Rearrangement of 2,3-epoxy alcohol dimethylthiocarbamate derivatives. Synthesis of 2,3-epithio alcohol derivatives under mild conditions

Article abstract of DOI:10.1021/jo101000u

(Figure presented) Transformation of representative 2,3-epoxy alcohols, including 3-trimethylsilyl- and 3-triphenylsilylglycidols, into the corresponding 2,3-epithio alcohol dimethylthiocarbamate derivatives under mild alkaline conditions is reported.

Full text of DOI:10.1021/jo101000u

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SCHEME 1. Attempted Preparation of Thiocarbamate 2a
Rearrangement of 2,3-Epoxy Alcohol
Dimethylthiocarbamate Derivatives. Synthesis of
2,3-Epithio Alcohol Derivatives under Mild Conditions
Przemyszaw Kalicki, Michaz Karchier, Karol Michalak, and
Jerzy Wicha*
Institute of Organic Chemistry, Polish Academy of Sciences,
ul. Kasprzaka 44/52, 01-224 Warsaw 48, Poland
jwicha@icho.edu.pl
aKey: (a) NaH, imidazole (cat.), THF, rt, and then ClC(S)NMe2.
Received May 21, 2010
of imidazole6 and then with the dimethylthiocarbamoyl
chloride1,7 [ClC(S)NMe2] in an attempt to prepare thio-
carbamate 2. The product, isolated in 67% yield, showed the
expected elemental composition (HRMS). However, its IR
and 13C NMR spectra indicated the presence of the dimethyl-
carbamate [-C(O)NMe2] group (ν 1705 cm-1, δ 156 ppm for
the carbonyl carbon atom) instead of the expected di-
methylthiocarbamate [-C(S)NMe2]. The presence of the
carbamate group in the product implied that the sulfur-
oxygen interchange has occurred at some stage during the
process. Two distinct structures were considered as a possi-
ble alternative to 2: the 2,3-epithio alcohol carbamate 3 or
epoxy thiol carbamate 4. The analysis of published data on
the NMR spectra of S-dimethylthiocarbamate and O-di-
methylthiocarbamates8 permitted the assignment of the thi-
irane structure (3) to the product.9 Compound 3 decomposed
with an expulsion of sulfur on heating (to afford the (E)-3-
phenylprop-2-enyl dimethylcarbamate10) in an analogous
manner as it was reported for the respective free epithio
alcohol.11,12
Transformation of representative 2,3-epoxy alcohols,
including 3-trimethylsilyl- and 3-triphenylsilylglycidols,
into the corresponding 2,3-epithio alcohol dimethylthio-
carbamate derivatives under mild alkaline conditions is
reported.
In conjunction with a project on the synthesis of certain
natural products ongoing in our laboratory, we were inter-
ested in preparing dialkylaminothiocarbamate derivatives of
a model 2,3-epoxy alcohol. The presence of both strongly
nucleophilic (dialkylthiocarbamate) and electrophilic (oxirane)
moieties in close proximity was an intriguing feature of such
structure. No prior reports of dialkylaminothiocarbamates of
2,3-epoxy alcohols could be found in the literature; however,
the dimethylthiocarbamate group has been used as a specific
protective group for a range of alcohols,1 and several reports
on the chemistry of 2,3-epoxy alcohol thiocarbonyl imidazo-
lides2 and some other sulfur-containing derivatives have
been published.3
It was anticipated that 3 is formed by the rearrangement of
thiocarbamate 2, but no confirmation of the intermediate
presence could be found in the NMR spectra of crude
product. Intramolecular oxirane-thiirane interchange re-
actions involving thiourea and other thiocarbamate deriva-
tives are well-documented. However, an acid catalyst is
usually required.11-13
(7) (a) Sato, S.; Furukawa, N. In Science of Synthesis; Knight, J. G., Ley,
S. V., Eds.; Georg Thieme Verlag: Stuttgart-New York, 2005; Vol. 18,
pp 949-951. (b) Ponaras, A. A. In Encyclopedia of Reagents for Organic
Synthesis; Paquette, L. A., Ed.; Wiley: New York, 1995; Vol. 3,
pp 2174-2176.
(8) (a) Pontes, R. M.; Basso, E. A.; dos Santos, F. P. J. Org. Chem. 2007,
72, 1901-1911. (b) Lemire, A. E.; Thompson, J. C. Can. J. Chem. 1975, 53,
3732–3738.
The 3-phenylglycidol4,5 1 (Scheme 1) was treated first with
sodium hydride in THF in the presence of a catalytic amount
(1) Barma, D. K.; Bandyopadhyay, A.; Capdevila, J. H.; Falck, J. R. Org.
Lett. 2003, 5, 4755–4757.
(9) The reported spectral data are compiled in the Supporting Information.
(10) Overman, L. E.; Campbell, C. B.; Knoll, F. M. J. Am. Chem. Soc.
1978, 100, 4822–4834.
(11) Gao, Y.; Sharpless, K. B. J. Org. Chem. 1988, 53, 4114–4116.
(12) For reviews on thiiranes, see: (a) Fokin, A. V.; Allakhverdiev, M. A.;
Kolomiets, A. F. Russ. Chem. Rev. 1990, 59, 405–424. (b) Dittmer, D. C. In
Comprehensive Heterocyclic Chemistry; Katritzky, A. R., Rees, C. W., Eds.;
Pergamon Press: Oxford, 1984; Vol. 7, pp 178-179.
(13) For leading references, see: (a) Brodwell, F. G.; Andersen, H. M.
J. Am. Chem. Soc. 1953, 75, 4959–4962. (b) Pickenhagen, W.; Bronner-
Schindler, H. Helv. Chim. Acta 1984, 67, 947–952. (c) Branalt, J.;
Kvarnstrom, I.; Classon, B.; Samuelsson, B. J. Org. Chem. 1996, 61, 3604–
3610.
(2) (a) Barton, D. H. R.; Hay Motherwell, R. S.; Motherwell, W. B.
J. Chem. Soc., Perkin Trans. 1 1981, 2363–2367. (b) Goto, M.; Miyoshi, I.;
Ishii, Y.; Ogasawara, Y.; Kakimoto, Y. I.; Nagumo, S.; Nishida, A.;
Kawahara, N.; Nishida, M. Tetrahedron 2002, 58, 2339–2350.
(3) (a) Nuretdinova, O. N.; Novikova, V. G. Izv. Akad. Nauk SSSR, Ser.
Khim. 1982, 2363–2366. (b) Allakhverdiev, M. A.; Farzaliev, W. M.; Kha-
lilova, A. Z. Zh. Org. Khim. 1984, 20, 1350–1351.
(4) Hanson, R. M.; Sharpless, K. B. J. Org. Chem. 1986, 51, 1922–1925.
(5) Yadav, J. S.; Rao, K. V.; Prasad, A. R. Synthesis 2006, 3888–3894.
(6) Barton, D. H. R.; McCombie, S. W. J. Chem. Soc., Perkin Trans. 1
1975, 1574–1585.
5388 J. Org. Chem. 2010, 75, 5388–5391
Published on Web 07/14/2010
DOI: 10.1021/jo101000u
r
2010 American Chemical Society

Kalicki et al.
JOCNote
SCHEME 2. Preparation and Rearrangement of 2,3-Epoxy
Alcohol Thiocarbamates with a Secondary Carbon Atom at
Position 2a
SCHEME 3. Preparation and Rearrangement of 3-Silylglycidol
Thiocarbamatesa
aKey: (a) NaH, imidazole (cat.) and then ClC(S)NMe2; (b) TCDI,
CH2Cl2, rt; (c) Me2NH in Et2O, THF, rt and then CHCl3, reflux, 2 h;
(d) LiAlH4, Et2O, -78 °C.
aKey: (a) NaH, imidazole (cat.), THF, rt, and then ClC(S)NMe2;
(b) LiAlH4, Et2O, -78 °C.
small amount of (2E)-5-phenylpent-2-en-1-ol (>10%). The
optical rotation of this product ([R]22D þ125.0 (c 1.0, CHCl3))
corresponded to that reported previously.15 Therefore, on
the route from 5a to 9a, the inversion of configuration at
both stereogenic centers has occurred. Reduction of 8a with
lithium aluminum hydride under similar conditions led to a
mixture of products.
To determine the scope of the rearrangement, a few
selected epoxy alcohols were submitted to the reaction with
dimethylthiocarbamoyl chloride under analogous condi-
tions, and the products were investigated.
Glycidol 5a14 (2S,3S:2R,3R, 94:6 er by HPLC, Scheme 2)
afforded the intermediate 6a, which was rearranging into two
products at room temperature. 1H and 13C NMR spectra of a
sample of the crude material in CDCl3 solution at the 30 min
intervals allowed the observation of the declining signals of
6a (that completely disappear within 6 h). The products
(65% yield, 2:1 ratio by 1H NMR) were separated by
chromatography and were identified as 7a and 8a, respec-
tively. Both products showed in their IR spectra absorption
at 1700-1710 cm-1 and in their 13C NMR spectra a signal at
δ 156.03-155.93 ppm. The 1HNMRspectrumof7a (600MHz)
showed signals of two geminal protons at δ 4.12 and
4.07 ppm, indicating that the carbamate substituent is attac-
hed to a primary carbon atom. The coupling pattern of C-1,
C-2, and C-3 protons determined by the HSQC technique
corroborated the internal location of the epithio group. The
lack of the NOE effect between protons at C-2 (δ 2.92 ppm)
and C-3 (δ 2.76 ppm) and the presence of the NOE ef-
fect between protons at C-2 and C-4 (δ Ha, 2.13 and Hb,
1.82 ppm), as well as C-3 and C-1 (δ Ha, 4.12 and Hb, 4.07
ppm), showed their trans orientation. In the 1H NMR
spectrum of 8a, the signal of one proton deshielded by the
carbamate group appeared at δ 4.45 ppm (C-3). The coupling
pattern of the C-2 proton and the vicinal protons corresponded
to the epithio group’s terminal location, but the relative con-
figuration around C-2 and C-3 could not be confirmed.
The reduction of the epithio carbamate 7a with lithium
aluminum hydride in Et2O at -78 °C afforded the known
epithio alcohol 9a in 84% yield (er 93:7) contaminated with a
Geraniol 2,3-epoxide16 5b afforded unstable carbamate 6b
that could be identified by the 1H and 13C NMR spectra. This
product on standing in a chloroform solution for 6 h
afforded a mixture of 7b and 8b in a ratio of ca. 1:1 and
80% yield. The isomers were separated by chromatography.
Reduction of the epithio carbamate 7b with lithium alumi-
num hydride in Et2O at -78 °C gave the epithio alcohol 9b in
46% yield (Scheme 2).
(2S,3S)-3-(Trimethylsilyl)glycidol17 10 ([R]23 -24.7, er
D
95:5, Scheme 3) was converted into the unstable thio-
carbamate 12 that rearranged in a CHCl3 solution at rt within
20 h to give (2R,3S)-silyl thiirane18 15 as the only product
(62% yield). Reduction of 15 with lithium aluminum hydride
in Et2O at -78 °C afforded epithio alcohol 17 (65% yield,
[R]21D -9.1, er 95:5 by HPLC).
Treatment of 3-(triphenylsilyl)glycidol19 11 with sodium
hydride and then ClC(S)NMe2 provided O-[(E)-3-phenyl-
prop-2-enyl]dimethylthiocarbamate in line with the earlier
reported observation on reaction of triphenylsilyl oxiranes
with nucleophilic reagents.20 However, when 11 was allowed
(15) Uenishi, J.; Motoyama, M.; Nishiyama, Y.; Hirota, Y.; Kubo, Y.
Heteroat. Chem. 1994, 5, 51–59.
(16) Taber, D. F.; Houze, J. B. J. Org. Chem. 1994, 59, 4004–4006.
(17) (a) Katsuki, T. Tetrahedron Lett. 1984, 25, 2821–2822. (b) Raubo, P.;
Wicha, J. Synth. Commun. 1993, 23, 1273–1288.
(18) (a) Barberi, G. J. Organomet. Chem. 1976, 117, 157–158. (b) Bonini,
B. F.; Mazzanti, G.; Sarti, S.; Zanirato, P.; Maccagnani, G. J. Chem. Soc.,
Chem. Commun. 1981, 822–823. (c) Barbaro, G.; Battaglia, A.; Giorgianni,
P.; Maccagnani, G.; Macciantelli, D.; Bonini, B. F.; Mazzanti, G.; Zani, P.
J. Chem. Soc., Perkin Trans. 1 1986, 381–385.
(19) Raubo, P.; Wicha, J. Tetrahedron: Asymmetry 1995, 6, 577–586.
(20) Achmatowicz, B.; Jankowski, P.; Wicha, J.; Zarecki, A. J. Organo-
met. Chem. 1998, 558, 227–230.
(14) Barrow, R. A.; Hemscheidt, T.; Liang, J.; Paik, S.; Moore, R. E.;
Tius, M. A. J. Am. Chem. Soc. 1995, 117, 2479–2490.
J. Org. Chem. Vol. 75, No. 15, 2010 5389

Kalicki et al.
JOCNote
SCHEME 4. Rearrangement of a 2,3-Epoxy Alcohol Thiocarbamate with Position 3 Sterically Hindereda
a
˚
Key: (a) t-BuOOH, Ti(Oi-Pr)4, 4 A MS, CH2Cl2; (b) NaH, imidazole (cat.), THF, rt and then ClC(S)NMe2; (c) Bu4NF, THF, rt.
SCHEME 5. Rearrangement of 2,3-Epoxy Alcohol Thiocarba-
to react with thiocarbonyldiimidazole (TCDI) in THF at
room temperature, the stable thiocarbonyl imidazolide 13
was formed. This derivative was treated with dimethylamine
to afford epoxy dimethylthiocarbamate 14 that rearranged
to afford epithio dimethylcarbamate 16 (80% yield from 13).
Allylic alcohol 1821 (Scheme 4) was subjected to the Sharp-
less asymmetric epoxidation4,22 using L-(þ)-diisopropyl tar-
trate. Epoxy alcohol 19, formed as the major product, was
isolated by chromatography (86% yield).23 This product was
treated with sodium hydride and then with ClC(S)NMe2
under the standard conditions. Carbamate 20, identified by
mates with a Tertiary Carbon Atom at Position 2a
1
its H NMR spectra, was allowed to rearrange in CHCl3
solution at room temperature (6 h). The resulted thiirane 21
was isolated by chromatography (67% yield).24 Compound
21 was crystalline but formed clusters of thin needles. Grati-
fyingly, the alcohol 22, prepared by removal of the protecting
group, gave material suitable for the single-crystal X-ray ana-
lysis. The X-ray structure of 22 (for the ORTEP projection, see
the Supporting Information) confirmed the terminal position
of the epithio group and the configuration assignments.
Finally, the epoxy alcohols 24 and 25 (Scheme 5), prepared
from known25 16R,17R-epoxy-3β-hydroxypregn-5-en-20-
one 23 using the standard procedures,26 were examined.
Alcohol 24 was transformed as described above into thiocar-
bamate 26 that was stable on storage and could be recovered
unchanged after heating in refluxing toluene for a few hours.
However, when 26 was heated in DMF27 at 160 °C, a rearrange-
ment occurred, affording a single product in 76% yield. The
X-ray analysis of this product revealed structure 28 (for the
ORTEP projection, see Supporting Information).
aKey: (a) NaBH4, MeOH; (b) NaH, imidazole (cat.), THF, rt and then
ClC(S)NMe2; (c) DMF, heating.
SCHEME 6. Proposed Mechanism for 2,3-Epoxy Alcohol
O-Thiocarbamate Rearrangements
Epimeric alcohol 25 was transformed into the respective
dimethylthiocarbamate (27) that rearranged in DMF solu-
tion at slightly lower temperature (130 °C) to afford thiol
carbamate 29 (82% yield). Its structure was elucidated from
the IR, 1H, and 13C NMR spectra.
(21) Ponce, M. A.; Erra-Balsells, R.; Bruttomesso, A. C.; Gros, E. G.
Helv. Chim. Acta 2004, 87, 2987–3003.
(22) Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102, 5974–
5976.
(23) Gravanis, A.; Calogeropoulou, T.; Castanas, E.; Margioris, A.;
Charalambopoulos, I.; Avlonitis, N.; Minas, V.; Alexaki, V.-I.; Tsatsanis,
C.; Alexis, M. N.; Remboutsika, E.; Vergou, V.; Neophytou, C. WO Patent
2008155534, 2008.
(24) Thiocarbamate 20 was contaminated with a small amount (∼10%)
of a byproduct to which the structure of the respective carbamate was
assigned. The contamination presumably reflects the presence of dimethyl-
carbamoyl chloride in the reagent used.
(25) Litvinovskaya, R. P.; Drach, S. V.; Khripach, V. A. Russ. J. Org.
Chem. 2001, 37, 787–792.
(26) Das, R.; Kirk, D. N. J. Chem. Soc., Perkin Trans. 1 1984, 1821–1831.
For details, see Supporting Information.
(27) Chochrek, P.; Wicha, J. J. Org. Chem. 2007, 72, 5276–5284.
The following mechanistic explanation of the observed
rearrangements is proposed (Scheme 6). In structure A, the
attack of the thiocarbamate sulfur atom occurred at position
5390 J. Org. Chem. Vol. 75, No. 15, 2010

Kalicki et al.
JOCNote
and then evaporated, and the product was chromatographed on
silica gel (5 g, EtOAc/hexanes, 5:95) to give 15 (colorless oil,
2, leading to intermediate B. The latter rearranged into C,
and then the thiolate anion substituted the carbamate C-O
bond either in the 3 or 1 position, affording the final product
D or E. When position 3 was activated by a phenyl or silyl
group, the substitution occurred exclusively at that position.
Conversely, the oxirane derivative with position 3 sterically
shielded furnished product with the thiirane group at posi-
tion 1,2.
In structure F, with the tertiary position 2 at higher
temperatures in DMF, attack of the sulfur atom at position
3 took place and was followed by repositioning of the
epoxide function affording S-dimethylthiocarbamate G.
In conclusion, a rearrangement of dimethylthiocarbamate
derivatives of 2,3-epoxy alcohols leading to the respective
dimethylcarbamates of 2,3-epithio alcohols has been ob-
served. The rearrangement appears general for substrates,
with position 2 existing as a secondary carbon atom. The
transformation of oxirane into thiirane occurs with the
inversion of configuration at both stereogenic centers. 3-Silyl-
glycidols are converted into respective 3-silylthiirane deri-
vatives in high yield. The rearrangement provides a new
approach to thiirane derivatives under mild alkaline condi-
tions. The mechanism of the rearrangements is proposed.
Some carbamates of epithio alcohols are reduced with
lithium aluminum hydride to the respective epithio alcohols.
62%): [R]23 = -18.3 (c 1.41, CHCl3); HPLC UV detection,
D
Chiralpak AS-H, i-PrOH/hexanes, 2:98, 4.7 min (95%), 5.0 min
(5%); IR 1710 cm-1; 1H NMR (500 MHz, CDCl3) δ 4.18 (dd,
J = 11.3, 6.0 Hz, 1H), 4.11 (dd, J = 11.3, 6.6 Hz, 1H), 2.92 (q,
J = 6.3 Hz, 1H) overlapping 2.90 (s, 6H), 1.75 (d, J = 6.6 Hz,
1H), 0.04 (m, 9H); 13C NMR (125 MHz, CDCl3) δ 156.06, 70.33,
36.39 (br), 36.01, 35.83 (br), 27.89, -3.12. HRMS ESI: calcd for
C9H19O2NNaSSi [M þ Na]þ, 256.0798; found, 256.08049.
Signals of O-[(2S,3S)-3-(trimethylsilyl)oxiran-2-yl]methyl di-
1
methylthiocarbamate (12) were assigned as follows: H NMR
(400 MHz, CDCl3) δ 4.98 (dd, J = 12.0, 2.4 Hz, 1H), 4.08 (dd,
J = 12.0, 7.1 Hz, 1H), 3.35 (s, 3H), 3.17-3.11 (m,1H) over-
lapping 3.14 (s, 3H), 2.12 (d, J = 3.6 Hz, 1H), 0.06 (s, 9H); 13
C
NMR (100 MHz, CDCl3) δ 187.69, 73.54, 53.12, 48.31, 42.80,
37.84, -3.76.
[(2R,3S)-3-(Trimethylsilyl)thiiran-2-yl]methanol (17). A solu-
tion of 15 (80 mg, 0.34 mmol) in Et2O (3 mL) was added
dropwise to LiAlH4 (130 mg, 3.4 mmol) in Et2O (5 mL) stirred
at -78 °C. The suspension was stirred at -78 °C for 24 h, and
then the reaction was quenched with saturated aq Na2SO4. The
mixture was stirred for 30 min at rt and then diluted with Et2O
(10 mL) and hexanes (10 mL), and some Na2SO4 was added.
After 0.5 h, the mixture was filtered through a plug of cotton and
the solid was washed with Et2O. The combined filtrates were
evaporated. The residue was chromatographed on deactivated
silica gel (4 g, EtOAc/hexanes, 7:93) to give 17 (36 mg, colorless
oil, 65%): [R]21 -9.1 (c 1.6, CHCl3); HPLC UV detection,
D
Experimental Section
Chiralpak AS-H, i-PrOH/hexanes, 2:98, 6.6 min (5%), 8.5 min
(95%); IR 3369 (br), 1249 (s), 840 (s) cm-1; 1H NMR (600 MHz,
CDCl3) δ 3.97 (dd, J = 11.8, 3.8 Hz, 1H), 3.64 (dd, J = 11.8, 4.9
Hz, 1H), 3.04 (ddd, J = 6.8, 4.8, 3.9 Hz, 1H), 1.88 (d, J = 6.9 Hz,
1H), 1.85 (s, 1H), 0.07 (s, 9H); 13C NMR (150 MHz, CDCl3) δ
64.77, 41.76, 26.56, -2.98. HRMS EI: calcd for C6H14OSiS
[M]þ, 162.05347; found, 162.05292.
[(2R,3S)-3-(Trimethylsilyl)thiiran-2-yl]methyl dimethylcarba-
mate (15). Sodium hydride (55%, 44 mg, 0.5 mmol) was added
to a stirred solution of [(2S,3S)-3-(trimethylsilyl)oxiran-2-yl]-
methanol17 (10) {[R]23D -24.7 (c 1.9, CHCl3), HPLC, RI detec-
tion, Chiralpak AS-H, i-PrOH/hexanes, 5:95, 6.3 min (96%), 6.9
min (4%)} (73 mg, 0.5 mmol) and imidazole (3 mg, 0.05 mmol)
in THF (3 mL). After 15 min, dimethylcarbamoyl chloride
(93 mg, 0.75 mmol) was added and stirring was continued for
30 min. The mixture was then diluted with hexanes (10 mL) and
washed with water (2 ꢀ 10 mL). The organic solution was dried,
and the solvent was evaporated to give crude 12 (130 mg).
A solution of this product in CHCl3 (2 mL) was left at rt for 20 h
Supporting Information Available: General and experimen-
tal procedures for 3, 6a,b-9a,b, 13, 14, 16, and 19-29 and NMR
spectra of all new compounds (1H and 13C). ORTEP plots and
crystallographic details (CIF files) for 22 and 28. This material is
available free of charge via the Internet at http://pubs.acs.org.
J. Org. Chem. Vol. 75, No. 15, 2010 5391