Expeditious and practical synthesis of various substituted taurines from amino alcohols

Article abstract of DOI:10.1055/s-2007-1000861

Various substituted taurines have been synthesized expeditiously and practically in satisfactory to good yields directly from amino alcohols using a two-step, one-pot procedure, in which the amino alcohols undergo sulfuric acid esterification and subsequent sodium sulfite substitution. Treatment of amino-substituted secondary alcohols using the same procedure gave 2-substituted or 1,2-disubstituted taurines, indicating the formation of aziridines as intermediates during the substitution step. This method is one of the most efficient routes for preparing structurally diverse 2-substituted and 1,2- and 2,2-disubstituted taurines. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-1000861

PAPER
197
Expeditious and Practical Synthesis of Various Substituted Taurines from
Amino Alcohols
Expeditious
a
nd Practica
e
l
Synthesis
i
of Substitute
Z
d Taurine
s
from
h
A
mino Alc
a
ohols ng,a Boyuan Wang,a Ning Chen,b Da-Ming Du,a Jiaxi Xu*a,b
a
Beijing National Laboratory for Molecular Sciences (BNLMS), Key Laboratory of Bioorganic Chemistry and Molecular Engineering
of the Ministry of Education, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, P. R. of China
b
College 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 3 October 2007; revised 26 October 2007
ing reaction of episulfides with nitrogen nucleophiles
(ammonia or amines) and subsequent reactions gave
1-substituted and 1,1- and 1,2-disubstituted taurines.13,14
Ring opening of aziridines with sulfur nucleophiles
Abstract: Various substituted taurines have been synthesized expe-
ditiously and practically in satisfactory to good yields directly from
amino alcohols using a two-step, one-pot procedure, in which the
amino alcohols undergo sulfuric acid esterification and subsequent
sodium sulfite substitution. Treatment of amino-substituted second- (sulfite, bisulfite, or thioacetic acid) and subsequent reac-
ary alcohols using the same procedure gave 2-substituted or 1,2-di-
tions led to 2-substituted and 1,2- and 2,2-disubstituted
taurines.15,16 Obviously, there has been much focus on
substituted taurines, indicating the formation of aziridines as
intermediates during the substitution step. This method is one of the
vicinal amino alcohol derivatives as starting materials for
most efficient routes for preparing structurally diverse 2-substituted
the synthesis of substituted taurines because the function-
and 1,2- and 2,2-disubstituted taurines.
al group alternation process from a hydroxy to a sulfonic
Key words: amino acids, aminoalkanesulfonic acids, amino alco-
acid group is quite feasible. However, this simple alterna-
hols, sulfates, taurines
tion process generally took multiple reaction steps to oc-
cur in all the reported methods.7–11 Herein, we present an
expeditious and practical method to synthesize 2-substi-
Taurine and substituted taurines, a class of aminoalkane-
tuted and 1,2- and 2,2-disubstituted taurines directly from
sulfonic acids, are important naturally occurring amino
amino alcohols in a one-pot reaction.
acids1 that have been found in many mammalian tissues,2
marine algae, fish, and shellfish.3 They are also significant
sulfur analogues of naturally occurring aminocarboxylic
acids and are involved in various physiological process-
es.4 In addition, their derivatives, such as sulfonopeptides,
have been widely used as enzyme inhibitors over the last
two decades because of their tetrahedral structural proper-
ties.1 As the attention on taurine and substituted taurines
increased in the fields of both biological and pharmaceu-
tical chemistry,5 we dedicated ourselves to developing an
efficient method to synthesize structurally diverse substi-
tuted taurines.
It is well-known that taurine has been manufactured in in-
dustry from aminoethanol via esterification with sulfuric
acid and subsequent displacement with sodium sulfite.17
Surprisingly, a similar method has not been used to pre-
pare substituted taurines. Therefore, we wished to estab-
lish a synthetic route from amino alcohols, parallel to the
industrial one, to give substituted taurines in a one-pot
procedure, and then to develop this method into a general
approach toward structurally diverse substituted taurines.
We selected (S)-phenylalaninol (1a) to prepare (S)-2-ami-
no-3-phenylpropanesulfonic acid (2a) as a model reaction
(Scheme 1 and Table 1, entry 1). First, water was distilled
off of a mixture of alcohol 1a and sulfuric acid to afford a
monosulfate.15,18 Then, the displacement of the sulfate
with a sulfite was conducted in a refluxed aqueous solu-
tion. After one day, about 44% of the sulfate was convert-
ed into the desired substituted taurine 2a; the conversion
was complete in three days. After extraction and crystalli-
zation from methanol, the pure substituted taurine 2a was
obtained in an overall yield of 67%. For a more conve-
nient procedure, after removal of water, the obtained sul-
fate can be used without purification; directly dissolving
the sulfate obtained from 1a in water, followed by the re-
Gold and co-workers reported the synthesis of 1-substitut-
ed taurines via sodium sulfite addition of nitroalkenes and
subsequent reduction.6 Aminoalkyl halides and methane-
sulfonates of b-amino alcohols have been converted into
2-substituted taurines via sulfite displacement.7–9 The
thioacetates of various b-amino alcohols are important in-
termediates and have been widely used to prepare 1- and
2-substituted and 1,2- and 2,2-disubstituted taurines via
performic acid oxidation.8,10,11 Cordero et. al synthesized
2-substituted, 1,2-disubstituted, and 1,2,2-trisubstituted
taurines by the aminosulfonation of olefins and subse-
quent hydrolysis.12 Recently, our group developed some
novel methods to synthesize substituted taurines from
three-membered heterocyclic compounds: The ring-open-
R1
H2N
R1
H2N
R2
R1
HO3S
1. H2SO4
R2
R3
1. H2SO4
R2
R3
SO3H
OH
NH2
2. Na2SO3
R3 = H
2. Na2SO3
SYNTHESIS 2008, No. 2, pp 0197–0200
x
x
.
x
x
.2
0
0
7
R1 and/or R2 = H
2
1
2
Advanced online publication: 18.12.2007
DOI: 10.1055/s-2007-1000861; Art ID: F18007SS
© Georg Thieme Verlag Stuttgart · New York
Scheme 1 Synthesis of substituted taurines from amino alcohols

198
W. Zhang et al.
PAPER
rines (Scheme 1 and Table 1). As a result, a variety of
amino-substituted primary alcohols, including optically
pure (S)-phenylglycinol (1b) and (S)-prolinol (1c) (entries
2 and 3, respectively) and linear and cyclic 2,2-disubsti-
tuted glycinols 1d–i (entries 4–9, respectively), were
successfully converted into their corresponding 2-sub-
stituted, 2,N-alkylene-substituted, and 2,2-disubstituted
taurines 2b–i in satisfactory to good yields. Notwithstand-
ing, (S)-phenylglycinol (1b) easily underwent elimination
of water to generate a-aminostyrene which further forms
acetophenone in the esterification step, which significant-
ly impaired the overall yield. However, the monosulfate
of 1b gave rise to 2-phenyl-substituted (S)-taurine 2b in
satisfactory yield (69% yield). The reactions of the opti-
cally pure amino alcohols, on the basis of their specific ro-
tations compared with reported ones,15,16 gave the
corresponding optically pure taurines without racemiza-
tion.
Table 1 Synthesis of Substituted Taurines
Entry Amino alcohol
Taurine
Overallyielda
(%)
H2N
H2N
SO3H
SO3H
OH
1
67
Bn
2a
Bn
1a
H2N
H2N
OH
29
2
69b
Ph
Ph
1b
2b
SO3H
OH
3
63
N
H
N
H
1c
2c
H2N
H2N
OH
SO3H
SO3H
4
74
75
66
2d
H2N
1d
H2N
Next, we attempted to prepare 1-substituted and 1,2-di-
substituted taurines from amino-substituted secondary al-
cohols 1-aminopropan-2-ol (1j), 1-aminohexan-2-ol (1k),
and trans-2-aminocyclohexanol (1l). However, the ana-
lytical data of the products from the reactions of the first
two compounds indicated that 2-aminopropanesulfonic
acid (2j)15 and 2-aminohexanesulfonic acid (2k)12 (entries
10 and 11, respectively) were obtained instead of the cor-
responding 1-substituted taurines. trans-2-Aminocyclo-
hexanol (1l) gave rise to trans-2-aminocyclo-
hexanesulfonic acid (2l)16 (entry 12).
SO3H
5
6
1e
2e
H2N
H2N
OH
SO3H
Ph
Ph
2f
1f
H2N
H2N
OH
OH
SO3H
SO3H
7
8
79
67
1g
H2N
2g
H2N
The above results suggested that a neighboring-group par-
ticipation mechanism was occurring in the sulfite dis-
placement reaction. First, amino-substituted secondary
alcohol sulfates 3 go through an acid–base reaction with
sodium sulfite, resulting in deprotonized aminoalkyl sul-
fates 4, which then produce aziridines 5 via an intramolec-
ular cyclization. Subsequent ring opening with a bisulfite,
which specifically takes place on the less-substituted car-
bon of the aziridine ring,19 converts the aziridines into 2-
substituted taurines, e.g. 2j and 2k from amino alcohols 1j
and 1k, respectively (Scheme 2), and trans-2-aminocy-
clohexanesulfonic acid (2l) from trans-2-aminocyclohex-
anol (1l) (Scheme 3). The reaction path is analogous to
that of the displacement of amino-substituted secondary
alcohol methanesulfates with sodium sulfite.15 All of the
reactions of amino-substituted primary alcohol sulfates
gave rise to 2-substituted and 2,2-disubstituted taurines.
Even in the reaction of (S)-phenylglycinol sulfate (3b), no
visible trace of the 1-phenyl-substituted taurine was de-
tected in the reaction mixture by NMR spectroscopic anal-
ysis. If (S)-phenylglycinol sulfate (3b) undergoes
intramolecular cyclization during the substitution, it
would give rise to (S)-2-phenylaziridine (5b) as an inter-
mediate. Although in ring-opening reactions, 2-phenyl-
aziridine is generally attacked preferentially at the
benzylic carbon atom of the aziridine by most nucleo-
1h
H2N
2h
H2N
OH
SO3H
SO3H
9
73
2i
H2N
1i
10
11
62
76
H2N
OH
2j
1j
nBu
H2N
SO3H
H2N
OH
nBu
1k
2k
2l
NH2
NH2
12
75
OH
SO3H
( )
( )
1l
a Total yield from the amino alcohol.
b Yield from the sulfate.
action with sodium sulfite afforded the desired taurine 2a
in the same overall yield.
After successfully preparing 2-benzyl-substituted (S)-tau- philes,19 both sulfite and bisulfite attack the less-substitut-
rine 2a, we were eager to test the generality of this method ed carbon atom of the ring in our current and previous
for synthesizing 2-substituted and 2,2-disubstituted tau- experiments.15 It is a pity that it cannot be used as a probe
Synthesis 2008, No. 2, 197–200 © Thieme Stuttgart · New York

PAPER
Expeditious and Practical Synthesis of Substituted Taurines from Amino Alcohols
199
to identify the reaction process of the substitution of ami- gave rise to the corresponding 2-substituted and 2,2-di-
no-substituted primary alcohol sulfates. Thus, it is diffi- substituted taurines. Amino-substituted secondary alco-
cult to determine whether amino-substituted primary hols also produced 2-substituted taurines using the same
alcohol sulfates undergo the cyclization and ring-opening procedure, indicating that the neighboring amino group
process. On the basis of these results, we assume that ami- participates in an intramolecular cyclization to form an
no-substituted primary alcohol sulfates undergo a dual aziridine during the sodium sulfite substitution step. With
pathway (direct substitution plus the cyclization and ring- the combined advantages of using commercially available
opening process) to generate 2-substituted and 2,2-disub- or easily prepared starting materials and simple glassware,
stituted taurines in the sodium sulfite substitution step.
having foolproof operations, and giving satisfactory
yields, the reported synthetic route is a highly efficient
and low-cost method with significant industrial potential.
It is applicable to the large-scale preparation of various
substituted taurines, including the optically pure com-
pounds.
H2SO4
Na2SO3
–
OSO3
OH
H3N+
H2N
H2N
∆
– NaHSO3
R3
R3
1
4
3
–
OSO3
NaHSO3
NH2
HN
HO3S
Melting points were measured on a Yanaco MP-500 melting point
apparatus and are uncorrected. Infrared spectra were determined on
a Nicolet AVATAR 330 FTIR spectrometer. 1H and 13C NMR spec-
tra were recorded on Varian Mercury 200 or Varian Mercury Plus
300 spectrometers in D2O or HCO2H, respectively. Mass spectra
were obtained on a Brucker ESQUIRE-LC ESI ion trap mass spec-
trometer. High-resolution mass spectrometry was carried out on an
Agilent LC/MSD TOF mass spectrometer. The amino alcohols used
were commercially available or were prepared via the reduction of
the corresponding amino acids,11,20 which were synthesized from
the corresponding ketones using the Strecker amino acid synthe-
sis,21 or by ammonia ring opening of epoxides.10c The analytical
data of all the known compounds synthesized are identical to those
reported in the literature.11,12,15,16
–
R3
– HSO4
R3
R3
2
5
j: R3 = Me
k: R3 = n-Bu
Scheme 2 Reaction path of amino-substituted secondary alcohols in
the synthesis of substituted taurines
+NH3
NH2
OH
NH2
H2SO4
Na2SO3
∆
– NaHSO3
–
–
n
n
OSO3
n
OSO3
( )-1
( )-3
( )-4
Substituted Taurines 2; General Procedure
NH2
NaHSO3
A cold mixture of 98% H2SO4 (1.00 g, 10 mmol) and H2O (1 mL)
was added to amino alcohol 1 (10 mmol) in H2O (1 mL) in an ice–
water bath at 0–5 °C. The mixture was heated to 120–130 °C and
then H2O was carefully distilled off in vacuo to afford sulfate 3 as a
solid or oily residue. The oily residue could be crystallized (EtOH)
to give colorless crystals or could be used directly.
NH
–
– HSO4
n
n
SO3H
( )-5
( )-2
Scheme 3 Reaction path of 2-aminocycloalkanols in the synthesis
of substituted taurines
To a solution of sulfate 3 (ca. 10 mmol) in H2O (20 mL) was added
Na2SO3 (2.52 g, 20 mmol). The resulting mixture was stirred under
reflux for 1–3 d. After removal of the solvent, the solid residue was
crystallized (MeOH or MeOH–Et2O) to afford substituted taurine 2
as colorless crystals.
According to the reaction path discussed above, a less ba-
sic environment might keep the sulfates of amino-substi-
tuted secondary alcohols
3
from undergoing
deprotonization, and thus avoid the formation of aziri-
dines 5 during the sulfite displacement step. Therefore, we
selected sodium bisulfite, instead of sodium sulfite, as the
nucleophile to react with sulfates 3, expecting the forma-
tion of 1-substituted taurines. Unfortunately, low conver-
sion of 3 was obtained when sodium bisulfite was added
in stoichiometric amounts because the sulfurous acid gen-
erated through the acid–base reaction decomposed. An in-
crease in the conversion was observed when the reaction
was conducted in the presence of excess sodium bisulfite;
however, the products were still 2-substituted taurines 2 in
all cases.
2-Amino-2-methylbutanesulfonic Acid (2e)
Colorless crystals.
Yield: 1.25 g (75%).
Mp 306–308 °C (dec).
IR (neat): 3145.8 (NH), 1205.6 (SO2), 1041.4 (SO2) cm–1.
1H NMR (200 MHz, D2O): d = 0.87 (t, J = 7.4 Hz, 3 H), 1.36 (s, 3
H), 1.59–1.87 (m, 2 H), 3.09 (d, J = 15.2 Hz, 1 H), 3.18 (d, J = 15.2
Hz, 1 H).
13C NMR (75.5 MHz, HCO2H): d = 6.7, 21.8, 31.4, 55.3, 57.2.
MS (ESI): m/z = 168 [M + H]+.
HRMS: m/z [M + H]+ calcd for C5H13NO3S: 168.0694; found:
168.0695.
In summary, various substituted taurines, including linear
2-substituted and 2,2-disubstituted taurines and cyclic
2,N-alkylene-substituted and 1,2- and 2,2-disubstituted
taurines, were synthesized expeditiously from the corre-
sponding amino alcohols via esterification with sulfuric
acid and subsequent substitution with sodium sulfite in a
one-pot procedure. Amino-substituted primary alcohols
2-Amino-2-methyl-4-phenylbutanesulfonic Acid (2f)
Colorless crystals.
Yield: 1.61 g (66%).
Mp 338 °C (dec).
Synthesis 2008, No. 2, 197–200 © Thieme Stuttgart · New York

200
W. Zhang et al.
PAPER
IR (neat): 3066.2 (NH), 1146.8 (SO2), 1039.0 (SO2) cm–1.
(3) Wickberg, B. Acta Chem. Scand. 1957, 11, 506.
(4) For a review, see: Huxtable, R. J. Physiol. Rev. 1992, 72,
101.
1H NMR (200 MHz, D2O): d = 1.46 (s, 3 H), 1.80–1.97 (m, 1 H),
2.03–2.18 (m, 1 H), 2.52–2.76 (m, 2 H), 3.18 (d, J = 15 Hz, 1 H),
3.31 (d, J = 15 Hz, 1 H), 7.15–7.32 (m, 5 H).
13C NMR (75.5 MHz, HCO2H): d = 22.6, 28.9, 40.0, 55.4, 56.8,
126.4, 128.2, 128.6, 140.3.
MS (ESI): m/z = 244 [M + H]+.
HRMS: m/z [M + H]+ calcd for C11H17NO3S: 244.1007; found:
(5) (a) Sinnecker, S.; Svensen, N.; Barr, E. W.; Ye, S.;
Bollinger, J. M. Jr.; Neese, F.; Krebs, C. J. Am. Chem. Soc.
2007, 129, 6168. (b) Guz, G.; Oz, E.; Lortlar, N.; Ulusu, N.
N.; Nurlu, N.; Demirogullari, B.; Omeroglu, S.; Sert, S.;
Karasu, C. Amino Acids 2007, 32, 405. (c) Giordano, C.;
Lucente, G.; Masi, A.; Paradisi, M. P.; Sansonea, A.;
Spisani, S. Bioorg. Med. Chem. 2006, 14, 2642.
(6) Gold, M. H.; Skebelsky, M.; Lang, G. J. Org. Chem. 1951,
16, 1500.
(7) (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.
244.1007.
(1-Aminocyclopentyl)methanesulfonic Acid (2g)
Colorless crystals.
Yield: 1.41 g (79%)
Mp 278–280 °C (dec).
(8) (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.
(9) (a) Braghiroli, D.; Mussati, E.; Di Bella, M.; Saladini, M.
Tetrahedron: Asymmetry 1996, 7, 831. (b) Braghiroli, D.;
Di Bella, M. Tetrahedron Lett. 1996, 37, 7319.
(10) (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.
Heteroat. Chem. 2005, 16, 466.
IR (neat): 3338.6 (NH), 1087.6 (SO2), 1047.3 (SO2) cm–1.
1H NMR (300 MHz, D2O): d = 1.67–1.75 (m, 4 H), 1.79–1.88 (m, 2
H), 1.92–2.02 (m, 2 H), 3.23 (s, 2 H).
13C NMR (75.5 MHz, HCO2H): d = 22.8, 36.5, 56.1, 63.7.
MS (ESI): m/z = 180 [M + H]+.
HRMS: m/z [M + H]+ calcd for C6H13NO3S: 180.0694; found:
180.0693.
(1-Aminocycloheptyl)methanesulfonic Acid (2i)
Colorless crystals.
Yield: 1.51 g (73%).
(11) Wang, B. Y.; Zhang, W.; Zhang, L. L.; Du, D.-M.; Liu, G.;
Xu, J. X. Eur. J. Org. Chem. 2008, DOI: 10.1002/
ejoc.200700791.
(12) Cordero, F. M.; Cacciarini, M.; Machetti, F.; De Sarlo, F.
Eur. J. Org. Chem. 2002, 1407.
Mp 330 °C (dec).
IR (neat): 3151.4 (NH), 1197.0 (SO2), 1050.8 (SO2) cm–1.
1H NMR (300 MHz, D2O): d = 1.32–1.60 (m, 8 H), 1.74–1.82 (m, 2
H), 1.92–1.99 (m, 2 H), 3.19 (s, 2 H).
13C NMR (75.5 MHz, HCO2H): d = 21.2, 29.0, 37.0, 56.4, 60.5.
MS (ESI): m/z = 208 [M + H]+.
HRMS: m/z [M + H]+ calcd for C8H17NO3S: 208.1007; found:
(13) Huang, J. X.; Wang, F.; Du, D.-M.; Xu, J. X. Synthesis 2005,
2122.
(14) Huang, J. X.; Du, D.-M.; Xu, J. X. Synthesis 2006, 315.
(15) Xu, J. X. Tetrahedron: Asymmetry 2002, 13, 1129.
(16) Hu, L. B.; Zhu, H.; Du, D.-M.; Xu, J. X. J. Org. Chem. 2007,
72, 4543.
208.1008.
(17) (a) Rumpf, P. Bull. Soc. Chim. Fr. 1955, 945. (b) Kanetani,
F.; Tanaka, T.; Nakano, S.; Negoro, K. Nippon Kagaku
Kaishi 1982, 824. (c) Senoo, A.; Enomoto, T.; Nagata, T.
Jpn. Kokai Tokkyo Koho 1995, 5; Chem. Abstr. 1995, 123,
285232.
(18) (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.
Acknowledgment
This work was supported in part by the National Natural Science
Foundation of China (Project Nos. 20272002, 20472005, and
20772005) and Peking University (President’s Undergraduate Re-
search Fellowship).
(19) Ma, L. G.; Xu, J. X. Prog. Chem. 2004, 16, 220.
(20) McKennon, M.; Meyers, A. I.; Drauz, K.; Schwarm, M. J.
Org. Chem. 1993, 58, 3568.
References
(1) For a 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.
(21) Steiger, R. E. Org. Synth. 1944, 24, 9.
Synthesis 2008, No. 2, 197–200 © Thieme Stuttgart · New York