Systematic evaluation of the palladium-catalyzed hydrogenation under flow conditions

Article abstract of DOI:10.1016/j.tet.2014.05.038

Four types of heterogeneous Pd catalysts (10% Pd/C, 10% Pd/HP20, 0.5% Pd/MS3A, and 0.3% Pd/BN) were applied to the flow hydrogenation to systematically evaluate the appropriate conditions for the reduction of a wide variety of reducible functionalities. The use of 10% Pd/C and 10% Pd/HP20 allowed the hydrogenation of various reducible functionalities by a single-pass of the substrate-MeOH solution through the catalyst cartridge, while 0.5% Pd/MS3A and 0.3% Pd/BN catalyzed a novel chemoselective hydrogenation; only alkene, alkyne, azide, and nitro functionalities could be reduced with other coexisting reducible functionalities intact.

Full text of DOI:10.1016/j.tet.2014.05.038

Tetrahedron 70 (2014) 4790e4798
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Systematic evaluation of the palladium-catalyzed hydrogenation
under flow conditions
*
Tomohiro Hattori, Aya Tsubone, Yoshinari Sawama, Yasunari Monguchi ,
*
Hironao Sajiki
Laboratory of Organic Chemistry, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu 501-1196, Japan
a r t i c l e i n f o
a b s t r a c t
Article history:
Four types of heterogeneous Pd catalysts (10% Pd/C, 10% Pd/HP20, 0.5% Pd/MS3A, and 0.3% Pd/BN) were
applied to the flow hydrogenation to systematically evaluate the appropriate conditions for the reduction
of a wide variety of reducible functionalities. The use of 10% Pd/C and 10% Pd/HP20 allowed the hy-
drogenation of various reducible functionalities by a single-pass of the substrateeMeOH solution
through the catalyst cartridge, while 0.5% Pd/MS3A and 0.3% Pd/BN catalyzed a novel chemoselective
hydrogenation; only alkene, alkyne, azide, and nitro functionalities could be reduced with other coex-
isting reducible functionalities intact.
Received 3 March 2014
Received in revised form 7 May 2014
Accepted 8 May 2014
Available online 21 May 2014
Keywords:
Chemoselectivity
Flow conditions
Hydrogenation
Palladium
Ó 2014 Elsevier Ltd. All rights reserved.
Supported catalysts
1. Introduction
liquid (or length of catalyst cartridge), reaction temperature, and
hydrogen pressure.
The continuous flow system for hydrogenation is a technology
that significantly achieves high reaction efficiency compared to the
batch (non-flow) system in a flask or reaction vessel, etc., by the
secure communication of hydrogen gas and the substrate solution
We have recently developed a variety of palladium catalysts
immobilized on macromolecules, such as a synthetic adsorbent
4
5
(DIAION HP20), molecular sieves (MS3A and MS5A), and boron
6
nitride (BN). The catalyst activity of 10% Pd/HP20, 0.5% Pd/MS3A,
1,2
with a solid catalyst inserted in a narrow channel. The catalyst,
which is generally packed in a cartridge, can be reused without its
replacement by a new one after each reaction. The danger of the
ignition of flammable catalysts could also be avoided because of no
contact with air. Furthermore, a simple concentration of the
resulting solution (reaction mixture), which is passed through the
catalyst, is only required to obtain the desired product. Therefore,
the continuous flow hydrogenation using solid catalysts has drawn
a great deal of attention in the synthetic organic chemistry com-
munity over the past decade from practical points of view.1e3
The hydrogenation reactions using a variety of supported cata-
lysts under continuous flow conditions have been applied for the
reduction of various reducible functionalities.1,2 However, no sys-
tematic evaluation of each catalyst for the hydrogenation of the
functionalities based on optimization of the reaction conditions has
ever been investigated due to a lot of variable parameters, such as
solvent, concentration of the substrate solution, flow rate of the
and 0.3% Pd/BN for the hydrogenation under batch conditions was
found to be significantly dependent on the characteristic features of
the supports; i.e., 10% Pd/HP20 has a strong catalyst activity com-
parable to 10% Pd/C, while 0.5% Pd/MS3A and 0.3% Pd/BN were
useful for the chemoselective hydrogenation of alkynes, alkenes,
and azides, while leaving the other functionalities including nitro
groups intact. The chemoselectivity of 0.5% Pd/MS3A is achieved by
the partial suppression of palladium catalyst activity based on the
chemical properties of MS3A, such as a coordination ability of ox-
ygen atoms on the surface of the support (MS3A) to the palladium
metal. The specific catalyst activity of 0.5% Pd/BN would be attrib-
uted to the moderate interaction of palladium metal with BN sur-
face by the conjugation effect between unoccupied orbital of boron
7
atoms and nitrogen lone pairs of BN. In this paper, we report
a systematic study of the hydrogenation of a variety of reducible
functional groups using 10% Pd/C, 10% Pd/HP20, 0.5% Pd/MS3A, and
0.3% Pd/BN as catalysts under continuous flow reaction conditions
Ò
using a flow hydrogenation reactor, H-Cube (ThalesNano Nano-
technology, Inc.) that can control the temperature and hydrogen
pressure up to 100 C and 100 bar, respectively.
*
Corresponding authors. Tel./fax: þ81 58 230 8109; e-mail addresses: mon-
ꢀ
guchi@gifu-pu.ac.jp (Y. Monguchi), sajiki@gifu-pu.ac.jp (H. Sajiki).
0
040-4020/$ e see front matter Ó 2014 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2014.05.038

T. Hattori et al. / Tetrahedron 70 (2014) 4790e4798
4791
2
. Results and discussion
We next investigated the catalyst activity of the 10% Pd/C (Cat-
alyst A) and 10% Pd/HP20 (Catalyst B) for the hydrogenation of
various reducible functionalities in MeOH under continuous and
We first investigated the solvent effect of the 10% Pd/C-catalyzed
hydrogenation of benzophenone (1, 1 mmol) at a concentration of
.05 M and flow rate of 1 mL/min under 1 bar hydrogen (Table 1).
The reactions in MeOH, EtOH, cyclopentyl methyl ether (CPME),
single-pass flow reaction conditions (1 mL/min) (Table 2). The
1
0
resulting reaction solution was concentrated in vacuo and its
H
NMR was measured to determine the product ratio. As the reaction
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
cyclohexane, and EtOAc were carried out at 25 C, 50 C, 75 C, and
was incomplete at 25 C, the temperature was raised to 50 C, 75 C,
ꢀ
ꢀ
1
00 C in a single-pass manner, in which a substrate solution passes
and 100 C. When the reaction was still incomplete, the hydrogen
through the catalyst cartridge (ca. 0.3 mL inside volume) only once
the transit time of the reaction solution in the cartridge was ca.
5 s; entries 1e8). MeOH was found to be the most appropriate
pressure was then increased to 50 or 80 bar, and the reaction was
ꢀ
ꢀ
ꢀ
ꢀ
(
1
monitored again at 25 C, 50 C, 75 C, and 100 C under each hy-
drogen pressure. Alkynes (Table 2, entries 1, 2 and 27e30), alkenes
(entries 3, 4 and 23e26), azides (entries 5e10), nitro groups (en-
tries 11e14), and aromatic carbonyl groups (entries 15e22) were
readily hydrogenated to the corresponding reduced products at
solvent, and diphenylmethane (3) was obtained as the sole product
via hydrogenolysis of the intermediary diphenylmethanol (2) at
ꢀ
5
0
C (entry 2) under ordinary pressure. The increase in the sub-
ꢀ
strate concentration to 0.1 M and higher markedly reduced the
conversion ratio of 1 (entries 2 vs 9 and 10). Therefore, the fol-
lowing investigation was performed in MeOH as the solvent at the
substrate concentration of 0.05 M.
25 C or by a minor tuning of the temperature in some instances.
When benzaldehyde was used as a substrate (entries 15e18), the
corresponding benzyl alcohol was selectively obtained as a single
product, and further hydrogenolysis to form the toluene derivative
never took place (entries 16 and 18). The hydrogenation has been
generally employed for the efficient removal of the protecting
groups, such as the benzyl ether for alcohols, benzyl ester for car-
boxylic acids, and benzylcarbamate (N-Cbz) for amines. Therefore,
the development of quick and reliable deprotection methods is
demanded. When 10% Pd/C was used as a catalyst for the reduction
Table 1
Solvent effect on hydrogenation of the benzophenone under the flow conditions
ꢀ
of benzyl cinnamate at 25 C under 1 bar hydrogen gas, only the
alkene moiety was selectively hydrogenated without the hydro-
genolysis of the benzyl ester (Entry 23), while the selectivity could
not be achieved by the use of 10% Pd/HP20, which led to the for-
mation of a mixture with dihydrocinnamic acid by the partial re-
moval of the benzyl group (entry 25). The benzyl ester was
completely cleaved with an increase in temperature using either
ꢀ
Ratio 1:2:3a
Entry
Solvent
Temp ( C)
Concentration (M)
1
2
3
4
5
6
7
8
9
MeOH
MeOH
EtOH
EtOH
CPME
25
50
25
100
25
100
100
100
50
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.1
2:16:82
0:0:100
25:64:11
3:9:88
100:0:0
91:1:8
ꢀ
ꢀ
10% Pd/C (100 C) or 10% Pd/HP20 (50 C) as a catalyst (entries 24
and 26). Although the 10% Pd/C-catalyzed chemoselective hydro-
genation of the alkyne moiety of N-Cbz-4-ethynylaniline was dif-
ficult to achieve even under ordinary temperature and pressure
(entry 27), 10% Pd/HP20 smoothly and selectively catalyzed the
CPME
Cyclohexane
EtOAc
MeOH
MeOH
98:0:2
100:0:0
55:0:45
88:0:12
10
50
0.5
ꢀ
a
reaction at 25 C under 1 bar hydrogen pressure to give N-Cbz-4-
Determined by GCeMS. CPME: cyclopentyl methyl ether.
ethylaniline probably due to the slightly low catalyst activity for
Table 2
Scope of substrate catalyzed by 10% Pd/C or Pd/HP20
ꢀ
Ratioa
Yield (%)b
100
Entry
1
Substrate
Catalyst
H
2
pressure (bar) Temp ( C)
Product
A
1
1
25
25
d
2
3
B
A
d
d
100
88
1
1
1
25
25
25
4
5
B
A
d
d
84
79
6
B
1
25
d
79
(
continued on next page)

4792
T. Hattori et al. / Tetrahedron 70 (2014) 4790e4798
Table 2 (continued )
ꢀ
Ratioa
Yield (%)b
Entry
Substrate
Catalyst
H
2
pressure (bar) Temp ( C)
Product
7
8
9
A
A
B
B
1
1
1
1
75
100
75
Trace: >99
d
90
d
88
d
11:89
d
1
0
1
100
1
A
A
B
B
A
1
1
1
1
1
25
50
77:28
d
78
d
76
d
1
1
1
1
2
3
4
5
d
75
13:87
100
100
d
43:57
1
1
6
7
A
B
50
1
75
d
77
100
65:35
d
1
1
8
9
B
A
50
1
50
25
d
87
2:16:82
d
2
2
2
0
1
2
A
B
B
1
1
1
50
50
d
98
d
95
53:47
d
100
2
2
2
2
3
4
5
6
A
A
B
B
1
1
1
1
25
100
25
d
100
100
d
d
11:89
d
50
100
27
A
1
25
16:53:31
d

T. Hattori et al. / Tetrahedron 70 (2014) 4790e4798
4793
Table 2 (continued )
Entry Substrate
ꢀ
Ratioa
Yield (%)b
Catalyst
H
2
pressure (bar) Temp ( C)
Product
28
29
30
A
1
1
75
25
75
d
100
78
B
B
d
d
50
81
3
3
3
1
A
B
B
50
50
50
100
100
100
d
100
d
2
12:88
d
3c
99
3
3
4
5
A
B
1
1
50
50
d
d
100
100
3
3
3
3
6
7
8
9
A
A
B
A
50
80
80
1
100
100
100
25
48:52
d
d
81
84
94
d
d
40
B
1
25
d
100
4
1
2
A
B
80
80
100
100
No reaction
No reaction
d
d
100d
100d
4
a
b
c
Determined by 1H NMR.
Isolated yield.
The reaction was carried out at flow rate of 0.5 mL/min.
d
Yield of the recovered starting material.
the hydrogenolysis of the N-Cbz group compared to 10% Pd/C (Entry
9). An increase in hydrogen pressure to 50 bar was required for the
complete removal of the N-Cbz protecting group using the 10% Pd/
product (entries 39 and 40). On the other hand, the aromatic cyano
functionality was never reduced by the present flow hydrogenation
even under 80 bar hydrogen pressure (entries 41 and 42).
Based on these results, both 10% Pd/C and 10% Pd/HP20 were
found to possess an approximate and strong catalytic activity for
the flow hydrogenation. It is noteworthy that the distinct chemo-
selective hydrogenation leaving the benzyl alcohol, benzyl ester or
N-Cbz group intact could be achieved by the selection of the cata-
lyst or simply tuning the reaction temperature or hydrogen
pressure.
The use of 0.5% Pd/MS3A and 0.3% Pd/BN, which have been
developed as chemoselective hydrogenation catalysts under the
batch reaction conditions, was next investigated to anticipate the
appearance of the novel chemoselectivity based on the enhanced
reactivity under the flow hydrogenation conditions (Table 3). Al-
kyne, alkene, and aromatic azide functionalities were smoothly
hydrogenated by a single-pass over each catalyst under 1 bar
2
HP20 (entry 30), while the same result was obtained by just in-
ꢀ
creasing the temperature to 75 C under 1 bar hydrogen pressure by
the 10% Pd/C-catalyzed hydrogenation (entry 28). Similarly, ali-
phatic N-Cbz group could also be removed using 10% Pd/C under
5
0 bar hydrogen pressure (entry 31), while a minor tuning of the
flow rate of the substrate solution was required for the complete
conversion in the case of 10% Pd/HP20 (entries 32 and 33). The aryl
benzyl ether underwent hydrogenolysis to the corresponding al-
cohol by each catalyst (entries 34 and 35). Although aliphatic
benzyl ether was comparatively tolerant under the present single-
pass flow conditions (entry 36), its hydrogenolysis was achieved at
ꢀ
1
00 C under 80 bar hydrogen pressure (entries 37 and 38). The
hydrogenation of styrene oxide readily and regioselectively pro-
ceeded at room temperature to afford phenethyl alcohol as the sole

4794
T. Hattori et al. / Tetrahedron 70 (2014) 4790e4798
Table 3
Scope of substrate catalyzed by 0.5% Pd/MS3A or 0.3% Pd/BN
ꢀ
Ratioa
Yield (%)b
Entry
Substrate
Catalyst
H
2
pressure (bar)
Temp ( C)
Product
1
2
C
1
1
25
25
d
d
97
99
D
3
4
5
C
D
C
1
1
1
25
25
25
d
d
d
91
89
78
6
7
D
C
1
1
25
d
76
100
20:80
d
8
9
C
50
1
100
100
50
d
76
d
90
D
D
33:67
1
0
50
d
1
1
1
2
C
1
1
75
25
d
d
77
93
D
13
C
1
50
d
90
1
1
4
5
D
C
1
25
25
d
94
50
25:75
d

T. Hattori et al. / Tetrahedron 70 (2014) 4790e4798
4795
Table 3 (continued )
ꢀ
Ratioa
Yield (%)b
Entry
Substrate
Catalyst
H
2
pressure (bar)
Temp ( C)
Product
1
1
1
1
6
7
8
9
C
50
50
50
1
50
d
86
D
D
C
75
29:71
d
d
100
100
89
No reaction
No reaction
d
100c
2
2
0
1
D
C
1
1
100
100
d
d
100c
78
2
2
2
2
3
4
D
D
D
1
1
25
90:10
42:58
21:89
d
d
d
100
100
50
2
2
2
2
2
5
6
7
8
9
C
C
D
D
C
1
50
1
100
100
100
100
100
23:77
d
d
100
11:89
d
50
1
100
No reaction
No reaction
No reaction
No reaction
No reaction
No reaction
d
100c
3
3
3
3
3
0
1
2
3
4
D
C
1
100
100
100
100
100
d
d
d
d
d
100c
100c
100c
90c
50
50
80
80
D
C
D
88c
a
b
c
Determined by 1H NMR.
Isolated yield.
Yield of the recovered starting material.
ꢀ
hydrogen at 25 C (entries 1e14 and 21e28), while the increased
hydrogen pressure was required for the completion of hydrogena-
tion of aliphatic azide (entries 15e18). Interestingly, the hydroge-
nation of the aromatic nitro group, which never proceeds under
benzyl ether protecting groups was also examined. When 0.5% Pd/
MS3A was used as a catalyst, these protecting groups were tolerant
under the hydrogenation conditions (entries 21, 25, 26, 29, 31, and
33), and either the alkyne or alkene functionality was selectively
hydrogenated by controlling the reaction temperature or hydrogen
pressure (entries 21 and 26). 0.3% Pd/BN also showed a catalyst
activity similar to the 0.5% Pd/MS3A for the hydrogenolysis of
benzyl ester (entries 27 and 28), benzyl ether (entries 30 and 34),
and aliphatic N-Cbz group (entry 32), although the deprotection of
the N-Cbz protecting group of 4-ethynylaniline (aromatic N-Cbz
group) partially occurred (entries 22e24) even under ordinary
pressure and temperature (entry 22).
0
.5% Pd/MS3A and 0.3% Pd/BN-catalyzed batch hydrogenation
conditions, was completed by adjusting the hydrogen pressure and
temperature (entries 7e12). The scope of the expansion of re-
ducible functional groups would occur from the increased re-
activity due to the secure contact of the substrate with hydrogen
and the catalyst inside the narrow flow line. The aromatic aldehyde
5
,6
ꢀ
never underwent the hydrogenation even at 100 C (entries 19 and
2
0). The selective hydrogenation of the azido group was achieved
leaving a carbonyl functionality on the aromatic ring untouched
entries 13 and 14). The deprotection of the N-Cbz, benzyl ester, and
Fig. 1 shows that the catalyst activity of 10% Pd/C, 10% Pd/HP20,
0.5% Pd/MS3A, and 0.3% Pd/BN for the hydrogenation of various
(

4796
T. Hattori et al. / Tetrahedron 70 (2014) 4790e4798
Fig. 1. Catalyst activities of 10% Pd/C, 10% Pd/HP20, 0.5% Pd/MS3A, and 0.3% Pd/BN under batch and flow conditions.
reducible functionalities under the batch and flow conditions. The
functionalities inside the framework of each catalyst in the figure
could be reduced by the hydrogenation using the corresponding
catalyst. 10% Pd/C and 10% Pd/HP20 were so active under flow
conditions as well as batch conditions that a wide range of func-
tionalities could be completely reduced in the single-pass manner.
On the other hand, 0.5% Pd/MS3A and 0.3% Pd/BN could function as
the chemoselective hydrogenation catalysts even under the flow
Therefore, the present flow method does not require any purifica-
tion of products to remove the residual palladium species. Fur-
thermore, the catalysts inside the cartridge should be quite stable,
and these features should meet the demands for the industrial
9
applications.
3. Conclusion
8
conditions, and the framework of the reducible functionalities was
expanded to the nitro groups due to the effective flow reaction
system.
We have established a general hydrogenation method of a vari-
ety of reducible functionalities using four different types of het-
erogeneous Pd catalysts under continuous and single-pass flow
reaction conditions by the systematic study of various parameters.
When 10% Pd/C or 10% Pd/HP20 was used as a catalyst, the hy-
drogenation of various reducible functionalities was completed just
within approximately 15 s during the single-pass process through
the catalyst cartridge (ca. 0.3 mL inside volume and 1 mL/min flow
rate). Novel chemoselectivities under 0.5% Pd/MS3A or 0.3% Pd/BN-
catalyzed hydrogenation conditions were also achieved. Namely,
nitro groups, which were tolerant under batch hydrogenation
conditions, could be reduced to the corresponding amines under
the present flow system. Thus, alkyne, alkene, azide, and nitro
functionalities could be reduced in the presence of aromatic car-
bonyl and benzyl ester functionalities. In addition, the catalyst ac-
tivities have continued throughout the repeated use of all four
catalysts packed in a cartridge (30 mm long-cartridge, ca. 0.3 mL
volume) without replacement over the course of the last one-and-
a half years since the Pd metal never leached out during the re-
action. 10% Pd/C and 10% Pd/HP20-packed cartridges have espe-
cially been reused at least 100 times. The procedure for the
isolation of products is very simple; thus, only a simple concen-
tration of the reaction mixture is required. The present study could
provide the appropriate and standard reaction conditions for the
flow hydrogenation of various reducible functionalities, and pro-
vide a direction for its good practical application.
The high stability of the active palladium species on the re-
spective supports is one of the great advantages of using a hetero-
geneous catalyst, because there is no requirement for the
troublesome removal procedure of metal residue from the reaction
mixture. We then determined the leaching of the palladium species
each from 10% Pd/C, 10% Pd/HP20, 0.5% Pd/MS3A, and 0.3% Pd/BN
on a 10 mmol reaction scale (Tables 4 and 5). All reactions pro-
ceeded in the same manner as on the 1 mmol scale, as described
above in Tables 2 and 3, and the palladium leaching was never
detected in the resulting reaction solution by inductively coupled
plasma-atomic emission spectrometry (ICP-AES) (<1 ppm).
Table 4
Scale-up and leaching tests for 10% Pd/C and 10% Pd/HP20-catalyzed flow
hydrogenation
Entry
Catalyst
Ratio 1:2a
Leaching
1
2
10% Pd/C
10% Pd/HP20
0:100
57:43
<1 ppm
<1 ppm
a
Determined by 1H NMR.
4. Experimental section
Table 5
Scale-up and leaching tests for 0.5% Pd/MS3A and 0.3% Pd/BN-catalyzed flow
hydrogenation
4.1. General
All reagentsandsolvents were obtainedfromcommercial sources
and used without further purification. 10% Pd/C (dry type) was ob-
1
tained from N.E. Chemcat Co. (Japan). H NMR spectra were mea-
sured by a JEOL JMN AL-400 spectrometer (400 MHz) using CDCl
CD OD as the solvent. Chemical shifts ( ) were expressed in parts per
million and internally referenced (0.00 ppm for tetramethylsilane/
CDCl or 3.30 ppmfor CD OD). Mass spectra (EI)were taken on a JEOL
3
or
3
d
Entry
Catalyst
Yield (%)a
Leaching
1
2
0.5% Pd/MS3A
0.3% Pd/BN
100
100
<1 ppm
<1 ppm
3
3
JMS Q1000GC Mk II Quad GC/MS. All products are known com-
a
Determined by 1H NMR.
1
pounds. The H NMR spectra of the products were identical with

T. Hattori et al. / Tetrahedron 70 (2014) 4790e4798
4797
1
those of the corresponding authentic samples from commercial
sources or those in the literature, see Supplementary data.
22) from benzophenone (182 mg, 1 mmol). H NMR
d
þ
(CDCl
3
) 4.00
(2H, s), 7.23e7.31 (10H, m); MS (EI) m/z (%) 168 (M , 100).
4
.3.8. 3-Phenylpropionic acid benzyl ester (Table 2, entry 23; Table 3,
4
.2. Typical procedure for the palladium-catalyzed hydroge-
5
b
entries 26 and 28). Obtained (240 mg, 100% for Table 2, entry 23;
nation under the flow conditions (Tables 2 and 3)
2
2
d
40 mg, 100% for Table 3, entry 26; 239 mg, 100% for Table 3, entry
1
8) from cinnamic acid benzyl ester (238 mg, 1 mmol). H NMR
A solution of the substrates possessing reducible functional
groups (1 mmol) within the molecule in MeOH (20 mL) was flowed
at 1 mL/min into the catalyst-packed cartridge (10% Pd/C, 10% Pd/
HP20, 0.5% Pd/MS3A, or 0.3% Pd/BN; 30 mm long-cartridge, ca.
(CDCl
3
) 2.63 (2H, t, J¼7.8 Hz), 2.93 (2H, t, J¼7.8 Hz), 5.01 (2H, s),
þ
7.13e7.32 (10H, m); MS (EI) m/z (%) 240 (M , 10), 180 (36), 91 (100).
4
2
.3.9. 3-Phenylpropionic acid (Table 2, entries 24 and
0
.3 mL volume) under 1, 50, or 80 bar hydrogen gas at 25, 50, 75, or
5
b
6) . Obtained (150 mg, 100% for Table 2, entry 24; 150 mg, 100%
ꢀ
Ò
1
00 C using H-Cube (ThalesNano Nanotechnology Inc.). Catalyst
cartridges were filled with 10% Pd/C (99.4 mg), 10% Pd/HP20
101.4 mg), 0.5% Pd/MS3A (99.6 mg), and 0.3% Pd/BN (99.7 mg). The
for Table 2, entry 26) from cinnamic acid benzyl ester (238 mg,
1
1
mmol). H NMR
d
(CDCl
3
) 2.69 (2H, t, J¼8.0 Hz), 2.98 (2H, t,
(
þ
J¼8.0 Hz), 7.21e7.33 (5H, m); MS (EI) m/z (%) 150 (M , 18), 104
reaction mixture was passed through the catalyst cartridge once
and MeOH (the carrier solvent) was concentrated in vacuo to give
an analytically pure product. The obtained product was identified
(100).
4
.3.10. 4-Ethylaniline (Table 2, entries 28 and 30).5b Obtained
1
by H NMR measurement.
(121 mg, 100% for Table 2, entry 28; 98 mg, 81% for Table 2, entry
1
3
3
0) from 4-ethynylaniline (117 mg, 1 mmol). H NMR d (CDCl ) 1.10
4
.3. Spectral data of products
(3H, t, J¼8.0), 2.45 (2H, q, J¼8.0), 3.42 (2H, br s), 6.51 (2H, d, J¼8.0),
þ
6
.89 (2H, d, J¼8.0); MS (EI) m/z (%) 121 (M , 35), 106 (100).
4
2
.3.1. Bibenzyl (Table 2, entries 1 and 2; Table 3, entries 1 and
). Obtained (182 mg, 100% for Table 2, entry 1; 182 mg, 100% for
5
b
4.3.11. N-Cbz-4-ethylaniline (Table 2, entry 29; Table 3, entry
5
b
Table 2, entry 2; 177 mg, 97% for Table 3, entry 1; 180 mg, 99% for
Table 3, entry 2) from diphenylacetylene (178 mg, 1 mmol). H NMR
d
21). Obtained (255 mg, 100% for Table 2, entry 29; 199 mg, 78%
1
1
for Table 3, entry 21) from 4-ethynylaniline (117 mg, 1 mmol). H
þ
(CDCl
3
) 2.93 (4H, s), 7.19e7.31 (10H, m); MS (EI) m/z (%) 182 (M ,
NMR
d
(CDCl
3
) 1.20 (3H, t, J¼7.6 Hz), 2.59 (2H, q, J¼7.6 Hz), 5.18 (2H,
21), 91 (100).
s), 6.68 (1H, br s), 7.1 (2H, d, J¼8.4 Hz), 7.24e7.40 (7H, m); MS (EI) m/
z (%) 147 (4-EtPheN]C]O, 100). Molecular ion peak was not lo-
cated in the mass spectrum.
4.3.2. 1, 2-Dimethoxy-4-propylbenzene (Table 2, entries 3 and 4;
5
b
Table 3, entries 3 and 4). Obtained (158 mg, 88% for Table 2, entry
; 151 mg, 84% for Table 2, entry 4; 164 mg, 91% for Table 3, entry 3;
60 mg, 89% for Table 3, entry 4) from 1,2-dimethoxy-4-
3
1
4.3.12. 1-Decylamine (Table 2, entries 31 and 33).15 Obtained
(157 mg, 100% for Table 2, entry 31; 155 mg, 99% for Table 2, entry
1
1
propenylbenzene (178 mg, 1 mmol). H NMR
d
(CDCl
3
) 0.93 (3H, t,
33) from N-(benzyloxycarbonyl)decylamine (291 mg, 1 mmol). H
J¼7.6 Hz), 1.59e1.65 (2H, m), 2.52 (2H, t, J¼7.8 Hz), 3.83 (3H, s), 3.85
NMR
d
(CDCl
3
) 0.88 (3H, t, J¼6.4 Hz), 1.27e1.32 (16H, m), 1.48 (2H,
þ
þ
(
3H, s), 6.70e6.78 (3H, m); MS (EI) m/z (%) 180 (M , 53), 151 (100).
s), 2.70 (2H, d, J¼7.2 Hz); MS (EI) m/z (%) 62 (M , 42), 31 (100).
4
.3.3. Ethyl 4-Aminobenzoate (Table 2, entries 5 and 6; Table 3, en-
4.3.13. Hydroquinone (Table 2, entries 34 and 35).16 Obtained
10
tries 5 and 6). Obtained (130 mg, 79% for Table 2, entry 5; 130 mg,
9% for Table 2, entry 6; 129 mg, 78% for Table 3, entry 5; 125 mg,
6% for Table 3, entry 6) from ethyl 4-azidobenzoate (191 mg,
(110 mg, 100% for Table 2, entry 34; 110 mg, 100% for Table 2, entry
1
7
7
1
4
35) from 4-(benzyloxy)phenol (200 mg, 1 mmol). H NMR
þ
d
(CD
3
OD) 6.61 (4H, s),; MS (EI) m/z (%) 108 [(Mꢁ2) , 100]. The MS
1
mmol). H NMR
d
(CDCl
3
) 1.37 (3H, t, J¼6.9 Hz), 4.05 (2H, br s),
spectrum of the product was identical with that of the authentic
sample obtained from commercial source (TCI), although molecular
ion peak was not located.
.33 (2H, q, J¼6.9 Hz), 6.65 (2H, d, J¼8.6 Hz), 7.87 (2H, d, J¼8.6 Hz);
þ
MS (EI) m/z (%) 165 (M , 42), 120 (100).
4
.3.4. Phenethylamine (Table 2, entries 8 and 10; Table 3, entries 16
4.3.14. Ethylene glycol (Table 2, entries 37 and 38).17 Obtained
11
and 18). Obtained (109 mg, 90% for Table 2, entry 8; 107 mg, 88% for
Table 2, entry 10; 104 mg, 86% for Table 3, entry 16; 108 mg, 89% for
Table 3, entry 18) from 2-phenylethylazide (147 mg,1 mmol). H NMR
(50.3 mg, 81% for Table 2, entry 37; 52.1 mg, 84% for Table 2, entry 38)
1
from 1,2-bis(benzyloxy)ethane (242 mg, 1 mmol). H NMR
d
3
(CDCl )
1
þ
2.01 (2H, br s), 3.74 (4H, s); MS (EI) m/z (%) 62 (M , 42), 31 (100).
d
(CDCl
3
) 1.31 (2H, br s), 2.75 (2H, t, J¼7.0 Hz), 2.97 (2H, t, J¼7.0 Hz),
þ
4.3.15. Phenethyl alcohol (Table 2, entries 39 and 40).18 Obtained
115 mg, 94% for Table 2, entry 39; 122 mg, 100% for Table 2, entry
40) from styrene oxide (31.8 mL, 1 mmol). H NMR d (CDCl ) 2.10
3
7
.19e7.22 (3H, m) 7.30 (2H, m); MS (EI) m/z (%) 121 (M ,12), 30 (100).
(
.3.5. 2, 6-Xylidine (Table 2, entries 12 and 14).12 Obtained
1
4
(
1
94.0 mg, 78% for Table 2, entry 12; 92.0 mg, 76% for Table 2, entry
4) from 2, 6-dimethylnitrobenzene (151 mg, 1 mmol). H NMR
(1H, s), 2.83 (2H, t, J¼6.8 Hz), 3.80 (2H, t, J¼6.8 Hz), 7.19e7.31 (5H,
1
þ
m); MS (EI) m/z (%) 122 (M , 11), 91 (100).
d
(CDCl
3
) 2.18 (6H, s), 3.56 (2H, br s), 6.63 (1H, t, J¼8.0 Hz), 6.94 (2H,
þ
d, J¼8.0 Hz); MS (EI) m/z (%) 121 (M , 100).
4.3.16. 2-Methyl-1,4-phenylenediamine (Table 3, entries
8
and
5
b
10). Obtained (93 mg, 76% for Table 3, entry 8; 110 mg, 90% for
4
.3.6. Anisalchol (Table 2, entries 16 and 18).13 Obtained (106 mg,
Table 3, entry 10) from 2-azido-5-nitrotoluene (178 mg,1 mmol). H
1
7
9% for Table 2, entry 16; 120 mg, 87% for Table 2, entry 18) from
NMR
d
(CDCl
3
) 2.12 (3H, s), 3.26 (4H, br s), 6.45e6.55 (3H, m); MS
1
þ
p-anisaldehyde (121
mL, 1 mmol). H NMR
d
(CDCl
3
) 3.78 (3H, s),
(EI) m/z (%) 122 (M , 100).
4
.58 (2H, s), 6.88 (2H, d, J¼8.8 Hz), 7.23 (2H d, J¼8.8 Hz); MS (EI) m/z
þ
(
%) 138 (M , 66), 77 (100).
4.3.17. 3-(4-Aminophenyl)propan-1-ol (Table 3, entries 11 and
19
1
2). Obtained (116 mg, 77% for Table 3, entry 11; 140 mg, 93% for
4
.3.7. Diphenylmethane (Table 2, entries 20 and 22).14 Obtained
Table 3, entry 12) from 4-nitrocinnamyl alcohol (179 mg, 1 mmol).
1
(
165 mg, 90% for Table 2, entry 20; 160 mg, 95% for Table 2, entry
H NMR
d
(CDCl
3
) 1.82 (2H, m), 2.57 (2H, t, J¼7.2), 2.93 (2H, br s),

4798
T. Hattori et al. / Tetrahedron 70 (2014) 4790e4798
3
.62 (2H, t, J¼6.6 Hz), 6.62 (2H, d, J¼8.6 Hz), 6.98 (2H, d, J¼8.6 Hz);
2. For the general study for the heterogeneous flow hydrogenation: (a) Sachse, A.;
Linares, N.; Barbaro, P.; Fajula, F.; Galarneau, A. Dalton Trans. 2013, 42,
þ
MS (EI) m/z (%) 151 (M , 13), 106 (100).
1378e1384; (b) Linares, N.; Hartmann, S.; Galarneau, A.; Barbaro, P. ACS Catal.
2
012, 2, 2194e2198; (c) O’Brien, M.; Taylor, N.; Polyzos, A.; Baxendale, I. R.; Ley,
4
.3.18. 4-Aminobenzophenone (Table 3, entries 13 and 14).5b
S. V. Chem. Sci. 2011, 2, 1250e1257; (d) Oyamada, H.; Naito, T.; Kobayashi, S.
Beilstein J. Org. Chem. 2011, 7, 735e739; (e) Bryan, M. C.; Wernick, D.; Hein, C. D.;
Petersen, J. V.; Eschelbach, J. W.; Doherty, E. M. Beilstein J. Org. Chem. 2011, 7,
Obtained (177 mg, 90% for Table 3, entry 13; 185 mg, 94% for Table 3,
entry 14) from 4-azidobenzophenone (223 mg, 1 mmol). H NMR
1
1141e1149; (f) Ekholm, F. S.; Mandity, I. M.; Fueloep, F.; Leino, R. Tetrahedron
d
(CDCl
3
) 4.24 (2H, br s), 6.65 (2H, m), 7.44 (2H, t, J¼7.6 Hz), 7.61 (1H, t,
Lett. 2011, 52, 1839e1841; (g) Bakker, J. J. W.; Zieverink, M. M. P.; Reintjens, R.
W. E. G.; Kapteijn, F.; Moulijn, J. A.; Kreutzer, M. T. ChemCatChem 2011, 3,
þ
J¼6.4 Hz), 7.70e7.72 (4H, m); MS (EI) m/z (%) 197 (M , 29),120 (100).
1155e1157; (h) Clapham, B.; Wilson, N. S.; Michmerhuizen, M. J.; Blanchard, D.
P.; Dingle, D. M.; Nemcek, T. A.; Pan, J. Y.; Sauer, D. R. J. Comb. Chem. 2008, 10,
88e93; (i) Ueno, M.; Suzuki, T.; Naito, T.; Oyamada, H.; Kobayashi, S. Chem.
Commun. 2008, 1647e1649; (j) Knudsen, K. P.; Holden, J.; Ley, S. V.; Ladlow, M.
Adv. Synth. Catal. 2007, 349, 535e538; (k) Horv ꢀa th, H. H.; Papp, G.; Csaj aꢀ gi, C.;
Jo oꢀ , F. Catal. Commun. 2007, 8, 442e446; (l) Jones, R. V.; Godorhazy, L.; Varga,
N.; Szalay, D.; Urge, L.; Darvas, F. J. Comb. Chem. 2006, 8, 110e116; (m)
Franckevicius, V.; Knudsen, K. R.; Ladlow, M.; Longbottom, D. A.; Ley, S. V.
Synlett 2006, 889e892; (n) Saaby, S.; Knudsen, K. R.; Ladlow, M.; Ley, S. V. Chem.
Commun. 2005, 2909e2911; (o) Yoswathananont, N.; Nitta, K.; Nishiuchi, Y.;
Sato, M. Chem. Commun. 2005, 40e42.
4
.4. Scale-up and Pd-leaching assay for the palladium-
catalyzed hydrogenation under flowconditions (Tables 4 and 5)
4.4.1. For 10% Pd/C and 10% Pd/HP20 (Table 4). A solution of ben-
zophenone (1.82 g,10 mmol) in MeOH (200 mL) was flowed at 1 mL/
min into the 10% Pd/C or 10% Pd/HP20-packed cartridge under 1 bar
hydrogen gas at 50 C. The collected reaction mixture was diluted
ꢀ
with ethyl acetate to 100 mL of the total volume using a volumetric
flask, and the residual palladium species was measured by an ICP-
AES analysis [ICPS-8100 (Shimadzu, Kyoto)]. The palladium leach-
ing was not detected within the detection limit (<1 ppm).
3. For the study for the application of heterogeneous flow hydrogenation: (a)
Cooper, C. G. F.; Lee, E. R.; Silva, R. A.; Bourque, A. J.; Clark, S.; Katti, S.; Nivor-
orozhkin, V. Org. Process Res. Dev. 2012, 16, 1090e1097; (b) Liu, J.; Fitzgerald, A.
E.; Mani, N. S. Synthesis 2012, 44, 2469e2473; (c) Colombo, E.; Ratel, P.; Mou-
nier, L.; Guillier, F. J. Flow Chem. 2011, 1, 68e73; (d) Tarleton, M.; McCluskey, A.
Tetrahedron Lett. 2011, 52, 1583e1586; (e) Gutmann, B.; Roduit, J.-P.; Roberge,
D.; Kappe, C. O. Chem.dEur. J. 2011, 17, 13146e13150; (f) Glasnov, T. N.; Kappe,
C. O. Adv. Synth. Catal. 2010, 352, 3089e3097; (g) Baumann, M.; Baxendale, I. R.;
Ley, S. V. Synlett 2010, 749e752.
4.4.2. For 0.5% Pd/MS3A and 0.3% Pd/BN (Table 5). A solution of
diphenylacetylene (1.78 g, 10 mmol) in MeOH (200 mL) was flowed
4
5
6
. (a) Monguchi, Y.; Fujita, Y.; Endo, K.; Takao, S.; Yoshimura, M.; Takagi, Y.;
Maegawa, T.; Sajiki, H. Chem.dEur. J. 2009, 15, 834e837; (b) Monguchi, Y.;
Sakai, K.; Endo, K.; Fujita, Y.; Niimura, M.; Yoshimura, M.; Mizusaki, T.; Sawama,
Y.; Sajiki, H. ChemCatChem 2012, 4, 546e558.
. (a) Maegawa, T.; Takahashi, T.; Yoshimura, M.; Suzuka, H.; Monguchi, Y.; Sajiki,
H. Adv. Synth. Catal. 2009, 351, 2091e2095; (b) Takahashi, T.; Yoshimura, M.;
Suzuka, H.; Maegawa, T.; Sawama, Y.; Monguchi, Y.; Sajiki, H. Tetrahedron 2012,
68, 8293e8299.
. (a) Yabe, Y.; Yamada, T.; Nagata, S.; Sawama, Y.; Monguchi, Y.; Sajiki, H. Adv.
Synth. Catal. 2012, 354, 1264e1268; (b) Yabe, Y.; Sawama, Y.; Monguchi, Y.;
Sajiki, H. Chem.dEur. J. 2013, 19, 484e488; (c) Yabe, Y.; Sawama, Y.; Yamada, T.;
Nagata, S.; Monguchi, Y.; Sajiki, H. ChemCatChem 2013, 5, 2360e2366.
at 1 mL/min into the 0.5% Pd/MS3A or 0.3% Pd/BN-packed cartridge
ꢀ
under 1 bar hydrogen gas at 50 C. The collected reaction mixture
was diluted with ethyl acetate to 100 mL of the total volume using
a volumetric flask, and the residual palladium species was measured
by an ICP-AES analysis [ICPS-8100 (Shimadzu, Kyoto)]. The palla-
dium leaching wasnotdetected within the detection limit (<1 ppm).
Acknowledgements
We sincerely thank Dr. Zsolt Lepp, ThalesNano Nanotechnology,
7. Yabe, Y.; Sawama, Y.; Monguchi, Y.; Sajiki, H. Catal. Sci. Technol. 2014, 4,
60e271.
2
Inc., and Dr. Yuko Kawahashi and Mr. Satoshi Ohtsu, Ikeda Scientific
8
. Kobayashi et al. reported a flow chemoselective hydrogenation of chalcone. The
alkene moiety of chalcone was smoothly hydrogenated in the presence of the
aromatic carbonyl group using polysilane-supported palladium catalysts de-
veloped by them, see Ref. 2d and 2i.
Ò
Co., Ltd., for the kind assistance and use of the H-Cube continuous
flow hydrogenator without charge. We highly appreciate the kind
gift of 10% Pd/C and ICP-AES measurement by the N.E. Chemcat
Corporation. T.H. thanks the Sasakawa Scientific Research Grant
from the Japan Science Society (Grant no. 25-302) for the partial
financial support of this study.
9. The catalysts could be repeatedly used without significant decrease of the
catalyst activity
10. Maejima, T.; Shimoda, Y.; Nozaki, K.; Mori, S.; Sawama, Y.; Monguchi, Y.; Sajiki,
H. Tetrahedron 2012, 68, 1712e1722.
1
1
1. Szostak, M.; Sautier, B.; Spain, M.; Procter, D. J. Org. Lett. 2014, 16, 1092e1095.
2. Yang, H.; Cui, X.; Deng, Y.; Shi, F. ChemCatChem 2013, 5, 1739e1743.
13. Hattori, K.; Sajiki, H.; Hirota, K. Tetrahedron 2001, 57, 4817e4824.
4. Mori, A.; Mizusaki, T.; Ikawa, T.; Maegawa, T.; Sawama, Y.; Monguchi, Y.; Sajiki,
H. Chem.dEur. J. 2007, 13, 1432e1441.
Supplementary data
1
Supplementary data related to this article can be found at http://
dx.doi.org/10.1016/j.tet.2014.05.038.
15. Bartoli, G.; Antonio, G. D.; Givannini, R.; Giuli, S.; Lanari, S.; Paoletti, M.; Mar-
cantoni, E. J. Org. Chem. 2008, 73, 1919e1924.
1
1
1
6. Toda, F.; Tanaka, K.; Iwata, S. J. Org. Chem. 1989, 54, 3007e3009.
7. Gottlieb, H. E.; Kotlyar, V.; Nudelman, A. J. Org. Chem. 1997, 62, 7512e7515.
8. Fern aꢀ ndez-Salas, J. A.; Manzini, S.; Nolan, S. P. Chem. Commun. 2013,
758e9760.
9. Moreau, E.; Fortin, S.; Desjardins, M.; Rousseau, J. L. C.; Petitclerc, E.; Gau-
dreault, R. C. Bioorg. Med. Chem. 2005, 13, 6703e6712.
References and notes
9
1
. Reviews: (a) Chemical Reactions and Processes under Flow Conditions; Luis, S. V.,
Garcia-Verdugo, E., Eds.; RSC: Cambridge, UK, 2010; (b) Irfan, M.; Glasnov, T. N.;
Kappe, C. O. ChemSusChem 2011, 4, 300e316.
1