Chemoselective hydrogenation method catalyzed by Pd/C using diphenylsulfide as a reasonable catalyst poison

Article abstract of DOI:10.1016/j.tet.2006.09.094

While Pd/C is one of the most useful catalysts for hydrogenation, the high catalyst activity of Pd/C causes difficulty in its application to chemoselective hydrogenation between different types of reducible functionalities. In order to achieve chemoselective hydrogenation using Pd/C, we investigated catalyst poison as a controller of the catalyst activity. We found that the addition of Ph₂S (diphenylsulfide) to the Pd/C-catalyzed hydrogenation reaction mixture led to reasonable deactivation of Pd/C. By the use of the Pd/C-Ph₂S catalytic system, olefins, acetylenes, and azides can be selectively reduced in the coexistence of aromatic carbonyls, aromatic halides, cyano groups, benzyl esters, and N-Cbz (benzyloxycarbonyl) protecting groups. The present method is promising as a general and practical chemoselective hydrogenation process in synthetic organic chemistry.

Full text of DOI:10.1016/j.tet.2006.09.094

Tetrahedron 62 (2006) 11925–11932
Chemoselective hydrogenation method catalyzed by Pd/C using
diphenylsulfide as a reasonable catalyst poison
Akinori Mori, Tomoteru Mizusaki, Yumi Miyakawa, Eri Ohashi, Tomoko Haga,
*
Tomohiro Maegawa, Yasunari Monguchi and Hironao Sajiki
Laboratory of Medicinal Chemistry, Gifu Pharmaceutical University, 5-6-1 Mitahora-higashi, Gifu 502-8585, Japan
Received 30 August 2006; accepted 21 September 2006
Available online 27 October 2006
Abstract—While Pd/C is one of the most useful catalysts for hydrogenation, the high catalyst activity of Pd/C causes difficulty in its appli-
cation to chemoselective hydrogenation between different types of reducible functionalities. In order to achieve chemoselective hydrogena-
tion using Pd/C, we investigated catalyst poison as a controller of the catalyst activity. We found that the addition of Ph2S (diphenylsulfide) to
the Pd/C-catalyzed hydrogenation reaction mixture led to reasonable deactivation of Pd/C. By the use of the Pd/C–Ph2S catalytic system,
olefins, acetylenes, and azides can be selectively reduced in the coexistence of aromatic carbonyls, aromatic halides, cyano groups, benzyl
esters, and N-Cbz (benzyloxycarbonyl) protecting groups. The present method is promising as a general and practical chemoselective hydro-
genation process in synthetic organic chemistry.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
complex [Pd/C(en)],3 and in the hydrogenation of aromatic
ketones using Pd/C(en), a selective partial reduction was
achieved to afford the corresponding benzyl alcohol without
hydrogenolysis, although Pd/C-catalyzed hydrogenation
removed the carbonyl oxygen from the aromatic ketone
derivatives (Scheme 2).3
Palladium on activated carbon (Pd/C) is extensively used
as a heterogeneous catalyst for hydrogenation in synthetic
organic chemistry because of its high catalyst activity, cost-
efficiency, easy separation from the reaction mixture, and
reusability.1 However, Pd/C is too active to catalyze selective
hydrogenation among the different types of reducible func-
tionalities. Deactivator of the catalyst is recognized as a cat-
alyst poison and it is reported that the deactivation effect
depends on the kind or/and amount of the catalyst poison.1b
Therefore, an appropriate use of the catalyst poison in Pd/C-
catalyzed hydrogenation could control the catalyst activity
leading to chemoselective hydrogenation.1 We have reported
a method of chemoselective hydrogenation of olefin or ben-
zyl ester functionalities without deprotection of the O-benzyl
protecting groups by the addition of nitrogenous catalyst poi-
sons such as NH3, pyridine, or 2,20-dipyridyl (Scheme 1).2
We also developed a carbon-supported Pd-ethylenediamine
10% Pd/C
H2, < 24 h
Ar
R
O
Ar
R
OH
10% Pd/C(en)
H2
Ar
R
Scheme 2.
In order to establish a catalytic hydrogenation system pos-
sessing a distinct chemoselectivity, we focused on sulfur-
containing compounds with the expectation that they should
work more effectively as catalyst poisons than nitrogenous
compounds. Sulfur-containing catalyst poisons have been
reported: quinoline-S is used for Rosenmund reduction in
order to avoid the over-reduction of aldehydes to the corre-
sponding alcohols;4 thiophene or butylmercaptan is used
for the selective reduction of olefin tolerating O-benzyl
protecting groups;5 platinum sulfide (PtS) catalyzes the
conversion from halonitrobenzenes to haloanilines without
dehalogenation.6 During our effort to establish a chemo-
selective hydrogenation method using Pd/C by the addition
of sulfur-containing compounds, we found that the addition
OBn
Ph
Ph
OBn
Pd/C, H2 (1 atm)
nitrogen-containing base
(NH3, Pyridine, 2,2'-Dipyridyl)
CO2Bn
CO2H
BnO
Scheme 1.
BnO
* Corresponding author. Tel.: +81 58 237 3931; fax: +81 58 237 5979;
e-mail: sajiki@gifu-pu.ac.jp
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.09.094

11926
A. Mori et al. / Tetrahedron 62 (2006) 11925–11932
of diphenylsulfide (Ph2S) moderately depressed the catalyst
activity of Pd/C to acquire distinguishing chemoselectivity
on hydrogenation.7 In this paper, we describe detailed results
and discussion about the scope of the chemoselective hydro-
genation using the Pd/C–Ph2S system.
give 3a exclusively (entry 12). Dimethylsulfide (Me2S), di-
methylsulfoxide (Me2SO), and dimethylsulfone (Me2SO2)
were not effective to achieve the chemoselectivity to 2a
(entries 13–15). Compared with the results in entries 5 and
13, the benzene ring is likely to play an important role as
well as the sulfur atom to attain the desired chemoselectivity.
The benzene rings of Ph2S may be able to coordinate with Pd
metal in a similar manner to that of a Pd-p-aryl complex or
adsorb to the hydrophobic charcoal of Pd/C, leading to the
stronger poisoning effect of Pd/C. Eventually, we chose the
catalytic amount (0.01 equiv toward the substrate) of Ph2S
as the optimum additive for chemoselective hydrogenation
because of its moderate strength as a catalyst poison, cost-
efficiency, and odorless nature.
2. Results and discussion
We initially examined the suppressing effect of sulfuric
catalyst poisons on the Pd/C-catalyzed hydrogenolysis of
chalcone (1a) possessing an aromatic ketone and an olefin
functionality within the molecule (Table 1). Both olefin
and aromatic ketone of 1a were readily reduced under the
Pd/C-catalyzed hydrogenation conditions without any cata-
lyst poison (entry 1); 0.01 equiv of diphenyldisulfide (Ph2S2)
and thiophenol (PhSH) deactivated the Pd/C completely and
no reaction took place (entries 2 and 3). Pd/C-catalyzed hy-
drogenation with 0.01 equiv of diphenylsulfide (Ph2S) is the
best combination for the chemoselective hydrogenation
between olefin and aromatic ketone (entry 5): olefin was re-
duced to alkane without the reduction of the ketone. The ole-
fin moiety was successfully reducing even with increased
amount (to 0.1 equiv) of Ph2S (entry 6). Unfavorable forma-
tion of 3a was detected, when the amount of Ph2S was
reduced to 0.001 equiv (entry 4). In contrast, diphenylsul-
fone (Ph2SO2) and diphenylsulfoxide (Ph2SO) were inade-
quate to inhibit the over-reduction of aromatic ketone to
3a (entries 7 and 8). Next, we assessed the addition effect
of aliphatic sulfur-containing compounds. While the addi-
tion of alkyl thiols to the reaction mixture brought about
strong inhibition of the reaction of 1a (entries 9–11), thio-
ether, 2-(methylthio)ethanamine, exerted a milder effect to
Next, we investigated the chemoselectivity in the hydro-
genation of carbonyl compounds containing an alkene or
alkyne moiety under our optimal conditions (Table 2). The
carbonyl moiety was not reduced in all cases, while the
alkene or alkyne moiety within the molecule was smoothly
hydrogenated (entries 1–5).
We attempted to apply the reaction conditions to an alkene
possessing an aromatic aldehyde in the molecule (Scheme 3).
Contrary to our expectation, it was difficult to block the hy-
drogenation of the aromatic aldehyde to the corresponding
benzyl alcohol under the same conditions due to the high re-
activity of aromatic aldehyde toward the hydrogenation.
Table 2. Selective hydrogenation of olefin in the presence of aromatic or
aliphatic ketone
Ph2S (0.01 equiv)
10% Pd/C (10 wt %)
O
O
R1
R2
R1
R'2
MeOH, H2 (1 atm)
rt, 24 h
Table 1. Assessment of additives for chemoselective hydrogenation
between olefin and aromatic ketone using chalcone (1a) as a substrate
(R1 = Ph or alkyl)
Additive (0.01 equiv)
10% Pd/C (10 wt %)
O
O
OH
Entry
1
Substrate
Product
Yield (%)
quant
+
+
Ph
Ph
MeOH, H2 (1 atm)
rt, 24 h
Ph
Ph
Ph
Ph Ph
Ph
O
O
1a
2a
3a
4a
Ph
O
Ph
Ph
Ph
1a
2a
Entry
Additive
1a:2a:3a:4aa
O
1
2
3
4
5
6
7
8
None
Ph2S2
PhSH
Ph2S (0.001 equiv)
Ph2S
Ph2S (0.1 equiv)
Ph2SO
Ph2SO2
0:0:0:100
100:0:0:0
100:0:0:0
0:94:6:0
0:100:0:0
0:100:0:0
0:93:7:0
2
3
4
99
Ph
Ph
Ph
Ph
1b
2b
O
O
Ph
quant
84a
Ph
Ph
0:0:100:0
Ph
2a
1c
9
77:23:0:0
HS
O
O
Ph
Ph
HS
OH
10
11
100:0:0:0
100:0:0:0
1d
2d
HS
NH2
O
O
68b
MeS
NH2
5
12
0:100:0:0
3
3
13
14
15
Me2S
Me2SO
Me2SO2
0:42:58:0
0:0:100:0
0:0:48:52
1e
2e
a
The reaction was completed within 13 h.
The reaction was completed within 1.5 h. The low isolated yield of 2e was
due to the volatile nature.
b
The ratio was determined based on 1H NMR analysis.
a

A. Mori et al. / Tetrahedron 62 (2006) 11925–11932
11927
Ph2S (0.01 equiv)
10% Pd/C (10 wt %)
O
O
Me
O
OH
H
H
+
+
MeOH, H2 (1 atm)
rt, 24 h
O
O
O
3a
4a
5a
6a
4a : 5a : 6a = 50 : 9 : 41
Scheme 3. First attempt for chemoselective hydrogenation of olefin in the presence of aromatic aldehyde.
We have reported that the choice of solvent was an important
factor to control the chemoselective suppression of epoxi-
des3c,e or silyl ethers8 under the hydrogenation conditions.
In the former case, use of THF instead of MeOH as a solvent
achieved the Pd/C(en)-catalyzed chemoselective hydroge-
nation of olefin, nitro, and azide moieties with retention of
the epoxide functions. In the latter case, TBDMS (tert-butyl-
dimethylsilyl) and TES (triethylsilyl) ethers were cleanly
deprotected in MeOH under the Pd/C-catalyzed hydrogena-
tion conditions, while neither TBDMS nor TES ether was
cleaved in AcOEt (ethyl acetate) or MeCN (acetonitrile), re-
spectively. With an expectation of complete suppression of
the reduction of the aromatic aldehydes, hydrogenolysis of
3a in a variety of solvents was investigated (Table 3). The
hydrogenation of the aldehyde moiety of 3a proceeded in
MeOH (Scheme 3 and Table 3, entry 1), whereas the alde-
hyde moiety survived completely in THF, AcOEt, MeCN,
or 1,4-dioxane (entries 2–5). These solvents made the
chemoselective reduction of 3a possible between the alkene
moiety and the aldehyde moiety, because such solvent may
be able to coordinate to Pd/C and further reduce the catalyst
activity.
chemistry. Complete inhibition of the hydrogenolysis of ar-
omatic chlorides using our chemoselective hydrogenation
method was achieved (entry 1) and the olefin moiety was
hydrogenated smoothly and selectively without dechlorina-
tion (entries 2–5). However, the addition of 0.01 equiv of
Ph2S was insufficient to prevent debromination and an in-
crease in the amount of Ph2S was required (entries 6 and
7). With use of 0.1 equiv of Ph2S, the olefin moiety was se-
lectively hydrogenated without debromination of the corre-
sponding aromatic bromide (entry 8). In the case of the
aromatic iodide as a substrate, no deiodination was also ob-
served (entry 9). These results show that our hydrogenation
conditions using Ph2S are useful in the selective hydrogena-
tion of olefins without the reduction of aromatic halides.
Benzyl ester and N-Cbz (benzyloxycarbonyl) protecting
groups are widely used due to their easy deprotectable
nature.9 However, the selective hydrogenation of other re-
ducible functionalities without deprotection of benzyl ester
or N-Cbz protective group is very difficult to attain at a prac-
tically useful level. Only a few methods are known in the lit-
erature. Zappia et al. reported that use of 3% Pd/C in AcOEt
led to the selective hydrogenation of olefin leaving the ben-
zyl ester or N-Cbz protective group intact, but these protec-
tive groups were time-dependently taken off under their
conditions.10 We also reported that aliphatic N-Cbz protec-
tive groups were not cleaved by hydrogenolysis using Pd/
C(en) as a catalyst, while aromatic N-Cbz protective groups
could not survive under the same conditions;3a,f,i Pd/Fib
could also hydrogenate the olefin moiety selectively without
the deprotection of both benzyl ester and the N-Cbz protec-
tive group in THF.11 We attempted to apply the present Pd/
C–Ph2S system to the selective hydrogenation of olefin in
the presence of benzyl ester or the N-Cbz protective group
(Table 6). The selective hydrogenation of olefin was
achieved without hydrogenolysis of the coexisting benzyl
ester (entries 1–5). Both aliphatic and aromatic N-Cbz
The results of the hydrogenation of a variety of aromatic
aldehydes in AcOEt are summarized in Table 4. Aromatic
aldehydes with an electron-donating group on the benzene
ring never hydrogenate (entries 1–3) and a coexisting olefin
in the molecule was selectively hydrogenated to the corre-
sponding alkane (entries 2 and 3). Aryl aldehydes bearing
an electron-withdrawing group on the benzene ring did also
not undergo the reduction under these reaction conditions
(entries 4–7).
We next investigated the selectivity of the hydrogenation
between olefin and aromatic halide moieties (Table 5). A se-
lective hydrogenation method without hydrogenolysis of
aromatic halides could be useful for synthetic organic
Table 3. Solvent effect on the hydrogenation of an aromatic aldehyde
Ph2S (0.01 equiv)
10% Pd/C (10 wt %)
O
O
Me
OH
H
H
Solvent, H2 (1 atm)
rt, 24 h
O
O
O
O
4a
5a
6a
3a
Entry
Solvent
3a:4a:5a:6aa
1
2
3
4
5
MeOH
THF
AcOEt
MeCN
1,4-Dioxane
0:50:9:41
0:100:0:0:0
0:100:0:0:0
0:100:0:0:0
0:100:0:0:0
The ratio was determined based on 1H NMR analysis.
a

11928
A. Mori et al. / Tetrahedron 62 (2006) 11925–11932
Table 4. Suppression of the hydrogenation of aromatic aldehyde and selec-
tive hydrogenation of olefin in the presence of aromatic aldehyde
Table 5. Suppression of the hydrogenation of aromatic halide and selective
hydrogenation of olefin in the presence of aromatic halide
Ph2S (0.01 equiv)
Ph2S (0.01 equiv)
O
O
10% Pd/C (10 wt %)
AcOEt, H2 (1 atm)
rt, 24 h
X
X
10% Pd/C (10 wt %)
MeOH, H2 (1 atm)
rt, 24 h
H
H
R
R'
R
R'
(X = Cl, Br, I)
Entry
1
Substrate
Product
Yield (%)a
O
Entry
1
Substrate
Product
Yield (%)a
75b
MeO
MeO
H
99b
Cl
Recovery
No reaction
OMe
3c
9a
O
O
O
O
H
H
2
3
98
97
2
3
4
5
91
Cl
O
Cl
O
10b
9b
3a
4a
O
O
O
O
Ph
Ph
H
H
95
Cl
Cl
O
O
9c
10c
3d
4d
O
O
O
H
Recovery
Recovery
92b,c
NH2
NH2
4
5
90c
NC
Cl
Cl
3e
9d
10d
O
O
O
H
96b
CO2H
CO2H
HO2C
99
Cl
Cl
3f
9e
10e
O
H
Br
6
Recovery
94b,c
6
7
8
No reaction
>99d,e
82b,d
>99e,f
96b
Ph
11a
3g
O
O
O
H
H
No reaction
7
93b,d
Br
11b
4h
3h
O
O
a
Isolated yield.
b
c
d
Isolated yield of the recovered substrate.
MeCN was used as a solvent.
Small amount of intractable material contained.
Br
Br
11c
12c
protective groups were stable under the hydrogenation con-
ditions (entries 6–8). Our method is proved to be useful for
the selective hydrogenation of the alkene moiety in the pres-
ence of benzyl ester or the N-Cbz protective group.
9
No reaction
I
13a
a
Isolated yield.
Isolated yield of the recovered substrate.
b
c
d
e
f
The yield was determined based on 1H NMR analysis.
Ph2S (0.5 equiv) was used.
Aromatic cyano groups are also known as a reducible func-
tionality under Pd/C-catalyzed hydrogenation conditions.
We examined if a cyano group could undergo the reduction
under our conditions (Table 7). The hydrogenation of an
Determined by GC–MS analysis. A trace of debromination was detected.
Ph2S (0.1 equiv) was used.

A. Mori et al. / Tetrahedron 62 (2006) 11925–11932
11929
Table 6. Selective hydrogenation of olefin in the presence of benzyl ester or
N-Cbz protective group
Table 7. Suppression on the hydrogenation of aromatic cyano group
Ph2S (0.01 equiv)
Ph2S (0.01 equiv)
10% Pd/C (10 wt %)
MeOH, H2 (1 atm)
rt, 24 h
CN
CN
10% Pd/C (10 wt %)
MeOH, H2 (1 atm)
rt, 24 h
R-CO2Bn
R' CO2Bn
R
R'
R-NCbz
R'-NCbz
Entry
1
Substrate
Result
Entry
1
Substrate
Product
CO2Bn
Yield (%)a
CN
Recovery of substrate, 100%a
Recovery of substrate, 100%a
CO2Bn
100b
100b
quant
MeO
14a
15a
18a
18b
3e
CN
CN
CO2Bn
CO2Bn
2
3
2
14b
15b
O
O
CO2Bn
CO2Bn
14c
15c
H
3
Recovery of substrate, 94%b,c
CO2Bn
CO2Bn
4
5
6
95
94
14d
CO2Bn
14e
15d
CO2Bn
15e
Determined by 1H NMR.
Isolated yield of the recovered substrate.
MeCN was used as a solvent.
a
b
c
Ph
Ph
Table 8. Pd/C–Ph2S catalyzed hydrogenation of azide
N
N
Ph2S (0.01 equiv)
quant
Cbz
Cbz
N3
NH2
10% Pd/C (10 wt %)
17a
16a
R
R'
MeOH, H2 (1 atm)
rt, 24 h
NHCbz
NHCbz
7
98
99
Entry
1
Substrate
Product
Yield (%)a
quant
16b
17b
MeO
N3
MeO
MeO
NH2
MeO
N
N
8
OMe
19a
OMe
Cbz
16c
Cbz
20a
17c
N3
NH2
a
Isolated yield.
The yield was determined based on 1H NMR analysis.
b
2
quant
HO2C
HO2C
19b
20b
aromatic cyano group did not proceed, regardless of whether
the benzene ring was substituted with an electron-donating
group or an electron-withdrawing group (entries 1–3).
a
Isolated yield.
currently it seems difficult to achieve good selectivity in
the hydrogenation of nitro groups.
Next, we investigated the catalyst poison effect of Ph2S to-
ward an azide functionality (Table 8). The addition of Ph2S
to the reaction mixture did not affect the reduction of azide
and the corresponding amine was obtained quantitatively
(entries 1 and 2).
We investigated the reusability of the catalyst without further
addition of Ph2S using benzyl cinnamate (14e) as a substrate
(Table 10). The hydrogenation using fresh Pd/C and Ph2S
proceeded selectively (Table 6, entry 5 and Table 10, entry
1). The activity of the recycled Pd/C was notably decreased
and the reduction of the olefin moiety was even incomplete
(entries 2 and 3). These results suggest that recycling the
Pd/C used for the hydrogenation seems difficult.
Several methods for the selective reduction of the nitro
group in the presence of other functionalities such as aro-
matic carbonyls, aromatic halides, and nitriles have been
also reported.6,12 Application of the present method to nitro
compounds was attempted (Table 9). The hydrogenation of
21a was not complete, but led to the formation of a complex
mixture (entry 1). As shown in entries 2 and 3, the hydroge-
nation of nitro compounds substituted with either an elec-
tron-donating (21b) or electron-withdrawing group (21c)
on the benzene ring resulted in incompletion. Hence,
3. Conclusion
During the investigation of the influence of sulfur-containing
catalyst poison toward Pd/C in hydrogenation, we found that

11930
A. Mori et al. / Tetrahedron 62 (2006) 11925–11932
Table 9. Attempt on the Pd/C–Ph2S catalyzed hydrogenation of nitro
compound
and dehydrated DMF were purchased from Wako Pure
Chemical Industries, Ltd. and used without purification.
CH2Cl2 was distilled from calcium hydride. All other re-
agents were purchased from commercial sources and used
without further purification. Flash column chromatography
was performed with silica gel Merck 60 (230–400 mesh
ASTM), or Kanto Chemical Co., Inc. 60N (63–210 mm
spherical, neutral). 1H NMR and 13C NMR spectra were re-
corded on a JEOL AL 400 spectrometer or JEOL EX 400
Ph2S (0.01 equiv)
NO2
NH2
10% Pd/C (10 wt %)
R
R'
MeOH, H2 (1 atm)
rt, 24 h
Entry
1
Substrate
Result
Yield (%)a
—
NO2
spectrometer (400 MHz for 1H NMR and 100 MHz for 13
C
Complex mixtureb
NMR). Chemical shifts (d) are expressed in parts per million
and are internally referenced (0.00 ppm for TMS for CDCl3
for 1H NMR and 77.0 ppm for CDCl3 for 13C NMR). EI and
FAB mass spectra were taken on a JEOL JMS-SX102A
instrument.
21a
NO2
NO2
NH2
2
67c
MeO
MeO
22b
21b
4.2. Synthesis of the substrate
NH2
4.2.1. 1-Bromo-4-(2-propenyloxy)benzene (11c).13 To
a solution of 4-bromophenol (1.73 g, 10.0 mmol) and potas-
sium carbonate (1.52 g, 11.0 mmol) in acetone (10.0 mL)
was added allylbromide (0.96 mL, 11.0 mmol) and refluxed
for 8 h. Et2O (30 mL) and water (30 mL) were added and the
layers were separated. The aqueous layer was extracted with
Et2O (30 mL) and the combined organic layers were washed
with brine (30 mL), dried over MgSO4, and concentrated
under reduced pressure to afford 11c in 93% yield (1.98 g)
3
53d
O
O
21c
22c
The yield was determined based on 1H NMR analysis.
a
Nitro, amine, and diazo compounds were observed by 1H NMR.
Thirty-three percent of the substrate remained intact.
Forty-seven percent of the substrate remained intact.
b
c
d
1
as a colorless oil. H NMR spectrum of 11c was identical
to that in the literature.14
Table 10. Reuse of Pd/C
Ph2S (0.01 equiv)
4.2.2. Synthesis of benzyl ester.11c To a solution of carbox-
ylic acid (10.0 mmol), EDC$HCl (2.30 g, 12.0 mmol), and
DMAP (122 mg, 1.00 mmol) in CH2Cl2 (15 mL) was added
benzyl alcohol (1.04 g, 10.0 mmol). After a certain reaction
time, chloroform (50 mL) and water (50 mL) were added
and the layers were separated. The aqueous layer was ex-
tracted with chloroform (50 mL) and the combined organic
layers were washed with brine (100 mL), dried over
MgSO4, and concentrated under reduced pressure. The resi-
due was purified by flash column chromatography on silica
gel to afford 14c or 14d.
10% Pd/C (10 wt %)
CO2Bn
CO2Bn
CO2H
+
Ph
Ph
Ph
MeOH, H2 (1 atm)
rt, 24 h
14e
15e
23e
Entry
Reuse
14e:15e:23ea
1
2
3
—
First
Second
0:100:0
8:92:0
80:20:0
The ratio was determined based on 1H NMR analysis.
a
Ph2S was an appropriate catalyst poison to degrade the activ-
ity of Pd/C moderately and developed a chemoselective
hydrogenation method using the combination of Pd/C and
Ph2S. The addition of only a catalytic amount (0.01–
0.1 equiv) of Ph2S to Pd/C-catalyzed hydrogenation mix-
tures led to the complete chemoselective hydrogenation of
olefin and azide functionalities in the presence of other
reducible functional groups, such as aromatic carbonyl, aro-
matic halide, aromatic cyano group, benzyl ester, and N-Cbz
protective group. The other distinctive features of this
method are the non-use of expensive reagents and the simple
and virtually odorless operation. The present chemoselective
hydrogenation method should be practically useful in syn-
thetic organic, medicinal, and process chemistry fields.
4.2.2.1. (2E,4E)-Benzyl hexa-2,4-dienoate (14c). Ob-
tained from sorbic acid (1.12 g, 10.0 mmol), EDC$HCl
(1.92 g, 10.0 mmol), DMAP (122 mg, 1.00 mmol), and ben-
zyl alcohol (1.04 mL, 10.0 mmol) according to the general
procedure for the synthesis of the substrate (Section 4.2.2)
after 48 h of the reaction followed by flash column chroma-
tography on silica gel (n-hexane) in 90% yield (1.82 g) as
1
a colorless oil. H NMR (CDCl3) d 7.38–7.26 (m, 6H),
6.20–6.15 (m, 2H), 5.82 (d, 1H, J¼15.9 Hz), 5.19 (s, 2H),
1.85 (d, 3H, J¼5.6 Hz); MS (EI) m/z 202 (M+, 15), 157
(25), 91 (100); HRMS (EI) Calcd for C13H14O2 (M+):
202.0994. Found: 202.0985.
4.2.2.2. Benzyl vinylbenzoate (14d).11c Obtained from
4-vinylbenzoic acid (500 mg, 3.37 mmol), EDC$HCl
(959 mg, 5.00 mmol), DMAP (61.1 mg, 0.500 mmol), and
benzyl alcohol (0.350 mL, 3.38 mmol) according to the
general procedure for the synthesis of the substrate (Section
4.2.2) after 43 h of the reaction followed by flash column
chromatography on silica gel (n-hexane/n-hexane/Et2O¼
4. Experimental
4.1. General
Pd/C (10%) was purchased from Aldrich (catalog no.
205699). MeOH and AcOEt for HPLC, dehydrated THF,

A. Mori et al. / Tetrahedron 62 (2006) 11925–11932
11931
4/1) in 92% yield (737 mg) as a colorless oil. 1H NMR spec-
to afford the mixture of 1a–4a. The ratio of the mixture
was determined by 1H NMR analysis.
trum of 14d was identical to that in the literature.11c
4.2.3. Synthesis of N-Cbz protecting group.11c To a solu-
tion of the amine (5.00 mmol) in THF was added N-(benzyl-
oxycarbonyloxy)succinimide (1.45 g, 6.00 mmol). After a
certain reaction time, AcOEt (150 mL) and water (100 mL)
were added and the layers were separated. The organic layer
was washed successively with water (100 mL) and brine
(100 mL), dried over MgSO4, and concentrated under re-
duced pressure. If necessary, the residue was applied to flash
column chromatography on silica gel to afford 15a–15c.
4.4. Typical procedure for the chemoselective hydro-
genation of olefins in the presence of Ph2S as a
catalyst poison (Tables 2, 5–9, and Scheme 3)
Substrate (500 mmol), 10% Pd/C (10 wt % of the substrate),
diphenylsulfide (0.84 mL, 5.00 mmol), and MeOH (2.0 mL)
were added to a test tube and the system was sealed with a
septum. After two vacuum/H2 cycles to replace the air inside
with hydrogen, the mixture was vigorously stirred at room
temperature (ca. 20 ꢀC) under ordinary hydrogen pressure
(balloon) for 24 h. The reaction mixture was filtered using
a membrane filter (Millipore, MillexÒ-LH, 0.45 mm) and
the filtrate was concentrated to provide the product.
4.2.3.1. Benzyl diallylcarbamate (16a).11c Obtained
from diallylamine (1.23 mL, 10.0 mmol) and N-(benzyloxy-
carbonyloxy)succinimide (2.91 g, 12.0 mmol) according
to the general procedure for the synthesis of the substrate
(Section 4.2.3) after 67 h of the reaction followed by flash
column chromatography on silica gel (n-hexane) in 97%
4.5. Procedure for Table 3
Compound 3a (81.1 mg, 500 mmol), 10% Pd/C (8.2 mg,
10 wt % of 3a), diphenylsulfide (0.84 mL, 5.00 mmol), and
solvent (2.0 mL) were added to a test tube and the system
was sealed with a septum. After two vacuum/H2 cycles to
replace the air inside with hydrogen, the mixture was vigor-
ously stirred at room temperature (ca. 20 ꢀC) under ordinary
hydrogen pressure (balloon) for 24 h. The reaction mixture
was filtered using a membrane filter (Millipore, MillexÒ-LH,
0.45 mm) and the filtrate was concentrated to provide the
product.
1
yield (2.24 g) as a colorless oil. H NMR spectrum of 16a
was identical to that in the literature.11c
4.2.3.2. Benzyl 4-vinylphenylcarbamate (16b).11c Ob-
tained from 4-vinylaniline (1.00 g, 8.39 mmol) and N-
(benzyloxycarbonyloxy)succinimide (2.45 g, 10.1 mmol)
according to the general procedure for the synthesis of the
substrate (Section 4.2.3) after 7 h of the reaction without
any purification in 92% yield (1.99 g) as a pale yellow solid.
1H NMR spectrum of 16b was identical with that in the
literature.11c
4.6. Investigation of solvent effect on the hydrogenation
of aromatic aldehyde (Table 4)
4.2.3.3. Benzyl allylphenylcarbamate (16c).11c Ob-
tained from N-allylaniline (1.33 g, 10.0 mmol) and N-
(benzyloxycarbonyloxy)succinimide (2.91 g, 12.0 mmol)
according to the general procedure for the synthesis of the
substrate (Section 4.2.3) after 7 h of the reaction followed
by flash column chromatography on silica gel (n-hexane)
Substrate (500 mmol), 10% Pd/C (10 wt % of the substrate),
diphenylsulfide (0.84 mL, 5.00 mmol), and AcOEt (2.0 mL)
were added to a test tube and the system was sealed with
a septum. After two vacuum/H2 cycles to replace the air in-
side with hydrogen, the mixture was vigorously stirred at
room temperature (ca. 20 ꢀC) under ordinary hydrogen pres-
sure (balloon) for 24 h. The reaction mixture was filtered us-
ing a membrane filter (Millipore, MillexÒ-LH, 0.45 mm) and
the filtrate was concentrated to provide the product.
1
in 81% yield (2.18 g) as a colorless oil. H NMR spectrum
of 16c was identical with that in the literature.11c
4.2.3.4. 5-Azide-1,2,3-trimethoxybenzene (19a).15 To
a solution of 3,4,5-trimethoxyaniline (916 mg, 5.00 mmol)
and concentrated hydrochloric acid (11.3 mL) in water
(20 mL) was added dropwise a solution of sodium nitrite
(362 mg, 5.20 mmol) in water (12.5 mL) at 0–5 ꢀC and the
mixture was stirred at 0–5 ꢀC. After 1 h, the mixture was fil-
tered and the filtrate was added to a solution of sodium azide
(325 g, 12.5 mmol) in water (12.5 mL) and stirred for 6 h.
The mixture was filtered to afford 19a in 76% yield
4.7. Procedure for reuse of Pd/C (Table 10)
In entry 1, 14e (200 mg, 839 mmol), 10% Pd/C (20 mg,
10 wt % of 14e), diphenylsulfide (1.38 mL, 8.39 mmol), and
MeOH (2.0 mL) were added to a test tube and the system
was sealed with a septum. After two vacuum/H2 cycles to
replace the air inside with hydrogen, the mixture was vigor-
ously stirred at room temperature (ca. 20 ꢀC) under ordinary
hydrogen pressure (balloon) for 24 h. The reaction mixture
was filtered using a Kiriyama funnel (8 mm diameter, filter
paper 5C, 1 mm, Kiriyama Glass Works Co.), the filtrate
was concentrated to provide the product, and filtered Pd/C
was dried under reduced pressure for 24 h. In entries 2–4, ac-
cording to the procedure in entry 1, the reaction was carried
out without the addition of Ph2S.
1
(795 mg) as a pale yellow solid. H NMR spectrum of 19a
was identical with that in the literature.16
4.3. Optimization of the reaction conditions (Table 1)
Compound 1a (208 mg, 1.00 mmol), 10% Pd/C (20.8 mg,
10 wt % of 1a), an additive (0.01 mmol), and MeOH
(2.0 mL) were added to a test tube and the system was sealed
with a septum. After two vacuum/H2 cycles to replace the air
inside with hydrogen, the mixture was vigorously stirred at
room temperature (ca. 20 ꢀC) under ordinary hydrogen pres-
sure (balloon) for 24 h. The reaction mixture was filtered
using a membrane filter (Millipore, MillexÒ-LH, 0.45 mm)
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