Enantioselective synthesis of 1,1,1-trifluoroalkan-2-ols by ruthenium- catalyzed hydrogenation

Article abstract of DOI:10.1016/S0040-4039(00)00643-2

The highly enantioselective synthesis of 1,1,1-trifluoroalkan-2-ols has been achieved by hydrogenating 1,1,1-trifluoroalkan-2-one enol acetates in the presence of chiral ruthenium catalysts. An enol acetate, 2-acetoxy-3,3,3- trifluoro-1-(phenylthio)propen

Full text of DOI:10.1016/S0040-4039(00)00643-2

Tetrahedron Letters 41 (2000) 4603±4607
Enantioselective synthesis of 1,1,1-tri¯uoroalkan-2-ols by
ruthenium-catalyzed hydrogenation
Yoshichika Kuroki, Daisuke Asada, Yuko Sakamaki and Katsuhiko Iseki*
MEC Laboratory, Daikin Industries, Ltd., Miyukigaoka, Tsukuba, Ibaraki 305-0841, Japan
Received 22 March 2000; accepted 14 April 2000
Abstract
The highly enantioselective synthesis of 1,1,1-tri¯uoroalkan-2-ols has been achieved by hydrogenating
1,1,1-tri¯uoroalkan-2-one enol acetates in the presence of chiral ruthenium catalysts. An enol acetate,
2-acetoxy-3,3,3-tri¯uoro-1-(phenylthio)propene, can be successfully transformed into enantiomerically
pure tri¯uorolactic acid. # 2000 Elsevier Science Ltd. All rights reserved.
Keywords: asymmetric synthesis; catalysts; ¯uorine and compounds; hydrogenation.
The catalytic asymmetric synthesis of chiral ¯uoroorganic compounds has played an important
role in the development of medicines and materials in consideration of the in¯uence of ¯uorine's
unique properties.1 Homochiral a-tri¯uoromethyl alcohols are versatile intermediates for the
synthesis of anti-ferroelectric liquid crystalline molecules.2 A variety of asymmetric catalyses for
preparing the alcohols have been reported.3 7 However, their synthesis has drawbacks such as
insucient levels of enantioselectivity, low catalytic eciencies and limited scope of the substrates.
This paper discloses herein the catalytic asymmetric hydrogenation of 1,1,1-tri¯uoroalkan-2-one
enol acetates (1) catalyzed by ruthenium±chiral ligand complexes to provide 1,1,1-tri¯uoroalkan-2-ol
acetates (2) with high enantioselectivity.
The enol acetate 1 was prepared in yields greater than 90% by treatment of 1,1,1-tri¯uoroalkan-2-
one (3) with acetic anhydride and pyridine at room temperature. The NOE observation between
the ¯uorine atoms and the ole®nic proton H-3 disclosed that the (Z)-ole®n 1 was obtained as the
sole product (Fig. 1).8
The asymmetric hydrogenation reactions of (Z)-2-acetoxy-1,1,1-tri¯uorododec-2-ene (1a),
chosen as the model substrate, were carried out using four ruthenium and rhodium complexes in
order to examine their ability as chiral catalysts.9,10 The results are summarized in Table 1. The
reaction using a 1.0 mol% cationic ruthenium catalyst, [RuCl((R)-binap)(p-cymene)]Cl (4),11 was
* Corresponding author. Tel: +00 81 298 58 5060; fax: +00 81 298 5082; e-mail: katsuhiko.iseki@daikin.co.jp
0040-4039/00/$ - see front matter # 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00643-2

4604
Figure 1.
conducted in MeOH at 50ꢀC and 4 atm H2 for 18 h to a€ord (R)-2-acetoxy-1,1,1-tri-
¯uorododecane (2a) in >99% ee and 98% yield (entry 1). Use of EtOH and i-PrOH in place of
MeOH did not a€ect the enantioselectivity but remarkably suppressed the hydrogenation rate
(entries 2 and 3),12 suggesting that protons from protic solvents are incorporated into the C-2 and
C-3 positions.13,14 The incorporation may be sluggish in EtOH and i-PrOH. Decreasing the
reaction temperature to 0ꢀC completely disturbed the hydrogenation (entry 4). The catalyst 4
mediated the hydrogenation without the loss of either enantioselectivity or activity with a catalyst
loading as low as 0.04 mol% although a prolonged reaction time was necessary (entries 5 and 6).
Table 1
Enantioselective hydrogenation reactions of 2-acetoxy-1,1,1-tri¯uorododec-2-ene (1a) in the presence of chiral ruthe-
nium and rhodium complexes

4605
Although two other ruthenium catalysts, RuCl2((S)-binap) (5)15 and [RuCl((R)-biphemp)(p-
cymene)]Cl (6),16 also gave excellent optical yields (entries 7 and 8), a cationic rhodium catalyst,
[Rh(cod)((S,S)-Me-duphos)]OTf, (7)3b,17 showed a slightly lower enantioselectivity (92% ee,
entry 9). The nearly enantiopure 2a was deacetylated without racemization by treatment with
K2CO3 in MeOH at room temperature to quantitatively give the corresponding a-tri¯uoromethyl
alcohol.
Table 2 summarizes the results obtained from the hydrogenation of a variety of enol acetates
1b±j using a 0.1 mol% ruthenium catalyst, either 4, 5, or 6, in MeOH at 50 or 100ꢀC for 42 h. The
hydrogenation reactions of (Z)-2-acetoxy-1,1,1-tri¯uorohept-2-ene (1b) and (Z)-2-acetoxy-1,1,1-
tri¯uorodec-2-ene (1c) proceeded in the presence of the catalyst 5 at 100ꢀC and 10 atm H2 to give
the corresponding products, 2b and 2c, with 98% ee in 94% yield (entries 1 and 2). Enol acetates
having the branched alkyl group R (1d and 1e) were hydrogenated using the catalyst 4 at 50ꢀC
and 4 atm H2 to a€ord the (R)-acetates with enantiomeric excesses of >99% and 95%, respec-
tively (entries 3 and 4). However, the attachment of a phenyl group at the ole®nic carbon failed in
the reaction under the same conditions (entry 5). The hydrogenation of an ethoxycarbonyl-
containing substrate 1g was carried out in EtOH with an excellent level of enantioselectivity
although the chemical yield was not very good (entry 6). The enol acetate 1h bearing a phenylthio
moiety at the ole®nic carbon was hydrogenated using the catalyst 6 at 100ꢀC and 20 atm H2, and
gave the corresponding product 2h in 83% yield and 89% ee (entry 7). Replacement of the acetyl
of 1a with a benzoyl group did not a€ect the yield and enantioselectivity (Table 1, entry 5 vs
Table 2, entry 8). The enol acetate 1j having a penta¯uoroethyl group in place of the CF3 is also a
good substrate for the hydrogenation (entry 9).
Table 2
Enantioselective hydrogenation of various enol esters 1b±j catalyzed by chiral ruthenium complexes (4±6)

4606
Finally, the optically active 2-acetoxy-1,1,1-tri¯uoro-3-(phenylthio)propane (2h) was shown to be
a useful intermediate for preparing the enantiomerically pure tri¯uorolactic acid (8) in Scheme 1.
The treatment of (S)-2h (89% ee) with SO2Cl2 and pyridine in CH2Cl2 at room temperature for 3
h a€orded the a,a-dichlorosul®de 9 in quantitative yield.23 The hydrolysis of 9 by re¯uxing in a
mixture of 12 M HCl and MeOH (3:20) for 40 h and in 2 M HCl for 18 h gave the acid 8 in 80%
yield. A single recrystallization of this material from Et2O±CHCl3 provided a 61% recovery of
25
D
rt
D
the homochiral (R)-(+)-8 {‰ꢀŠ +21.1 (c 0.95, EtOH), lit.24 ‰ꢀŠ +21.0 (c 1.98, EtOH)}.
Scheme 1. Preparation of enantiomerically pure (R)-(+)-tri¯uorolactic acid (8)
In conclusion, we have described the highly enantioselective hydrogenation of 1,1,1-tri-
¯uoroalkan-2-one enol acetates mediated by chiral ruthenium catalysts. Applications of this
method to the synthesis of versatile chiral ¯uorinated molecules are now being carried out.
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4607
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