Highly chemoselective hydrogenation method using novel finely dispersed palladium catalyst on silk-fibroin: Its preparation and activity

Article abstract of DOI:10.1016/j.tet.2004.11.080

A palladium-fibroin complex (Pd/Fib) was prepared by soaking silk-fibroin in MeOH solution of Pd(OAc)₂ for 2 days (under Ar atmosphere) - 4 days (under air). Pd(OAc)₂ was gradually absorbed by fibroin and the rapid reduction of fibroin conjugated Pd(OAc)₂ proceeded with MeOH as a reductant at room temperature to be the Pd(0) complex. Pd/Fib catalyzed chemoselective hydrogenation of acetylenes, olefins and azides in the presence of aromatic ketones and aldehydes, halides, N-Cbz protective groups and benzyl esters which are readily hydrogenated using Pd/C or Pd/C(en) as a catalyst.

Full text of DOI:10.1016/j.tet.2004.11.080

Tetrahedron 61 (2005) 2217–2231
Highly chemoselective hydrogenation method using novel
finely dispersed palladium catalyst on silk-fibroin:
its preparation and activity
*
Takashi Ikawa, Hironao Sajiki and Kosaku Hirota
*
Laboratory of Medicinal Chemistry, Gifu Pharmaceutical University, 5-6-1 Mitahora-higashi, Gifu 502-8585, Japan
Received 25 October 2004; accepted 29 November 2004
Available online 19 January 2005
Abstract—A palladium–fibroin complex (Pd/Fib) was prepared by soaking silk-fibroin in MeOH solution of Pd(OAc)2 for 2 days (under Ar
atmosphere)—4 days (under air). Pd(OAc)2 was gradually absorbed by fibroin and the rapid reduction of fibroin conjugated Pd(OAc)2
proceeded with MeOH as a reductant at room temperature to be the Pd(0) complex. Pd/Fib catalyzed chemoselective hydrogenation of
acetylenes, olefins and azides in the presence of aromatic ketones and aldehydes, halides, N-Cbz protective groups and benzyl esters which
are readily hydrogenated using Pd/C or Pd/C(en) as a catalyst.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
biological materials, not to mention fibers.4 In particular,
fibroin is approximately 370 kDa molecular mass and
consists of mainly glycine, alanine, serine and tyrosine,
and very few residues of sulfur amino acids,5 which can be a
strong catalyst poison of metals.
Catalytic hydrogenation using a heterogeneous catalyst has
been a powerful tool for functional group transformation in
both the laboratory and industrial plant.1 Pd/C, a hetero-
geneous catalyst, has many advantages over homogeneous
catalysts, such as stability of the catalysts, ease of separation
from the reaction mixture upon completion of the reaction, a
good possibility of recyclability, cost reduction and high
catalytic ability. However, the high catalytic activity of
Pd/C makes it difficult to attain chemoselective reduction
among some reducible functional groups. Recently, we
reported several chemoselective hydrogenation methods
using a Pd/C-ethylenediamine complex [Pd/C(en)].2,3
Further development of novel catalysts for chemoselective
hydrogenation methods will reinforce the versatility of
synthetic processes.
The formation of fibroin heavy metal (Cu, Cr, Zn, Ni, Sn and
so on) complexes has long been studied in connection with
increasing the strength, weight and luster of heavy metal
absorbed silk.6 Many of the electron-rich functional groups
in the protein easily bind with the metal surface, leading
to the bioconjugate. During 1956–1962,7 Akabori and
co-workers reported silk protein-supported zero-valent
metal catalyst for asymmetric hydrogenation. According
to their reported procedure,7b silk fibroin was boiled for
8 min in 0.1 N AcOH containing PdCl2 and the resulting
chelate was reduced under hydrogen (80 kg/cm2) in an
autoclave. Based upon Akabori’s preparation method,7
fibroin of the silk fibroin-supported palladium catalyst was
most likely denatured under the drastic reaction conditions
for the reason that the fibroin was exposed to the strongly
acidic conditions derived from liberating HCl from PdCl2 in
boiling 0.1 N AcOH. This could be due to the fact that the
silk palladium-catalyzed asymmetric hydrogenations are
inefficient inasmuch as the reproducibility of the method
was invariably poor.7 To our best knowledge, no applicable
protein-supported metal catalyst has, as yet, been reported.
Quite recently, Zhou et al. reported a core-shell nano-
structured gold colloid-silk fibroin bioconjugate.8 We report
herein a preparation method of a novel Pd–fibroin (Pd/Fib)
On the other hand, the silk secreted from the silk gland of
the silkworm Bombyx mori is composed of two principal
components of proteins, fibroin and sericins, characterized
by their solubility and stability in hot water, which enables
the industrial degumming of the silk threads. Recently,
fibroin and sericines have come to be considered a useful
bio-material accounting for a wide variety of interesting
properties such as in food, cosmetics, medical and
Keywords: Silk-fibroin; Hydrogenation; Palladium catalyst;
Chemoselective.
* Corresponding authors. Tel.: C81 58 237 3931x225; fax: C81 58 237
5979 (H.S.); e-mail: sajiki@gifu-pu.ac.jp
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.11.080

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T. Ikawa et al. / Tetrahedron 61 (2005) 2217–2231
catalyst under mild and nearly neutral reaction conditions
and its application to highly chemoselective hydrogenation
methods.9
2. Results and discussion
We chose Pd(OAc)2 as a palladium source for the new
Pd–fibroin catalyst (Pd/Fib) to avoid the strongly acidic
conditions derived from released HCl from PdCl2. The Pd
absorption (1w10 wt% of the silk fibroin) onto the silk
fibroin was initiated by soaking silk fibroin [Fig. 1(a)] into a
dark rust-colored MeOH solution of Pd(OAc)2 [0.0235 mol/l,
Fig. 1(b)] at room temperature in air. The colorless fibroin
was time-dependently changed to black, which suggests the
formation of zero-valent Pd. The liquid phase also changed
gradually from rust to thoroughly colorless-clear [Fig. 1(c)–
(e)] for 4 days, indicating the slow but complete adsorption
of Pd(OAc)2 on the silk fibroin and the rapid formation of
the zero-valent Pd/Fib via oxidation of the silk fibroin or
MeOH. Since no formation of black turbidity or silver
mirror was observed during the deposition of Pd(0) onto the
silk fibroin, it can be presumed that the formation of Pd(0)
occurs only on the fibroin fiber. Although the preparation
time of Pd/Fib could be reduced under Ar atmosphere, the
preparation was carried out under atmospheric conditions
from a practical standpoint. After simple filtration, the
obtained Pd/Fib [Fig. 1(f)] was stable for more than three
years at room temperature in air (in a capped vial) and is
non-pyrophoric. The Pd/Fib can be used by cutting up the
black yarn (Pd/Fib fiber) with scissors and is removed easily
from the reaction mixture using a pair of tweezers or by
simple filtration.
Figure 2. Silver mirror of palladium.
properties (Scheme 1). On the other hand, the formation of a
silver mirror of palladium metal on the side face of the
Erlenmeyer flask was observed when only the MeOH
solution of Pd(OAc)2 was allowed to stand in the absence of
fibroin fiber at room temperature for 4 days (Fig. 2).
Scanning electron microscopy (SEM) images proved the
high dispersion of amorphous palladium metal particles
[Fig. 3(b)–(d)] on the smooth surface of the silk fibroin
[Fig. 3(a)]. The variation of the Pd content only made a
difference in the density of the Pd particles. This
homogeneous dispersion was attributed to an interaction
between the Pd(OAc)2 and amino acids of the silk fibroin,
increasing the resistance to the growth of the Pd cluster.9
Figure 1. Preparation of Pd/Fib catalyst.
The quantitative analysis of the formation of acetic acid10
and formaldehyde11 was carried out to gain insight into the
reduction of Pd(OAc)2. For the reason that 90% of acetic
acid and 70% of formaldehyde were determined from the
filtered clear solution of Fig. 1(e), MeOH contributed to the
reduction of Pd(OAc)2 which was strongly adsorbed and
coordinated by silk fibroin, while the Tyr and/or Ser
residues of silk fibroin also display strong electron-donating
Figure 3. SEM image of original fibroin fiber (a), 1% (b), 2.5% (c) and 10%
Pd/Fib (d).
It is well known that the Pd/C-catalyzed hydrogenation of
aromatic carbonyls easily occurs to form methylene
compounds via formation of the intermediary benzyl
alcohol (Scheme 2).1 Therefore, it is extremely difficult to
achieve the chemoselective hydrogenation of olefin and
acetylene functionalities leaving intact the aromatic ketone
Scheme 1. Mechanism of Pd/Fib generation.

T. Ikawa et al. / Tetrahedron 61 (2005) 2217–2231
2219
interest in the use of Pd/Fib as a catalyst for the
chemoselective hydrogenation, we found that 2.5% Pd/Fib
surprisingly exhibited no catalyst activity toward the
hydrogenation of aromatic carbonyl compounds
(Scheme 3).
To explore the scope of the 2.5% Pd/Fib catalyst, the
chemoselective hydrogenation of olefins in the presence of
an aromatic carbonyl group within the molecule was carried
out at room temperature (Table 1). Although aromatic
ketones (1a–1f) were never reduced, hydrogenation activity
of 2.5% Pd/Fib toward olefins is retained (entries 1–6).
Moreover, the aromatic aldehyde (1g) was also stable under
hydrogenation conditions using 2.5% Pd/Fib even under
5 atm pressure of hydrogen (entry 7). Although partial
reduction of the aromatic aldehyde of o-allyloxybenzalde-
hyde (1h) was observed in MeOH, CH2Cl2 or THF as a
solvent, the use of AcOEt as a solvent caused the perfect
suppression of the reduction of the aromatic aldehyde group
of 1h (entry 8 and Scheme 4).
Scheme 2. Reduction of aromatic carbonyl using Pd/C and Pd/C(en).
and aldehyde. Recently, we have reported a chemoselective
hydrogenation method of aromatic carbonyls to form benzyl
alcohols without hydrogenolysis of the intermediary benzyl
alcohol using Pd/C(en) as a catalyst.12 Following our
Scheme 3. Catalytic activity of 2.5% Pd/Fib toward the hydrogenation of
aromatic ketone.
Table 1. Chemoselective hydrogenation of olefin in the presence of aromatic carbonyl using 2.5% Pd/Fib catalysta
Entry
1
Substrate
Time (h)
30
Product
Yield (%)b
97 (99c, 97d)
1a
2a
2
3
3
100
99
2b
1b
37
2c
1c
4
46
74e
1d
2d
5
6
2
quant
99
1e
2e
10
1f
2f
7
8
24
27
100c,e
100f
1g
2g
1h
2h
a Unless otherwise specified, reactions were performed in 5 mL of MeOH under ambient hydrogen pressure at room temperature.
b Isolated yield.
c 5 atm pressure of hydrogen.
d The reaction was performed at 50 8C.
e 5 mL of CH2Cl2 was used as a solvent.
f
5 mL of AcOEt was used as a solvent.

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T. Ikawa et al. / Tetrahedron 61 (2005) 2217–2231
the formation of a cyclic intermediate (A), which is obtained
by the coordination of Pd metal with the olefin and aldehyde
functionalities, is a key step of the competitive hydro-
genation of the olefin and aldehyde of 2h (Figure 4). Since
the use of AcOEt as a solvent, which is a better ligand than
the aromatic aldehyde of 2h, should inhibit the formation of
the cyclic intermediate (A), the selective hydrogenation was
achieved in AcOEt.
While aromatic carbonyl groups were usually not reduced
using 2.5% Pd/Fib (Table 1), aromatic ketones which
possess ester or other ketone moieties at the a position were
exceptionally reduced under the same conditions (Table 2).
For example, methyl benzoylformate (1i), aromatic b-keto-
ester, was reduced to the corresponding alcohol (3i).
Regrettably, stereoselectivity of 3i was extremely poor
(only 4% ee). Benzil (1j) and 1-phenylpropane-1,3-dione
(1k) which are aromatic 1,2-diketone were also reduced to
the corresponding a-hydroxyketones. Again, we expected
the formation of the neighboring-carbonyl group related
cyclic palladium coordinated intermediate to be a key step
of the exceptional reduction of the carbonyl group.
Scheme 4. Solvent effect toward the hydrogenation of the aromatic
aldehyde (1h).
While the aromatic aldehyde of 1g was not reduced even
under 5 atm pressure of hydrogen using 2.5% Pd/Fib
catalyst in MeOH, the aldehyde of 1h was partially reduced
under ambient pressure of hydrogen in MeOH (entry 7 and
Scheme 4). On the other hand, o-propyloxybenzaldehyde
(2h) which possesses no olefin moiety was entirely
recovered under the same hydrogenation conditions in
MeOH (Scheme 5). According to these experimental results,
the aldehyde of 1h was partially reduced before the
saturation of the olefin. Although the exact process of the
partial reduction of 1h is unclear, it has been proposed that
It is well known that aromatic chlorides are much less
reactive than aromatic bromides and iodides toward the
hydrogenation conditions and, hence, the dechlorination of
aromatic chloride cannot readily be achieved and the
hydrodechlorination reactions are very frequently incom-
plete but proceeded.13 Needless to say, Pd/C(en)2 or
commercial Pd/C1-catalyzed chemoselective hydrogenation
with retention of aromatic halides could not be accom-
plished,13 whereas aromatic halides entirely tolerate the
hydrogenation using 2.5% Pd/Fib (Table 3). Although
partial hydrogenolysis of 4-chlorobiphenyl (4b) and
4-bromobiphenyl (4c) was observed in MeOH (entries 2
and 4), the use of THF as a solvent perfectly suppressed the
partial hydrogenolysis (entries 3 and 5). 4-Fluorobiphenyl
(4a) and 2-iodobiphenyl (4d) were stable under the
hydrogenation conditions in MeOH.
Scheme 5. Catalyst activity of 2.5% Pd/Fib toward the hydrogenation of
aromatic aldehyde (2h) in MeOH.
Figure 4. Cyclic coordination of 1h with Pd (0).
Table 2. Reducible aromatic carbonyls under the hydrogenation conditions using 2.5% Pd/Fiba
Entry
1
Substrate
Time (h)
8
Product
Yield (%)b
98
1i
3i
2
3
46
43
98c
1j
3j
d
—
1k
3k 3k0
(85
:
15)e
a Unless otherwise specified, reactions were performed in 5 mL of MeOH under hydrogenation conditions at room temperature.
b Isolated yield.
c Under 5 atm pressure of hydrogen.
d Under 10 atm pressure of hydrogen.
e Determined by 1H NMR (starting material was disappeared).

T. Ikawa et al. / Tetrahedron 61 (2005) 2217–2231
Table 3. Catalytic activity of 2.5% Pd/Fib toward the hydrogenolysis of aromatic halides
2221
Entry
1
Substrate
Solvent
MeOH
4:5a
Recovery (%)
95
100:0
4a
4b
4c
2
3
MeOH
THF
95:5
100:0
—
99
4
5
MeOH
THF
84:16
100:0
—
91
6
MeOH
100:0
98
4d
1
a Determined by H NMR.
Table 4. Chemoselective hydrogenation of olefin and azide in the presence of aromatic halide using 2.5% Pd/Fib catalysta
Entry
1
Substrate
Time (h)
24
Product
Yield (%)b
100c
4e
6e
2
3
4
20
21
12
98
4f
6f
99d
4g
6g
100
4h
6h
5
6
24
24
91
4i
6i
6j
100c
4j
7
3
94
4k
6k
a Unless otherwise specified, reactions were performed in 5 mL of MeOH under ambient hydrogen atmosphere at room temperature.
b Isolated yield.
1
c Performed in CD3OD as a solvent and determined by H NMR.
d Performed in 15 mL of MeOH.

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T. Ikawa et al. / Tetrahedron 61 (2005) 2217–2231
Consequently, the chemoselective hydrogenation of a
variety of substrates containing aromatic halides and olefin
or azide functions within a molecule was carried out at room
temperature (Table 4). First, 4-chloro and 4-bromo styrenes
(4e and 4j) were hydrogenated using 2.5% Pd/Fib in
CD3OD because of the low boiling point of the products.
Not only chloride but also bromide was never cleaved while
the olefin was chemoselectively hydrogenated (entries 1 and
6). In addition, only the olefin moiety in compounds 4f–4h
containing aromatic chloride and ketone was selectively
hydrogenated, to give the corresponding saturated com-
pounds 6f–6h (entries 2–4). The azide group of 4i was also
hydrogenated to the corresponding amine (6i) (entry 5).
Furthermore, 2.5% Pd/Fib did not catalyze the hydrogeno-
lysis of even multi-brominated aromatic bromide (4k) and
the chemoselective hydrogenation of the olefins was
achieved (entry 7). According to these results, 2.5% Pd/
Fib catalyst is obviously applicable to the chemoselective
hydrogenation of olefin and azide functions distinguishing
the aromatic halides.
Despite numerous literature precedents, chemoselective
reduction of reducible functionalities such as alkynes,
alkenes and azides remains a challenge in organic
synthesis.1 Especially, while benzyl ester or N-Cbz
protective groups are widely used in organic synthesis,
they are labile under hydrogenation conditions, and it is
extremely difficult to keep such groups intact during a
synthetic process involving hydrogenation steps.14 In order
to solve this problem, Misiti et al. have reported 3% Pd/
C-catalyzed selective hydrogenation of a di-substituted
olefin of g-amino-a,b-unsaturated (conjugate) esters in the
presence of a benzyl ester or N-Cbz protective group.15
However, the method has limitation with regard to gener-
ality, and the stability of the benzyl esters and N-Cbz groups
under the conditions was time-dependent.15,16 During our
efforts to extend the applicability of the Pd/Fib catalyst, we
found that Pd/Fib indicates almost no catalytic activity
towards the hydrogenolysis of benzyl ether and benzyl ester
compared with Pd/C and Pd/C(en)2a (Scheme 6). The
hydrogenolysis of 4-benzyloxyphenylacetic acid benzyl
ester (7a) catalyzed by 2.5% Pd/Fib resulted in no reaction
even after 12 h under ordinary hydrogen pressure (recovery
of the starting material 7a in 99%). On the other hand, the
use of 5% Pd/C (Aldrich)1 as a catalyst resulted in the
hydrogenolysis of both the benzyl ether and the benzyl ester
of 7a to give the corresponding 4-hydroxyphenylacetic acid
(8a) in 99% isolated yield. 5% Pd/C(en) catalyzed
Scheme 6. Catalytic activity of Pd catalysts toward the hydrogenation of
benzyl ether and ester.
Table 5. Chemoselective hydrogenation of olefin and azide functionalities in the presence of a benzyl ester using 2.5% Pd/Fib catalysta
1
1
Substrate
Solvent
Time (h)
7
Product
Yield (%)b
91c
THF-d8
EtCO2Bn 10b
7b
7c
2
THF-d8
7
iPrCO2Bn 10c
93c
3
MeOH
18
77d
7d
10d
4
5
6
MeOH
THF
8
PrOCH2CO2Bn 10e
99
98
97
7e
24
6
7f
10f
MeOH
7g
10g
7
8
MeOH
MeOH
12
17
100 (100)e
7h
10h
100
7i
10i
a Unless otherwise specified, reactions were performed in 5 mL of the solvent under ambient hydrogen pressure at room temperature.
b Isolated yield.
c Performed in THF-d8 (0.75 mL) and determined by 1H NMR.
d Under 5 atm pressure of hydrogen.
e The reaction was performed at 50 8C.

T. Ikawa et al. / Tetrahedron 61 (2005) 2217–2231
2223
chemoselective hydrogenation of only the benzyl ester of 7a
with retention of the benzyl ether to give the corresponding
4-benzyloxyphenylacetic acid (9a) in 94% isolated yield.2a
Judging from these results so far obtained, we are now in a
position to disclose that the Pd/Fib catalyst is very efficient
for chemoselective hydrogenation with retention of the
benzyl ester within a molecule.
To explore the scope of the 2.5% Pd/Fib catalyst, the
hydrogenation of a number of substrates containing a benzyl
ester was investigated (Table 5). The terminal and internal
olefin and azide functionalities were selectively reduced in
the presence of a,b-unsaturated (conjugated) benzyl esters
(7b–7d, 7f and 7h) (entries 1–3, 5 and 7), a non-conjugated
benzyl ester (7e) (entry 4) and benzoic acid benzyl ester
derivatives (7g, 7h and 7i) (entries 6, 7 and 8). A feature of
the hydrogenation of benzyl ester derivatives is that the
catalyst activity of Pd/Fib toward the benzyl esters is
strongly influenced by the solvent. The benzyl esters of
substrates 7b, 7c and 7f were partially or completely
hydrogenolized in MeOH as a solvent. However, no
hydrogenolysis of the benzyl ester was observed in THF
as a solvent as can be seen from entries 1, 2 and 5. On
occasions when the partial hydrogenolysis of the benzyl
ester of the substrate occurred in MeOH, the use of THF as a
solvent gave satisfactory results (entries 1, 2 and 5).2a,b,17,18
Scheme 7. Catalytic activity of Pd catalysts toward the N-Cbz group of
aliphatic and aromatic amines.
N-Cbz (carbobenzoxy) protective groups are easily depro-
tected under hydrogenation conditions using Pd/C as a
catalyst.19 Recently, we reported the Pd/C(en) catalyzed-
chemoselective hydrogenation with retention of the N-Cbz
protective group of aliphatic amines although the chemo-
selective hydrogenation with retention of the aromatic
Scheme 8. Hydrogenation of 7f and 14b using commercial 5% Pd/C
catalyst.
Table 6. Chemoselective hydrogenation of olefin and acetylene in the presence of aromatic N-Cbz group using 2.5% Pd/Fib catalysta
Entry
1
Substrate
Solvent
THF
Time (h)
5
Product
Yield (%)b
92
14b
16b
2
3
MeOH
THF
48
34
97
14c
16c
99c
14d
16d
4
MeOH
22
100
14e
16e
5
MeOH
32
92d
14f
16f
a Unless otherwise specified, reactions were performed in 5 mL of the solvent under ambient hydrogen pressure at room temperature.
b Isolated yield.
c Under 10 atm pressure of hydrogen.
d Under 3 atm pressure of hydrogen.

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T. Ikawa et al. / Tetrahedron 61 (2005) 2217–2231
N-Cbz groups or benzyl esters could not be accom-
plished.2a,17,20 Although the hydrogenation of the substrate
(11) containing an N-Cbz group of aliphatic amine and
olefin functionalities within a molecule catalyzed by 5% Pd/
C gave totally saturated and simultaneously deprotected
product 12 as the sole product, the use of 5% Pd/C(en)
catalyst in THF resulted in entirely chemoselective
hydrogenation and the N-Cbz protective group was tolerated
under the reaction conditions (Scheme 7). However, the
N-Cbz protective group of an aromatic amine is easily
deprotected under the same reaction conditions,2a,17 for
instance, the N-Cbz protective group of aniline (14a) was
smoothly deprotected under the hydrogenation conditions
using Pd/C(en) in THF.2a,17 During our efforts to overcome
this problem, we found that 2.5% Pd/Fib possesses no
catalyst activity toward the hydrogenolysis of the aromatic
N-Cbz group (14a) (Scheme 7).
silk fibroin support toward the zero valent palladium metal
and the significant decrease in the active surface area of
palladium metal by the formation of a minute cluster (Figure
3). In the Pd/Fib catalyst, the original affinity of palladium
to aromatic carbonyls, halides, benzyl esters and N-Cbz
protective groups was drastically and selectively reduced by
fibroin.
3. Conclusion
Silk-fibroin supported palladium catalyst (Pd/Fib) was
prepared by incipient wetness impregnation with a rust-
colored MeOH solution of Pd(OAc)2. After the palladium
(II) was absorbed completely in the fibroin, the zero-valent
Pd was formed on the fibroin fiber via oxidation by MeOH
as a reductant. The Pd/Fib catalyst, black-colored yarn,
shows chemoselectivity in hydrogenation of acetylene,
olefin and azide functionalities in the presence of aromatic
ketone, aldehyde and halide, benzyl ester and aromatic
N-Cbz protective groups. These novel chemoselective
hydrogenation methods using Pd/Fib should contribute to
broad organic synthetic chemistry fields.
The catalyst activity of 2.5% Pd/Fib toward reducible
functionalities is much lower than the catalyst activity of
Pd/C and Pd/C(en). The olefins of 7f and 14b were
completely hydrogenated within an hour together with the
partial hydrogenolysis of benzyl ester and N-Cbz, respec-
tively (Scheme 8) with commercial 5% Pd/C as a catalyst,
while the complete hydrogenation of the olefins required
much longer time with Pd/Fib (24 and 5 h, respectively;
Table 5, entry 5 and Table 6, entry 1). Therefore, some
sterically hindered olefins such as 7d (Table 5, entry 3), 14d
(Table 6, entry 3), trans-stilben (17) and some cinnamate
type compounds (18 and 19) were irreducible under ambient
pressure of hydrogen using the 2.5% Pd/Fib (Figure 5) with
exceptional result (e.g. Table 5, entries 5 and 7). In addition,
a competitive experiment using cis-Jasmone (20) which has
a di-substituted cis-olefin and a tetra-substituted olefin as a
substrate indicated that only the cis-olefin was chemoselec-
tively reduced to the corresponding dihydrojasmone (21).
Consequently, the hydrogenation using 2.5% Pd/Fib can
distinguish between hindered and unhindered olefins and the
chemoselective hydrogenation of unhindered olefin was
efficiently achieved (Scheme 9).
4. Experimental
4.1. General
1H and 13C NMR spectra were recorded on a JEOL AL 400
spectrometer, JEOL EX 400 spectrometer, or a JEOL GL
270 spectrometer with tetramethylsilane or residual pro-
tiated solvent used as a reference. Elemental analyses were
performed by YANACO CHN CORDER MT-5 instrument.
EI and FAB Mass spectra were taken on a JEOL JMS-
SX102A instrument. SEM (Scanning Electron Microscopy)
image were taken on a JEOL JSM-T330A. Flash column
chromatography was performed with silica gel Merck 60
(230–400 mesh ASTM) according to the method of Still.21
MeOH for HPLC and AcOEt dehydrated were purchased
from Wako Pure Chemical Industries, Ltd. and used without
purification. THF was distilled from sodium benzophenone
ketyl. CH2Cl2 was distilled from calcium hydride. All other
reagents were purchased from commercial sources and used
without further purification.
4.1.1. Preparation of silk fibroin. Raw silk of Bombyx mori
(10.0 g) wrapped in gauze was soaked in an aqueous
solution (1.00 L) of Na2CO3 (500 mg, 6.02 mmol), Na2S2O4
(100 mg, 0.57 mmol) and ethylenediaminetetraacetic acid
dipotassium salt dihydrate (400 mg, 0.99 mmol) and boiled
for an hour. The resulting silk was washed vigorously with
water and dried in the shade to afford silk fibroin (7.83 g.
Anal. Found: C, 47.57; H, 6.38; N, 18.37: sample 1.779 mg:
ash 0.02 mg).
Figure 5. Irreducible olefins under ambient pressure of hydrogen using
2.5% Pd/Fib in MeOH.
4.1.2. Preparation of 2.5% Pd/Fib. To a rust-colored
solution of palladium acetate (1.06 g, 4.72 mmol) in MeOH
(200 mL) at room temperature was soaked silk fibroin
(20.0 g) for 4 days. The silk fiber changed gradually from
white to black and the solution also changed gradually from
rust to thoroughly colorless-clear. The resulting black fiber
was filtered, washed vigorously with MeOH (500 mL), and
Scheme 9. Chemoselective hydrogenation between two different olefins.
The chemoselectivity of the hydrogenation could be
attributable to the catalyst poison effect of the coordinated

T. Ikawa et al. / Tetrahedron 61 (2005) 2217–2231
2225
dried under reduced pressure to give the 2.5% Pd/Fib. [1]
Anal. Found: C. 45.25; H, 5.99; N, 16.97: sample 1.92 mg:
ash 0.01 mg. [2] Anal. Found: C. 46.56; H, 6.18; N, 17.95:
sample 1.704 mg: ash 0.07 mg. [3] Anal. Found: C. 46.76;
H, 6.25; N, 18.05: sample 1.766 mg: ash 0.04 mg.
127.1, 52.3; MS (EI) m/z 167 (MC, 38%), 140 (35%), 138
(99%), 127 (34%), 125 (100%), 111 (35%), 102 (36%),
89 (29%), 77 (56%), 75 (45%), 51 (37%), 50 (42%);
HRMS (EI) Calcd for C10H12O2 (MC): 167.0250. Found:
167.0245.
4.1.3. Quantitative analysis of aldehyde.10 To a solution of
palladium acetate (52.7 mg, 0.23 mmol) in MeOH
(10.0 mL) under Ar atmosphere at room temperature was
soaked silk fibroin (1.00 g) for 4 days. The filtrate was
diluted 200 times with distilled water. A mixture of the
sample solution (5.00 mL) and acetylacetone solution
(5.00 mL) which was prepared by distilled ammonium
acetate (15.0 g), acetic acid (0.30 mL) and acetylacetone
(0.20 mL) to the 100 mL with water was heated on a hot
water bath for 10 min. The absorbance was determined by
254 nm. Calibration curve of formaldehyde was obtained by
plotting peak size on the y-axis versus sample concentration
on the x-axis for a series of samples with known
concentrations using the data for the 1.25, 2.50 and
5.00 mg/mL standard solutions of formaldehyde.
4.1.7.2. Benzyl 4-benzyloxyphenylacetate (7a).2a To a
solution of 4-benzyloxyphenylacetic acid (2.42 g,
10.0 mmol) and Et3N (1.40 mL, 10.0 mmol) in THF
(20.0 mL) at room temperature was added benzyl bromide
(1.19 mL, 10.0 mmol). The solution was stirred at room
temperature for 24 h, after which time the solvent was
removed under vacuum pressure. The residue was extracted
with ether (100 mL) and water (100 mL). The organic layer
was washed with brine (100 mL), dried over MgSO4 and
concentrated under reduced pressure. The residue was
applied to flash silica gel column chromatography to afford
benzyl 4-benzyloxyphenylacetate (7a) as a colorless solid
1
(2.19 g, 88%). H NMR (CDCl3): dZ7.30–7.49 (m, 10H),
7.20 (d, JZ8.8 Hz, 2H), 6.93 (d, JZ8.8 Hz, 2H), 5.12 (s,
3H), 5.05 (s, 3H), 3.60 (s, 3H); 13C NMR (CDCl3): dZ
173.6, 159.8, 138.8, 138.8, 137.7, 132.3, 132.2, 130.4,
130.0, 130.0, 129.8, 129.3, 71.8, 68.4, 42.3; MS (EI) m/z
332 (MC,), 242, 149, 91 (100%). Anal. Calcd for C22H20O3:
C, 79.49; H, 6.06. Found: C, 79.21; H, 6.10.
4.1.4. Quantitative analysis of acetic acid.11 To a solution
of palladium acetate (52.7 mg, 0.23 mmol) in MeOH
(10.0 mL) under Ar atmosphere at room temperature
was soaked silk fibroin (1.00 g) for 4 days. The filtrate
was diluted 10 times with distilled water. The solution was
titrated with 0.01 N NaOH solution in the presence of
phenolphthalein which was standardized by potassium
hydrogen phthalate solution.
4.1.7.3. Benzyl allyloxyacetate (7e). To a solution of
benzyl glycolate (0.83 g, 5.00 mmol) and NaH (240 mg,
6.00 mmol) in DMF (10.0 mL) was added allyl bromide
(0.43 mL, 5.00 mmol). The solution was refluxed for 21 h,
after which time the solvent was removed under vacuum
pressure. The residue was extracted with ethyl acetate
(50 mL) and water (50 mL). The organic layer was washed
with brine (50 mL), dried over MgSO4 and concentrated
under reduced pressure. The residue was applied to flash
silica gel column chromatography (hexane/etherZ20:1) to
afford benzyl allyloxyacetate (7e) as a pale yellow oil
4.1.5. Formation of silver mirror of palladium. The
MeOH (10.0 mL) solution of palladium acetate (52.7 mg,
0.23 mmol) was allowed to stand in the absence of fibroin
fiber under Ar atmosphere at room temperature for 4 days.
The formation of a silver mirror of palladium metal on the
side face of the Erlenmeyer flask was observed.
1
(499 mg, 48%). H NMR (CDCl3): dZ7.37–7.33 (m, 5H),
4.1.6. Preparation of 1, 5 and 10% Pd/Fib. Silk fibroin
(1.00 g) was soaked in a rust-colored solution of palladium
acetate (1%: 21.2 mg, 5%: 106 mg, 10%: 211 mg) in MeOH
(30.0 mL) at room temperature for 4 days. The resulting
black fiber was filtered, washed vigorously with MeOH
(100 mL), and dried under reduced pressure to give the 1%
Pd/Fib. Anal. Found: C. 47.11; H, 6.18; N, 18.20: sample
2.309 mg: ash 0.08 mg. 5% Pd/Fib Anal. Found: C. 45.79;
H, 6.02; N, 17.59: sample 1.934 mg: ash 0.09 mg. 10%
Pd/Fib Anal. Found: C, 45.93; H, 6.04; N, 17.83: sample
1.797 mg: ash 0.13 mg.
5.96–5.86 (m, 1H), 5.29 and 5.23 (each d, JZ171.1,
10.8 Hz, each 1H), 5.20 (s, 2H), 4.13 (s, 2H), 4.10 (d, JZ
5.9 Hz, 2H); 13C NMR (CDCl3): dZ170.2, 135.4, 133.7,
128.6, 128.4, 127.6, 127.0, 118.2, 72.4, 67.1, 66.5; MS
(FAB: Gly) m/z 207 (MCCH, 9%), 149 (7%), 131 (5%);
HRMS (FAB: Gly) Calcd for C11H15O3 (MCCH):
207.1021. Found: 207.1025.
4.1.7.4. Benzyl 4-vinylbenzoate (7g). To a solution of
4-vinylbenzoic acid (0.74 g, 5.00 mmol), EDC$HCl (1.15 g,
6.00 mmol) and DMAP (61.1 mg, 0.50 mmol) in CH2Cl2
(15.0 mL) was added benzyl alcohol (541 mg, 5.00 mmol).
After the solution was refluxed for 1 h, the mixture was
extracted with chloroform (50 mL!2) and water (50 mL).
The organic layer was washed with brine (100 mL), dried
over MgSO4 and concentrated under reduced pressure. The
residue was applied to flash silica gel column chroma-
tography (hexane/etherZ100:1) to afford benzyl 4-vinyl-
4.1.7. Synthesis of substrate.
4.1.7.1. 2-Chlorobenzylazide (4i). To a solution of
2-chlorobenzylchloride (1.61 g, 10.0 mmol) in DMF
(10.0 mL) at room temperature was added sodium azide
(1.95 g, 30.0 mmol). The solution was stirred at room
temperature for 48 h, after which time the solvent was
removed under vacuum pressure. The residue was extracted
with ethyl acetate (100 mL) and water (100 mL). The
organic layer was washed with brine (100 mL), dried over
MgSO4 and concentrated under reduced pressure to afford
2-chlorobenzylazide (4i) as a colorless oil (1.03 g, 62%).
1H NMR (CDCl3): dZ7.29–7.43 (m, 4H), 4.26 (s, 2H);
13C NMR (CDCl3): dZ133.8, 133.3, 130.0, 129.8, 129.6,
1
benzoate (7g) as a pale yellow oil (0.93 g, 78%). H NMR
(CDCl3): dZ8.03 (d, JZ8.3 Hz, 2H), 7.47–7.34 (m, 7H),
6.75 (dd, JZ10.7, 17.6 Hz, 1H), 5.86 and 5.38 (each d, JZ
17.6 Hz, each 1H), 5.36 (s, 2H); 13C NMR (CDCl3): dZ
116.2, 142.1, 136.1, 136.0, 130.0, 129.3, 128.6, 128.2,
128.2, 126.1, 116.5, 66.7; MS (EI) m/z 238 (MC, 40%), 131

2226
T. Ikawa et al. / Tetrahedron 61 (2005) 2217–2231
(100%), 91 (46%), 77 (15%); HRMS (EI) Calcd for
C16H14O2 (MC): 238.0994. Found: 238.0985.
7.35 (m, 7H), 5.38 (s, 2H), 4.42 (s, 2H); 13C NMR (CDCl3):
dZ165.9, 140.5, 135.9, 130.2, 130.1, 128.6, 128.3, 128.2,
127.9, 66.8, 54.3; MS (EI) m/z 267 (MC, 28%), 239 (50%),
160 (40%), 132 (96%), 91 (100%), 77 (35%); HRMS (EI)
Calcd for C15H13N3O2 (MC): 267.1008. Found: 267.1000.
4.1.7.5. Benzyl 2-(benzyloxycarbonyl)cinnamate (7h).
To a solution of 2-carboxycinnamic acid (0.96 g,
5.00 mmol), EDC$HCl (2.30 g, 12.0 mmol) and DMAP
(112 mg, 1.00 mmol) in CH2Cl2 (10.0 mL) was added
benzyl alcohol (1.08 g, 10.0 mmol). The solution was stirred
at room temperature for 48 h, after which time the solvent
was removed under vacuum pressure. The residue was
extracted with ethyl acetate (100 mL) and water (100 mL).
The organic layer was washed with brine (100 mL), dried
over MgSO4 and concentrated under reduced pressure. The
residue was applied to flash silica gel column chroma-
tography (hexane/etherZ20:1) to afford benzyl 2-(benzyl-
oxycarbonyl)cinnamate (7h) as a colorless oil (958 mg,
51%). 1H NMR (CDCl3): dZ8.52 (d, JZ15.6 Hz, 1H), 7.99
(d, JZ7.8 Hz, 1H), 7.33–7.59 (m, 13H), 6.34 (d, JZ15.6 Hz,
1H), 5.36 (s, 2H), 5.26 (s, 2H); 13C NMR (CDCL3): dZ
166.5, 166.2, 144.4, 136.5, 136.1, 135.6, 132.4, 130.9, 130.0,
129.4, 128.6, 128.4, 128.4, 128.2, 128.0, 120.8, 67.2, 66.3;
MS (EI) m/z 372 (MC, 5%), 28 (100%), 91 (100%), 105
(12%), 77 (10%), 44 (10%); HRMS (EI) Calcd for C24H20O4
(MC): 372.1364. Found: 372.13615.
4.1.7.7. N-(Benzyloxycarbonyl)diallylamine (11).17 To
a solution of diallylamine (1.94 g, 20.0 mmol) in CH2Cl2
(10.0 mL) was added N-(benzyloxycarbonyloxy)succini-
mide (5.48 g, 22.0 mmol). The solution was stirred at
room temperature for 7 h, after which time the solvent was
removed under vacuum pressure. The residue was extracted
with ethyl acetate (50 mL) and water (50 mL). The organic
layer was washed with water (30 mL), sat. NaHCO3
solution (30 mL) and brine (30 mL), dried over MgSO4
and concentrated under reduced pressure to afford N-(ben-
zyloxycarbonyl)diallylamine (11) as a yellow oil (2.52 g,
55%). 1H NMR (CDCl3): dZ7.30–7.36 (m, 5H), 5.70–5.83
(m, 2H), 5.15 (s, 2H), 5.05–5.19 (m, 2H), 3.87–3.90 (m,
2H); HRMS (EI) Calcd for C14H18NO2 (MC): 232.1337.
Found: 232.1346.
4.1.7.8. N-(Benzyloxycarbonyl)aniline (14a).24 To a
solution of aniline (0.46 g, 5.00 mmol) in THF (10.0 mL)
was added N-(benzyloxycarbonyloxy)succinimide (1.45 g,
6.00 mmol). After the solution was stirred at room
temperature for 20 h, the mixture was extracted with ethyl
acetate (150 mL) and water (100 mL!2). The organic layer
was washed with brine (100 mL), dried over MgSO4 and
concentrated under reduced pressure. The residue was
applied to flash silica gel column chromatography (hexane/
etherZ20:1) to afford N-(benzyloxycarbonyl)aniline (14a)
4.1.7.6. Benzyl 4-azidomethylbenzoate (7i). To a
solution of 4-hydroxymethylbenzoic acid (1.52 g,
10.0 mmol), Et3N (1.70 mL, 12.0 mmol) in CH2Cl2
(10.0 mL) was added benzyl bromide (1.20 mL,
10.0 mmol). After the solution was stirred at room
temperature for 23 h, the mixture was extracted with
chloroform (100 mL) and water (100 mL). The organic
layer was washed with sat. NaHCO3 solution (100 mL) and
brine (100 mL), dried over MgSO4 and concentrated under
reduced pressure. The residue was applied to flash silica gel
column chromatography (hexane/etherZ2:1) to afford
benzyl 4-hydroxymethylbenzoate22 as a colorless solid
1
as a colorless solid (1.08 g, 95%). H NMR (CDCl3): dZ
7.65–7.25 (m, 1H), 7.06 (t, JZ7.3 Hz, 1H), 6.72 (brs, NH),
5.20 (s, 2H). Anal. Calcd for C14H13NO2: C, 73.99; H, 5.77;
N, 6.16. Found: C, 73.98; H, 5.61; N, 6.13.
4.1.7.9. N-Benzyloxycarbonyl-4-vinylaniline (14b).17
To a solution of 4-vinylaniline (1.00 g, 8.39 mmol) in
CH2Cl2 (10.0 mL) was added N-(benzyloxycarbonyloxy)-
succinimide (2.45 g, 10.1 mmol). The solution was stirred at
room temperature for 7 h, after which time the solvent was
removed under vacuum pressure. The residue was extracted
with ethyl acetate (50 mL) and water (50 mL). The organic
layer was washed with water (30 mL), sat. NaHCO3
solution (30 mL) and brine (30 mL), dried over MgSO4
and concentrated under reduced pressure to afford
N-benzyloxycarbonyl-4-vinylaniline (14b) as a pale yellow
1
(1.14 g, 47%). H NMR (CDCl3): dZ8.07 (d, JZ8.3 Hz,
2H), 7.46–7.32 (m, 7H), 5.37 (s, 2H), 4.77 (d, JZ5.9 Hz,
2H), 1.77 (t, JZ5.9 Hz, OH). Anal. Calcd for C15H14O3: C,
74.36; H, 5.82. Found: C, 74.47; H, 5.92.
To a solution of benzyl 4-hydroxymethylbenzoate (0.30 g,
1.24 mmol) in CCl4 (10.0 mL) was added Ph3P (0.52 g,
2.00 mmol). The solution was refluxed for 18 h, after which
time the solvent was removed under vacuum pressure. The
residue was applied to a flash silica gel column chroma-
tography (hexane/etherZ50:1) to afford benzyl 4-chloro-
1
1
methylbenzoate23 (0.26 g, 82%). H NMR (CDCl3): dZ
solid (1.99 g, 92%). H NMR (CDCl3): dZ7.35–7.40 (m,
9H), 6.67 (dd, JZ10.8, 17.6 Hz, 2H), 5.66 (d, JZ17.6 Hz,
1H), 5.20 (s, 2H). Anal. Calcd for C16H15NO2: C, 75.87; H,
5.97; N, 5.53. Found: C, 75.79; H, 5.99; N, 5.54.
8.07 (d, JZ8.3 Hz, 2H), 7.46–7.32 (m, 7H), 5.37 (s, 2H),
4.60 (s, 2H); MS (EI) m/z 262 (MCC2, 10%), 260 (MC,
33%), 155 (32%), 153 (100%), 91 (64%).
To a solution of benzyl 4-chloromethylbenzoate (0.26 g,
0.96 mmol) in DMF (10.0 mL) was added NaN3 (0.20 g,
3.00 mmol). The solution was stirred at room temperature
for 12 h, after which time the solvent was removed under
vacuum pressure. The residue was extracted with ethyl
acetate (100 mL) and water (100 mL). The organic layer
was washed with brine (100 mL), dried over MgSO4 and
concentrated under reduced pressure to afford benzyl
4-azidomethylbenzoate (7i) as a pale yellow oil (0.26 g,
98%). 1H NMR (CDCl3): dZ8.10 (d, JZ7.8 Hz, 2H), 7.47–
4.1.7.10. N-Allyl-N-(benzyloxycarbonyl)aniline (14c).17
To a solution of N-allylaniline (1.33 g, 10.0 mmol) in
CH2Cl2 (10.0 mL) was added N-(benzyloxycarbonyloxy)-
succinimide (2.91 g, 12.0 mmol). The solution was stirred at
room temperature for 7 h, after which time the solvent was
removed under vacuum pressure. The residue was extracted
with ethyl acetate (50 mL) and water (50 mL). The organic
layer was washed with water (30 mL), sat. NaHCO3
solution (30 mL) and brine (30 mL), dried over MgSO4
and concentrated under reduced pressure to afford

T. Ikawa et al. / Tetrahedron 61 (2005) 2217–2231
2227
N-allyl-N-(benzyloxycarbonyl)aniline (14c) as a yellow oil
(2.28 g, 85%). H NMR (CDCl3): dZ7.19–7.40 (m, 10H),
Calcd for C21H23NO4: C, 71.37; H, 6.56; N, 3.96. Found: C,
71.31; H, 6.53; N, 3.91.
1
5.86–5.98 (m, 1H), 5.16 (s, 2H), 5.10–5.20 (m, 2H), 4.26–
4.29 (m, 2H); HRMS (EI) Calcd for C17H17NO2 (MC):
267.1259. Found: 267.1250.
4.1.7.13.
N-Benzyloxycarbonyl-4-ethynylaniline
(14f).26 To a solution of 4-ethynylaniline (0.58 g,
5.00 mmol) in THF (10.0 mL) was added N-(benzyloxy-
carbonyloxy)succinimide (2.18 g, 9.00 mmol). The solution
was stirred at room temperature for 36 h, after which time
the solvent was removed under vacuum pressure. The
residue was extracted with ethyl acetate (50 mL) and water
(50 mL). The organic layer was washed with water (30 mL),
sat. NaHCO3 solution (30 mL) and brine (30 mL), dried
over MgSO4 and concentrated under reduced pressure. The
residue was applied to flash silica gel column chroma-
tography (hexane/etherZ10:1) to afford N-benzyloxy-
carbonyl-4-ethynylaniline (14f) as a flesh-colored solid
(1.17 g, 93%); mp 98.5–99 8C. 1H NMR (CDCl3): dZ7.45–
7.34 (m, 9H), 6.70 (brs, NH), 5.20 (s, 2H), 3.02 (s, 1H); 13C
NMR (CDCl3): dZ152.9, 138.3, 135.8, 133.0, 128.7, 128.5,
128.4, 118.2, 116.9, 83.5, 76.5, 67.2; MS (EI) m/z 251 (MC,
22%), 207 (12%), 91 (100%). Anal. Calcd for C16H13NO2:
C, 76.48; H, 5.21; N, 5.57. Found: C, 76.63; H, 5.24;
N, 5.49.
4.1.7.11. Cinnamyl N-(benzyloxycarbonyl)anthranil-
ate (14d). To a solution of cinnamyl anthranilate (1.20 g,
5.00 mmol) and NaH (60% dispersion in mineral oil, 0.36 g,
9.00 mmol) in THF (20.0 mL) was added benzyl chloro-
formate (1.29 g, 9.00 mmol). After the solution was stirred
at room temperature for 46 h, the mixture was extracted
with ethyl acetate (100 mL) and phosphate buffer (100 mL).
The organic layer was washed with brine (100 mL), dried
over MgSO4 and concentrated under reduced pressure. The
residue was applied to flash silica gel column chroma-
tography (hexane/etherZ20:1) to afford cinnamyl N-(ben-
zyloxycarbonyl)anthranilate (14d) as a colorless solid
(1.15 g, 59%); mp 72–72.5 8C. 1H NMR (CDCl3): dZ
10.59 (s, NH), 8.47 (d, JZ7.8 Hz, 1H), 8.47 (d, JZ7.8 Hz,
1H), 8.07 (d, JZ7.8 Hz, 1H), 7.54 (t, JZ7.8 Hz, 1H), 7.44–
7.25 (m, 5H), 7.04 (t, JZ7.8 Hz, 1H), 6.74 (d, JZ15.9 Hz,
1H), 6.38 (dt, JZ15.9, 6.3 Hz, 1H), 5.22 (s, 2H), 4.96 (d,
JZ6.3 Hz, 2H). Anal. Calcd for C24H21NO4: C, 74.40; H,
5.46; N, 3.62. Found: C, 74.42; H, 5.52; N, 3.66.
4.1.7.14. Methyl 4-bromocinnamate (18). To a solution
of 4-bromocinnamic acid (2.27 g, 10.0 mmol) in DMF
(5.00 mL) was added N,N-dimethylformamide dimethyl-
acetal (13.3 ml, 100 mmol). The solution was stirred at
room temperature for 24 h, after which time the solvent was
removed under vacuum pressure. The residue was extracted
with ethyl acetate (100 mL) and water (100 mL). The
organic layer was washed with sat. NaHCO3 solution
(100 mL), water (100 mL) and brine (100 mL), dried over
MgSO4 and concentrated under reduced pressure to afford
methyl 4-bromocinnamate (18) as a colorless solid
4.1.7.12. 50-Hexenyl 4-(benzyloxycarbonylamino)-
benzoate (14e). To a solution of 4-aminobenzoic acid
(1.37 g, 10.0 mmol) in THF (10.0 mL) was added N-(ben-
zyloxycarbonyloxy)succinimide (2.91 g, 12.0 mmol). The
solution was stirred at room temperature for 48 h, after
which time the solvent was removed under vacuum
pressure. The residue was extracted with ethyl acetate
(100 mL) and water (100 mL!2). The organic layer was
washed with brine (100 mL), dried over MgSO4 and
concentrated under reduced pressure. The residue was
applied to flash silica gel column chromatography (chloro-
form/methanolZ100:1) to afford 4-(benzyloxycarbonyl-
amino)benzoic acid25 as a fresh-colored solid (crude)
1
(1.53 mg, 64%); mp 88–93 8C. H NMR (CDCl3): dZ7.62
(d, JZ15.9 Hz, 1H), 7.52 (d, JZ8.6 Hz, 2H), 7.38 (d, JZ
8.6 Hz, 2H), 6.43 (d, JZ15.9 Hz, 1H), 3.81 (s, 3H);
13C NMR (CDCl3): dZ167.2, 143.5, 133.3, 132.1, 129.4,
124.5, 118.5, 51.8; MS (EI) m/z 242 (MCCH, 82%), 240
(MCKH, 84%), 211 (97%), 209 (100%), 183 (24%), 181
(24%), 102 (86%). Anal. Calcd for C10H9O2Br: C, 49.82; H,
3.76. Found: C, 49.83; H, 3.77.
1
(2.21 g, 81%). H NMR (CD3OD): dZ7.93 (d, JZ8.8 Hz,
2H), 7.54 (d, JZ8.8 Hz, 2H), 7.42–7.30 (m, 5H), 5.19 (s,
2H); MS (EI) m/z 271 (MC, 14%), 227 (11%), 91 (100%).
To a solution of 4-(benzyloxycarbonylamino)benzoic acid
(1.63 g, 6.00 mmol), EDC$HCl (1.38 g, 7.20 mmol) and
DMAP (0.60 g, 0.60 mmol) in CH2Cl2 (10.0 mL) was added
5-hexene-1-ol (601 mg, 6.00 mmol). After the solution was
refluxed for 2 h, the mixture was extracted with CH2Cl2
(100 mL) and water (100 mL). The organic layer was
washed with brine (100 mL), dried over MgSO4 and
concentrated under reduced pressure. The residue was
applied to flash silica gel column chromatography (chloro-
form) to afford 50-hexenyl 4-(benzyloxycarbonylamino)-
benzoate (14e) as a colorless solid (1.27 g, 60%); mp 58–
59 8C. 1H NMR (CDCl3): dZ7.99 (d, JZ8.8 Hz, 2H), 7.47–
7.35 (m, 7H), 6.93–6.87 (brs, NH), 5.87–5.77 (m, 1H), 5.22
(s, 2H), 5.03 and 4.98 (each d, JZ17.1, 9.8 Hz, each 1H),
4.30 (t, JZ7.1 Hz, 2H), 2.13 (q, JZ7.1 Hz, 2H), 1.81–1.74
(m, 2H), 1.61–1.50 (m, 2H); 13C NMR (CDCl3): dZ166.2,
152.8, 142.0, 138.4, 135.7, 130.9, 128.7, 128.5, 128.4,
125.3, 117.6, 114.8, 67.3, 64.8, 33.3, 28.2, 25.3; MS (EI)
m/z 353 (MC, 5%), 271 (7%), 227 (9%), 163 (34%), 146
(100%), 108 (24%), 91 (72%), 82 (42%), 44 (46%). Anal.
4.1.7.15. Ethyl 4-(N-bezyloxyxcarbonylamino)cinna-
mate (19). To a solution of ethyl 4-aminocinnamate
(761 mg, 4.00 mmol) in THF (10.0 mL) was added
N-(benzyloxycarbonyloxy)succinimide (1.16 g, 4.80 mmol).
The solution was refluxed for 48 h, after which time the
solvent was removed under vacuum pressure. The residue
was extracted with ethyl acetate (100 mL) and water
(100 mL). The organic layer was washed with brine
(100 mL), dried over MgSO4 and concentrated under
reduced pressure. The residue was applied to flash silica
gel column chromatography (hexane/etherZ10:1) to afford
ethyl 4-(N-bezyloxyxcarbonylamino)cinnamate (19) as a
1
colorless solid (405 mg, 31%); mp 119–121 8C. H NMR
(CDCl3): dZ7.62 (d, JZ15.9 Hz, 1H), 7.35–7.49 (m, 9H),
6.78 (s, 1H), 6.34 (d, JZ15.9 Hz, 1H), 5.21 (s, 2H), 4.25 (q,
JZ7.2 Hz, 2H), 1.33 (t, JZ7.2 Hz, 3H); 13C NMR (CDCl3):
dZ167.2, 153.0, 143.9, 139.6, 135.8, 129.7, 129.1, 128.7,
128.5, 128.4, 118.5, 116.9, 67.3, 60.4, 14.3; MS (EI) m/z
325 (MC, 42%), 281 (20%), 91 (100%). Anal. Calcd for

2228
T. Ikawa et al. / Tetrahedron 61 (2005) 2217–2231
C19H19O2NO4: C, 70.14; H, 5.89; N, 4.30. Found: C, 70.17;
H, 5.94; N, 4.33.
Commercially available (Aldrich), 99% as a light green
solid; mp 129–131 8C. 1H NMR (CDCl3): dZ7.26 and 7.88
(each d, JZ8.3 Hz, each 2H), 3.29 (t, JZ6.6 Hz, 2H), 2.81
(t, JZ6.6 Hz, 2H), 2.41 (s, 3H); 13C NMR (CDCl3): dZ
197.5, 178.8, 144.1, 133.9, 129.3, 128.2, 33.0, 28.1, 21.6;
MS (EI) m/z 192 (MC, 10%), 119 (100%), 91 (32%), 65
(10%). Anal. Calcd for C11H12O3: C, 68.72; H, 6.30. Found:
C, 68.73; H, 6.27.
4.1.8. General procedure of chemoselective hydrogen-
ation using 2.5% Pd/Fib. After two vacuum/H2 cycles to
remove air from the round-bottom flask, a mixture of the
substrate (1.00 mmol), 2.5% Pd/Fib (10 wt% of the
substrate) in methanol (5.00 mL) was vigorously stirred at
room temperature (ca. 20 8C) or at 50 8C under ambient
pressure of hydrogen (balloon). The reaction mixture was
filtered through a filter paper, and the filtrate was
concentrated under reduced pressure to afford the product.
4.1.8.7. 4-(2-Phenylethyl)benzaldehyde (2g).29 Yield
100% as a light yellow solid. 1H NMR (CDCl3): dZ9.97 (s,
1H), 7.79 (d, JZ8.3 Hz, 2H), 7.14–7.32 (m, 9H), 2.92–3.03
(m, 4H); 13C NMR (CDCl3): dZ192.0, 149.1, 140.9, 134.6,
129.9, 129.2, 128.4, 126.2, 38.0, 34.7; MS (EI) m/z 210
(MC, 35%), 107 (28%), 91 (100%), 77 (25%). Anal. Calcd
for C15H14O$1/2H2O: C, 82.16; H, 6.89. Found: C, 82.51;
H, 6.56.
4.1.8.1. 3-Phenylpropiophenone (2a).27 Yield 97% as a
1
colorless solid; mp 74–75 8C. H NMR (CDCl3): dZ7.96
(d, JZ7.3 Hz, 2H), 7.56 (t, JZ7.3 Hz, 1H), 7.45 (t, JZ
7.3 Hz, 2H), 7.20–7.35 (m, 5H), 3.31 (t, JZ7.6 Hz, 2H),
3.07 (t, JZ7.6 Hz, 2H); 13C NMR (CDCl3): dZ199.2,
141.3, 136.9, 133.0, 128.6, 128.5, 128.4, 128.0, 126.1, 40.4,
30.1; MS (EI) m/z 210 (MC, 65%), 105 (100%), 77 (40%).
Anal. Calcd for C15H14O: C, 85.68; H, 6.71. Found: C,
85.54; H, 6.68.
4.1.8.8. 2-Propyloxybenzaldehyde (2h).30 Yield 100%
1
as a light yellow oil. H NMR (CDCl3): dZ10.53 (s, 1H),
7.83 (dd, JZ1.4, 7.9 Hz, 1H), 7.53 (dt, JZ0.65, 7.9 Hz,
1H), 7.01 (t, JZ7.9 Hz, 1H), 6.98 (d, JZ7.9 Hz, 1H), 4.05
(t, JZ6.8 Hz, 2H), 1.84–1.93 (m, 2H), 1.08 (t, JZ7.3 Hz,
3H); 13C NMR (CDCl3): dZ189.9, 189.8, 161.6, 135.9,
128.2, 120.5, 112.5, 70.0, 22.5, 10.5; MS (EI) 166 (MCC2,
25%), m/z 164 (MC, 28%), 123 (65%), 121 (100%), 120
(35%), 57 (29%); HRMS (EI) Calcd for C10H12O2 (MC):
164.0837. Found: 164.0835.
4.1.8.2. 1,5-Diphenylpentane-1-one (2b).28 Yield 100%
1
as a yellow oil. H NMR (CDCl3): dZ7.94 (d, JZ7.3 Hz,
2H), 7.14–7.57 (m, 8H), 2.99 (t, JZ7.3 Hz, 2H), 2.67 (t, JZ
7.6 Hz 2H), 1.68–1.84 (m, 4H); 13C NMR (CDCl3): dZ
142.2, 137.0, 132.9, 128.5, 128.4, 128.3, 128.0, 125.8,
125.7, 38.4, 35.8, 31.1, 24.0; MS (EI) m/z 238 (MC, 29%),
133 (34%), 120 (87%), 105 (100%), 91 (40%), 77 (60%);
HRMS (EI) Calcd for C17H18O (MC): 238.1358. Found:
238.1365.
4.1.8.9. Methylmanderate (2i). Commercially available
(Aldrich), 98% as a colorless solid. 1H NMR (CDCl3): dZ
7.30–7.43 (m, 5H), 5.18 (s, 1H), 3.76 (s, 3H).
4.1.8.3. 4-Hydroxy-3-propylacetophenone (2c). Yield
99% as a green solid; mp 93–95 8C. 1H NMR (CDCl3): dZ
7.79 (s, 1H), 6.91 and 7.73 (each d, JZ8.3 Hz, each 1H),
2.64 (t, JZ7.8 Hz, 2H), 2.58 (s, 3H), 1.64–1.69 (m, 2H),
0.97 (t, JZ7.3 Hz, 3H); 13C NMR (CDCl3): dZ198.7,
159.4, 131.2, 129.5, 129.1, 128.6, 115.1, 31.9, 26.2, 22.6,
13.9; MS (EI) m/z 178 (MC, 30%), 163 (100%), 149 (23%).
Anal. Calcd for C11H14O2$1/10: C, 73.39; H, 7.95. Found:
C, 73.46; H, 7.95.
4.1.8.10. Benzoin (2j). Commercially available
(Aldrich), 98% as a colorless solid. 1H NMR (CDCl3):
dZ7.92 (d, JZ7.7 Hz, 2H), 7.53 (t, JZ7.7 Hz, 1H), 7.40 (t,
JZ7.7 Hz, 2H), 7.34–7.27 (m, 5H), 5.96 (d, JZ6.1 Hz, 1H),
4.55 (d, JZ6.1 Hz, OH).
4.1.8.11. 4-Chloroethylbenzene (6e). Commercially
available (TCI), 100%. 1H NMR (CDCl3): dZ7.14 and
7.22 (each d, JZ8.3 Hz, each 2H), 2.59 (q, JZ7.7 Hz, 2H),
1.86 (t, JZ7.7 Hz, 3H); MS (EI) m/z 140 (MC, 35%), 127
(31%), 125 (100%), 105 (40%).
4.1.8.4. 2-Propyl-4,6-dibenzoylresorcinol (2d). Yield
74% as a light green solid; mp 167–169 8C. 1H NMR
(CDCl3): dZ13.16 (s, 2H), 7.88 (s, 1H), 7.38–7.58 (m,
12H), 2.76 (t, JZ7.6 Hz, 2H), 1.62–1.71 (m, 2H), 1.04 (t,
JZ7.3 Hz, 3H); 13C NMR (CDCl3): dZ200.3, 167.4, 140.4,
137.5, 131.9, 128.8, 118.4, 112.0, 24.1, 21.6, 14.2; MS (EI)
m/z 360 (MC, 55%), 332 (24%), 331 (100%), 332 (24%),
253 (16%), 175 (33%), 105 (16%), 77 (16%). Anal. Calcd
for C23H20O4: C, 76.65; H, 5.59. Found: C, 76.44; H, 5.64.
4.1.8.12. 40-Chloro-3-phenylpropiophenone (6f).31
Yield 98% as a colorless solid; mp 78–80 8C. H NMR
1
(CDCl3): dZ7.42, 7.89 (each d, JZ8.3 Hz, each 2H), 7.19–
7.32 (m, 5H), 2.37 (t, JZ7.7 Hz, 2H), 3.06 (t, JZ7.7 Hz,
2H); 13C NMR (CDCl3): dZ198.0, 141.0, 139.5, 135.2,
129.5, 128.9, 128.5, 128.4, 126.2, 40.4, 30.0; MS (EI) m/z
246 (MC, 15%), 244 (55%), 141 (34%), 139 (100%), 111
(30%), 105 (15%), 91 (14%), 77 (13%); HRMS (EI) Calcd
for C15H13OCl (MC): 244.0655. Found: 244.0661. Anal.
Calcd for C15H13OCl: C, 73.62; H, 5.35. Found: C, 73.70;
H, 5.21.
4.1.8.5. 3-Benzoylpropionic acid (2e). Commercially
available (Aldrich), 98% as a yellow solid; mp 117–119 8C.
1H NMR (CDCl3): dZ7.98 (d, JZ7.4 Hz, 2H), 7.57 (t, JZ
7.4 Hz, 1H), 7.47 (t, JZ7.4 Hz, 2H), 3.32 (t, JZ6.6 Hz,
2H), 2.82 (t, JZ6.6 Hz, 2H); 13C NMR (CDCl3): dZ197.8,
178.5, 136.4, 133.3, 128.0, 33.1, 28.0; MS (EI) m/z 178
(MC, 8%), 105 (100%), 77 (39%). Anal. Calcd for
C10H10O3: C, 67.39; H, 5.66. Found: C, 67.55; H, 5.59.
4.1.8.13. 3-(4-Chlorophenyl)propiophenone (6g).32
Yield 99% as a light green solid; mp 53–55 8C. H NMR
1
(CDCl3): dZ7.94 (d, JZ6.8 Hz, 2H), 7.17–7.60 (m, 7H),
3.04 and 3.28 (each t, JZ7.6 Hz, each 2H); 13C NMR
(CDCl3): dZ198.8, 139.7, 133.1, 129.8, 129.5, 129.2,
128.5, 128.0, 122.5, 40.1, 29.3; MS (EI) m/z 244 (MC,
4.1.8.6. 3-(4-Methylbenzoyl)propionic acid (2f).

T. Ikawa et al. / Tetrahedron 61 (2005) 2217–2231
2229
1
48%), 105 (100%), 77 (42%). Anal. Calcd for C15H13OCl:
C, 73.62; H, 5.35. Found: C, 73.66; H, 5.34.
98% as a colorless oil. H NMR (CDCl3): dZ7.18–7.37
(m, 10H), 5.11 (s, 2H), 2.97 (t, JZ7.8 Hz, 2H), 2.69 (t, JZ
7.8 Hz, 2H); 13C NMR (CDCl3): dZ173.0, 140.7, 136.2,
128.8, 128.6, 128.5, 126.6, 66.6, 36.1, 31.2; MS (EI) m/z
240 (MC, 5%), 180 (60%), 149 (26%), 107 (78%), 91
(100%), 77 (15%); HRMS (EI) Calcd for C16H16O2 (MC):
240.1150. Found: 2240.1160.
4.1.8.14. 2,3-Dichloro-4-sec-pentanoylphenoxyacetic
acid (6h).33 Yield 100% as a colorless solid. 1H NMR
(CDCl3): dZ6.80 and 7.27 (each d, JZ8.6 Hz, each 2H),
4.81 (s, 2H), 3.17–3.82 (m, 1H), 1.75–7.82 (m, 1H), 1.41–
1.47 (m, 1H), 1.17 (d, JZ6.8 Hz, 3H), 0.93 (t, JZ7.3 Hz,
3H); 13C NMR (CDCl3): dZ206.6, 172.5, 155.5, 135.2,
131.4, 126.9, 110.8, 65.6, 46.8, 26.0, 15.6, 11.6; MS (FAB:
Gly) m/z 307 (MCC2, 15%), 305 (MC, 25%). Anal. Calcd
for C13H14O4Cl$1/4H2O: C, 50.56; H, 4.74. Found: C,
50.64; H, 4.65.
4.1.8.23. Benzyl 4-ethylbenzoate (10g). Yield 97% as a
pale yellow oil. H NMR (CDCl3): dZ8.00 (d, JZ8.3 Hz,
1
2H), 7.46–7.25 (m, 7H), 5.36 (s, 2H), 2.70 (q, JZ7.7 Hz,
2H), 1.25 (t, JZ7.7 Hz, 3H); 13C NMR (CDCl3): dZ166.5,
149.9, 136.2, 129.8, 128.5, 128.1, 127.9, 127.6, 126.1, 66.4,
28.9, 15.2; MS (EI) m/z 240 (MC, 30%), 133 (100%), 91
(36%); HRMS (EI) Calcd for C16H16O2 (MC): 240.1150.
Found: 224. 1139.
4.1.8.15. 2-Chlorobenzylamine (6i). Commercially
available (TCI), 91% as a colorless oil. H NMR (CDCl3):
1
dZ7.18–7.39 (m, 4H), 3.94 (s, 2H), 2.57 (s, 1H); MS (EI)
265 (20%), 264 (18%), 230 (17%), 154 (19%) m/z 140
(MCK1, 25%), 127 (29%), 125 (100%), 91 (25%), 89
(24%).
4.1.8.24. Benzyl-2-(benzyloxycarbonyl)propionate
(10h). Yield 100% as a colorless oil. H NMR (CDCl3):
1
dZ7.95 (d, JZ7.2 Hz, 1H), 7.44–7.24 (m, 13H), 5.33 (s,
2H), 5.09 (s, 2H), 3.30 (t, JZ7.7 Hz, 2H), 2.70 (t, JZ
7.7 Hz, 2H); 13C NMR (CDCl3): dZ172.8, 167.0, 142.5,
136.0, 135.9, 132.3, 131.2, 131.0, 129.3, 128.6, 128.5,
128.3, 128.3, 128.2, 128.2, 128.1, 126.5, 66.7, 66.2, 35.8,
29.9; MS (EI) m/z 374 (MC, 3%), 265 (10%), 177 (53%),
149 (18%), 91 (100%); HRMS (EI) Calcd for C24H22O4
(MC): 374.1511. Found: 374.1518.
4.1.8.16. 4-Bromoethylbenzene (6j). Commercially
available (TCI), 100%. 1H NMR (CDCl3): dZ7.17 and
7.44 (each d, JZ8.3 Hz, each 2H), 2.66 (q, JZ7.7 Hz, 2H),
1.26 (t, JZ7.7 Hz, 3H).
4.1.8.17. Dipropyl 2,3,4,5-tetrabromophthalate (6k).34
Yield 94% as a colorless solid; mp 61–62 8C. H NMR
1
(CDCl3): dZ4.27 (t, JZ6.6 Hz, 4H), 1.75 (m, 4H), 1.01 (t,
JZ7.6 Hz, 6H); 13C NMR (CDCl3): dZ164.8, 138.3, 135.4,
132.0, 122.7, 68.5, 21.7, 10.4; MS (EI) m/z 566 (MC, 12%),
524 (9%), 483 (29%), 482 (40%), 481 (30%), 466 (60%),
465 (100%), 464 (65%), 420 (12%).
4.1.8.25. Benzyl 4-aminomethylbenzoate (10i).37 Yield
100%. 1H NMR (CDCl3): dZ8.04 (d, JZ8.3 Hz, 2H), 7.46–
7.26 (m, 7H), 5.36 (s, 2H), 3.94 (s, 2H); MS (EI) m/z 241
(MC, 20%), 240 (29%), 150 (40%), 134 (75%), 106 (100%),
91 (90%).
4.1.8.18. Benzyl propionate (10b). Commercially
available (Aldrich), 91% determined by 1H NMR.
1H NMR (THF-d8): dZ7.29–7.20 (m, 5H), 5.02 (m, 2H),
2.29–2.25 (m, 2H), 1.02 (t, JZ7.8 Hz, 3H).
4.1.8.26. N-Benzyloxycarbonyl-4-ethylaniline (16b).2a
Yield 97% as a pale yellow powder; mp 72–72.5 8C. H
NMR (CDCl3): dZ7.41–7.26 (m, 7H), 7.13 (d, JZ8.3 Hz,
2H), 6.60 (brs, NH), 5.19 (s, 2H), 2.60 (q, JZ7.6 Hz, 2H),
1.21 (t, JZ7.6 Hz, 3H); 13C NMR (CDCl3): dZ153.5,
139.6, 136.2, 135.4, 128.6, 128.3, 128.3, 119.0, 66.9, 28.2,
15.7.
1
4.1.8.19. Benzyl isobutylate (10c). Commercially avail-
able (TCI), 93% determined by 1H NMR. 1H NMR
(THF-d8): dZ7.29–7.20 (m, 5H), 5.02 (s, 2H), 2.52–2.46
(m, 1H), 1.08 (d, JZ7.0 Hz, 6H).
4.1.8.27. N-Benzyloxycarbonyl-N-propylaniline (16c).
Yield 97% as a light brown oil. 1H NMR (CDCl3): dZ7.37–
7.19 (m, 10H), 5.14 (s, 2H), 3.64 (t, JZ7.4 Hz, 2H), 1.59–
1.43 (m, 2H), 0.87 (t, JZ7.4 Hz, 3H); 13C NMR (CDCl3):
dZ155.5, 141.9, 136.8, 128.9, 128.3, 127.7, 127.5, 127.3,
126.6, 67.0, 52.1, 21.5, 11.1; MS (EI) m/z 269 (MC, 30%),
196 (20%), 91 (100%); HRMS (EI) Calcd for C17H19NO2
(MC): 269.1420. Found: 269.1416.
4.1.8.20. Benzyl 2-methylbutylate (10d).35 77% as a
colorless oil. 1H NMR (CDCl3): dZ7.36–7.31 (m, 5H), 5.12
(s, 2H), 2.45–2.40 (m, 1H), 1.74–1.67 (m, 1H), 1.53–1.46
(m, 1H), 1.16 (d, JZ7.2 Hz, 3H), 0.90 (t, JZ7.2 Hz, 3H);
13C NMR (CDCl3): dZ176.6, 136.3, 128.5, 128.1, 128.0,
66.0, 41.1, 26.8, 16.6, 11.6; MS (EI) m/z 192 (MC, 25%),
181 (67%), 180 (50%), 179 (40%), 165 (25%), 108, (20%),
91 (100%), 57 (43); HRMS (EI) Calcd for C12H16O2 (MC):
192.1150. Found: 192.1156.
4.1.8.28. 3-Phenylpropyl N-(benzyloxycarbonyl)-
anthranilate (16d). Yield 99% as a pale yellow solid; mp
40–41 8C. 1H NMR (CDCl3): dZ10.59 (s, NH), 8.46 (d, JZ
7.8 Hz, 1H), 7.97 (d, JZ7.8 Hz, 1H), 7.53 (t, JZ7.8 Hz,
1H), 7.43–7.20 (m, 5H), 5.21 (s, 2H), 4.32 (t, JZ7.0 Hz,
2H), 2.78 (t, JZ7.0 Hz, 2H), 2.14–2.07 (m, 2H); 13C NMR
(CDCl3): dZ168.0, 153.4, 141.7, 140.9, 136.1, 134.5,
130.8, 128.5, 128.4, 128.2, 126.1, 118.8, 114.7, 66.8, 64.6,
32.3, 30.1; MS (EI) m/z 389 (MC, 10%), 226 (9%), 208
(18%), 118 (40%), 117 (32%), 91 (100%); HRMS (EI)
Calcd for C24H23NO4 (MC): 389.1633. Found: 389.1627.
4.1.8.21. Benzyl propyloxyacetate (10e). Yield 99% as
a light brown oil. 1H NMR (CDCl3): dZ7.37–7.33 (m, 5H),
5.20 (s, 2H), 4.12 (s, 2H), 3.49 (t, JZ7.2 Hz, 2H), 1.69–1.60
(m, 2H), 0.93 (t, JZ7.2 Hz, 3H); 13C NMR (CDCl3): dZ
170.5, 135.5, 128.5, 128.4, 73.5, 68.2, 66.4, 22.7, 10.4; MS
(FAB, NBA) m/z 209 (MCCH, 20%); HRMS (FAB, NBA)
Calcd for C12H17O3 (MCCH): 209.1178. Found: 209.1172.
4.1.8.22. Benzyl 3-phenylpropionate (10f).36 Yield

2230
T. Ikawa et al. / Tetrahedron 61 (2005) 2217–2231
5. (a) Lucas, F. Nature 1966, 210, 952–953. (b) Mita, K.;
4.1.8.29. Hexyl 4-(benzyloxycarbonylamino)benzoate
1
Ichimura, S.; James, T. C. J. Mol. Evol. 1994, 38, 583–592.
6. (a) Hojo, N.; Shirai, H. SEN-I GAKKAISHI 1966, 22, 527–531.
(b) Koide, N.; Inagaki, N.; Katsuura, K. SEN-I GAKKAISHI
1977, 33, T166–T169. (c) Shimizu, F.; Sakaguchi, I. SEN-I
GAKKAISHI 1980, 36, T127–T131.
(16e). Yield 100% as a colorless solid; mp 85–86 8C. H
NMR (CDCl3): dZ7.99 (d, JZ8.8 Hz, 2H), 7.47–7.34 (m,
7H), 6.86 (brs, NH), 5.22 (s, 2H), 4.29 (t, JZ7.0 Hz, 2H),
1.78–1.71 (m, 2H), 1.43–1.32 (m, 6H), 0.90 (t, JZ7.0 Hz,
3H); 13C NMR (CDCl3): dZ166.2, 152.8, 141.9, 135.7,
130.9, 128.7, 128.5, 128.4, 125.4, 117.6, 67.4, 65.0, 31.5,
28.7, 25.7, 22.5, 14.0; MS (EI) m/z 355 (MC, 18%), 311
(12%), 163 (44%), 146 (42%), 91 (100%); HRMS (EI)
Calcd for C21H25NO4 (MC): 355.1784. Found: 355.1793.
7. (a) Akabori, S.; Sakurai, S.; Izumi, Y.; Fujii, Y. Nature 1956,
178, 323–324. (b) Izumi, Y. Bull. Chem. Soc. Jpn 1959, 32,
932–936. 936–942 and 942–945. (c) Akamatsu, A.; Izumi, Y.;
Akabori, S. Bull. Chem. Soc. Jpn 1961, 34, 1067–1072.
(d) Akamatsu, A.; Izumi, Y.; Akabori, S. Bull. Chem. Soc. Jpn
1961, 35, 1706–1711.
4.1.8.30. Dihydrojasmone (21). Commercially available
1
8. Zhou, Y.; Chen, W.; Itoh, H.; Naka, K.; Ni, Q.; Yamane, H.;
Chujo, Y. Chem. Commun. 2001, 2518–2519.
(TCI), 60% as a colorless oil. H NMR (CDCl3): dZ2.49–
2.47 (m, 2H), 2.37–2.47 (m, 2H), 2.16 (t, JZ7.3 Hz, 2H),
2.05 (s, 3H), 1.68–1.24 (m, 6H), 0.87 (t, JZ7.3 Hz, 3H); MS
(EI) m/z 166 (MC, 15%), 151 (58%), 137 (30%), 123 (25%),
110 (100%), 105 (24%), 81 (24%), 67 (29%); HRMS (EI)
Calcd for C11H18O (MC): 166.1358. Found: 166.1364.
9. Sajiki, H.; Ikawa, T.; Hirota, K. Tetrahedron Lett. 2003, 44,
171–174. Sajiki, H.; Ikawa, T.; Hirota, K. Tetrahedron Lett.
2003, 57, 4837–4839.
10. Day, R. A.; Underwood, A. L. Quantitative Analysis; Prentice-
Hall: Engewood Cliffs, 1967.
11. Nash, T. Biochemistry 1953, 55, 416–421.
4.1.9. General procedure of hydrogenation using 5%
Pd/C or Pd/C(en) (Schemes 7 and 8). After two vacuum/
H2 cycles to remove air from the reaction tube, a mixture of
the substrate (1.00 mmol), 5% Pd/C or Pd/C(en) (10 wt%
of the substrate) in the solvent (1.00 mL) was vigorously
stirred at room temperature (ca. 20 8C) or at 50 8C under
ambient pressure of hydrogen (balloon). The reaction
mixture was filtered using a membrane filter (Millipore
Millexw-LG, 0.20 mm). The quantitative conversion of 11
and 14a, and the product ratio of 7f and 14b were confirmed
12. Sajiki, H.; Hattori, K.; Hirota, K. J. Chem. Soc., Perkin Trans.
1 1998, 4043–4044. Hattori, K.; Sajiki, H.; Hirota, K.
Tetrahedron 2001, 57, 4817–4824.
13. It is well known that aromatic chlorides are much less reactive
than aromatic bromides and iodides and, hence, the dechlori-
nation of aromatic chloride cannot readily be achieved and the
hydrodechlorination reactions are very frequently incom-
plete,1 see: (a) Hara, R.; Sato, K.; Sun, W.-H.; Takahashi, T.
Chem. Commun. 1999, 845–846. (b) Sajiki, H.; Kume, A.;
Hattori, K.; Hirota, K. Tetrahedron Lett. 2002, 43, 7247–7250.
14. Green, T. W.; Wuts, P. G. M. Protective Groups in Organic
Synthesis, 3rd ed.; Wiley: New York, 1999.
1
by H NMR of the crude mixture.
15. Misiti, D.; Zappia, G.; Monach, G. D. Synthesis 1999,
873–877.
Acknowledgements
16. (a) Kuzuhara et al. have reported the chemoselective
hydrogenation of an azido group in the presence of an
aliphatic N-Cbz protective group using Raney Ni, which must
be added into the reaction mixture in small portions with
careful monitoring to avoid cleavage of the N-Cbz group.
Kuzuhara, H.; Mori, O.; Emoto, S. Tetrahedron Lett. 1976,
379–382. (b) Shinada and Ohfune et al. reported a chemo-
selective hydrogenation of olefin and benzyl ester functional-
ities in the presence of N-Cbz and benzyl ether protective
groups using Pd/C while the stability of the N-Cbz group under
the conditions was time-dependent. Shinada, T.; Hayashi, K.;
Yoshida, Y.; Ohfune, Y. Synlett 2000, 1506–1508.
We are very grateful to Drs Hiromi Yamada and Kozo
Tsubouchi of National Institute of Agrobiological Sciences
for valuable discussions and help with the preparation of
Pd/Fib catalyst.
References and notes
1. For selected reviews on reductions, see: (a) Larock, R. C.
Comprehensive Organic Transformations, 2nd ed.; Wiley-
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