One-step exchange-labelling of pyridines and other N-heteroaromatics using deuterium gas: catalysis by heterogeneous rhodium and ruthenium catalysts

Article abstract of DOI:10.1016/j.tetlet.2006.05.106

A wide range of pyridines and other nitrogen heteroaromatics can be labelled with deuterium at room temperature and pressure by isotopic exchange with deuterium gas in THF in the presence of rhodium black, ruthenium black or 5% rhodium on alumina. The lab

Full text of DOI:10.1016/j.tetlet.2006.05.106

Tetrahedron Letters 47 (2006) 5025–5028
One-step exchange-labelling of pyridines and other
N-heteroaromatics using deuterium gas: catalysis by
heterogeneous rhodium and ruthenium catalysts
Efstathios Alexakis, John R. Jones and William J. S. Lockley*
Chemistry, School of Biomedical and Molecular Sciences, University of Surrey, Guildford, Surrey GU2 7XH, UK
Received 2 April 2006; revised 10 May 2006; accepted 17 May 2006
Abstract—A wide range of pyridines and other nitrogen heteroaromatics can be labelled with deuterium at room temperature and
pressure by isotopic exchange with deuterium gas in THF in the presence of rhodium black, ruthenium black or 5% rhodium on
alumina. The labelling is rapid, isotope efficient and applicable to both electron-rich and electron-poor substrates. In a few cases,
a degree of reduction accompanies the exchange.
ꢀ 2006 Elsevier Ltd. All rights reserved.
Pyridine and other N-heteroaromatic sub-units occur in
many industrially important chemicals including a range
of agrochemical and pharmaceutical agents. Methods
for labelling these units with isotopes of hydrogen are
therefore of interest since they provide routes to the tri-
tium-labelled compounds for use in environmental,
absorbtion, distribution, metabolism or toxicokinetic
radiotracer studies. They also provide access to the deu-
terium-labelled compounds for use in stable-isotope
tracer studies or for GC–MS or LC–MS internal
standardisation.
idine moiety has only been observed as an artefact5
alongside the labelling of other targeted molecular sites.
Only a few methods describe the direct exchange-label-
ling of unactivated N-heteroaromatics using an isotopic
hydrogen gas donor with commonly available catalysts.6
One such report, describes the use of 5% ruthenium on
carbon catalyst for the labelling of pyridines using deu-
terium gas and deuterated methanol.6b Unfortunately,
we have shown that the isotopic labelling achieved with
this method results to a significant degree from the deu-
terated solvent as well as from the D2 gas, rendering the
method unsuitable for tritium labelling applications. An
additional drawback of the method is that the activity of
the catalyst is very low, necessitating the use of pressu-
rised D2, again an undesirable operation with the tritium
isotope.
Unfortunately, efficient methods for direct labelling of
such N-heterocyclics via isotopic exchange are quite lim-
ited. Most involve a requirement for a directing group
within the substrate to facilitate ortho-labelling1 or for
some other such activating substituent.2 Others necessi-
tate the use of isotopic water in conjunction with a
Group VIII metal3 with the consequent problems of
potential radiotoxicity, or of product radiolysis, should
high specific activity tritium-labelling be required. Some-
times, reaction conditions involve acid-catalysis or very
high temperatures.4 In many cases, labelling of the pyr-
Recognising all the above limitations, we have screened
other potential Group VIII metal catalysts for this type
of deuterium gas exchange process (Scheme 1) so as to
identify systems with greater potential for use with both
the deuterium and tritium isotopes.
R
R
D2 / GpVIII metal catalyst
THF / RT / 2 h
Keywords: Pyridine; N-Heteroaromatic; a-Exchange; Deuteration;
Tritiation; Ruthenium black; Rhodium black; Rhodium on alumina;
Isotope-exchange; Deuterium gas.
R= range of substituents
including fused-ring analogues
N
D
N
D
*
Corresponding author. Tel.: +44 (0)1483 686828; fax: +44 (0)1483
686851; e-mail: w.lockley@surrey.ac.uk
Scheme 1.
0040-4039/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.05.106

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E. Alexakis et al. / Tetrahedron Letters 47 (2006) 5025–5028
A wide range of supported and unsupported noble metal
catalysts were screened and three catalysts were identi-
fied, which transferred the isotope efficiently from deute-
rium gas to the substrate. Moreover, these catalysts were
far more active than the literature catalyst, allowing
their use at ambient temperature and pressure in non-
hydroxylic solvents. The active catalysts were rhodium
black, ruthenium black and 5% rhodium on alumina.
Next, these new catalysts were evaluated against a panel
of pyridines and other N-heteroaromatics specifically
selected to investigate various stereoelectronic and
regiochemical aspects of the labelling processes.
expected bidentate complexation with the surface. How-
ever phthalazine, another bidentate substrate, and
2-bromopyridine, both of which are able to bind
strongly, and which were indeed recovered unlabelled
from a previous study,6b were nevertheless labelled by
the new catalysts.
In common with many other metal-catalysed isotopic
exchange methods7 the procedure appears to be appli-
cable to both electron-rich and electron-deficient
substrates. Moreover, various fused-ring pyridine
analogues are labelled. Both these behaviours bode well
for the general applicability of the method.
The results of this study are summarised in Table 1.
In a few cases, a degree of reduction or other decompo-
sition accompanied the isotope exchange, though for
most substrates examined this behaviour was absent or
of marginal significance. Moreover, selection of a different
catalyst can avoid such behaviour in some cases (see
Table 1).
Overall, the data shows that many N-heteroaromatics
can be efficiently labelled using this simple procedure.
1
2
Moreover, combined H and H NMR studies demon-
strated clearly that the procedure leads to highly regio-
selective (and in many cases regiospecific) labelling in
positions a to nitrogen.
An important parameter for any labelling reaction is the
isotopic incorporation and this was satisfactorily high
under the simple protocol utilised.8 Indeed in separate
experiments with no changes of deuterium gas it was
close to the equilibrium value calculated for the
exchangeable hydrogen isotope pool in the reactions.
Six of the substrates (3- and 4-acetylpyridine, 7,8-benzo-
quinoline, 2-phenylpyridine, 4-dimethylaminopyridine
and 2-methoxypyridine) were selected to check for con-
comitant labelling at other favourable sites via base-cata-
lysed, ortho-directed1 or heteroatom-directed methyl/
methylene labelling processes.1c,d,5d However, only one
example of such behaviour was observed: both a- and
ortho-labelling1 was observed with 2-phenylpyridine.
The method has also proved amenable to use with the
tritium isotope, at least at low specific activity. Thus
exchange of 4,40-bipyridyl with deuterium tritide over
rhodium black yielded [2,6,20,60-2H, 2,6,20,60-3H]4,40-
bipyridyl in a single high-yielding exchange step. 3H
NMR analysis of this product showed a single triton
resonance corresponding to tritium-labelling exclusively
at the a-positions. There were no other resonances,
Previous work has shown that tight binding of the sub-
strate to the catalyst surface can inhibit labelling in me-
tal catalysed exchange3b,i,6b and indeed 2,20-bipyridyl
does show a reduced extent of labelling in comparison
with the 4,40-linked analogue, consistent with the
Table 1. Labelling of pyridines and other nitrogen heteroaromatics using heterogeneous Ru and Rh catalysts and deuterium gas in tetrahydrofuran
at ambient temperature and pressure
Substrate
Deuterium labelling a to nitrogen
Rh black
Ru black
5% Rh/alumina
a
3-Acetylpyridine
4-Acetylpyridine
3-Aminoquinoline
7,8-Benzoquinoline
2-Benzylpyridine
4-Benzylpyridine
2,20-Bipyridyl
—
99%
0%
99%
0%
8%
0%a
0%
47%
0%a
47%
62%(C-1)
87%(C-3)
9%
85%
11%
23%
27%
99%
83%
43%
0%
22%
76%
19%
75%
0%
50%
11%(C-1)
11%c(C-3)
4%
83%
0%
99%
83%
90%a
99%
99%
35%
75%
28%
4,40-Bipyridyl
2-Bromopyridine
4-Dimethylaminopyridine
Isoquinoline
100%
90%(C-1)
86%(C-3)
16%
2-Methoxypyridine
4-Methylpyridine
2-Phenylpyridine
Phthalazine
98%a
20%b
61%
27%
53%c
Quinoline
99%a
Conditions: The substrate (ca. 0.13 mmol) and catalyst (10 mg) in THF (1 ml) were stirred under D2 gas for 2 h at ambient pressure and temperature,
replacing the D2 gas twice during the course of the exchange.
a Indicates concomitant decomposition or significant reduction under the reaction conditions.
b In addition there was ca. 35 atom % D at each of the ortho-positions of the phenyl ring.
c Indicates a small amount of concomitant reduction.

E. Alexakis et al. / Tetrahedron Letters 47 (2006) 5025–5028
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Acknowledgements
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8. 4,40-Bipyridyl (22 mg) and rhodium black (10 mg) were
dissolved in dry THF (1.0 ml) and stirred under deuterium
gas at room temperature and pressure for 5 h. During this
period, the deuterium gas (99 atom % D) was replaced five
times. The catalyst was filtered off and washed with THF
and the combined filtrates evaporated under a stream of
nitrogen to yield essentially pure labelled bipyridyl (22 mg,

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E. Alexakis et al. / Tetrahedron Letters 47 (2006) 5025–5028
98%), which was crystallised by dissolution in a minimum
(0.1H, d, J = 6.0 Hz, residual a-protons) ppm. 2H NMR
(CHCl3, 77 MHz) d 8.76 (s, a-deuterons) ppm, EI-MS
(M+4 · 2H) gives 160.093 amu, C10H42H4 requires
160.093 amu. The overall a-deuteration achieved by this
procedure was 97.5 atom %.
of dichloromethane and treatment with hexane to yield
[2,6,20,60-2H4]4,40-bipyridyl (first crop, 15 mg, 67%, mp
112–113 ꢁC) (authentic unlabelled standard, 112–113 ꢁC),
1H NMR (CDCl3, 500 MHz) d 7.56 (4H, s, b-protons), 8.76