or the alkynylation of trifluoromethyl aryl ketones.6 A couple
of years ago, Shibasaki and Kanai et al. reported the copper(I)
alkoxide-catalyzed enantioselective alkynylation of triflu-
oromethyl ketones to provide trifluoromethyl-substituted
tertiary propargyl alcohol up to 52% ee.6 Although the result
of 52% ee is moderate, to our knowledge, this is the highest
value for the catalytic enantioselective synthesis of pharma-
ceutically important aryl trifluoromethyl propargyl alcohols
so far reported. We now report the first examples of the
catalytic asymmetric direct trifluoromethylation of propargyl
ketones 1 by trimethylsilyl trifluoromethane (Me3SiCF3) to
produce desired trifluoromethyl-propargyl alcohols 2 with a
quaternary carbon center up to 96% ee. The catalyst
combination composed of cinchona alkaloid 3a and tetra-
methyl ammonium fluoride (Me4NF) was found to be very
general for this transformation. The resulting trifluoromethyl-
propargyl alcohols can be further transformed, yielding the
biologically attractive aryl heteroaryl trifluoromethyl carbinols
4 (Scheme 1).
ously unknown catalytic asymmetric trifluoromethylation
processes of alkynyl aryl ketones to produce tertiary alcohols
that contain a trifluoromethyl group at a propargyl position
was of interest.6 Our initial attempt at asymmetric trifluo-
romethylation of ethynyl phenyl ketone 1a with Me3SiCF3
in the presence of catalytic amounts of N-3,5-bis(trifluorom-
ethylbenzyl)cinchonium bromide 3b and Me4NF gave a
disappointing result (Table 1, entry 1), presumably resulting
from deprotonation of the alkynyl proton. Reaction of
methylethenyl phenyl ketone 1b with Me3SiCF3, under the
same reaction conditions, also gave a complex mixture
containing only a trace of the desired 1,2-addition product
(entry 2). The unsuccessful results should be explained by
the existence of a reactive hydrogen atom in the substrates
1. Our strategy then turned to the trifluoromethylation of
phenyl trimethylsilylethynyl ketone 1c, which does not
contain reactive hydrogen atoms. However, the attempt also
led to a complex mixture of compounds (entry 3). In our
fourth experiments using phenylethynyl phenyl ketone 1d,
we were able to obtain the desired product with an ee of
40% in 54% yield (entry 4). Changing the chiral catalyst 3b
for 3a resulted in a good yield of 2d with better enantiose-
lectivity of 51% (entry 5). Gratifyingly, when the reaction
was carried out using sterically demanding tert-butylethynyl
phenyl ketone 1e, the desired compound 2e was obtained in
96% with 94% ee, although the loss of chemical yield was
observed after the treatment with tetrabutylammonium fluo-
ride (nBu4NF) (entry 6).
Scheme 1. Asymmetric Trifluoromethylation of Alkynyl
Ketones and Its Application to Aryl Heteroaryl Trifluoromethyl
Carbinols
Encouraged by the result, the scope of this trifluoro-
methylation reaction was investigated with a range of alkynyl
ketones (entries 7-22). The reaction is remarkably general.
To allow for comparisons, all reactions were conducted with
10 mol % chiral catalyst on a 0.2 mmol scale and 2.0 equiv
of the Me3SiCF3. Reactions were not individually optimized
to establish the generality of the procedure. Most reactions
were complete in 1-3 h at -60 °C to -50 °C. In all cases,
the initial adduct was a trimethylsilyl-ether that was removed
by treatment with nBu4NF to provide the alcohol product 2.
All of the reactions proceeded in essentially quantitative yield
as confirmed by TLC analysis, but the isolated yield of 2
was often lower due to loss of the product during the
treatment with nBu4NF to remove a trimethylsilyl group. High
enantioselectivities were obtained for all cases up to 96%
ee, with these being almost independent of the functional
groups such as alkyl and sterically demanding alkyl, aryl,
halogenyl, and methoxy moieties, as well as the positions
of the aromatic ring (entries 8-16). For another aromatic
analogue 1p bearing a bulky naphthyl group, we also
obtained the trifluoromethylated product 2p in good yield
with high enantioselectivity of 93% ee (entry 17). Cinnamyl-
substituted alkynyl ketone 1q is also a suitable substrate for
3a/Me4NF-catalyzed asymmetric trifluoromethylation with
83% ee (entry 18). A remarkable feature of this method is
that the reaction is applicable not only for tert-butyl-
substituted ethynyl ketones but also other sterically demand-
ing ethynyl ketones. Namely, the aryl alkynyl ketones 1r-u
with sterically demanding hydroxypropyl tethers were nicely
converted to the corresponding trifluoromethylated propargyl
In the 21st century, high enantioselectivity has been
achieved consistently in the asymmetric addition to carbonyl
compounds.1 This is not the case for the addition of
Me3SiCF3, in which selectivity is generally very low and
substrates lack scope.4,7 Since 2007, we disclosed enanti-
oselective trifluoromethylation of aryl alkyl ketones, aryl
aldehydes, and azomethine imines using Me3SiCF3 in the
presence of a catalytic quantity of a chiral phase transfer
catalyst to provide trifluoromethyl derivatives with a high
degree of enantioselectivity.8 Motivated by theses favorable
outcomes, the application of these methodologies to previ-
(5) To our knowledge, enantioselective arylation of trifluoromethyl
alkenyl ketones has not been reported. For a related reaction, see: (a) Tur,
F.; Saa´, J. M. Org. Lett. 2007, 9, 5079–5082. (b) Saa´, J. M.; Tur, F.;
Gonza´lez, J. Chirality 2009, 21, 836–842.
(6) (a) Motoki, R.; Tomita, D.; Kanai, M.; Shibasaki, M. Tetrahedron
Lett. 2006, 47, 8083–8086. (b) Motoki, R.; Kanai, M.; Shibasaki, M. Org.
Lett. 2007, 9, 2997–3000. For a related reaction, see: (c) Nishiyama, H.;
Ito, J. Chem. Commun. 2010, 46, 203–212.
(7) (a) Iseki, K.; Nagai, T.; Kobayashi, Y. Tetrahedron Lett. 1994, 35,
3137–3138. (b) Hagiwara, T.; Kobayashi, T.; Fuchigami, T. Main Group
Chem. 1997, 2, 13–15. (c) Kuroki, Y.; Iseki, K. Tetrahedron Lett. 1999,
40, 8231–8234. (d) Caron, S.; Do, N. M.; Arpin, P.; Larive´e, A. Synthesis
2003, 1693–1698. (e) Roussel, S.; Billard, T.; Langlois, B. R.; Saint-James,
L. Chem.sEur. J. 2005, 11, 939–944. (f) Nagao, H.; Yamane, Y.;
Mukaiyama, T. Chem. Lett. 2007, 36, 666–667. (g) Zhao, H.; Qin, B.; Liu,
X.; Feng, X. Tetrahedron 2007, 63, 6822–6826
.
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