An efficient synthesis of (R)-3-aminothiolane

Article abstract of DOI:10.3184/174751911X13237056070415

An efficient synthesis of (R)-3-aminothiolane is described based on a one-pot tandem hydroxyl activation-intramolecular cyclisation of Ts-protected-D-methioninol in the presence of methanesulfonyl chloride/pyridine. Removal of the tosyl group then gave (R)-3-aminothiolane in good yield. (R)-3-Aminothiolane derivatives are important building blocks for the synthesis of biologically active compounds.

Full text of DOI:10.3184/174751911X13237056070415

JOURNAL OF CHEMICAL RESEARCH 2011
RESEARCH PAPER 729
DECEMBER, 729–730
An efficient synthesis of (R)-3-aminothiolane
Xianhua Pan, Xiaohu Tao, Libo Ruan, Yiming Li, Wenhua Ou and Feng Liu*
School of Perfume and AromaTechnology, Shanghai Institute ofTechnology, 100 Haiquan Rd. Shanghai, 201418, P. R. China
An efficient synthesis of (R)-3-aminothiolane is described based on a one-pot tandem hydroxyl activation-intramo-
lecular cyclisation of Ts-protected-D-methioninol in the presence of methanesulfonyl chloride/pyridine. Removal of
the tosyl group then gave (R)-3-aminothiolane in good yield. (R)-3-Aminothiolane derivatives are important building
blocks for the synthesis of biologically active compounds.
Keywords: (R)-3-aminothiolane, intramolecular cyclisation, pharmaceutical synthesis
(R)-3-Aminothiolane and the related sulfone derivatives have
been used as important building blocks for the synthesis of
biologically active compounds including pharmaceuticals1–9.
Efforts have been made to develop a simple synthetic route
for the preparation of this compound. In 1984, Jones and
McElhinney synthesised racemic 3-aminothiolane from tetra-
hydrothiophen-3-one10. After zinc bromide catalysed conden-
sation of D-methioninol with benzonitrile and subsequent acid
cyclisation, basic hydrolysis, Ashton et al. produced optically
pure (R)-3-aminothiolane.3 However, given the relatively low
yield and strict reaction condition, there is still room for
improvement. We report here a novel synthetic route for the
preparation of (R)-3-aminothiolane.
In conclusion, a highly efficient and practical approach to
(R)-3-aminothiolane has been developed by a one-pot tandem
hydroxyl activation and base catalysed intramolecular cyclisa-
tion. The overall yield of the route is 70% for four steps.
Further application of this approach is currently underway in
our laboratory.
Experimental
Melting points were determined with a SGW X-4 micro melting point
1
apparatus. H NMR spectras were recorded using Avance 400 MHz
spectrometer. ESI-MS were recorded on Dionex MSOPlus mass spec-
trometer. High resolution mass spectra were recorded on Finnigan
MAT XL95 mass spectrometer. Optical rotations were obtained on a
Perkin-Elmer 241 Autopol polarimeter.
The synthesis was started from D-methionine 1 (Scheme 1),
which on NaBH4/I2 reduction in THF gave D-methioninol 2
in 91% yield11. The amino group was protected as its tosyl
derivative (TsCl, Et3N, CH2Cl2, room temperature) 3. The
alcohol 3 was treated with methanesulfonyl chloride in
pyridine at 0 °C and then at 70 °C. This activated the hydroxyl
group to promote an intramolecular cyclisation, probably via
the key intermediate 4 to produce (R)-4-methyl-N-(tetrahydro-
thiophen-3-yl)-benzenesulfonamide 5 in 89% yield. The tosyl
group was removed by stirring the compound 5 in the presence
of conc. HCl and AcOH under reflux. After vacuum distilla-
tion of the crude product, (R)-3-aminothiolane was isolated in
87% yield.
D-Methioninol (2): A mixture of D-methionine 1 (14.9 g, 100 mmol)
and sodium borohydride (2.28 g, 60 mmol) was stirred in tetrahydro-
furan (100 mL) at 0 °C. This solution was kept below 10 °C while
drops of iodine (13.97 g, 55 mmol) in tetrahydrofuran (10 mL) were
added. After the addition, the mixture was stirred at refluxing
temperature for 6 h. Then after cooling to ambient temperature, MeOH
was added to the reaction mixture which was stirred until the evolu-
tion of gas had ceased. The mixture was concentrated under reduced
pressure, the residue was dissolved in ethyl acetate (50 mL) and
washed with sat. NaCl. Then the organic layer was dried, filtered,
and concentrated under vacuum to give a pale yellow crude residue
(12.3 g, 91%), which was directly used without any further purifica-
1
tion. H NMR (400 MHz, CDCl3) δ 3.89 (br s, 2H), 3.62–3.55 (m,
1H), 3.42–3.29 (m, 1H), 2.98–2.92 (m, 1H), 2.89 (br s, 1H), 2.60–2.51
Scheme 1 Reagents and conditions: (a) NaBH4, I2, THF, 0 °C, 91%; (b) TsCl, Et3N, CH2Cl2, 99%; (c) MsCl, Pyridine, 0 °C then 70 °C,
89%; (4) conc.HCl, AcOH, reflux, 87%.
* Correspondent. E-mail: liufeng@sit.edu.cn

730 JOURNAL OF CHEMICAL RESEARCH 2011
(m, 2H), 2.14 (s, 3H), 1.94–1.85 (m, 1H), 1.81–1.77 (m, 1H). ESI-MS
m/z: 136.2 (M+H)+.
cooling to room temperature, the reaction mixture was concentrated in
a vacuum, H2O (150 mL) and ethyl acetate (150 mL) were added and
the aqueous layer treated with 2N NaOH until a pH of 10 was reached.
The aqueous phase was then extracted with EtOAc (100 mL × 3), the
combined organic layers were washed with sat. NaCl (150 mL), dried
over anhyd. Na2SO4, filtered, concentrated and distilled to give a pale
(R)-N-[1-Hydroxy-4-(methylthio)butan-2-yl]-4-methylbenzenesul-
fonamide (3): A magnetically stirred solution containing D-methi-
oninol 2 (3 g, 22.5 mmol) in dichloromethane (20 mL) and triethyl-
amine (4.54 g, 45 mmol) was treated with toluene-p-1-sulfonyl
chloride (5.13 g, 27 mmol) in dichloromethane (20 mL) dropwise
below 10 °C. The mixture was then stirred at room temperature for
3 h before 1N HCl (50 mL) was added. The layers were separated, the
organic layer was washed with sat. NaCl (50 mL), dried over anhy-
drous Na2SO4, filtered and concentrated to provide the crude product.
Recrystallisation from MeOH gave (R)-N-[1-hydroxy-4-(methylthio)-
butan-2-yl]-4-methylbenzenesulfonamide 3 (6.48 g) as a pale yellow
yellow oil 6 (7.67 g, 74.5 mmol, 87%), b.p. 45–48 °C (10 mm Hg).
[α]D20 = + 35.62 (c 1.0, acetone). [lit.12 of (S)-3-aminothiolane. [α]D
=
22
–37.77 (c 1.0, acetone) The optical rotation of (R)-3-aminothiolane
was not quoted in the literature and hence the value of the (s)-enantio-
mer is given here]. 1H NMR (400 MHz, CDCl3) δ 3.75–3.73 (m, 1 H),
3.05–2.98 (m, 3 H), 2.85–2.78(m, 1 H), 2.09–2.01 (m, 1 H), 1.99
(br s, 2H), 1.92–1.88 (m, 1 H). MS-ESI(m/z): 104.2 [M+H]+.
1
solid. [α]D20 = + 18.2 (c 1.0, MeOH); m.p. 105–108 °C. H NMR
(400 MHz, CDCl3) δ 7.86 (d, J = 8.2 Hz, 2H), 7.37 (d, J = 8.0 Hz, 2H),
5.01 (d, J = 8.1 Hz, 1H), 4.01 (d, J = 8.6Hz, 1H), 3.88 (br s, 1H),
3.55–3.37 (m, 2H), 2.61–2.48 (m, 2H), 2.45 (s, 3H), 2.12 (s, 3H),
1.91–1.75 (m, 2H). ESI-MS (m/z) 312.1 (M + Na)+. HRMS Calcd. for
C12H19NO3S2Na (M + Na)+ requires 312.0704, found 312.0697.
(R)-4-Methyl-N-(tetrahydrothiophen-3-yl)-benzenesulfonamide (5):
A solution of (R)-N-(1- hydroxy-4-(methylthio)butan-2-yl)-4-methyl-
benzenesulfonamide 3 (5.78 g, 20 mmol) in pyridine (50 mL) was
treated with methanesulfonyl chloride (2.74 g, 24 mmol) dropwise
while keeping the internal temperature between 0 and 5 °C. After the
addition was complete, stirring was continued for another 8 h at 70 °C.
The system was then cooled to room temperature and quenched with
1N HCl until a pH of 5 was reached. The precipitate was removed by
filtration, and the filtrate was extracted with ethyl acetate (30 mL × 3).
The combined organic layers were washed with saturated sodium
bicarbonate solution and brine, dried over MgSO4, and evaporated in
vacuum. Recrystallisation from EtOH-H2O (8:1) gave 5 (4.57 g, 17.8
mmol, 89%) as a bright yellow powder. [α]D20 = + 58.31 (c 1.0, CHCl3).
The authors are grateful to Zhejiang Hisoar Pharmaceutical
Co., Ltd for financial support.
Received 15 November 2011; accepted 1 December 2011
Paper 1100984 doi: 10.3184/174751911X13237056070415
Published online: 27 December 2011
References
1
2
3
U. Baettig, I. Bruce and S.J. Watson, WO 2010063802.
J. Neil and J. Simon, WO 2008148790.
T.D. Ashton, K.M. Aumann, S.P. Baker, C.H. Schiesser and P.J. Scammells,
Bioorg. Med. Chem. Lett., 2007, 17, 6779.
4
5
C. Hansch, A. Leo and C. Schmidt, J. Med. Chem., 1980, 23, 1095.
R.D. Elliott, J.R. Piper, C.R. Stringfellow and T.P. Johnston, J. Med. Chem.,
1972, 15, 595.
6
7
B. Unterhalt and M. Moellers, Archiv. Pharmazie, 1990, 317.
P.E. Bender, C.D. Perchonock, W.G. Groves, R.C.J. Smith, O.D. Stringer,
R. Sneed, J.H. Schlosser, L.S. Hostelley and B.Y.H. Hwang, J. Med. Chem.,
1983, 26, 1218.
1
M.p. 91–95 °C. H NMR (400 MHz, CDCl3) δ 7.80 (d, J = 8.2 Hz,
2H), 7.35 (d, J = 8.1 Hz, 2H), 4.99 (d, J = 8.2 Hz, 1H), 4.08 (dt,
J = 8.7, 4.4 Hz, 1H), 2.97-2.73 (m, 3H), 2.53 (dd, J = 11.2, 3.7 Hz,
1H), 2.46 (s, 3H), 2.02 (dt, J = 11.7, 4.9 Hz, 1H), 1.93 (ddd, J = 12.8,
8.1, 4.0 Hz, 1H). MS-ESI(m/z): 280.1 [M+Na]+. HRMS calcd for
C11H15NNaO2S2 (M + Na)+ requires 280.0442, found 280.0437.
(R)-3-Aminothiolane (6): A mixture of 5 (22 g, 85.6 mmol), conc.
HCl (150 mL) and AcOH (50 mL) was stirred at 100 °C for 8 h. After
8
9
F. Duane, P.C. Morrow, H.T. Johnson, W. David and L. Donald, J. Med.
Chem., 1973, 16, 736.
B.J. Broughton, P. Chaplen, W.A. Freeman, P.J. Warren, K.R.H. Wooldridge
and D.E. Wright, J. Chem. Soc., Perkin Trans1, 1975, 857.
10 J. Jones and R. McElhinney, Chem. Commun., 1984, 1501.
11 M.J. Fan, G.Q. Li and Y.M. Liang, Tetrahedron, 2006, 62, 6782.
12 E. Dehmlow and R. Westerheide, Synthesis, 1992, 947.

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