A new reaction of 2-(phenylsulfonyl)-3-phenyloxaziridine (davis reagent): Oxidation of thiolates to sulfinates. Application to the synthesis of sulfones

Article abstract of DOI:10.1021/ol990170k

(Matrix Presented) The first efficient and general method for the generation of sulfinate anions by oxidation of the corresponding thiolates is described. The oxidizing agent employed is the classical 2-(phenylsulfonyl)-3-phenyloxaziridine, commonly known as the Davis reagent. Subsequent S-alkylation of the sulfinates under phase-transfer catalysis affords sulfones 6 in 71-91% isolated yields (10 examples).

Full text of DOI:10.1021/ol990170k

ORGANIC
LETTERS
1999
Vol. 1, No. 8
1177-1180
A New Reaction of
2-(Phenylsulfonyl)-3-phenyloxaziridine
(Davis Reagent): Oxidation of Thiolates
to Sulfinates. Application to the
Synthesis of Sulfones
,†
Franck Sandrinelli, Ste´phane Perrio,* and Pierre Beslin
Laboratoire de Chimie Mole´culaire et Thio-organique (Associe´ au CNRS, UMR 6507),
ISMRA-UniVersite´ de Caen, 6 bouleVard du Mare´chal Juin, F-14050 Caen, France
stephane.perrio@ismra.fr
Received July 19, 1999
ABSTRACT
The first efficient and general method for the generation of sulfinate anions by oxidation of the corresponding thiolates is described. The
oxidizing agent employed is the classical 2-(phenylsulfonyl)-3-phenyloxaziridine, commonly known as the Davis reagent. Subsequent S-alkylation
of the sulfinates under phase-transfer catalysis affords sulfones 6 in 71−91% isolated yields (10 examples).
We have recently reported the first efficient procedure for
the oxidation of aromatic thiolates (ArS-) into the corre-
sponding sulfenates (ArSO-).1 The oxidant employed was
an unusual racemic N-sulfonyloxaziridine2 derived from
pinacolone. In situ S-alkylation of the sulfenate anion with
aliphatic halides led to sulfoxides in good to excellent yields
(Scheme 1). The overall sequence allowed a new and
In this Letter are described the different results obtained
with our initial investigations using classical (()-trans-2-
(phenylsulfonyl)-3-phenyloxaziridine4 1, commonly known
as the Davis reagent.5
Scheme 1
A preliminary experiment starting from disubstituted
thiophenol 26 quickly established that the reaction of the
corresponding lithium thiolate with 1 equiv of the Davis
oxaziridine7 1 under the previously used conditions, followed
by addition of ethyl iodide, did not result in the formation
(2) Shimizu, M.; Ishida, T.; Fujisawa, T. Chem. Lett. 1994, 1403-1406.
(3) Hall, N. Science 1994, 266, 32-34.
convenient synthesis of sulfoxides from thiols, with the major
advantage3 of being executable in one pot.
(4) (a) Davis, F. A.; Sheppard, A. C. Tetrahedron 1989, 45, 5703-5742.
(b) Davis, F. A.; Haque, M. S. Oxygen-Transfer Reactions of Oxaziridines.
In AdVances in Oxygenated Processes; Baumstark, A. L., Ed.; JAI Press
INC.: Greenwich, 1990; Vol. 2, pp 61-116. (c) Chen, B.-C.; Davis, F. A.
In Encyclopedia of Reagents for Organic Synthesis; Paquette, L. A., Ed.;
John Wiley & Sons: Chichester, 1995; Vol. 6, pp 4054-4057.
† Tel: +33 (0) 23145-2884. Fax: +33 (0) 23145-2877.
(1) Sandrinelli, F.; Perrio, S.; Beslin, P. J. Org. Chem. 1997, 62, 8626-
8627.
10.1021/ol990170k CCC: $18.00 © 1999 American Chemical Society
Published on Web 09/13/1999

of the expected sulfoxide. Instead, sulfide 3 was produced
preferentially oxidized by oxaziridine 1 to the corresponding
sulfinic acid even in the presence of a large excess of thiol.13a
The reason for this is that the intermediate sulfenic acid is
an “R-effect” nucleophile14 which is much more nucleophilic
than the thiol. Similarly, treatment of trialkyl(phenylthio)-
silanes PhSSiR3 with 1 equiv of oxaziridine 1 or m-CPBA
afforded a 50% yield of the corresponding trialkylsilyl
benzenesulfinates PhS(O)OSiR3.13b,c
and isolated in 47% yield (Scheme 2).8 This result was
Scheme 2
On the basis of these results, we reasoned that by using 2
equiv of oxaziridine 1 we might effect complete conversion
into the sulfinate, thereby providing straightforward access
to these species and thence to sulfones.15 Particularly
noteworthy is that despite some inspired efforts directed at
this oxidative transformation, there is still no practical and
efficient general procedure available.16-18 A major reason
for this is probably the lack of suitability of the few oxidants
so far investigated (molecular oxygen,16a-f superoxide anion,16g
iodine,16h and hydrogen peroxide16i). Following the same
procedure as above, but using 2 equiv of oxidant 1, an 80%
yield of sulfone 4 was obtained.
particularly intriguing, since TLC analysis of the reaction
mixture immediately after addition of the oxaziridine re-
vealed complete consumption of the oxidant, but without
detection in the crude mixture of any oxidation products.
We finally reasoned that (i) the Davis reagent had oxidized
the thiolate twice to afford a 1:1 mixture of the sulfinate
-
salt (ArSO2 ) and unreacted thiolate (ArS-)9 and that (ii)
(13) (a) Davis, F. A.; Billmers, R. L. J. Am. Chem. Soc. 1981, 103, 7016-
7018. (b) Davis, F. A.; Rizvi, S. Q. A.; Ardecky, R.; Gosciniak, D. J.;
Friedman, A. J.; Yocklovich, S. G. J. Org. Chem. 1980, 45, 1650-1653.
(c) Refvik, M. D.; Schwan, A. L. Can. J. Chem. 1998, 76, 213-220.
(14) Kice, J. L.; Cleveland, J. P. J. Am. Chem. Soc. 1973, 95, 104-109.
(15) For a mild and simple preparation of sulfinates, sulfonyl chlorides,
and sulfonamides from thioanisoles, see: De Vleeschauwer, M.; Gauthier,
J. Y. Synlett 1997, 375-377.
(16) Reported oxidation reactions with oxygen or superoxide anion suffer
from at least one of the following drawbacks: lack of selectivity with
formation of other unwanted oxidation products alongside the anticipated
sulfinate or requirement of unusual conditions (for example, electrochemical
generation of thiolates or use of resin-supported arenethiolates): (a)
Claessen, P. J. Prakt. Chem. 1877, 15, 193-222. (b) Young, M. B.; Young,
H. A.; Kleiber, M. J. Am. Chem. Soc. 1941, 63, 1488. (c) Berger, H. Recl.
TraV. Chim. Pays-Bas 1963, 82, 773-789. (d) Shell Internationale Research
Maatschappij Neth. Patent Appl. 287, 952, 1963; Chem. Abstr 1965, 63,
9815f. (e) Degrand, C.; Lund, H. Acta Chem. Scand. Ser. B 1979, 33, 512-
514. (f) Weber, J. V.; Schneider, M.; Paquer, D.; Faller, P. Sulfur Lett.
1985, 3, 45-50. (g) Oae, S.; Takata, T.; Kim, Y. H. Tetrahedron 1981, 37,
37-44. (h) Doerr, I. L.; Wempen, I.; Clarke, D. A.; Fox, J. J. J. Org. Chem.
1961, 26, 3401-3409. The report involving hydrogen peroxide was much
more attractive. However, the yields were highly structure dependent and
formation of over-oxidation products, i.e., sulfonic acids, could not be
avoided: (i) Kamiyama, T.; Enomoto, S.; Inoue, M. Chem. Pharm. Bull.
1988, 36, 2652-2653.
(17) The analogous reaction, in nonbasic conditions, has been investigated
with considerable success. Direct oxidation of aliphatic and aromatic thiols
with 2 equiv of m-CPBA afforded the corresponding sulfinic acids in high
purity and good yield: (a) Filby, W. G.; Gu¨nther, K.; Penzhorn, R. D. J.
Org. Chem. 1973, 38, 4070-4071. More recently, dimethyldioxirane was
found to be a very effective oxidant for aliphatic thiols, though a variety of
other oxidation products were isolated when using benzylic or aromatic
substrates: (b) Gu, D.; Harpp, D. N. Tetrahedron Lett. 1993, 34, 67-70.
(18) This reaction is somewhat more commonplace with thiolates
coordinated to transition elements. See, for example: (a) Kumar, M.; Colpas,
G. J.; Day, R. O.; Maroney, M. J. J. Am. Chem. Soc. 1989, 111, 8323-
8325. (b) Schrauzer, G. N.; Zhang, C.; Chadha, R. Inorg. Chem. 1990, 29,
4104-4107. (c) Grapperhaus, C. A.; Darensbourg, M. Y. Acc. Chem. Res.
1998, 31, 451-459. (d) Cocker, T. M.; Bachman, R. E. J. Chem. Soc.,
Chem. Commun. 1999, 875-876. (e) Sloan, C. P.; Krueger, J. H. Inorg.
Chem. 1975, 14, 1481-1485. (f) Adzamli, I. K.; Libson, K.; Lydon, J. D.;
Elder, R. C.; Deutsch, E. Inorg. Chem. 1979, 18, 303-311. (g) Yamanari,
K.; Kawamoto, T.; Kushi, Y.; Komorita, T.; Fuyuhiro, A. Bull. Chem. Soc.
Jpn. 1998, 71, 2635-2643. (h) Murata, M.; Kojima, M.; Hioki, A.;
Miyagawa, M.; Hirotsu, M.; Nakajima, K.; Kita, M.; Kashino, S.;
Yoshikawa, Y. Coord. Chem. ReV. 1998, 174, 109-131. (i) Connick, W.
B.; Gray, H. B. J. Am. Chem. Soc. 1997, 119, 11620-11627. (j) Miyashita,
Y.; Sakagami, N.; Yamada, Y.; Konno, T.; Okamoto, K.-I. Bull. Chem.
Soc. Jpn. 1998, 71, 2153-2160. (k) Pin, C.-W.; Peng, J.-J.; Shiu, C.-W.;
Chi, Y.; Peng, S.-M.; Lee, G.-H. Organometallics 1998, 17, 438-445. (l)
Lee, M.-T.; Hsueh, C.-C.; Freund, M. S.; Ferguson, G. S. Langmuir 1998,
14, 6419-6423.
the alkylation step had failed to trap the sulfinate salt,10,11
which had then undergone extraction into the aqueous layer
on workup.12 Sulfide 3 was also isolated as the sole product
when the reaction was repeated with either a large excess of
electrophile (10 equiv) or an extended reaction time of up
to 3 days. However, on addition of an equal volume of DMF
to the THF solution,11 alkylation of both presumed sulfur
species occurred and we were able to isolate an equimo-
lecular mixture of sulfide 3 and sulfone 4 (Scheme 2).
Analogies can be drawn with various literature observa-
tions.13 Davis’ group showed that tert-butanethiol was
(5) See, for example: (a) Pearson, A. J.; Chang, K. J. Org. Chem. 1993,
58, 1228-1237. (b) Mithani, S.; Drew, D. M.; Rydberg, E. H.; Taylor, N.
J.; Mooibroek, S.; Dmitrienko, G. I. J. Am. Chem. Soc. 1997, 119, 1159-
1160.
(6) This aromatic thiol was used for much of the initial work owing to
its ease of handling (not malodorous, relatively high molecular weight).
(7) The oxaziridine is readily prepared by literature procedures from
benzaldehyde via an N-sulfonylimine: (a) Vishwakarma, L. C.; Stringer,
O. D.; Davis, F. A. Org. Synth. 1988, 66, 203-210. (b) Davis F. A.;
Chattopadhyay, S.; Towson, J. C.; Lal, S.; Reddy T. J. Org. Chem. 1988,
53, 2087-2089.
(8) The imine PhCHdNSO2Ph derived from the oxaziridine was present
in the crude product. Small amounts of benzaldehyde and benzenesulfona-
mide, resulting from partial hydrolysis of the imine on workup, were also
detected.
(9) Similar results involving a selective double oxidation have also been
observed in transition metal chemistry with ruthenium9a and tungsten9b
thiolates. The oxidants employed were respectively dimethyldioxirane and
m-CPBA: (a) Schenk, W. A.; Frisch, J.; Adam, W.; Prechtl, F. Inorg. Chem.
1992, 31, 3329-3331. (b) Weinmann, D. J.; Abrahamson, H. B. Inorg.
Chem. 1987, 26, 3034-3040.
(10) Sulfinates are ambident nucleophiles. With soft electrophiles such
as alkyl halides, the alkylation occurs predominantly at sulfur to give
sulfones: Simpkins N. S. Sulphones in Organic Synthesis; Baldwin, J. E.,
Magnus P. D., Eds.; Pergamon Press: Oxford, 1993; Vol. 10, pp 11-15.
(11) The failure of the alkylation reaction of lithium alkenylsulfinate salts
with THF as solvent has already been reported: Dishington, A. P.;
Douthwaite, R. E.; Mortlock, A.; Muccioli, A. B.; Simpkins, N. S. J. Chem.
Soc., Perkin Trans. 1 1997, 323-337.
(12) (a) For a recent example of sulfinate salt extraction from an organic
phase on aqueous workup, see: (a) Fleming, I.; Frackenpohl, J.; Ila, H. J.
Chem. Soc., Perkin Trans. 1 1998, 1229-1235. Sulfinate salts are not
protonated by simple workup; for example, the pKa value of benzenesulfinic
acid is 1.29: (b) Veltwisch, D.; Janata, E.; Asmus, K. D. J. Chem. Soc.,
Perkin Trans. 2 1980, 146-153.
1178
Org. Lett., Vol. 1, No. 8, 1999

An important feature of this sequence is the impressive
rapidity of the double oxidation reaction, which on TLC
evidence was almost immediate at very low temperatures,
in contrast, e.g., with oxaziridine-mediated oxidations of
sulfides to sulfones.19 By way of comparison, oxidation of
methyl phenyl sulfide with 2.5 equiv of the same oxaziridine
took more than 3 days to go to completion at room
temperature.19 Furthermore, potential side products arising
from addition of the sulfinate anion to the liberated imine
were not formed.20
The alkylation conditions described above (1:1 THF/DMF
mixture) were, however, none too satisfactory in terms of
efficiency and ease of purification of the products, lengthy
reaction times, and a large excess of electrophiles being
required. An additional problem was the presence in the
crude product of the N-sulfonylimine PhCHdNSO2Ph.
Optimization of the conditions was far from trivial and was
not helped by the relative lack of literature information on
the alkylation of lithium arenesulfinates,21 most examples
having focused on the sodium analogues, and especially the
commercially available sodium benzene- and p-toluenesul-
finate.21,22 Investigation of various conditions suitable for
sodium salts showed the lithiated derivatives to be insuf-
ficiently reactive.
Of all the conditions we investigated, using thiophenol 5a
for optimization of the sequence, the best results were
obtained by isolation of the intermediate sulfinate and
subsequent alkylation under phase-transfer catalysis. After
the oxidation step, the reaction mixture was poured onto a
mixture of ethyl acetate and distilled water. The liberated
imine remained dissolved in the organic layer whereas the
sulfinate was extracted into the aqueous phase. After
evaporation of H2O, the lithium sulfinate was quantitatively
isolated in high purity as stable white crystals.23 The salt
was then reacted in a 3:3:4 toluene/acetone/water mixture24
in the presence of a catalytic amount of tetra-N-butylam-
monium bromide with one of five electrophiles (1.5 equiv).
The yields of the resulting sulfones were uniformly high
(75-91%), as shown in Table 1 (entries 1-5). To assess
the practical utility of this method, the reaction with allyl
bromide as the electrophile (entry 3) was scaled up. Starting
from 1 g of thiophenol 5a (9 mmol) and 4.9 g of oxaziridine
1 (18.9 mmol), no drop in efficiency was observed and the
anticipated sulfone 6a3 was isolated in 94% yield.
Table 1
isolated
yield
(%)b,c
entry thiol
R1
R2
R3
sulfonea
ref
1
2
3
4
5
6
7
8
9
5a
5a
5a
5a
5a
H
H
H
H
H
H
Me
Et
Allyl
Bn
6a 1
6a 2
6a 3
6a 4
6a 5
6b
6c
6d
6e
6f
75
75
91
85
79
77
74
80
76
71
25a
25b
25a
25a
25c
25d
25e
25f
25g
H
H
H
H
H
H
H
F
CH2CtCMe
5b CO2Me
5c Me
5d OMe
Me
Et
Et
Et
5e
5f
H
H
10
SEt Me
a The electrophiles used to introduce the R3 substituent were MeI, EtI,
CH2dCHCH2Br, PhCH2Br, and MeCtCCH2Br. b The reaction time for the
alkylation reaction, arbitrarily set at 24 h, could be shortened considerably.
For example, the yield of sulfone 6a1 had already reached 70% after 1 h
(compare with entry 1). c Yield calculated from starting thiol.
substrates was extended to thiols 5b-f containing common
substituents or functional groups (Table 1, entries 6-10).
In all cases, the intermediate sulfinates were isolated in
quantitative yield and were then subjected to the alkylation
conditions. Once again, the anticipated sulfones 6b-f were
formed in good to excellent yield. Sulfinic esters ArS(O)-
OR resulting from the competing O-alkylation were not
detected, except when ethyl iodide was used (less than 10%).
Application of the sequence to thiol 5f26 with an ethylthio
substituent selectively furnished sulfone 6f, which is other-
wise difficult to prepare27 (Table 1, entry 10). Oxidation took
place at the anionic sulfur center, without affecting the sulfide
(25) (a) Ali, M. H.; Bohnert, G. J. Synth. Commun. 1998, 28, 2983-
2998. (b) Ishida, M.; Minami, T.; Agawa, T. J. Org. Chem. 1979, 44, 2067-
2073. (c) Padwa, A.; Filipkowski, M. A.; Kline, D. N.; Murphree, S. S.;
Yeske, P. E. J. Org. Chem. 1993, 58, 2061-2067. (d) Bowden, K.; Rehman,
S. J. Chem. Res., Synop. 1997, 406-407. (e) Jones, I. W.; Tebby, J. C.
Phosphorus Sulfur 1978, 5, 57-60. (f) Dabrowska, U.; Stachura, R.;
Dabrowski, J. Rocz. Chem. 1970, 44, 1751-1755. (g) Dumont, J.-M.;
Rumpf, P. Bull. Soc. Chim. Fr. 1962, 1213-1218.
(26) Thiol 5f was prepared by heating 1,4-dichorobenzene with an excess
of sodium ethanethiolate in refluxing DMF followed by acidification. See:
Testaferri, L.; Tiecco, M.; Tingoli, M.; Chianelli, D.; Montanucci, M.
Synthesis 1983, 751-755.
(27) The oxidation of bis-sulfide 7 with 2 equiv of oxaziridine 1 led to
a different result, with the formation of the bis-sulfoxide 8 in 89% yield.
Having established these suitable conditions, the range of
(19) Davis, F. A.; Jenkins, R., Jr.; Yocklovich, S. G. Tetrahedron Lett.
1978, 19, 5171-5174.
(20) By comparison, the oxidation of benzenethiol afforded a very
complex mixture, from which was isolated adduct PhCH(SO2Ph)NHSO2-
Ph, resulting from addition of the intermediate sulfinic acid to the imine.
See ref 13a.
(21) The Chemistry of Sulfinic Acids and their DeriVatiVes-The Chem-
istry of Functional Groups; Patai, S., Ed.; John Wiley & Sons: Chichester,
1990.
(22) Macke, J. D. In Encyclopedia of Reagents for Organic Synthesis;
Paquette, L. A., Ed.; John Wiley & Sons: Chichester, 1995; Vol. 7, pp
4512-4515.
(23) The sulfinate salts may be contaminated with up to 5% benzene-
sulfonamide. Copies of 1H and 13C NMR spectra are provided as Supporting
Information.
(24) We preferred to use toluene instead of benzene: Crandall, J. K.;
Pradat, C. J. Org. Chem. 1985, 50, 1327-1329.
(28) No dibenzyl sulfoxide or dibenzyl sulfone, even as trace amounts,
was detected; the starting sulfide was recovered quantitatively after column
chromatography.
Org. Lett., Vol. 1, No. 8, 1999
1179

group. A remarkable chemoselectivity was also observed
when an equimolar mixture of benzenethiolate and dibenzyl
sulfide was treated with 2 equiv of oxaziridine 1.28 In the
presence of octyl methyl sulfide, oxidation was slightly less
selective, with the aliphatic sulfoxide detected and isolated
in 7% yield.
double oxidation were formed, with no evidence of mono-
oxidation, even if a single equivalent of this oxidant was
used. In contrast, with the oxaziridine recently introduced
by us, which has tert-butyl and methyl substituents, it was
possible to stop at the mono-oxidation stage.1 Future work
will seek to identify the origin of this difference in behavior
by screening a wider range of oxaziridines (does this result
from steric effects, electronic factors, or a difference in
oxidizing power?). Application to the rapid synthesis of 11C-
labeled sulfones for biological studies using positron emission
tomography is also underway.
In summary, we have succeeded in developing the first
high-yield procedure for converting aromatic thiolates into
the corresponding sulfinates. The oxidant is the classical
oxaziridine derived from benzaldehyde (Davis reagent).
Subsequent alkylation of these sulfinates with alkyl halides
affords the corresponding sulfones in high yield. We believe
the overall sequence holds much promise in synthesis on
account of its high efficiency, compatibility with a large
variety of substrates, chemoselectivity, technical simplicity,
and convenient workup. The lithium sulfinates thus formed
can also be used as precursors for the synthesis of sulfonyl
chlorides or sulfonamides.21 The only limitation of which
we are aware is the availability of the starting thiols.
Furthermore, this study extends still further the already
impressive synthetic utility of oxaziridines4a,b and illustrates
clearly how a slight modification in the oxaziridine structure
can dramatically alter its reactivity. Thus, with the Davis
oxaziridine possessing a phenyl substituent on the carbon
atom of the three-membered ring, products arising from a
Acknowledgment. We gratefully acknowledge financial
support from the Ministe`re de l’Education Nationale de
l’Enseignement Supe´rieur et de la Recherche (F. Sandrinelli).
We also thank Marco Greb of the University of Wu¨rzburg
(Germany) for a technical contribution to this work.
Supporting Information Available: Experimental pro-
cedures and spectroscopic data for the lithium sulfinates
prepared from thiols 5a-b, 5e-f, and compounds 3/4/6f/8.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL990170K
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Org. Lett., Vol. 1, No. 8, 1999