Angewandte
Communications
Chemie
Micellar Catalysis
An Improved System for the Aqueous Lipshutz–Negishi
Cross-Coupling of Alkyl Halides with Aryl Electrophiles
Vasudev R. Bhonde, Brian T. OꢀNeill, and Stephen L. Buchwald*
Abstract: The development of a palladacyclic precatalyst
supported by a new biaryl(dialkyl)phosphine ligand (VPhos)
in combination with octanoic acid/sodium octanoate as
a simple and effective surfactant system provided an improved
catalyst system for the rapid construction of a broad spectrum
of alkylated scaffolds from alkyl zinc reagents generated in
situ.
cross-coupling reactions with secondary alkyl nucleophiles
have found significant success.[3–6] However, there is still
a need for generally more effective and convenient methods.
An alternative and direct strategy for constructing
3
2
À
C(sp ) C(sp ) carbon–carbon bonds is the coupling of aryl
and alkyl halides via aliphatic zinc intermediates that are
generated in situ. By the use of shelf-stable alkyl halides, this
approach obviates the need to preform and/or store organo-
zinc reagents and is thus more amenable to parallel synthesis.
The research groups of Weix, Gong, and Molander have
described important nickel-catalyzed versions of this pro-
cess.[9] Our study, however, was inspired by the pioneering
efforts of Lipshutz and co-workers, in which alkyl zinc
reagents were generated in situ and successfully cross-coupled
with aryl bromides under micellar conditions with a palladium
catalyst.[10] One drawback is that competitive reduction of the
aryl halide was often observed, and a significant excess of the
alkyl halide was required to suppress this side reaction.
Furthermore, despite a generally broad reaction scope, few
non-aromatic heterocyclic halides or (hetero)aryl chlorides
were evaluated in detail in these studies.
C
onvenient methods for the preparation of heteroarenes
appended with saturated heterocycles are increasingly impor-
tant in the pharmaceutical industry, particularly in medicinal
chemistry. In many research areas, the installation of non-
aromatic heterocycles is used to survey binding-pocket
interactions and build
a structure–activity relationship
(SAR). Several advanced clinical candidates and drugs
possessing these scaffolds have been shown to offer improved
prospects for clinical survival, possibly linked to reduced
receptor promiscuity and improved physiochemical proper-
ties.[1] The availability of a general process to readily couple
a variety of non-aromatic heterocycles to heteroarenes would
enable the rapid construction of candidate molecules and
expedite the search for therapeutic agents.
A plausible representation of the catalytic cycle of
a palladium-catalyzed alkyl–aryl reductive coupling reaction
and potential undesired pathways is shown in Scheme 1a. The
catalytic cycle operates by the oxidative addition of aryl
halide 1, followed by transmetalation of the alkyl zinc species
3, which is generated in situ from an aliphatic halide 2, and
reductive elimination from the resulting intermediate com-
plex B to deliver the desired sp3–sp2 cross-coupled product 4.
Nonproductive b-hydride elimination from palladium(II)
intermediate B would generate complex C. Species C could
form isomerized product 5 after further migratory insertion
and reductive elimination from intermediate D, or produce
reduced arene 6 by direct reductive elimination.
The transition-metal-catalyzed cross-coupling of secon-
À
dary alkyl organometallic reagents, R M (R = sec-alkyl, M =
B, Zn, Sn, Mg), is a useful method for attaching saturated
heterocycles onto hetero(aryl) halides.[2–6] However, there are
few general procedures that enable this approach and utilize
shelf-stable precursors. The most popular alkyl nucleophiles
used in cross-coupling reactions, alkyl boronates and alkyl
zinc reagents, have drawbacks for use in a drug-discovery
setting. Alkyl boronic acids, trifluoroboronates, and N-
methyliminodiacetic acid (MIDA) boronates are shelf-
stable, but their slow rate of alkyl transfer and/or often
facile protodeboronation in aqueous media limits their
utility.[7] In contrast, secondary alkyl zinc reagents undergo
more rapid transmetalation but suffer from limited bench-top
stability and often must be prepared immediately before
use.[8] Despite these issues, nickel- and palladium-catalyzed
Importantly, the transmetalation of 3 with A must be
faster than the protonation of organozinc species 3 by water.
Likewise, the oxidative addition of aryl halide 1 must be faster
than the reaction of 1 with zinc (Scheme 1b). Therefore, to
limit these side reactions and provide the desired product in
high yield, the catalyst must display high turnover frequency
(TOF). Palladium precatalysts developed in our laboratory
reliably and efficiently generate monoligated palladium
intermediates, L1Pd0, which undergo rapid oxidative addition
with aryl halides.[11] We felt that these precatalysts could serve
as an effective system to control the unwanted reduction of
the aryl halide by zinc. We have also demonstrated that, with
[*] Dr. V. R. Bhonde, Prof. Dr. S. L. Buchwald
Department of Chemistry, Room 18–490
Massachusetts Institute of Technology
Cambridge, MA 02139 (USA)
E-mail: sbuchwal@mit.edu
Dr. B. T. O’Neill
Pfizer Worldwide Medicinal Chemistry
Pfizer Worldwide Research and Development
Groton, CT 06340 (USA)
3
2
À
an appropriate ligand, C(sp ) C(sp ) Negishi coupling reac-
tions of preformed secondary alkyl zinc reagents with
heteroaryl bromides proceed with excellent levels of regio-
selectivity.[4b,c] We wondered whether our broadly applicable
Supporting information and ORCID(s) from the author(s) for this
Angew. Chem. Int. Ed. 2016, 55, 1849 –1853
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1849