In Situ Generated Fluorinated Iminium Salts for Difluoromethylation and Difluoroacetylation

Article abstract of DOI:10.1021/acs.orglett.5b02184

The use of TFEDMA, a fluoroalkyl amino reagent, for the difluoromethylation and difluoroacylation of arenes, heteroarenes, and C-H acidic compounds is reported. This approach allows for an efficient access to difluoromethylated products of high added valu

Full text of DOI:10.1021/acs.orglett.5b02184

Letter
pubs.acs.org/OrgLett
In Situ Generated Fluorinated Iminium Salts for Difluoromethylation
and Difluoroacetylation
Etienne Schmitt,† Baptiste Rugeri,† Armen Panossian,† Jean-Pierre Vors,‡ Sergii Pazenok,§
and Frederic R. Leroux*,†
́
́
†CNRS-University of Strasbourg (ECPM), UMR CNRS 7509, LCR Bayer-CNRS C2OF, 25 Rue Becquerel, 67087 Strasbourg,
France
‡Bayer S.A.S., 14 Impasse Pierre Baizet, BP99163, Lyon 69263 Cedex 09, France
§Bayer CropScience AG, Alfred-Nobel-Strasse 50, 40789 Monheim, Germany
S
* Supporting Information
ABSTRACT: The use of TFEDMA, a fluoroalkyl amino reagent, for the difluoromethylation and difluoroacylation of arenes,
heteroarenes, and C−H acidic compounds is reported. This approach allows for an efficient access to difluoromethylated
products of high added value in good to excellent yields and with scale-up possibilities.
methods for the introduction of the CF2H unit under industrially
compatible conditions.
oday, organofluorine compounds play a key role in life
1
Tscience oriented research.
In small molecule research
In the present work, we report access to a variety of
difluoromethylated and difluoroacylated building blocks. The
reactions are based on the in situ preparation of difluoromethy-
lated iminium salts via Lewis acid mediated activation of 1,1,2,2-
tetrafluoro-N,N-dimethylethan-1-amine (1a; TFEDMA).
TFEDMA belongs to the so-called fluoroalkyl amino reagents
(FAR). So far, three of them are commercially available, i.e.,
TFEDMA (1a), N,N-diethyl-2-chloro-1,1,2-trifluoroethan-1-
amine (Yarovenko reagent), and N,N-diethyl-1,1,2,3,3,3-hexa-
fluoropropan-1-amine (Ishikawa reagent).12 They can be readily
prepared from commercially available bulk fluoro olefins
(chemicals frequently employed for polymers) by a hydro-
amination reaction.13
TFEDMA and its congeners are effective reagents for the
conversion of R−OH into R−F. The utility of TFEDMA has
recently been reviewed,14 and efforts have been undertaken to
extend its scope to different types of reaction.15 Very recently, we
became interested in the use of FAR’s in the synthesis of
difluoromethylated pyrazoles and developed two different
approaches toward them.16 The reactivity of these fluoroalkyl-
amines is based on a negative hyperconjugation between the
nitrogen lone pair of the amino group and the adjacent
difluoromethyl group (see 1b in Scheme 1). It has been shown
that TFEDMA affords, after activation with a Lewis acid like BF3·
Et2O, an iminium salt such as 1c with Vilsmeier-type reactivity
(Scheme 1). Based on our previous studies, we were convinced
(SMR) in medicinal and agricultural sciences, fluoroalkyl units
are popular functional groups as they can improve the binding
affinity, the physicochemical properties, and the metabolic
stability of molecules.1a,2 The incorporation of a difluoromethyl
group (−CF2H) into organic molecules has become highly
attractive due to its hydrogen-bonding potency.1a,2a,3 In addition,
the CF2H group is a more lipophilic H-bond donor than either an
OH or NH, offering the potential for improved membrane
permeability.
The difluoromethylation of aromatics or heteroaromatics is
often based on the reaction of aldehydes with SF4, a highly toxic
gas requiring specialized equipment, or with aminosulfur
trifluorides (e.g., DAST, Deoxofluor), which cannot be easily
employed on an industrial scale.4 In addition, a lack of functional
group tolerance and/or harsh reaction conditions is a real
synthetic restriction. Although recent years have witnessed the
development of good methods, in particular organometallic ones,
for the late-stage installation of trifluoromethyl groups,2b,5
difluoromethylation is still in its infancy. Amii reported, for
example, the Cu-catalyzed cross-coupling of α-trialkylsilyl
difluoroacetates with aryl iodides.6 Baran et al. developed the
radical difluoromethylation of heteroaromatic compounds with
zinc difluoromethanesulfinate Zn(SO2CF2H)2.7 Hartwig8 and
Qing9 succeeded in the difluoromethylation of arenes and
heteroarenes with Cu−CF2H. Prakash et al. reported on the use
of copper iodide and Bu3SnCF2H.10 Finally, Gooßen disclosed
an elegant Sandmeyer-type difluoromethylation process.11
Nevertheless, there is still a tremendous need for efficient
Received: July 29, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b02184
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Letter
Scheme 1. TFEDMA (1a), Iminium Form (1b), Activated
Iminium Salt (1c), and Acetamide (1d) Resulting from
Hydrolysis
Scheme 3. Reaction of Activated TFEDMA 1c with Silyl Enol
Ethers
that FARs could be further exploited for the introduction of
−CF2H groups (or analogues). In fact, for the introduction of a
difluoromethyl fragment at an early stage, one can employ either
difluoroacetyl chloride (difficult to prepare, low boiling, and
rather air- and moisture- sensitive), difluoroacetic anhydride
(expensive and one loses 0.5 equiv in the synthesis), or ethyl
difluoroacetate (which requires further activation with organo-
metallic reagents or strong bases).
Therefore, we decided to study the reactivity of activated
TFEDMA 1c toward various substrates and to investigate its
scope and limitations for the synthesis of difluoromethylated
building blocks. Compound 1c could be isolated after activation
of TFEDMA 1a with BF3·Et2O in anhydrous CH2Cl2 or Et2O
and stored several days as a stable reagent under inert
atmosphere in the refrigerator or more conveniently directly
used after quick activation in dry MeCN.
First, we studied the reactivity of activated TFEDMA toward
vinyl ethers and ketene acetals which reacted smoothly and
afforded, after cyclization of the intermediates with hydrazine,
the corresponding pyrazoles in good to excellent yields (Scheme
2). When 1c was reacted with 2-methoxypropene and further
a
b
1
Conversion by H NMR. Isolated yield.
purify and were prone to degradation. When treated with methyl
hydrazine, 5a,b cyclized to a 1:1 mixture of the corresponding
bicyclic compounds 5e/5f. Fortunately, in situ cyclization of the
iminium intermediate 5 allowed for the regioselective synthesis
of 5c (92:8) and 5e (one regioisomer).
Scheme 2. Reaction of Activated TFEDMA 1c with Vinyl
Ethers
The silyl enol ether of acetophenone similarly reacted with 1c,
and X-ray crystallographic analysis of 6a18 revealed a Z
configuration (Figure 1).19 When 6a was reacted with methyl
Figure 1. Crystallographic structure of 6.19
a
b
hydrazine, a 1:1 pair of N-methylpyrazoles 7a and 7b was
obtained. Once again, in situ cyclization of the iminium salt 6
afforded N-methylpyrazole 7a in excellent regioselectivity
(94:6). The reaction with hydrazine hydrate and hydroxyl-
amine·HCl provided pyrazole 7c and isoxazole 8 in 68% yield
each. The silyl enol ether of acetylacetone gave methyl pyrazole
9a as one single regioisomer after in situ cyclization of the
iminium salt 9 with methyl hydrazine (Scheme 3).
Next, we investigated the reaction of activated TFEDMA 1c
with various CH-acidic compounds, namely malononitrile and
ethyl cyanoacetate, in order to access the corresponding
difluoro(dimethylamino)ethylidenes 10 and 11 (Scheme 4).
The best results were obtained when 1c was combined with
the CH-acidic compound and the mixture rapidly treated with
F NMR yield using PhF as internal standard. Isolated yield.
cyclized with methyl hydrazine, a pair of regioisomers 2a/2b in a
43:57 ratio was obtained quantitatively. Similarly, 1c reacted with
a ketene acetal (1,1-difluoro-4,4-dimethoxybut-3-en-2-one17)
and in situ cyclized with methyl hydrazine to afford 3,5-
bis(difluoromethyl)pyrazole 3. 2,2-Dimethyl-4-methylene-1,3-
dioxolane led to the one-pot formation of 3-(difluoromethyl)-5-
(hydroxymethyl)pyrazole 4 in moderate yield.
Next, we studied the reactivity of activated TFEDMA 1c
toward silyl enol ethers (Scheme 3). The commercially available
silyl enol ethers of cyclopentanone and cyclohexanone were
reacted with the iminium salt 1c affording the difluorohydrox-
yethylidene cycloalkyl ketones 5a,b. They were rather tedious to
Hunig’s base (DIPEA). The products 10 and 11 were efficiently
̈
B
DOI: 10.1021/acs.orglett.5b02184
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Letter
assistance or the reaction of organolithiums. When 1c and the
desired arene were heated in MeCN for 20 min under an inert
atmosphere, using microwave irradiation, a series of difluoroacy-
lated aromatics with electron-donating group(s) (14a−e) such
as OMe, NMe2, Me, etc. became accessible in good to excellent
yields with a regioselectivity governed by the substituents
(Scheme 6). To overcome the regioselectivity issues and to
Scheme 4. Reaction of Activated TFEDMA 1c with
Malononitrile and Ethyl Cyanoacetate
Scheme 6. Using TFEDMA as Difluoroacylating Agent for
Arenes
a
b
19F NMR yield using PhF as internal standard. Isolated yield.
converted into difluoromethylated 5-aminopyrazoles. Methyl
hydrazine afforded the N-Me pyrazoles 12a and 13a in almost
quantitative yield. A similar result was obtained for the reaction of
10 with hydrazine hydrate yielding the NH-pyrazole 12b. In
contrast, 11 led to NH-pyrazole 13b in a low 44% yield. The yield
was improved to 87% by employing BOC-hydrazide instead of
hydrazine hydrate (Scheme 5). When the cyclization was
Scheme 5. Synthesis of 3-(Fluoroalkyl)-5-aminopyrazoles and
-isoxazoles
broaden the substrate scope, we demonstrated that halogen/
metal interconversions could be employed to convert aryl halides
into difluoracyl derivatives. In fact, bromine/lithium exchange
followed by trapping with N,N-dimethyldifluoroacetamide (1d)
(derived from TFEDMA by hydrolysis) provided the desired
difluoroacylated products 14f−h in good yields (Scheme 6).
Several electron-rich heterocycles were also successfully
difluoroacylated (Scheme 7). Pyrrole afforded compound 15a
a
b
19F NMR yield using PhF as internal standard. Isolated yield.
Scheme 7. Difluoroacylation of Electron-Rich Heterocycles
performed with hydroxylamine, the corresponding isoxazoles
12c and 13c were obtained almost quantitatively. The structures
of 10 and 13c were confirmed by single-crystal X-ray diffraction
(Figure 2).19 In the case of the N-methylpyrazoles 12a and 13a,
Figure 2. Crystallographic structure of 10 (left) and 13c (right).19
a
b
1
Conversion by H NMR. Isolated yield.
the regioselectivity was evaluated as 99:1 and the structure of
1
isolated products confirmed by H/13C HMBC experiments
with 1c, which in turn could be difluoroacylated to give 15b.
Furan reacted with 1c to give the highly sensitive and volatile
product 16. Thiophene gave quantitatively the volatile derivative
17, and 3-aminopyrazole provided compound 18 in good yield.
As expected, both pyrazole and imidazole were unreactive
toward 1c. Nitrogen-based benzo-fused heterocycles like indoles
and methylene indolines were efficiently difluoroacylated using
1c, providing compounds 19 (see crystallographic structure in
Figure 3)19 and 20 in excellent yields. In contrast, oxygen-based
precursors like benzofuran were not compatible with this
reaction.
(correlations between N-CH3 protons and C-NH2 carbon).
Finally, we studied the use of activated TFEDMA 1c as a
difluoroacyl transfer reagent for aromatic and heteroaromatic
compounds. Wakselman reported in 1975 on the use TFEDMA
and its analogues with electron-rich aromatics.15c N,N-
Diethylaniline, N,N-dimethyl-m-toluidine, 1-(dimethylamino)-
naphthaline, indole, thiophene, and N-methylpyrrole underwent
difluoroacylation in low yields with limited substrate scope.12a−c
We were able to extend the scope of this reaction for the
difluoroacylation of arenes by employing either microwave
C
DOI: 10.1021/acs.orglett.5b02184
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
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ASSOCIATED CONTENT
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The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.5b02184.
Experimental procedures and compound characterization
(PDF)
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(19) CCDC 1415347 (6), 1415348 (13c), 1415349 (10), and
1415350 (19) contain the supplementary crystallographic data for this
paper. These data can be obtained free of charge from the Cambridge
Crystallographic Data Centre via http://www.ccdc.cam.ac.uk/data_
request/cif, 2015.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: frederic.leroux@unistra.fr.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the CNRS France (Centre National de la Recherche
Scientifique) and the University of Strasbourg and are very
grateful to Bayer S.A.S. for a grant to E.S. The French Fluorine
Network (GIS Fluor) is also acknowledged.
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DOI: 10.1021/acs.orglett.5b02184
Org. Lett. XXXX, XXX, XXX−XXX