New catalytic oxidation of trifluoromethyl carbinols by a ruthenium(II) complex

Article abstract of DOI:10.1016/S0040-4039(00)00378-6

The first catalytic oxidation of trifluoromethyl carbinols has been accomplished by a novel ruthenium(II) complex using sodium periodate as an oxidant. Trifluoromethyl ketones were obtained under mild conditions and in excellent yields. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00378-6

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 3327–3330
New catalytic oxidation of trifluoromethyl carbinols by a
ruthenium(II) complex
Venkitasamy Kesavan,a Danièle Bonnet-Delpon, Jean-Pierre Bégué,a,∗ Abirami Srikanth b and
Srinivasan Chandrasekaran b
aLaboratoire BIOCIS associé au CNRS, Centre d’Etudes Pharmaceutiques, Rue J. B. Clément, 92296 Châtenay-Malabry,
France
bDepartment of Organic Chemistry, Indian Institute of Science, Bangalore 560 012, India
Received 23 December 1999; accepted 2 March 2000
Abstract
The first catalytic oxidation of trifluoromethyl carbinols has been accomplished by a novel ruthenium(II)
complex using sodium periodate as an oxidant. Trifluoromethyl ketones were obtained under mild conditions and
in excellent yields. © 2000 Elsevier Science Ltd. All rights reserved.
Fluorinated ketones, especially trifluoromethyl ketones, are of great interest because of their remar-
kable ability to function as enzyme inhibitors,1 and because of their role as building blocks for trifluo-
romethyl heterocycles2 and as monomers for novel polymeric materials.3 Besides traditional methods
involving the addition of Grignard or organo lithium reagents to trifluoroacetic acid,4 other more recent
methods such as the Wittig reaction with trifluoroacetamides,5 or the reaction of acid chlorides with
trifluoroacetic anhydride6 brought great improvement to the access to trifluoromethyl ketones.
On the other hand, the facile addition of TMSCF3 to aldehydes constitutes excellent access to tri-
fluoromethyl carbinols.7,8 However, their oxidation to ketones is not straightforward. Classical oxidation
10
1a
procedures such as the use of MnO2,9 KMnO4 and CrO3 are often unsuccessful or require harsh
conditions which are not suitable for some functional groups. Swern and modified Moffat oxidation
methodologies very often fail or poorly succeed in the case of fluoroalkyl alcohols,11 despite some
described examples.12 The only reliable procedure available in the literature is the oxidation by the
Dess–Martin reagent.13 However, its explosive nature and high air and moisture sensitivity limit its
utility. To the best of our knowledge, no catalytic method for this oxidation has been reported so far.
So there is still a need for a new methodology for the oxidation of trifluoromethyl carbinols. There
has been considerable interest in recent years in the use of oxoruthenium complexes as catalysts for
organic oxidation.14 In this communication, we wish to report our successful efforts on the oxidation of
∗
Corresponding author. Fax: 33 1 46 83 57 38; e-mail: jean-pierre.begue@cep.u-psud.fr (J.-P. Bégué)
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00378-6
tetl 16658

3328
trifluoromethyl carbinols using a novel ruthenium(II) complex RuCl2(biox)2 1 which is known to oxidise
olefins to epoxides in very good yields in a stereospecific manner under aerobic conditions.15
Initial studies focused on the oxidation of 5-phenyl-1,1,1-trifluoropentan-2-ol 2 under aerobic condi-
tions: trifluoromethyl carbinol 2 was treated with 2.5 mol% of RuCl2(biox)2 1 in dichloromethane using
pivalaldehyde as the co-reductant in an atmosphere of oxygen. After 48 h at ambient temperature only
a 30% conversion was observed. When the reaction was run at reflux temperature in dichloromethane,
no change in the conversion was observed. With 1.5 equivalents of NaIO4 and 2.5 mol% of 1, a 45%
conversion was observed at room temperature after 48 h. There was further optimisation to afford the
corresponding trifluoromethyl ketone 3 in 84% yield after 32 h by performing the reaction at reflux
temperature in dichloromethane.16 We have checked that NaIO4 acts as a co-oxidant and not as an
active oxidant: when the reaction was performed without a ruthenium catalyst the starting alcohol 2
was recovered. A series of fluorinated carbinols have been prepared18 and subjected to oxidation with
RuCl2(biox)2 1 under the optimised conditions. The results are summarised in Table 1.
With 1.5 equivalents of NaIO4, 2.5 mol% of 1 at reflux in CH2Cl2, phenyl-substituted 1,1,1-
trifluoropentan-2-ols could be oxidised to the corresponding ketones in good yields. 5-Phenyl-1,1,1-
trifluoropentan-2-ol 2, 5-(4-methoxyphenyl)-1,1,1-trifluoropentan-2-ol 4 and 5-(4-chlorophenyl)-1,1,1-
trifluoropentan-2-ol 6 exhibited similar reactivity leading to the corresponding ketones 3, 5 and 7 in good
yields with no detectable influence of the substituents.
1-Phenyl-2,2,2-trifluoroethanol 8 could be easily and quantitatively oxidised to afford 2,2,2-
trifluoroacetophenone 9. Only 76% of the product could be isolated because of the volatility of ketone
9. Under similar reaction conditions, 1-(4-methoxyphenyl)-2,2,2-trifluoroacetophenone 11 and 1-(3,4-
dimethoxyphenyl)-2,2,2-trifluoroacetophenone 13 were obtained in excellent yields by oxidation of the
corresponding alcohols 10 and 12, respectively. As expected, the oxidation of these aromatic alcohols
was easier than that of alkyl-substituted alcohols, with a shorter reaction time (8 h), and it could even
been carried out at room temperature with a prolonged reaction time (24 h).
The efficiency of this methodology was proven in the oxidation of α,α-disubstituted alcohols: although
the conversion of 1-cyclohexyl-2,2,2-trifluoroethanol 16 into ketone 17 was very slow (50 h) the reaction
went to completion and the lower isolated yield was due to the volatility of ketone 17. The reaction
was also successful with long chain alcohols such as 18 and 20, which are usually less reactive.13
Thus, oxidation of 1,1,1-trifluoromethyl dodecan-2-ol 18 and 1,1,1-trifluoromethyl nonadecan-2-ol 20
afforded ketones 19 and 21 in quantitative yields. To oxidise these trifluoromethyl carbinols, only the
CrO3/pyridine mixture under severe conditions1a and the Dess–Martin reagent are described in the
literature. The trifluoromethyl alcohol 2219 derived from lithocholic acid was selectively oxidised to
the corresponding ketone 2320 in 90% yield after 22 h.
We have also shown, in the reaction with the pyridyl alcohol 24,21 that the oxidation is chemoselective.
After 10 h, the trifluoromethyl ketone 25 was obtained as the only product and was isolated in an excellent
yield (87%).
Thus, we have developed the first catalytic method for the oxidation of trifluoromethyl carbinols using
sodium periodate and RuCl2(biox)2 1 with high efficiency. Even alkyl trifluoromethyl carbinols and α,α-
disubstituted ones can be converted in high yields into ketones. The pyridyl moiety remains unaffected
under these oxidation conditions.

3329
Table 1
Oxidation of trifluoromethyl carbinol with RuCl2(biox)2
Acknowledgements
We thank CEFIPRA for the financial support and a research associateship grant (V.K.).

3330
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16. Typical procedure: NaIO4 (0.320 mg, 1.5 mmol, 1.5 equiv.) and RuCl2(biox)2 1 (4.5 mg, 0.01 mmol, 0.0045 equiv.) was
added to a solution of alcohol 2 (218 mg, 1 mmol) in CH2Cl2 (4 mL), and the mixture was refluxed until disappearance
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the presence of TBAF.8
23
1
19. Mp: 77–79°C [α]D +43 (c 1, CHCl3), IR (Nujol) 2910, 1370, 1250, 1020, 978 cm−1. H NMR (CDCl3, 200 MHz):
0.52–1.92 (m, 35H), 0.93 (s, 3H), 1.12 (s, 3H), 2.15 (s, 3H), 4.65 (m, 1H), 5.2 (m, 1H). 13C NMR (CDCl3, 50 MHz): 12.3,
13.4, 18.7, 21.1, 22.4, 25.6, 26.3, 27.4, 28.8, 30.5, 31.8, 33.2, 33.7, 34.1, 37.6, 47.3, 73.9, 76.2 (q, J=33 Hz), 112.6 (q,
J=288 Hz), 170.2. 19F NMR (CDCl3, 188 MHz): 80.1 (d, J=4.2 Hz). Analysis for C25H44O3F3: calcd: C, 66.80; H, 9.86.
Found: C, 66.88; H, 9.72.
20. Mp: 63–65°C [α]D23 +55 (c 1, CHCl3), IR (Nujol) 2915, 1745, 1372, 1260, 1014, 978 cm−1. 1H NMR (CDCl3, 200 MHz):
0.45–1.94 (m, 33H), 0.93 (s, 3H), 1.15 (s, 3H), 2.10 (s, 3H), 4.62 (m, 1H). 13C NMR (CDCl3, 50 MHz): 11.8, 13.4, 18.9,
190.1, 21.6, 22.4, 25.3, 26.1, 27.4, 28.2, 30.9, 31.4, 33.0, 32.7, 34.1, 38.6, 46.3, 72.9, 114.7 (q, J=290 Hz), 170.2, 190.1 (q,
J=33 Hz). 19F NMR (CDCl3, 188 MHz): 79.5 (s). Analysis for C25H42O3F3: calcd: C, 67.08; H, 9.45. Found: C, 67.15; H,
9.56.
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