H. Sajiki et al.
for the second H-D exchange reaction, the deuterium effi-
ciency only slightly increased to 77% (entry 4) and even the
third run also gave only an 81%-deuterated product
(entry 5). The addition of neither DCl nor AcOD had a sig-
nificant effect on the deuterium incorporation (entries 6 and
7) and the use of Na2CO3 as an additive caused a drastic de-
crease in the deuterium efficiency (entry 8). We also exam-
efficiency increased with time up to 95% (72 h) at room
temperature (entry 6). No further significant improvement
was observed even after 120 h (entry 7).
Scope and limitation of Pd/C-catalyzed H-D exchange reac-
tion at room temperature: Table 3 summarizes the results of
the H-D exchange reaction at the benzylic positions of vari-
ous substrates. For the simple alkyl benzenes, the corre-
sponding deuterated compounds were obtained with a
nearly quantitative D content (entries 1–3). On the other
hand, the use of 4-ethylbenzoic acid (4) and methyl 4-ethyl-
benzoate (5), which possess the electron-withdrawing car-
boxylic acid or corresponding methyl ester, produced a
lower deuterium efficiency (entries 4 and 5),[23b] while the
drawback was overcome by the use of the corresponding
sodium salt (6), and a nearly quantitative D content was
achieved (entry 6). The deuteration of sodium 5-phenylpen-
tanoate (7) also smoothly proceeded (entry 7). A very poor
deuterium incorporation was observed using substrates bear-
ing an amino group since the amino group should be a
strong catalyst poison of Pd/C (entries 8, 10 and 12–14, 0–
39% D contents).[28] The lower D content on the benzylic
position adjacent to the amino group of 5,6,7,8-tetrahydro-1-
naphthylamine (15) was observed (13% at C1 position)
when compared to the other benzylic position located at a
position distant from the amino group (59% at C2 position)
(entry 15). The H-D exchange efficiencies of the amine de-
rivatives were significantly enhanced in the cases of the hy-
drochlorides, of which the lone pair on the nitrogen atom
that causes the catalyst poisonous was occupied (entries 9
and 11). Furthermore, nearly no deuterium incorporation
was observed when 2-phenylethyl alcohol (16) and the cor-
responding methyl ether (17) were employed as substrates
(entries 16 and 17) although 3-phenyl-1-propanol (18) and
8-phenyl-1-octanol (19) possessing a longer side chain was
efficiently deuterated ([D]18 and [D]19 with 92 and 94% D
content, respectively, entries 18 and 19). The deuteration of
2-benzylphenol (20), the hydroxyl group and the benzylic
position located in the spatial vicinity, also gave a low D
content (29%, entry 20). The deuterium incorporation on
the branched benzylic position (methine; 21 and 22) also
proceeded without any problems (entries 21 and 22). These
reactions were very clean and no column chromatographic
separation was required to obtain the spectrally pure deuter-
ated products. It is worth noting that the reaction is totally
regioselective and virtually no competitive deuteration on
the other positions including the aromatic ring was observed
(confirmed by 2H NMR spectroscopy).
ined the effects of nBu4N(HSO4) (phase transfer catalyst),
R
sodium dodecyl sulfate (SDS, ionic surfactant) or Tritonꢁ X-
100 (nonionic surfactant), since the present H-D exchange
reaction presumably occurred in a three-phase system in
D2O (aqueous phase), diphenylmethane (1, organic phase),
and Pd/C (solid phase), as these additives could not increase
the deuterium efficiency contrary to our expectation (en-
tries 9–11). Furthermore, the increased amount of 10%
Pd/C (30 wt% of the weight of substrate 1) improved the
deuterium efficiency to 84% (entry 12), but the use of 5%
Pd/C (10 wt% of the weight of 1) significantly reduced the
efficiency (entry 13). Another heterogeneous palladium cat-
alyst, Pd/Al2O3, was ineffective for this reaction (entry 14).
The Pd/C-catalyzed H-D exchange reaction selectively pro-
ceeded at the benzylic site at room temperature; however,
the maximum D content of the desired deuterated product
([D]1) was unfortunately 84% (Table 1, entry 12). Such deu-
terium efficiency degree is presumably caused by the simul-
À
taneous reverse reaction from the generated C D bond to
À
the C H bond, since the reaction was carried out in a large
volume of H2 gas in a balloon [Eq. (2)].
Hence, the effect of the H2-gas volume toward the reac-
tion was studied in detail (Table 2). H2 gas is essential for
the H-D exchange reaction (entry 1). The reaction under
excess H2 gas (balloon, ca. 2 L, 82 mmol) gave the desired
[D]1 with a 66% D content after 24 h (entry 2), and the
elongation of the reaction time (72 h) did not significantly
increase the deuterium efficiency (entry 3). On the other
hand, the use of catalytic amounts (0.7 equiv, ca. 0.70 mmol
of H2 (17 mL) vs. 1.00 mmol of 1) of H2 gas in a hydrogen-
charged sealed test tube gave better results. The deuterium
Table 2. Assessment of Pd/C-H2-catalyzed H-D exchange reaction of di-
phenylmethane (1) in D2O.[a]
Entry
H2
t [h]
D content [%][b]
1
2
3
4
5
6
7
none[c]
balloon (ca. 2 L)
balloon (ca. 2 L)
17 mL
17 mL
17 mL
24
24
72
24
48
0
66
73
60
84
95
96
Application of heating conditions for the benzylic position
selective H-D exchange reaction: The benzylic site-selective
H-D exchange reaction required a long reaction time (72 h)
at room temperature to accomplish the quantitative deuteri-
um incorporation; indeed carboxylic acid (4), ester (5),
amine (8, 10 and 12–15), alcohol (16 and 20) and ether (17)
derivatives were not completely applicable as substrates. We
then optimized the reaction temperature of the deuteration
72
120
17 mL
[a] Unless otherwise noted, 1.0 mmol of diphenylmethane (1) was used
and the reactions were carried out under a H2 atmosphere (17 mL) using
10% Pd/C (10 wt% of the weight of 1) in D2O (0.50 mL) at room tem-
perature. [b] The D content was determined by 1H NMR. [c] The reaction
was performed under atmospheric air.
666
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Chem. Eur. J. 2008, 14, 664 – 673