Silver-catalyzed oxidative activation of benzylic C-H bonds for the synthesis of difluoromethylated arenes

Article abstract of DOI:10.1002/anie.201400225

A mild and catalytic method to form difluoromethylated arenes through the activation of benzylic C-H bonds has been developed. Utilizing AgNO₃ as the catalyst, various arenes with diverse functional groups undergo activation/fluorination of ben

Full text of DOI:10.1002/anie.201400225

Angewandte
Chemie
DOI: 10.1002/anie.201400225
Fluorination
À
Silver-Catalyzed Oxidative Activation of Benzylic C H Bonds for the
Synthesis of Difluoromethylated Arenes**
Peng Xu, Shuo Guo, Liyan Wang, and Pingping Tang*
Abstract: A mild and catalytic method to form difluoro-
À
methylated arenes through the activation of benzylic C H
bonds has been developed. Utilizing AgNO3 as the catalyst,
various arenes with diverse functional groups undergo activa-
À
tion/fluorination of benzylic C H bonds with commercially
available Selectfluor reagent as a source of fluorine in aqueous
solution. The reaction is operationally simple and amenable to
gram-scale synthesis.
Scheme 1. Synthesis of difluoromethylated arenes.
neurs and co-workers recently reported a silver-catalyzed
F
luorinated compounds are important in pharmaceuticals,
fluorodecarboxylation to prepare difluoromethylarenes from
a-fluoroarylacetic acids.[9] Baran and co-workers reported the
direct difluoromethylation of heteroarenes with zinc difluoro-
methanesulfinate (DFMS), however, reactions with arenes
were not reported.[10] Zhang and co-workers reported a palla-
dium-catalyzed difluoroalkylation of aryl boronic acids to
form difluoromethylated arenes.[11] In addition to the recent
success in using cross-coupling reactions to prepare fluoro-
alkyl compounds,[12] methods for the transformation of C-
agrochemicals, and materials.[1] The introduction of fluorine
atoms into small molecules often improves their lipophilicity
and metabolic stability. In addition, 18F-labeled organic
compounds are clinically used as radiotracers for positron
emission tomography (PET).[2] The difluoromethyl group
(CF2) is of interest in medicinal chemistry because it is
isosteric with the hydroxy group, and is found in various
biologically active compounds.[3] However, methods for the
synthesis of difluoromethylated arenes are limited.[4] Herein,
we present a mild and catalytic method to form difluoro-
methylated arenes through activation/fluorination of benzylic
3
3
[13–16]
À
À
(sp ) H bonds to C(sp ) F bonds were also developed.
In 2006, Sanford reported a palladium-catalyzed benzylic
fluorination.[13] Recently, Groves and co-workers reported
manganese-catalyzed fluorination of unactivated C(sp ) H
and benzylic C H bonds. Lectka and co-workers reported
a copper-catalyzed fluorination of unactivated C(sp ) H, an
3
À
À
C H bonds with the commercially available Selectfluor
[14]
À
reagent as the source of fluorine. This is the first example of
3
À
À
the use of silver catalysis for the activation of benzylic C H
À
bonds to prepare difluoromethylated arenes (Scheme 1).
Traditional methods for the synthesis of difluoromethy-
lated arenes through deoxyfluorination of aldehydes or
ketones with SF4, N,N-diethylaminosulfur trifluoride
(DAST), and derivatives of DAST suffer from poor func-
tional-group compatibility.[5] Recently, Amii and co-workers
reported a copper-catalyzed three-step route to difluoro-
methylarenes, however, the final step was limited to electron-
deficient aryl iodides and required high temperature
(> 1708C).[6] The groups of Hartwig[7] and Surya Prakash[8]
presented a one-step copper-mediated transformation of
iodoarenes into difluoromethylarenes, respectively. Gouver-
iron-catalyzed fluorination of benzylic C H, and a photo-
catalyzed fluorination of aliphatic groups.[15] Inoue reported
3
À
a metal-free fluorination of C(sp ) H bonds using a catalytic
N-oxyl radical generated from N,N-dihydroxypyromelliti-
mide.[16] During the preparation of our manuscript, Chen
and co-workers reported a diarylketone-catalyzed selective
À
activation of benzylic C H bonds for the synthesis of mono-
and difluoromethylated arenes using visible light.[17] This was
À
the first report of a selective activation of a benzylic C H
bond to form difluoromethylated arenes. In the course of
a research program toward the synthesis of difluoromethy-
lated arenes, we were inspired by Grovesꢀ finding of
difluoromethylated arenes in 5% yield during the manga-
[14b]
À
nese-catalyzed monofluorination of benzylic C H bonds.
[*] P. Xu, S. Guo, L. Wang, Prof. Dr. P. Tang
State Key Laboratory and Institute of Elemento-Organic Chemistry,
Nankai University, Collaborative Innovation Center of Chemical
Science and Engineering (Tianjin)
Thus, we reasoned that difluoromethylated arenes could be
obtained through transition-metal-catalyzed oxidative acti-
À
vation of benzylic C H bonds based on Grovesꢀ previous
report.
Tianjin 300071 (China)
E-mail: ptang@nankai.edu.cn
Herein we report the first example of a silver-catalyzed
[**] We gratefully acknowledge the State Key Laboratory of Elemento-
Organic Chemistry for generous start-up financial support. This
work was supported by the “1000 Youth Talents Plan”, and the
Natural Science Foundation of Tianjin (Grant No. 13JCYBJC36500).
Prof. Tobias Ritter and Prof. Jennifer M. Murphy are greatly
acknowledged for helpful comments.
À
oxidative activation of a benzylic C H bond to prepare
difluoromethylated arenes with Selectfluor under mild con-
ditions. Initial investigations focused on the silver-catalyzed
À
activation of the benzylic C H bond of 4-fluoro-2-methyl-
benzoic acid (1i). This substrate was selected because it could
generate the acyloxy radical in the presence of silver(I) and
peroxydisulfate, which may facilitate an intramolecular
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201400225.
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abstraction of a benzylic C H through 1,5-hydrogen transfer
from the benzylic position to the acyloxy radical.[18] After
extensive screening with AgNO3 as the catalyst, the reaction
of 4-fluoro-2-methylbenzoic acid (1i) with Selectfluor and
Na2S2O8 in acetonitrile/H2O (v:v = 1:1) at 808C for 3 h under
N2 atmosphere led to the formation of difluoromethylated
arenes (2i) in 89% yield, determined by 19F NMR analysis of
the crude product. The control experiment was performed in
the absence of a silver salt and the difluoromethylated
product was obtained in only 20% yield. In addition, no
desired product was generated when the reaction was
performed without both AgNO3 and Na2S2O8. Several silver
transformation of a heteroaromatic substrate (1x) to the
difluoromethylated product (2x) proceeded under standard
reaction conditions in 11% yield with 71% monofluorination
by-product. When 20 mol% of AgNO3, 5.0 equivalents of
Na2S2O8, and 4.0 equivalents of Selectfluor were used in the
reaction, the yield of difluoromethylated product increased to
82% and no monofluorination by-product was observed. To
prove both the practicality and effectiveness of this method
for large-scale synthesis, 2o was prepared on a gram scale
under the reaction conditions with 2.5 equivalents of Select-
fluor in 86% yield of isolated product.
Although the detailed mechanism of this reaction is
currently unclear, some preliminary studies indicate that
a radial-chain mechanism or single-electron transfer (SET)
may be involved in this transformation. No difluoromethy-
lated arene was formed when 2.0 equivalents of the radical
inhibitor butylated hydroxytoluene (BHT) or 2,2,6,6-tetra-
methyl-1-piperidinyloxy (TEMPO) were added to the reac-
tion. In addition, yields were much higher in the strict absence
of O2 than in its presence.[20] Together, these observations
suggest the involvement of a free radical in the reaction. To
gain further insights into the reaction mechanism, the
intermolecular kinetic isotope effect (KIE) was measured
(Scheme 2). The modest primary KIE values were observed
À
salts catalyzed the activation of benzylic C H bonds with
equal efficiency, but AgNO3 was ultimately chosen as the
catalyst because it formed difluoromethylated arenes in the
same yield range of yields and is less expensive than other
silver salts (see the Supporting Information for more details).
Also, water proved to be essential for the reaction, as no
difluoromethylated products resulted when the reaction was
performed in anhydrous acetonitrile. The role of water has
not yet been established. The reaction was found to be
sensitive to the amounts of Na2S2O8 and Selectfluor. The
difluorination yield increased in the presence of Na2S2O8, and
switching the fluorine source from Selectfluor to N-fluoro-
benzenesulfonimide (NFSI) led to no reaction at all. Na2S2O8
is believed to oxidize the silver(I) salt to a silver(II) species
and to facilitate the formation of difluoromethylated arenes
(see Scheme 3). After thorough optimization of the reaction
conditions, reactions with 10 mol% of AgNO3, 0.5 equiva-
lents of Na2S2O8, and 3.0 equivalents of Selectfluor produced
the desired products in high yields.
Using the optimized conditions, the substrate scope was
subsequently investigated. A variety of methylated arenes (1)
were smoothly transformed into the corresponding difluor-
omethylated arenes (2) with yields of isolated products
ranging from 42% to 93% (Table 1). A variety of function-
alities, such as a ketone, ester, carboxylic acid, amide,
sulfonamide, aromatic fluoride, chloride, or bromide, were
well tolerated under the reaction conditions. In general,
methylated arenes without ortho substituents (1a, 1c to 1h)
reacted more slowly, and required high catalyst loadings and
a higher amount of Selectfluor. For example, the trans-
formation of toluene to the difluoromethylbenzene (2a)
proceeded under standard reaction conditions in 60% yield.
When 20 mol% of AgNO3 and 4.0 equivalents of Selectfluor
were used in the reaction, the yield increased to 85%.
Notably, heteroaromatic substrates (1x, 1y, and 1z) were also
successfully employed to provide the corresponding difluor-
omethylated arenes (2x, 2y, and 2z). Some substrates (1j, 1m,
1w, 1y, 1z) were poorly soluble in MeCN/H2O and thus gave
the corresponding products in moderate yields. The reaction
also worked with ethyl benzene derivatives (1aa, 1bb, and
1cc) and heteroatom-substituted alkyl-chain derivative (1ee).
No selectivity was observed for a substrate with competitive
benzylic positions (1dd) and 2,5-bis(difluoromethyl)benz-
amide (2dd) was obtained. The total yield of mono- and
trifluoromethylarene by-products was limited to less than
10% in all cases. For some substrates, this required additional
optimization of the reaction conditions. For example, the
Scheme 2. Mechanism study.
from competition experiments of monofluorination using
a 1:1 mixture of toluene and [D8]toluene (kH/kD = 1.6) and
a 1:1 mixture of benzyl fluoride and [D7]benzyl fluoride (kH/
kD = 2.2) in excess under the reaction conditions, which
À
indicated that the C H bond cleavage step might be involved
in the rate-limiting step of this transformation.[21]
A mechanism can be proposed based on our findings
(Scheme 3). It is known[18] that in the presence of silver(I)
salts, a peroxydisulfate anion disproportionates into a sulfate
dianion and a sulfate radical anion [Eq. (1)]. The silver(I) salt
is oxidized to a silver(II) species by peroxydisulfate [Eq. (1)],
a sulfate radical anion [Eq. (2)], or an aminium radical cation
[Eq. (3)]. The silver(II) species oxidizes the benzylic C H
bond (A) in turn to a benzylic radical (B). The substrates that
contain a carbonyl group in the ortho position might have
À
2
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[a]
À
Table 1: Scope of the silver-catalyzed activation of benzylic C H bonds for the synthesis of difluoromethylated arenes.
[a] Reaction conditions: substrate 1 (1.0 equiv), AgNO3 (10 mol%), Na2S2O8 (0.5 equiv), Selectfluor (3.0 equiv), 808C, N2. Yields refer to isolated
product with a purity of more than 98%, unless otherwise noted. [b] Yields were determined by integration of the 19F NMR spectrum using
fluorobenzene as an internal standard. [c] 20 mol% of AgNO3 was used. [d] 4.0 equiv of Selectfluor was used. [e] 5.0 equiv of Na2S2O8 was used.
[f] 5.0 equiv of Selectfluor was used. [g] 3.0 equiv of F-TEDA-PF6[19] was used. [h] 5.0 equiv of F-TEDA-PF6 was used. [i] 608C was used. F-TEDA-PF6 =
1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(hexafluorophosphate).
a weak coordination between the carbonyl group and the
silver(II) species, which may facilitate an intramolecular
difluoromethylated arenes. Excess reagents and, in some
cases, a higher catalyst loading are required to obtain high
yields, which is a current limitation of this method. On the
other hand, the commercial availability and air/moisture
stability of both the fluorine reagent and the silver catalyst
render this new radical fluorination a safe method of practical
value in the synthesis of difluoromethylarenes.
À
abstraction of a benzylic C H to form a benzylic radical.
Selectfluor is known to react through a radical mechanism,[22]
and thus reacts with the benzylic radical (B) to form
a monofluorinated intermediate (C), which can generate
a benzylic radical (D) again with the silver(II) species, and
then form difluoromethylated products (E) with Selectfluor.
In summary, we presented the first example of a silver-
Received: January 9, 2014
Revised: March 17, 2014
Published online: && &&, &&&&
À
catalyzed oxidative activation of a benzylic C H bond with
the commercially available Selectfluor reagent for the prep-
aration of difluoromethylated arenes. The reaction proceeds
under mild conditions, tolerates various functionalities, and is
amenable to the gram-scale synthesis of functionalized
À
Keywords: arenes · C H activation · fluorination · silver ·
synthetic methods
.
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Scheme 3. Proposed mechanism for the silver-catalyzed activation of
À
benzylic C H bonds for the synthesis of difluoromethylated arenes.
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Chemie
Communications
Fluorination
P. Xu, S. Guo, L. Wang,
P. Tang*
&&&& — &&&&
Silver-Catalyzed Oxidative Activation of
Selectfluor serves as the fluorine source
methylated arenes with various functional
À
Benzylic C H Bonds for the Synthesis of
Difluoromethylated Arenes
and AgNO3 as the catalyst in the oxidative
groups into difluoromethylated arenes.
The reaction is operationally simple and
amenable to gram-scale synthesis.
À
activation of benzylic C H bonds. This
method was developed to transform
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These are not the final page numbers!