A xanthate transfer radical process for the introduction of the Trifluoromethyl group

Article abstract of DOI:10.1021/ol0156446

(matrix presented) S-Trifluoromethyl xanthates efficiently add to unactivated alkenes by a radical mechanism to give adducts with a trifluoromethyl group at the least hindered terminus of the olefin.

Full text of DOI:10.1021/ol0156446

ORGANIC
LETTERS
2001
Vol. 3, No. 7
1069-1071
A Xanthate Transfer Radical Process for
the Introduction of the Trifluoromethyl
Group
Fre´de´rique Bertrand,† Virginie Pevere,‡ Be´atrice Quiclet-Sire,† and
,†,§
Samir Z. Zard*
Institut de Chimie des Substances Naturelles, C.N.R.S., 91198 Gif-sur-YVette, France,
Rhodia Recherches, CRL, 85 AV. des Fre`res Perret, BP 62, 69192 Saint-Fons, France,
and Laboratoire de Synthe`se Organique associe´ au CNRS Ecole Polytechnique,
91128 Palaiseau, France
sam.zard@icsn.cnrs-gif.fr
Received February 1, 2001
ABSTRACT
S-Trifluoromethyl xanthates efficiently add to unactivated alkenes by a radical mechanism to give adducts with a trifluoromethyl group at the
least hindered terminus of the olefin.
The trifluoromethyl group appears in a large number of
biologically active structures of interest to the pharmaceutical
and agrochemical industry.1 The presence of the fluorinated
motif increases the lipophilicity as well as the metabolic
stability, often resulting in an improved activity profile in
comparison with the nonfluorinated analogues. As a conse-
quence, a large number of methods have been devised to
introduce the trifluoromethyl group and research in this area
is still intense.2 In the case of aliphatic derivatives, various
reagents equivalent to the trifluoromethyl anion and cation
have been described but the trifluoromethyl radical remains
perhaps the most useful species for the practical, large scale
preparation of trifluoromethylated synthons. Trifluoromethyl
halides, especially bromo- and iodotrifluoromethane, have
proved to be the most practical reagents in this respect, but
their industrial production is being phased out because of
their presumed deleterious effect on the ozone layer. Other
routes involving trifluoromethanesulfonyl halides or tri-
fluorothioacetates3 and the decarboxylation of trifluoroacetic
acid via its Barton ester have been described.4 As part of
our ongoing study of the radical and nonradical chemistry
of xanthates and related dithiocarbonyl derivatives,5 we have
found that trifluoroacetonyl radicals can be generated and
(2) (a) Hudlicky, M. Chemistry of Organic Fluorine Compounds; Ellis
Horwood Ltd: Chichester, 1992. (b) Hudlicky, M.; Pavlath, A. E. Chemistry
of Organic Fluorine Compounds II; ACS Symposium Series: American
Chemical Society: Washington, DC, 1995. (c) Rozen, S.; Filler, R.
Tetrahedron 1985, 41, 1111-1153. (d) Be´gue´, J. P.; Bonnet-Delpon, D.
Tetrahedron 1991, 47, 3207-3258. (e) McClinton, M. A.; McClinton, D.
A. Tetrahedron 1992, 48, 6555-6666. (f) Lin, P.; Jiang, J. Tetrahedron
2000, 56, 3635-3671.
† Institut de Chimie des Substances Naturelles, C.N.R.S.
‡ Rhodia Recherches, CRL.
§ Laboratoire de Synthe`se Organique associe´ au CNRS Ecole Polytech-
nique.
(1) (a) SelectiVe Fluorination in Organic and Bioorganic Chemistry;
Welch, J. T., Ed.; ACS Symposium Series 456, American Chemical
Society: Washington, DC, 1991. (b) Welch, J. T.; Eswarakrishnan, S.
Fluorine in Bioorganic Chemistry; Wiley: New York, 1991. (c) Mann, J.
Chem. Soc. ReV. 1987, 16, 381-436. (d) Schlosser, M. Tetrahedron 1978,
34, 3-17. (e) Haas, A.; Lieb, M. Chimia 1985, 39, 134-140. (f) Hewitt,
C. D.; Silvester, M. J. Aldrichimica Acta 1988, 21, 3-10. (g) Filler, A.;
Kobayashi, Y. Biomedical Aspects of Fluorine Chemistry; Kodansha Ltd:
Tokyo, 1981. (h). Banks, R. E.; Smart, B. E.; Tatlow, J. C. Organofluorine
Chemicals and their Industrial Applications; Ellis Horwood Ltd: Chichester,
1979.
(3) (a) Huang, W.-Y.; Chen, J.-L.; Hu, L.-Q. Bull Soc. Chim. Fr. 1986,
881-884. (b) Kamigata, N.; Fukushima, T.; Terakawa, Y.; Yoshida, M.;
Sawada, H. J. Chem. Soc., Perkin Trans. 1 1991, 627-633. (c) Lan-Hargest,
H.-Y.; Elliott, J. D.; Eggleston, D. S.; Metcalf, B. W. Tetrahedron Lett.
1987, 28, 6557-6560. (d) Billard, T.; Roques, N.; Langlois, B. R.
Tetrahedron Lett. 2000, 41, 3069-3072.
(4) Barton, D. H. R.; Lacher, B.; Zard, S. Z. Tetrahedron 1986, 42,
2325-28.
(5) For a review of this work, see: (a) Zard, S. Z. Angew. Chem., Int.
Ed. Engl. 1997, 36, 672-685. (b) Quiclet-Sire, B.; Zard, S. Z. Phosphorus,
Sulfur Silicon 1999, 153-154, 137-134.
10.1021/ol0156446 CCC: $20.00 © 2001 American Chemical Society
Published on Web 03/15/2001

captured in a useful manner to give a variety of densely
functionalized trifluoromethyl ketones.6 In the present study,
we describe the extension of this approach to the production
of trifluoromethyl radicals.
The mechanistic picture underlying our work is outlined
in Scheme 1. Rupture of the sulfide bond in xanthate 1
Barton and co-workers in 1962.7 We later showed that the
mechanism is in fact a radical chain rather than a radical
recombination, as initially proposed.8
We elected to prepare the O-phenethyl xanthate 1a rather
than the simpler O-ethyl analogue 1 (R ) Et) in order to
avoid having to handle a potentially volatile and perhaps
malodorous substance.9 The intermediate acyl xanthate 6 was
not isolated but simply heated in the presence of lauroyl
peroxide to trigger the radical chain reaction leading to the
desired xanthate 1a via loss of carbon monoxide.10 In this
way, compound 1a was isolated in a non-optimized yield of
nearly 40%. It is important to use the xanthate salt 5 as the
limiting reagent and to add it to the trifluoroacetic anhydride.
The reason is that the desired S-acyl xanthate 6 can be
completely decomposed by a small amount of the xanthate
salt 5 through an ionic chain reaction leading ultimately to
xanthic anhydride 7 and trifluorothioacetic anhydride 9. Thus,
as outlined in Scheme 2, nucleophilic addition of 5 to the
thiocarbonyl group of 6 leads to anhydride 7 and sodium
thiofluoroacetate 8 (addition of 5 to the carbonyl group of 6
results in a degenerate reaction). In a second step, addition
of thiofluoroacetate 8 to the carbonyl group of 6 gives
anhydride 9 and the initial xanthate salt 5 to propagate the
chain (similarly, addition of 8 to the thiocarbonyl group of
6 also results in a degenerate reaction).
Scheme 1
With a ready supply of xanthate 1a, we examined its
potential as a trifluoromethyl transfer agent. Indeed, a smooth
reaction took place upon heating 1a with various function-
alized, unhindered terminal alkenes in refluxing 1,2-dichloro-
ethane in the presence of lauroyl peroxide as initiator.10 Our
results are compiled in Table 1. A variety of useful functional
groups are tolerated, and the unoptimized yields are quite
acceptable, except for phenyl vinyl sulfone 3i (for entries f
and i, the yield in parentheses is based on unconsumed
starting material). The cause of the low yield is not clear in
this case but may be due to the reluctance of the electrophilic
trifluoromethyl radical to react with an electrophilic olefin.
One important aspect of the xanthate transfer technology
is the possibility of starting another radical sequence from
the product, since it is itself a xanthate. This is illustrated
by the transformation in Scheme 3. Addition of the elements
of xanthate 1a to protected N-allyl p-fluoroaniline 3j gives
adduct 4j in 64% yield. Exposure of the latter to stoichio-
following the initiation step leads to the desired trifluoro-
methyl radical, which then adds to the olefinic trap 3. The
chain process is finally propagated by the reversible transfer
of the xanthate group to give 4. The reaction of the
trifluoromethyl radical with its xanthate precursor 1, although
fast, is degenerate and does not therefore interfere with the
desired pathway.
Unlike most xanthates we have examined so far and which
were simply prepared by substitution of a halide or sulfonate
with a xanthate salt, the synthesis of an S-trifluoromethyl
xanthate of structure 1 was far from trivial. Direct substitution
of a trifluoromethyl halide is not only difficult but also
defeats the purpose of this work since the industrial produc-
tion of trifluoromethyl halides will cease in the future. After
some experimentation, we found the decarbonylation of an
S-trifluoroacetyl xanthate, as depicted in Scheme 2, to be
the most convenient route. This ingenious process, applied
to non-fluorinated carboxylic acids, was first reported by
Scheme 2
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Org. Lett., Vol. 3, No. 7, 2001

Scheme 3
Table 1. Radical Reaction of Xanthate 1a with Olefins 3a-3i
(R ) CH2CH2Ph)
simple. The conditions are neutral and the method is
compatible with a wide variety of functional groups of
interest to medicinal chemists. Finally, no heavy metals are
involved and the process is in principle applicable to the
generation and capture of higher perfluoroalkyl radicals.
Acknowledgment. We wish to thank Rhodia and the
CNRS for very generous financial support to one of us (F.B.).
Supporting Information Available: Full analytical data
for all new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL0156446
(8) Delduc, P.; Tailhan, C.; Zard, S. Z. J. Chem. Soc., Chem. Commun.
1988, 308-310.
(9) The synthesis of O-ethyl-S-trifluoromethyl xanthate using the photo-
chemical decomposition of the corresponding S-trifluoroacetyl xanthate as
well as one example of UV mediated addition to 1-decene have been claimed
in a patent: Langlois, B.; Roques, N.; Wakselman, C.; Tordeux, M.; Forat,
G. (Rhoˆne-poulenc Agrochimie) WO 9626185.
(10) Typical experimental procedure: (a) Synthesis of 1a. To an ice-
cooled solution of trifluoroacetic anhydride (13.3 mL; 90.1 mmol) in
anhydrous acetonitrile (40 mL) was added dropwise a solution of sodium
O-phenethyl xanthate (10 g; 45.0 mmol) in anhydrous acetonitrile under
an inert atmosphere. Once the addition was complete, the mixture was heated
to reflux for 15 min; then three portions of lauroyl peroxide (907 mg; 4.5
mmol) were added at intervals of 1.5 h. The solvent was then evaporated
under reduced pressure and the residue taken up in dichloromethane. The
organic layer was washed with saturated sodium bicarbonate, dried, and
evaporated. Chromatography of the residue on silica (heptane) did not give
a totally pure material, so further purification was accomplished by
distillation in a Kugelruhr apparatus (80 °C/0.1 Torr) to give the desired
xanthate in 38% yield as a pale yellow oil. (b) General procedure for the
radical additions to olefin: A solution of the xanthate (1 mmol) and olefin
(2-5 mmol) in 1,2-dichloroethane (ca. 1 mL) was heated to reflux for 15
min; then lauroyl peroxide (2.5 mol %) was added every 1.5 h until almost
complete consumption of the xanthate. The solvent was then removed under
reduced pressure and the residue purified by chromatography on silica.
(11) Ly, T.-M.; Quiclet-Sire, B.; Sortais, B.; Zard, S. Z. Tetrahedron
Lett. 1999, 40, 2533-2536.
metric amounts of lauroyl peroxide leads ultimately to
indoline 10 in 60% yield.11
In summary, the present approach to trifluoromethylated
derivatives is efficient, flexible, and experimentally quite
(6) Denieul, M.-P.; Quiclet-Sire, B.; Zard, S. Z. J. Chem. Soc., Chem.
Commun. 1996, 2511-2512
(7) Barton, D. H. R.; George, M. V.; Tomoeda, M. J. Chem. Soc. 1962,
1967-1974.
Org. Lett., Vol. 3, No. 7, 2001
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