Iridium-catalysed labelling of anilines, benzylamines and nitrogen heterocycles using deuterium gas and cycloocta-1,5-dienyliridium(I) 1,1,1,5,5,5-hexafluoropentane-2,4-dionate

Article abstract of DOI:10.1016/S0040-4039(03)00750-0

A wide range of variously substituted anilines, benzylamines, and nitrogen heterocycles may be conveniently deuterated by exchange with deuterium gas and cycloocta-1,5-dienyliridium(I) 1,1,1,5,5,5-hexafluoropentane-2,4-dionate. The isotopic exchange can b

Full text of DOI:10.1016/S0040-4039(03)00750-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 3959–3961
Iridium-catalysed labelling of anilines, benzylamines and
nitrogen heterocycles using deuterium gas and
cycloocta-1,5-dienyliridium(I)
1,1,1,5,5,5-hexafluoropentane-2,4-dionate
Michael J. Hickey,a John R. Jones,b Lee P. Kingston,a William J. S. Lockley,b,* Andrew N. Mather,a
Barry M. McAuleya and David J. Wilkinsona
aAstraZeneca R&D Charnwood, Bakewell Rd, Loughborough, Leics. LE11 5RH, UK
bDepartment of Chemistry, University of Surrey, Guildford, Surrey GU2 7XH, UK
Received 31 January 2003; revised 7 March 2003; accepted 21 March 2003
Abstract—A wide range of variously substituted anilines, benzylamines, and nitrogen heterocycles may be conveniently deuterated
by exchange with deuterium gas and cycloocta-1,5-dienyliridium(I) 1,1,1,5,5,5-hexafluoropentane-2,4-dionate. The isotopic
exchange can be carried out efficiently in dimethylformamide or dimethylacetamide, hence it is directly applicable to the
deuteration of polar compounds such as pharmaceuticals. Isotope incorporation is rapid and yields ortho-regiospecificity. © 2003
Elsevier Science Ltd. All rights reserved.
The preparation of organic compounds labelled with
isotopic hydrogen is of essential importance in the
chemical, biological and environmental sciences. Hence
numerous methodologies have been developed for the
fluoropentane-2,4-dionate (1), may be used to deuterate
compounds using deuterium gas. Moreover with some
substrates, particularly benzylamines, anilines and some
N-heterocycles the activity of this catalyst is maintained
even in DMF or dimethylacetamide (Scheme 1). This is
particularly useful for pharmaceuticals, agrochemicals
and suchlike agents, which are usually polar and insol-
uble in hydrochlorocarbons. A simple, high-yielding,
single-step preparation of the catalyst from a readily
available commercial precursor is described.7
3
2H- and H-labelling of organic substrates. Possibly the
most versatile of these approaches is ortho-directed
deuteration. The isotope for such ortho-exchange pro-
cedures may derive from D2O,1 T2O,2 D2 gas3 or T2
gas.4 In the former case either RhCl3·3H2O or Ru-
(Acac)3 have been utilised in dipolar aprotic solvents,
whilst in the latter case variants of the Crabtree
catalyst5 are utilised, though reactions here are limited
to non-polar solvents, typically dichloromethane.
Recently we reported the development of a new range
of improved catalysts based upon cycloocta-1,5-
dienyliridium(I) acetylacetonate, several of which
demonstrate excellent isotopic exchange catalysis with a
D2O donor.6 We now report that one of these com-
plexes, cycloocta-1,5-dienyliridium(I) 1,1,1,5,5,5-hexa-
Keywords: ortho-labelling; cycloocta-1,5-dienyliridium(I) 1,1,1,5,5,5-
hexafluoropentane-2,4-dionate; deuteration; CH-activation; isotope-
exchange;
anilines.
cycloocta-1,5-diene; acetylacetonate; benzylamines;
* Corresponding author. Tel.: +44 (0)1483 686828; fax: +44 (0)1483
686851; e-mail: w.lockley@surrey.ac.uk
Scheme 1.
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00750-0

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M. J. Hickey et al. / Tetrahedron Letters 44 (2003) 3959–3961
To ascertain the generality of the labelling procedure, 1
was assessed8 against a panel of substrates chosen to
encompass a range of electronic and steric influences.
The regiochemistry of labelling was analysed by 2H
and/or 1H NMR and the degree of labelling determined
by LC–MS. The results are given in Table 1.
gen was subsequently replaced by deuterium. This
should significantly reduce radioactive waste when the
catalyst is used with tritium.
The catalytic activity observed could be mediated
through an iridium dionate hydride species. If so, the
precipitation of iridium during the deuteration of some
substrates would reflect a low degree of stabilisation by
the dionate ligand. Alternatively, in view of the
labelling of anilines, which cannot form five-ring
cyclometalated intermediates, the reaction may be
mediated via precipitated iridium metal or even by an
iridium colloid or cluster generated in situ.9 The contin-
ued effectiveness of the catalytic system in the presence
of mercury argues against this explanation;10 however,
the iridium precipitate formed during the deuteration of
4-aminobenzoic acid does demonstrate some catalytic
activity. Interestingly, the regiochemistry of deuteration
for this latter substrate (ortho to NH2) is opposite to
that observed when a D2O donor is used (ortho to
CO2H), suggesting different mechanisms for these two
reactions. More detailed mechanism studies are ongo-
ing and will be reported elsewhere.
Definitive assignment of the labelling regiochemistry by
2H NMR was possible in many cases and the deuterium
was shown to be located at positions ortho to the
directing group. In some cases assignment was pre-
cluded by the overlap of NMR resonance positions,
compounded by the low spectral dispersion of
deuterium.
The catalyst proved effective in labelling all the sub-
strates, recoveries were good and deuteration was
observed whether the substrates were electron-rich or
poor. Benzylamines could be unsubstituted, mono- or
di-substituted at, or a to, nitrogen. The labelling of
anilines was particularly facile, either directly with the
aniline itself or via the reduction of the corresponding
nitro-compound.
Studies of the reaction time-course, with both 4-
methoxybenzylamine and 7,8-benzoquinoline, showed
that equilibrium was reached within 3–4 h even with
sub-stoichiometric quantities of catalyst. Moreover,
pre-treatment of the system with hydrogen gas showed
no effect upon the labelling efficiency when the hydro-
Acknowledgements
The authors would like to thank J. Gardiner and the
Physical Sciences Group at AstraZeneca R&D Charn-
wood together with J. P. Bloxsidge and R. G. B.
Chaudry, both of the University of Surrey, for their
support with spectroscopic analysis.
Table 1.
References
Substrate
Atom% D
Regiochemistry
(No. of atoms)
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1-(4-Fluorophenyl)ethylamine 66 (2)
1,1-Diphenylmethylamine
1,2-Diphenylethylamine
4-Iodobenzylamine
3-Methoxybenzylamine
4-Methoxybenzylamine
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Benzylamine
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50 (4)
57 (4)
42 (2)
48 (2)
55 (2)
69 (2)
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a
a
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7,8-Benzoquinoline
a Labelling regiochemistry assigned as ‘ortho’ from proton NMR and
MS.
b Labelling regiochemistry assigned as ‘ortho’ from deuterium NMR.
c Labelling regiochemistry not assigned.

M. J. Hickey et al. / Tetrahedron Letters 44 (2003) 3959–3961
3961
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layer was evaporated under a slow stream of nitrogen,
leaving clumps of purple crystals in the residual aqueous
phase. The aqueous supernatant was decanted and the
crystals washed twice more by decantation with 2.0 ml
portions of water. Finally, the crystals were filtered and
dried overnight over silica gel leaving cycloocta-1,5-
dienyliridium(I) 1,1,1,5,5,5-hexafluoropentan-2,4-dionate
(412.5 mg, 91%) as a fine free-flowing claret-coloured
1
solid. H NMR l (CDCl3) 1.75 (4H, q, J=7.5 Hz), 2.30
(4H, m), 4.31 (4H, s), 6.32 (1H, s) ppm. 13C NMR l
(CDCl3) 31.1, 62.6, 93.1, 118.5 (quartet), 174.3 (quartet)
ppm. MS (EI mode) m/z 508/506 a.m.u. Found C,
30.55%; H, 2.91%, req. C, 30.67%; H, 2.95%.
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8. A typical deuteration protocol is as follows: The sub-
strate (0.04 mmol) and catalyst (0.01 mmol) were dis-
solved in DMF or DMA (250 ml) and stirred under
deuterium gas for 4 h at room temperature. The labelled
substrate was then isolated by a suitable solvent extrac-
tion procedure, e.g. for anilines and benzylamines, an
ether/hydrochloric acid partition, basification with
NaOH solution, extraction into ether and removal of the
solvent under a stream of dry nitrogen.
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7. Commercial
[di-m-chlorobis[1,2,5,6-h)-1,5-cyclooctadi-
ene]diiridium (300 mg) was stirred under nitrogen in
vacuum degassed ether (6.0 ml) at which point it was
only partly dissolved. 1,1,1,5,5,5-Hexafluoro-2,4-pentane-
dione (300 ml) in ether (0.6 ml) was then added via a
syringe and the reaction stirred for 10 min. Sodium
hydroxide solution (1 M, 1.25 ml) was then added, drop-
wise via a syringe. During this phase the remaining
crystals of the precursor dissolve and the mixture became
a deep claret colour. Water (3.0 ml) was then added,
again via a syringe, and the resulting biphasic mixture
stirred under nitrogen for a further 10 min. The ether