Isotopic Labelling of Functionalised Arenes Catalysed by Iridium(I) Species of the [(cod)Ir(NHC)(py)]PF6 Complex Class

Article abstract of DOI:10.1055/s-0035-1560518

Iridium(I) complexes of the type [(cod)Ir(NHC)(Py)]PF₆ have been exposed as efficient catalysts in the area of hydrogen-isotope exchange. More specifically, by an ortho-directed C-H activation process, high levels of deuterium incorporation hav

Full text of DOI:10.1055/s-0035-1560518

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© Georg Thieme Verlag Stuttgart · New York
2016, 27, 111–115
letter
111
P. W. Cross et al.
Letter
Synlett
Isotopic Labelling of Functionalised Arenes Catalysed by Iridium(I)
Species of the [(cod)Ir(NHC)(py)]PF6 Complex Class
Paul W. C. Crossa
John M. Herbertb,1
PF6
N
William J. Kerr*a
Alan H. McNeillb,1
Laura C. Patersona
Ir
NHC
D
DG
DG
D
a University of Strathclyde, Department of Pure & Applied
Chemistry, WestCHEM, 295 Cathedral Street, Glasgow G1 1XL,
UK
D
2 (1 atm), r.t.
R
R
DG = directing group
NHC = IMes, Ii-Pr, SIMes
10 examples
up to 99% D
w.kerr@strath.ac.uk
b Department of Isotope Chemistry and Metabolite, Sanofi-
Synthélabo, Willowburn Avenue, Alnwick, Northumberland
NE66 2JH, UK
Dedicated to Professor Steven V. Ley, with much gratitude and
respect, on the occasion of his 70th birthday
Received: 22.09.2015
Accepted after revision: 14.10.2015
Published online: 28.10.2015
change with high levels of incorporation using low levels of
catalyst and encompasses a comprehensive range of sub-
strates including ketone, amide, nitro, and a spectrum of
heterocyclic functionality, and, most recently, primary sul-
fonamides7 and esters,6f which were previously less accessi-
ble targets. Indeed, the developed series of iridium com-
plexes have emerged to become some of the most active
species now known in this area of labelling chemistry.
DOI: 10.1055/s-0035-1560518; Art ID: st-2015-d0757-l
Abstract Iridium(I) complexes of the type [(cod)Ir(NHC)(Py)]PF6 have
been exposed as efficient catalysts in the area of hydrogen-isotope ex-
change. More specifically, by an ortho-directed C–H activation process,
high levels of deuterium incorporation have been achieved using low
levels of catalyst over a range of functionalised aromatic compounds.
Additionally, the developed protocol has been extended to include a se-
lected pharmacological target, where chemoselective labelling is ob-
served within such a multifunctional substrate.
X
X
T/D
R1
R2
R2
Ir (cat.)
D or T source
Key words iridium, C–H activation, hydrogen-isotope exchange, deu-
teration
D/T
R1
via
X
Isotopic labelling with heavy hydrogen isotopes (D2 and
T2) is widely used as a means to monitor the biological fate
of a potential drug molecule.2 In relation to this, methods
that deliver hydrogen-isotope exchange (HIE) are of appre-
ciable importance in accessing such isotopically labelled
species, whilst also being central to the provision of analo-
gous deuterated compounds for use as internal standards as
aligned with mass spectrometry,3 for kinetic isotope stud-
ies,4 and for the alteration of reaction pathways in total syn-
thesis.5 As such, direct, flexible, and selective means of in-
troducing hydrogen isotopes continues to be the focus of
considerable research attention. In this regard, studies from
our laboratory have shown that a range of iridium complex-
es of the type [(cod)Ir(IMes)(PR3)]X are very effective ho-
mogeneous catalysts which mediate the exchange of hydro-
gen with deuterium (or tritium) by an ortho-directed C–H
activation process.2c,6 The key to their applicability in this
area lies with the ability of such complexes to selectively
target unactivated C–H bonds, whilst simultaneously allow-
ing convenient isotope incorporation with the use of, prac-
tically convenient, deuterium or tritium gas (Scheme 1).
Our developing methodology in this domain allows ex-
T/D
Ir
R2
R1
Scheme 1 HIE process
In addition to an isotopic-exchange process, our
[(cod)Ir(IMes)(PR3)]X complexes have been shown to per-
form as effective hydrogenation catalysts, delivering re-
duced products under notably mild reaction conditions.8 In
relation to this, studies by Nolan et al. have divulged that
iridium species with the alternative specific combination of
a bulky N-heterocyclic carbene (NHC) and a pyridine ligand
represent appreciably robust complexes that are active
within both alkene hydrogenation9 and transfer hydrogena-
tion protocols.10 In view of these findings, and based on the
knowledge that judicious and careful manipulation of the
ligands supporting the iridium centre is critical for success
within HIE processes, we turned our attention to the appli-
cation of the general class of Ir(NHC)(py) complexes within
our developing HIE procedures. Herein, we report an
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P. W. Cross et al.
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assessment of iridium(I) complexes of the type
[(cod)Ir(NHC)(py)]PF6 as an additional series of C–H activa-
tion catalysts in the deuteration of a range of functionalised
arene substrates.
Our initial investigations involved the preparation of
catalysts 3a–c9,10 via the modified preparative procedure
shown in Table 1. In this regard, the desired NHC was react-
ed with readily accessible [(cod)Ir(py)2]PF6 (2)11 by a simple
ligand-exchange reaction in toluene. Pleasingly, the desired
complexes were obtained in very good chemical yield in ev-
ery case. Moreover, this procedure allowed the preparation
of these extremely stable catalyst species on gram scale.
lyst series is key to the high levels of activity shown,6 we
were conscious that these same steric constraints may dis-
favour the initial coordination of larger and more tetrahe-
dral directing functional units such as sulfonamides.7 Hav-
ing stated this, we were able to induce high levels of incor-
poration within compound 5i, albeit by moving to a much
higher catalyst loading of 50 mol%. Similarly, an increased
loading of 10 mol% was required to more effectively deliver
deuterated ester 5j at a level of 94% D incorporation under
ambient conditions; again, this was a pleasing outcome giv-
en the well-documented difficulties arising with such a
weakly binding aromatic ester group.6f,13
At this point, it is important to reflect on the prepara-
tion and performance of this [(cod)Ir(NHC)(py)]PF6 complex
class and their new application as C–H bond activation cat-
alysts, as compared to our existing and more well-estab-
lished [(cod)Ir(IMes)(PR3)]PF6 series. In relation to this, both
catalyst classes are readily accessible and provide stable and
readily handled species for use in HIE processes. Indeed, ac-
cess to the NHC–pyridine complexes described here is rela-
tively more direct overall, notwithstanding the require-
ment for the use of a glove box technique at the outset of
the preparative process.12 With regards to catalyst perfor-
mance within the described HIE processes, in an overall
qualitative sense, the NHC–pyridine complexes generally
compare well with our existing NHC–phosphine series, es-
pecially when considering, for example, substrates such as
acetophenone (4a), benzophenone (4b), and 2-phenylpyra-
zole (4g).6a,d Additionally, this current set of catalysts deliv-
ered good levels of isotopically labelled benzamide 5c
across the series, where the [(cod)Ir(IMes)(PR3)]PF6 com-
plexes delivered somewhat more variable results with this
primary amide substrate.6a,d Moreover and as described
above, moving to slightly increased catalyst loading, 3c was
able to accommodate ester functionality at ambient tem-
peratures, whereas our previous [(cod)Ir(IMes)(PR3)]PF6
systems employed moderately elevated temperatures to de-
liver similar levels of incorporation in ester-containing
compounds at lower catalyst loading.6f
Encouraged by the results obtained to this stage, we
looked to more fully probe the reaction parameters in an at-
tempt to explore the wider capability of the NHC–pyridine
catalyst series within these HIE processes. As such, varying
levels of catalyst loading were explored, as well as a study
on the reaction rate. Despite lower quantities of catalyst be-
ing utilisable in the HIE of acetophenone (4a),15 it was rec-
ognised that a reliable quantity of 5 mol% of the requisite
iridium species was optimal over a range of substrates. In
addition to these experiments, as shown within Table 2, we
were pleased to realise that our developed labelling proto-
col was indeed more rapid than anticipated. As detailed, af-
ter only 30 minutes, using 5 mol% of SIMes catalyst 3c, com-
parably high levels of incorporation were achieved with the
majority of substrates tested as part of our studies. In con-
trast, at 30 minutes reaction time the more demanding sub-
Table 1 Preparation of Iridium Complexes 3a–c12
PF6
R
N
N
Ir
1. KH, THF, r.t., 20 h
Cl
R
2. [(cod)Ir(py)2]PF6 (2)
toluene, r.t., 2 d
N
N
R
N
R
1
3
Entry NHC
Catalyst
Yield (%)
1
2
3
IMes R = 2,4,6-trimethylphenyl
Ii-Pr R = isopropyl
3a
3b
3c
88
82
97
SIMes R = 2,4,6-trimethylphenyl
Having successfully prepared complexes 3a–c, we
looked to the standard HIE protocol developed within our
laboratory for the labelling of a variety of substrates. As
shown in Scheme 2, catalysts 3a–c displayed very good lev-
els of efficiency in our labelling protocol. Using only 5 mol%
catalyst loading, high levels of deuterium incorporation at
the expected ortho positions were achieved for the selected
substrates over 16 hours. Ketone, amide, pyrazole, and im-
idazole functionalities were all viable within this system,
with catalyst 3c, derived from SIMes, proving the most ac-
tive in the majority of cases. Notable examples include the
labelling of benzamide 4c; despite this substrate previously
requiring extremely high levels of catalyst and delivering
variable results,13a,b complexes 3a–c delivered consistently
high isotope incorporations for this substrate within our
study. The [(cod)Ir(NHC)(py)]PF6 complex class was also
able to deliver very good levels of deuteration with acetani-
lide (4f) facilitating isotope exchange in C–H bonds posi-
tioned five bonds away from the required coordinating
functionality, that is, via a six-membered metallacyclic in-
termediate (6-mmi). This process is believed to be energeti-
cally more demanding and, as such, often leads to lower
levels of deuteration.6a,d Moreover, the delivery of deuteri-
um-labelled heterocyclic derivatives 5g and 5h displays ad-
ditional versatility and illustrates the overall robustness of
this catalytic system. Whilst we believe that the encum-
bered nature of the iridium centre within this wider cata-
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P. W. Cross et al.
Letter
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D
DG
DG
3a–c (5 mol%)
D2, CH2Cl2, 16 h
4
5
D
R
R
D
O
D
D
O
D
D
O
D
O
D
D
O
D
NH2
NMe2
NEt2
5c
5a
5d
5e
D
5b
D
D
3a: 89%; 3b: 81%;
3c: 94%
3a: 68%; 3b: 82%;
3c: 94%
3a: 87%; 3b: 90%;
3c: 72%
3a: 50%; 3b: 88%;
3c: 96%
3a: 98%; 3b: 60%;
3c: >99%
D
H
N
D
D
D
D
O
D
NH
O
O
S
D
N
N
N
NH2
OEt
O
D
D
D
5f
5g
5h
5i
5j
3a: 11%; 3b: 10%;
3c: 7% (87%)a
3a: 8%; 3b: 10%;
3c: 58% (94%)b
3a: 93%; 3b: 92%;
3c: 89%
3a: 89%; 3b: 97%;
3c: 92%
3a: 74%; 3b: 75%;
3c: 90%
Scheme 2 HIE reaction scope.14 Average 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 shown, e.g., 94% for the two possible positions in 5a indicates 1.88 D incorporation. a Reac-
tion run using 50 mol% catalyst. b Reaction run using 10 mol% catalyst.
strates, benzamide (4c), 2-phenylimidazole (4h), and ethyl
benzoate (4j) did not deliver the high levels of incorpora-
tion obtained over the more prolonged 16 hours process.
functionalised drug scaffolds is central to the application of
HIE catalysis, especially as aligned to the endeavours of
pharmaceutical partners. In this instance we were pleased
to obtain 86% D incorporation using 20 mol% of catalyst, al-
beit over 42 hours. Notably, the observed labelling was
completely selective, with incorporation occurring at the
least hindered site of the complex drug target and as direct-
ed by the adjacent amide functionality via a five-membered
metallacyclic intermediate (5-mmi).
Table 2 HIE Time Study Using Catalyst 3c
D
DG
DG
D
3c (5 mol%)
D2, CH2Cl2, time
R
R
4
5
O
O
Entry
Product
% D after 30 mina
% D after 16 ha
1
2
3
4
5
6
7
8
9
5a
5b
5c
5d
5e
5f
96
94
89
94
EtO
D
33
72
O
O
N
90
96
S
N
O
97
>99
89
H
O
75
MeO
6
5g
5h
5j
89
92
Figure 1 HIE of a pharmaceutical agent SR 121463. Reagents and con-
ditions: 3c (20 mol%), D2, CH2Cl2, 42 h, 86% D.
10
90
30 (65)b
58 (94)b
a Average incorporation into the positions shown over two separate reac-
tion runs; the percentage given refers to the level of D incorporation over
the total number of positions shown, e.g., 96% for the two possible posi-
tions in 5a indicates 1.92 D incorporation. b Reaction run using 10 mol%
catalyst.
In summary, we have revealed the escalated capability
of complexes of the type [(cod)Ir(NHC)(py)]PF6 within tran-
sition-metal catalysis. Specifically, such complexes have
been shown to perform within an ortho-directed C–H acti-
vation and HIE process, delivering high levels of deuterium
incorporation over a series of functionalised aromatic sub-
strates. The established system displays notable efficacy
under mild reaction conditions and over short reaction
In an extension of these studies and to further illustrate
the capability of catalysts of type 3, we applied the SIMes-
derived complex 3c in the HIE of Sanofi-Synthélabo’s phar-
macological target 6 (Figure 1). The ability to label fully
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, 111–115

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P. W. Cross et al.
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times. From these studies, catalyst 3c has proven to be the
most versatile and broadly applicable of the series applied,
and also providing high levels of selective isotopic labelling
within a fully functional drug target. With HIE now a key
procedure in the optimisation of the drug discovery pro-
cess, the results presented in this study are of direct value
and importance to pharmaceuticals partners. Indeed, ongo-
ing studies within our laboratory have the goal of discover-
ing catalysts that are compatible with increasingly complex
organic molecules and alternative druglike substrates, as
well as in the establishment of alternative C–H bond activa-
tion processes in a wider sense.
Compd. Radiopharm. 2013, 56, 451. For examples of HIE at ole-
finic C–H bonds, see: (h) Kerr, W. J.; Mudd, R. J.; Paterson, L. C.;
Brown, J. A. Chem. Eur. J. 2014, 20, 14604.
(7) Kerr, W. J.; Reid, M.; Tuttle, T. ACS Catal. 2015, 5, 402.
(8) Bennie, L. S.; Fraser, C. J.; Irvine, S.; Kerr, W. J.; Andersson, S.;
Nilsson, G. N. Chem. Commun. 2011, 47, 11653.
(9) Lee, H. M.; Jiang, T.; Stevens, E. D.; Nolan, S. P. Organometallics
2001, 20, 1255.
(10) Hillier, A. C.; Lee, H. M.; Stevens, E. D.; Nolan, S. P. Organometal-
lics 2001, 20, 4246.
(11) Crabtree, R. H.; Morehouse, S. M.; Quirk, J. M. Inorg. Synth. 1986,
24, 173.
(12) Typical Procedure for the Preparation of Catalysts 3a–c
An oven-dried Schlenk flask was charged with NHC salt 1 (2.49
mmol) and evacuated for 30 min. The flask was then transferred
into a nitrogen-filled glove box and isolated KH (2.49 mmol)
was added. The flask was then attached to a Schlenk line
(argon/vacuum), evacuated once, and filled with argon. Anhy-
drous THF (30 mL) was added, and the slow evolution of hydro-
gen was observed. The resulting solution was then allowed to
stir for 20 h at r.t. after which time the reaction mixture was fil-
tered through a dry filter stick into an oven-dried Schlenk flask.
The THF was evaporated, and the resulting free carbene was
extracted into anhydrous toluene (30 mL). The resulting toluene
solution was filtered through another dry filter stick into a pre-
viously evacuated and oven-dried Schlenk flask containing
[(cod)Ir(py)2]PF6 (2, 1.66 mmol). The reaction was allowed to
stir for 2 d at r.t. under an argon atmosphere. After this time, the
mixture was filtered to yield the desired iridium complex 3.
(13) (a) Cross, P. W. C.; Ellames, G. J.; Gibson, J. S.; Herbert, J. M.; Kerr,
W. J.; McNeill, A. H.; Mathers, T. W. Tetrahedron 2003, 59, 3349.
(b) Ellames, G. J.; Gibson, J. S.; Herbert, J. M.; McNeill, A. H. Tet-
rahedron 2001, 57, 9487. (c) Shu, A. Y. L.; Chen, W.; Heys, J. R.
J. Organomet. Chem. 1996, 524, 87. (d) Heys, J. R.; Shu, A. Y. L.;
Senderoff, S. G.; Phillips, N. M. J. Labelled Compd. Radiopharm.
1993, 33, 431. (e) Piola, L.; Fernández-Salas, J. A.; Manzini, S.;
Nolan, S. P. Org. Biomol. Chem. 2014, 12, 8683.
Acknowledgment
We thank the University of Strathclyde for postgraduate studentship
funding (PWCC) and Sanofi-Synthélabo for further contributions, in-
cluding financial support. Mass spectrometry data were acquired at
the EPSRC UK National Mass Spectrometry Facility at Swansea Uni-
versity.
References and Notes
(1) Present address: Isotope Chemistry and Metabolite Synthesis,
Covance Laboratories Limited, Willowburn Avenue, Alnwick,
Northumberland NE66 2JH, UK.
(2) For selected reviews, see: (a) Atzrodt, J.; Derdau, V.; Fey, T.;
Zimmermann, J. Angew. Chem. Int. Ed. 2007, 46, 7744. (b) Salter,
R. J. Labelled Compd. Radiopharm. 2010, 53, 645. (c) Nilsson, G.
N.; Kerr, W. J. J. Labelled Compd. Radiopharm. 2010, 53, 662.
(d) Allen, P. H.; Hickey, M. J.; Kingston, L. P.; Wilkinson, D. J.
J. Labelled Compd. Radiopharm. 2010, 53, 731. (e) Lockley, W. J.
S.; McEwen, A.; Cooke, R. J. Labelled Compd. Radiopharm. 2012,
55, 235. (f) Isin, E. M.; Elmore, C. S.; Nilsson, G. N.; Thompson, R.
A.; Weidolf, L. Chem. Res. Toxicol. 2012, 25, 532.
(3) For selected examples, see: (a) Lin, D.-L.; Chang, W.-T.; Kuo, T.-
L.; Liu, R.-H. J. Anal. Toxicol. 2000, 24, 275. (b) Atzrodt, J.;
Derdau, V. J. Labelled Compd. Radiopharm. 2010, 53, 674.
(4) For selected examples, see: (a) Heinekey, D. M. J. Labelled
Compd. Radiopharm. 2007, 50, 1063. (b) Parkin, G. J. Labelled
Compd. Radiopharm. 2007, 50, 1088.
(14) Representative Procedure for Isotopic Labelling: Acetophe-
none (4a) Using Catalyst 3c (Scheme 2)
A 100 mL, three-necked round-bottom flask was fitted with
two stopcock valves and a Suba-Seal and was flame-dried under
vacuum. The flask was then placed under a nitrogen atmo-
sphere and evacuated three times. The flask was then charged
with catalyst 3c (34 mg, 0.042 mmol) and CH2Cl2 (5 mL), and
then purged with nitrogen. The solution was allowed to stir
under an atmosphere of nitrogen for 15 min prior to the addi-
tion of acetophenone (4a, 100 mg, 0.83 mmol). The Suba-Seal
was then replaced with a greased glass stopper, and the solution
was stirred whilst being cooled to –78 °C in a dry ice–acetone
slurry. The flask was twice evacuated and flushed with nitro-
gen. Upon a third evacuation, an atmosphere of deuterium gas
was introduced via a balloon. The cold bath was removed, and
the flask was allowed to warm to r.t. NOTE: The glass stopper
was physically restrained as the reaction mixture warms. The
resulting mixture was stirred vigorously for 16 h before remov-
ing excess deuterium gas and replacing with air. The reaction
mixture and washings (CH2Cl2) were transferred into a single-
necked flask before removing the solvent under reduced pres-
sure. The catalyst complex was then precipitated by the addi-
tion of PE–Et2O (1:1, 10 mL) to the reaction residues. The cata-
lyst was then removed by filtration through a plug of silica, and
the resulting filtrate was concentrated under reduced pressure.
The level of deuterium incorporation in the substrate was deter-
(5) For selected examples, see: (a) Miyashita, M.; Sasaki, M.;
Hattori, I.; Sakai, M.; Tanino, K. Science 2004, 305, 495.
(b) Quasdorf, K. W.; Huters, A. D.; Lodewyk, M. W.; Tantillo, D.
J.; Garg, N. K. J. Am. Chem. Soc. 2012, 134, 1396.
(6) (a) Brown, J. A.; Irvine, S.; Kennedy, A. R.; Kerr, W. J.; Andersson,
S.; Nilsson, G. N. Chem. Commun. 2008, 1115. (b) Cochrane, A.
R.; Idziak, C.; Kerr, W. J.; Mondal, B.; Paterson, L. C.; Tuttle, T.;
Andersson, S.; Nilsson, G. N. Org. Biomol. Chem. 2014, 12, 3598.
(c) Kennedy, A. R.; Kerr, W. J.; Moir, R.; Reid, M. Org. Biomol.
Chem. 2014, 12, 7927. (d) Brown, J. A.; Cochrane, A. R.; Irvine, S.;
Kerr, W. J.; Mondal, B.; Parkinson, J. A.; Paterson, L. C.; Reid, M.;
Tuttle, T.; Andersson, S.; Nilsson, G. N. Adv. Synth. Catal. 2014,
356, 3551. (e) Atzrodt, J.; Derdau, V.; Kerr, W. J.; Reid, M.;
Rojahn, P. Tetrahedron 2015, 71, 1924. (f) Devlin, J.; Kerr, W. J.;
Lindsay, D. M.; McCabe, T. J. D.; Reid, M.; Tuttle, T. Molecules
2015, 20, 11676. For a recent disclosure of the use of complexes
of the type [(cod)Ir(NHC)Cl], see: (g) Cochrane, A. R.; Irvine, S.;
Kerr, W. J.; Reid, M.; Andersson, S.; Nilsson, G. N. J. Labelled
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mined by 1H NMR to be 94%. The integrals were calibrated
against a peak corresponding to a position not expected to be
labelled. The equation below was used to calculate the extent of
labelling:
Acetophenone (4a)
1H NMR (400 MHz, CDCl3): δ = 2.45 (s, 3 H), 7.32 (t, 2 H, J = 8.0
Hz), 7.41 (t, 1 H, J = 8.0 Hz), 7.81 (d, 2 H, J = 8.0 Hz) ppm. Label-
ling expected at δ = 7.81 ppm. Determined against integral at
δ = 2.45 ppm.
% D = 100 – [(residual integral/no. of labelling sites) × 100]
(15) In experiments using 2.5 mol% of catalysts 3a or 3c in CH2Cl2
over 16 h at r.t., 81% and 90% D incorporation was obtained,
respectively, in the labelling of acetophenone (4a).
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, 111–115