134.4, 138.6, 194.1.
HRMS (ESI): m/z [M + H]+ calcd for C12H14NOS: 220.0796; found:
220.0789.
S-2-Cyanoethyl Thioacetate (2a)21
Yield: 468 mg (72.6%); yellowish liquid; Rf = 0.65 (PE–EtOAc,
8:1).
1H NMR (300 MHz, CDCl3): δ = 2.37 (s, 3 H, CH3CO), 2.66 (t,
J = 6.9 Hz, 2 H, CH2), 3.10 (t, J = 6.9 Hz, 2 H, CH2).
S-2-Cyanopropan-2-yl Thioacetate (2b)22
Yield: 326 mg (45.5%); brown oil; Rf = 0.62 (PE–EtOAc, 8:1).
1H NMR (400 MHz, CDCl3): δ = 1.42 (d, J = 7.2 Hz, 3 H, CH3CO),
2.31 (s, 3 H, CH3CO), 2.67 (dd, J = 6.4, 17.0 Hz, 1 H, CH2CN),
2.73 (dd, J = 5.2, 17.0 Hz, 1 H, CH2CN), 3.74 (ddq, J = 5.2, 6.4,
7.2 Hz, 1 H, CHS).
Synthesis of 1-Substituted Homotaurines 4b–g; General Proce-
dure
To a suspension of LiAlH4 (304 mg, 8 mmol) in anhydrous Et2O (20
mL) in an ice–water bath, was added a solution of S-cyanoethyl
thioacetate 2 (1 mmol) in anhydrous Et2O (10 mL) dropwise. After
the resulting solution was stirred in the ice-water bath for 12 h, the
excess LiAlH4 was quenched by adding H2O (5 mL). The mixture
was filtered through Celite and the filter cake was washed with
CH2Cl2 (3 × 25 mL) and EtOAc (3 × 25 mL). The combined liquid
phase was separated and the organic phase was dried over sodium
sulfate and evaporated in vacuo to obtain a malodorous yellow oil,
which was dissolved in anhydrous formic acid (4 mL). To the solu-
tion was added H2O2 (30% in H2O, 1 mL). The resulting solution
was stirred for 12 h to complete the reaction and decompose the ex-
cess H2O2. After removal of the solvents, a yellow odorless oil res-
idue was obtained that was crystallized from a mixture of EtOH and
Et2O to give the corresponding 1-substituted homotaurine as color-
less crystals.
S-2-Cyano-1-phenylethyl Thioacetate (2c)22
Yield: 426 mg (41.5%); yellow needle crystals; mp 76–77 °C;
Rf = 0.59 (PE–EtOAc, 8:1).
1H NMR (400 MHz, CDCl3): δ = 2.38 (s, 3 H, CH3CO), 3.02 (d,
J = 8 Hz, 2 H, CH2CN), 4.84 (t, J = 8 Hz, 1 H, CH), 7.31–7.40 (m,
5 H, ArH).
13C NMR (100 MHz, CDCl3): δ = 25.5, 30.4, 43.6, 116.9, 127.4,
128.7, 129.1, 137.5, 193.9.
S-1-(2-Chlorophenyl)-2-cyanoethyl Thioacetate (2d)
Yield: 819 mg (68.3%); yellowish crystals; mp 89−90 °C; Rf = 0.55
(PE–EtOAc, 8:1).
IR (KBr): 2248 (CN), 1697 (C=O) cm–1.
1H NMR (400 MHz, CDCl3): δ = 2.42 (s, 3 H, CH3CO), 3.08 (dd,
J = 6.0, 17.0 Hz, 1 H, CH2CN), 3.14 (dd, J = 7.2, 17.0 Hz, 1 H,
CH2CN), 5.34 (dd, J = 6.0, 7.2 Hz, 1 H, CHS), 7.31–7.49 (m, 4 H,
ArH).
13C NMR (100 MHz, CDCl3): δ = 24.7, 30.7, 41.1, 117.0, 127.9,
129.7, 130.2, 130.6, 133.5, 135.2, 193.7.
HRMS (ESI): m/z [M + H]+ calcd for C11H11ClNOS: 240.0250;
found: 240.0251.
1-Aminobutane-3-sulfonic Acid (4b)
Yield: 83 mg (54.0%); colorless crystals; mp 290–292 °C.
IR (KBr): 3448 (C=O), 1215 and 1169 (SO2) cm–1.
1H NMR (400 MHz, D2O): δ = 1.25 (d, J = 6.9 Hz, 3 H, CH3), 1.80
(dddd, J = 6.4, 7.3, 9.1, 14.0 Hz, 1 H, CH2), 2.12 (dddd, J = 6.2, 6.5,
9.3, 14.0 Hz, 1 H, CH2), 2.95 (ddq, J = 6.2, 7.3, 6.9 Hz, 1 H, CHS),
3.09 (ddd, J = 6.4, 9.3, 12.8 Hz, 1 H, CH2N), 3.10 (ddd, J = 6.5, 9.1,
12.8 Hz, 1 H, CH2N).
13C NMR (100 MHz, D2O/HCOOH): δ = 15.1, 29.1, 37.8, 53.5.
HRMS (ESI): m/z [M + H]+ calcd for C4H12NO3S: 154.0538; found:
S-1-(3-Chlorophenyl)-2-cyanoethyl Thioacetate (2e)
Yield: 809 mg (67.5%); yellowish crystals; mp 65–67 °C; Rf = 0.50
(PE–EtOAc, 8:1).
IR (KBr): 2251 (CN), 1696 (C=O) cm–1.
154.0535.
1H NMR (400 MHz, CDCl3): δ = 2.39 (s, 3 H, CH3CO), 3.00 (dd,
J = 7.3, 17.0 Hz, 1 H, CH2CN), 3.05 (dd, J = 6.4, 17.0 Hz, 1 H,
CH2CN), 4.80 (dd, J = 6.4, 7.3 Hz, 1 H, CHS), 7.24–7.34 (m, 4 H,
ArH).
13C NMR (100 MHz, CDCl3): δ = 25.3, 30.5, 43.1, 116.6, 125.7,
127.7, 129.0, 130.4, 135.0, 139.6, 193.4.
3-Amino-1-phenylpropane-1-sulfonic Acid (4c)
Yield: 135 mg (62.5%); colorless crystals; mp 313–314 °C.
IR (KBr): 3407 (OH, NH), 1238 and 1177 (SO2) cm–1.
1H NMR (400 MHz, D2O): δ = 2.35 (dddd, J = 5.2, 10.4, 10.6,
13.7 Hz, 1 H, CH2), 2.50 (dddd, J = 4.8, 6.3, 10.8, 13.7 Hz, 1 H,
CH2), 2.76 (ddd, J = 5.2, 10.8, 12.2 Hz, 1 H, CH2N), 2.93 (ddd,
J = 6.3, 10.6, 12.2 Hz, 1 H, CH2N), 4.03 (dd, J = 4.8, 10.4 Hz, 1 H,
CHS), 7.34 (s, 5 H, ArH).
HRMS (ESI): m/z [M + H]+ calcd for C11H11ClNOS: 240.0250;
found: 240.0253.
S-1-(4-Chlorophenyl)-2-cyanoethyl Thioacetate (2f)
Yield: 791 (66.0%); yellowish crystals; mp 82–83 °C; Rf = 0.55
(PE–EtOAc, 8:1).
IR (KBr): 2251 (CN), 1691 (C=O) cm–1.
13C NMR (100 MHz, D2O): δ = 28.3, 37.5, 63.4, 128.7, 128.9,
129.1, 134.4.
HRMS (ESI): m/z [M + H]+ calcd for C9H14NO3S: 216.0694; found:
216.0691.
Synthesis 2012, 44, 2225–2230
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of 1-Substituted Homotaurines
2229
3-Amino-1-(2-chlorophenyl)propane-1-sulfonic Acid (4d)
ice–water bath. Then CbzCl (0.4 mL, 0.51 g, 3 mmol) was added
dropwise slowly. After stirring overnight, the mixture was extracted
with CH2Cl2 (3 × 25 mL) and EtOAc (3 × 25 mL). The combined
organic phase was dried over anhydrous sodium sulfate and concen-
trated in vacuo. The residue was purified by flash column chroma-
tography on silica gel (PE–EtOAc, 3:1) to afford benzyl N-(3-
mercaptopropyl)carbamate (5) as colorless crystals [Rf = 0.13 (silica
gel plate; PE–EtOAc, 3:1)].
Yield: 188 mg (75.2%); colorless crystals; mp 332–333 °C.
IR (KBr): 3437 (OH, NH), 1224 and 1175 (SO2) cm–1.
1H NMR (400 MHz, D2O): δ = 2.35 (dddd, J = 5.1, 10.2, 11.0,
13.7 Hz, 1 H, CH2), 2.57 (dddd, J = 5.1, 5.1, 10.5, 13.7 Hz, 1 H,
CH2), 2.77 (ddd, J = 5.0, 10.5, 12.0 Hz, 1 H, CH2N), 3.02 (ddd,
J = 5.1, 11.0, 12.0 Hz, 1 H, CH2N), 4.74 (dd, J = 5.1, 10.2 Hz, 1 H,
CHS), 7.32 (d, J = 8.7 Hz, 2 H, ArH), 7.35 (d, J = 8.7 Hz, 2 H,
ArH).
13C NMR (100 MHz, D2O/HCOOH): δ = 29.4, 37.9, 59.1, 128.2,
129.2, 130.4, 130.5, 132.8, 135.5.
HRMS (ESI): m/z [M + H]+ calcd for C9H13ClNO3S: 250.0305;
The product was dissolved in anhydrous formic acid (4 mL). To the
solution was added H2O2 (30% in H2O, 1 mL) dropwise. After stir-
ring for 12 h, the solution was evaporated in vacuo to remove sol-
vents to give a yellow oil that was crystallized from a mixture of
EtOH and Et2O to afford pure homotaurine (4a).
found: 250.0313.
Benzyl N-(3-Mercaptopropyl)carbamate (5)23
Yield: 56 mg (25%); colorless crystals; mp 91–92 °C.
3-Amino-1-(3-chlorophenyl)propane-1-sulfonic Acid (4e)
Yield: 187 mg (74.8%); colorless crystals; mp 330–332 °C.
IR (KBr): 3421 (OH, NH), 1196 and 1037 (SO2) cm–1.
1H NMR (300 MHz, D2O): δ = 2.34 (dddd, J = 5.2, 10.4, 10.4,
13.7 Hz, 1 H, CH2), 2.52 (dddd, J = 4.8, 6.0, 10.4, 13.7 Hz, 1 H,
CH2), 2.79 (ddd, J = 5.2, 10.4, 12.8 Hz, 1 H, CH2N), 2.96 (ddd,
J = 6.0, 10.4, 12.8 Hz, 1 H, CH2N), 4.06 (dd, J = 4.8, 10.4 Hz, 1 H,
CHS), 7.28–7.42 (m, 4 H, ArH).
13C NMR (75 MHz, D2O/HCOOH): δ = 23.6, 32.7, 52.7, 122.8,
123.9, 124.2, 125.6, 129.2, 131.8.
1H NMR (400 MHz, CDCl3): δ = 1.93 (quint, J = 6.8 Hz, 2 H, CH2),
2.73 (t, J = 6.8 Hz, 2 H, CH2S), 3.32 (q, J = 6.8 Hz, 2 H, CH2N),
5.11 (s, 2 H, CH2), 7.33–7.36 (m, 5 H, ArH).
13C NMR (100 MHz, CDCl3): δ = 29.3, 35.8, 39.6, 66.6, 128.1,
128.4, 136.5, 156.4.
Homotaurine (4a)
Yield: 34 mg (24.3%; two steps, overall yield from 2a); colorless
crystals; mp 293–295 °C (Lit.24 294–295 °C).
1H NMR (400 MHz, D2O): δ = 2.04 (quint, J = 8.0 Hz, 2 H, CH2),
2.95 (t, J = 8.0 Hz, 2 H, CH2N), 3.09 (t, J = 8.0 Hz, 2 H, CH2SO3).
HRMS (ESI): m/z [M + Na]+ calcd for C9H12ClNNaO3S: 272.0124;
found: 272.0124.
3-Amino-1-(4-chlorophenyl)propane-1-sulfonic Acid (4f)
Yield: 214 mg (85.6%); colorless crystals; mp 334–336 °C.
Acknowledgment
The project was partly supported by the National Natural Science
Foundation of China (Nos. 20092013 and 20973013), and the Bei-
jing Natural Science Foundation (No. 2092022).
IR (KBr): 3438 (OH, NH), 1194 and 1170 (SO2) cm–1.
1H NMR (400 MHz, D2O): δ = 2.31 (dddd, J = 5.3, 10.4, 10.4,
13.7 Hz, 1 H, CH2), 2.53 (dddd, J = 4.9, 6.0, 10.4, 13.7 Hz, 1 H,
CH2), 2.79 (ddd, J = 5.3, 10.4, 12.7 Hz, 1 H, CH2N), 2.96 (ddd,
J = 6.0, 10.4, 12.7 Hz, 1 H, CH2N), 4.07 (dd, J = 4.9, 10.4 Hz, 1 H,
CHS), 7.32 (d, J = 8.7 Hz, 2 H, ArH), 7.35 (d, J = 8.7 Hz, 2 H,
ArH).
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis. SnufpgIorpi
o
nmitSartunpIoofprimntgirat
13C NMR (100 MHz, D2O/HCOOH): δ = 28.1, 37.3, 62.5, 127.3,
128.7, 130.4, 133.7.
References
HRMS (ESI): m/z [M + H]+ calcd for C9H13ClNO3S: 250.0305;
found: 250.0303.
(1) Fariello, R. G.; Golden, G. T.; Black, J. A. Epilepsia 1981,
22, 217.
(2) (a) Aisen, P. S.; Saumier, D.; Briand, R.; Laurin, J.; Gervais,
F.; Tremblay, D.; Garceau, A. Neurology 2006, 67, 1757.
(b) Aisen, P. S. CNS Drug 2005, 19, 989.
(3) Gervais, F.; Paquette, J.; Morissette, C.; Krzywkowski, P.;
Yu, M.; Azzi, M.; Lacombe, D.; Kong, X.; Aman, A.;
Laurin, J. Neurobiol. Aging 2007, 28, 537.
(4) Zornova, T.; Cano, M. J.; Polache, A.; Granero, L. CNS
Drug Rev. 2003, 9, 359.
(5) Wellendorph, P.; Høg, S.; Greenwood, J. R.; de Lichtenberg,
A.; Nielsen, B.; Frølund, B.; Brehm, L.; Clausen, R. P.;
Bräuner-Osborne, H. J. Pharmacol. Exp. Ther. 2005, 315,
346.
(6) Sen, N. P. Can. J. Chem. 1962, 40, 2189.
(7) Zhang, Q. C.; Ding, M.; Li, W. Z.; Cheng, Z. P.; Liang, L.
CN1442405, 2003; Chem. Abstr. 2003, 143, 172545.
(8) Ling, J. H.; Xu, W. CN101362709, 2008; Chem. Abstr.
2008, 150, 306210.
3-Amino-1-(4-methylphenyl)propane-1-sulfonic Acid (4g)
Yield: 189 mg (82.3%); colorless crystals; mp 350–352 °C.
IR (KBr): 3423 (OH, NH), 1208 and 1170 (SO2) cm–1.
1H NMR (400 MHz, D2O): δ = 2.16 (s, 3 H, CH3), 2.25 (dddd,
J = 5.2, 10.4, 10.4, 13.6 Hz, 1 H, CH2), 2.41 (dddd, J = 4.8, 6.0,
10.4, 13.6 Hz, 1 H, CH2), 2.66 (ddd, J = 5.2, 10.4, 12.4 Hz, 1 H,
CH2N), 2.84 (ddd, J = 6.0, 10.4, 12.4 Hz, 1 H, CH2N), 3.91 (dd,
J = 4.8, 10.4 Hz, 1 H, CHS),7.10 (d, J = 8.1 Hz, 2 H, ArH), 7.16 (d,
J = 8.1 Hz, 2 H, ArH).
13C NMR (100 MHz, D2O/HCOOH): δ = 20.8, 28.9, 38.1, 63.6,
129.6, 130.0, 131.9, 139.5.
HRMS (ESI): m/z [M + Na]+ calcd for C10H15NNaO3S: 252.0670;
found: 252.0678.
Synthesis of Homotaurine (4a)
To a suspension of LiAlH4 (304 mg, 8 mmol) in anhydrous Et2O (20
mL) in an ice–water bath, was added a solution of S-2-cyanoethyl
thioacetate (2a; 129 mg, 1 mmol) in anhydrous Et2O (10 mL) slowly
dropwise. The resulting mixture was stirred in the ice–water bath
for 12 h, then the excess LiAlH4 was quenched by adding H2O. The
resulting mixture was filtered through Celite and the filter cake was
washed with H2O (3 × 15 mL) and CH2Cl2 (3 × 10 mL). To the liq-
uid phase was added excess Et3N (3.3 mL, 2.31 g, 23 mmol) in the
(9) Smith, C. W.; Norton, D. G.; Ballard, S. A. J. Am. Chem.
Soc. 1953, 75, 748.
(10) Li, C. S.; Howson, W.; Dolle, R. E. Synthesis 1991, 244.
(11) (a) Abbenante, G.; Prager, R. H. Aust. J. Chem. 1990, 43,
213. (b) Abbenante, G.; Prager, R. H. Aust. J. Chem. 1992,
45, 1801. (c) Abbenante, G.; Prager, R. H. Aust. J. Chem.
1992, 45, 1791.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2012, 44, 2225–2230

2230
Y. Ma, J. Xu
PAPER
(17) (a) Xu, C. X.; Xu, J. X. Amino Acids 2011, 41, 195.
(b) Chen, N.; Xu, J. X. Tetrahedron 2012, 68, 2513.
(18) DiBiase, S. A.; Lipisko, B. A.; Haag, A.; Wolak, R. A.;
Gokel, G. W. J. Org. Chem. 1979, 44, 4640.
(19) (a) Huang, J. X.; Du, D.-M.; Xu, J. X. Synthesis 2006, 315.
(b) Yu, H.; Cao, S. L.; Zhang, L. L.; Liu, G.; Xu, J. X.
Synthesis 2009, 2205.
(20) Claisse, J. A. ZA6801861, 1969; Chem. Abstr. 1969, 72,
21696.
(21) Crouch Willie, W. US2630452, 1953; Chem. Abstr. 1953,
48, 7437.
(12) Bachand, B.; Atfani, M.; Samim, B.; Levesque, S.; Simard,
D.; Kong, X. Q. Tetrahedron Lett. 2007, 48, 8587.
(13) David, C.; Bischoff, L.; Meudal, H.; Mothe, A.; De Mota,
N.; DaNaschimento, S.; Llorens-Cores, C.; Fournie-Zaluski,
M.-C.; Roques, B. P. J. Med. Chem. 1999, 42, 5197.
(14) (a) Inguimbert, N.; Coric, P.; Dhotel, H.; Bonnard, E.;
Llorens-Cortes, C.; De Mota, N.; Fournie-Zaluski, M.-C.;
Roques, B. P. J. Peptide Res. 2005, 65, 175. (b) Hoegenauer,
K.; Hinterding, K.; Nussbaumer, P. Bioorg. Med. Chem.
Lett. 2010, 20, 1485.
(15) (a) Enders, D.; Berner, O. M.; Vignola, N.; Bats, J. W.
Chem. Commun. 2001, 2498. (b) Enders, D.; Harnying, W.
Synthesis 2004, 2910.
(22) Arpicco, S.; Dosio, F.; Brusa, P.; Crosasso, P.; Cattel, L.
Bioconjugate Chem. 1997, 8, 327.
(16) (a) Fulco, M. C.; Marinozzi, M.; Ergun, B. C.; Sardella, R.;
Natalini, B.; Pellicciari, R. Tetrahedron 2009, 65, 8756.
(b) Pellicciari, R.; Marinozzi, M.; Macchiarulo, A.; Fulco,
M. C.; Gafarova, J.; Serpi, M.; Giorgi, G.; Nielsen, S.;
Thomsen, C. J. Med. Chem. 2007, 50, 4630.
(23) Paulini, R.; Breuninger, D.; Von Deyn, W.; Bastiaans, H. M.
M.; Beyer, C.; Anspaugh, D. D.; Oloumi-Sadeghi, H. WO
2009156336, 2009; Chem. Abstr. 2009, 152, 97451.
(24) Feichtinger, H.; Ruhrchemie, A. G.; Oberhausen, H. Chem.
Ber. 1963, 96, 3068.
Synthesis 2012, 44, 2225–2230
© Georg Thieme Verlag Stuttgart · New York