Angewandte
Communications
Chemie
Synthetic Methods
Zirconocene-Mediated Carbonylative Coupling of Grignard Reagents
Melissa Moss, Xinping Han, and Joseph M. Ready*
Abstract: Organozirconocenes are versatile synthetic inter-
mediates that can undergo carbonylation to yield acyl anion
equivalents. Zirconocene hydrochloride ([Cp ZrHCl]) is often
2
the reagent of choice for accessing these intermediates but
generates organozirconocenes only from alkenes and alkynes.
This requirement eliminates a broad range of substrates. For
example, organozirconocenes in which the zirconium center is
bonded to an aromatic ring, a benzylic group, or an alkyl group
that possesses a tertiary or quaternary carbon atom a to the
carbon–zirconium bond can not be formed in this way. To
provide more generalized access to acyl zirconium reagents, we
explored the transmetalation of Grignard reagents with
zirconocene dichloride under a CO atmosphere. This protocol
generates acyl zirconium(IV) complexes that are inaccessible
with the Schwartz reagent, including those derived from
secondary and tertiary alkyl and aryl Grignard reagents.
H
art and Schwartz first described the use of zirconocene
hydrochloride for the functionalization of olefins in 1974,
[1]
Scheme 1. Synthesis and reactivity of acyl zirconocenes.
E =electrophile.
+
and since then organozirconocenes have emerged as one of
the most versatile classes of transition-metal derivatives in
[
2]
organic synthesis. These organometallic reagents can par-
ticipate in cross-coupling reactions, conjugate and nucleo-
bond. This requirement excludes broad substrate classes,
including aryl and benzyl zirconium complexes. We sought to
expand the variety of available organozirconium reagents
through transmetalation from readily available organometal-
lic species. Although unprecedented, such a process could
yield zirconium reagents that are currently inaccessible
through hydrozirconation, including aryl, benzyl, and tertiary
and secondary alkyl zirconocenes, and might reveal funda-
mental aspects of organozirconium chemistry.
[
2–5]
philic addition reactions, and halogenation.
Among the
most useful transformations of organozirconocenes is their
[
6]
carbonylation to yield acyl zirconium complexes. These
reagents serve as acyl anion equivalents and can undergo
oxidation to yield carboxylic acid derivatives and react in
CÀC bond forming processes to yield unsymmetrical ketones.
For example, acyl zirconium reagents add to ketones and
enones to form a-hydroxyketones and 1,4-diketones, respec-
[
7]
tively. Additionally, they couple with aryl and allyl electro-
We initiated our study by exploring the transmetalation of
Grignard reagents with zirconocene dichloride, [Cp ZrCl ].
[
8–10]
philes under metal-mediated conditions.
transformations of acyl zirconocenes have been developed to
Enantioselective
2
2
This approach avoids the use of the Schwartz reagent, which,
although synthetically useful, is expensive and has a short
[11]
generate optically active ketone derivatives.
[13–15]
Organozirconium reagents are generally prepared by the
hydrozirconation of olefins or alkynes. These hydrometala-
tion reactions are highly regioselective and generally provide
bench life and poor solubility.
Negishi and co-workers
had previously demonstrated that tert-butyl and isobutyl
Grignard reagents would react with zirconocene dichloride.
[12]
the less-hindered alkyl or vinyl zirconium intermediate.
However, the intermediate [(alkyl)ZrClCp ] complex under-
2
Indeed, the hydrozirconation of internal olefins usually forms
the terminal alkyl complex through an isomerization
sequence involving reversible hydrozirconation/b-hydride
went rapid loss of isobutylene to form [Cp Zr(H)Cl] in
2
[16–18]
situ.
From another relevant study, alkyl lithium and
Grignard reagents are known to reduce [Cp ZrCl ] to low-
2
2
[
1]
[19]
elimination (Scheme 1).
Additionally, hydrozirconation
valent zirconium complexes. By contrast, we were inter-
ested in accessing alkyl zirconium species and trapping them
with suitable electrophiles. Furthermore, we wanted to
exploit the ability of organozirconocenes to act as acyl
anion equivalents. Accordingly, we focused our studies on
accessing and functionalizing acyl zirconocenes from a diverse
collection of Grignard reagents.
necessarily results in a zirconium complex with a b-CÀH
[
*] M. Moss, X. Han, Prof. J. M. Ready
Department of Biochemistry, Division of Chemistry
UT Southwestern Medical Center
5323 Harry Hines Boulevard, Dallas, Texas 75390-0938 (USA)
E-mail: joseph.ready@utsouthwestern.edu
Taguchi and co-workers have developed an efficient
copper-catalyzed cross-coupling of acyl zirconocenes with
allylic or propargylic halides to give allylic or allenic
Angew. Chem. Int. Ed. 2016, 55, 1 – 6
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
1
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