Application of neutral iridium(I) N-heterocyclic carbene complexes in ortho-directed hydrogen isotope exchange

Article abstract of DOI:10.1002/jlcr.3084

Bench-stable complexes of the type [Ir(COD)(NHC)Cl] (NHC = N-heterocyclic carbene) have been investigated within the field of hydrogen isotope exchange. By employing a sterically encumbered NHC within such complexes and catalyst loadings of only 5 mol%, m

Full text of DOI:10.1002/jlcr.3084

Special Issue Article
Received 30 April 2013,
Revised 03 June 2013,
Accepted 04 June 2013
Published online 19 July 2013 in Wiley Online Library
(wileyonlinelibrary.com) DOI: 10.1002/jlcr.3084
Application of neutral iridium(I) N-heterocyclic
carbene complexes in ortho-directed hydrogen
isotope exchange†,‡
a
a
a
a
*
Alison R. Cochrane, Stephanie Irvine, William J. Kerr, Marc Reid,
Shalini Andersson,b and Göran N. Nilssonb
Bench-stable complexes of the type [Ir(COD)(NHC)Cl] (NHC = N-heterocyclic carbene) have been investigated within the field
of hydrogen isotope exchange. By employing a sterically encumbered NHC within such complexes and catalyst loadings of
only 5 mol%, moderate to high deuterium incorporations were achieved across a range of aromatic ketones and
nitrogen-based heterocycles. The simple and synthetically accessible catalysts reported herein present alternatives to
phosphine-based species and increase the available labelling systems with respect to established iridium-based isotope
exchange methodologies.
Keywords: ortho-hydrogen isotope exchange; N-heterocyclic carbene; deuteration; iridium
To circumvent issues of high catalyst loadings, our efforts have
focused on novel mixed NHC-phosphine systems, [(COD)Ir(NHC)
Introduction
In order to alter the properties of a drug candidate, the chemist
(PR3)]PF6, 1, as a means of introducing hydrogen isotopes with
must first have a flexible technique with which to study them. To
enhanced levels of overall efficiency (Figure 1). Preliminary
this end, hydrogen isotope exchange (HIE) is widely used as a
studies in this area have now allowed expedient access to a series
of novel iridium complexes,35 many of which were previously
means to monitor the biological fate of a potential drug
molecule.1,2 Indeed, since the pioneering work of Garnett
approaching half a century ago,3,4 research in the field of HIE
has undergone a remarkable evolution, with key developments
in synthetic strategies and analytical techniques making this
the preferred method in many absorption, distribution,
metabolism, and excretion studies.1
inaccessible.36,37 Moreover, by judicious and careful manipulation
of the ligands supporting the iridium centre, these electron-rich
and sterically encumbered catalysts have emerged to become
some of the most active species known in this area of labelling
chemistry.14,35,38 Additionally, and outside of labelling science,
the utility of these catalysts has recently been extended, with these
species now proving to be highly active in the selective reduction
of alkenes39 and in Z-selective dimerization of terminal alkynes.40
With close regard to the overall steric bulk of these complexes,
we have shown previously that more encumbered ligand
systems produce the most efficient catalysts.35 In relation to this,
and with the recent expansion in the range of NHC ligands
applicable in this area of chemistry, high-yielding syntheses of
Despite notable advances in heterogeneous5–11 and even
organocatalytic labelling protocols,12 it is homogeneous
transition metal-catalysed HIE methodologies that have received
greatest attention from the pharmaceutical industry. More
specifically, the development of ortho-directed HIE procedures
have allowed for the site-selective, and thus predictable,
labelling of aromatic substrates.13–15 The ultimate benefit of such
processes is manifested in the ability to label fully functionalised
drug candidates in one synthetic step, with no dependence on
(or necessity for) isotopically enriched starting materials. Indeed,
since Lockley's discovery in the early 1980s that aromatic
carboxylic acids and anilides could be labelled regioselectively
using RhCl3,16–18 a series of notable advances in ortho-directed
HIE have emerged in the 30 years that have followed. From
1992 onwards, the most remarkable advances have centred on
iridium-based catalysts akin to those first pioneered by Heys.19,20
In this regard, manipulation of the catalyst coordination sphere
has spawned a selection of useable Ir(I) species, including those
that employ bis-phosphine,21–26 bidentate phosphine,21,27
arsine23,27 and acetoacetate28,29 ligand systems. Among these,
commercially available Crabtree's catalyst, [(COD)Ir(PCy3)(py)]
PF6,30 is perhaps the most widely used, despite the regular
necessity for stoichiometric quantities of catalyst.22,31–34
aDepartment of Pure and Applied Chemistry, University of Strathclyde, Glasgow
G1 1XL, UK
bMedicinal Chemistry, AstraZeneca, R&D Mölndal, Mölndal SE-431 83, Sweden
*Correspondence to: Professor William J. Kerr, Department of Pure and Applied
Chemistry, University of Strathclyde, Glasgow G1 1XL, UK.
E-mail: w.kerr@strath.ac.uk
† This article is published in Journal of Labelled Compounds and
Radiopharmaceuticals as a special issue on Special Issue IIS 2012 Heidelberg
Conference, edited by Jens Atzrodt and Volker Derdau, Isotope Chemistry &
Metabolite Synthesis, DSAR-DD, Sanofi-Aventis Deutschland GmbH, Industriepark
Höchst G876, 65926 Frankfurt am Main, Germany.
‡ Supporting information may be found in the online version of this article.
J. Label Compd. Radiopharm 2013, 56 451–454
Copyright © 2013 John Wiley & Sons, Ltd.

A. R. Cochrane et al.
a glass stopper fitted with a Teflon® sleeve, and the reaction vessel was
cooled to À78 °C in a dry ice/acetone bath, prior to being purged twice
with nitrogen. The flask was then evacuated and filled with deuterium
gas via balloon. The flask was removed from the slurry and allowed to
warm to room temperature. (NOTE: the glass stopper must be physically
restrained as the reaction mixture warms to room temperature). The
reaction mixture was then allowed to stir vigorously at room temperature
for 16 h. The level of isotope incorporation into the substrate was
determined by 1H NMR analysis of the reaction products. As such, the
residual proton signal from the site of incorporation was compared
against that of a site where incorporation was not expected to occur.
Each reaction was carried out in duplicate.
Figure 1. HIE catalysts under study.
Results and discussion
catalyst intermediate structures, [(COD)Ir(NHC)Cl], 2a-d, have
facilitated the synthesis and diversification of structural
analogues of catalysts 1a-c. Moreover, as we have routinely
synthesised structures 2a-c en route to more intricate catalyst
systems such as 1, we were curious to note whether or not
complexes of type 2 were catalytically active within HIE
processes in their own right. In this article, we report for the first
time on the application of the less elaborate complexes 2a-d in
ortho-directed HIE processes, comparing their overall utility
relative to our more established catalyst systems.
In our initial experiments, chloro-carbene complexes 2a-d were
employed in the ortho-directed labelling of acetophenone, 3,
under our optimised reaction conditions (Scheme 1, Table 1).35
Interestingly, whereas complexes 2a and 2b, holding sterically
smaller NHC ligands, failed to catalyse the reaction to any
appreciable extent, more encumbered analogues 2c and 2d
proved to be remarkably efficient HIE catalysts. This supports
our previous hypothesis that
a
sterically encumbered
coordination sphere is a necessary trait in such HIE catalyst
systems.35,41 Having said this, it is also evident from these
reference reactions that, in moving from the optimum system
in 2c to an even more encumbered NHC, as in 2d, catalyst
efficiency deteriorates. Indeed, all attempts to form HIE catalysts
of type 1 from 2d have thus far failed,42 indicating that the ligand
sphere around the iridium centre is already too congested and
cannot accommodate the introduction of a phosphine ligand.
Having identified 2c as a highly efficient catalyst in the
labelling of acetophenone, we were keen to investigate the
effective substrate scope of this system (Scheme 2, Table 2).
Towards this aim, a series of para-substituted aryl ketones were
Experimental
For full details on all experimental procedures, including catalyst
syntheses and individual labelling reaction processes, please see the
Supporting Information.
Synthesis of catalyst 2c41a
A stock solution of 1 M sodium ethoxide was prepared by dissolving
sodium metal (0.25 g) in ethanol (10 mL). A solution of η4-cycloocta-
1,5-dieneiridium(I) chloride dimer (0.400 g, 0.595 mmol) in dry
benzene (10 mL) was prepared in a flame-dried Schlenk tube under
argon. To the benzene solution was added 1 M sodium ethoxide
(1.2 mL, 1.2 mmol), resulting in a red to yellow colour change. After
stirring the solution for 10 min at r.t., 1,3-dimesitylimidazolium
chloride (0.406 g, 1.191 mmol) was added in one portion. The solution
was stirred for 72 h at 45°C under Ar, resulting in a gradual colour
change from yellow to orange. The solvent was subsequently
removed in vacuo, and the residue purified directly via flash column
chromatography, eluting the yellow fraction with ethyl acetate/
hexanes (1:1). The combined yellow fractions were concentrated
under reduced pressure. The desired yellow, crystalline solid
precipitated from the resultant oil on addition of petroleum ether.
Scheme 1. Catalyst screening.
FTIR (neat):
3092, 3009, 2916, 2876, 1609 and 1485 cm-1.
δ 6.99–6.96 (2 × bs, 4H, ArH), 6.93 (s, 2H,
1H NMR
Table 1. Labelling of acetophenone
(400 MHz, CDCl3): ArH), 4.14–4.10 (m, 2H, COD CH), 2.96–
2.94 (m, 2H, COD CH), 2.34 (s, 12H, ArCH3),
Entry
Catalyst
% D‡
2.14 (s, 6H, ArCH3), 1.74–1.59 (m, 4H, COD
CH2) and 1.33–1.21 (m, 4H, COD CH2).
δ 181.0, 138.8, 137.6, 136.3, 134.6, 133.0,
1
2
3
4
2a
2b
2c
7
5
97
87
13C NMR
(100 MHz, CDCl3): 129.7, 128.3, 123.5, 82.8, 66.1, 51.6, 33.7,
2d
29.2, 21.4, 19.9 and 15.5.
aAverage incorporation into the positions shown over two
separate reaction runs; the percentage given refers to the
level of D incorporation over the total number of positions
possible, e.g. 97% for the two possible positions in Entry 3
indicates 1.94 D incorporation.
Standard hydrogen isotope exchange procedure
A flame dried and argon cooled 100 mL three-neck round bottomed
flask, equipped with two stopcock valves and a suba seal, was charged
with the iridium complex (5 mol%) and dry dichloromethane (2.5 mL),
followed by the substrate (0.215 mmol). The suba seal was replaced by
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Copyright © 2013 John Wiley & Sons, Ltd.
J. Label Compd. Radiopharm 2013, 56 451–454

A. R. Cochrane et al.
Figure 2. Labelling of aryl amides.
Scheme 2. Labelling of aryl ketones.
Table 2. Labelling of aryl ketones
Entry
X
R
% Da
1
2
3
4
5
6
7
8
9
OMe
Ph
F
Cl
Br
I
H
H
H
H
Me
Me
Me
Me
Me
Me
Ph
Et
n-Bu
t-Bu
97
84
77
76
62
15
94
93
62
41
Figure 3. Labelling of N-based heterocyclic compounds.
10
albeit with low overall levels of D incorporation. These
findings are in contrast to those reported previously when
catalysts 1a-c were employed, with high levels of deuterium
incorporation having been achieved across all substrates 7-10.35
Despite the good general levels of effectiveness found to
this stage with catalyst 2c, this highlights a notable limitation
in the utility of this species and, indeed, demonstrates
the necessity for the use of cationic NHC-phosphine
aAverage incorporation into the positions shown over two
separate reaction runs; the percentage given refers to the
level of D incorporation over the total number of positions
possible.
studied, with good to excellent levels of deuterium incorporation complexes of the type 1 towards achieving the widest
being achieved for both electron-donating and electron- possible substrate scope.
withdrawing substitution (Entries 1 and 2–4, respectively).
In our final study, we investigated the propensity for 2c to
However, on moving to bromo-derivatives or iodo-derivatives, mediate ortho-HIE using nitrogen-based heterocyclic functionalities
the labelling efficiency of 2c proved to be less effective (Entries as the key directing group. As such, we are pleased to report the
5 and 6, respectively); this reduced exchange efficiency could highly efficient labelling with pyridine, 11, pyrazole, 12, and
be a consequence of the relatively and perceived lowered imidazole, 13, using catalyst 2c under the remarkably mild reaction
electrophilicity of the chloro-carbene catalyst in combination conditions shown in Figure 3.
with less readily coordinating substrates. Our investigations then
progressed toward labelling more sterically encumbered aryl
ketones. Pleasingly, benzophenone and 1-phenyl-1-propanone
Conclusions
were both found to undergo highly efficient ortho-labelling with The results presented herein show that synthetically accessible
2c (Entries 7 and 8, respectively). On labelling further extended chloro-carbene complexes, such as 2c and 2d, bearing sterically
and branched alkyl derivatives of acetophenone, more moderate encumbered NHC ligands, are effective catalysts for the ortho-
levels of deuterium incorporation were achieved under the directed labelling of simple organic substrates. Moreover,
operative reaction conditions (Entries 9 and 10).
complex 2c proved to be more generally efficient than 2d,
To further investigate the variety of substrates amenable to suggesting an optimal ligand size in the former species; for
deuterium labelling with chloro-carbene catalyst 2c, a series of further studies showing the more limited applicability of 2d,
aryl amides was investigated. Unfortunately, in all cases, lowered see the Supporting Information. Although this overall study
levels of deuterium incorporation were observed (Figure 2). This provides more direct evidence for the necessity for more
observation held true for benzamide, 7, and toluoyl amide, elaborate and activated complexes, such as 1, this work expands
8, which would be labelled via a five-membered metallocycle the range of HIE catalysts available to the labelling chemist, with
(5-mmi), and for acetanilide, 9, in which deuterium would the establishment of ortho-directed HIE protocols using a simple
be incorporated via a more energetically demanding 6-mmi. and readily accessible chloro-iridium(NHC) species. Moreover,
Interestingly, in the case of benzanilide, 10, which has the this work also supports our further explorations into the
capacity to be labelled via both 5-mmi and 6-mmi, almost development of extended novel catalysts for application in HIE
exclusive labelling in the a-ring (via a 5-mmi) was found, and other transformations.
J. Label Compd. Radiopharm 2013, 56 451–454
Copyright © 2013 John Wiley & Sons, Ltd.
www.jlcr.org

A. R. Cochrane et al.
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Acknowledgements
The authors are grateful to both AstraZeneca (ARC, SI) and The
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acquired at the EPSRC UK National Mass Spectrometry Facility
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Conflict of Interest
The authors did not report any conflict of interest.
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J. Label Compd. Radiopharm 2013, 56 451–454