Pd-catalyzed α-arylation of α,α-difluoroketones with aryl bromides and chlorides. A route to difluoromethylarenes

Article abstract of DOI:10.1021/ja501117v

We report the Pd-catalyzed α-arylation of α,α- difluoroketones with aryl and heteroaryl bromides and chlorides catalyzed by an air- and moisture-stable palladacyclic complex containing P(t-Bu)Cy₂ as ligand. The combination of this Pd-catalyzed arylation and base-induced cleavage of the acyl-aryl C-C bond within the α-aryl-α,α- difluoroketone constitutes a one-pot, two-step procedure to synthesize difluoromethylarenes from aryl halides. A broad range of electronically varied aryl and heteroaryl bromides and chlorides underwent these two transformations, providing α-aryl-α,α-difluoroketones, difluoromethylarenes, and difluoromethylheteroarenes in high yields.

Full text of DOI:10.1021/ja501117v

Communication
pubs.acs.org/JACS
Pd-Catalyzed α‑Arylation of α,α-Difluoroketones with Aryl Bromides
and Chlorides. A Route to Difluoromethylarenes
Shaozhong Ge, Wojciech Chaładaj, and John F. Hartwig*
Department of Chemistry, University of California, Berkeley, California 94720, United States
S
* Supporting Information
enolates with aryl electrophiles are limited to reactions that
ABSTRACT: We report the Pd-catalyzed α-arylation of
α,α-difluoroketones with aryl and heteroaryl bromides and
chlorides catalyzed by an air- and moisture-stable
palladacyclic complex containing P(t-Bu)Cy2 as ligand.
The combination of this Pd-catalyzed arylation and base-
induced cleavage of the acyl−aryl C−C bond within the α-
aryl-α,α-difluoroketone constitutes a one-pot, two-step
procedure to synthesize difluoromethylarenes from aryl
halides. A broad range of electronically varied aryl and
heteroaryl bromides and chlorides underwent these two
transformations, providing α-aryl-α,α-difluoroketones, di-
fluoromethylarenes, and difluoromethylheteroarenes in
high yields.
require stoichiometric amounts of copper, high temperatures,
or both.6 Because of the severity of these reaction conditions,
the scope of these coupling reactions is narrow and does not
encompass haloarenes containing many of the common
functional groups of medicinally important compounds.
We report the synthesis of a wide range of α-aryl- and α-
heteroaryl-α,α-difluoroketones by palladium-catalyzed coupling
of aryl and heteroaryl halides with difluoroacetophenones. We
show that the products of these reactions can be converted, in
addition to alcohols and amines by standard functional group
interconversions, to the corresponding difluoromethylarenes by
C−C bond cleavage. The reactions occur with an air-stable
palladium catalyst and aryl halide as limiting reagent, thereby
constituting a practical method to create a large family of
difluoroalkylarene and heteroarene derivatives.
We initiated our studies by seeking to develop a mild, high-
yielding Pd-catalyzed α-arylation of α,α-difluoroacetophenones.
Prior studies on this reaction required an excess of toxic
tributyltin fluoride,7 impractically high catalyst loadings (10 mol
% Pd and 20 mol % ligand), and temperatures (130−160 °C)
that were high enough to limit the tolerance of the process to
auxiliary functionality and to lead to product mixtures that
contained several materials resulting from P−C bond cleavage
of the phosphine.6b
romatic compounds containing a fluorine atom or a
Atrifluoromethyl group on an aromatic ring are now
widespread in medicinal chemistry.1 It is well established that
fluorine and trifluoromethyl substituents modulate the lipo-
philicity and metabolic stability of organic compounds; they
also alter the non-covalent interactions of the aryl group,
providing a method to affect binding affinities and selectivities.2
However, compounds containing more complex alkyl groups
with fluorine atoms at the benzylic position are less studied
because they are challenging to prepare. Reliable methods to
form a carbon−carbon bond between an aryl electrophile and a
difluoroalkyl nucleophile have not been developed.3
This limitation on the coupling of aryl electrophiles with
fluoroalkyl nucleophiles arises from several properties of
fluoroalkyl groups. First, a majority of coupling reactions
mediated by transition metal complexes form the aryl−alkyl
bond by reductive elimination from an arylmetal alkyl
intermediate,4 and this reductive elimination is slow when the
alkyl group contains fluorine on the α carbon. Second, there are
few methods to prepare α,α-difluoroalkylmetal reagents;5
therefore, transition-metal complexes containing an α,α-
difluoroalkyl group are rare.
We chose the direct arylation of α,α-difluoroacetophenone
with bromobenzene shown in Scheme 1 as a model reaction to
Scheme 1. α-Arylation of α,α-Difluoroacetophenone with
PhBr Catalyzed by Complex 1
The carbonyl functionality is one of the cornerstones of
organic chemistry because it can be transformed into a wide
range of functional groups, including alcohols, amines, alkyl
groups, and esters. Considering the versatile chemistry of the
carbonyl functionality, we considered that an approach to
prepare a variety of alkylarenes containing fluorine on the
benzylic carbon atom would result from the coupling of aryl
halides with fluorinated enolates. This coupling and subsequent
derivatization could afford a variety of α-aryl-α,α-difluoro-
carbonyl compounds. However, the couplings of fluorinated
identify an active Pd catalyst and reaction components to
conduct this transformation under relatively mild conditions.
We tested this reaction with Pd catalysts generated from 5
mol % of Pd(dba)2 and a range of bisphosphines (BINAP,
BIPHEP, DPPF, and DCPF) and monophosphines (PCy3, P(t-
Bu)Cy2, P(t-Bu)2Cy, P(t-Bu)3, P(t-Bu)2Ph, P(t-Bu)Ph2,
Received: February 1, 2014
Published: March 3, 2014
© 2014 American Chemical Society
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a
Table 1. α-Arylation of α,α-Difluoroacetophenone with Aryl Bromides and Aryl Chlorides Catalyzed by Complex 1
a
Conditions A: α,α-difluoroacetophenone (0.400 mmol), aryl bromide (0.800 mmol), Cs2CO3 (0.800 mmol), complex 1 (8.0 μmol), toluene (1
mL), 100 °C, 24 h. Conditions B: aryl bromide or aryl chloride (0.200 mmol), α,α-difluoroacetophenone (0.400 mmol), K3PO4(H2O) (0.800
b
mmol), complex 1 (2 μmol), toluene (1 mL), 100 °C for aryl bromide and 110 °C for aryl chloride, 30 h. Yields were determined by 19F NMR
c
d
e
spectroscopy with 1-bromo-4-fluorobenzene as internal standard. Complex 1 (20 μmol, 5 mol %). 120 °C. Complex 1 (4 μmol, 2 mol %).
PCy2Ph, PAd2(n-Bu), SPhos, and Q-Phos) in the presence of
relatively weak base Cs2CO3 at 80 °C (see Table S1 in the
Supporting Information). We found that the reaction catalyzed
by the combination of Pd(dba)2 (5 mol %) and the rarely
utilized phosphine P(t-Bu)Cy2 or PAd2(n-Bu) (6 mol %)
afforded the coupled product in 84% yield; the same reaction
with P(t-Bu)Cy2 as ligand at 100 °C afforded the coupled
product in 95% yield.
To render the catalyst convenient to use, we prepared a
single-component palladacyclic complex 1 containing P(t-
Bu)Cy2 as the dative ligand. Similar palladacyclic precursors
have been used for C−C and C−N cross-coupling reactions.8
The model reaction occurred in high yields in the presence of
1−2 mol % of complex 1 as catalyst and Cs2CO3 as base with
ketone as the limiting reagent (conditions A) or in the presence
of K3PO4(H2O) as base with bromobenzene as the limiting
reagent (conditions B) in toluene at 100 °C (Scheme 1).
Selected results of our studies on the reaction scope are
summarized in Table 1. These reactions were conducted under
the two sets of conditions having ketone or haloarene as the
limiting reagent (conditions A and B, as in Scheme 1). In
general, a wide range of electronically varied aryl bromides and
aryl chlorides underwent this cross-coupling process with α,α-
difluoroacetophenone in high yields. Reactions of aryl chlorides
afforded the coupled products in yields that were comparable to
those of reactions of the corresponding aryl bromides under
conditions B (2a, 2c, 2e−2j, 2l, 2h, 2x, and 2z).
These arylation reactions tolerate a range of functionalities,
including nitro (2d), ether (2g, 2i, and 2l), thioether (2h),
ester (2q and 2u), non-enolizable ketone (2s), and carbamate
(2v) moieties. Reactions of substrates bearing both bromo and
chloro substituents occurred selectively at the bromide (2n),
leaving the C−Cl bond intact and accessible for further
functionalization. Free hydroxyl, aniline, amine, cyano,
enolizable ketone, or aldehyde functionalities are not
compatible with the reaction conditions. However, aryl
bromides containing a dimethylamino (2o) or dimethylamino-
methyl (2p) group, protected alcohol (2q), protected aldehyde
(2r), or protected enolizable ketone (2t) coupled with α,α-
difluoroacetophenone in high yields. The scope of the reaction
also encompassed α,α-difluoroacetophenones containing a
variety of electronically varied aryl groups.9 The reactions of
these ketones with 4-chloroanisole were conducted under
conditions B with 2 mol % of complex 1, and the coupled
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products (3a−3e in Table 1) were isolated in high yields (84−
92%).
Scheme 2. Base-Induced C−C Cleavage of α-Aryl-α,α-
difluoroketones
The coupling of difluoroacetophenone also occurred with
brominated nitrogen-containing heterocycles, such as bromo-
pyridine, quinolines, and isoquinoline (2w−2z). For these
reactions a higher catalyst loading (5 mol %) (2w, 2y, and 2z
with conditions A) and temperature (120 °C) (2w) were used
to obtain good yields of the coupled products.
These coupling reactions can be conducted without a drybox
and on a larger scale. The coupling of α,α-difluoroaceto-
phenone with 2-(3-bromophenyl)-1,3-dioxolane conducted
outside a drybox on a 2 mmol scale catalyzed by only 0.5
mol % of complex 1 occurred in a high yield (89%) similar to
that of the reaction conducted inside a drybox on a smaller
scale (2r, Table 1). Thus, these reactions should be practical for
a number of applications in medicinal chemistry.
Having demonstrated the α-arylation and the C−C bond
cleavage as individual steps, we developed a one-pot procedure
for the synthesis of difluoromethylarenes. The scope of aryl
bromides and aryl chlorides that undergo the combination of α-
arylation and the base-induced C−C bond cleavage is
summarized in Table 2. In many cases, the resulting
The α-aryl-α,α-difluoroacetophenone products of the cou-
pling process undergo reactions characteristic of typical
carbonyl functionality. For example, they undergo nucleophilic
addition of Grignard reagents to form tertiary alcohols, and
they are reduced by NaBH4 to afford primary alcohols (see the
Supporting Information for details). Of particular interest, the
C−C bond adjacent to the carbonyl group in these ketones can
be readily cleaved to afford difluoromethylarenes (ArCF2H).
Aromatic compounds containing a difluoromethyl (CF2H)
group are valuable for medicinal chemistry because the
difluoromethyl group can act as a bio-isostere of alcohols and
thiols and as a lipophilic hydrogen bond donor.10 However,
methods for the introduction of the difluoromethyl group onto
arenes are limited, and each method has significant limitations.
The most common method to access these difluoromethyl-
arenes is the deoxofluorination of benzaldehydes with sulfur
tetrafluoride and N,N-diethylaminosulfur trifluoride deriva-
tives.11 However, these fluorinating reagents are highly sensitive
toward moisture and can undergo explosive decomposition
upon heating. Amii’s group reported a three-step sequential
reaction sequence comprising copper-mediated cross-coupling
of aryl iodides with α-silyldifluoroacetates, hydrolysis of the α-
aryldifluoroacetates, and decarboxylation of the resulting α-
aryldifluoroacetic acids.6a,12 However, these sequential reactions
occurred in overall modest yields, required 200 °C for the
decarboxylation of α-aryl-difluoroesters containing electron-
neutral aryl groups, and did not occur with those containing
electron-rich aryl groups. Baran and co-workers reported a
direct introduction of the difluoromethyl group onto
heteroarenes with zinc difluoromethanesulfinate.13 However,
reactions with arenes have not been reported thus far, and the
regioselectivity for reactions of heteroarenes is distinct from
that of halogenated heteroarenes. Finally, our group and
Prakash’s group recently reported copper-mediated difluoro-
methylation of aryl iodides with Me3SiCF2H and n-
Bu3SnCF2H, respectively, but the scope of these reactions is
limited to aryl iodides.14
a
Table 2. One-Pot Synthesis of Difluoromethylarenes
Our investigation of the base-induced cleavage of the α-aryl-
α,α-difluoroketone products to form difluoromethylarene was
spurred by the observation of small but significant amounts of
4-difluoromethylquinoline (13%) from the coupling of α,α-
difluoroacetophenone with 4-bromoquinoline (Scheme 2A).
We found that the analogous base-induced C−C cleavage of
isolated α-phenyl-α,α-difluoroacetophenone (2e) occurred in
the presence of KOH and H2O in toluene at 100 °C (Scheme
2B) to afford (difluoromethyl)benzene in quantitative yield in 2
h, as determined by 19F NMR spectroscopy.
a
Conditions: step 1, aryl bromide or aryl chloride (0.200 mmol), α,α-
difluoroacetophenone (0.400 mmol), K3PO4(H2O) (0.800 mmol),
complex 1 (2 μmol), toluene (1 mL), 100 °C for aryl bromide and
110 °C for aryl chloride, 30 h; step 2, KOH (100 mg), H2O (50 μL),
100 °C, 2 h. Yields are determined by 19F NMR spectroscopy with 1-
bromo-4-fluorobenzene as internal standard. Isolated yields are shown
b
in parentheses for products with high boiling points. Step 2 was
conducted at room temperature.
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difluoromethylarenes are volatile, and the yields of these
reactions were determined by 19F NMR spectroscopy with 1-
bromo-4-fluorobenzene as an internal standard. Isolated yields
were obtained for the reactions affording the difluoromethyl-
arenes with high boiling points.
ACKNOWLEDGMENTS
■
Financial support was provided by NIH (GM-58108). W.C.
thanks the Foundation for Polish Science for postdoctoral
fellowships. We thank Johnson-Matthey for PdCl2.
The scope of aryl bromides and aryl chlorides that undergo
this transformation mirrors the scope of aryl bromides and aryl
chlorides that undergo Pd-catalyzed α-arylation of α,α-
difluoroacetophenone described in Table 1. In general, a wide
range of electronically varied aryl bromides and aryl chlorides
underwent this reaction sequence to afford the corresponding
difluoromethylarenes in high yields. Reactions of aryl chlorides
afforded the desired products in yields comparable to those of
the reactions of aryl bromides (4b−4j, 4m, 4p, and 4x). Like
the single-step coupling reaction, the sequential reactions
tolerate a range of functionalities, including ether (4d, 4g, and
4i), thioether (4h), ester (4r and 4v), non-enolizable ketone
(4t), and carbamate (4w) moieties. Reactions of 1-bromo-4-
chlorobenzene occurred selectively at the bromide (4o), and
aryl bromides containing N,N-dimethylamino (4p), dimethyl-
aminomethyl (4q), protected alcohol (4r), protected aldehyde
(4s), and protected enolizable ketone (4u) functionality
reacted to form the corresponding difluoromethylarenes in
high yields. Brominated nitrogen-containing heterocycles, such
as quinolines (4x and 4y) and isoquinoline (4z), also gave the
difluoromethyl heteroarenes in good yields.
In summary, we have developed a convenient and efficient
protocol for the coupling of α,α-difluoroketones with aryl and
heteroaryl bromides and chlorides catalyzed by a single-
component, moisture- and air-stable palladacyclic precatalyst
1. The mechanism of this reaction likely comprises oxidative
addition of the aryl halide, generation of an arylpalladium
fluoroenolate complex, and reductive elimination of the α-aryl-
α,α-difluoroketone product from the arylpalladium fluoroeno-
late complex. Reductive elimination reactions from perfluoro-
alkyl complexes have been limited to those from complexes of
bisphosphines that bind with large bite angles or from
complexes of phosphines containing extremely hindered
substituents.15 The catalyst used for the difluoroenolate
coupling reported here contains a ligand that has rarely been
used for catalysis but contains standard alkyl substituents.
Studies to understand the relationship between reductive
elimination from perfluoroalkyl complexes and fluorinated
enolate complexes will be the subject of future work.
REFERENCES
■
(1) (a) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Chem.
Soc. Rev. 2008, 37, 320. (b) Wang, J.; San
́
chez-Rosello,
́
M.; Acena, J.
̃
L.; del Pozo, C.; Sorochinsky, A. E.; Fustero, S.; Soloshonok, V. A.;
Liu, H. Chem. Rev. 2014, 114, 2432.
(2) (a) Banks, R. E.; Smart, B. E.; Tatlow, J. C. Organofluorine
Compounds: Principles and Commercial Applications; Plenum: New
York, 2000. (b) Kirsch, P. Modern Fluoroorganic Chemistry; Wiley-
VCH Verlag GmbH & Co. KGaA: Weinheim, 2013.
(3) Feng, Z.; Min, Q.-Q.; Xiao, Y.-L.; Zhang, B.; Zhang, X. Angew.
Chem., Int. Ed. 2014, 53, 1669.
́
(4) Enchavarren, A. M.; Cardenas, D. J. In Metal-Catalyzed Cross-
Coupling Reactions; de Meijere, A., Diederich, F., Eds.; Wiley-VCH
Verlag GmbH & Co. KGaA: Weinheim, 2008; Vol. 1, p 1.
(5) Zemtsov, A. A.; Kondratyev, N. S.; Levin, V. V.; Struchkova, M.
I.; Dilman, A. D. J. Org. Chem. 2013, 79, 818.
(6) (a) Fujikawa, K.; Fujioka, Y.; Kobayashi, A.; Amii, H. Org. Lett.
2011, 13, 5560. (b) Guo, C.; Wang, R.-W.; Qing, F.-L. J. Fluorine
Chem. 2012, 143, 135.
(7) Guo, Y.; Shreeve, J. n. M. Chem. Commun. 2007, 3583.
(8) (a) Kinzel, T.; Zhang, Y.; Buchwald, S. L. J. Am. Chem. Soc. 2010,
132, 14073. (b) Bruno, N. C.; Buchwald, S. L. Org. Lett. 2013, 15,
2876. (c) Bruno, N. C.; Tudge, M. T.; Buchwald, S. L. Chem. Sci. 2013,
4, 916.
(9) Reactions of aliphatic ketones RCH2C(O)CF2H so far occur at
the non-fluorinated methylene position.
(10) (a) Araoz, R.; Anhalt, E.; Rene, L.; Badet-Denisot, M.-A.;
́ ́
Courvalin, P.; Badet, B. Biochemistry 2000, 39, 15971. (b) Hope, H. R.
J. Lipid Res. 2000, 41, 1604.
(11) (a) Markovskij, L. N.; Pashinnik, V. E.; Kirsanov, A. V. Synthesis
1973, 787. (b) Middleton, W. J. J. Org. Chem. 1975, 40, 574.
(c) Dolbier, W. R.; Xie, P.; Zhang, L.; Xu, W.; Chang, Y.; Abboud, K.
A. J. Org. Chem. 2008, 73, 2469.
(12) Fujikawa, K.; Kobayashi, A.; Amii, H. Synthesis 2012, 44, 3015.
(13) Fujiwara, Y.; Dixon, J. A.; Rodriguez, R. A.; Baxter, R. D.; Dixon,
D. D.; Collins, M. R.; Blackmond, D. G.; Baran, P. S. J. Am. Chem. Soc.
2012, 134, 1494.
(14) (a) Fier, P. S.; Hartwig, J. F. J. Am. Chem. Soc. 2012, 134, 5524.
(b) Prakash, G. K. S.; Ganesh, S. K.; Jones, J.-P.; Kulkarni, A.; Masood,
K.; Swabeck, J. K.; Olah, G. A. Angew. Chem., Int. Ed. 2012, 51, 12090.
(15) (a) Grushin, V. V.; Marshall, W. J. J. Am. Chem. Soc. 2006, 128,
12644. (b) Cho, E. J.; Senecal, T. D.; Kinzel, T.; Zhang, Y.; Watson, D.
A.; Buchwald, S. L. Science 2010, 328, 1679.
ASSOCIATED CONTENT
■
S
* Supporting Information
Detailed experimental procedure, characterization of all
1
compounds, and H and 13C NMR spectra of all compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
jhartwig@berkeley.edu
Notes
The authors declare the following competing financial
interest(s):A provisional patent application has been filed by
the University of California. J.F.H. is a founder of Catylix; he
and the company may benefit financially from the expected
results of the PHS-funded research conducted in his laboratory.
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