DOI: 10.1002/open.201500160
Organocatalyzed Trifluoromethylation of Ketones and
Sulfonyl Fluorides by Fluoroform under a Superbase
System
Satoshi Okusu, Kazuki Hirano, Etsuko Tokunaga, and Norio Shibata*[a]
Fluoroform (HCF3, HFC-23) is a side product in the manufacture
of polytetrafluoroethylene (Teflon). Despite its attractive prop-
erties, taming HCF3 for trifluoromethylation is quite problemat-
ic owing to its low acidity and the lability of the naked trifluor-
omethyl carbanion generated from HCF3. Herein we report the
organic-superbase-catalyzed trifluoromethylation of ketones
and arylsulfonyl fluorides by HCF3. The reactions were carried
out by using a newly developed “superbase organocatalyst
system” consisting of catalytic amounts of P4-tBu and
N(SiMe3)3. A series of aryl and alkyl ketones were converted
into the corresponding a-trifluoromethyl carbinols in good
yields under the organocatalysis conditions in THF. The super-
base organocatalytic system can also be applied to the trifluor-
omethylation of arylsulfonyl fluorides for biologically important
aryl triflones in THF or DMF in good yields. Protonated P4-tBu,
H[P4-tBu]+, is suggested to be crucial for the catalytic process.
This new catalytic methodology using HCF3 is expected to
expand the range of synthetic applications of trifluoromethyla-
tion.
reagent is less ideal due to the expense of its preparation and
the fact that it is mostly prepared from ozone-depleting bro-
motrifluoromethane.[5] Therefore, inexpensive and environmen-
tally friendly alternatives to the Ruppert–Prakash reagent have
long been required.
Fluoroform (HCF3, HFC-23) is a side product in the manufac-
ture of polytetrafluoroethylene (Teflon). In view of its attractive
properties (ozone friendly, nontoxic, and inexpensive), it is not
surprising that there have been many attempts to use HCF3
for trifluoromethylation reactions.[6] However, taming HCF3 is
quite problematic due to its low acidity (pKa =27 in H2O) and
the lability of the naked trifluoromethyl carbanion generated
from HCF3.[7] During the last five years, the chemistry of HCF3
has made significant progress with the use of organometallics
as represented by Cu (Grushin), K (Prakash), and others.[8] In
late 2012, we reported that a sterically demanding organic su-
perbase, 1-tert-butyl-4,4,4-tris(dimethylamino)-2,2-bis[tris(dime-
thylamino)phosphoranylidenamino]-2l,5,4l,5-catenadi(phospha-
zene) (P4-tBu) effectively generates a trifluoromethyl carbanion
from HCF3 without decomposition to difluorocarbene that un-
dergoes successful addition to aromatic aldehydes, ketones,
and disulfides.[9] Our method does not require organometallics,
and the corresponding trifluoromethylation products are ob-
tained in good to high yields. However, this reaction needs
a stoichiometric amount of P4-tBu. The development of effi-
cient organocatalytic processes for HCF3 trifluoromethylation is
considered to be one of the greatest challenges in fluorine
chemistry. The seminal work by Langlois and co-workers[6e] on
trifluoromethylation with HCF3 clearly illustrates the validity of
this approach. Herein we disclose a catalytic version of this
HCF3 trifluoromethylation. The key to this catalytic reaction is
the combination of organic superbases. A wide variety of
diaryl, aryl-alkyl, and dialkyl ketones 1 are nicely trifluorome-
thylated by HCF3 under a newly developed “superbase-organo-
catalysis” of P4-tBu/N(SiMe3)3 in THF to provide a wide range of
trifluoromethylated carbinols 2. This superbase organocatalytic
system consisting of P4-tBu and N(SiMe3)3 also realized a catalyt-
ic trifluoromethylation of arylsulfonyl fluorides 3 with HCF3 in
THF or DMF to furnish biologically important fluorinated com-
pounds of aryltriflones 4 in good yields (Scheme 1). Protonated
P4-tBu (H[P4-tBu]+) is suggested to be crucial for the catalytic
process.
Organofluorine compounds have gained much attention in the
research and development of pharmaceuticals, agrochemicals,
and advanced materials.[1] In particular, trifluoromethyl-contain-
ing organic molecules have become primary synthesis targets
in recent years given their impressive successful history in
bringing new drugs to the market.[1c,e,2] Methods for the intro-
duction of CF3 groups into target substrates (i.e., trifluorome-
thylation), have therefore been actively researched world-
wide.[3] A popular and convenient method for trifluoromethyla-
tion is the use of (trifluoromethyl)trimethylsilane (CF3SiMe3, the
Ruppert–Prakash reagent).[4] The Ruppert–Prakash reagent is
used in a variety of nucleophilic trifluoromethylations, and its
use has been expanded to the radical or oxidative trifluorome-
thylation reaction. Despite its wide utility, the Ruppert–Prakash
[a] S. Okusu, K. Hirano, E. Tokunaga, Prof. Dr. N. Shibata
Department of Nanopharmaceutical Sciences and Department of Frontier
Materials, Nagoya Institute of Technology, Gokiso, Showa-ku, Nagoya 466-
8555 (Japan)
Supporting information for this article is available on the WWW under
ꢀ 2015 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.
distribution in any medium, provided the original work is properly cited,
the use is non-commercial and no modifications or adaptations are
made.
We initiated our investigations with the reaction of benzo-
phenone (1a) and HCF3 (Table 1). First, trifluoromethylation of
1a in THF took place under our previous stoichiometric condi-
tions,[9] but with a catalytic amount of P4-tBu (30 mol%); owing
to the superbase character of P4-tBu, this trifluoromethylation
ChemistryOpen 2015, 4, 581 – 585
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ꢀ 2015 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim