Palladium Catalysis Enables Benzylation of α,α-Difluoroketone Enolates

Article abstract of DOI:10.1002/anie.201604149

A palladium-catalyzed decarboxylative benzylation reaction of α,α-difluoroketone enolates is reported, in which the key C(α)?C(sp³) bond is generated by reductive elimination from a palladium intermediate. The transformation provides convergent access to α-benzyl-α,α-difluoroketone-based products, and should be useful for accessing biological probes.

Full text of DOI:10.1002/anie.201604149

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Communications
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International Edition: DOI: 10.1002/anie.201604149
German Edition: DOI: 10.1002/ange.201604149
Synthetic Methods
Palladium Catalysis Enables Benzylation of a,a-Difluoroketone
Enolates
Ming-Hsiu Yang, Jordan R. Hunt, Niusha Sharifi, and Ryan A. Altman*
Abstract: A palladium-catalyzed decarboxylative benzylation
reaction of a,a-difluoroketone enolates is reported, in which
3
À
the key C(a) C(sp ) bond is generated by reductive elimina-
tion from a palladium intermediate. The transformation
provides convergent access to a-benzyl-a,a-difluoroketone-
based products, and should be useful for accessing biological
probes.
T
he a,a-difluoroketone is a privileged substructure in
medicinal chemistry.[1] For this substructure, the electron-
withdrawing fluorine atoms encourage rehybridization of the
2
3
=
sp -hybridized C O to form sp -hybridized hydrates or hemi-
hydrates,[2] which can then interact with aspartyl proteases
through noncovalent hydrogen-bonding networks involving
water molecules, and with serine proteases through reversible
covalent interactions.[1] In addition, a subset of a-benzyl-a,a-
difluoroketone derivatives also have demonstrated choles-
terol-lowering,[3] analgesic,[4] anxiolytic,[5] and pro-inflamma-
tory[6] activities (Figure 1). Thus, convergent and mild strat-
egies for accessing a-benzyl-a,a-difluoroketone-based sub-
structures should be useful for developing new therapeutic
candidates and biological probes.
Figure 1. a-Benzyl-a,a-difluoroketone motifs in bioactive molecules.
icochemical properties that preclude formation of the
3
À
A convergent preparation of this substructure would
C(a) C(sp ) bond. Specifically, the strong inductive effect
3
À
involve a transformation capable of generating a C(a) C(sp )
of the two fluorine atoms[9a] decreases the charge density of an
enolate at the a-position,[9b] and thus reduces the nucleophi-
licity of the anion and disfavors reactions with sp3-based
electrophiles (Figure 2c). As a result, a,a-difluoroketone
enolates react by SN2 reactions at the O to generate
difluorovinyl ethers, instead of at C(a) (Figure 2d).[10]
Because of these two factors, only two manuscripts describe
SN1- or SN2-like alkylation reactions of a,a-difluoroketones,
and both require stoichiometric amounts of metal reagents to
promote the reactions (Figure 2e).[11]
Because of this intrinsically poor reactivity, several
alternative strategies for accessing a-benzyl-a,a-difluoroke-
tones have been developed, including: 1) deoxyfluorination
of a-ketoesters using strong fluorinating reagents, followed by
addition of organolithium or Grignard reagents to the
resulting a,a-difluoroester, for which the strong bases and
harsh reagents destroy many functional groups;[3] 2) 1,2-
addition of a-lithio-b,b-difluorovinyl ethers to aldehydes
followed by deoxygenation (or cyclization) of the resulting
alcohol, which only accesses a small subset of products;[12] 3) a
single radical addition reaction of an aldehyde to a (2,2-
difluorovinyl)benzene;[13] and 4) a late-stage electrophilic
difluorination of prefunctionalized imines using Selectfluor/
NFSI followed by acid-mediated hydrolysis—not a convergent
strategy, which also generates a mixture of fluorinated
products for substrates bearing two sites capable of under-
going imine-enamine isomerization.[14] However, none of
bond, presumably by reacting a nucleophilic a,a-difluoroke-
tone enolate with an sp3-hybridized benzylic electrophile
(Figure 2a). Alkylation of ketone enolates with sp3-based
electrophiles is a fundamental transformation for accessing
a broad spectrum of a-functionalized ketones.[7] However,
nucleophilic substitution reactions of a,a-difluorinated eno-
lates with sp3-based electrophiles have not been generally
developed, because of two problems. First, chemoselective
formation of a,a-difluoroketone enolates presents challenges,
because deprotonation of a,a-difluoromethyl ketones produ-
ces enolates at the nonfluorinated position under both
thermodynamic and kinetic conditions (Figure 2b),[8] and
upon trapping, cannot afford a-functionalized-a,a-difluoro-
ketones. Second, a,a-difluoroenolates possess unique phys-
[*] M.-H. Yang, J. R. Hunt, Prof. Dr. R. A. Altman
Department of Medicinal Chemistry
The University of Kansas
1251 Wescoe Hall Drive, Lawrence, KS 66045 (USA)
E-mail: raaltman@ku.edu
Dr. N. Sharifi
Department of Medicinal Chemistry, Faculty of Pharmacy
Tehran University of Medical Science
16 Azar St., Tehran 1417614411 (Iran)
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201604149.
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Table 1: Palladium-catalyst promotes decarboxylative benzylation reac-
tion of a,a-difluoroenolates.[a]
[a] Standard reaction conditions: 1a–1a’’ (1.0 equiv), [Pd(PPh3)4]
(2.5 mol%), o-xylene (0.05m), 1208C, 15 h. The reported data represents
an average of two independent experiments. [b] The yields were
determined by 19F NMR spectroscopy using a,a,a-trifluorotoluene and
fluorobenzene (1a and 1a’) and by 1H NMR spectroscopy using CH2Br2
(1a’’) as an internal standard. [c] Yield of isolated product.
Thorough and systematic screening of palladium-based
catalysts and precatalysts, and P-based ligands identified
[Pd(PPh3)4] as an efficient catalyst for the present reaction.[17]
Additionally, certain biarylmonophosphine-based ligands
derived from S-Phos, X-Phos, and Ru-Phos scaffolds[18] also
generated the coupled product.[17] After optimization, the
final system (2.5 mol% [Pd(PPh3)4]/o-xylene/1208C) readily
generated
the
desired
a-benzyl-a,a-difluoroketone
(Table 1b, entry 1), thus confirming our hypothesis that
À
transition-metal catalysis should form the critical C(a)
C(sp3) bond.
Figure 2. Underdeveloped reactions of a,a-difluoroketone enolates
with sp3-hybridized electrophiles. LDA=lithium diisopropylamide,
THF=tetrahydrofuran, TMS=trimethylsilyl.
However, this catalyst system only coupled the a,a-
difluorinated substrate, while the mono- and nonfluorinated
substrates did not provide the expected products (entries 2
and 3). This dramatic fluorine effect facilitated the present
reaction with neutral and even electron-deficient benzyl
esters, while some other transformations involving oxidative
addition of [Pd(PPh3)4] into nofluorinated benzyl esters
typically require an extended conjugated system or an
electron-rich benzylic moiety.[19] This phenomenon likely
reflects the strong s-withdrawing inductive effect of the two
fluorine atoms, which increases the electrophilicity of the
substrate, and accelerates the oxidative addition step to
generate the high-energy dearomatized p-benzyl intermedi-
ate (A).[20] In contrast, we believe that the fluorine substitu-
ents likely do not accelerate the decarboxylation step of the
reaction. Despite the increased stability of the a,a-difluori-
nated enolate (ketone-CF2H pKa = 20.2; ketone-CFH2 pKa =
21.7; ketone-CH3 pKa = 24.7),[21] rehybridization of a,a-
difluorinated enolate carbanions from C(sp3) to C(sp2)
actually occurs more slowly than for nonfluorinated eno-
lates,[22] which contradicts the trend observed (Table 1b).
3
À
these reactions convergently generates the key C(a) C(sp )
bond.
To complement these known strategies, a desirable and
convergent alternative for accessing a-benzyl-a,a-difluoro-
ketones involves the net reaction of an a,a-difluoroketone
enolate with an sp3-based electrophile (Figure 2a). Although
recently reported reactions have coupled a,a-difluoroketone
enolates with aryl[15] and allyl electrophiles,[16] never has
a palladium-based catalytic system effectively promoted the
benzylation reaction of a,a-difluoroketone enolates
(Table 1a). In this reaction, a decarboxylative strategy
would chemoselectively generate the appropriate a,a-
3
À
difluoroenolate, and the critical C(a) C(sp ) bond would
form by reductive elimination from a high-energy [LnPd-
(benzyl)(a,a-difluoroenolate)] intermediate (Table 1b, A).
Herein, we report such a palladium-catalyzed process which
accomplishes a net benzylation of a,a-difluoroketone eno-
lates to provide a-benzyl-a,a-difluoroketones.
2
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Table 2: Decarboxylative difluorobenzylation of substrates bearing dis-
Table 3: Decarboxylative difluorobenzylation of substrates bearing dis-
tinct benzyl moieties.[a]
tinct ketone moieties.[a]
[a] Standard reaction conditions: 5a–f (1.0 equiv), [Pd(PPh3)4]
(2.5 mol%), o-xylene (0.05m), 1208C, 15 h. Yield was determined by
19F NMR spectroscopy using a,a,a-trifluorotoluene as an internal
standard. The value within parentheses indicates the yield of the isolated
product. [b] 1308C, 24 h. [c] 24 h.
tone moieties (Table 3). Reactions of substrates bearing
electron-rich, electron-neutral, and electron-withdrawing
aryl a,a-difluoroketones provided the corresponding prod-
ucts 6a–c in high yields under the standard reaction con-
ditions. Further, both S- and N-containing heteroaryl a,a-
difluoroketone moieties were tolerated (6d,e), and at an
increased temperature, the reaction of an aliphatic a,a-
difluoroketone substrate afforded the product 6 f in reason-
able yield.
[a] Standard reaction conditions: 3a–p (1.0 equiv), [Pd(PPh3)4]
(2.5 mol%), o-xylene (0.05m), 1208C, 15 h. 19F NMR Yields were
determined using a,a,a-trifluorotoluene as an internal standard. The
value within parentheses indicates the yield of the isolated product.
[b] 24 h. [c] [Pd(PPh3)4] (5.0 mol%). [d] [Pd(PPh3)4] (5.0 mol%), 1408C.
[e] [Pd(PPh3)4] (20 mol%), 1408C, o-xylene (0.01m), 24 h. [f] [Pd(PPh3)4]
(5.0 mol%), 1408C, 24 h. [g] 1408C, 16 h. [h] [PdCp(h3-1-Ph-C3H4)]
(2.0 mol%), PhXPhos (4.0 mol%), 1558C, 15 h. Ts=4-toluenesulfonyl.
As previously noted, alkylation reactions of a,a-difluor-
oketone enolates suffer from two classical problems, namely,
generation of the appropriate enolate[8] and alkylation at C(a)
instead of at O.[10] Although examples 4a–p and 6a–f confirm
A variety of substrates bearing electron-rich, electron-
neutral, and electron-deficient benzylic moieties underwent
the decarboxylative reaction to generate a-benzyl-a,a-
difluoroketones (Table 2). Generally, the optimized reaction
conditions converted electron-rich, electron-neutral, and
weakly electron-deficient substrates into the products 4a–h
in high yields. However, moderately electron-deficient sub-
strates required higher catalyst loading and/or reaction
temperatures to provide good yields of the products 4i,j.
Further, substrates bearing strong electron-withdrawing
groups were less active, and generated the products 4k,l in
lower yields, even after optimization. This trend implicates
the intermediacy of [Pd(p-benzyl)(a,a-difluoroenolate)]
(A),[20] as electron-donating groups stabilize the intermediate
and facilitate the reaction, and electron-withdrawing groups
destabilize the intermediate and retard the reaction. While
the electronic nature of the substrates affected the outcome of
the reaction, steric effects did not impede the reaction.
Reactions of ortho-substituted benzyl esters afforded prod-
ucts in comparably high yields relative to the analogous para-
substituted substrates (4m,n versus 4a,b). Further, N-con-
taining heterobenzyl substrates also tolerated the present
reaction conditions, and provided the corresponding products
in modest-to-high yields (4o,p).
the ability of the palladium-catalyzed system to generate the
3
À
C(a) C(sp ) bond, most of the substrates do not bear
enolizable hydrogen atoms at the nonfluorinated a-position
of the ketone, and therefore cannot form a nonfluorinated
enolate. As such, these substrates do not confirm whether the
palladium-catalyzed decarboxylative protocol would selec-
tively generate the fluorinated enolate. To address this
concern, we explored the reaction of aliphatic substrate 7,
which could theoretically decarboxylate and isomerize to
generate the undesired enolate 8a at a nonfluorinated
position (Scheme 1). Subjection of 7 to [Pd(PPh3)4] at
1408C, generated the product 9 in 53% yield upon isolation,
The decarboxylative reaction also successfully produced
products bearing a variety of aryl and alkyl a,a-difluoroke-
Scheme 1. Decarboxylative strategy chemoselectively generates the
desired enolate.
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3
À
formed a key C(a) C(sp ) bond. This method facilitates the
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Acknowledgments
We thank the donors of the Herman Frasch Foundation for
Chemical Research (701-HF12), and the National Science
Foundation (CHE-1455163) for supporting this work. Addi-
tional financial support from the University of Kansas Office
of the Provost, Department of Medicinal Chemistry, and
General Research Fund (2506008) is gratefully acknowl-
edged. Support for the NMR instrumentation was provided
by the NIH Shared Instrumentation Grant (S10OD016360),
the NSF Major Research Instrumentation Grant (9977422),
and the NIH Center Grant (P20 GM103418).
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[17] For the detailed screening conditions, please see the Supporting
Information.
Keywords: chemoselectivity · fluorine · palladium ·
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Received: April 28, 2016
Published online: && &&, &&&&
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M.-H. Yang, J. R. Hunt, N. Sharifi,
R. A. Altman*
&&&& — &&&&
Palladium Catalysis Enables Benzylation
of a,a-Difluoroketone Enolates
Alkylation reactions of a,a-difluoroketone
enolates with sp3-based electrophiles
have been underdeveloped because of
intrinsically weak nucleophilicity and
chemoselective formation associated
with this enolate. Reported herein is
a palladium-catalyzed decarboxylative
benzylation of a,a-difluoroketone eno-
lates, in which the external a,a-difluoro-
enolate, formed in situ, underwent
reductive elimination from a palladium-
(II) intermediate to generate the key
3
À
C(a) C(sp ) bond.
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