Efficient synthesis of β-hydroxy sulfides by microwave-promoted ring opening in (+)-3-carene trans-epoxide with sodium thiolates

Article abstract of DOI:10.1016/j.mencom.2011.07.006

Reaction of (+)-3-carene trans-epoxide with sodium thiolates in methanolic solution in a microwave oven at 140 °C for 35-40 min affords corresponding (1S,3S,4S,6R)-4-sulfanylcaran-3-ols in 75-95% yields.

Full text of DOI:10.1016/j.mencom.2011.07.006

Mendeleev
Communications
Mendeleev Commun., 2011, 21, 192–193
Efficient synthesis of b-hydroxy sulfides by microwave-promoted
ring opening in (+)-3-carene trans-epoxide with sodium thiolates
Alexander M. Agafontsev,a Nikolay B. Gorshkova and Alexey V. Tkachev*a,b
a N. N.Vorozhtsov Novosibirsk Institute of Organic Chemistry, Siberian Branch of the Russian Academy of
Sciences, 630090 Novosibirsk, Russian Federation. Fax: +7 383 330 9752; e-mail: atkachev@nioch.nsc.ru
b Department of Natural Sciences, Novosibirsk State University, 630090 Novosibirsk, Russian Federation
DOI: 10.1016/j.mencom.2011.07.006
Reaction of (+)-3-carene trans-epoxide with sodium thiolates in methanolic solution in a microwave oven at 140°C for 35–40 min
affords corresponding (1S,3S,4S,6R)-4-sulfanylcaran-3-ols in 75–95% yields.
b-Hydroxyalkyl sulfides are very important organic compounds
which can be used as starting material in syntheses of cyclic
sulfides,1 allylic alcohols,2 benzoxathiepin derivatives,3 benzo-
thiazepines,4 keto thiones,5 leucotrienes,6 etc. Moreover, b-hydroxy-
alkyl sulfides are utilized as S,O-ligands in asymmetric synthesis.7
The main strategy for their preparation includes ring opening of
epoxides with S-nucleophiles using heterogeneous or homo-
geneous catalysts like liquid proton acids or Lewis acids,8 solid
Lewis acids,9 and bases10 in usual organic solvents,8–10 in water,11
in perfluorinated alcohols,12 or without solvents.13 Syntheses of
chiral b-hydroxyalkyl sulfides are carried out either from chiral
epoxides or chiral thiols,6,7 or from achiral precursors in the
presence of chiral auxiliary.14 Microwave irradiation is known
to promote many organic reactions, including synthesis of the
simplest b-hydroxyalkyl sulfides.9,11
O
H
1
10
2
5
RSNa / MeOH,
microwave
irradiation,
140 °C,
1
OH
8
9
3
11
6
4
7
OH
S
12
35–40 min
2, 83%
OH
11
13
12
14
15
S
3, 95%
Many naturally occurring terpenes like 3-carene, limonene,
and a- and b-pinenes are considered as primary source of chirality
in enantioselective syntheses and can be easily transformed to
the corresponding labile epoxides. 3-Carene-derived trans-epoxide
1 is important and popular model for adopting different synthetic
schemes to terpene series. Epoxide 1 was studied in reactions
with thiophenol in ethanol,15 with isothiuronium salts,16,17 and
thiourea,18 with thiols in ethanol19 and in DMSO.20 The corre-
sponding b-hydroxycaranyl sulfides were the main products in
all the cases, although the procedures were sophisticated and
prolonged (5–50 h) and provided moderate yields of the products
even when 10-fold excess of a thiol was used.20
OH
17
13
15
11
S
12
14
16
4, 91%
OH HO
S
S
11
5, 75%
Here we report a plain and practical means for the preparation
of b-hydroxycaranyl sulfides by treatment of trans-epoxide 1
with sodium thiolates under microwave irradiation.
OH
HO
11
The reaction of trans-epoxide 1 with sodium thiolates was
carried out in a Single-Mode Microwave reactor Discover™ System
S-Class (CEM corp., USA) using a special 15 ml sealed reaction
vessel. According to TLC the period of 35–40 min is sufficient
for the reaction completion providing the desired sulfides 2–6 in
very good preparative yields (Scheme 1).†
High resolution mass spectrometry of all the compounds syn-
thesized gave the correct molecular formula, whereas IR spectra
detected formation of the hydroxyl group. Analysis of high-field
2D 1H–1H and 13C–1H-correlation NMR spectra of the products
2,‡ 3,§ 4,§ 5, ¶ and 6†† showed that in all the compounds the carane
carbon frame has the same set of heteroatomic functions attached
and the same configurations of the asymmetric carbons C(3) and
C(4). Configuration of the benzylthio derivative 3 had been estab-
lished earlier.17 In our hands, the benzylthio derivative prepared
via benzylthiuronium salt17 is identical (IR, NMR) to that syn-
S
S
12
6, 81%
Scheme 1 (The numbering scheme is given for NMR interpretation only).
†
Typical synthetic procedure. Sodium (5–10 mmol) was dissolved in a
solution of thiol (1 equiv.) in MeOH (5–10 ml). The resulting mixture was
kept at room temperature for 30 min and then added to trans-epoxide 1
(1 equiv.). The reaction mixture was subjected to MW-irradiation at 140°C
for 35–40 min. The solvent was distilled off, the residue was treated with
ButOMe (20 ml) and water (20 ml). The organic layer was separated, the
aqueous phase was extracted with ButOMe (2×20 ml). The combined
organic extract was dried (Na2SO4) and concentrated in vacuo to leave the
crude product (90–99%) as viscous yellowish oil which was then purified
by column chromatography (SiO2, hexane–EtOAc) to afford the target com-
pound 2 (83% yield), 3 (95%), 4 (91%), 5 (75%), or 6 (81%).
© 2011 Mendeleev Communications. All rights reserved.
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Mendeleev Commun., 2011, 21, 192–193
This work was supported in part by the Russian Foundation
SR
OH
SR
for Basic Research (grant no. 10-03-00346-a). The authors are
grateful to the ATIC of the Novosibirsk State University for per-
mission to use the equipment for microwave-assisted syntheses.
SR
Scheme 2
Online Supplementary Materials
Supplementary data associated with this article can be found
in the online version at doi:10.1016/j.mencom.2011.07.006.
thesized by the microwave-assisted method newly developed.
So, all the derivatives 2–6 (Scheme 1) have the same 1S,4S,3S,6R-
configuration, the derivatives of 1,2-dithioethane (5) and 1,3-di-
thiopropane (6) being C2-symmetrical.
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The reaction of trans-epoxide 1 with sodium thiolates proceeds
as typical SN2 epoxide ring cleavage in boat-like conformation
of six-membered carbocycle with nucleophilic attack at the less
substituted carbon C(4) with inversion of configuration of the
carbon C(4) and retention of configuration at C(3) (Scheme 2).
Due to trans-disposition of the two heteroatomic functions at the
carbons C(3) and C(4), the six-membered carbocycle in products
2–6 exists as more or less distorted boat conformation (see vicinal
1
couplings in H NMR spectra), degree of the distortion being
dependent on the nature of the sulfur-containing substituent at
the carbon C(4).
‡
(1S,3S,4S,6R)-4-(2-Hydroxyethylthio)caran-3-ol 2: yield 83%, colour-
29
less oil, [a] +77 (c 0.90, CHCl3). IR (c 2%, CHCl3, nmax/cm–1): 3594,
589
3582. 1H NMR (300 MHz, CDCl3) d: 0.64 (ddd, 1H, H-1, J 9.0, 8.0 and
7.1 Hz), 0.73 (ddd, 1H, H-6, J 9.0, 7.8 and 7.6 Hz), 0.91 (ddd, 1H, Hpro-R-5,
J 14.5, 11.2 and 7.6 Hz), 0.93 (s, 3H, H-8 or H-9), 0.98 (s, 3H, H-8 or
H-9), 1.07 (dd, 1H, Hpro-R-2, J 15.3 and 7.1 Hz), 1.11 (s, 3H, H-10), 1.83
(dd, 1H, Hpro-S-2, J 15.3 and 8.0 Hz), 2.05 (ddd, 1H, Hpro-S-5, J 14.5, 7.8
and 4.7 Hz), 2.66 (ddd, 1H, H-4, J 11.2 and 4.7 Hz). 13C NMR (75 MHz,
CDCl3) d: 15.1 (C8, 1JCH 3×124 Hz, 2,3JCH 3×4 Hz), 17.8 (C1 or C6), 18.4
(C7), 22.9 (C1 or C6), 26.4 (C5), 26.8 (C10, 2,3JCH 3, 3 and 2 Hz), 28.1 (C9),
33.2 (C2, 1JCH 2×125 Hz), 35.3 (C11, 1JCH 2×138 Hz, 2,3JCH 2×3 Hz), 53.6
(C4, 1JCH 142 Hz), 61.0 (C12, 1JCH 2×144 Hz, 2,3JCH 2×3 Hz). MS, m/z (%):
230.1338 (11, [M]+, calc. for [C12H22O2S]+: 230.1335), 187 (81), 185 (45),
152 (30), 137 (30), 134 (23), 126 (32), 119 (40), 109 (54), 107 (25), 93 (48),
83 (68), 71 (32), 67 (42), 55 (26).
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Catal., 2009, 351, 920.
§
For characteristics of compounds 3 and 4, see Online Supplementary
Materials.
¶
1,2-Bis[(1S,3S,4S,6R)-3-hydroxycaran-4-ylthio]ethane 5: yield 75%,
23
colourless oil, [a] +90 (c 1.59, CHCl3). IR (c 2% in CHCl3, nmax/cm–1):
589
3579, 1134. 1H NMR (300 MHz, CDCl3) d: 0.65–0.80 (m, 4H, H-1 and
H-6), 0.96 (s, 6H, H-8 or H-9), 1.02 (s, 6H, H-8 or H-9), 1.14 (ddd, 2H,
Hpro-R-5, J 14.7, 9.9 and 5.7 Hz), 1.22 (s, 6H, H-10), 1.30 (dd, 2H, Hpro-R-2,
J 15.2 and 6.6 Hz), 1.95 (dd, 2H, Hpro-S-2, J 15.2 and 7.9 Hz), 2.21 (ddd,
2H, Hpro-S-5, J 14.6, 8.0 and 5.8 Hz), 2.45 (br.s, 2H, OH), 2.64 (m, 4H,
H-11), 2.70 (dd, 2H, H-4, J 9.5 and 5.5 Hz). 13C NMR (75 MHz, CDCl3)
d: 15.73 (C8), 17.93 (C5), 18.39 (C6), 22.2 (C1), 25.97 (C7), 28.37 (C9),
28.71 (C10), 33.46 (C2), 34.20 (C11), 51.93 (C4), 71.54 (C3). MS, m/z (%):
398.2312 (1, [M]+, calc. for [C22H38O2S2]+: 398.2308), 245 (17), 213 (97),
195 (21), 185 (31), 167 (19), 153 (29), 135 (100), 127 (15), 119 (21), 109
(32), 93 (90), 81 (17), 67 (17).
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†† 1,3-Bis[(1S,3S,4S,6R)-3-hydroxycaran-4-ylthio]propane 6: yield 81%,
29
colourless oil, [a] +99 (c 1.37, CHCl3). IR (c 2% in CHCl3, nmax/cm–1):
589
3586. 1H NMR (300 MHz, CDCl3) d: 0.65–0.80 (m, 4H, H-1 and H-6),
0.96 (s, 6H, H-8 or H-9), 0.99 (s, 6H, H-8 or H-9), 1.11 (dddd, 2H, Hpro-R-5,
J 14.5, 9.7 and 6.3 Hz), 1.19 (s, 6H, H-10), 1.24 (dd, 2H, Hpro-R-2, J 15.0
and 6.3 Hz), 1.86 (t, 4H, H-12, J 7.1 Hz), 1.92 (dd, 2H, Hpro-S-2, J 15.0 and
8.6 Hz), 2.20 (ddd, 2H, Hpro-S-5, J 14.5, 7.9 and 5.2 Hz), 2.45 (br.s, 2H, OH),
2.64 (m, 4H, H-11), 2.67 (dd, 2H, H-4, J 9.8 and 5.5 Hz). 13C NMR (75 MHz,
CDCl3) d: 16.01 (C8), 18.90 (C6), 19.01 (C5), 22.50 (C1), 26.66 (C7), 27.70
(C9), 28.90 (C10), 30.12 (C12), 32.01 (C2), 33.45 (C11), 53.95 (C4), 73.03 (C3).
MS, m/z (%): 412.2450 (12, [M]+, calc. for [C23H40O2S2]+: 412.2464),
259 (100), 241 (22), 185 (22), 153 (21), 135 (75), 109 (32), 107 (23), 106
(23), 95 (30), 93 (66), 81 (20), 71 (24), 67 (24), 43 (24), 43 (68), 41 (25).
20 V. V. Plemenkov, G. Sh. Bikbulatova, N. P. Artemova, L. N. Surkova,
A. V. Iliasov and A. A. Nafikova, USSR Inventor’s Certificate 1498760,
C07C, 1989; Byull. Otkryt. Izobret., 1989, no. 29, 77.
Received: 1st March 2011; Com. 11/3688
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