SELECTIVE TRITIO-DEHALOGENATIONS 559
Table 1 Deuteration of aryl bromide 5 under a range of conditions
Ratio
Entry
D
2
pressure
Catalyst
Base
SM
Product
De–Bn
1
2
3
4
1 atm
1 atm
1 atm
200 mbar
PtO
PtO
2
Et
X
X
X
X
X
X
X
X
3
N
15
20
5
70
0
70
50
99
99
30
30
55
5
0
5
10
1
1
55
50
40
25
100
25
40
0
2
Pd(OH)
PtO 5 min
0 min
Pd(OH)
0 min
2
2
3
5
6
200 mbar
200 mbar
2
5 min
2
5% Pd/C20 min
type35 60 min
0
of deuterium (entry 3), significant amounts of debenzy-
lation were still observed. On switching to a partial
pressure of deuterium gas (entries 4 and 5), to reflect the
conditions under which the tritiation would be per-
formed, sufficient selectivity for the desired product
could not be achieved, even when using Type 35 5% Pd/
One such precursor was the iodobenzoic acid 8,
however, since we required a phenylacetic acid moiety,
this precursor had to be first homologated as shown in
Scheme 3. This was achieved using a two step Arndt–
Eistert rearrangement of the diazoketone 9 using silver
oxide. Following standard bromination of the toluene
compound 10 and reaction of the resulting benzyl
bromide with the secondary amine afforded the desired
aryl iodide 11. The optimized deuterium exchange
conditions of Pd(OH)2 in ethanol, initially identified for
the bromo derivative, were used and found to selectively
incorporate deuterium without any debenzylation after
2 h reaction time (100% product); after 20h reaction
time, there was around 50% debenzylation.
1
C (entry 6), which is recommended for such reactions.
Whilst the debenzylation of amines is a well-known
reaction under reductive conditions in the presence of
2
palladium we hoped that by switching to the aryl iodide
we might be able to achieve better selectivity than was
observed with the aryl bromide. Initial attempts to
synthesize the iodo compound using firstly Buchwald
exchange chemistry to convert the bromo derivative 5 to
the iodo derivative and secondly using electrophilic
iodination conditions (e.g. TFA and N-iodosuccinimide)
on the parent compound were unsuccessful. Conse-
quently, the synthesis of the iodo-derivative was under-
taken from a commercially available iodo-precursor.
Having now identified conditions which gave rise to
good deuterium incorporation and selectivity, the
reaction could be carried out with tritium in an
analogous manner. Therefore, the aryl iodide 11 was
reduced under a partial pressure of tritium gas
O
I
O
I
N
+
(35%)
O
0
Br
N
i) (COCl)2
Ag O
NBS
OH
2
O
O
ii) TMSCHN2
MeoH reflux
I
methyl formate
halogen lamp
O
I
(87%)
(80% crude)
8
9
1
R2
R1
K CO3
2
75% atom abundance
N
H
MeOH
(
40%)
R2
N
R2
R1
R1
O
~100mbar D2 EtOH
Pd(OH) rt
O
N
O
O
2H
I
2
11
Scheme 3
Copyright # 2007 John Wiley & Sons, Ltd.
J Label Compd Radiopharm 2007; 50: 558–560
DOI: 10.1002.jlcr