Chemistry - A European Journal
10.1002/chem.201603603
COMMUNICATION
Pd-PEPPSI-IHeptCl: A General Purpose, Highly Reactive Catalyst
for the Selective Coupling of Secondary Alkyl Organozincs.
Bruce Atwater,[a] Nalin Chandrasoma,[a] David Mitchell,[c] Michael J. Rodriguez,[c] and Michael G.
Organ*[a,b]
Abstract: Pd-PEPPSI-IHeptCl, a new, very bulky yet flexible Pd-NHC
complex has been evaluated in the cross-coupling of secondary
alkylzinc reactants with a wide variety of oxidative addition partners
in high yields and excellent selectivity. The desired, direct reductive
elimination branched products were obtained with no sign of
migratory insertion across electron-rich and electron poor aromatics
and all forms of heteroaromatics (5- and 6-membered). Impressively,
there is no impact of substituents at the site of reductive elimination
(i.e., ortho or even di-ortho), which has not yet been demonstrated
by another catalyst system to date.
After decades of targeting structurally simplified molecules that
are more straightforward to prepare as potential leads in the
pharmaceutical industry, the current trend is to move back
Figure 1. Mechanism of cross-coupling of secondary metal alkyls.
toward compounds that are more architecturally complex or
more ‘natural product-like’. There are many reasons for this
including better on-target specificity, reduced toxicity, and
there is the possibility of forming elimination products at various
improved phamacokinetic properties of potential drug
stages in the catalytic cycle (Figure 1). Agostic interactions
candidates.[1] This movement in the pharmaceutical industry has
between the electron poor metal centre and the electron rich
created challenges for synthetic chemists leading to invigorated
adjacent C-H bonds can progress along the reaction coordinate
interest in the development of reactions that generate tertiary
toward beta hydride elimination (BHE) (i.e., from intermediate 4
to 6a). Dissociation of the resultant olefin (7) at this stage can
and quaternary carbon centres.[2] In particular there is increasing
interest in the preparation such centres where at least one of the
drain off all the alkyl starting material into the undesired
substituents is an aryl or heteroaryl moiety.[3] Interestingly, a
corresponding unsaturated byproduct and, because the reaction
similar trend in materials science has also been developing over
conditions are typically basic, the metal hydride can be readily
the last few years where organic light-emitting diodes (OLEDs),
reduced rendering this destructive pathway catalytic. If the
for example, now contain more complex alkyl chains to better
resultant olefin reinserts into the metal hydride with the same
solubilize the typically crystalline aromatic cores and to fine-tune
regiochemistry (i.e., 4 6a 4) the event is essentially of no
their electronic properties.[4] Here cross-coupling presents a very
consequence. However, if the olefin rotates, or dissociates and
direct route to these motifs of increasing sp3 character.
subsequently re-associates about the metal hydride bond with
In the last few years there has been growing interest in the
development of catalysts that can effectively generate
connections between sp2 and sp3 centres.[3] On the surface of it,
the reaction seems straightforward enough as the mechanism is
believed to be very similar to the well-known analogous coupling
of two sp2 centres that leads, for example, to biaryls. The key
difference is that there is no possibility of forming constitutional
isomers with these type of products. However, with alkyl centres
alternate regiochemistry, and reinsertion now occurs, the
isomeric metal alkyl results in a process known as migratory
insertion (MI) (i.e., 4 6a 6b 8).
We,[5] and others,[3] have been investigating the cross-
coupling of secondary metal alkyls to aryl- and heteroaryl-motifs
with the intention of producing single products with the desired
connectivity (i.e., 5a with no MI). During the course of these
investigations it was found that good, and in a limited number of
cases, outstanding selectivity for the desired branched products
could be achieved with 6-membered ring aryl and heteroaryl
oxidative addition partners.[5c] The key is to favour RE at the cost
of the undesired BHE. We have shown by computation that if
BHE occurs the opportunity now exists to form a more stable
metal alkyl.[5b] That is, if R1 is an alkyl group and R2 = H, the
equilibrium will be driven to the formation of 8. If that transpires,
the fate of the reaction is determined as the barrier to RE from
the lower energy metal alkyl is also greatly reduced and this will
drain the reaction in the direction of the undesired isomer (5b).
[a]
[b]
Dr. Bruce Atwater, Dr. Nalin Chandrasoma, and Professor Michael
G. Organ, Department of Chemistry, York University, 4700 Keele
Street, Toronto, Ontario, Canada, M3J1P3
Professor Michael G. Organ, Director, Centre for Catalysis
Research and Innovation (CCRI) and Department of Chemistry,
University of Ottawa, Ottawa, Ontario, Canada,
Email: organ@uottawa.ca
[c]
Dr. David Mitchell and Dr. Michael J. Rodriguez
Lilly Research Laboratories, Indianapolis, IN 46285
There is an electronic contribution to this selectivity whereby
a more electron-poor metal centre will have a lower reduction
Supporting information for this article is given via a link at the end of
the document.
Atwater, Bruce
