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reduction determined the product ratio, selectively yielding
the corresponding alcohol side product (2B, Table 4, entry 4).
On replacing the fluorine atom on phenyl ring A by chlorine
Table 3. Selective continuous deuteration of trans-chalcone (1) with Lin-
dlar catalyst (Scheme 2).
[
a]
[
b]
[c]
[c]
Entry p [bar] T [8C] Runs
Product ratio [%]
Total conv. [%]
(
(E)-1-(2-chlorophenyl)-3-(4-methoxyphenyl)prop-2-en-1-one, 3),
1
A
1B
CF deuteration with Lindlar catalyst (under the previously set
conditions) resulted in a conversion of only 41%, and the con-
version remained below the optimum after further consecutive
1
2
3
4
5
6
70
80
90
100
100
80
20
20
20
20
60
20
1
1
1
1
1
2
86
92
90
87
68
83
14
8
10
13
32
17
95
98
99
98
97
99
[
d]
circulations (Table 4, entries 5–7). With Pt/Al O at 100 bar and
2
3
1008C, complete conversion occurred, but, unlike the cases of
trans-chalcone (1) and fluorine-substituted 2, the over-reduc-
tion to the corresponding deuterated alcohol did not go to
completion, and a 3A/3B product ratio of around 1:1 was ob-
served (Table 4, entry 8 versus Table 4, entry 4 and Table 1,
entry 10). This led us to conclude that the reactivity of the
chalcones in deuteration reactions depends strongly on the
presence and the nature of the substituents on aromatic
ring A. We next attempted the deuteration of 3 with 5% Pt/
Al O under milder conditions (100 bar and 208C) to limit the
À1
[
1
[
[
a] Reaction conditions: c
1
=1 mgmL in ethyl acetate, Lindlar catalyst,
À1
mLmin flow rate. [b] Number of circulations through the CF reactor.
c] Determined by H NMR spectroscopic analysis of the crude material.
1
d] Deuterium content=98%.
ketone/alcohol ratio of 92:8 were found; higher pressures im-
proved slightly the formation of the over-reduction product.
On increasing the temperature above 208C, over-reduction to
the subsequent alcohol occurred and the product ratio de-
creased (Table 3, entry 5). Recirculation through the CF reactor
had a similar negative effect on the product ratio (Table 3,
2
3
over-reaction. We were pleased to find that the formation of
the desired dideuteroketone (3A) was exclusive under these
conditions, and a recirculation through the reactor led to an
excellent conversion of 99% (Table 4, entries 9 and 10). CF
deuteration of (E)-1-(2-bromophenyl)-3-(4-methoxyphenyl)-
prop-2-en-1-one (4) and (E)-1-(2-iodophenyl)-3-(4-methoxyphe-
nyl)prop-2-en-1-one (5) with 5% Pt/Al O at 100 bar and 208C
À1
entry 6), and thus 80 bar, 208C, and 1 mLmin with a single
run were accepted as the optimum conditions for the CF syn-
thesis of 1A (Table 3, entry 2). The incorporation of deuterium
into the chalcone skeleton was highly selective under these
final conditions as, besides some minor alcohol formation, the
reduction of the aromatic rings was not detectable and the
deuterium content (which reflects the deuterium incorporation
ratio over incidental hydrogen addition) was as high as 98%.
Substituted antidiabetic chalcones (2–5) were next subjected
to deuteration for the selective synthesis of potentially bioac-
tive dideuterochalcones. With (E)-1-(2-fluorophenyl)-3-(4-meth-
oxyphenyl)prop-2-en-1-one as starting material (2, Scheme 2),
an excellent deuterated ketone/alcohol ratio of 97:3 and
a moderate conversion of 72%
2
3
gave similar results to those for 3. After recirculation, almost
complete conversion and exclusive dideuteroketone formation
were found (Table 4, entries 11, 12, 14, and 15). Interestingly,
on increase of the reaction temperature to 1008C, no over-re-
duction occurred, and the desired substituted dideuterochal-
cones could be isolated exclusively in quantitative conversions
within a single run (Table 4, entries 13 and 16).
To understand the differences between the reactivities of
the various chalcone derivatives, the atomic radii of the halo-
gen substituents should be taken into consideration. In the
were obtained with Lindlar cata-
[
a]
lyst under the previously opti-
Table 4. Selective continuous deuteration of various halogen-containing chalcones (2–5, Scheme 2).
mized
reaction
conditions
[
b]
[c]
[c]
À1
Entry Starting material Catalyst
p [bar] T [8C] Runs
Product ratio [%]
Total conv. [%]
(80 bar, 208C, 1 mLmin within
A
B
a single run; Table 4, entry 1).
The conversion was readily im-
proved by increasing the
number of discrete runs
through the instrument, at the
expense of a negligibly small
decrease in product selectivity
1
2
3
4
5
6
7
8
9
1
2
2
2
2
3
3
3
3
3
3
4
4
4
5
5
5
Lindlar catalyst
Lindlar catalyst
Lindlar catalyst
80
80
80
100
80
80
20
20
20
100
20
20
20
100
20
20
20
20
100
20
20
100
1
2
3
1
1
2
3
1
1
2
1
2
1
1
2
1
97
96
95
5
97
99
100
52
100
100
100
100
100
100
100
100
3
4
5
95
3
1
0
48
0
0
0
72
82
92
97
41
47
60
100
90
99
92
98
100
93
98
5% Pt/Al
2
O
3
Lindlar catalyst
Lindlar catalyst
Lindlar catalyst
80
5% Pt/Al
5% Pt/Al
5% Pt/Al
5% Pt/Al
5% Pt/Al
5% Pt/Al
5% Pt/Al
5% Pt/Al
5% Pt/Al
2
O
2
O
2
O
2
O
2
O
2
O
2
O
2
O
2
O
3
3
3
3
3
3
3
3
3
100
100
100
100
100
100
100
100
100
(Table 4, entries 2 and 3). The
0
best results were achieved after
three consecutive circulations,
with a conversion of 92% and
an excellent selectivity towards
1
1
1
1
2
3
0
0
0
0
14
1
1
5
6
2
A (Table 4, entry 3). Similarly
0
100
as for the unsubstituted model
À1
À1
[a] Reaction conditions: c=1 mgmL in ethyl acetate, 1 mLmin flow rate. The deuterium content was
compound, with 5% Pt/Al O3
2
1
ꢀ
97% in each experiment. [b] Number of circulations through the CF reactor. [c] Determined by H NMR spec-
under harsh reaction conditions
troscopic analysis of the crude material.
(100 bar and 1008C), the over-
&
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4
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