Pd-catalyzed α-arylation of trimethylsilyl enolates of α,α-difluoroacetamides

Article abstract of DOI:10.1021/ja508590k

We report the arylation and heteroarylation of α,α-difluoro-α-(trimethylsilyl)acetamides with aryl and heteroaryl bromides catalyzed by an air- and moisture-stable palladacyclic complex containing P(t-Bu)₂Cy as ligand. A broad range of electronically varied aryl and heteroaryl bromides underwent this transformation to afford α-aryl-α,α-difluoroacetamides in high yields. Due to the electrophilicity of the fluorinated amide, this palladium-catalyzed cross-coupling reaction provides a versatile platform to generate a range of α,α-difluoro carbonyl compounds, such as α-aryl-α,α-difluoroketones, -acetaldehydes, -acetates, and acetic acids, and difluoroalkyl derivatives, such as 2-aryl-2,2-difluoroethanols and -ethylamines, under mild conditions.

Full text of DOI:10.1021/ja508590k

Communication
pubs.acs.org/JACS
Pd-Catalyzed α‑Arylation of Trimethylsilyl Enolates of α,α-
Difluoroacetamides
Shaozhong Ge, Sophie I. Arlow, Michael G. Mormino, and John F. Hartwig*
Department of Chemistry, University of California, Berkeley, California 94720, United States
S
* Supporting Information
Thus, the coupling of aryl and heteroaryl halides with
difluoroalkyl nucleophiles would be a valuable reaction for the
synthesis of fluoroalkylarenes. However, the coupling reaction
between an aryl electrophile and a difluoroalkyl nucleophile
occurs with limited scope. For example, the Pd-catalyzed
coupling of aryl halides with difluorinated enolates of carbonyl
compounds has been reported with only 1,1-difluoro-
acetophenone derivatives.7 These reactions occur, in part,
because difluoroacetophenones are more acidic than their non-
fluorinated congeners8 and can be deprotonated with insoluble
inorganic bases. The copper-catalyzed coupling of aryl halides
with the silyl enolate of 1,1-difluoroacetate has been reported,
but it requires aryl iodides as the coupling partner.9
The Pd-catalyzed coupling of an aryl bromide with the
enolate of a 1,1-difluorocarboxylic acid derivative could provide
a general route to a variety of functionalized α,α-difluoro-
alkylarenes due to the versatile reactivity of carboxylic acid
derivatives. However, the couplings of aryl halides with α,α-
difluorocarboxylic acid derivatives are distinct from those of a
difluoroacetophenone because the fluorinated carboxylic acid
derivatives are less acidic than their non-fluorinated ana-
logues,10 and they are not stable to soluble strong bases. Thus,
the generation of the difluoroenolate of a carboxylic acid
derivative by deprotonation is challenging. In addition, the rate
of reductive elimination of fluoroalkylpalladium complexes is
slower than that of their non-fluorinated analogues,11 and this
slow rate of reductive elimination could cause the catalytic
reaction to require temperatures at which the enolates of
difluorocarboxylic acid derivatives are unstable.
ABSTRACT: We report the arylation and heteroarylation
of α,α-difluoro-α-(trimethylsilyl)acetamides with aryl and
heteroaryl bromides catalyzed by an air- and moisture-
stable palladacyclic complex containing P(t-Bu)2Cy as
ligand. A broad range of electronically varied aryl and
heteroaryl bromides underwent this transformation to
afford α-aryl-α,α-difluoroacetamides in high yields. Due to
the electrophilicity of the fluorinated amide, this
palladium-catalyzed cross-coupling reaction provides a
versatile platform to generate a range of α,α-difluoro
carbonyl compounds, such as α-aryl-α,α-difluoroketones,
-acetaldehydes, -acetates, and acetic acids, and difluoroalkyl
derivatives, such as 2-aryl-2,2-difluoroethanols and -ethyl-
amines, under mild conditions.
luorine-containing aromatic compounds are widespread in
Fmedicinal chemistry and material sciences due to their
unique stability, reactivity, and biological properties.1 Com-
pounds containing a fluorinated aromatic ring or trifluoro-
methyl group have been studied extensively.2 Molecules
containing an α,α-difluorobenzyl unit (ArCF2−) are particularly
desirable building blocks for medical chemistry because they
contain two fluorine atoms at a metabolically labile benzylic
position.3 However, methods for the introduction of function-
alized α,α-difluoroalkyl groups onto arenes are limited.
Classic methods to prepare these α,α-difluorobenzylic
compounds rely on gem-deoxodifluorination of benzoyl
derivatives with sulfur tetrafluoride and N,N-diethylaminosulfur
trifluoride derivatives.4 Oxidative desulfurization-difluorination
of 1-aryl-1,3-dithiolanes with the combination of oxidant and
Olah’s reagent also provides such compounds.4 However, these
reactions occur with limited scope. In addition, the fluorinating
reagents for these reactions are highly sensitive toward moisture
and may undergo explosive decomposition upon heating.
Alternatively, gem-difluorination of benzylic C−H bonds could
be conducted, but this reaction occurred with limited scope.5
Cross-coupling reactions could be envisioned to form
products containing fluorine in the benzylic position. The
cross-coupling of α,α-difluoroalkyl halides (XCF2R, X = Cl, Br,
or I) with arylboronic acids catalyzed by transition metal
complexes is one approach to α,α-difluorobenzylic compounds
that has been reported recently.6 However, boronic acids are
not as accessible and widely available a partner for cross
coupling as are aryl halides, and the coupling of α,α-
difluoroalkyl halides with heteroaryl boronates was not
reported.
We show that these challenges can be met by conducting the
coupling of aryl and heteroaryl bromides with the silicon
enolates of α,α-difluoroacetamides in the presence of a highly
active palladium catalyst. The reactions of the silicon enolates
of α,α-difluoroacetamides with a range of aryl and heteroaryl
bromides occur when catalyzed by an air- and moisture-stable
palladacyclic complex containing the sterically hindered P(t-
Bu)2Cy as ligand and KF as activator of the enolate (eq 1). The
carbonyl unit in these products is more electrophilic than that
of a non-fluorinated amide; this property can be exploited to
convert the coupled products to a variety of α,α-difluoro-
benzylic compounds.
Received: August 20, 2014
© XXXX American Chemical Society
A
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Journal of the American Chemical Society
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We initiated our studies of Pd-catalyzed α-arylation of α,α-
difluoroacetamides by evaluating reactions of an aryl bromide
with the silicon enolate of the amide. We tested a variety of
single-component palladacyclic catalyst precursors containing
simple trialkyl phosphine ligands12 and various solvents for the
coupling reaction of 1-bromo-4-tert-butylbenzene with N,N-
diethyl-α,α-difluoro-α-(trimethylsilyl)acetamide. The results of
these experiments are summarized in Table 1.
bromide occurred, and the coupled product formed in nearly
quantitative yield.
With an active catalyst in hand and reliable conditions
identified for this Pd-catalyzed arylation reaction, we studied
the scope of aryl bromides that undergo this cross-coupling
reaction. These results are summarized in Table 2. In general, a
wide range of electronically varied aryl bromides reacted to give
the corresponding coupled products in high yields (68−93%)
with 1 mol % of [Pd3].
Table 1. Evaluation of Pd-Catalyst Precursors and Solvents
for the Model Arylation of a Difluoroacetamide
a
Table 2. Pd-Catalyzed Coupling of N,N-Diethyl-α,α-
a
difluoro-α-(trimethylsilyl)acetamide with Aryl Bromides
a
Conditions: aryl bromide (0.400 mmol), α,α-difluoro-α-(trimethyl-
silyl)acetamide (0.800 mmol), KF (1.20 mmol), [Pd] (4.0 μmol),
b
solvent (1 mL), 100 °C, 30 h. Determined by GC analysis with
dodecane as internal standard.
The reactions were conducted with 1-bromo-4-tert-butylben-
zene as the limiting reagent and 1 mol % Pd precatalyst in the
presence of KF at 100 °C. They were conducted in 1,4-dioxane
with palladacyclic complexes [Pd1]−[Pd4] containing trialkyl-
phosphines possessing different steric properties (PCy3,
PCy2(t-Bu), PCy(t-Bu)2, and P(t-Bu)3; entries 1−4). Reactions
catalyzed by the PCy3- and P(t-Bu)3-ligated Pd-complexes
occurred to low conversion of aryl bromide and afforded the
coupled product in low yields (entries 1 and 4). The reaction
conducted with [Pd2] ligated by PCy2(t-Bu) occurred to
modest conversion of aryl bromide and gave the coupled
product in modest yield (entry 2). However, the reaction
catalyzed by [Pd3] containing PCy(t-Bu)2 as ligand occurred to
full conversion and afforded the coupled product in 87% yield
(entry 3).
The solvent effect on this reaction was pronounced. The
reaction catalyzed by 1 mol % of [Pd3] in toluene occurred to
low conversion of the aryl bromide (28%), but with good mass
balance (entry 5). The reaction in DMF led to full conversion
of the aryl bromide, but formed predominantly the hydro-
debromination product tert-butylbenzene and less than 5% of
the coupled product (entry 6). The reaction conducted in
DMSO proceeded to both low conversion and low yield (<5%,
entry 8). The reaction in THF (entry 7) occurred similarly to
the reaction in 1,4-dioxane (entry 3). Analysis of the conversion
of the trimethylsilyl enolate of α,α-difluoroacetamide showed
that it was fully consumed during the reactions in 1,4-dioxane,
DMF, THF, and DMSO (entries 3 and 6−8), but that the mass
balance was not as high as it was for the reaction in toluene
(entry 5). Given the high yield of the reaction in 1,4-dioxane,
but the higher mass balance of the reaction in toluene, we
tested the reaction in a mixture of 1,4-dioxane and toluene (v/v
1:1, entry 9). In this solvent system, full conversion of the aryl
a
Conditions: aryl bromide (0.400 mmol), N,N-diethyl-α,α-difluoro-α-
(trimethylsilyl)acetamide (0.800 mmol), KF (1.2 mmol), [Pd3] (2.2
mg, 4.0 μmol, 1 mol %), toluene (0.5 mL), and 1,4-dioxane (0.5 mL),
100 °C, 30 h. [Pd3] (4.3 mg, 8.0 μmol, 2 mol %), 24 h. 1-Bromo-4-
(1,1-diethoxyethyl)benzene was used. [Pd3] (8.5 mg, 16.0 μmol, 4
b
c
d
mol %), 24 h.
The data in Table 2 show that the electronic properties of
the aryl bromides have little influence on the yields of this
cross-coupling process. Products formed from the reactions of
electron-deficient (2a−2c) and electron-rich (2f−2k) aryl
bromides were isolated in yields as high as those from reactions
of electron-neutral aryl bromides (2d and 2e). However, the
reaction of the most electron-deficient 1-bromo-4-benzotri-
fluoride was slower than the reactions of the more electron-rich
aryl bromides when conducted in the presence of 1 mol %
[Pd3] and afforded the coupled product (2a) in only a modest
yield (53%). The same reaction catalyzed by 2 mol % [Pd3]
gave the desired product in high yield (82%).
This coupling reaction tolerates a range of functionalities,
including thioether (2h), ether (2i, 2j, and 2n), ester (2q and
2s), and carbamate (2t) moieties. Reactions of aryl halides
B
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bearing both bromo and chloro substituents occurred
selectively at the bromide (2o) under standard conditions,
leaving the C−Cl bond intact. Enolizable ketone, aldehyde, free
hydroxyl, and arylamino groups are not compatible with the
reaction conditions. However, aryl bromides containing an
enolizable ketone (2p, the protecting group was removed upon
workup under acidic conditions) or aldehyde (2r) protected as
the diethyl acetal, an alcohol protected as the acetyl ester (2s),
and aniline protected as the Boc carbamate (2t) afforded the
corresponding coupled products in high yields.
This arylation reaction also occurred with brominated
nitrogen-containing heterocycles, such as bromopyridines,
bromoquinolines, and bromoisoquinolines (2u−2z). For
these reactions of nitrogen-containing heterocycles, a higher
catalyst loading (4 mol %) was required to obtain the coupled
products in good yields.
(trimethyl)silylacetamide conducted outside a drybox on 4.0
mmol scale catalyzed by 1 mol % of [Pd3] occurred in a yield
(90%) that was similar to that of the reaction assembled in a
drybox on a smaller scale (0.400 mmol, Table 2, 2p). Thus,
these coupling reactions can be conveniently conducted on a
scale that would allow practical applications in medicinal and
likely process chemistry.
An important feature of carboxylic acid derivatives is the
ability to convert one of the functional groups to another and
to reduce them to the corresponding alcohols and amines.
However, the amide is typically the most stable carboxylic acid
derivative and, therefore, is not the preferred synthetic
intermediate to form other products in this class. We
considered that the two fluorine atoms on the α carbon of
the coupled products could cause the carbonyl group in α,α-
difluoroacetamides to be more electrophilic than the carbonyl
group of their non-fluorinated congeners and the amides
prepared in this work to be more reactive toward nucleophiles
than typical amides. At the same time, conditions for reducing
the amide could lead to hydrodefluorination. Thus, we
conducted studies to evaluate the reactivity of the α-aryl-α,α-
difluoroacetamide products of this coupling process toward
reactions that would form a range of α,α-difluoroalkylarenes.
The results in Scheme 1 show that the α-aryl-α,α-
difluoroacetamides undergo a series of transformations under
conditions more typical of the reactions of esters than of the
reactions of amides. These difluoroamides can be reduced (A,
Scheme 1) to tertiary amines (8), primary alcohols (9), or
The scope of α,α-difluoro-α-(trimethyl)silylacetamides that
undergo this coupling reaction is summarized in Table 3. For
Table 3. Pd-Catalyzed Coupling of α,α-Difluoro-α-
a
(trimethylsilyl)acetamides and Aryl Bromides
Scheme 1. Transformations of α-Aryl-α,α-
difluoroacetamides
a
Conditions: aryl bromide (0.400 mmol), α,α-difluoro-α-(trimethyl-
silyl)acetamide (0.800 mmol), KF (1.2 mmol), [Pd3] (6.5 mg, 12
b
c
μmol), 1,4-dioxane (1.0 mL), 110 °C, 24 h. 100 °C. Toluene (1.0
d
mL), 1,4-dioxane (1.0 mL), 100 °C. [Pd3] (8.6 mg, 16 μmol),
e
toluene (0.5 mL), 1,4-dioxane (0.5 mL), 100 °C, 48 h. The
corresponding aryl chloride (0.400 mmol) was used.
each amide, we studied the arylation with three electronically
varied aryl bromides (4-bromobenzotrifluoride, 1-bromo-4-
(tert-butyl)benzene, and 1-(benzyloxy)-4-bromobenzene). The
α,α-difluoro-α-(trimethylsilyl)acetamides that undergo this
reaction include acyclic N,N-dialkyl amides (3a−3c) and alkyl
benzyl amides (4a−4c). They also include a series of cyclic
amides, such as the pyrrolidinyl (5a−5c), piperidinyl (6a−6c),
and morpholinyl (7a−7c) amides. These amides reacted with
the selected electronically varied aryl bromides to afford the
coupled products in 54−89% yield.
These coupling reactions can be conducted on a larger scale
and without a drybox. The reaction of 1-bromo-4-(1,1-
diethoxyethyl)benzene with N,N-diethyl-α,α-difluoro-α-
C
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aldehydes (10) without hydrodefluorination. Morpholine
amides are known to act as surrogates for Weinreb amides,
which can be converted selectively to ketones,13 and the
difluoromorpholine amide 7c reacted with n-butyllithium to
form difluorobenzylic alkyl ketone 12. This ketone product is
not accessible by the Pd-catalyzed α-arylation of difluoromethyl
butyl ketone.14 Piperidinyl difluoroamide 6 was transformed to
the corresponding methyl ester (11a) by reaction with
methanol and Me3SiCl (12 h at 70 °C). In addition, N,N-
diethyl difluoroamides underwent hydrolysis more readily to
afford α-aryl-α,α-difluoroacetic acid (13a) than the correspond-
ing non-fluorinated amides.
The silicon enolates of difluoro esters, so far, do not undergo
the same coupling as the amides, but we developed a simple
one-pot method to form the 1-aryl-1,1-difluoro esters via the
palladium-catalyzed coupling of difluoroamides. The reaction
sequence comprising Pd-catalyzed arylation of piperidinyl α,α-
difluoroacetamide and methanolysis of the resulting amide
products (B, Scheme 1) formed methyl α-aryl-α,α-difluoro-
acetates 13b−13d.
ACKNOWLEDGMENTS
■
We thank the NIH (GM-58108) for support of this work and
Johnson-Matthey for Pd(OAc)2. Dr. Wojciech Chaładaj is
acknowledged for the initial synthesis of [Pd3].
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A similar protocol was developed for the transformation of
aryl bromides to α-aryl-α,α-difluoroacetic acids. As shown in
part C of Scheme 1, a series of α-aryl-α,α-difluoroacetic acids
containing electron-rich, electron-poor, and functionalized aryl
groups were prepared in good to excellent yields by a sequence
comprising Pd-catalyzed α-arylation of piperidinyl α,α-difluoro-
acetamide and hydrolysis of the resulting amide products to the
acids at 70 °C.
In summary, we have developed a convenient and efficient
protocol for the α-arylation and heteroarylation of the
trimethylsilyl enolates of α,α-difluoroacetamides with aryl and
heteroaryl bromides catalyzed by a single-component air- and
moisture-stable palladacyclic precatalyst [Pd3]. A broad range
of aryl and heteroaryl bromides, including those of basic
nitrogen heterocycles, were coupled with α,α-difluoro-α-
(trimethylsilyl)acetamides in high isolated yields. The α-aryl-
α,α-difluoroacetamide products of these coupling reactions can
be converted to 2-aryl-2,2-difluoroethanols and -ethylamines, as
well as α-aryl-α,α-difluoroketones, -acetaldehydes, -acetates,
and -acetic acids. Therefore, this Pd-catalyzed cross-coupling of
aryl halides with α,α-difluoro-α-(trimethylsilyl)acetamides
provides a method to prepare a variety of valuable building
blocks containing fluorine atoms at the metabolically labile
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ASSOCIATED CONTENT
■
S
* Supporting Information
Detailed experimental procedures, and characterization of all
compounds, including 1H and 13C NMR spectra. This material
is available free of charge via the Internet at http://pubs.acs.org.
(14) The arylation occurs at nonfluorinated α-methylene of
difluoromethyl butyl ketone; see ref 7a.
AUTHOR INFORMATION
■
Corresponding Author
jhartwig@berkeley.edu
Notes
The authors declare the following competing financial
interest(s): A 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.
D
dx.doi.org/10.1021/ja508590k | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX