A direct approach to α-hydroxy and α-chloro trifluoromethyl derivatives

Article abstract of DOI:10.1016/j.tetlet.2004.11.086

S-1-Acyloxy-2,2,2-trifluoroethyl and S-1-chloro-2,2,2-trifluoroethyl dithiocarbonates add efficiently to various functionalised olefins to give the corresponding adducts via a radical chain reaction initiated by a small amount of lauroyl peroxide. S-1-Acyloxy-2,2,2-trifluoroethyl and S-1-chloro-2,2,2- trifluoroethyl dithiocarbonates add efficiently to various functionalised olefins to give the corresponding adducts via a radical chain reaction initiated by a small amount of lauroyl peroxide.

Full text of DOI:10.1016/j.tetlet.2004.11.086

Tetrahedron
Letters
Tetrahedron Letters 46 (2005) 455–459
A direct approach to a-hydroxy and a-chloro
trifluoromethyl derivatives
Lucie Tournier and Samir Z. Zard*
` ´
Laboratoire de Synthese Organique associe au CNRS, Ecole Polytechnique, 91128 Palaiseau, France
Received 11 October 2004; revised 10 November 2004; accepted 16 November 2004
Available online 2 December 2004
This article is dedicated with respect to the memory of Professor Georges Bram
Abstract—S-1-Acyloxy-2,2,2-trifluoroethyl and S-1-chloro-2,2,2-trifluoroethyl dithiocarbonates add efficiently to various function-
alised olefins to give the corresponding adducts via a radical chain reaction initiated by a small amount of lauroyl peroxide.
Ó 2004 Elsevier Ltd. All rights reserved.
As part of our studies on the development of new routes
to organofluorine compounds,1 we have recently de-
scribed the use of a-acetamido trifluoromethyl xanthate
1 as a powerful reagent for the introduction of geminal
amido and trifluoromethyl groups through radical addi-
tion to olefins (Fig. 1).2,3
expected to be weaker. If successful, this would signifi-
cantly expand the scope of this technology for the prep-
aration of trifluoromethyl derivatives since a direct route
to a-hydroxy and a-chloro trifluoromethyl structures
would be at hand. Such motifs are present in a number
of pharmaceutically important compounds,4 some
examples of which are given in Figure 2. Such a-trifluo-
romethyl alcohols are usually prepared by reaction of
RupertÕs reagent, or an equivalent source of trifluorom-
ethyl anion, with an aldehyde, or by reduction of the
corresponding trifluoromethyl ketone.5
In this particular reagent, the carbon–sulfur bond is
weakened by an anomeric type effect due to the lone pair
on the nitrogen (in essence, a lone pair–r* interaction),
and this may explain in part the remarkable efficiency of
the chain process. In order to ascertain the importance
of such an effect, we explored the possibility of using
the analogues 2 and 3 (Fig. 1), where the interaction
of the C–S r* with the lone pair on the heteroatom is
The synthesis of xanthate 2 proved to be relatively
straightforward. Thus, treatment of the hemiacetal of
OH
O
O
F3C
O
N
R
G
S
G
R
S
Befloxatone
O
F3C
S
OEt
F
3C
S
OEt
OH
(Lauroyl
Peroxide)
F3C
1: G=NHAc
2: G=OAc
3: G=Cl
DCE
Inhibitor of the biosynthesis of cholesterol in HepG2 cells
Figure 1. Synthetic route to a-amino, a-hydroxy, and a-chloro
trifluoromethyl derivatives (DCE = 1,2-dichloroethane).
OH
H
Ph
N
F3C
O
Keywords: Trifluoromethyl; Radical chain reaction; Dithiocarbonate.
Inhibitor of histone deacetylases
*
Corresponding author. Tel.: +33 1 6933 4872; fax: +33 1 6933
3851; e-mail addresses: zard@poly.polytechnique.fr; tetlet@
polytechnique.fr
Figure 2. Some biologically active trifluoromethyl-hydroxy deriva-
tives.
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.11.086

456
L. Tournier, S. Z. Zard / Tetrahedron Letters 46 (2005) 455–459
OMe
(a)
OH
S
(b)
OAc
S
S
OMe
S
(a)
OH
S
Cl
(b)
80%
69%
F3C
F3C
OEt
F3C
OE
OH
S
F3C
F3C
OEt
F3C
OEt
OH
S
S
69%
18%
2a
2
2a
3
Scheme 1. Synthetic route to xanthate 2.6 Reagents: (a) KSC(@S)OEt,
H2SO4, acetone; (b) Ac2O, H2SO4, acetone.
Scheme 2. Synthetic route to xanthate 3.8 Reagents: (a) KSC(@S)OEt,
H2SO4, acetone; (b) PCl5.
trifluoroacetaldehyde with potassium O-ethylxanthate
in acetone and sulfuric acid gave xanthate 2a, which
was directly acetylated with acetic anhydride and a small
amount of sulfuric acid (Scheme 1). All the reagents are
commercially available and the procedure is easy to
scale up.
place smoothly as shown by the first three examples in
Table 2.7
We found that it was more satisfactory not to isolate the
reagent or any of the intermediates for that matter, but
to purify only the radical addition product 5. The over-
all unoptimised yield from the hemiacetal of trifluoro-
acetaldehyde was quite acceptable in most cases.
We were delighted to find that compound 2 indeed
underwent the radical addition almost as efficiently as
our first reagent. A high yield of adducts 2a could be se-
cured, merely by heating the two components together
in refluxing 1,2-dichloroethane (DCE) with the por-
tion-wise addition of a small amount of dilauroyl perox-
ide (DLP). The results are compiled in Table 1.7
The adducts lend themselves to a number of useful
transformations (Scheme 3). For example, exposure of
product 4b in THF to a solution of TBAF in THF re-
sulted in the formation of the pent-1-ene 6 in good yield
(74%).9 In the case of 5i, derived from N-vinyl pyrroli-
done, refluxing in chlorobenzene caused the elimination
of the xanthate to give olefin 7 in quantitative yield.
As with previous additions involving xanthates, the
present transformation occurs under mild, neutral con-
ditions and is therefore compatible with a variety of
functional groups. The easy synthesis of intermediate
2a directly from the hemiacetal of trifluoroacetaldehyde
and potassium O-ethylxanthate suggested the possibility
of accessing the corresponding chloride 3, by reaction
with PCl5 for example. In the event, xanthate 3 could
be prepared from 2a but in poor yield, as outlined in
Scheme 2. Compound 3 turned out to be somewhat
unstable to purification but its radical additions took
Alternatively, the xanthate group in the adduct can be
used to implement another radical reaction (Scheme
4). This is illustrated by the reductive cleavage using a
tin free procedure we developed a few years ago,10 as
shown by the transformation of 8 and 5c into com-
pounds 9 and 10, respectively.
In the case of adduct 4g, refluxing in the same solvent
with a gradual addition of peroxide induced ring-closure
Table 1. Radical additions of xanthate 2 to various olefins (Xa = S–C(@S)OEt)
Olefin
Reaction time (h)
Adduct
Yield %
78
Isomeric ratio
1/1
O
O
OAc Xa
4.5
4a
4b
N
N
F3C
F3C
O
O
OAc Xa
SiMe3
O
1.5
80
2/3
SiMe3
OAc Xa
OAc Xa
1.5
1.5
3
4c
4d
4e
4f
79
82
92
88
1/1
1/1
3/2
3/2
F3C
F3C
OAc
O
C(OEt)2
CN
C(OEt)2
OAc Xa
OAc Xa
CN
F3C
F3C
3
O
O
Br
N
Br
8
4g
71
1/1
OAc Xa
N
SO2Me
F3C
SO2Me

L. Tournier, S. Z. Zard / Tetrahedron Letters 46 (2005) 455–459
Table 2. Radical additions of xanthate 3 to various olefins
457
Olefin
Reaction time (h)
Adduct
Yield %
88
Isomeric ratio
Cl
Xa
Xa
SiMe3
OAc
1.5
5a
5b
2/3
6/1
SiMe3
OAc
F3C
Cl
1.5
3
74
65
F3C
O
O
Cl
Xa
Xa
5c
1/1
N
N
O
F3C
O
Cl
F3C
3
3
3
5
5da
5ea
5f
55
1/1
3/2
2/1
1/1
O
O
O
Cl
Xa
Xa
Xa
O
27
P(OMe)2
P(OMe)2
F3C
Cl
52a
49a
CN
CN
F3C
Cl
C(OEt)2
O
5g
C(OEt)2
F3C
Cl
Xa
5
5
5h
5i
28a
22a
2/1
1/1
O
F3C
Cl
Cl
Xa
O
Cl
N
F3C
N
O
a Yield based on the hemiacetal of trifluoroacetaldehyde (yield over three steps; Xa = S–C(@S)OEt).
O
TBAF
OAc Xa
OAc
O
O
S
SiMe3
O
NH
F3C
F3C
F3C
THF
74%
120% DLP
NH
O
4b
6
O
F3C
propan-2-ol
reflux
F3C
8
9
OAc Xa
PhCl
reflux
OAc
S
OEt
62%
N
F3C
N
quantitative
5i
7
O
O
O
N
110% DLP
O
Scheme 3. Transformation of adducts.
Cl
O
N
propan-2-ol
reflux
Cl
O
S
O
F3C
F3C
O
5c
10
78%
S
OEt
onto the aromatic ring gave the corresponding indoline
11 in 88% yield as a 1/1 mixture of diastereoisomers.11
SO2Me
N
MeO2S
O
N
Br
120% DLP
O
S
Finally, we found that exposure of the benzoate ana-
logue of reagent 2, alone, to a stoichiometric amount
of dilauroyl peroxide furnished a surprisingly good yield
of dimer 13 as a 1/1 mixture of the meso and dl isomers
(Scheme 5).
F3C
F3C
1,2-DCE
reflux
S
OEt
11
Br
4g
88%
isomeric ratio: 1/1
Scheme 4. Radical transformation of adducts.
The benzoate derivative was preferred for isolation pur-
poses. A simple route is thus in hand for accessing a pro-
tected form of 1,1,1,4,4,4-hexafluoro-2,3-butanediol, a
hitherto not easily available derivative.12 The formation
of dimer 13, which parallels a similar dimerisation previ-
ously observed with acetamido analogue 1,1 is not sur-
prising, a priori. What is surprising is the high yield of
homo-dimer in a medium that in principle contains
other radical species. We have observed such selectivity
previously in dimer formation when stabilised radicals
such as benzyl radicals were generated using xanthate
chemistry.13 Vidal and co-workers14 also very recently
reported the quantitative formation of a highly substi-
tuted dibenzyl dimer when the corresponding xanthate
was exposed to stoichiometric amounts of peroxide.
These various observations have profound mechanistic

458
L. Tournier, S. Z. Zard / Tetrahedron Letters 46 (2005) 455–459
O
O
In the present case, the two-step addition fragmentation,
combined with the high radicophilicity of the thio-
carbonyl group, results in a very powerful and self-
regulating radical transfer process.
140% DLP
S
O
O
CF3
O
BzCl
reflux
F3C
F3C
S
OEt
O
65%
isomeric ratio: 1/1
13
12
In summary, we have described preliminary results that
expand vastly our previous study. Access to a large vari-
ety of trifluoromethylated structures is now possible
using cheap and readily available starting materials.
Fluorinated compounds are crucially important to the
pharmaceutical and agrochemical industries because of
the profound influence that fluorine atoms have on bio-
logical activity.15
Scheme 5. Dimerisation of xanthate 12.
O
.
O
C11H23
C11H23
H23C11
O
- CO2
OBz
O
S
slow
F3C
S
OEt
Acknowledgements
12
C11H23
OEt
S
OBz
S
S
We wish to thank Rhodia Chimie Fine for generous
financial support to one of us (L.T.) and Drs. Jean-Marc
Paris and Franc¸ois Metz of Rhodia for friendly
discussions.
.
fast
.
H
23C11
+
F3C OBz
S
OEt
12
CF3
OBz
F3C
15
14
OBz
References and notes
CF3
S
OBz
S
F3C
.
OBz
OEt
F3C
1. Gasgoz, F.; Zard, S. Z. Org. Lett. 2003, 5, 2655–2657.
2. (a) Boivin, J.; Elkaim, L.; Zard, S. Z. Tetrahedron 1995,
51, 2573–2584; (b) Boivin, J.; Elkaim, L.; Zard, S. Z.
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16
13
Scheme 6. Mechanism for formation of dimer 13.
implications concerning the xanthate transfer process,
which set this method apart from the general Kharasch
type atom or group transfer reactions and explain its
considerable efficiency and generality. As outlined in
Scheme 6, decomposition of dilauroyl peroxide pro-
duces undecyl radicals. These rapidly add to the thiocar-
bonyl group of the xanthate to give 14 and are thus
effectively removed from the medium. The reverse reac-
tion is possible but is slow compared to the fragmenta-
tion that leads to radicals 15, since these are more
stabilised than simple undecyl radicals.
3. (a) Zard, S. Z. Angew. Chem., Int. Ed. Engl. 1997, 36, 672–
684; (b) Quiclet-Sire, B.; Zard, S. Z. Phosphorus, Sulfur,
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Koenig, J.; Jegham, S.; George, P.; Durant, F. Bioorg.
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Wada, C.; Garland, R.; Curtin, M.; Michaelides, M.; Li,
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Three different radicals thus remain in the medium: rad-
icals 15 as well as tertiary radicals 14 and 16. The last
two are stabilised by three heteroatoms, with no possi-
bility for disproportionation, and are quite hindered.
They do not therefore participate to any significant ex-
tent in radical–radical interactions. This leaves radicals
15 to undergo homo-coupling to give the observed
dimer 13. The presence of the xanthate thus ensures that
very few reactive radicals remain in the medium. These
radicals are stored as 14 or 16 and are liberated accord-
ing to their relative stabilities. A sufficiently high con-
centration of the more stabilised radicals is released to
give homo-dimer 13. Such an automatic regulation of
the concentration of the various radicals according to
their relative stabilities is not as effective in the case
of traditional Kharasch type reactions, where
exchange (usually of halides or chalcogenides) occurs
in one step.
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6. Synthesis of xanthate 2: to a solution of 2,2,2-trifluoro-1-
methoxy-ethanol (300 mg, 2.31 mmol) in 5 ml of acetone
was added portionwise potassium O-ethylxanthate
(737 mg, 4.62 mmol). The resulting mixture was cooled
at 0 °C and sulfuric acid (123.6 lL, 4.62 mmol) was added

L. Tournier, S. Z. Zard / Tetrahedron Letters 46 (2005) 455–459
459
dropwise. After 1 h at 0 °C, the mixture was warmed to
3H), 4.75 (q, J = 6.8 Hz, 2H), 6.27 (q, J = 8.4 Hz, 1H). 13
C
NMR (100 MHz, CDCl3) d 13.9, 22.6 (q, J = 35 Hz), 71.5,
121.1 (q, J = 280 Hz), 211.1. IR (CCl4) 2986, 2939, 1442,
1370, 1344, 1194, 1131, 1032 cmÀ1. MS (CI + NH3) m/z
239 (MH+).
room temperature, and concentrated under reduced
pressure. Ether was then added to the residue to precip-
itate the excess of xanthate salt, which was removed by
filtration. The filtered organic layer was concentrated to
give 2a (351 mg, 69%) as a yellow oil. To a solution of
xanthate 2a in 5 mL of acetone at 0 °C was added
dropwise 123.6 lL (2.31 mmol) of sulfuric acid, and then
217 lL (2.31 mmol) of acetic anhydride. After 1 h at 0 °C,
the mixture was brought to room temperature, and
concentrated under reduced pressure. The residue was
purified by flash column chromatography (silica gel,
eluant: ethyl acetate–petroleum ether 1/9) to give 2
(372 mg, 89%) as a yellow oil. 1H NMR (400 MHz,
CDCl3) d 1.48 (t, J = 5.8 Hz, 3H), 2.21 (s, 3H), 4.71 (q,
J = 5.8 Hz, 2H), 7.32 (q, J = 6.0 Hz, 1H). 13C NMR
(100 MHz, CDCl3) d 12.5, 21.0, 57.6 (q, J = 38 Hz), 70.4,
123.0 (q, J = 280 Hz), 206.9. IR (CCl4) 2986, 2939, 1778,
1442, 1370, 1344, 1194, 1131, 1032 cmÀ1. MS (CI + NH3)
m/z 262 (MH+), 279 (MNH4+).
9. We have found this to be a general method for the
introduction of allyl groups starting from xanthates.
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7. Typical procedure for radical addition: n mmol of xanthate
and 2n mmol of olefin dissolved in 1,2-dichloroethane
(2n mL) were refluxed for 15 min under argon. Dilauroyl
peroxide was then added portionwise (5 mol% every 1.5 h)
to the refluxing solution. When the xanthate was totally
consumed, the crude mixture was cooled to room
temperature, the solvent removed under reduced pressure,
and the residue purified by flash column chromatography.
8. Synthesis of xanthate 3: xanthate 2a (1.38 g, 6.3 mmol) and
phosphorus pentachloride (1.30 g, 6.3 mmol) were stirred
at room temperature for 1 h. The mixture was then
concentrated under reduced pressure and purified by flash
column chromatography (silica gel, eluent: ethyl acetate–
petroleum ether 1/9) to give 3 (270.7 mg, 18%) as a yellow
oil. 1H NMR (400 MHz, CDCl3) d 1.49 (t, J = 6.8 Hz,