Tetrahedron Letters
Nucleophilic addition of benzylboronates to activated ketones
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Jacob C. Hayes, Michael R. Hollerbach, Timothy J. Barker
Department of Chemistry and Biochemistry, College of Charleston, Charleston, SC 29424, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
A method has been developed for the addition of benzylboronic acid pinacol ester to activated ketones
including trifluoromethyl ketones in good yields. The use of DABCO as an additive was found to enhance
the rate and efficiency of this reaction. In reactions of ketones with a second carbonyl group present such
as an ester or amide, good chemoselectivity for the ketone was observed. Competition experiments sug-
gest an electrophile relative reactivity order of CF2H ketone > CF3 ketone > aldehyde under these reaction
conditions.
Received 6 November 2019
Revised 5 December 2019
Accepted 6 December 2019
Available online xxxx
Keywords:
Boron
Ó 2019 Elsevier Ltd. All rights reserved.
Trifluoromethyl ketone
Alkylboronic esters
Lewis base
Introduction
Organofluorine molecules have been developed for many appli-
cations including their use in medicinal chemistry, agrochemistry
and polymer chemistry [1,2]. Fluorine substituents have been
found to alter the lipophilicity and metabolic stability of com-
pounds, resulting in drug candidates with favorable therapeutic
profiles [1,3]. Trifluoromethyl groups are increasingly present in
molecules with biological activity [4]. Our research group has been
developing alkylboronates as nucleophiles with carbonyl elec-
trophiles [5] and sought to evaluate trifluoromethyl ketones to
expand this methodology.
Fig. 1. Medicinally relevant trifluoromethyl alcohols.
The trifluoromethyl alcohol motif is found in numerous phar-
maceutically relevant molecules [4]. Compounds with a trifluo-
romethyl alcohol have found relevance as sleep inducers [6], as
anti-inflammatory drugs [7,8], and as cholesteryl ester transfer
protein inhibitors (Fig. 1) [3,9]. Trifluoromethyl alcohols such as
those synthesized in this report have previously been evaluated
as anti-fertility drugs [10]. Common syntheses of trifluoromethyl
alcohols have been performed through addition of an anionic CF3
group to a ketone or aldehyde [11–18]. Alternatively, nucleophilic
addition to a trifluoromethyl ketone has been reported using
dialkylzinc reagents with additives required to prevent competi-
tive reduction of the trifluoromethyl ketones [19,20]. Previous
work in our laboratory revealed that activation of an alkylboronic
ester with a Lewis base formed a nucleophilic boronate intermediate
[5,21–24]. These nucleophiles were found to react with aldehydes
and imines [5,25]. This report will highlight trifluoromethyl
ketones as electrophiles in 1,2-nucleophilic addition reactions with
benzylboronate nucleophiles and examine competition experi-
ments between trifluoromethyl ketones and other carbonyl
electrophiles to determine their relative reactivity in this reaction.
Results and discussion
We began our studies with ketone electrophiles by activating
the benzylboronic ester with sec-butyl lithium [5,25,26]. While
examining polar aprotic additives for the reaction with ketones
[5,27], the use of 1,4-diazabicyclo[2.2.2]octane (DABCO) as an
additive increased the rate of the 1,2-addition and subsequent
yield of alcohol product (Table 1). It is assumed DABCO coordinates
the lithium counterion, making the boronate nucleophile more
reactive. All substrates exhibited an increase in yield when using
DABCO as an additive. Reactions employing trifluoromethyl
ketones with electron-donating groups provided the most dra-
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Corresponding author.
0040-4039/Ó 2019 Elsevier Ltd. All rights reserved.
Please cite this article as: J. C. Hayes, M. R. Hollerbach and T. J. Barker, Nucleophilic addition of benzylboronates to activated ketones, Tetrahedron Letters,