Nickel-Catalyzed Negishi Cross-Coupling of Bromodifluoroacetamides

Article abstract of DOI:10.1021/acs.orglett.6b00232

A nickel-catalyzed Negishi coupling of bromodifluoroacetamides with arylzinc reagents has been developed. This reaction allows access to difluoromethylated aromatic compounds containing a variety of aryl groups and amide moieties. Furthermore, highly effe

Full text of DOI:10.1021/acs.orglett.6b00232

Letter
pubs.acs.org/OrgLett
Nickel-Catalyzed Negishi Cross-Coupling of
Bromodifluoroacetamides
Atsushi Tarui, Saori Shinohara, Kazuyuki Sato, Masaaki Omote, and Akira Ando*
Faculty of Pharmaceutical Sciences, Setsunan University, 45-1 Nagaotogecho, Hirakata, Osaka 573-0101, Japan
S
* Supporting Information
ABSTRACT: A nickel-catalyzed Negishi coupling of bromodifluoroacetamides with arylzinc reagents has been developed. This
reaction allows access to difluoromethylated aromatic compounds containing a variety of aryl groups and amide moieties.
Furthermore, highly effective transformation of the functionalized difluoromethyl group (−CF2CONR1R2) was realized via
microwave-assisted reduction under mild conditions. The notable features of this strategy are its generality and its use of a low-
cost nickel catalyst and ligand; thus, this reaction provides a facile method for applications in drug discovery and development.
luorine-functionalized aromatic compounds are of great
there has been only one report on the introduction of CF2−
carboxylic acid structures to aromatics using a nickel catalyst,
from Zhang and cowokers;14 therefore, the cross-coupling of a
bromodifluoroacetic acid derivative using a nickel catalyst is
attractive.15 Herein we report the nickel-catalyzed cross-coupling
reaction of bromodifluoroacetamides with arylzinc reagents. In a
further demonstration of the synthetic utility of this method, we
have also addressed the transformation of the fluoroalkyl chain
on the arylated product.
We initiated our studies of the nickel-catalyzed α-arylation of
an α,α-difluoroacetic acid derivative by evaluating the reaction of
bromodifluoroacetamide 1 with an arylzinc reagent. With a
combination of 5 mol % NiCl2·DME and 6 mol % bisoxazoline
ligand, the reaction of 1 with 4-methoxyphenylzinc chloride (2b)
gave the corresponding product 3b in 86% yield (Table 1, entry
1). On the basis of Inoue’s report,8 a stoichiometric amount of
tetramethylethylenediamine (TMEDA) with respect to the
amount of arylzinc reagent was used as an additive; however,
the yield of 3b was decreased, and 1 was recovered in 52% yield
(Table 1, entry 2). A half equivalent of TMEDA was effective in
the reaction, providing a 91% yield of 3b (Table 1, entry 3).
Decreasing the loading of 2b led to a lower yield of 3b (Table 1,
entries 4 and 5). When the reaction of arylzinc reagent 2b with
ethyl bromodifluoroacetate instead of 1 was examined, the
corresponding α-aryl-α,α-difluoroacetate was obtained in only
42% yield with no recovery of bromodifluoroacetate (Scheme 1).
This suggested that the high electrophilicity of the CF2−ester
moiety led to decomposition of the bromodifluoroacetate. Thus,
bromodifluoroacetamides are suitable for this Negishi cross-
coupling reaction. Although we screened other ligands and
1
Fimportance in both the life and materials sciences. Among
such compounds, molecules containing an α,α-difluorobenzyl
unit (ArCF2−) are especially desirable structures for use in
medicinal chemistry because the two fluorine atoms are
contained at a metabolically labile benzylic position.2 Addition-
ally, the difluoromethyl carboxylic acid structures
(CF2CONR1R2, CF2CO2Et, and CF2PO(OEt)2) are very
attractive structures, as the functionalized difluoromethyl group
can be easily transformed into other fluorine-containing groups
because of the strong electrophilicity of the CF2−carbonyl
group.3 The use of a copper difluoroacetate reagent4 and the
copper-catalyzed cross-coupling reaction5−7 are among the most
well-known methods for the functionalized fluorination of
arenes. During the past few years, such functionalized
fluorinations have been achieved using transition-metal-
catalyzed cross-coupling reactions and visible-light photoredox
reactions.3,8−10 However, these reported coupling reactions need
an expensive palladium catalyst and complex ligands or require as
fluorinated building blocks trimethylsilyl difluoroacetic acid
derivatives that are not commercially available. It also can be
difficult to control the regioselectivity of the product using
multisubstituted substrates in the visible-light-induced reaction.
Therefore, convenient methods for the introduction of a
functionalized CF2 group to arenes remain scarce. We recently
reported the cross-coupling reaction of fluorinated β-lactams
with arylmetal species in the presence of a nickel catalyst.11 We
hypothesized that the synthesis of functionalized difluoromethy-
lated arenes could be realized using a bromodifluoroacetic acid
derivative instead of a fluorinated β-lactam. However, the
reductive elimination of the fluoroalkylmetal complex is slower
than that of nonfluorinated analogues.12 Furthermore, it is more
difficult to achieve reductive elimination from a nickel complex
than from a palladium complex.13 To the best of our knowledge,
Received: January 23, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b00232
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Table 1. Optimization of the Nickel-Catalyzed Arylation of
Bromodifluoroacetamide
Scheme 2. Nickel-Catalyzed Negishi Coupling of
Bromodifluoroacetamide 1 with Arylzinc Chlorides
a
entry
equiv of 2b
additive (equiv)
time (h)
3b/1 yield (%)
1
2
3
4
5
3
−
0.5
3
86/−
11/52
91/−
80/10
68/28
3
TMEDA (3)
TMEDA (1.6)
TMEDA (0.8)
TMEDA (0.6)
3
0.5
3
1.5
1.2
3
Scheme 1. Reaction of Ethyl Bromodifluoroacetate with 2b
solvent systems, no improvement in the product yields was
observed (for details, see the Supporting Information).
With the optimized reaction conditions in hand, a wide variety
of arylzinc reagents were investigated for use in this method
(Scheme 2). Generally, electron-rich and electron-neutral
arylzinc reagents provided the corresponding α-aryldifluoroace-
tamides in high yields (3a−d, 3i, and 3j). Meta and ortho
substituents on the arylzinc reagents did not affect the reaction
yield and afforded the coupled products in high yields (3e−g).
However, the highly sterically hindered arylzinc reagent 2h was
not a suitable substrate, providing the product in low yield
together with the recovery of 1 in 45% yield. Importantly,
versatile ester and nitrile functional groups were tolerated rather
well (3l and 3m). Arylzinc reagent 2k with an acetal group was
also a suitable coupling partner, providing the acetal-deprotected
product 3k in good yield. In contrast to previously reported
difluoromethylations of aromatics,9,13 our nickel-catalyzed α-
arylation of bromodifluoroacetamides progressed smoothly in a
short time and at low temperature, except for ortho-substituted
substrates. However, alkyl and heteroarylzinc reagents did not
provide the corresponding coupled products.
To further demonstrate the generality of this reaction, the
structurally diverse bromodifluoroacetamides 4−11 were
prepared, and their reactions with arylzinc chlorides were
examined.16 The results are summarized in Scheme 3. Both
cyclic and acyclic N,N-dialkylamides were suitable as coupling
partners, giving the corresponding products in high yields (12b,
13a, 14a). As piperizine- and N-arylpiperazineamides are
featured as substructures in many bioactive compounds, these
successful results are of particular significance for drug
discovery.17 In addition, N-hydrogen-containing bromodifluor-
oacetamides could also be used for this coupling to afford the
corresponding products (15a, 16a, 17a, 18a, 19a). However,
when the reaction of N-unsubstituted bromodifluoroacetamide
was conducted using 3 equiv of phenylzinc chloride, the coupling
product (17a) was obtained only in low yield (36%). The same
a
b
Reaction conditions: 1 (0.5 mmol), 2 (3 equiv), THF (5 mL). The
c
yield of 1 is shown in parentheses. (4-(Diethoxymethyl)phenyl)zinc
chloride was used as the arylzinc reagent. The arylzinc chloride was
prepared via Knochel’s direct zincation in the presence of magnesium.
d
reaction using 5 equiv of phenylzinc chloride gave the desired
product in moderate yield (47%). In addition, a phenylalanine
derivative afforded the peptidyl coupling product 18a, but an
aniline derivative gave the corresponding coupling product 19a
in only 13% yield, with the aniline derivative recovered in 78%
yield. This suggests that acidic N-arylamides suppress the
coupling process.
To demonstrate the synthetic utility of the products obtained
in the reaction, we examined the reduction of α-aryl-α,α-
difluoroacetamide 3b to give amine 20. Following Hartwig’s
report on the borane reduction of α-aryl-α,α-difluoroaceta-
mides,3 we attempted the reduction of α-aryl-α,α-difluoroaceta-
mide 3b using borane as the reductant. The reaction of 3b with
the BH3−THF complex was carried out in CH2Cl2 with heating
and provided the corresponding amine 20 without hydro-
defluorination. Despite the long reaction time (26 h), the
moderate yield of 20 was not improved, and the starting material
3a was recovered (Scheme 4).18 However, when microwave
heating was applied to this reaction, the reduced product 20 was
obtained in 88% yield after only 20 min, and no side product was
observed under these reaction conditions.19
In conclusion, we have developed a convenient method for the
synthesis of α-aryl-α,α-difluoroacetamides via a nickel-catalyzed
Negishi coupling reaction. This coupling reaction allows access
to difluoromethylated aromatics containing a variety of aryl
groups and amide moieties. Further structural conversion of the
CF2−amide was realized by microwave-assisted borane reduc-
B
DOI: 10.1021/acs.orglett.6b00232
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a
Scheme 3. Scope of Bromodifluoroamides for This Reaction
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: aando@pharm.setsunan.ac.jp.
Author Contributions
All authors have given approval to the final version of the
manuscript.
Notes
The authors declare no competing financial interest.
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ASSOCIATED CONTENT
■
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* Supporting Information
The Supporting Information is available free of charge on the
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