Practical, efficient synthesis of N-mono-substituted β-amino tertiary thiols via reductive ring-opening of 3-thiazolines

Article abstract of DOI:10.1007/s11164-012-0705-8

An efficient synthesis of N-mono-substituted β-amino tertiary thiols by reductive ring-opening of 3-thiazolines, obtained by use of the Asinger reaction, is described. This synthesis be regarded as a complementary approach for aminolytic ring-opening of t

Full text of DOI:10.1007/s11164-012-0705-8

Res Chem Intermed (2013) 39:767–770
DOI 10.1007/s11164-012-0705-8
Practical, efficient synthesis of N-mono-substituted
b-amino tertiary thiols via reductive ring-opening
of 3-thiazolines
•
Song Xin Zhang Dengfeng Su Jiangtao
•
Received: 29 May 2012 / Accepted: 25 June 2012 / Published online: 10 July 2012
Ó Springer Science+Business Media B.V. 2012
Abstract An efficient synthesis of N-mono-substituted b-amino tertiary thiols by
reductive ring-opening of 3-thiazolines, obtained by use of the Asinger reaction, is
described. This synthesis be regarded as a complementary approach for aminolytic
ring-opening of thiiranes.
Keywords Asinger reaction Á b-Amino tertiary thiols
A variety of methods are used to prepare b-amino ethanethiols. One of the most
intriguing routes involves addition of amines to thiiranes in benzene (Scheme 1).
The mechanism of the reaction involves SN2-type nucleophilic attack of the amine
on the thiirane. This reaction is usually suitable for addition of secondary amines to
thiiranes, and N,N-bis-substituted b-amino tertiary thiols are obtained in good yield
[1]. This procedure is not suitable for addition of primary amines to thiiranes to
prepare the corresponding N-mono-substituted b-amino tertiary thiols, however,
because of a competing reaction. Alternatives include addition of aromatic primary
amines to thiiranes or activation by a thiophilic metal cation, for example silver
nitrate [2].
We failed to obtain N-mono-substituted dimethylcysteamine by addition of
primary amines to thiiranes. Unexpected compounds were obtained during our
research on the Asinger reaction and further experiments proved the method enabled
efficient synthesis of N-mono-substituted b-amino tertiary thiols.
The Asinger reaction is a simple but powerful multi-component reaction which
has been used for synthesis of 3-thiazolines for more than three decades. A variety
S. Xin Á Z. Dengfeng Á S. Jiangtao (&)
Department of Pharmaceutical Engineering, Hubei University of Technology,
Wuhan 430068, Hubei, China
e-mail: jiangtsu@yahoo.com.cn
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S. Xin et al.
Scheme 1 Addition of amines
to thiiranes
R1
R1
R2
S
+
N
HN
HS
R'
R2
R
R'
N
X
NaSH, NH3, RCOR'
NaBH4,HCl
SH
OHC
R
HCl
N
S
H
Scheme 2 Synthetic route
of sulfur-containing heterocyclic imines with different substituents have been
synthesized by use of the modified Asinger reaction [3, 4]. More compounds have
obtained by further treatment, for example addition, reduction, or ring-opening. For
example, dimethylcysteamine hydrochloride has been obtained from 2-isopropyl-
5,5-dimethylthiazolidine by use of NaBH4 as reducing reagent and phenylhydrazine
as carbonyl reagent [5, 6]. In our work we found that when the structure of the
aldehyde or ketone was changed, a series of N-mono-substituted-2-amino-2,2-
dimethylethanethiols were readily obtained. This result was not reported, and we
found it could be used to obtain N-mono-substituted b-amino tertiary thiols.
The procedure is as follows. The 2-halo-2-methylpropanal, aqueous ammonia,
sodium hydrogen sulfide, and aldehyde or ketone are reacted in a one-pot procedure.
The 3-thiazolines were obtained as the main products in the reaction mixtures, in
accordance with the Asinger reaction; the intermediate could also be separated and
identified.1 Without separation and further purification, the mixture was acidified to
pH 2 with 2 M HCl, and NaBH4 was added to the mixture. When the aqueous layer
was concentrated the ring-opened product was formed (Scheme 2). Crystallization
from a mixture of methanol and ether furnished the product, the N-substituted
secondary amine 2,2-dimethylethanethiol hydrochloride salt. In a typical procedure,
used to produce compound 3, acetone was slowly added dropwise to a mixture of
ammonia (25 %) and sodium hydrogen sulfide monohydrate with vigorous stirring at
a temperature below 10 °C. A solution of 2-bromo-2-methylpropanal in dichloro-
methane was then added dropwise to the mixture over a period of 1.5 h. Evaporation
of the organic solvents under reduced furnished the 3-thiazoline main product as a
yellow oil. A suspension of the 3-thiazoline was reduced by NaBH4 in acidic solution
(pH 2), and the mixture was extracted twice with methyl tertiary butyl ether. The
colorless aqueous solution was evaporated to dryness and the residue was
recrystallized from a mixture of methanol and methyl tertiary butyl ether. The pure
product was obtained as a white powder.
According to the mechanism of the Asinger reaction, 2-mercapto-2-methylprop-
anal was the intermediate; this was cyclized without separation and purification.
1
1
Data for 3-thiazolines related to 3: H NMR (CDCl3): 1.56 (s, 6H, C (CH3)2), 1.67 (s, 6H, C(CH3)2),
6.90 (s, H, =CH); related to 5: 1H NMR (CDCl3): 1.57 (s, 6H, C(CH3)2), 5.50 (s, 1H, CH), 7.26 (s,
1H, =CH), 7.46–7.52 (m, 5H, Ph–H)
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Practical, efficient synthesis of N-mono-substituted b-amino tertiary thiols
769
CHO
e
H
N
N
HS
R
HS
R
HS
CHO
N
a
H
N
H
d
N
N
R
R
CHO
CHO
R
R
c
b
S
S
S
S
S
S
Scheme 3 Previous synthetic method: a S2Cl2 b NH2R c NaBH4 d LiAlH4 e Br2,NaSH
Table 1 The structures of the compoundsa
Compound Aldehyde
(ketone)
Product
Yield Data
(%)
1
2
HCHO
62
50
1H NMR (D2O): 1.36 (s, 3H),
1.39 (s, 6H), 3.06 (s, 2H);13C
NMR (D2O): 29.77, 40.84,
51.23, 68.82; MS: 120
SH
N
H
([M ? H]); M.p: 158–160 °C
(CH3)CHCHO
1H NMR (D2O): 0.92 (d, 6H),
0.97 (s, 6H), 1.96–1.98 (m,
1H), 2.83 (s, 2H), 2.94 (d, 2H),
3.15 (s, 2H);13C NMR (D2O):
19.18, 25.30, 29.15, 41.61,
55.45, 59.56; MS: 162
SH
N
H
([M ? H]); M.p: 204–206 °C
3
4
CH3COCH3
42
1H NMR (D2O): 1.30 (s, 6H),
1.43 (s, 6H), 3.07 (s, 2H),
3.32–3.35 (m, 1H); 13C NMR
(D2O): 17.95 (a), 29.18 (b),
41.66 (c), 52.01 (d), 56.64 (e);
MS: 148 ([M ? H]); M.p:
113–115 °C
1H NMR (D2O): 0.90 (t, 3H),
1.10 (d, 3H), 1.51 (s, 6H),
2.87–2.91 (m, 2H), 3.04 (s,
2H), 4.46–4.50 (m, 1H); 13C
NMR (D2O): 9.24, 14.82,
25.02, 29.05, 41.62, 51.82,
57.12; MS: 162 ([M ? H]);
M.p: 223–225 °C
a
e
d
c
SH
b
a
N
H
b
CH3CH2COCH3
42
SH
N
H
5
PhCHO
67
1H NMR (D2O): 1.31 (s, 6H),
3.03 (s, 2H), 4.19 (s, 2H),
7.40–7.43 (m, 5H). 13C NMR
(D2O): 29.09, 41.32, 51.57,
58.57, 128.83, 129.32, 130.22,
132.59; MS: 196 ([M ? H]);
M.p: 166–168 °C
SH
Ph
N
H
a
1H NMR, 13C NMR, MS, and M.p. data are listed. The atoms in compound 3 are labeled. Yields were
calculated relative to 2-bromo-2-methylpropanal
123

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S. Xin et al.
In our work, 3-thiazolines were effective intermediates for mercapto group
protection. The strongly acidic conditions also reduced polymerization during
reduction and ring-opening. The mercapto group in the title compounds could be
identified by use of an acidic solution of NaNO2; a green color were observed. In a
previous synthetic route starting from 2,2,5,5-tetramethyl-3,4-dithiahexane-1,6-dial
a secondary amine was formed, with the disulfide bond being broken by use of a
reducing agent, for example LiAlH4 [7]. Compared with this method (Scheme 3),
our method is much simpler.
In conclusion, there are several advantages to this procedure. First, the reaction
can be performed cleanly, thus eliminating the hazards and odor associated with
thiiranes. Second, the reaction can be regarded as a complementary approach for
aminolytic ring-opening of thiiranes. Finally, the yield is moderate and the purity of
the desired products is high, thus eliminating the need for chromatographic
purification (Table 1).
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