Deuterium exchange mediated by an iridium-phosphine complex formed in situ

Article abstract of DOI:10.1016/S0040-4039(01)01266-7

Bis(triorganophosphine)(cyclooctadiene)iridium(I) tetrafluoroborates, 2, are readily generated in situ and utilised for the exchange of deuterium into a variety of aromatic substrates. The efficiencies of deuterium exchange using 2 formed in this way are comparable to those observed in exchange processes where the isolated pre-catalysts were used.

Full text of DOI:10.1016/S0040-4039(01)01266-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 6413–6416
Deuterium exchange mediated by an iridium–phosphine complex
formed in situ
George J. Ellames,a Jennifer S. Gibson,a John M. Herbert,a,* William J. Kerrb and
Alan H. McNeilla
aIsotope Chemistry and Metabolite Synthesis Department, Sanofi-Synthe´labo, Willowburn Ave., Alnwick,
Northumberland NE66 2JH, UK
bDepartment of Pure and Applied Chemistry, University of Strathclyde, 295 Cathedral St., Glasgow G1 1XL, UK
Received 22 May 2001; revised 3 July 2001; accepted 12 July 2001
Abstract—Bis(triorganophosphine)(cyclooctadiene)iridium(I) tetrafluoroborates, 2, are readily generated in situ and utilised for
the exchange of deuterium into a variety of aromatic substrates. The efficiencies of deuterium exchange using 2 formed in this way
are comparable to those observed in exchange processes where the isolated pre-catalysts were used. © 2001 Elsevier Science Ltd.
All rights reserved.
A number of reports have appeared describing the use
of iridium complexes to mediate incorporation of tri-
tium and deuterium into arenes at positions ortho to a
directing group such as a carbonyl,1–4 the isotopic
hydrogen thereby being incorporated at a position
where it is essentially inert in metabolic or uncatalysed
exchange processes, as illustrated in general form in
Scheme 1. A small number of such catalysts, including
complexes 12 and 2a,3 are commercially available, while
others, such as the bis(triphenylphosphine) complex,
2b,4 are relatively simple to prepare. We were interested
in investigating the possibility that complexes bearing
different ligands at the iridium centre might offer a
range of different substrate selectivities and, rather than
attempt the preparation and isolation of a wide variety
of complexes, an attractive option was to examine the
formation of complexes in situ. In addition, the deuter-
ation of substrates such as ethyl benzoate mediated by
isolated 2b gave inconsistent results; these were
attributed to degradation of the complex on standing,
and it was hoped that complexes formed in situ would
be of a more consistent quality. This preliminary disclo-
sure of results in this area is occasioned by the recent
presentation of similar work by Salter et al.5
Since pre-catalysts 2a and 2b have been reported as
efficient mediators of the deuteration of a variety of
aromatic substrates,2,3 these were chosen for compara-
tive studies. Deuterium exchange of a range of sub-
strates was examined using pre-formed complexes, and
also using the corresponding species prepared by varia-
tions on two in situ methods.
Three approaches were examined for the generation of
catalytically active iridium species in situ. In the pre-
ferred procedure (Method A), the readily available
chloro-1,5-cyclooctadieneiridium(I) dimer was treated
with phosphine (4 molar equivalents) and silver tetra-
fluoroborate (2 molar equivalents) in dichloromethane.
After filtration to remove silver salts, the solution was
diluted to a concentration of 10 mmol/ml and this
solution added to the substrate, which was then
exposed to deuterium gas. Alternatively, the complex
could be generated in the presence of the substrate, and
the mixture exposed to deuterium without removal of
Scheme 1. Generalised form of deuterium exchange mediated
by iridium complexes.
Keywords: iridium complexes; deuterium exchange; isotope exchange.
* Corresponding author.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01266-7

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Table 1. Comparison of results from deuterium exchange mediated by 2a
the silver salts (Method B). In either case, TLC of the
solution formed indicated rapid formation of complex
2. Where they were not removed, it was clear that silver
salts were often reduced during the course of the
exchange to give metallic silver so, aside from the
possibility that sensitive substrates might be oxidised, it
was very probable that the reduction of silver(I)
involved concomitant oxidation of deuterium to form
deuterons. These may protonate basic substrates (and
thereby reduce their ligating ability), exchange at labile
sites (which was indeed observed with ketone sub-
strates) and possibly promote degradation of the cata-
lyst. Consequently, where silver salts were not removed
from the system, it was desirable to add two molar
equivalents of sodium carbonate as a mild base. Alter-
natively (Method C), the presence of silver salts could
be avoided entirely by treatment of commercially avail-
able bis(1,5-cyclooctadiene)iridium tetrafluoroborate
with triphenylphosphine (2 molar equivalents) in the
presence of a substrate and deuterium gas. Clearly, in
the last case, coordination of phosphines will not occur
until after removal of a cyclooctadiene ligand, and it is

G. J. Ellames et al. / Tetrahedron Letters 42 (2001) 6413–6416
6415
entirely possible that exposure of the mixture to deu-
terium might result in the formation of a mixture of
iridium complexes.
process promoted by the pre-formed catalyst results in
reduction to aniline, with concomitant 95% ortho-
deuteration. Since aniline itself incorporated only 5% of
deuterium under the same conditions, it is entirely
possible that deuterium exchange in this instance occurs
at an intermediate stage, or prior to the reduction
process.
Based on experiments with the isolated complex 2b, it
was found that, as observed previously with 1,6 a 2:1
substrate/catalyst ratio gave reasonable results with the
majority of substrates, although it must be stressed that
this ratio often did not correspond to the optimum for
maximum exchange; this ratio was used in most cases
throughout this study. Exchange processes carried out
using the in situ methods proceeded at rates compara-
ble to those observed using the isolated complex, and
were essentially complete within a matter of a few
hours. Again, as observed with 1,6 the degree of deuter-
ation is affected considerably by the removal of samples
during the exchange process. For example, where timed
deuterations of acetophenone with 2b were conducted
as separate experiments, complete deuteration occurred
within 2.5 h. In contrast, removal of samples from a
single exchange reaction over a short period resulted in
loss of catalytic activity, so that exchange remained
incomplete and the eventual degree of deuteration was
only around half of that observed otherwise. This may
be due to nothing more than loss of deuterium or
ingress of air through the rubber septum and, as a
consequence, all-glass systems were used for the deuter-
ations which followed.
In line with the concerns mentioned above over the
homogeneity of the catalytic species involved in
Method C, the results using this method are also poorer
than those from Method A. The reduced efficiency of
Method B compared to Method A may be the result of
degradation of the catalyst, either by acid or by sil-
ver(I)-mediated oxidation of the phosphine ligand; cer-
tainly, significant quantities of phosphine oxides were
detectable in the mixtures formed from exchange reac-
tions conducted without removal of the silver salts.
That said, in situ catalytic exchange is surprisingly
robust. Complexes 2 are air-sensitive but, whereas iso-
lated 2b was not stable to storage even under an inert
atmosphere, filtered solutions of the same complex
retained catalytic activity for at least 7 days when
stored under nitrogen at room temperature. In contrast,
solutions of 2a lost much of their activity over the same
period, even when stored under nitrogen at −20°C; the
loss of catalytic activity was accompanied by disappear-
ance of the characteristic ruby-red colour to give a pale
yellow solution characteristic of inactive oligomeric spe-
cies such as those characterised previously.7 As one
might reasonably expect, formation of the complex
using an excess of phosphine ligand generates a coordi-
natively saturated species which is catalytically inactive,
but a deficiency of phosphine ligand does not result in
a significant loss of catalytic activity (Table 2).
Selected results obtained upon deuterium exchange of a
selection of substrates with 2a and 2b, and with the
corresponding species formed in situ, are presented in
Table 1. In all cases, the principal measurement of
deuterium incorporation was by mass spectrometry,
with NMR spectra being acquired for representative
samples to confirm that incorporation had occurred
only at the ortho-sites, as expected.6 Method A gives
results which are both reproducible and reasonably
consistent with the results obtained using the isolated
pre-catalyst. As a rule, slightly lower levels of deu-
terium incorporation were observed using the com-
plexes formed in situ than was observed using the
isolated complexes, but the former is a consistently
good guide to the latter. Notable exceptions are the
deuteration of acetanilide mediated by 2b, where the in
situ method is the more efficient, and the deuteration of
In summary, we have demonstrated that it is feasible to
generate pre-catalysts 2 in situ and that the method
provides a comparatively robust means of assaying the
activity of different iridium catalysts towards a variety
of substrates. The method is presently being applied to
the development of a panel of complexes in order to
facilitate the selection of catalysts for the tritiation of
drug development candidates; further details of the
process and of the evaluation of other iridium–phos-
phine complexes will be described in future
publications.
nitrobenzene mediated by 2a. In the latter case, the
.
Table 2. Comparison of different iridium/triphenylphos-
phine ratios (Method B)a
Substrate
Using
[Ir(cod)Cl]2-4PPh3-
2AgBF4
Using
[Ir(cod)Cl]2-2PPh3-
2AgBF4
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