DOI: 10.1002/anie.201101691
Fluorine Chemistry
Synthesis of gem-Difluorinated Cyclopropanes and Cyclopropenes:
Trifluoromethyltrimethylsilane as a Difluorocarbene Source**
Fei Wang, Tao Luo, Jinbo Hu,* Ying Wang, Hema S. Krishnan, Parag V. Jog, Somesh K. Ganesh,
G. K. Surya Prakash,* and George A. Olah
Difluorocyclopropanes and difluorocyclopropenes are
becoming an important class of compounds in organofluorine
chemistry. Introduction of a fluorine atom onto a cyclo-
propane ring is known to alter the structure and reactivity of
the molecule because of the high electronegativity and small
efficient reactions of difluorocarbene with alkenes. Some of
the reagents used previously include sodium chlorodifluoro-
acetate (or sodium bromodifluoroacetate),[7] PhHgCF3 and
[8]
[9]
Me3SnCF3
(Seyferth
reagents), FSO2CF2CO2SiMe3
(TFDA),[6h,10] and Zn/CF2Br2.[11] However, most of these
reagents suffer from disadvantages such as harsh reaction
conditions, high toxicity, lack of commercial availability, and/
or low product yields. Recently, Hu and co-workers reported
that TMSCF2Cl can act as an efficient difluorocarbene
precursor under chloride-ion catalysis at 1108C.[12] However,
TMSCF2Cl is not commercially available and its preparation
requires the use of ozone-depleting CBrClF2.[13]
size of the fluorine atom, and consequently the increase in the
[1]
À
C F bond polarity. Fluorine substituents also raise the
biological activity, the bioavailability, and in some cases the
potency of known biologically active molecules.[1] The
difluoromethylene group is also considered as a bioisostere
for an oxygen atom in biological studies.[2]
Recently, a unique application of difluorocyclopropanes
to trap the 1,3-diradical formed during the mechanochemical
activation of the polybutadiene backbone was reported.[3]
Besides biological and polymeric applications, difluorocyclo-
propanes are synthetically useful substrates for a variety of
reactions such as thermal rearrangements, bimolecular reac-
tions, carbocation, carbanion, and radical chemistry.[4]
For substrates that are thermally unstable, the above-
mentioned methods and reagents could be a serious limita-
tion, and development of better difluorocarbene precursors
that can generate difluorocarbenes at lower temperatures is
required. There are only few reports[14] that discuss difluoro-
[15]
carbene generation at room temperature with Ph3P/CF2Br2,
The synthesis of difluorocyclopropanes and difluorocy-
clopropenes can be achieved in various ways. However, a
[2+1] cycloaddition reaction of difluorocarbene to an alkene
or an alkyne has proven to be the most efficient method to
date.[4,5] This result has led to considerable efforts in devel-
oping reagents that can act as a source of difluorocarbene.
Owing to the interaction of the lone pairs of electrons on the
fluorine substituents with the carbene center, difluorocarbene
is a relatively stabilized carbene species (with a singlet ground
state) and is therefore less reactive than other dihalocar-
benes.[6] This could be one of the reasons why difluorocar-
benes do not react well with electron-poor alkenes. Higher
temperatures are often required for the generation as well as
or at low temperatures (below À788C) with bis(trifluoro-
methyl) cadmium, which is a highly pyrophoric reagent, as a
source. Again, the use of cadmium or phosphines and the lack
of commercial availability of these reagents is a severe
limitation. Trifluoromethyltrimethylsilane (Me3SiCF3 or
TMSCF3), commonly known as the Ruppert–Prakash
reagent, is readily available and is the most widely used
nucleophilic trifluoromethylating agent for a variety of
Table 1: Optimization of reaction conditions.
Entry
1 (equiv)
Solvent
Initiator
Yield [%][a]
[*] F. Wang, T. Luo, Prof. Dr. J. Hu
Key Laboratory of Organofluorine Chemistry, Shanghai Institute
of Organic Chemistry, Chinese Academy of Sciences
345 Ling-Ling Road, Shanghai, 200032 (China)
Fax: (+86)21-6416-6128
1
2
3
4
5
5
5
5
THF
THF
THF
THF
TBAT
TBAF[b]
TMAF
TMAO
NaI
82
37
0
0
0
E-mail: jinbohu@sioc.ac.cn
5
5
THF
6
7
8
9
10
11
12
5
5
5
5
1
2
2.5
monoglyme
diethyl ether
toluene
acetonitrile
THF
TBAT
TBAT
TBAT
TBAT
TBAT
TBAT
TBAT
54
21
0
Dr. Y. Wang, H. S. Krishnan, Dr. P. V. Jog, Dr. S. K. Ganesh,
Prof. Dr. G. K. S. Prakash, Prof. Dr. G. A. Olah
Loker Hydrocarbon Research Institute and
Department of Chemistry, University of Southern California
University Park, Los Angeles, CA 90089-1661 (USA)
Fax: (+1)213-740-6679
0
40
80
83
THF
THF
E-mail: gprakash@usc.edu
[**] Support of our work by the National Natural Science Foundation of
China (20772144, 20825209, 20832008) and financial support by the
Loker Hydrocarbon Research Institute is gratefully acknowledged.
[a] Yield of isolated product. [b] 1.0m solution in THF. TBAT=tetrabu-
tylammonium triphenyldifluorosilicate, TBAF=tetrabutylammonium
fluoride, TMAF=tetramethylammonium fluoride, TMAO=trimethyla-
mine oxide. Optimized reaction conditions (entry 12) are highlighted in
bold.
Supporting information for this article is available on the WWW
Angew. Chem. Int. Ed. 2011, 50, 7153 –7157
ꢀ 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
7153