Efficient synthesis of primary 2-aminothiols from 2-aminoalcohols and methyldithioacetate

Article abstract of DOI:10.1016/j.tetlet.2008.09.014

Various primary 2-aminothiols have been prepared by a general and efficient method, in three steps, starting from commercially available 2-aminoalcohols and methyldithioacetate as a convenient source of sulfur.

Full text of DOI:10.1016/j.tetlet.2008.09.014

Tetrahedron Letters 49 (2008) 6553–6555
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Efficient synthesis of primary 2-aminothiols from 2-aminoalcohols
and methyldithioacetate
*
*
Guillaume Mercey, Delphine Brégeon, Annie-Claude Gaumont, Jocelyne Levillain , Mihaela Gulea
Laboratoire de Chimie Moléculaire et Thio-Organique, ENSICAEN, Université de Caen Basse-Normandie, CNRS, 6 Boulevard du Maréchal Juin, 14050 Caen, France
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 29 July 2008
Revised 1 September 2008
Accepted 3 September 2008
Available online 7 September 2008
Various primary 2-aminothiols have been prepared by a general and efficient method, in three steps,
starting from commercially available 2-aminoalcohols and methyldithioacetate as a convenient source
of sulfur.
Ó 2008 Elsevier Ltd. All rights reserved.
Keywords:
Aminothiol
Aminoalcohol
Dithioester
Thioamide
Thiazoline
2-Aminothiols constitute an important class of compounds for
medicinal and synthetic chemistry. Some of them (e.g., cysteine,
homocysteine, cysteamine, and penicillamine) are naturally occur-
ring and are involved in important biological processes. They are
constituents of complex biomolecules such as peptides and coen-
zyme A. Their biological and physicochemical specificities are
especially due to the properties of the thiol function (acidity, metal
affinity). They found various applications as enzyme inhibitors,1
radioprotective agents,2 as intermediates for the synthesis of a
number of biologically active compounds,3 or in peptide synthesis
(when attached through their thiol group on resins4). More re-
cently, 2-aminothiols and their thioethers derivatives have been
used as ligands for organometallic catalysis.5
ganic synthetic chemistry,10 the opposite process, which consists
of preparing a primary aminothiol via a thiazoline, was used
only in a few cases11 but, to our knowledge, was never described
and developed as a general method for such purpose. The meth-
od uses simple starting materials: commercially available 2-ami-
noalcohols and
handle.
a dithioester which are easy to access and
Various enantiopure 2-amino alcohols 1a–h (see Table 1) have
been transformed into the corresponding aminothiols using meth-
yldithioacetate (MeCS2Me) as the sulfur source.12 Thiazoline pre-
cursors 3 were prepared using a two-step sequence that was
previously reported by some of us.13 Thus, in a first step, thioacy-
lation of the aminoalcohols using methyldithioacetate led to thio-
Most of the methods reported for the preparation of 2-amino-
thiols start from 2-aminoalcohols. The main drawback of these
methods is probably that a multi-step sequence is generally re-
quired, including addition of a sulfur nucleophile and protection/
deprotection of amino and thiol groups.6 A few other methods
are limited by less accessible starting materials such as thiiranes,7
aziridines,8 or 2-thiazolidinones.9 Thus, developing a convenient
method for the synthesis of a wide range of 2-aminothiols remains
a challenge for organic chemists.
amides 2, which were transformed in
a second step by
intramolecular cyclization via mesylate into thiazolines
a
3
(Scheme 1). Yields obtained after each step are given in Table 1.
The obtained thiazolines were hydrolyzed in acidic medium in a
refluxing 5 M aqueous solution of HCl. After 12–72 h, the desired
aminothiols 4a,c–f were obtained and isolated as their hydrochlo-
ride derivatives in good yields (Scheme 1, Table 1). The hydrolysis
of thiazoline 3b was particularly slow; the reaction was stopped
after 192 h at 70% conversion, which explains the lower yield
(58% obtained for aminothiol 4b).
This Letter describes an efficient and general method to pre-
pare primary 2-aminothiols via thiazolines. Although the use of
2-aminothiols as precursors of thiazolines is well known in or-
In the case of thiazoline 3g derived from L-serine methyl ester,
the acidic hydrolysis also transformed the ester group into the car-
boxylic acid derivative, leading to product 4g0 (Scheme 1, Table 1).
This product, which represents the
compared with a commercial sample,14 and the two compounds
were found to be identical (same 1H NMR spectra and [
]D). In
L-cysteine hydrochloride, was
* Corresponding authors.
E-mail addresses: jocelyne.levillain@ensicaen.fr (J. Levillain), mihaela.gulea@
ensicaen.fr (M. Gulea).
a
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.09.014

6554
G. Mercey et al. / Tetrahedron Letters 49 (2008) 6553–6555
Table 1
Transformation of 2-aminoalcohols 1 into 2-aminothiols 4 (amino alcohol?thioamide?thiazoline?aminothiol)
Amino alcohol
R
Configuration
Thioamide 2 (yield %)
Thiazoline 3 (yield %)
Aminothiol 4 (yield %)
2-Aminobutanol 1a
Et
i-Pr
i-Bu
t-Bu
Ph
Bn
R
S
S
S
R
S
S
R
2a (89)
2b (78)
2c (93)
2d (43)
2e (89)
2f (65)
2g (90)
2h (97)
3a (52)
3b (63)
3c (86)
3d (71)
3e (58)
3f (60)
3g (71)
3h (73)
4a (84)
L
L
L
-Valinol 1b
-Leucinol 1c
-tert-Leucinol 1d
4b (58)a
4c (97)a
4d (82)a
4e (94)a
4f (81)a
4g0 (94)a,b
4h0 (87)c
2-Phenylglycinol 1e
L-Phenylalaninol 1f
L-Serine methyl ester 1g
L-Methioninol 1h
CO2Me
CH2CH2SMe
a
Isolated as the hydrochloride salt.
The carboxylic acid derivative 4g0 was obtained under acidic hydrolysis conditions from 3g (transformation of R = CO2Me into CO2H).
The N-acetyl aminothiol 4h0 was obtained from 3h instead of the N-deprotected derivative.
b
c
MsCl, NEt3,
MeCS2Me
HO
HO
CH2Cl2,
S
S
HClaq 5M
58-97%
NEt3, THF, rt
30 min, rt
Me
4a-f, 4g', 4h'
H2N
R
R
N
H
Me
Yields %
58-97%
SH
N
3a-h
R
(see Table 1)
1a-h
2a-h
SH
Ph
SH
SH
SH
Ph
SH
HCl.H2N
HCl.H2N
HCl.H2N
HCl.H2N
HCl.H2N
HCl.H2N
HCl.H2N
4b
4d
4f
4e
4a
4c
SH
SH
O
CO2H
Me
N
H
SMe
4g'
4h'
Scheme 1.
the case of thiazoline 3h derived from L-methioninol, the acidic
MeCS2Me
HO
HO
hydrolysis at reflux led to a complex mixture of products. Perform-
ing the reaction at room temperature for 16 h afforded N-acetyl
aminothiol 4h0, which was the expected product resulting from
the thiazoline ring-opening without deprotection of the amino
group (Scheme 1, Table 1).
S
NEt3, THF, rt
N
H
2i
Me
64%
H2N
OH
OH
1i
MsCl, NEt3,
CH2Cl2,
30 min, rt
With achiral 2-amino-1,3-propanediol 1i, thioamide 2i was eas-
ily prepared by thioacylation of 1i with methyldithioacetate
(Scheme 2). When the intramolecular cyclization was performed
via a mesylate, a mixture of products was obtained, from which
only the O-mesylated thiazoline 3i0 was isolated in low yield
(30%) and characterized. By using Mitsunobu reaction conditions,
the racemic thiazoline 3i bearing unprotected hydroxy group was
obtained in excellent yield (92%). Acidic hydrolysis at reflux of this
thiazoline led to the expected aminothiol hydrochloride rac-4i in
good yield (84%). To access this aminothiol in enantiopure form,
the carboxylic ester function of thiazoline 3g was first reduced
with NaBH4 into alcohol to give the corresponding enantiopure
thiazoline (R)-3i, which was then hydrolyzed under acidic condi-
tions to afford the desired aminothiol 4i as its R-enantiomer.
Finally, the methodology was tested on one example of 1,2-
S
N
2i
+
Me
other products
3'i (30%)
OMs
HClaq 5M,
reflux
PPh3, DEAD
HS
S
THF, 0 °C-rt, 24 h
2i
Me
HCl.H2N
rac-4i
84%
92%
N
OH
OH
rac-3i
NaBH4, MeOH,
HClaq 5M,
reflux
HS
S
S
0 °C to rt, 2 h
Me
Me
HCl.H2N
(R)-4i
82%
81%
N
N
CO2Me
disubstituted aminoalcohol, the D-norephedrine. The thioacylation
OH
3g
(R)-3i
OH
led to thioamide 2j in 69% yield. The intramolecular cyclization via
a mesylate led to the expected thiazoline 3j (with inversion of con-
figuration at the carbon bearing the hydroxy group) as the major
product, together with its diastereomer 3j0, which results from a
partial epimerisation at the benzylic position under the conditions
used (Scheme 3). The two diastereomers were separated by chro-
matography on silica gel to give pure 3j (65%) and 3j0 (8%).
In conclusion, we have succeeded in preparing various primary
2-aminothiols, most of them in an enantiopure form, by a general
and efficient method, starting from commercially available
Scheme 2.
2-aminoalcohols and methyldithioacetate as a convenient source
of sulfur.15 Compared to other methods starting from an amino-
alcohol, our method reduces the reaction sequence to three steps,
by combining the introduction of the sulfur atom and the protec-
tion of the amino group in the thioacylation step, the deprotection
of both amino and thiol functions through thiazoline formation

G. Mercey et al. / Tetrahedron Letters 49 (2008) 6553–6555
6555
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Ph
S
Me
Me
N
MeCS2Me
NEt3,
THF/H2O, rt
MsCl, NEt3,
CH2Cl2,
30 min, rt
Me
3j' (8%)
HO
Ph
HO
Ph
S
+
69%
Ph
HCl.H2N
Me
Me
N
H
S
Me
1j: D-Norephedrine
(1 , 2
N
2j
Me
S
R)
3j (65%)
HClaq 5M,
reflux
HS
HCl.H2N
Ph
Me
3j
45%
4j
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Scheme 3.
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and the acidic hydrolysis of the thiazoline. The extension of the
method to access secondary aminothiols is currently under inves-
tigation in our laboratory.
10. See preparation of thiazolines from 2-aminothiols in two reviews and the
references cited therein: (a) Fustero, S.; Salavert, E.; Navarro, A.; Mojarrad, F.;
Fuentes, A. S.. In Targets in Heterocyclic Systems; Attanasi, O. A., Spinelli, D., Eds.;
Italian Society of Chemistry, 2001; Vol. 5, pp 235–270; (b) Gaumont, A.-C.;
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Acknowledgments
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12. Methyldithioacetate was prepared according to: Westmijze, H.; Kleijn, H.;
Meijer, J.; Vermeer, P. Synthesis 1979, 432–434.
We gratefully acknowledge the ‘Ministère de la Recherche
et des Nouvelles Technologies’ (Grant for G.M.), the ‘PUNCHOrga’
(Pôle Universitaire Normand de Chimie Organique), the ‘Région
Basse-Normandie’, the CNRS (Centre National de la Recherche
Scientifique), and the European Union (FEDER funding) for the
financial support.
13. (a) Leflemme, N.; Marchand, P.; Gulea, M.; Masson, S. Synthesis 2000, 1143–
1147; (b) Abrunhosa, I.; Gulea, M.; Levillain, J.; Masson, S. Tetrahedron:
Asymmetry 2001, 12, 2851–2859.
Supplementary data
14. The sample was purchased from Sigma–Aldrich.
15. Typical procedure to transform 2-aminoalcohol
aminothiol 4, in three steps:
1 into the corresponding 2-
Supplementary data (spectral data of compounds 2a–j, 3a–j,
4a–g, 4i, and 4j) associated with this article can be found, in the
online version, at doi:10.1016/j.tetlet.2008.09.014.
(i) Thioacylation: A mixture of 2-aminoalcohol (47 mmol), methyldithioacetate
(5 g, 47 mmol, 1 equiv), and triethylamine (6.6 mL, 47 mmol, 1 equiv) in THF
(7 mL) was stirred at room temperature for 15 h. Then, the mixture was
concentrated under reduced pressure. The crude product was purified by flash
chromatography on silica gel to afford thioamide 2.
References and notes
(ii) Cyclization: Under nitrogen atmosphere, to a stirred mixture of thioamide
2
(15 mmol) and mesylchloride (1.7 mL, 22.5 mmol, 1.5 equiv) in
1. See, for examples: (a) Ocain, T. D.; Rich, D. H. Biochem. Biophys. 1987,
145, 1038–1042; (b) Chan, W. W.-C. Biochem. Biophys. 1983, 116, 297–
302; (c) Bienvenue, D. L.; Bennett, B.; Holz, R. C. J. Inorg. Biochem. 2000, 78,
43–54.
2. See, for examples: (a) Schumacher, C. P. K.; Robbe, Y.; Sicart, M.-T.; Subra, G.;
Delard, R.; Dubois, J.-B. Il Farmaco 1998, 53, 118–124; (b) Handrick, G. R.;
Atkinson, E. R.; Granchelli, F. E.; Bruni, R. J. J. Med. Chem. 1965, 8, 763–766; (c)
Chiotellis, E.; Stassinopoulou, C. I.; Varvarigou, A.; Vavouraki, H. J. Med. Chem.
1982, 1370–1374.
3. See, for examples: (a) deSolms, S. J.; Guliani, E. A.; Graham, S. L.; Koblan, K. S.;
Mosser, N. E.; Kohl, S. D.; Oliff, A. I.; Pompliano, D. L.; Rands, E.; Scholz, T. H.;
Wiscount, C. M.; Gibbs, J. B.; Smith, R. L. J. Med. Chem. 1998, 41, 2651–2656; (b)
Park, J. D.; Kim, D. H. J. Med. Chem. 2002, 45, 911–918; (c) Ocain, T. D.; Rich, D.
dichloromethane (25 mL) was added dropwise triethylamine (6.3 mL,
45 mmol, 3 equiv) at 0 °C. Stirring was maintained at room temperature for
30 min, then Et2O (15 mL) was added to precipitate the triethyl ammonium
salt. After filtration, solvents were evaporated and the residual oil was purified
by flash chromatography on silica gel affording thiazoline 3.
(iii) Hydrolysis: Thiazoline
3 (2 mmol) was placed in a degazed aqueous
solution of HCl 5 N (10 mL), under nitrogen atmosphere. The mixture was
heated under reflux for 24–192 h. After cooling to room temperature, the
aqueous layer was washed with ether (3 ꢀ 5 mL), then with dichloromethane
(3 ꢀ 5 mL). After removal of the water under vacuum, the residue was
triturated with acetone, filtered, and dried to give the corresponding
aminothiol hydrochloride 4.