Organic Letters
Letter
in high yields. Electron-rich aryl titanates provided products in
slightly higher yields than the corresponding electron-poor
counterparts. In the latter case yields were diminished in favor
of the formation of the homocoupled product. The
substitution pattern of the nucleophile favors meta- and para-
substituents, while low conversion and a poor mass balance
were observed for the ortho-substituted analogs.22 Esters,
nitriles, tertiary amines, (thio)ethers, bromides, protected
aldehydes, trifluoromethoxy, and silyl groups can be present
in the nucleophile structure leaving the catalytic process
unaffected.23
Scheme 6. Scope of a One-Pot Sequential Cross-Coupling
Reaction
a
The reaction can be easily scaled up to a gram scale. As such,
the compound 1ah was obtained in 91% yield and 98% ee on a
5 mmol scale (1.5 g of the starting benzyl bromide).
Additionally, the reaction is not limited to benzylic electro-
philes. Aliphatic α-CF3-alkyl bromides undergo an efficient
transformation under similar conditions, providing the product
4 in 91% yield and 95% ee. Moreover, aryltitanates can be
prepared in situ starting from the corresponding aryl iodides via
halogen−magnesium exchange with iPrMgCl·LiCl and further
transmetalation to Ti(OiPr)4 without significant effect on the
reaction outcome (1al and 1am; see SI for details).
Interestingly, benzyl chlorides also can be efficiently utilized
in the reaction, yet in somewhat lower yields. As such, α-CF3-
4-chlorobenzyl chloride 2a′ was converted to the correspond-
ing benzhydryl 1a under similar reaction conditions in a 79%
yield and 97% ee (Scheme 5).
a
Reactions were performed on 0.5 mmol scale in duplicate. Isolated
yields are given. NMR yields are given in square brackets.
Scheme 5. Cross-coupling of α-CF3-Benzyl Chlorides
selectivity of the reaction, giving rise to the formation of the
undesired symmetrical benzhydryl. The attempts to introduce
an aryl moiety bearing electron-poor substituents on the
second step increases amounts of product of formal
dechlorodefluorination. Thus, compounds containing two
electron-poor aryls are obtained only in moderate yields
(1h). Additionally, this approach allows for a facile creation of
deuterium-labeled analogues of this family of compounds
(1ba-D) using easy-to-prepare halothane-D (5-D).
In conclusion, we have developed a method for the
preparation of α-CF3-substituted benzhydryls via an enantio-
selective nickel-catalyzed cross-coupling reaction. The use of
an aryltitanate-based nucleophile enabled the synthesis of a
variety of a chiral 1,1-diaryl-2,2,2-trifluoroethanes starting from
α-CF3-benzyl bromides in high yields and excellent enantio-
selectivities. Remarkably, our approach allows this reaction to
be performed with electronically diverse electrophiles and
nucleophiles including those bearing electron-donating sub-
stituents. Alternatively, the same family of products can be
obtained under similar conditions as a one-pot two-step
sequence starting from a cheap, commercially available
anesthetic halothane in good yields and excellent enantiose-
lectivities. To the best of our knowledge, it represents the first
use of halothane as a CF3-group donor in asymmetric catalysis.
Mechanistic studies of aryltitanium involved asymmetric cross-
coupling reactions are underway in our laboratories.
The unexpectedly high reactivity of α-CF3-benzyl chlorides
led us to explore another approach toward synthesis of
compounds of family 1. We envisioned that starting from 1-
chloro-1-bromo-2,2,2-trifluoroethane, or halothanea cheap
commercially available anestheticit is possible to perform a
sequential one-pot cross-coupling reaction24 to prepare benzyl
chlorides in situ followed by their conversion to 1. If viable, the
use of such a starting material in the catalytic asymmetric
cross-coupling protocol would allow for the creation of α-CF3-
diarylmethanes through a rapid increase of a molecular
complexity.
Gratifyingly, halothane undergoes a smooth reaction to
provide the corresponding α-CF3-benzyl chloride in a nearly
quantitative yield under similar conditions. Moreover, both
steps can be performed as a one-pot sequence without addition
of extra amounts of the catalyst in the second step.25
Regarding the scope, we were pleased to see that this
strategy allows for the creation of a variety of enantioenriched
diarylmethanes (Scheme 6). The preparation of diaryltrifluoro-
ethanes bearing both electron-rich and electron-poor aromatic
motifs in any combination is feasible under the designed
protocol. Generally, high yields are obtained if aryl titanates
bearing electron-donating substituents are employed on each
reaction step (1b). However, the use of less electron-rich
coupling partners results in a yield decrease regardless of the
stage of employment. As such, the use of electron-poor
aryltitanates on the first step of the sequence affects the
ASSOCIATED CONTENT
* Supporting Information
■
sı
The Supporting Information is available free of charge at
Experimental procedures, characterization data, nuclear
magnetic resonance and high performance liquid
chromatography spectra of new compounds (PDF)
D
Org. Lett. XXXX, XXX, XXX−XXX