Investigations of isotope scrambling during the deuterodechlorination of ortho-chloroacetanilide

Full text of DOI:10.1002/jlcr.1227

Journal of Labelled Compounds and Radiopharmaceuticals
J Label Compd Radiopharm 2007; 50: 505–506.
Published online in Wiley InterScience
JLCR
(www.interscience.wiley.com). DOI: 10.1002/jlcr.1227
Short Research Article
Investigations of isotope scrambling during the
deuterodechlorination of ortho-chloroacetanilidey
WILLIAM J. S. LOCKLEY1,*, JOHN R. JONES1 and DAVID J. WILKINSON2
1 Department of Chemistry, University of Surrey, Guildford GU2 7XH, UK
2 AstraZeneca R&D Charnwood, Bakewell Rd, Loughborough, Leics LE11 5RH, UK
Received 26 July 2006; Accepted 15 December 2006
Keywords: dehalogenation; dechlorination; deuteration; isotope-scrambling
Introduction
Initial screening of a range of palladium catalysts for
maximum isotopic labelling (still only ca. 80%D in the
best case) whilst maintaining a deficiency of D2 gas
defined the test reaction: ortho-chloroacetanilide
(0.5 mmol), 5% palladium on carbon paste (Aldrich
26,670-7, 30 mg) and triethylamine (100 ml) in THF
(2 ml) with D2 (0.36 mmol) at ambient temperature and
pressure.
The dehalogenation of haloaromatics is a facile and
common approach to labelling organic compounds with
hydrogen isotopes. However, the dehalogenation of
haloaromatics frequently yields low atom% abundance
due to isotopic scrambling at the labelled site. The
behaviour is particularly acute with chloroaromatics.
A
few studies have attempted to investigate the
In common with previous work the current (exten-
sive) studies failed to identify all the processes involved
in this complex scrambling process. However some
interesting observations were made and useful conclu-
sions can be drawn.
parameters controlling this behaviour but usually with
only partial success.1a–c Recently the observation of a
large deuterium isotopic effect in ortho-deuterated
anilides2 provided a simple method with which to
study this scrambling by 1H-NMR.
N-deuteration of the substrate showed that the
scrambling probably did not arise from the amide NH.
Perhaps surprisingly, addition of D2O to the system
showed only a small increase in %D in the product,
whilst addition of H2O showed no obvious decrease.
Addition of drying agents or use of newly dried solvent
had no effect. 2H-NMR studies, using excess D2,
showed the formation of exchangeable3 deuteron
signals with time (these corresponded to amide ND
and HOD/Et3NDCl resonances only: there was no
detectable labelling of the solvent or triethylamine a-
or b-protons)z but the rate was slow compared with the
dehalogenation reaction and, significantly, was unre-
lated to the %D of the o-deuteroacetanilide product,
which proved essentially constant from the earliest
sampling point (1 h, 18% reaction) to the completion of
the dehalogenation reaction at (5 h, 100% reaction).
However, very significant decreases in %D (43 and
Results and discussion
The model reaction chosen was the deuterodechlorina-
tion of ortho-chloroacetanilide (Scheme 1).
O
O
D2
H
H
N
N
Et3N
Cl
D
Et3NDCl
+
5%Pd/C
THF
Scheme 1
*Correspondence to: William J. S. Lockley, Department of Chemistry,
University of Surrey, Guildford GU2 7XH, UK. E-mail: w.lockley@
survey.ac.uk
yProceedings of the Ninth International Symposium on the Synthesis
and Applications of Isotopically Labelled Compounds, Edinburgh,
16–20 July 2006.
z The authors would like to thank Dr Cor Janssen for the
opportunity to analyse similar reactions carried out with
tritium via 3H-NMR. These studies confirmed that tritiated
water was formed in all the solvents studied (including THF)
whilst the solvents themselves remained unlabelled.
Copyright # 2007 John Wiley & Sons, Ltd.

506 W. J. S. LOCKLEY ET AL.
49%) were observed when delays of 7 and 18 h were
introduced before the addition of the substrate, or if the
rate of the dehalogenation was decreased by addition of
0.004mol/mol of iodobenzene (a catalyst poison for
dehalogenation, reduction from 80%D to 21%D). In
these cases the competing H2O/D2 isotope equilibration
could well have been the dominant process leading to the
very low %D achieved. Given the known3b fractionation
of H2 isotopomers on Pd it is possible that even minor
H/D exchange processes could lead to an over-representa-
tion of the key (i.e. reactive) HD or H2 on the catalyst
and hence to scrambling in the product.
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Studies are continuing. However, in view of our results
it would seem advisable to: (a) avoid methanol as solvent;
(b) ensure that the rate of any target dechlorination
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Copyright # 2007 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2007; 50: 505–506
DOI: 10.1002.jlcr