Highly enantioselective transfer hydrogenation of fluoroalkyl ketones

Article abstract of DOI:10.1021/ol062358r

(Chemical Equation Presented) The asymmetric transfer hydrogenation of fluoroalkyl ketones mediated by [Ru(η⁶-arene)((S,S)-R ₂NSO₂DPEN)] catalysts using HCO₂H-Et ₃N afforded the corresponding alcohols

Full text of DOI:10.1021/ol062358r

ORGANIC
LETTERS
2006
Vol. 8, No. 26
5935-5938
Highly Enantioselective Transfer
Hydrogenation of Fluoroalkyl Ketones
Damjan Sˇ
terk,† Michel Stephan,*,†,‡ and Barbara Mohar*,†
Laboratory of Organic and Medicinal Chemistry, National Institute of Chemistry,
HajdrihoVa 19, SI-1001 Ljubljana, SloVenia, and PhosPhoenix SARL,
115, rue de l’Abbe´ Groult, F-75015 Paris, France
mstephan@phosphoenix.com; barbara.mohar@ki.si
Received September 26, 2006
ABSTRACT
The asymmetric transfer hydrogenation of fluoroalkyl ketones mediated by [Ru(
afforded the corresponding alcohols with high ee’s and in excellent yields.
η −Et3N
6-arene)((S,S)-R2NSO2DPEN)] catalysts using HCO2H
Selectively fluorinated chiral organics have played an
important role in the development of medicines, agrochemi-
cals, and materials owing to the unique properties of the
fluorine atom.1 In particular, optically active R-trifluoro-
methyl alcohols are of interest as they are potentially useful
in the synthesis of various trifluoromethyl-containing chiral
structures.2
The preparation of fluoroalkyl alcohols via enantioselective
reduction of the corresponding ketones is a convenient
synthetic approach. Such compounds were prepared through
hydroboration using a stoichiometric amount of DIP-
chloride,3 Rh- or Ru-catalyzed asymmetric hydrogenation at
10-50 atm of H2,4 or relying upon microorganisms.5
However, these routes are not general to access a variety of
substrates and suffer from obvious technical difficulties.
Asymmetric transfer hydrogenation has received consider-
able attention in the past decade with promising success since
the discovery of the Ru(II)-N-tosyl-1,2-diphenylethylenedi-
amine (Ru(II)-TsDPEN) catalyst by Noyori et al.6
We were interested to extend our ongoing research
program in asymmetric reductions to the reduction of
fluoroorganics. Accordingly, we undertook the task of
investigating asymmetric transfer hydrogenation of a string
of fluoroalkyl ketones using our Ru(II)-R2NSO2DPEN
catalyst system. This catalyst system is prepared in situ by
heating [RuCl2(η6-arene)]2 and (S,S)-R2NSO2DPEN ligands
(1a-d) in DMF at 80 °C for 20 min. Noteworthy is that
both enantiomers of DPEN are commercially available, and
our catalysts proved to be excellent for the asymmetric
transfer hydrogenation of various classes of ketones.7 Bearing
this in mind and on the basis of limited literature results,8
we anticipated a high ee for the product alcohols in the
† National Institute of Chemistry.
‡ PhosPhoenix SARL.
(1) (a) Enantiocontrolled Synthesis of Fluoro-organic Compounds;
Soloshonok, V. A., Ed.; Wiley: Chichester, 1999. (b) Ma, J.; Cahard, D.
Chem. ReV. 2004, 104, 6119-6146. (c) Mohar, B.; Sˇterk, D.; Ferron, L.;
Cahard, D. Tetrahedron Lett. 2005, 46, 5029-5031 and references cited
therein.
(2) (a) Mikami, K. In Asymmetric Fluoroorganic Chemistry: Synthesis,
Application and Future Directions; Ramachandran, P. V., Ed.; American
Chemical Society: Washington, DC, 2000; pp 255-269. (b) Mikami, K.;
Itoh, Y.; Yamanaka, M. Chem. ReV. 2004, 104, 1-16.
(3) Ramachandran, P. V.; Teodorovic´, A. V.; Brown, H. C. Tetrahedron
1993, 49, 1725-1738.
(4) (a) Ohkuma, T.; Koizumi, M.; Doucet, H.; Pham, T.; Kozawa, M.;
Murata, K.; Katayama, E.; Yokozawa, T.; Ikariya, T.; Noyori, R. J. Am.
Chem. Soc. 1998, 120, 13529-13530. (b) Kuroki, Y.; Sakamaki, Y.; Iseki,
K. Org. Lett. 2001, 3, 457-459. (c) Jeulin, S.; de Paule, S. D.; Ratovelo-
manana-Vidal, V.; Geˆnet, J.-P.; Champion, N.; Dellis, P. Angew. Chem.,
Int. Ed. 2004, 43, 320-325.
(5) (a) Fujisawa, T.; Onogawa, Y.; Sato, A.; Mitsuya, T.; Shimizu, M.
Tetrahedron 1998, 54, 4267-4276. (b) Nakamura, K.; Matsuda, T.; Shimizu,
M.; Fujisawa, T. Tetrahedron 1998, 54, 8393-8402. (c) Matsuda, T.;
Harada, T.; Nakajima, N.; Itoh, T.; Nakamura, K. J. Org. Chem. 2000, 65,
157-163.
(6) (a) Hashiguchi, S.; Fujii, A.; Takehara, J.; Ikariya, T.; Noyori, R. J.
Am. Chem. Soc. 1995, 117, 7562-7563. (b) Fujii, A.; Hashiguchi, S.;
Uematsu, N.; Ikariya, T.; Noyori, R. J. Am. Chem. Soc. 1996, 118, 2521-
2522.
(7) Sˇterk, D.; Stephan, M.; Mohar, B. Tetrahedron: Asymmetry 2002,
13, 2605-2608.
10.1021/ol062358r CCC: $33.50
© 2006 American Chemical Society
Published on Web 11/18/2006

reduction of fluoroalkyl ketones. Such fluorinated ketones
are either commercially available or easily accessible in 1-2
steps according to reported literature procedures.3,9
cym)((S,S)-1c)], benzyl trifluoromethyl ketone was reduced
with 97% ee (S) in 2 h with a S/C ) 200 (entries 9-12),
whereas phenyl acetone was reduced with ∼5% ee and 13%
conversion in 2 h using a S/C ) 100 (Figure 1). As an
exception to this trend, 2,2,2-trifluoroacetophenone was
reduced in 2 h albeit with 38% ee (R) (entry 7), and
acetophenone was reduced with 95% ee (S) using a S/C )
100 in 24 h (50% conversion).7 Here, the sense of asymmetric
induction is unchanged. Thus, one can conclude that in the
particular case of 2,2,2-trifluoroacetophenone the CF3 group
behaves as a smaller group to the Ph. It is noteworthy to
mention that octafluoroacetophenone was exceptionally reac-
tive and was reduced in the presence or absence of the
catalyst giving rise to the racemic alcohol (entry 8).
Reduction of cyclohexyl trifluoromethyl ketone using [Ru-
(mesitylene)((S,S)-1d)] led to 66% ee (S) (entries 5 and 6).
In this case, the sense of asymmetric induction is opposite
to the one observed with 2,2,2-trifluoroacetophenone and
follows the general observed trend of enantioselectivity.
Hexyl, (2-phenyl)ethyl, benzyl, (pyridin-2-yl)methyl, (py-
ridin-4-yl)methyl, (pyrimidin-4-yl)methyl, and (benzoxazol-
2-yl)methyl trifluoromethyl ketones were reduced using
[Ru(η6-arene)((S,S)-1a-d)] with high ee’s (93-99% (S))
(entries 1-4, 9-12, and 15-25). With low catalyst loading
(S/C ) 2000), benzyl trifluoromethyl ketone was reduced
with 97% ee in 20 h (entry 11). Benzyl perfluoropropyl
ketone was reduced equally well with a high ee as in the
case of the trifluoromethyl analogue (entries 13 and 14).
Although a S/C ) 200 and 2 h were sufficient for the
complete reduction of hexyl, (2-phenyl)ethyl, benzyl, and
(pyridin-2-yl)methyl trifluoromethyl ketones, in the case of
(pyridin-4-yl)methyl and (benzoxazol-2-yl)methyl trifluo-
romethyl ketones, 8 h was needed to achieve full conversion,
and with (pyrimidin-4-yl)methyl trifluoromethyl ketone, a
S/C ) 25 and 4 h were required.
In addition, we investigated the reduction of 1-(pyridin-
2-yl)ethyl trifluoromethyl ketone as we anticipated a dynamic
kinetic resolution to occur during the reaction (entries 18-
20). In a preliminary experiment using HCO2H-Et3N (5:
2), a dr of 54:46 was obtained with 99% and 94% ee,
respectively. Interestingly, the dr ratio was significantly
improved reverting to HCO2H-Et3N (3:2). Thus, a dr of 78:
22 was attained with 99% and 84% ee, respectively. The ee
of the major (+)-erythro enantiomer was increased to 100%
by recrystallization.
Transfer hydrogenation of 1,1,1-trifluoro-5,5-dimethyl-2,4-
hexanedione occurred regioselectively with the sole reduction
of the trifluoromethylcarbonyl group (entries 26 and 27). The
product alcohol was obtained with excellent ee (99%).
γ-Fluorinated â-keto esters are interesting substrates to
undergo reduction to the chiral γ-fluoro â-hydroxy esters
which are useful building blocks. Several research groups
were active in developing methods for their reduction.4c,11
From the first result of the test substrate ethyl 2,2,2-
Thus, a variety of fluoroalkyl ketones were reduced on a
1 mmol scale under our standard conditions at room
temperature using HCO2H-Et3N (5:2) in DMF and catalyzed
by [Ru(η6-arene)((S,S)-R2NSO2DPEN)] with a substrate/
catalyst molar ratio (S/C) of 200-2000. The results of
transfer hydrogenation of selected fluoroalkyl ketones are
presented in Table 1. To the best of our knowledge, this
present work constitutes the first extended study of asym-
metric reduction of various classes of fluoroalkyl ketones
under transfer hydrogenation conditions.
As we have previously reported, transfer hydrogenation
using our [Ru(η6-arene)((S,S)-R2NSO2DPEN)] catalysts with
HCO2H-Et3N can be best carried out in polar media such
as DMF, DMA, NMP, and the like.7 The η6-arene ligand
(i.e., benzene, p-cymene, mesitylene, 1,3,5-triethylbenzene,
hexamethylbenzene) can influence the outcome of the
reduction. For example, the catalyst possessing η6-arene )
benzene leads in general to 10-20% lower ee’s, and the one
with η6-arene ) hexamethylbenzene is less active compared
to the rest. The modification of the R2NSO2 group in the
R2NSO2DPEN ligand can serve to fine tune the enantio-
selectivity (ee enhancement up to 2%) against a selected
target. These observations are also valid for the fluoroalkyl
ketones in Table 1.
In general, Ru(II)-R′′SO2DPEN catalysts with R′′ ) Ar,
RF, or R2N only reduce activated ketones (i.e., aryl ketones,
R- and â-keto esters, R,â-unsaturated ketones, 1,2-di-
ketones)10 with high optical and chemical yields. As can be
seen from Table 1, various classes of fluoroalkyl ketones
can be reduced using our catalytic system leading to very
high ee’s and in a consistent manner. Thus, alkyl, arylmethyl,
(2-aryl)ethyl, and (alkoxycarbonyl)methyl trifluoromethyl
ketones and their perfluoroalkyl higher homologues were
reduced to their corresponding alcohols with up to 99% ee
within 2 h using a S/C ) 200.
Fluoroalkyl ketones constitute suitable substrates for
transfer hydrogenation compared to their nonfluorinated
counterparts, and trifluoromethyl ketones are reduced in a
faster rate than phenyl ketones. For example, using [Ru(p-
(8) (a) Tada, K.; Miura, T. JP 2003034665, 2003; Chem. Abstr. 2002,
137, 369737. (b) Sˇterk, D.; Stephan, M.; Mohar, B. Tetrahedron Lett. 2004,
45, 535-537.
(9) (a) Linderman, R. J.; Lonikar, M. S. J. Org. Chem. 1988, 53, 6013-
6022. (b) Xavier, C. J. Org. Chem. 1987, 52, 5026-5030. (c) Kawase, M.;
Teshima, M.; Saito, S.; Tani, S. Heterocycles 1998, 48, 2103-2109. (d)
Archer, S.; Perianayagam, C.; Sevenard, D. V.; Lork, E. J. Fluorine Chem.
2004, 125, 125-128. (e) Archer, S.; Perianayagam, C. J. Med. Chem. 1979,
22, 306-309.
(10) (a) Zanotti-Gerosa, A.; Hems, W.; Groarke, M.; Hancock, F.
Platinum Metals ReV. 2005, 49, 158-165 and references cited therein. (b)
Hannedouche, J.; Clarkson, G. J.; Wills, M. J. Am. Chem. Soc. 2004, 126,
986-987. (c) Mohar, B.; Valleix, A.; Desmurs, J.-R.; Felemez, M.; Wagner,
A.; Mioskowski, C. J. Chem. Soc., Chem. Commun. 2001, 2572-2573.
(11) (a) Sayo, N.; Akutagawa, S.; Saito, T.; Noyori, R.; Kumobayashi,
H.; Takaya, H. EP295109, 1988; Chem. Abstr. 1989, 111, 39010. (b) von
Arx, M.; Mallat, T.; Baiker, A. Angew. Chem., Int. Ed. 2001, 40, 2302-
2305. (c) Xu, C.; Yuan, C. Tetrahedron 2005, 61, 2169-2186.
5936
Org. Lett., Vol. 8, No. 26, 2006

Table 1. Transfer Hydrogenation of Fluoroalkyl Ketonesa
a HCO2H-Et3N (5:2) (420 µL) was added to a mixture of the ketone (1 mmol) and the preformed [RuCl(η6-arene)((S,S)-R2NSO2DPEN)] in DMF (1 mL)
and was left under stirring at 25 °C until GC indicated 100% conversion. Isolated yield: 85-98%. b Determined by chiral GC unless otherwise noted.
c HCO2H-Et3N (3:2) used. d Determined by 19F NMR of its (1S)-camphanic acid ester. e ee after upgrading by recrystallization. f Assigned by comparing
the sign of the optical rotation of the isolated product with the lit. data. g Assigned by analogy with the tR of chiral GC analysis of related homologous
alcohols of the table. h Determined by X-ray analysis. i Determined by X-ray analysis of its (1S)-camphanic acid ester. For further details, see Supporting
Information.
trifluoroacetoacetate, we were pleased to find that our catalyst
system (S/C ) 2000) is able to furnish under mild conditions
the corresponding γ-trifluoro â-hydroxy ester with a superior
ee (98%) (entries 29 and 30) compared to the results of other
metal-catalyzed hydrogenations (using 1 mol % of [RuBr-
(S-difluorphos)] at 10 bar H2, 110 °C, 1 h, 70% ee4c and
using [RuHCl(binap)2], S/C ) 1000, at 80 kg/cm2 H2, 30
°C, 16 h, 46% ee11a) or transfer hydrogenations (using [Ru-
(p-cym)(TsDPEN)], S/C ) 500, HCO2H-Et3N (5:2), THF,
35 °C, 15 h, 96% ee).8a Reduction of ethyl 4,4,5,5,5-
pentafluoro-3-oxopentanoate revealed similar efficiency of
the catalyst (99% ee) (entries 31-33). Further investigation
with R-trifluoroacetyl-lactones (C4 and C5) showed that a
dynamic kinetic resolution occurred during the transfer
hydrogenation (entries 34-36). With the lactone C4, a dr of
89:11 (syn/anti) was obtained with 97% (S,S-syn) and 81%
(anti) ee, respectively. Lactone C5 behaved in a similar
manner giving rise to a dr of 88:12 (syn/anti) with 96% (S,S-
syn) and 94% (anti) ee, respectively. The 96% ee of the major
S,S-syn-enantiomer was increased to 100% by recrystalli-
zation, and its absolute configuration was confirmed by X-ray
analysis of its (1S)-camphanic acid ester.
Org. Lett., Vol. 8, No. 26, 2006
5937

In summary, this work constitutes the first extended study
of asymmetric reduction of various classes of fluoroalkyl
ketones under transfer hydrogenation conditions. Chiral
R-trifluoromethyl alcohols and their perfluoroalkyl higher
homologues were prepared in excellent optical (up to 100%
ee) and chemical yields (85-100%) through ketone reduction
catalyzed by our Ru(II)-R2NSO2DPEN (0.05-0.5 mol %)
complexes using HCO2H-Et3N in DMF at room tempera-
ture. Several fluoroalkyl ketones were asymmetrically re-
duced for the first time. This asymmetric approach allows
easy isolation of the chiral fluoroalkyl alcohol in either
enantiomeric form, and new opportunities for industrial
synthetic implementation may evolve. Further synthetic
applications of this catalytic system are in progress.
Acknowledgment. Financial support from the Ministry
of Higher Education, Science and Technology of the
Republic of Slovenia through grant P1-242 is kindly
acknowledged. We thank as well Dr. Barbara Modec
(University of Ljubljana) for X-ray structure analysis.
Figure 1. General sense of asymmetric transfer hydrogenation
catalyzed by [Ru(η6-arene)((S,S)-R2NSO2DPEN)].
The analysis of the results of transfer hydrogenation using
our Ru(II)-R2NSO2DPEN catalyst of 2,2,2-trifluoroacetophe-
none, cyclohexyl, or alkyl trifluoromethyl ketones, ethyl
2,2,2-trifluoroacetoacetate and ethyl benzoylacetate,7 brings
us to establish the relative order of magnitude of group
bulkiness as follows: Ph > CF3 > cHex > CH2. Interestingly
enough, in the reduction of trifluoromethyl ketones with DIP-
chloride, the CF3 group behaves as though it is bulkier than
Ph.3
Supporting Information Available: Experimental pro-
cedures and characterization data for chiral fluoroalkyl
alcohols. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL062358R
5938
Org. Lett., Vol. 8, No. 26, 2006