was obtained as a side product in both cases (entries 9 and
10). On the other hand, increasing the reaction temperature to
908C improved the conversion to 95% without any side prod-
uct formation (entry 11). Alternatively, connecting a second
identical catalyst column after the first column enabled the de-
sired product to be afforded in 98% yield even at 60 and 708C
(entry 12). Interestingly, performing the reaction under batch
conditions gave a complex mixture (entry 13). Although direct
comparison between the result in a batch system and that in
a flow system is difficult, the flow condition is the key to ach-
ieving high conversion and selectivity.
Table 1. Optimization of Flow Hydrogenation of decanenitrile (1a).
Entry
Pd
[mmol]
2nd
support
Temp.
[8C]
Time
[h]
Conv.
[%][a]
Yield
[%][a]
1[b]
2
3
4
5
6
7
8[c]
9[d]
10[e]
11
12[f]
13[g]
0.045
0.045
0.045
0.045
0.18
0.18
0.18
0.18
0.18
0.18
0.18
0.36
2.5 mol%
Al2O3
Al2O3
SiO2
C
Al2O3
SiO2
C
SiO2
SiO2
SiO2
SiO2
SiO2
SiO2
60
60
60
60
80
80
80
80
80
80
90
70–60
90
3
3
19
76
<16
73[h]
With optimized reaction conditions in hand, the substrate
scope of the reaction with respect to nitriles was investigated.
The reaction was performed for 18 h, and analyzed at 3, 6, and
18 h stages after the flow started. First, aromatic nitriles were
tested. Generally, aromatic nitriles are more easily reduced to
primary amines, which allowed the reaction temperature to be
decreased to 608C and the pressure of H2 to 50 kPa(G). Fur-
thermore, the flow rate could be increased to 0.2 mLminÀ1,
which could produce more than 40 mmol of the product for
18 h continuous-flow reaction. By using benzonitrile or m- or
p-Me substituted benzonitrile derivatives as substrates, the
products were obtained in almost quantitative yields (Table 2,
entries 1–3). A sterically demanding o-Me substituent deriva-
tive required higher H2 pressure to achieve a quantitative yield
(entry 4). Higher pressure of H2 was also required for electron-
donating p-OMe and OH-substituted derivatives (entries 5 and
6). On the other hand, electron-poor aromatic substrates pro-
duced benzylic alcohols as side products. However, changing
the solvent system to an anhydrous system completely sup-
pressed the formation of side products (entries 7–9). Heteroar-
omatic nitriles also gave corresponding amines in excellent
yields (entries 10 and 11). Interestingly, when DMPSi-Pd/Al2O3
was used as a catalyst, hydrogenation of the pyridine ring also
took place to give a complex mixture. Furthermore, a dinitrile
could be reduced to the corresponding diamine in an almost
quantitative yield (entry 12). It should be noted that, in all
cases, almost pure compounds were obtained in excellent
yields through simple evaporation of the solvent, and the
yields were stable for at least 18 h under continuous-flow
conditions.
3 (18)
3 (18)
3 (18)
3 (18)
23 (23)
80 (33)
82 (84)
89 (89)
85 (56)
86
95
92
95
99
23 (23)
80 (33)
68 (70)[i]
89 (89)
79 (49)
86
85
81
95
98
3 (18)
3
3
3
3
3
3
ND
complex
1
[a] Determined by using H NMR analysis; numbers in parenthesis are the
results after 18 h. [b] Without HCl. [c] H2 pressure=250 kPa(G). [d] Con-
centration=0.1m. [e] Flow rate=0.05 mLminÀ1. [f] Connecting a second
identical catalyst column after the first column; reaction temperature for
first column: 708C, second column: 608C. [g] Reaction was performed
under batch conditions; ND=not determined. [h] Side product, 1-decanol
was obtained in 3% yield. [i] 1-Decanol was obtained in 12 (11)% yield.
proved both the conversion and the selectivity (entry 2). Con-
sidering that amine salts are more stable than free amines and
are easily purified by recrystallization, we prepared amine salts
instead of free amines in this investigation. To improve the se-
lectivity, alternative second supports were investigated. By
using SiO2 as the second support, the primary amine salt was
obtained in 23% yield without any side products formation
(entry 3). The catalyst activity was not lost during 15 h further
reaction. On the other hand, the use of commercially available
Pd/C led to excellent reactivity and selectivity for the first 3 h;
however, after 18 h, the reactivity dropped significantly
(entry 4). For a more detailed comparison of these catalysts
with higher conversion, the loading of Pd was increased to
0.18 mmol and the reaction temperature was increased to
808C. Under these conditions, DMPSi-Pd/Al2O3 gave a slightly
improved conversion; however, a significant amount of an al-
cohol was produced and almost the same result was obtained
after 18 h (entry 5). However, by using DMPSi-Pd/SiO2 as the
catalyst, the conversion improved dramatically without any for-
mation of side products (entry 6). Pd/C also gave a good con-
version for the first 3 h; however, a non-negligible amount of
a secondary amine was produced and, moreover, the catalyst
activity was significantly diminished after 18 h (entry 7). We de-
cided to use DMPSi-Pd/SiO2 as an optimal catalyst and other
reaction conditions were examined. Increasing the H2 pressure
did not improve the conversion (entry 8). Decreasing the con-
centration and the flow rate improved the conversion to 95
and 92%, respectively. However, 10% of the secondary amine
Next, more demanding aliphatic nitriles were employed as
substrates by connecting two catalyst columns. As described
in the optimization section, two connected columns heated at
70 and 608C, respectively, were used for aliphatic substrates.
At first, primary nitriles were reduced to the corresponding
amines in excellent yields (Table 2, entries 1 and 2). More steri-
cally demanding secondary and tertiary nitriles also gave the
desired amines in excellent yields (entries 3 and 4). The low re-
action temperature means that acetonitrile (b.p. 828C) could
be employed in this reaction to afford an almost quantitative
yield (entry 5). Furthermore, an ester group is tolerant under
the conditions, giving the amino ester in EtOH/dioxane
(entry 6). Finally, by using DMPSi-Pd/Al2O3, adiponitrile was
converted into 1,6-hexamethylene diamine, which is an indus-
trially important process (entry 7).
&
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