COMMUNICATION
gem-Difluorination of 2,2-diaryl-1,3-dithiolanes by SelectfluorH and
pyridinium polyhydrogen fluoride
V. Prakash Reddy,*a Ramesh Alleti,a Meher K. Perambuduru,a Urs Welz-Biermann,b Herwig Buchholzb and
G. K. Surya Prakash*b
Received (in Corvallis, OR) 14th September 2004, Accepted 26th October 2004
First published as an Advance Article on the web 8th December 2004
DOI: 10.1039/b414254c
resulting dithiolanes were allowed to react with solutions of PPHF
and SelectfluorH (Table 1). The reactions{ were rapid even at 0 uC,
and in about 5 to 10 min complete conversion of the substrate to
the gem-difluoro compounds was observed. A variety of ring-
halogenated and alkoxy substituted 2,2-diaryl-13-dithiolanes (1),
gave the corresponding gem-difluoro compounds (2) as the only
products, as shown by the GC/MS of the corresponding reaction
mixtures at the end of the reaction. The reaction was, however,
inefficient for the alkyl aryl ketones: acetophenone dithiolane (3)
gave the corresponding gem-difluoromethylene compound, 4, and
acetophenone in a ratio of 6 : 4 under these conditions. The
dithiolane derived from p-bromobenzaldehyde, 6, gave p-bromo-
benzaldehyde (7) in quantitative yield after aqueous work up
(Scheme 1).{ The lower yields observed for compound 3, and
quantitative conversion of compound 6 and dithiolane derived
from cyclododecanone to the corresponding carbonyl compounds
may be explained in terms of the relatively unstable nature of the
incipient carbocation intermediates involved in these reactions.
We have found that the reactions of these dithiolanes with
SelectfluorH in aqueous acetonitrile or in aqueous PPHF give the
corresponding carbonyl compounds as the only reaction products,
in accordance with the observations of Wong and coworkers.17 In
anhydrous CH2Cl2, there was no noticeable reaction of dithiolanes
with either HF or SelectfluorH alone under the reaction conditions
used in our work. Thus the combination of SelectfluorH with
PPHF has a synergistic effect in the formation of the gem-
difluoromethylene compounds.
2,2-Diaryl-1,3-dithiolanes, readily obtainable from diaryl
ketones, were transformed into the corresponding gem-difluoro
compounds using a novel reagent combination involving
SelectfluorH and pyridinium polyhydrogen fluoride (PPHF)
under mild conditions in moderate to good yields.
There has been growing interest in the applications of gem-
difluorinated organic compounds in biological and medicinal
chemistry.1,2 These compounds are isosteric and isopolar analo-
gues of the corresponding ethers, and have found a wide range of
biological applications.3 For example, they can be potentially used
as enzyme inhibitors.4 We have earlier reported synthetic methods
for the preparation of the gem-difluoro compounds involving the
reaction of hydrazones with N-bromosuccinimide in pyridinium
polyhydrogen fluoride (PPHF).5 The synthesis of gem-difluori-
nated compounds can also be achieved by the reaction of 1,3-
dithiolanes with sulfuryl chloride fluoride (SO2ClF) or sulfuryl
chloride (SO2Cl2) in PPHF.6 Katzenellenbogen and coworkers
have reported the desulfurative gem-difluorinations of dithiolanes
using 1,3-dibromo-5,5-dimethylhydantoin in PPHF.7 Motherwell
has transformed dithioketals to gem-difluoro compounds by
reaction with 4-methyl(difluoroiodo)benzene.8 Dithiolanes were
also transformed to the gem-difluoro compounds by reaction with
hexafluoropropene-diethylamine/1,3-dibromo-5,5-dimethylhydan-
toin,9 tetrabutylammonium dihydrogen trifluoride and
N-haloamides,10 and by the anodic desulfurization in Et3N?3HF.11
The direct transformation of the carbonyl compounds into gem-
difluoro compounds can also be achieved using SF4 and
diethylaminosulfur trifluoride (Et2NSF3), although these reactions
require extreme conditions and give poor yields for deactivated
carbonyl compounds.12,13 Chambers and coworkers have found
that the dithiolane derivatives of diaryl ketones react with
elemental fluorine–iodine mixtures to give the corresponding
gem-difluoro compounds.14,15 The later reaction in aqueous
medium resulted in the hydrolysis of the substrates to the
corresponding carbonyl compounds.
We now disclose that the reactions of 2,2-diaryl-1,3-dithiolanes
with SelectfluorH and PPHF readily give the corresponding gem-
difluoro compounds under mild reaction conditions. Recently,
there has been an enormous interest in the applications of
SelectfluorH as an electrophilic fluorinating agent.16 We also note
the limitations of this reagent combination.
We have synthesized the 2-aryl-1,3-dithiolanes from the
corresponding diaryl ketones using the reported methods.7 The
*preddy@umr.edu (V. Prakash Reddy)
gprakash@usc.edu (G. K. Surya Prakash)
Scheme 1 Reactions of dithiolanes with SelectfluorH/PPHF.
This journal is ß The Royal Society of Chemistry 2005
654 | Chem. Commun., 2005, 654–656