Anion effects to deliver enhanced iridium catalysts for hydrogen isotope exchange processes

Article abstract of DOI:10.1039/c4ob01570c

Synthesis of a series of iridium(i) complexes of the type [(COD)Ir(IMes)(PPh₃)]X (X = BF₄, OTf, and BArF) has been established. Application of these species in mild hydrogen isotope exchange processes revealed more efficient catalysis and, further, a wider solvent scope when employing larger, more weakly coordinating counterions.

Full text of DOI:10.1039/c4ob01570c

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Anion effects to deliver enhanced iridium catalysts
for hydrogen isotope exchange processes†
Cite this: Org. Biomol. Chem., 2014,
12, 7927
Alan R. Kennedy, William J. Kerr,* Rory Moir and Marc Reid
Received 24th July 2014,
Accepted 1st September 2014
DOI: 10.1039/c4ob01570c
www.rsc.org/obc
Synthesis of a series of iridium(I) complexes of the type [(COD)-
Ir(IMes)(PPh3)]X (X = BF4, OTf, and BArF) has been established.
Application of these species in mild hydrogen isotope exchange
processes revealed more efficient catalysis and, further, a wider
solvent scope when employing larger, more weakly coordinating
counterions.
Ionic transition metal complexes play a central role in catalysis
and organic synthesis. Although it is more common to tune
the properties of such catalysts via manipulation of the co-
ordinated ligands on the transition metal cation, the past two
decades have witnessed a significant increase in studies of
the effects of changing the negatively charged counterion.1 In
Fig. 1 HIE catalysts bearing different counterions.
contribution, we report the syntheses and application in HIE
most cases where the counterion plays a spectator role, of complexes 1b–d, counterion variations of our flagship cata-
lyst, 1a (Fig. 1).9,10 As has been demonstrated by Pfaltz and
moving to larger, more weakly coordinating counterions has
others in iridium-based catalysis,4 we hypothesised that
evidenced a positive influence on catalyst efficiency across
various methodologies, with examples spanning palladium,2 moving to larger counterions, such as tetrakis[3,5-bis(trifluoro-
rhodium,3 and iridium4 catalyses, among others.1a,b Having
methyl)phenyl] borate (BArF), would enhance the activity and
stated this, there also exist some cases in which the ability
of the counterion to coordinate to the inner sphere of the ings. Furthermore, as wider preparative applications of HIE
longevity of the proposed new Ir species at lower catalyst load-
transition metal cation is essential for overall structural
stability.5 Furthermore, changing the counterion has also
require catalysts operable in a more expansive array of solvent
media,8d,9b,11 we theorised that the more diffuse counterions
been documented to completely alter reaction pathways in would enhance the solvent scope of the catalyst beyond that
both transition metal complex synthesis6 and organic
synthesis.7
which we have already reported.9 To substantiate these propo-
sals, it was necessary to study complexes bearing counterions
both larger and smaller than for catalyst 1a.
We began our studies with the syntheses of novel complexes
1b and 1c, using the general method shown in Table 1. Start-
ing from the chloro-carbene complex, 2,12,13 the choice of
silver salt used to the abstract the chloride ligand simul-
taneously delivered the counterion of choice (after addition of
PPh3). Both complexes were isolated in acceptable yields by
simple trituration from ethyl acetate.
Our interest in this field stems from the development of
cationic iridium(I) N-heterocyclic carbene (NHC)-phosphine
complexes for pharmaceutically-relevant hydrogen isotope
exchange (HIE) processes.8,9 To date, we have reported on the
development and application of several such complexes, all of
which bear the hexafluorophosphate counterion.8c,9 In this
In turning our attention to the synthesis of complex 1d, the
lack of a commercially available source of AgBArF prompted
the search for a silver-free synthetic route. In this regard, it
was hypothesised that the chloro-carbene intermediate, 2, may
be circumvented if the parent imidazolium salt required to
provide the NHC ligand was partnered with a large and weakly
Department of Pure and Applied Chemistry, WestCHEM, University of Strathclyde,
Glasgow G1 1XL, Scotland, UK. E-mail: w.kerr@strath.ac.uk;
Fax: +44 (0)141-548-4822; Tel: +44 (0)141-548-2959
†Electronic supplementary information (ESI) available: Details of all experi-
mental procedures (catalyst syntheses and deuterium labelling) are provided.
CCDC 1001847–1001850. For ESI and crystallographic data in CIF or other elec-
tronic format see DOI: 10.1039/c4ob01570c
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Table 1 General procedure for the syntheses of complexes 1b and 1c
Entry
X
Catalyst
% Yield
1
2
BF4
OTf
1b
1c
80
69
Fig. 2 Molecular structure of catalyst 1d as determined by X-ray
crystallography.
Scheme 1 Silver-free synthesis of complex 1d.
coordinating counterion such as BArF. Indeed, this approach
has promising literature precedent relating to iridium com-
plexes bearing
a
chelating carbene-phosphine ligand.14
Accordingly and as detailed in Scheme 1, this approach was
successfully realised for our monodentate NHC-phosphine
ligand combination. Firstly, NHC precursor, 4, was synthesised
by salt metathesis from 3. Following in situ generation of
[(COD)Ir(PPh3)Cl] from 5 and PPh3, 4 was added followed by
base to yield the desired complex, 1d, in good yield, and on
gram scale.
All novel compounds, 1b–d and 4, were characterised by
NMR (1H, 13C, 31P, 19F, and 11B), IR, melting point, HRMS, and
X-ray crystallography. Of particular note is the X-ray structure
determination of complex 1d, which reveals the similar size of
the BArF counterion relative to the cationic portion of the
complex (Fig. 2).‡
To investigate the impact of the series of counterions in
iridium-based HIE processes, model reactions employing aceto-
phenone, 6, as the substrate were undertaken. In particular,
the effect of catalyst loading on the labelling efficacy of com-
plexes 1a–d was scrutinised. As shown in Scheme 2, the effect
of changing the counterion was clearly drawn out at the most
accessible and commonly applied reaction temperature of
25 °C. As predicted, the relative efficiency of each catalyst
increases in order of increasing counterion volume.15 Catalysts
Scheme 2 Assessment of counterion effects on catalyst efficiency.
1c and 1d, bearing the OTf and BArF counterions, respectively,
are more active than parent catalyst, 1a, and the catalyst
bearing the small BF4 counterion, 1b. Notably, the reactivity of
the triflate catalyst, 1c, contrasts with observations made by
Pfaltz and co-workers during their study on the counterion
effects in olefin hydrogenation using PHOX-type chelating
ligands.4b Where these previous studies showed complete
shutdown of catalytic activity using the triflate species, we have
evidenced that both triflate and BArF counterions perform
equally well (and, indeed, better than the parent catalyst, 1a) at
25 °C within HIE processes. Presumably, this difference in the
effectiveness of triflate across these two systems is related to
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the different orientations of the ancillary ligands in the active
catalyst forms. For bidentate PHOX ligands, the coordinating
groups adopt a cis configuration, allowing coordination of the
dipolar triflate anion to the iridium centre. In catalyst series 1,
the bulky NHC and phosphine ligands are known to rest trans
to one another in the active form.9c Therefore, triflate coordi-
nation may be blocked by the more effective combined steric
bulk of a trans NHC-phosphine system relative to the more
open cis-coordinated PHOX ligands.
Next, we explored the effective solvent scope of catalyst 1
with different counterions. Previously, we have identified 2-
MeTHF, MTBE, and Et2O as viable alternatives to DCM using
catalyst 1a.9b Therefore, we compared the applicable solvent
scope of 1a versus the most non-polar derivative, 1d, across a
wider range of solvents than previously explored. Using the
same reference reaction as shown in Scheme 2 (5 mol% cata-
lyst, 25 °C), we screened a series of ethereal, alcoholic, ester,
Fig. 4 Counterion influence on alcohol, ester, chlorinated, and aro-
matic solvent scope. Results are reported as an average of two runs.
chlorinated, and aromatic solvents. Firstly, we were encour- producing almost quantitative D-incorporation. In contrast, a
aged to note that the more soluble catalyst, 1d, was generally stark difference in deuterium labeling efficiency was recorded
superior to parent catalyst, 1a, within HIE for the range of between 1a and 1d when using toluene as the solvent. Again,
ether and carbonate solvents tested (Fig. 3). For dioxane, catalyst 1d was superior to the less soluble catalyst, 1a. Finally,
MTBE, Et2O, and 2-MeTHF both catalysts were shown to it is also worth noting that more polar solvents DMSO and
perform equally well, with the larger counterion of 1d offering DMF were tested under the same reaction conditions with
slight improvements to an already efficient deuteration system. complex 1d, however, only very low levels of deuteration in
However, more significant improvements were recorded on acetophenone were detected (see ESI† for results).
i
comparing the activities of 1a and 1d in Pr2O, THF, and the
As stated in the introduction, owing to the highly variable
solubility profile of different drug classes, HIE processes with
recognised green solvents, CPME and dimethyl carbonate.16
Alcohol-derived solvents provided a more varied range of drug candidates require a flexible solvent choice. To explore
reaction efficiencies (Fig. 4). Notably, in all cases, catalyst 1d the potential benefits of expanded solvent scope with catalyst
displayed greater levels of activity and was more widely appli- 1d over 1a, we next turned our attention to the deuterium lab-
cable than 1a. The most significant reactivity from the alco- elling of drug molecule, Niclosamide, 8. Using catalyst 1a or
holic solvents shown was observed in the most sterically 1d in DCM, similarly moderate to good deuterium incorpor-
shielded (and presumably least coordinating) alcohol, tAmOH. ation was achieved across all four possible labelling sites
A similar pattern of reactivity was observed for ester sol- (Table 2, entries 1 and 2). This is presumed to be due to the
vents, and accompanied with higher overall levels of deuter- relative insolubility of 8 in DCM. On moving to 2-MeTHF as an
ium incorporation (Fig. 4). Again, the combination of catalyst alternative solvent (able to fully solubilise all reactants), cata-
1d and the most sterically encumbered solvent (iPrOAc over lyst 1a showed suppressed deuteration in positions a–c, and
EtOAc) proved most effective. Chlorinated solvents DCM and enhanced deuteration at position d (entry 3).17 Pleasingly and
DCE evidenced no difference in catalysts 1a and 1d, with both to excellently exemplify the effectiveness of the larger anionic
Table 2 Improved deuterium labelling of Niclosamide with 1da
Entry
Catalyst
X
Solvent
%Da
%Db
%Dc
%Dd
1
2
3
4
1a
1d
1a
1d
PF6
BArF
PF6
DCM
DCM
2-MeTHF
2-MeTHF
66
71
51
97
53
57
11
96
41
18
4
66
73
98
96
BArF
65
Fig. 3 Counterion influence on ether and carbonate solvent scope.
Results are reported as an average of two runs.
a Percent deuteration determined by 1H NMR.
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counterion, especially with more demanding pharmaceuti-
cally-related substrates, catalyst 1d in 2-MeTHF showed
improved labelling in all four positions over all other conditions
tested (entry 4 versus 1–3).
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Conclusions
In summary, we have reported on the syntheses of three novel
complexes of the type [(COD)Ir(IMes)(PPh3)]X (X = BF4, OTf,
and BArF), with the BArF complex having been accessed by a
modified and more direct preparative process. Application of
these complexes as catalysts in hydrogen isotope exchange has
demonstrated improved catalytic activity at lower catalyst load-
ings in the order X = BArF ≈ OTf > PF6 > BF4. Relative to the
parent complex (1a, X = PF6), 1d (X = BArF) possesses a
superior solubility profile and applicable solvent scope in HIE
processes. This is of fundamental importance to the delivery
of labelled drug candidates for use in absorption, distribution,
metabolism, excretion, and toxicology (ADMET) studies.
Accordingly, the complex 1d now provides a catalyst system of
wider potential applicability and effectiveness, in particular,
within pharmaceutical settings. Further and in relation to this,
the utility of improved solvent scope has been demonstrated
through improved global deuterium labelling of the drug
molecule Niclosamide in 2-MeTHF. Our on-going efforts in
this area are focused on the further application of optimal
catalyst, 1d, in labelling processes and to alternative C–H acti-
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10 Catalyst 1a is available commercially from Strem Chemi-
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via a 5-membered metallacycle (position d) is more facile
than via the 6-membered metallacycle (position c; see
ref. 9 for details). Additionally, coordination through
the nitro group (for labelling at a and b) is presumed to be
weaker than for the amide. For a recent discussion on the
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17 The increased selectivity for position d when using 1a in
2-MeTHF may be based on the increased polarity of the
solvent relative to DCM and the resultant increase in com-
petition between substrate and solvent for coordination to
iridium. Coordination of the amide carbonyl and labelling
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