Efficient synthesis of taurine and structurally diverse substituted taurines from aziridines

Article abstract of DOI:10.1021/jo070470c

(Chemical Equation Presented) Taurine and substituted taurines were synthesized efficiently from aziridines via ring-opening reaction with thioacetic acid, oxidation with performic acid, and hydrolysis in hydrochloric acid. The current method shows more benefit in purification and efficiency in the preparation of taurine and structurally diverse 2-substituted, 2,2-disubstituted, and 1,2-, 2,2-, and 2,N-alkylene taurines.

Full text of DOI:10.1021/jo070470c

oxidation with performic acid, and subsequent hydrogenolysis.6
2-Substituted taurines have been synthesized effectively via the
reduction of 2-nitroalkanesulfonic acids,7 from â-amino primary
alcohols via the sulfite displacement of their methane-
sulfonates8,9 or via the peroxy acid oxidation of their thio-
acetates,9 and via the sulfite ring-opening of aziridines.10 1,1-
Disubstituted taurines have been synthesized via the ammonia
ring-opening reaction of episulfides and subsequent oxidation
with performic acid.11 1,2-Disubstituted taurines have been
synthesized via the amino-sulfonation of olefins and subsequent
hydrolysis12 and the amine ring-opening reaction of episulfides
and subsequent oxidation with performic acid.6 Herein, we
present an expeditious and practical method for the synthesis
of 2-mono- and 1,2- and 2,2-disubstituted taurines from aziri-
dines.
Efficient Synthesis of Taurine and Structurally
Diverse Substituted Taurines from Aziridines
Libo Hu, Hui Zhu, Da-Ming Du, and Jiaxi Xu*
Beijing National Laboratory for Molecular Sciences (BNLMS),
Key Laboratory of Bioorganic Chemistry and Molecular
Engineering of Ministry of Education, College of Chemistry and
Molecular Engineering, Peking UniVersity, Beijing 100871,
People’s Republic of China
jxxu@pku.edu.cn
ReceiVed March 6, 2007
In our ongoing program aimed at the synthesis of structurally
diverse aminoalkanesulfonic acids, we have developed some
general methods to prepare 1-mono- and 1,1-disubstituted
taurines effectively from episulfides.6,11 We also found that
2-substituted taurines could be synthesized from aziridines via
the nucleophilic ring-opening reaction with sodium sulfite.10
However, purification is a tedious process to remove inorganic
salts in the sodium sulfite substitution method, especially for
large scaled preparations. We hoped to develop an efficient and
practical method to synthesize structurally diverse substituted
taurines, especially 2-mono- and 2,2-disubstituted taurines, from
various aziridines without the tedious purification. In order to
avoid inconvenience in purification in the final step, we sought
methods to remove inorganic salts prior to the final step or
without any inorganic salts in the whole preparartion. Peroxy
acid oxidation of vicinal aminoalkyl isothiocyanates and vicinal
amino primary mercaptans or their thioacetates should be an
alternative method to prepare 2-mono- and 2,2-disubstituted
taurines without the tedious purification.
Taurine and substituted taurines were synthesized efficiently
from aziridines via ring-opening reaction with thioacetic acid,
oxidation with performic acid, and hydrolysis in hydrochloric
acid. The current method shows more benefit in purification
and efficiency in the preparation of taurine and structurally
diverse 2-substituted, 2,2-disubstituted, and 1,2-, 2,2-, and
2,N-alkylene taurines.
We first selected (S)-2-benzylaziridine (1a) to prepare vicinal
aminoalkyl isothiocyanate via the nucleophilic ring-opening
reaction with potassium isothiocyanate. Unfortunately, no
reaction occurs even under the catalysis of BF3·Et2O (Table 1,
entries 1 and 2). We then attempted to prepare vicinal amino
primary mercaptan from (S)-2-benzylaziridine (1a) via the
nucleophilic ring-opening reaction with potassium thioacetate
and subsequent in situ basic hydrolysis of thioacetates during
workup (Scheme 1). Because amino mercaptans could be
partially oxidized to disulfides in air, the ring-opening products
were extracted from aqueous solution and oxidized directly to
the substituted taurines. However, potassium thioacetate under-
Aminoalkanesulfonic acids, especially taurine and substituted
taurines, are not only very important sulfur analogues of
naturally occurring aminocarboxylic acids, but also one class
of important naturally occurring amino acids,1 which have been
found in many mammalian tissues2 and in marine algae, fish,
and shellfish.3 They are involved in various physiological
processes.4 On the other hand, their derivatives, such as
sulfonopeptides, have been widely used as enzyme inhibitors
during the last two decades because of their tetrahedrally
structural properties.1 Aminoalkanesulfonic acids have played
more important roles in biological chemistry and medicinal
chemistry recently. Thus, an efficient synthetic method of
structurally diverse aminoalkanesulfonic acids is still desired.
1-Substituted taurines have been synthesized from â-amino
secondary alcohols via the peroxy acid oxidation of their
thioacetates5 and the amine ring-opening reaction of episulfides,
(6) Huang, J. X.; Wang, F.; Du, D. M.; Xu, J. X. Synthesis, 2005,
2122.
(7) Gold, M. H.; Skebelsky, M.; Lang, G. J. Org. Chem. 1951, 16, 1500.
(8) (a) Higashiura, H.; Morino, H.; Matsuura, H.; Toyomaki, Y.; Ienaga,
K. J. Chem. Soc., Perkin. Trans. 1 1989, 1479. (b) Braghiroli, D.; Di Bella,
M. Tetrahedron: Asymmetry 1996, 7, 2145. (c) Braghiroli, D.; Di Bella,
M. Tetrahedron Lett. 1996, 37, 7319.
* Author to whom correspondence should be addressed. Tel: +86-10-6275-
1497, Fax: +86-10-6275-1708.
(1) For a recent review, see: Xu, J. X. Chin. J. Org. Chem. 2003, 23, 1.
(2) For a review, see: Timothy, C.; Birdsall, N. D. Alt. Med. ReV. 1998,
3, 128.
(9) (a) Higashiura, K.; Ienaga, K. J. Org. Chem. 1992, 57, 764. (b) Moree,
W. J.; van der Marel, G. A.; Liskamp, R. M. J. Tetrahedron Lett. 1992, 33,
6389. (c) Moree, W. J.; van der Marel, G. A.; Liskamp, R. M. J. J. Org.
Chem. 1995, 60, 5157. (d) Monnee, M. C. F.; Marijne, M. F.; Brouwer, A.
J.; Liskamp, R. M. J. Tetrahedron Lett. 2000, 41, 7991.
(10) Xu, J. X. Tetrahedron: Asymmetry 2002, 13, 1129.
(11) Huang, J. X.; Du, D.-M.; Xu, J. X. Synthesis 2006, 315.
(12) Cordero, F. M.; Cacciarini, M.; Machetti, F.; De Sarlo, F. Eur. J.
Org. Chem. 2002, 1407.
(3) Wickberg, B. Acta Chem. Scand. 1957, 11, 506.
(4) For a review, see: Huxtable, R. J. Physiol. ReV. 1992, 72, 101.
(5) (a) Brouwer, A. J.; Monnee, M. C. F.; Liskamp, R. M. J. Synthesis
2000, 1579. (b) Lowik, D. W. P. M.; Liskamp, R. M. J. Eur. J. Org. Chem.
2000, 1219. (c) Xu, J. X.; Xu, S. Synthesis 2004, 276. (d) Xu, J. X.; Xu,
S.; Zhang, Q. H. Heteratom Chem. 2005, 16, 466.
10.1021/jo070470c CCC: $37.00 © 2007 American Chemical Society
Published on Web 05/12/2007
J. Org. Chem. 2007, 72, 4543-4546
4543

TABLE 1. Optimizing Reaction Conditions for Synthesis of 2-Substituted Taurinesa
reaction conditions in the
ring-openingb
entry
aziridine
solvent
nucleophile
overall yield, %c
1
2
3
4
5
6
7
8
9
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1b
MeCN
MeCN, BF3·Et2O
MeCN
EtOH/H2O, 95:5 (v/v)
THF
THF/H2O, 95:5 (v/v)
THF/H2O, 95:5 (v/v)
THF
THF
benzene
THF
benzene
KSCN
KSCN
AcSK
AcSK
AcSK
AcSK
AcSK
AcSH
AcSH
AcSH
AcSH
AcSH
RT to reflux for 12 h
reflux for 12 h
reflux for 12 h
reflux for 12 h
reflux for 12 h
reflux for 12 h
RT for 1d
reflux for 12 h
RT for 2d
RT for 2d
-
-
-
d
Tracee
40
40
55
61
87f
91
10
11
12
reflux for 12 h
RT for 2d
64
90
a Reaction was carried out in 10 mmol scale of aziridine with 20 mmol of nucleophile. b Ring-opening product was oxidized with performic acid for 1d
and hydrolyzed in hydrochloric acid overnight. c Overall yield from the aziridine in each of cases. d Adduct of thioacetate to acetonitrile [AcSC()NH)Me]
was obtained as a major product in the ring-opening reaction. e Ethanol ring-opening product 1-ethoxy-3-phenyl-2-propylamine was obtained as a major
product in the ring-opening reaction. f No obvious improvement in the yield (from 87% to 88%) was observed when the oxidation time was extended to 2
and 3 d.
SCHEME 1. Synthesis of Substituted Taurines
all of these intermediates could be converted to the final desired
products in these treatments. We first conducted the acidic ring-
opening reaction of (S)-2-benzylaziridine (1a) and (S)-2-
isobutylaziridine (1b) in THF and subsequent oxidation with
performic acid and hydrolysis in hydrochloric acid. The desired
substituted taurines 4a and 4b were obtained in yields of 61
and 64%, respectively (Table 1, entries 8 and 11). However,
some viscous byproducts were generated from the acidic ring-
opening reaction of THF and the subsequent oxidation. The yield
was improved by decreasing the temperature in the ring-opening
reaction (Table 1, entry 9). The yields were further improved
when the ring-opening reaction was conducted in benzene
(Table 1, entries 10 and 12). Although this procedure includes
multistep reactions, intermediates in the procedure can be used
directly without any purification. Furthermore, extraction and
chromatographic separation were avoided so that the workup
in the whole procedure is very simple. The current method
shows more benefit than the nucleophilic ring-opening reaction
with sodium sulfite in the purification (removal of inorganic
salts).10 To determine efficiency in each of steps, we also
separated, purified, and characterized the intermediates in the
synthesis of substituted taurines 4a and 4b. The results indicate
that almost quantitative yields were obtained in the oxidation
and hydrolysis steps for each of the reactions, and the ring-
opening steps are the yield-determining steps (see Experimental
Section).
went an addition with the solvent acetonitrile as previously
reported13 when the reaction was conducted in polar acetonitrile
(Table 1, entry 3). The ethanol ring-opening product was
obtained as a major product when the reaction was carried out
in a mixture of ethanol and water as solvents (Table 1, entry
4). The desired product 4a was obtained in about 40% yields
in a mixture of THF and water or in THF as solvents (Table 1,
entries 5 and 6). The yield was improved to 55% when the
reaction temperature was decreased to RT (Table 1, entry 7)
(Scheme 1).
Because of difficult extraction of amino mercaptans from
aqueous solution and low yields of the desired products, finally,
we attempted to prepare vicinal N-acetylamino primary mer-
captans from aziridines via the nucleophilic ring-opening
reaction with thioacetic acid. In this way, we could avoid the
use of any inorganic salt in the whole synthetic procedure. It is
well-known that the direct ring-opening product vicinal amino
mercaptan thioacetates favor an acyl shift to generate N-
acetylaminomercaptans,14 which could be partially oxidized to
disulfide derivatives in air. To avoid separation and identification
of these intermediates, the ring-opened products could be
oxidized directly and hydrolyzed to substituted taurines because
After successful preparation of (S)-2-benzyltaurine (4a) and
(S)-2-isobutyltaurine (4b), we hoped to develop this procedure
as a general, efficient, and practical method to synthesize
structurally diverse substituted taurines. A series of aziridines,
including 2-substituted, 2,2-disubstituted, bridged, and spiro
cyclic aziridines, were prepared from vicinal amino alcohols
via the Wenker reaction.10,15 Following this same procedure,
we synthesized taurine, 2-substituted, 2,2-disubstituted, and 1,2-,
2,2-, and 2,N-alkylene taurines in satisfactory to good total yields
(Scheme 2 and Table 2).
For aziridines with poor solubility in benzene, the ring-
opening reaction was conducted in polar solvent THF or a
mixture of benzene and diethyl ether.
The results indicate that the acidic ring-opening reaction of
aziridines with thioacetic acid shows the same regioselectivity
(13) Gauthier, J. Y.; Lebel, H. Phosphorus Sulfur Silicon Relat. Elem.
1994, 95, 96, 325.
(14) (a) Kuhn, R.; Quadbeck, G. Chem. Ber. 1951, 84, 844. (b) Hsu,
J.-L.; Fang, J.-M. J. Org. Chem. 2001, 66, 8573.
(15) (a) Wenker, H. J. Am. Chem. Soc. 1935, 57, 2328. (b) Leighton, P.
A.; Perkins, W. A.; Renquist, M. I. J. Am. Chem. Soc. 1947, 69, 1540.
4544 J. Org. Chem., Vol. 72, No. 12, 2007

SCHEME 2. Synthesis of Taurine and Substituted Taurines
from Aziridines and Thioacetic Acid
they could be prepared easily via the Wenker method from
commercially available vicinal amino alcohols. The current
method is a highly efficient and convenient way for both
laboratory and industrial large-scale preparation of highly pure
and structurally diverse taurines, including optically pure
substituted taurines.
Experimental Section
General Procedure for the Ring-Opening Reaction of Aziri-
dines with Thiolacetic Acid. To a solution of aziridine (10 mmol)
in 50 mL of benzene [or THF for aziridines 1c, 1d, 1g, 1h, 1:1
(v/v) mixture of benzene and diethyl ether for the aziridine 1i] was
added thioacetic acid (1.522 g, 20 mmol). The resulting mixture
was stirred at room temperature (about 10 °C) for 36 to 48 h. After
removal of the solvent, oily or crystalline product N-acetylamino
mercaptan was obtained and was used directly in the next step.
Further purification on silica gel column chromatography with
chloroform and methanol (1:1, v/v) as an eluent afforded pure
N-acetylamino mercaptan.
TABLE 2. Synthesis of Taurine and Substituted Taurines
(S)-N-(1-Mercaptomethyl-2-phenylethyl)acetamide (2a). Col-
orless crystals, yield 90%, mp 166-169 °C, lit.17 mp 70-71 °C;
[R]D20 ) -45.9 (c 1.13, CHCl3), Lit.17 [R]D20 ) -18.8 (c 1, CHCl3);
1
IR V (cm-1): 1708 (CdO); H NMR (200 MHz, CDCl3) δ: 1.94
(s, 3H), 2.75-2.85 (m, 1H), 2.89-3.01 (m, 2H), 2.98 (s, br, 1H),
3.55-3.65 (m, 1H), 4.36-4.46 (m, 1H), 6.52 (d, J ) 8.0 Hz, 1H),
7.17-7.33 (m, 5H); 13C NMR (50.0 MHz, CDCl3) δ: 23.2, 38.6,
42.8, 50.3, 126.7, 128.6, 129.2, 137.2, 170.4.
(S)-N-(1-Mercaptomethyl-3-methylbutyl)acetamide (2b). Yel-
low oil, yield 87%, [R]D20 ) -41.7 (c 1.30, CDCl3); IR V (cm-1):
1
1645.6 (CdO); H NMR (200 MHz, CDCl3) δ: 0.92 (d, J ) 6.4
Hz, 3H), 0.93 (d, J ) 6.6 Hz, 3H), 1.32-1.40 (m, 2H), 1.55-1.68
(m, 1H), 2.00 (s, 3H), 3.46-3.55 (m, 1H), 3.62-3.70 (m, 1H),
3.74 (s, br, 1H), 4.00-4.11 (m, 1H), 6.29 (d, J ) 8.2 Hz, 1H). 13
C
NMR (50.0 MHz, CDCl3) δ: 22.1, 22.9, 23.2, 24.8, 40.0, 49.8,
65.5, 171.2. MS (ESI) m/z: 176 [M + H]+; HRMS (ESI) Cacld.
+
for C8H17NOS [M + H] 176.1104; Found 176.1108.
General Procedure for the Oxidation of N-Acetylamino
Mercaptans with Performic Acid. H2O2 (30%) (15 mL) was
dissolved in 88% formic acid (35 mL) at 0 °C, and the mixture
was stirred at 0 °C for 1 h to afford performic acid. The
N-acetylamino mercaptan in 88% formic acid (5 mL) was carefully
added dropwise to the performic acid solution. The resulting solution
was allowed to warm to room temperature and stirred for 1 d. After
removal of the solvent, viscous oily or crystalline N-acetylami-
noalkanesulfonic acid was obtained and was used directly in the
next step. Further purification via crystallization from methanol or
washing with diethyl ether afforded pure N-acetylaminoalkane-
sulfonic acid.
a Total yield from aziridine. Ring-opening reaction was conducted in
benzene. b Ring-opening reaction was conducted in THF. c Ring-opening
reaction was conducted in benzene and diethyl ether (1:1, v/v).
(S)-2-Acetylamino-3-phenylpropane-1-sulfonic Acid (3a). Col-
in that the ring-opening occurs specifically at the less substituted
carbon atom in unsymmetric aziridines, following the rule
summarized previously by us.16 For bridged bicyclic aziridines
1g and 1h, trans-2-aminocycloalkanesulfonic acids 4g and 4h
were obtained due to the SN2 substitution in the acidic ring-
opening reaction. For optically pure aziridines, optically pure
taurines were obtained without racemerization through the whole
synthetic process on the basis of specific rotation comparison.
In summary, taurine and structurally diverse taurines, includ-
ing linear 2-substituted and 2,2-disubstituted taurines and cyclic
1,2-, 2,2-, and 2,N-alkylene taurines, were synthesized expedi-
tiously from various aziridines via the nucleophilic ring-opening
reaction with thioacetic acid, subsequent oxidation with per-
formic acid, and deacetylation in refluxing hydrochloric acid.
Although most of the aziridines are not commercially available,
20
orless crystals, yield 99%, mp 195-8 °C; [R]D ) +9.0 (c 1.34,
CH3OH); IR V (cm-1): 1679 (CdO), 1127 (SO2), 1023 (SO2); 1H
NMR (200 MHz, D2O) δ: 1.65 (s, 3H), 2.50-2.62 (m, 1H), 2.80-
2.98 (m, 3H), 4.20-4.36 (m, 1H), 7.09-7.13 (m, 5H). 13C NMR
(50.0 MHz, HCO2H) δ: 19.2, 38.9, 51.5, 52.5, 127.2, 128.6, 129.2,
135.4, 176.6; MS (ESI) m/z: 256 [M - H]-; Anal. Calcd for C11H15-
NO4S‚2HCO2H‚2/3H2O (361.37): C, 43.21; H, 5.67; N, 3.88.
Found: C, 43.02; H, 5.25; N, 4.30.
(S)-2-Acetylamino-4-methylpentane-1-sulfonic Acid (3b). Col-
orless oil, yield 99%, [R]D20 ) -18.2 (c 1.10, CH3OH); IR V (cm-1):
1650.2 (CdO), 1171.3 (SO2), 1037.8 (SO2); 1H NMR (200 MHz,
D2O) δ: 0.70 (d, J ) 6.8 Hz, 3H), 0.77 (d, J ) 6.8 Hz, 3H), 0.98-
1.25 (m, 2H), 1.30-1.50 (m, 1H), 1.82 (s, 3H), 3.25-3.53 (m,
1H), 3.70-3.80 (m, 1H), 3.89-4.09 (m, 1H); 13C NMR (75.5 MHz,
HCO2H) δ: 21.1, 21.4, 22.2, 24.3, 39.0, 47.7, 65.8, 175.0; MS
(17) Han, M. S.; Oh, D. J.; Kim, D. H. Bioorg. Med. Chem. Lett. 2004,
14, 701.
(16) Ma, L. G.; Xu, J. X. Chem. Prog. 2004, 16, 220.
J. Org. Chem, Vol. 72, No. 12, 2007 4545

(ESI) m/z: 222 [M - H]-; HRMS (ESI) Calcd for C8H17NO4S [M
(1-Amino-cyclohexyl)methanesulfonic Acid (4f). Colorless
crystals, mp 331 °C (dec); IR V (cm-1): 1187.5 (SO2), 1040.6 (SO2);
1H NMR (200 MHz, D2O) δ: 1.21-1.56 (m, 8H), 1.85-1.96 (m,
2H), 3.22 (s, 2H); 13C NMR (75.5 MHz, HCO2H) δ: 20.7, 23.7,
33.7, 53.6, 56.9; MS (ESI) m/z: 194 (M + H)+; Anal. Calcd for
C7H15NO3S (193.26): C, 43.50; H, 7.82; N, 7.25. Found: C, 43.19;
H, 7.96; N, 7.02.
-
- H] 222.0806; Found 222.0802.
General Procedure for the Deacetylation of N-Acetylami-
noalkanesulfonic Acids in Hydrochloric Acid. Crude N-acety-
laminoalkanesulfonic acid was dissolved in 10% hydrochloric acid
(50 mL), and the solution was refluxed overnight. After removal
of the solvent, the crude product was recrystallized from a mixture
of methanol and chloroform, or methanol and water, to afford the
pure product aminoalkanesulfonic acid.
Acknowledgment. This project was supported by National
Natural Science Foundation of China (Grant Nos. 20272002
and 20472005).
Taurines 4a and 4b were obtained in the yield of 99% from
purified N-acetyltaurines 3a and 3b.
(S)-2-Amino-4-methylpentane-1-sulfonic Acid (4b). Colorless
20
crystals, mp 343-6 °C (dec); [R]D ) +27.3 (c 1.03, HCO2H);
Supporting Information Available: Experimental details, ad-
1
IR V (cm-1): 1184.7 (SO2), 1039.9 (SO2); H NMR (200 MHz,
ditional analytical data, copies of 13C NMR spectra of known
D2O) δ: 0.81 (d, J ) 5.7 Hz, 3H), 0.82 (d, J ) 4.8 Hz, 3H), 1.45-
1.63 (m, 3H), 2.98 (dd, J ) 9.6, 15.0 Hz, 1H), 3.15 (dd, J ) 3.0,
15.0 Hz, 1H), 3.60 (dd, J ) 3.0, 9.6 Hz, 1H). 13C NMR (75.5 MHz,
HCO2H) δ: 20.8, 21.5, 23.8, 40.8, 48.1, 51.6; MS (ESI) m/z: 182
(M + H)+, 204 (M + Na)+; Anal. Calcd for C6H15NO3S‚1/2HCl
(199.48): C, 36.13; H, 7.83; N, 7.02. Found: C, 35.99; H, 7.56;
N, 7.00.
1
substituted taurines, and copies of H and 13C NMR spectra of
N-acetylamino mercaptans 2a and 2b, N-acetylaminoalkanesulfonic
acids 3a and 3b, taurine, and unknown substituted taurines. This
material is available free of charge via the Internet at http://pubs.
acs.org
JO070470C
4546 J. Org. Chem., Vol. 72, No. 12, 2007