Angewandte
Chemie
Difluoromethylation
In Situ Generation of Difluoromethyl Diazomethane for
3+2] Cycloadditions with Alkynes**
[
Pavel K. Mykhailiuk*
Dedicated to Professor Andrei Tolmachev on the occasion of his 58th birthday
Abstract: A novel approach to agrochemically important
difluoromethyl-substituted pyrazoles has been developed
based on the elusive reagent CF HCHN , which was synthe-
2
2
sized (generated in situ) for the first time and employed in
3+2] cycloaddition reactions with alkynes. The reaction is
[
extremely practical as it is a one-pot process, does not require
a catalyst or the isolation of the potentially toxic and explosive
gaseous intermediate, and proceeds in a common solvent,
namely chloroform, in air. The reaction is also scalable and
allows for the preparation of the target pyrazoles on gram
scale.
Scheme 1. Known trifluoromethylation (1) and unknown difluoromethy-
lation (2) reagents.
T
properties.
he derivatization of organic compounds with fluorinated
units often affects their physicochemical and biological
[1,2]
Consequently, approximately 20% of all phar-
maceuticals and agrochemicals contain at least one fluorine
atom. The trifluoromethyl and difluoromethyl groups are
used: Ma et al. have developed diverse [3+2] cycloadditions
[7]
of 1, and Molander and co-workers synthesized unique
[
3]
[8]
particularly prevalent. Chemists, however, mostly incorpo-
trifluoromethylated boronic acid derivatives. In total, more
[4]
rate these units by direct fluoroalkylation reactions and tend
to underestimate the corresponding building blocks. Hence,
novel reagents to synthesize trifluoromethyl- and difluoro-
methyl-substituted compounds are of value.
than 50 publications have appeared in this area over the past
[
9,10]
five years.
In 1971, Atherton, Fields, and Haszeldine reported
unsuccessful attempts to prepare the closest homologue of
[11]
[12]
In 1943, Gilman and Jones synthesized CF CHN (1) from
1, CF HCHN (2, Scheme 1). Despite other efforts, the
3
2
2 2
trifluoroethylamine hydrochloride and sodium nitrite
conceptually attractive reagent 2 has remained unknown to
date.
[
5]
(
Scheme 1). At first, this potentially toxic and explosive
gas did not find wide application in synthesis. The situation
drastically changed in 2010, when Morandi and Carreira
developed convenient conditions to generate 1 in situ in
It is rather surprising that at a time when chemists can
synthesize extremely complex compounds in more than 100
[
13]
chemical steps, a very small reagent with only two carbon
atoms and true potential for the synthesis of pharmaceuticals
is still unknown. In strict contrast to trifluoromethyl-contain-
[
6a]
a solution
and subsequently performed many catalytic
[
6]
transformations. Since then, reagent 1 has been frequently
[
14]
ing reagent 1, reagent 2 cannot be employed thus far. The
development of synthetic procedures that render this reagent
accessible and fill this gap in modern chemistry is therefore
urgently required.
[
15]
[
*] Dr. P. K. Mykhailiuk
Enamine Ltd.
Matrosova 23, 01103 Kyiv (Ukraine)
and
Taras Shevchenko National University of Kyiv
Chemistry Department
Volodymyrska 64, 01601 Kyiv (Ukraine)
E-mail: Pavel.Mykhailiuk@gmail.com
Homepage: http://www.enamine.net
Herein, the generation of chemical reagent 2 and a rep-
resentative first reaction, its [3+2] cycloaddition with alkynes,
are described for the first time. This transformation repre-
sents a novel synthetic approach for the generation of
[
16]
difluoromethyl-substituted pyrazoles,
which are valuable
[17]
building blocks for agrochemistry (Figure 1).
First, it was attempted to generate reagent 2 under
[
**] All chemicals were provided by Enamine Ltd. I am grateful to Dr. S.
Shishkina for X-ray studies, to Prof. T. Brigaud for insightful
comments on the reaction mechanism, to R. Iminov, B. Chalyk, V.
Arkhipov, and O. Mashkov for their help with managing this work,
and to C. Thinnes and Dr. V. Kubyshkin for proofreading the
manuscript.
conditions that were elaborated for the preparation of 1 in
[6a,9f,12,18]
aqueous media
(Scheme 2). In particular, difluoro-
ethylamine hydrochloride and sodium nitrite were reacted in
a suspension of water and dichloromethane at room temper-
ature to afford a mixture of difluoroethanol and diazoace-
taldehyde along with some unidentified products. Presum-
ably, difluoroethanol was obtained by the reaction of common
Angew. Chem. Int. Ed. 2015, 54, 1 – 5
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1
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