Hydrogen isotope exchange with highly active iridium(I) NHC/phosphine complexes: a comparative counterion study

Article abstract of DOI:10.1002/jlcr.3427

Herein, we present a range of substrates that undergo hydrogen isotope exchange with an iridium(I) N-heterocyclic carbene/phosphine complex bearing the less coordinating tetrakis[3,5-bis(trifluoromethyl)phenyl]borate counterion and compare these with labe

Full text of DOI:10.1002/jlcr.3427

Special issue article
Received 13 May 2016,
Accepted 14 June 2016
Published online in Wiley Online Library
(wileyonlinelibrary.com) DOI: 10.1002/jlcr.3427
Hydrogen isotope exchange with highly active
iridium(I) NHC/phosphine complexes: a
comparative counterion study
a
a
a
a
*
William J. Kerr, Richard J. Mudd, Philippa K. Owens, Marc Reid,
Jack A. Brownb and Sebastien Camposb
Herein, we present a range of substrates that undergo hydrogen isotope exchange with an iridium(I) N-heterocyclic
carbene/phosphine complex bearing the less coordinating tetrakis[3,5-bis(trifluoromethyl)phenyl]borate counterion
and compare these with labelling using the equivalent, more established hexafluorophosphate complex. The changes
in reactivity and selectivity of these complexes in a series of solvents are examined. Copyright © 2016 John Wiley &
Sons, Ltd.
Keywords: ortho-hydrogen isotope exchange; N-heterocyclic carbene; deuteration; iridium
NHC/phosphine complex 4, containing the BArF (tetrakis[3,5-bis
Introduction
(trifluoromethyl)phenyl]borate) counterion (Scheme 2).6b Herein,
The exchange of hydrogen in a C–H bond by deuterium or
we further expand upon this initial application of catalyst 4 and
tritium, through the process of hydrogen isotope exchange
extend the comparison of the PF6 and BArF counterions, with
(HIE), represents
a direct and economical method of
particular attention to the selectivity within the HIE processes
reported.
generating isotopically labelled molecules.1 Furthermore,
because of the growing demand for deuterium-labelled and
tritium-labelled compounds for use in determining the
pharmacokinetics of active pharmaceutical ingredients and
in mechanistic studies, there has been increased focus on
the development of catalysts capable of facilitating HIE in a
mild and efficient manner.2 Although a wide variety of metals
can catalyse the HIE process, iridium complexes are the most
widely utilised for directing group-assisted ortho-HIE
(Scheme 1).3
Experimental
For full details on all experimental procedures, including catalyst
syntheses and HIE processes, refer to the Supporting Information.
Results and discussion
Our studies commenced with
a
comparison of our
Historically, this iridium-catalysed, directed HIE process has
been commonly performed using Crabtree’s catalyst.4 However,
the necessity for a high, and, indeed, often stoichiometric,
catalyst loading has led to attention being turned to the use of
alternative catalyst species in recent years. In this regard, studies
within our laboratory have delivered a series of iridium(I)
complexes that are highly effective HIE catlaysts,5 and which
have proven applicable with a wider array of functional groups
commercially available catalyst 3, bearing the PF6 counterion,
with the equivalent catalyst 4, bearing the bulky, less
coordinating BArF unit. The labelling of a range of substrates,
featuring a variety of different directing groups (DG), was
evaluated with low loadings of catalysts 3 and 4 (Figure 1).
From our previous work, we had observed that both
complexes performed excellently with a simple ketone DG
(substrate 5).6b Pleasingly, upon extending these studies to
the weaker ester DG in 6, high levels of deuterium
incorporation were, again, observed with both catalysts. The
and reaction solvents than Crabtree’s catalyst.6
A key
breakthrough in this latter regard was the synthesis of cationic
N-heterocyclic carbene (NHC)/phosphine complexes bearing
alternative counterions to the traditional hexafluorophosphate
(e.g. complex 3). Specifically, improved catalyst activity and more
general solvent applicability was observed with Ir(I)
aDepartment of Pure and Applied Chemistry, WestCHEM, University of
Strathclyde, Glasgow, Scotland, UK
bGlaxoSmithKline R&D, Medicines Research Centre, Stevenage, England, UK
*Correspondence to: William J. Kerr, Department of Pure and Applied Chemistry,
WestCHEM, University of Strathclyde, Glasgow G1 1XL, Scotland, UK.
E-mail: w.kerr@strath.ac.uk
†Additional supporting information may be found in the online version of this
Scheme 1. Iridium-catalysed ortho-HIE.
J. Label Compd. Radiopharm 2016
article at the publisher’s web-site.
Copyright © 2016 John Wiley & Sons, Ltd.

W. J. Kerr et al.
similarly, with excellent levels of deuterium incorporation
observed ortho to the ketone DG and low levels observed ortho
to the nitro unit. Lower overall incorporation was observed in
THF following the same regioselectivity trend. Complex 4 also
delivered the same general ratio of labelling in toluene.
However, a change in selectivity was observed in this solvent
with catalyst 3. Specifically, enhanced levels of labelling were
now observed adjacent to the nitro DG, indicating that, with
the combination of a less coordinating solvent and the less
electrophilic catalyst 3, both DGs bind effectively, resulting in
exchange at both sites.
Scheme 2. Ir(I)-NHC/phosphine complexes for HIE.
Ethyl 4-nitrobenzoate 10 was next examined under the
same protocol. In accordance with our earlier substrate scope
study, elevated levels of deuterium incorporation were
observed with complex 4 in DCM, with a slight preference for
HIE ortho to the nitro DG with both catalysts. Notably, using
THF as the solvent significantly reduced HIE at both positions,
presumably because of the solvent versus substrate
competitive binding with these more weakly coordinating
DGs.6a,b In toluene, a low incorporation was observed with
complex 3; however, complex 4 proved more effective in this
case, delivering moderate levels of HIE.
Next, we examined diethyl 4-nitrobenzamide 11 under the
same reaction conditions. High levels of incorporation were
observed at both positions, with complex 3 delivering a
slightly increased deuterium incorporation compared with 4
(Figure 3). However, upon changing the solvent to THF, the
selectivity for HIE ortho to the amide DG was significantly
increased with both 3 and 4. In toluene, moderate to good
levels of deuterium incorporation were observed, with lowered
selectivity relative to THF.
Figure 1. ortho-HIE with a series of directing groups.a,b,c
amide DG in compound 7 delivered similar levels of HIE with
both complexes 3 and 4.
Importantly, nitrobenzene 8, which is known not to
undergo HIE with Crabtree’s catalyst,4b performed excellently
with both complexes, giving near quantitative incorporation
with catalyst 4.
Finally, we applied this developed understanding to
labelling of the antiandrogen drug, nilutamide 12. With
complex 3 in DCM, complete labelling ortho to the nitro DG,
via a five-membered metallacyclic intermediate (5-mmi) was
observed, in addition to a small amount of labelling directed
by the amide through a 6-mmi. Pleasingly, the use of complex
4 suppressed this latter pathway, resulting in almost exclusive
labelling ortho to the nitro DG. However, with THF as the
solvent, the level of incorporation was negligible in all
positions, in accordance with earlier observations that THF
binds preferentially to the catalyst in place of weakly directing
substrates. In toluene, very low levels of labelling were
observed; however, this is mainly attributed to the poor
solubility of 12 in this solvent.
We have previously reported on the utility of complexes 3 and
4 in a range of solvents.6a,b During these studies, in a single
example of a substrate containing two competing DGs, a
solvent-dependent variation in the selectivity of labelling was
observed. To further develop and understand this behaviour, a
number of multi-functional aromatic compounds were selected
for study, based upon our earlier substrate scope. Firstly, we
applied 4-nitroacetophenone 9 under our previously utilised
conditions with complexes 3 and 4, in dichloromethane (DCM),
THF and toluene (Figure 2). In DCM, both complexes performed
Figure 2. HIE on bifunctional substrates 9 and 10.
Figure 3. HIE on bifunctional substrates 11 and 12.
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J. Label Compd. Radiopharm 2016

W. J. Kerr et al.
[4] (a) A. Y. L. Shu, W. Chen, J. R. Heys, J. Organomet. Chem. 1996, 524,
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[5] (a) J. A. Brown, S. Irvine, A. R. Kennedy, W. J. Kerr, S. Andersson, G. N.
Nilsson, Chem. Commun. 2008, 1115–1117;
The studies reported herein have provided further evidence that
complex 4, bearing the less coordinating BArF counterion, is
more reactive than catalyst 3 with less coordinating DGs but that
the combination of counterion and solvent is vital in delivering a
site-selective HIE process. In conclusion, both catalysts 3 and 4
show excellent reactivity, with the specific choice of catalyst
and solvent dependent upon the substrate in question and the
required position of isotope incorporation.
(b) G. N. Nilsson, W. J. Kerr, J. Labelled Compd. Radiopharm. 2010, 53,
662–667;
(c) J. A. Brown, A. R. Cochrane, S. Irvine, W. J. Kerr, B. Mondal, J. A.
Parkinson, L. C. Paterson, M. Reid, T. Tuttle, S. Andersson, G. N. Nilsson,
Adv. Synth. Catal. 2014, 356, 3551–3562.
[6] (a) A. R. Cochrane, C. Idziak, W. J. Kerr, B. Mondal, L. C. Paterson, T.
Tuttle, S. Andersson, G. N. Nilsson, Org. Biomol. Chem. 2014, 12,
3598–3603;
Acknowledgements
The authors are grateful to the University of Strathclyde (RJM),
the Engineering and Physical Sciences Research Council (EPSRC)
and GlaxoSmithKline (PKO) and the Carnegie Trust (MR) for
funding.
(b) A. R. Kennedy, W. J. Kerr, R. Moir, M. Reid, Org. Biomol. Chem. 2014,
12, 7927–7931;
(c) W. J. Kerr, R. J. Mudd, L. C. Paterson, J. A. Brown, Chem. Eur. J. 2014,
20, 14604–14607;
(d) W. J. Kerr, M. Reid, T. Tuttle, ACS Catal. 2015, 5, 402–410;
(e) J. Atzrodt, V. Derdau, W. J. Kerr, M. Reid, P. Rojahn, R. Weck,
Tetrahedron 2015, 71, 1924–1929;
(f) J. Devlin, W. J. Kerr, D. M. Lindsay, T. J. D. McCabe, M. Reid, T. Tuttle,
Molecules 2015, 20, 11676–11698.
References
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Supporting information
Additional supporting information may be found in the online
[3] J. R. Heys, J. Labelled Compd. Radiopharm. 2007, 50, 770–778.
version of this article at the publisher’s web-site.
J. Label Compd. Radiopharm 2016
Copyright © 2016 John Wiley & Sons, Ltd.
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