Journal of Fluorine Chemistry
journal homepage: www.elsevier.com/locate/fluor
Short communication
Organocatalysis approach to trifluoromethylation with fluoroform
Yuan Zhang, Motohiro Fujiu, Hiroki Serizawa, Koichi Mikami *
Department of Applied Chemistry, Graduate School of Science and Engineering, Tokyo Institute of Technology, Meguro, Tokyo 152-8552, Japan
A R T I C L E I N F O
A B S T R A C T
Article history:
The organic base methodology exploits an access to generate the ‘‘trifluoromethyl anion’’ for carbonyl,
ester, acid halide, epoxide, deuterium donor, and carbon dioxide substrates to afford the
trifluoromethylation products with good overall efficiency even in organocatalysis conditions. The
Received 22 May 2013
Received in revised form 16 July 2013
Accepted 26 July 2013
NMR analysis of the mixture of fluoroform and P
addition of electrophiles, the trifluoromethylation products were obtained efficiently.
ß 2013 Published by Elsevier B.V.
4
-base shows no change thereof. However, on
Available online 6 August 2013
Keywords:
Fluoroform
Organic base
Organocatalysis
Epoxide
Carbon dioxide
1
. Introduction
approach, namely the activation of the parent trifluoromethane,
fluoroform, HFC-23 (H-CF ) as the simple and cheap trifluoro-
methyl carbanion source via deprotonation of a less acidic
(pK = 25–28 in water) and hence relatively inert carbon–hydrogen
(C–H) bond with organic base catalysis to avoid the facile -M-F
3
Current attention has greatly been focused on organofluorine
compounds from the viewpoint of their fruitful applications in
pharmaceutical [1] and material [2] sciences. Especially fluor-
omethyl compounds are employed as highly potent analogs with
lipophilicity, membrane permeability, aqueous solubility, and
metabolic stability for hydrocarbon analogs [3]. Therefore, the
development of synthetic methods for fluoromethylation with
a
a
elimination is the subject of this communication. Fluoroform is a
by-product in manufacturing polymers such as Teflon and PVDF
(polyvinylidene difluoride). Furthermore, fluoroform has great
global-warming potential and long atmospheric lifetime. There-
fore fluoroform is a must-consume compound by trifluoromethy-
lation. This direct trifluoromethylation method with fluoroform is
hopefully applicable to the asymmetric trifluoromethylation by a
chiral organic base (Scheme 1). Trifluoromethylation with fluoro-
form to carbonyl compound has been originally reported by Shono
using an electrogenerated base or strong inorganic bases such as t-
BuOK in DMF [11]. Then, Normant [12] and Langlois [13]
emphasized the importance of DMF to provide the DMF adduct
of fluoroform as a reservoir. Recently, Grushin [14] and Prakash
[15] reported the direct cupration in DMF and silylation in THF,
ether, or toluene of fluoroform, respectively. Quite recently,
Shibata has just reported the carbonyl addition reaction of
3
trifluoromethyl (CF ) substituent in particular into the hydrocar-
bon compounds is an increasingly important issue in modern
organofluorine chemistry [4]. Generally, synthetic methods of the
fluorine-containing compounds involve: (1) C–C bond forming
reactions with fluoromethylating reagents [5], (2) C–C bond
forming reactions employing fluorine-containing carbonyl com-
pounds as building blocks [6], and (3) C–F bond forming reactions
with fluorinating reagents [7]. The fluoromethylation, which can
be exploited in later stage fluorofunctionalization, is further
classified into nucleophilic, electrophilic, or radical reactions.
However, nucleophilic trifluoromethyl-metal reagents such as the
trifluoromethyl-lithium or -magnesium reagent [8] are generally
recognized unstable and hard to prepare owing to the facile
metal fluoride (M-F) elimination [9]. Therefore, trifluoromethylsi-
lane (Si-CF ) so called the Ruppert–Prakash reagents has been
widely used as the nucleophilic trifluoromethyl carbanion equiva-
lent via Si–C bond activation with fluoride [10]. Our direct
a
-
fluoroform using P
. Results and discussions
The trifluoromethylation of carbonyl compounds
4
-t-Bu base [16].
3
2
1
with
fluoroform was first scrutinized using an organic base such as
DBU (pKBH = 24.34 in acetonitrile), acyclic guanidine TMG
*
4
(pKBH = 23.3 in acetonitrile) and P -t-Bu base (pKBH = 42.7 in
acetonitrile), and cyclic guanidine (methyl TBD (pKBH = 25.49 in