Synthesis and reactivity of a stable crystalline diastereomerically pure trifluoromethanesulfinic acid derivative: (S)-(-)-1-trifluoromethylsulfinyl-(R)-4-phenyloxazolidin-2-one

Article abstract of DOI:10.1039/b303574c

Efficient synthesis of the title compound, the first diastereomerically pure trifluoromethanesulfinic acid derivative (8), has been achieved by direct trifluoromethanesulfinyla-tion of the lithiated (4R)-(-)-4-phenyloxazolidin-2-one; in contrast to the re

Full text of DOI:10.1039/b303574c

Synthesis and reactivity of a stable crystalline diastereomerically pure
trifluoromethanesulfinic acid derivative:
(S)-(2)-1-trifluoromethylsulfinyl-(R)-4-phenyloxazolidin-2-one
Vadim D. Romanenko, Claire Thoumazet, Vincent Lavallo, Fook S. Tham and Guy Bertrand*
UCR-CNRS Joint Research Chemistry Laboratory, UMR 2282, Department of Chemistry, University of
California, Riverside, CA 92521-0403, USA. E-mail: gbertran@mail.ucr.edu
Received (in Corvallis, OR, USA) 31st March 2003, Accepted 16th May 2003
First published as an Advance Article on the web 9th June 2003
Efficient synthesis of the title compound, the first diaster-
eomerically pure trifluoromethanesulfinic acid derivative
(8), has been achieved by direct trifluoromethanesulfinyla-
tion of the lithiated (4R)-(2)-4-phenyloxazolidin-2-one; in
contrast to the reaction between CF3S(O)Cl and (1R,2S,5R)-
(2)-menthol which occurs with low stereoselectivity ( < 10%
de), 8 affords the O-menthyl trifluoromethanesulfinate
Scheme 2 Reagents and conditions: (i) SOCl2 (1 eq.), 1,2,4-trichloro-
derivative in > 98% de.
benzene, 20 °C, 3 h; (ii) N-silver succinimide (1 eq.), toluene, 20 °C, 14
h.
Because of the high lipophilicity and electron-withdrawing
ability of the CF3S(O) functional group, trifluoromethane-
Close scrutiny of the literature reveals that among diverse
types of sulfinic acid derivatives, N-(alkane- and arene-sulfinyl)
imides are readily available and can be used as sulfinylation
agents.10 Treatment of 1, generated in situ from readily
available CF3S(O)OK and SOCl2, with the silver salt of
succinimide afforded 4 as a stable white crystalline solid (no
appreciable decomposition upon storage at rt for over one
month) in 72% yield (Scheme 2).
As expected, 4 reacts with a variety of proton-donor N–H, O–
H and C–H functionalities to give the corresponding products
resulting from nucleophilic displacement (Scheme 3). For
example, N-methylaniline is sufficiently nucleophilic to gen-
erate the corresponding sulfinamide 5. With N-methylpyrrole a
mixture of 2- and 3-trifluoromethylsulfinyl derivatives was
obtained in an 87 : 13 ratio, from which the major isomer 6 was
isolated in 67% yield by flash chromatography. The tri-
fluoromethanesulfinylation of (1S)-endo-(2)-borneol required
6 h at 60 °C, but is complete within 2 h at rt in the presence of
one equivalent of triethylamine. Derivative 7 was isolated in
92% yield, however with a very low diastereoselectivity
( < 10% de). This is in contrast to the effective production of
diastereomerically pure menthyl benzenesulfinate obtained
from N-(benzenesulfinyl)phthalimide and (1R,2S,5R)-
(2)-menthol.11 Thus, being useful as an easily handled reagent
for electrophilic trifluoromethylsulfinylation, compound 4
presents limited interest for the chiral version of nucleophilic
displacement reactions.
sulfinic acid derivatives are of great interest for the pharmaceu-
tical and agrochemical industries.1 Interestingly, although the
corresponding alkane and arene derivatives [R–S(O)X, R =
Alk, Ar; X = Alk2N or AlkO] belong to the oldest group of
chiral organosulfur compounds prepared as enantiopure spe-
cies,2 and despite their long recognized importance as inter-
mediates in many synthetic strategies,3 the synthesis of
optically active trifluoromethanesulfinic acid derivatives has
never been reported.
Current methods for the synthesis of trifluoromethanesulfinic
acid derivatives include nucleophilic trifluoromethylation of
sulfinyl chlorides via CF3SiMe3/F2 4 and the reaction of
nucleophilic HY-substrates with CF3SCl, followed by the
difficult selective mono-oxidation of the resulting CF3SY
species.5 The direct introduction of a CF3S(O) group into
organic molecules is a less popular strategy, probably because
trifluoromethanesulfinyl halides CF3S(O)F and CF3S(O)Cl are
highly toxic, volatile and poorly stable.6 Recently some
attention has been devoted to the preparation of elaborate new
trifluoromethanesulfinylation reagents. However, due to the
strong acid media necessary for the generation of the CF3S(O)+
cation,7 the scope of these new approaches has again been
limited to racemic compounds.
The condensation of an optically active secondary alcohol
with an alkane- or arene-sulfinyl chloride in the presence of a
base is a general method for the asymmetric synthesis of
sulfinate esters.2,8 However, we found that the degree of
asymmetric induction in the reaction of CF3S(O)Cl 1 with chiral
alcohols was quite low. For example, the condensation of 1 with
(1R,2S,5R)-(2)-menthol in the presence of triethylamine (tolu-
ene, 278 °C) afforded a 55 : 45 ratio of (Ss/Rs)-diastereomeric
In search for a more efficient stereocontrolling trifluor-
omethanesulfinylation agent, our investigations were extended
to Evans’-type chiral auxiliaries.12,13 CF3S(O)Cl cleanly re-
acted with optically active lithiated oxazolidin-2-ones; the
diastereoisomeric excesses were evaluated by 19F NMR
spectroscopy. Poor selectivities were obtained with (S)-
menthyl sulfinates 2,† whereas with diacetone- -glucose (pyr-
D
idine, thf, 278 °C) the corresponding DAG-sulfinates 3 were
obtained with only a 16% de (Scheme 1). For comparison, under
similar conditions, reactions with CH3S(O)Cl afforded the
DAG-(Rs)-sulfinate having a diastereomeric purity as high as
93%.9
Scheme 3 Reagents and conditions: (i) Me2NH (1.1 eq.), toluene, 20 °C, 3
h; (ii) N-methylpyrrole (1 eq.), chlorobenzene, 70 °C, 5 h; (iii) (1S)-endo-
(2)-borneol (1 eq.), Et3N (1 eq.), touene, 20 °C, 2 h.
Scheme 1
1680
CHEM. COMMUN., 2003, 1680–1681
This journal is © The Royal Society of Chemistry 2003

View Article Online
67.44, 72.08, 80.51, 83.36, 83.98, 105.30, 109.73, 112.78, 122.85 (q, JCF
=
336.8). [(Rs)-3]: 19F: 280.07, 1H: 1.32, 1.34, 1.42, 1.51 (4s, 12H,
OCMe2O), 3.90–4.20 (m, 4H, H-4, H-5, H-6), 4.70–4.76 (m, H-2, H-3),
5.96 (d, 1H, J = 3.6, H-1), 13C: 24.81, 26.15, 26.61, 26.75, 67.65, 71.83,
80.65, 83.61, 83.78, 105.39, 109.82, 112.78, 122.65 (q, JCF = 335.4). 4:
19F: 269.20, 13C: 28.8, 124.3 (q, JCF = 340), 172.4. 5: 19F: 277.0. 6: 19F:
279.43. 7: 19F: 280.75 and 281.40; [(Ss)-8]: 19F: 273.65, 1H: 4.48 (dd,
1H, J = 9.3, 4.5, H-5), 4.86 (t, 1H, J = 9.3, H-4), 5.39 (dd, 1H, J = 9.3,
4.5, H-5), 7.27–7.48 (m, 5H, Harom); 13C (C6D6): 53.0, 72.6, 123.3 (q, JCF
= 337.5), 126.9, 128.8, 128.9, 136.9, 155.2. [(Rs)-8]: 19F: 272.70; [(Ss)-9]:
278.21, 13C: 35.84, 36.53, 56.31, 68.14, 123.68 (q, JCF = 335.4), 126.98,
128.36, 128.81, 137.52, 156.47.
Scheme 4 Reagents and conditions: (i) CF3SOCl (1.1 eq.), thf, 278 °C, 6
h.
‡ Synthesis of (Ss)-8: To a solution of the (R)-(2)-4-phenyloxazolidin-
2-one (6 mmol) in thf (30 ml) under argon at 278 °C was added dropwise
4.4 ml of n-butyllithium (1.6 M in hexane, 7.0 mmol) over a 10 min period.
The solution was strirred at 278 °C for 30 min and then a solution of
CF3S(O)Cl (7.0 mmol) in toluene (10 ml) was added over a 30 min period.
After being stirred for 6 h at 278 °C, the solvent and volatile compounds
were removed. After extraction with toluene, a 93 : 7 mixture of (Ss)- and
(Rs)-diastereomers was obtained. Recrystallization from toluene–pentane (3
: 1) afforded pure (Ss)-8 in 75% yield. Mp 132–134 °C, [a]D = 2197 (c =
2, CHCl3).
§ Crystal data for [(Ss)-8]: C10H8F3NO3S, M = 279.23, monoclinic, a =
7.905(2), b = 8.231(2), c = 8.659(3) Å, b = 98.557(6)°, V = 557.1(3) Å3,
T = 223(2) K, space group P2(1), Z = 2, Mo-radiation, l = 0.71073 Å,
4183 reflections measured, 2409 [R(int) = 0.0180] independent reflections,
Flack parameter = 0.07(6), final R indices [I > 2s(I)]: R1 = 0.0284, wR2
= 0.0742, R indices (all data): R1 = 0.0294, wR2 = 0.0757. CCDC
reference number 207699. See http://www.rsc.org/suppdata/cc/b3/
b303574c/ for crystallographic data in CIF or other electronic format.
Fig. 1 Molecular structure of (Ss)-8.
(2)-4-benzyloxazolidin-2-one (58 : 42), (4R,5S)-(+)-4-methyl-
5-phenyloxazolidin-2-one (65 : 35), and (S)-(2)-4-isopropylox-
azolidin-2-one
(61
:
39).
However,
with
(R)-(2)-4-phenyloxazolidin-2-one not only an 86% de was
obtained, but the major diastereomer turned out to be crystalline
(Scheme 4). A single recrystallization from a toluene–pentane
mixture (3 : 1) was sufficient to isolate the desired tri-
fluoromethanesulfinic acid derivative 8 (75% yield) with a
diastereomeric purity greater than 98%.‡ The (Ss) configuration
at the sulfur atom has been determined by a single crystal X-ray
diffraction study (Fig. 1).§
The synthesis of diastereomerically pure sulfinylimide (Ss)-8
provides a basis for its use in asymmetric reactions (Scheme 5).
Derivative (Ss)-8 acts as a trifluoromethylsulfinylation agent.
For example, with (1R,2S,5R)-(2)-menthol, at 20 °C in ether in
the presence of triethylamine, the menthyl sulfinate (Ss)-2 was
isolated in 43% yield with a diastereoselectivity higher than
98%. On the other hand, (Ss)-8 can undergo a ring-opening
reaction. For example, it was successfully converted by
treatment with dimethylamine into the corresponding 2-ami-
noalcohol 9 ( > 98% de). The absolute configuration of the
products 2 and 9 was tentatively assigned on the basis of NMR
data.9 The retention of configuration at the sulfur centre has
been observed previously in the reaction of chiral N,N-
diisopropyl p-toluenesulfinamide with some alcohols catalyzed
by acids.14
1 Biomedical Frontiers of Fluorine Chemistry, eds. I. Ojima, J. M.
McCarthy and J. T. Welch, ACS Symposium Series, ACS, Washington,
D. C., 2000, pp. 1–24; Asymmetric Fluoroorganic Chemistry. Synthesis,
Applications, and Future Directions, ed. P. V. Ramachandran, ACS
Symposium Series 746, ACS, Washington, D. C., 2000, pp. 1–20.
2 (a) M. Mikolajczyk, J. Drabovicz and P. Kielbasinski, Chiral Sulfur
Reagents. Applications in Asymmetric and Stereoselective Synthesis,
CRC Press, Boca Raton, 1997; (b) M. Mikolajczyk and J. Drabowicz,
Top. Stereochem., 1982, 13, 334.
3 (a) S. M. Allin, in Organosulfur Chemistry. Synthetic and Ster-
eochemical Aspects, ed. P. Page, vol. 2, Academic Press, San Diego,
1998, pp. 41–61; (b) S. M. Allin, S. J. Shuttleworth and P. C. Bulman
Page, ibid, pp. 97–156; (c) P. Metzner and A. Thuillier, Sulfur Reagents
in Organic Synthesis, Academic Press, London, 1994, pp. 25–28; (d) S.
Oae, Organic Sulfur Chemistry: Structure and Mechanism, CRC Press,
Boca Raton, 1991, p. 67.
4 R. P. Singh and J. M. Shreeve, Chem. Commun., 2002, 1818; R. P.
Singh, G. Cao, R. L. Kirchmeier and J. M. Shreeve, J. Org. Chem., 1999,
64, 2873; V. N. Movchun, A. A. Kolomeitsev and Y. L. Yagupolskii, J.
Fluorine Chem., 1995, 70, 255.
5 T. Umemoto and T. Ishihara, J. Am. Chem. Soc., 1993, 115, 2156; D.
Hainzl, L. M. Cole and J. E. Casida, Chem. Res. Toxicol., 1998, 11,
1529; S.-L. Yu, D. T. Sauer and J. M. Shreeve, Inorg. Chem., 1974, 13,
484.
6 O. D. Gupta, W. A. Kamil and J. M. Shreeve, Inorg. Chem., 1985, 24,
2121; C. A. Burton and J. M. Shreeve, Inorg. Chem., 1977, 16, 1039.
7 T. Billard, A. Greiner and B. R. Langlois, Tetrahedron, 1999, 55, 7243;
C. Wakselman, M. Tordeux, C. Freslon and L. Saint-Jalmes, Synlett,
2001, 550.
8 J. Drabovicz, P. Kielbasinski and M. Mikolajczyk, in The Chemistry of
Sulfinic Acids, Esters and their Derivatives, ed. S. Patai, John Wiley &
Sons, Chichester, 1990, pp. 351–429; A. Nudelman, ibid, pp. 35–85; U.
Zoller, ibid, pp. 217–237.
9 I. Fernández, N. Khiar, J. M. Llera and F. Alcudia, J. Org. Chem., 1992,
57, 6789.
10 (a) D. N. Harpp and T. G. Back, J. Org. Chem., 1973, 38, 4328; (b) D.
N. Harpp, B. Friedlander, D. Mullins and S. M. Vines, Tetrahedron
Lett., 1977, 963.
Scheme 5 Reagents and conditions: (i) (1R,2S,5R)-(2)-menthol (3 eq.),
Et3N (1 eq.), ether, 20 °C, 24 h; (ii) Me2NH (neat), 210 °C, 1 h.
Further work is currently in progress to define the scope of
applications of diastereomerically pure N-trifluoromethane-
sulfinimides.
11 D. N. Harpp, S. M. Vines, J. P. Montillier and T. H. Chan, J. Org.
Chem., 1976, 41, 3987.
12 For a review see: D. J. Ager, I. Prakash and D. R. Schaad, Aldrichim.
Acta, 1997, 30, 3; D. J. Ager, I. Prakash and D. R. Schaad, Chem. Rev.,
1996, 96, 835.
13 D. A. Evans, M. M. Faul, L. Colombo, J. J. Bisaha, J. Clardy and J.
Cherri, J. Am. Chem. Soc., 1992, 114, 5997; J. P. Marino, S. Bogdan and
K. Kimura, J. Am. Chem. Soc., 1992, 114, 5566.
14 M. Mikolajczyk, J. Drabowicz and B. Bujnicki, Tetrahedron Lett., 1985,
26, 5699.
Notes and references
† Selected NMR [CDCl3, ppm (J/Hz)] data: [(Ss)-2]: 19F (ref. CFCl3):
281.32, 13C: 15.70, 20.75, 21.95, 23.37, 25.58, 31.94, 33.82, 42.29, 47.99,
84.60, 122.82 (q, JCF = 334.1). [(Rs)-2]: 19F: 280.71, 13C: 15.51, 20.82,
21.92, 23.18, 25.43, 32.05, 33.82, 48.18, 85.47, 122.88 (q, JCF = 335.4).
[(Ss)-3]: 19F: 281.08, 1H: 1.33, 1.35, 1.43, 1.51 (4s, 12H, OCMe2O),
3.94–4.25 (m, 4H, H-4, H-5, H-6), 4.61 (d, 1H, J = 3.6, H-2), 4.94 (d, 1H,
J = 2.7, H-3), 5.96 (d, 1H, J = 3.6, H-1), 13C: 24.84, 26.15, 26.61, 26.75,
CHEM. COMMUN., 2003, 1680–1681
1681