DOI: 10.1002/chem.201405114
Communication
&
Synthetic Methods
Iridium(I)-Catalyzed Regioselective CÀH Activation and Hydrogen-
Isotope Exchange of Non-aromatic Unsaturated Functionality
William J. Kerr,*[a] Richard J. Mudd,[a] Laura C. Paterson,[a] and Jack A. Brown[b]
formed earlier in the drug-design process.[5a,6] Recent studies
Abstract: Isotopic labelling is a key technology of increas-
from our own laboratory[7] have disclosed a series of highly
ing importance for the investigation of new CÀH activa-
active iridium(I) catalysts of the type [Ir(cod)(IMes)(PR3)]X
tion and functionalization techniques, as well as in the
(cod=1,5-cyclooctadiene) capable of delivering heavy isotopes
construction of labelled molecules for use within both or-
of hydrogen (deuterium and tritium) to aromatic molecules
ganic synthesis and drug discovery. Herein, we report for
through an ortho-directed CÀH insertion process under mild
the first time selective iridium-catalyzed CÀH activation
conditions (Scheme 1). Indeed, our developed methods have
and hydrogen-isotope exchange at the b-position of unsa-
turated organic compounds. The use of our highly active
[Ir(cod)(IMes)(PPh3)][PF6] (cod=1,5-cyclooctadiene) cata-
lyst, under mild reaction conditions, allows the regioselec-
tive b-activation and labelling of a range of a,b-unsaturat-
ed compounds with differing steric and electronic proper-
ties. This new process delivers high levels of isotope incor-
poration over short reaction times by using low levels of
catalyst loading.
The functionalization of aromatic CÀH bonds by transition-
metal-mediated CÀH activation has been widely developed in
the past several decades, delivering key compounds for use in
an array of chemical domains.[1] In contrast, regioselective acti-
Scheme 1. Previous and proposed labelling procedure.
vation of olefinic CÀH bonds has received much less attention,
with the majority of studies to date focused upon the applica-
tion of homogeneous organometallic complexes of rutheni-
um[2] and rhodium.[3] Indeed, very little knowledge exists sur-
rounding the use of iridium-based complexes in this area,[4] de-
spite their widespread activity in aromatic CÀH bond acti-
vation.[1a,b,h,k,o] In relation to this, transition-metal-mediated hy-
drogen-isotope exchange (HIE) is a technique of increasing
importance, often being used as a first step in creating new
CÀH activation methods and as a means to generate deuterat-
ed feed stocks for mechanistic studies.[5] Furthermore and im-
portantly for medicinal chemists, such direct and flexible label-
ling processes now represent a central tool for fast and effi-
cient incorporation of a tracer into drug candidates, enabling
various metabolic, stability, and toxicity studies to be per-
enabled access to a broad spectrum of labelled new chemical
entities of direct relevance to pharmaceutical partners and
have provided a platform for on-going CÀH activation endeav-
ours. Expanding on our initial developments, we now report
the first example of selective CÀH activation and hydrogen-iso-
tope exchange at the b-position of a range of a,b-unsaturated
moieties, extending the applicability of our emerging catalyst
series and addressing the requirement for mild and selective
means of accessing labelled olefinic substrates.[8]
Our initial studies involved the application of conditions de-
veloped in our laboratory for the isotopic labelling of aromatic
substrates.[7a] As such, (E)-4-phenylbutenone (6a) was treated
with just 0.5 mol% of our iridium catalyst series (5a–c) in di-
chloromethane and exposed to 1 atm of D2 gas (Table 1, en-
tries 1–3).[9] As was expected, and based on the differing steric
properties of our series of catalysts, varying results were ob-
tained. Catalyst 5a, bearing the smallest (PMe2Ph) phosphine
ligand, produced solely the reduced product 8a with quantita-
tive conversion (entry 1), with this result being somewhat ex-
pected due to our recent disclosure that such iridium com-
plexes can act as extremely efficient hydrogenation catalysts.[10]
Catalyst 5b, containing the bulky yet flexible tribenzylphos-
phine ligand, showed high levels of deuterium incorporation,
albeit with 8a remaining as the major product (entry 2). Pleas-
[a] Prof. Dr. W. J. Kerr, R. J. Mudd, Dr. L. C. Paterson
Department of Pure and Applied Chemistry, WestCHEM
University of Strathclyde, 295 Cathedral Street
Glasgow, Scotland, G1 1XL (UK)
[b] Dr. J. A. Brown
GlaxoSmithKline R&D, Medicines Research Centre
Gunnels Wood Road, Stevenage, England, SG1 2NY (UK)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201405114.
Chem. Eur. J. 2014, 20, 14604 – 14607
14604
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