Angewandte
Chemie
DOI: 10.1002/anie.201410039
Fluorine
Ligand-Controlled Regiodivergent Palladium-Catalyzed
Decarboxylative Allylation Reaction to Access a,a-Difluoroketones**
Ming-Hsiu Yang, Douglas L. Orsi, and Ryan A. Altman*
Dedicated to Professor Stephen L. Buchwald on the occasion of his 60th birthday
Abstract: a,a-Difluoroketones possess unique physicochem-
ical properties that are useful for developing therapeutics and
probes for chemical biology. To access the a-allyl-a,a-
difluoroketone substructure, complementary palladium-cata-
lyzed decarboxylative allylation reactions were developed to
provide linear and branched a-allyl-a,a-difluoroketones. For
these orthogonal processes, the fluorination pattern of the
substrate enabled the ligands to dictate the regioselectivity of
the transformations.
tion pattern of the substrate enables the ligands to dictate the
regioselectivity of the transformations.
a,a-Difluoroketones are a unique substructure in medic-
inal chemistry that inhibits serine and aspartyl proteases
through interactions with the nucleophilic residue of a pro-
tease or a water molecule in the active site of the protease to
form stable tetrahedral adducts.[8,9] Furthermore, this sub-
structure can also enhance bioactivities for non-protease
targets,[10] and it can serve as an intermediate for further
functionalization (Figure 1).[11] Therefore, strategies for
accessing a,a-difluoroketones should be useful for the devel-
opment of biological probes.
D
ecarboxylative coupling is a powerful method for the
À
construction of C C bonds that generates reactive organo-
metallic intermediates under mild conditions and releases
CO2 as the only byproduct.[1] Moreover, this strategy enables
the formation of reactive intermediates and regioselective
couplings to provide products that might be difficult to access
otherwise.[2] Whereas Pd-catalyzed decarboxylative allylation
reactions of soft carbon-based (e.g., malonates, b-diketones,
b-ketoesters) and heteroatom-based nucleophiles can provide
both branched[3] and linear[4] products, Pd-catalyzed allylation
reactions of hard enolate nucleophiles with monosubstituted
allylic substrates almost exclusively provide linear pro-
ducts.[1b,5] In a rare example, the use of stoichiometric Li
additives facilitated a Pd-catalyzed allylation of a ketone
enolate to provide this uncommon branched product.[6,7]
However, the ability of a ligand to control the regioselectivity
of Pd-catalyzed allylation reactions of ketone enolates has not
been demonstrated. Herein, we report complementary Pd-
catalyzed decarboxylative allylation reactions of hard fluori-
nated enolate nucleophiles that generate both linear and
branched products. Notably, in these reactions, the fluorina-
Figure 1. a,a-Difluoroketones serve as drugs, biological probes, and
synthetic intermediates.
Based on our ongoing studies aimed at accessing priv-
ileged fluorinated motifs using decarboxylative strategies,[12]
we envisioned that a decarboxylative reaction should afford
a-allyl-a,a-difluoroketones from allylic alcohols. Decarbox-
ylative allylation reactions of fluorine-containing nucleo-
philes are restricted to a-fluoroketones,[13] and decarboxyla-
tive reactions of a,a-difluoroketones have not been realized.
Furthermore, even simple allylation reactions of a,a-difluor-
oketone enolates have remained restricted to a single reaction
that uses stoichiometric amounts of copper,[14] and no
catalytic allylation reactions generate this substructure.
Initial attempts to develop a catalytic decarboxylative
allylation reaction to generate a-allyl-a,a-difluoroketones
revealed that a Pd-based catalyst could promote the desired
transformation [Eq. (1)]. A broad screen of P-based ligands
identified biaryl monophosphines[15] as privileged ligands for
the present reaction, and in fact, these ligands enabled access
to both the linear and branched products with high regiose-
lectivity (Table 1, entry 1). Specifically, tBuBrettPhos,[16] an
[*] M.-H. Yang, D. L. Orsi, Prof. Dr. R. A. Altman
Department of Medicinal Chemistry, University of Kansas
1251 Wescoe Hall Drive, Lawrence, KS 66045 (USA)
E-mail: raaltman@ku.edu
[**] We thank the Donors of the American Chemical Society Petroleum
Research Fund (5207-DNI1) and the Herman Frasch Foundation for
Chemical Research (701-HF12) for support of this research.
Additional financial support from the University of Kansas, Office of
the Provost, Department of Medicinal Chemistry and the General
Research Fund (2301795) is gratefully acknowledged. Support for
the NMR instrumentation was provided by an NSF Academic
Research Infrastructure Grant (9512331), an NSF Major Research
Instrumentation Grant (9977422), and an NIH Center Grant (P20
GM103418).
Supporting information for this article is available on the WWW
Angew. Chem. Int. Ed. 2015, 54, 1 – 6
ꢀ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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