Pd/C-catalyzed chemoselective hydrogenation in the presence of a phenolic MPM protective group using pyridine as a catalyst poison

Article abstract of DOI:10.1248/cpb.51.320

Employment of a Pd/C-pyridine combination as a catalyst is a very useful method for the selective removal (hydrogenolysis) of phenolic O-benzyl, N-Cbz and benzyl ester protective groups and for the selective hydrogenation of nitro and olefin functions of phenol derivatives protected with the MPM group. These discriminatory results are apparently attributable to the effect of pyridine. The MPM group could be extensively applied to chemoselective hydrogenation as a protective group for phenolic hydroxyl functions.

Full text of DOI:10.1248/cpb.51.320

320
Notes
Chem. Pharm. Bull. 51(3) 320—324 (2003)
Vol. 51, No. 3
Pd/C-Catalyzed Chemoselective Hydrogenation in the Presence of a
Phenolic MPM Protective Group Using Pyridine as a Catalyst Poison
Hironao SAJIKI* and Kosaku HIROTA*
Laboratory of Medicinal Chemistry, Gifu Pharmaceutical University; 5–6–1 Mitahora-higashi, Gifu 502–8585, Japan.
Received September 24, 2002; accepted December 9, 2002
Employment of a Pd/C–pyridine combination as a catalyst is a very useful method for the selective removal
(hydrogenolysis) of phenolic O-benzyl, N-Cbz and benzyl ester protective groups and for the selective hydrogena-
tion of nitro and olefin functions of phenol derivatives protected with the MPM group. These discriminatory re-
sults are apparently attributable to the effect of pyridine. The MPM group could be extensively applied to
chemoselective hydrogenation as a protective group for phenolic hydroxyl functions.
Key words Pd/C; chemoselectivity; MPM ether; hydrogenation; pyridine; catalyst poison
While numerous methods are reported in the literature for drogenolysis conditions. However, the stronger suppressive
the reduction using Pd/C, selective hydrogenation of re- effect of pyridine toward the hydrogenolysis became apparent
ducible functionalities, such as olefin, Cbz protective group, by detailed monitoring of the reaction progress (Fig. 1).
benzyl ester and nitro group, in the presence of a benzyl
It would be strongly desirable to develop a range of ben-
ether has not been fully addressed.1—3) Benzyl protection of a zyl-type protective groups possessing different stabilities
hydroxyl group is a widely used protective method in syn- against the Pd/C-catalyzed hydrogenolysis. There is only one
thetic chemistry because of the chemical stability and the effective report for the chemoselective suppression of the hy-
mild conditions involved in its removal by catalytic hy- drogenolysis of phenolic benzyl ethers using a sterically hin-
drogenolysis.4) A few selective reductions of other reducible dered 2,4-dimethylbenzyl group although the suppressive ef-
functionalities were previously accomplished in the presence fect is not perfect.14) These results had led us to investigate
of a benzyl ether by catalytic hydrogenation using a hetero- whether a combination of the addition of pyridine and the
geneous catalyst.5—8) Recently, we also found that addition of electronic or steric properties of the benzyl group can control
a nitrogen-containing base such as ammonia, triethylamine, the rate of cleavage, which should derive the hydrogenolysis-
pyridine, ammonium acetate, to a Pd/C-catalyzed reduction resistant benzyl protective groups of phenolic hydroxyl
system selectively suppressed the hydrogenolysis of an groups.
aliphatic benzyl ether with smooth hydrogenation of other re-
Hydrogenolysis of several 1,4-dibenzyloxybenzene deriva-
ducible functionalities such as olefin, N-Cbz, benzyl ester tives (3a—f) was carried out using 5% Pd/C and pyridine
and azido.9—11) However, the selective suppression of hy- combination (Table 1). The reaction was carried out under
drogenolysis using mild catalyst poisons was not applicable ordinary hydrogen pressure (balloon) using 0.5 eq of pyri-
to the benzyl protective group for phenolic hydroxyl func- dine and 5% Pd/C (10% of the weight of 3a—f) in MeOH at
tions. During the course of our further study on the Pd/C-cat- room temperature (rt) for 24 h. The products distributions
alyzed chemoselective hydrogenolysis, we found a significant were calculated based on the integration ratio of each peak of
difference in the suppressive effect on the hydrogenolysis of TLC scanner (Shimadzu CS-9000) and were corrected by
phenolic O-benzyl protective groups depending upon the ni- molar extinction coefficients of the substrates 3a—f, the
trogen-containing bases employed as an additive. By using a
Pd/C–2,2Ј-dipyridyl combination as a catalyst for the hydro-
genation, both aliphatic and phenolic O-benzyl protective
groups can be ultimately retained without any hydrogenoly-
sis.10—12) On the other hand, we continuously investigated
further applicable procedures for a chemoselective hydro-
genation without the hydrogenolysis of a benzyl-type protec-
tive group on phenolic hydroxyl functions. Herein, we report
the chemoselective suppression of the hydrogenolysis of the
p-methoxybenzyl (MPM) protective group for phenolic hy-
droxyl functions under the Pd/C-catalyzed hydrogenation
conditions in the presence of pyridine as a mild catalyst poi-
son.6)
Our initial studies were conducted using Boc–Tyr(Bn)–
OMe (1)11) as the reactant. The hydrogenolysis of the pheno-
lic benzyl ether of 1 was examined with different additives to
form Boc–Tyr–OMe (2), and the time course on the hy-
drogenolysis (balloon) of 1 using 5% Pd/C plus 0.5 eq of am-
monia or pyridine is shown in Fig. 1. The phenolic benzyl
ether of 1 could be rapidly cleaved within 2 h under both hy-
Fig. 1. Time Course on the Hydrogenolysis (Balloon) of 1 at Room Tem-
perature Using 5% Pd/C in the Presence of Ammonia or Pyridine
* To whom correspondence should be addressed. e-mail: sajiki@gifu-pu.ac.jp
© 2003 Pharmaceutical Society of Japan

March 2003
321
products 4a—f and 5. As shown in Table 1, the hydrogenoly- pressing the hydrogenolysis (compare entries 3 and 4) than
sis of substituted benzyl-type groups of 3b—f was especially the introduction of an ortho methyl group (compare entries 2
depressed by the addition of pyridine while at least one ben- and 3). This study identifies that the two major factors con-
zyl protective group of 3a—f was entirely hydrogenolyzed trolling the hydrogenolysis of the 2,4,6-trimethylbenzyl or
for 24 h in each case. It is interesting to note that the hy- MPM protective group are the affinity of pyridine for the pal-
drogenolysis of the 2,4,6-trimethylbenzyl group and p- ladium surface and the inhibitory action on the palladium
methoxybenzyl (MPM) group was perfectly suppressed surface (active site)–benzylic site conjugation by the elec-
under the reaction conditions (entries 5, 6). It is possible that tronic properties of the 2,4,6-trimethylbenzyl group and the
pyridine can compete with the 2,4,6-trimethylbenzyl group MPM group.
and the MPM group for the active sites on the palladium.
The present suppression method for the deprotection of
This was also strongly suggested in a control experiment the 2,4,6-trimethylbenzyl or MPM group of the phenolic hy-
where hydrogenolysis of substrates 3a—f without pyridine droxyl group can be applied to the selective hydrogenation of
proceeded much more smoothly (Table 1, the products ratios some substrates which possess other reducible functionali-
in parentheses). The suppressive effect of the hydrogenolysis ties, such as phenolic benzyl ether, N-Cbz, benzyl ester,
of substituted benzyl-type groups of 3b—f can be ascribed to nitro, or olefin functions, within the molecule. For synthetic
the electronic properties of the methyl and methoxy sub- purposes, it would be desirable to find a new protective
stituents on the benzene ring rather than the steric hindrance group which is more stable under various synthetic condi-
effect of methyl groups on the ortho positions of 3c—e since tions but more labile under the special deprotection process.
the introduction of the second methyl group on the para po- We anticipate that the MPM group, a popular protective
sition of the benzene ring was much more effective in sup- group of alcohols and phenols,15,16) would fulfill these crite-
ria, and it was chosen as a benzyl-type protective group for
Table 1. Effect of the Substituents on the Aromatic Ring of Benzyl Group
toward the Hydrogenolysis of 3a—f
further investigation because of its chemical stability and
concise and wide variety of procedures for the deprotection
(DDQ or CAN oxidation,17) TFA treatment,18) NaBH3CN–
BF3·Et2O reduction,19) and Pd/C-catalyzed hydrogenation17)).
To investigate the synthetic utility of these results, the se-
lective removal of MPM and benzyl groups was conducted
on substrates 6 (Chart 1). The results show that the benzyl
group of 6 can be cleanly removed from the phenolic hy-
droxyl group without deprotection of the MPM group to give
Products ratioa,b)
7 in 96% yield as the sole product. Though the debenzylation
Entry
Substrate (3)
R
was completed within 1 h, the reaction was allowed to stand
for 24 h to prove the selectivity of the deprotection (hy-
drogenolysis). The control experiment of the dipeptide, Boc–
Tyr(Bn)–Thr(MPM)–OMe (6) under the hydrogenolysis con-
ditions without pyridine results in the complete cleavage of
both benzyl and MPM ethers to give the corresponding
Boc–Tyr–Tyr–OMe (8) in 78% yield (Chart 1).
4 : 5
1
2
3a
3b
Bn
17 : 83 (0 : 100)
52 : 48 (0 : 100)
3
3c
32 : 68 (0 : 100)
To explore the generality of the chemoselective hydro-
genation of MPM ether derivatives some substrates possess-
ing other reducible functionalities were studied using 5%
Pd/C in the presence of 0.5 eq of pyridine. As shown in Table
2, the selective hydrogenolysis of O-Bn (entry 1), benzyl
ester (entry 4) and N-Cbz (entry 5) protective groups and the
selective hydrogenation of nitro (entry 3) and olefin (entry 2)
functionalities were entirely successful on substrates coexist-
ing with a phenolic O-MPM protective group. The MPM
4
5
6
3d
3e
3f
90 : 10 (60 : 40)
100 : 0 (89 : 11)
100 : 0 (49 : 51)
a) Reactions were followed by TLC scanner (Shimadzu CS-9000). b) The prod-
ucts ratios in parenthesis were obtained without pyridine.
Chart 1

322
Vol. 51, No. 3
Table 2. Chemoselective Hydrogenation Phenolic MPM Ethers in the Presence of Pyridine
Entry
1
Substrate (ROMPM)
Solvent
MeOH
Reaction time (h)
24b)
Product
Yield (%)a)
98
96
2
3
DMF
DMF
2
1
94
95
4
5
MeOH : Dioxane (1 : 1)
MeOH : Dioxane (1 : 1)
24c)
24d)
86
a) Isolated yield. b) Reaction was completed within 5 h by TLC scanner (Shimadzu CS-9000). c) Reaction was completed within 1 h by TLC scanner. d) Reaction was
completed within 2.5 h by the TLC scanner.
1,4-Dibenzyloxybenzene (3a) To a stirred mixture of 4-benzyloxyphe-
nol (4a) (1.00 g, 4.99 mmol) and NaH (60% w/w in mineral oil, 0.20 g,
5.00 mmol) in anhydrous N,N-dimethylformamide (DMF) (5 ml) was added
benzyl bromide (0.59 ml, 5.00 mmol) dropwise at rt. The mixture was stirred
groups can be thoroughly tolerated under the 5% Pd/C–pyri-
dine catalyzed hydrogenolysis conditions and the desired
product 4f, 7, 10, 12, 14 or 16 was obtained in excellent iso-
lated yield in each case.
at rt for 10 h, after which it was concentrated in vacuo. The residue was par-
In summary, we have described a novel and chemoselec- titioned between ether (50 ml) and water (50 ml). The ethereal layer was
washed with water (50 ml) and brine (50 ml), dried over MgSO4, and con-
tive hydrogenation method in the presence of phenolic MPM
centrated in vacuo to leave a solid residue, which was recrystallized from
ethers. While 5% Pd/C-catalyzed hydrogenolysis can be gen-
1
MeOH, providing 3a (1.39 g, 97%): mp 125—126 °C. H-NMR (400 MHz)
erally used for removal of MPM protective groups,15,17) the
d: 5.02 (4H, s), 6.91 (4H, s), 7.32—7.44 (10H, m). UV lmax (MeOH) nm
(e): 288 (2410), 226 (15600). LR-MS (EI) m/z: 290 (Mϩ). Anal. Calcd for
C20H18O2: C, 82.73; H, 6.25. Found: C, 82.66; H, 6.29.
addition of pyridine as a mild catalyst poison absolutely sup-
presses the hydrogenolysis of the phenolic O-MPM protec-
tive group.20) By using the 5% Pd/C–pyridine system as a
catalyst for the hydrogenation, the phenolic O-MPM protec-
tive group can be retained without hydrogenolysis. The reac-
tion is general for a variety of phenolic O-MPM ethers, and
the method would increase the utility of the MPM protective
group in synthetic chemistry.
1-Benzyloxy-4-(4-methylbenzyloxy)benzene (3b) Compound 3b was
prepared from 4-benzyloxyphenol (4a) (5.00 g, 24.97 mmol), 4-methylben-
zyl bromide (4.63 g, 25.00 mmol) and NaH (60% w/w in mineral oil, 1.00 g,
25.00 mmol) in anhydrous DMF (20 ml) by the procedure described for the
1
preparation of 3a (7.48 g, 98%): mp 123—124 °C. H-NMR (400 MHz) d:
2.35 (3H, s), 4.97 (2H, s), 5.01 (2H, s), 6.90 (4H, s), 7.18 (2H, d, Jϭ7.8 Hz),
7.30—7.33 (3H, m), 7.36—7.43 (4H, m). UV lmax (MeOH) nm (e): 289
(2680), 223 (19000). LR-MS (EI) m/z: 304 (Mϩ). Anal. Calcd for
C21H20O2·1/10H2O: C, 82.38; H, 6.65. Found: C, 82.44; H, 6.66.
Experimental
Unless otherwise noted, all materials were obtained from commercial sup-
1-Benzyloxy-4-(2-methylbenzyloxy)benzene (3c) Compound 3c was
pliers and used without further purification. Tetrahydrofuran (THF) was dis- prepared from 4-benzyloxyphenol (4a) (3.09 g, 15.40 mmol), 2-methylben-
tilled from sodium benzophenone ketyl immediately prior to use. Column zyl bromide (2.08 ml, 15.50 mmol) and NaH (60% w/w in mineral oil,
chromatography was carried out under air by flash method described by 0.62 g, 15.50 mmol) in anhydrous DMF (5 ml) by the procedure described
Still21) with silica gel (230—400 mesh, Merck). All reactions were moni- for the preparation of 3a (4.13 g, 88%): mp 92.5—93.5 °C. 1H-NMR
tored by thin-layer chromatography (TLC) performed on glass-backed silica (400 MHz) d: 2.52 (3H, s), 5.12 (2H, s), 5.15 (2H, s), 7.08 (4H, s), 7.38—
gel 60 F254, 0.2 mm plates (Merck), and compounds were visualized under 7.42 (3H, m), 7.45—7.59 (6H, m). UV lmax (MeOH) nm (e): 288 (2720).
UV light (254 nm). Melting points were determined on a Yanagimoto melt- LR-MS (EI) m/z: 304 (Mϩ). Anal. Calcd for C21H20O2: C, 82.86; H, 6.62.
ing point apparatus and are uncorrected. UV spectra were measured in EtOH Found: C, 82.67; H, 6.69.
with Shimadzu UV-260 spectrophotometer. 1H-NMR spectra were deter-
1-Benzyloxy-4-(2,4-dimethylbenzyloxy)benzene (3d) Compound 3d
mined with a JEOL GX-270 (270 MHz) or JEOL EX-400 (400 MHz). was prepared from 4-benzyloxyphenol (4a) (1.00 g, 4.99 mmol), 2,4-di-
Chemical shifts are given in parts per million from Me4Si as the internal methylbenzyl chloride (purity 90%, 0.81 ml, 5.00 mmol) and NaH (60%
standard in CDCl3 and coupling constants (J) were reported in hertz (Hz). w/w in mineral oil, 0.20 g, 5.00 mmol) in anhydrous DMF (5 ml) by the pro-
Low- and high-resolution mass spectra (LR- and HR-MS) were taken on a cedure described for the preparation of 3a (1.57 g, 99%): mp 72—73 °C
JMS-SX 102A machine. Microanalyses were accomplished at the Microana- (hexanes). 1H-NMR (270 MHz) d: 2.32 and 2.33 (each 3H, s), 4.94 and 5.02
lytical Laboratory of Gifu Pharmaceutical University.
(each 2H, s), 6.91 (4H, s), 7.01 (2H, d, Jϭ9.4 Hz), 7.28—7.44 (6H, m). UV
l
Time Course of Hydrogenation of N-Boc-O-benzyl-L-tyrosine Methyl
max (MeOH) nm (e): 288 (1370), 225 (13500). LR-MS (EI) m/z: 318 (Mϩ).
Ester (1) Monitored by a TLC Scanner (Fig. 1) A mixture of 111) Anal. Calcd for C22H22O2: C, 82.99; H, 6.96. Found: C, 82.99; H, 6.97.
(38.5 mg, 0.10 mmol), ammonia or pyridine (0.05 mmol), 5% Pd/C (3.9 mg)
1-Benzyloxy-4-(2,4,6-trimethylbenzyloxy)benzene (3e) Compound 3e
and MeOH (1 ml) was stirred under hydrogen atmosphere (balloon) at rt (ca. was prepared from 4-benzyloxyphenol (4a) (1.00 g, 4.99 mmol), 2,4,6-
20 °C). Reaction progress was monitored by TLC Scanner (Shimadzu CS- trimethylbenzyl chloride (0.84 g, 5.00 mmol) and NaH (60% w/w in mineral
9000) at 275 nm (Rf value of 1: 0.65, Rf value of 2: 0.39, ether : hexaneϭ oil, 0.20 g, 5.00 mmol) in anhydrous DMF (5 ml) by the procedure described
1
2 : 1). The yields were calculated on the integration ratio of each peak, which for the preparation of 3a (1.57 g, 95%): mp 83—84 °C (hexanes). H-NMR
were corrected by molar extinction coefficients of 1 and 2.
(400 MHz) d: 2.27 (3H, s), 2.34 (6H, s), 4.94 and 5.02 (each 2H, s), 6.91

March 2003
323
(2H, s), 6.93 (4H, s), 7.31—7.44 (5H, m). UV lmax (MeOH) nm (e): 288
(2600), 227 (26300). LR-MS (EI) m/z: 332 (Mϩ). Anal. Calcd for C23H24O2:
C, 83.10; H, 7.28. Found: C, 83.29; H, 7.38.
(15 ml) was added 4-methoxybenzyl chloride (1.49 g, 11.00 mmol) dropwise
at 0 °C. The mixture was stirred at rt for 12 h, and the reaction mixture was
poured into ice-water. The mixture was extracted with AcOEt (30 ml) and
the organic layer was washed with H2O (30 ml) and brine (30 ml), dried over
Na2SO4 and concentrated in vacuo. The residue was purified by flash silica
gel column chromatography (CHCl3), providing analytically pure 9 (2.44 g,
82%): mp 158—159 °C (MeOH). 1H-NMR (400 MHz) d: 3.79 and 3.82
(each 3H, s), 5.02 (2H, s), 6.31 (1H, d, Jϭ16.1 Hz), 6.92, 6.97, 7.35 and
7.47 (each 2H, d, Jϭ8.8 Hz), 7.65 (1H, d, Jϭ16.1 Hz). LR-MS (FAB) m/z:
298 (Mϩ). Anal. Calcd for C18H18O4: C, 72.47; H, 6.08. Found: C, 72.42; H,
6.14.
4-(4-Methoxybenzyloxy)-4؅-nitrobiphenyl (11) Compound 11 was
prepared from 4-hydroxy-4Ј-nitrobiphenyl (0.22 g, 1.00 mmol), 4-methoxy-
benzyl chloride (0.16 ml, 1.18 mmol) and NaH (60% w/w in mineral oil,
80 mg, 2.00 mmol) in anhydrous DMF (5 ml) by the procedure described for
the preparation of 9 (0.31 g, 93%): 1H-NMR (270 MHz) d: 3.83 (3H, s), 5.06
(2H, s), 6.94, 7.08, 7.38, 7.58, 7.69 and 8.27 (each 2H, d, Jϭ8.8 Hz). LR-
MS (EI) m/z: 335 (Mϩ). Anal. Calcd for C20H17NO4: C, 71.63; H, 5.11; N,
4.18. Found: C, 71.56; H, 5.15; N, 4.14.
Boc–Tyr(MPM)–OBn (13) Compound 13 was prepared from
Boc–Tyr–OBn (0.74 g, 2.00 mmol),22) 4-methoxybenzyl chloride (0.30 ml,
2.21 mmol) and NaH (60% w/w in mineral oil, 84 mg, 2.10 mmol) in anhy-
drous DMF (2 ml) by the procedure described for the preparation of 9
(0.97 g, 98%): mp 89—90 °C. 1H-NMR (400 MHz) d: 1.42 (9H, s), 3.02
(2H, br d, Jϭ5.9 Hz), 3.82 (3H, s), 4.46—4.63 (1H, m), 4.95 (2H, s), 4.97
(1H, br), 5.13 (2H, dd, Jϭ22.5, 12.2 Hz), 6.82 (2H, d, Jϭ8.3 Hz), 6.87—
6.95 (5H, m), 7.28—7.36 (7H, m). LR-MS (EI) m/z: 491 (Mϩ). HR-MS (EI)
m/z: 491.2319 (Calcd for C29H33NO6: 491.2308). Anal. Calcd for
C29H33NO6: C, 70.86; H, 6.77; N, 2.85. Found: C, 70.72; H, 6.84; N, 2.87.
1-Benzyloxy-4-(4-methoxybenzyloxy)benzene (3f) To a stirred mix-
ture of 4-benzyloxyphenol (4a) (1.00 g, 4.99 mmol) and NaH (60% w/w in
mineral oil, 0.20 g, 5.00 mmol) in anhydrous DMF (5 ml) was added 4-
methoxybenzyl chloride (0.67 ml, 5.00 mmol) dropwise at rt. The mixture
was stirred at rt for 10 h, after which it was concentrated in vacuo. The
residue was triturated with ether and H2O and the resulting solid product
was collected by filtration, which was recrystallized from MeOH–AcOEt,
providing 3d (1.57 g, 98%): mp 137.5—138.5°C. 1H-NMR (270 MHz) d:
3.81 (3H, s), 4.93 and 5.01 (each 2H, s), 6.90 (4H, s), 6.91 (2H, d,
Jϭ6.8 Hz), 7.30—7.45 (7H, m). UV lmax (MeOH) nm (e): 281 (3040), 229
(26700). LR-MS (EI) m/z: 320 (Mϩ). Anal. Calcd for C21H20O3: C, 78.73; H,
6.29. Found: C, 78.51; H, 6.16.
Hydrogenation of 3a—d Monitored by a TLC Scanner (Table 1)
After two vacuum/H2 cycles to remove air from the reaction tube, a mixture
of 3 (0.1 mmol), 5% Pd/C (10% of the weight of the substrate 1) in MeOH
(1 ml) with or without pyridine (0.05 mmol) was stirred under hydrogen at-
mosphere (balloon) at rt (ca. 20 °C) for 24 h. Reaction progress was moni-
tored by TLC Scanner (Shimadzu CS-9000). The yields were calculated on
the integration ratio of each peak, which were corrected by molar extinction
coefficients of 4a—f and hydroquinone (5). If the isolation of the product (4)
was necessary to measure the molar extinction coefficients, the reaction mix-
ture was filtered using a membrane filter (Millipore Dimex-13, 0.22 mm),
the filtrate was concentrated, and the residue was purified by silica gel col-
umn chromatography to provide pure 4.
4-Benzyloxyphenol (4a)22): UV lmax (EtOH) nm (e): 291 (2610), 225
(9980).
4-(4-Methylbenzyloxy)phenol (4b): mp 154.5—155.5 °C. 1H-NMR (400
MHz) d: 2.35 (3H, s), 4.39 (1H, s), 4.96 (2H, s), 6.75 and 6.85 (each 2H, d,
Jϭ8.8 Hz), 7.18 and 7.31 (each 2H, d, Jϭ7.8 Hz). UV lmax (MeOH) nm (e):
291 (2560), 221 (14600). LR-MS (EI) m/z: 214 (Mϩ). Anal. Calcd for
C14H14O2·1/10H2O: C, 77.83; H, 6.62. Found: C, 78.06; H, 6.61.
4-(2-Methylbenzyloxy)phenol (4c): mp 105—106 °C. 1H-NMR (400
MHz) d: 2.37 (3H, s), 4.40 (1H, s), 4.97 (2H, s), 6.77 and 6.88 (each 2H, d,
Jϭ8.8 Hz), 7.21—7.25 (3H, m), 7.39 (1H, d, Jϭ6.8 Hz). UV lmax (MeOH)
nm (e): 291 (2560). LR-MS (EI) m/z: 214 (Mϩ). Anal. Calcd for C14H14O2:
C, 78.48; H, 6.59. Found: C, 78.32; H, 6.64.
Cbz–Tyr(MPM)–OMe (15)
A mixture of Cbz–Tyr–OH (4.40 g,
13.95 mmol)22) and N,N-dimethylformamide dimethylacetal (2.78 ml, 20.86
mmol) in anhydrous DMF (10 ml) was stirred at rt for 15 h and the light yel-
low solution was poured into ice-water. The mixture was extracted with
AcOEt (200 ml) and the organic layer was washed with H2O (200 mlϫ2) and
brine (15 ml), dried over Na2SO4 and concentrated in vacuo. The colorless
waxy product, Cbz–Tyr–OMe,22) was used for the next reaction without fur-
1
ther purification (3.53 g, 77%): H-NMR (400 MHz) d: 3.08—3.12 (3H, m,
br), 3.79 (3H, s), 4.68 (1H, dd, Jϭ8.3, 4.4 Hz), 5.11 (2H, br s), 5.16 (2H, d,
Jϭ4.4 Hz), 5.27 (1H, br d, Jϭ8.3 Hz), 6.78 and 7.01 (each 2H, d, Jϭ8.3 Hz),
7.38—7.42 (5H, m).
1
4-(2,4-Dimethylbenzyloxy)phenol (4d): H-NMR (400 MHz) d: 2.32 and
2.34 (each 3H, s), 4.93 (2H, s), 6.76 and 6.86 (each 2H, d, Jϭ9.0 Hz), 7.01
(2H, d, Jϭ7.6 Hz), 7.03 (1H, s), 7.26 (2H, d, Jϭ7.6 Hz). UV lmax (MeOH)
nm (e): 291 (3750), 222 (22300). LR-MS (EI) m/z: 228 (Mϩ). HR-MS (EI)
m/z: 228.1145 (Calcd for C15H16O2: 228.1150).
To a stirred mixture of Cbz–Tyr–OMe (see above, 3.53 g, 10.72 mmol)
and NaH (60% w/w in mineral oil, 0.47 g, 11.80 mmol) in anhydrous DMF
(10 ml) was added 4-methoxybenzyl chloride (1.60 ml, 11.80 mmol) drop-
wise at 0 °C. The mixture was stirred at rt for 2 h, and the reaction mixture
was poured into ice-water. The mixture was extracted with AcOEt (50 ml)
and the organic layer was washed with H2O (50 ml) and brine (50 ml), dried
over Na2SO4 and concentrated in vacuo. The residue was purified by flash
silica gel column chromatography (hexanes to hexanes : etherϭ1 : 1) to give
a pale yellow waxy solid. The solid product was triturated with hexanes
(50 ml) and the resulting colorless solid was collected by filtration, which
was washed with hexanes (20 mlϫ3), providing analytically pure 15 (4.34 g,
90%): mp 82—83 °C. 1H-NMR (270 MHz) d: 3.03—3.05 (2H, m), 3.72 and
3.82 (each 3H, s), 4.61—4.64 (1H, m), 4.95 and 5.10 (each 2H, s), 5.15—
5,21 (1H, m), 6.87, 6.91 and 7.00 (each 2H, d, Jϭ8.8 Hz), 7.34—7.36 (7H,
m). LR-MS (FAB) m/z: 450 (Mϩϩ1). Anal. Calcd for C26H27NO6: C, 69.47;
H, 6.05; N, 3.12. Found: C, 69.42; H, 6.25; N, 3.19.
4-(2,4,6-Trimethylbenzyloxy)phenol (4e): 1H-NMR (400 MHz) d: 2.29
(3H, s), 2.36 (6H, s), 4.90 (1H, br, deuterium exchangeble), 4.95 (2H, s),
6.77 and 6.90 (each 2H, d, Jϭ8.8 Hz), 6.91 (2H, s). UV lmax (MeOH) nm
(e): 291 (3110), 224 (20600). LR-MS (EI) m/z: 242 (Mϩ). HR-MS (EI) m/z:
242.1318 (Calcd for C16H18O2: 242.1307).
1
4-Methoxybenzyloxyphenol (4f): mp 136—137 °C. H-NMR (400 MHz)
d: 3.81 (3H, s), 4.49 (1H, s), 4.93 (2H, s), 6.75 and 6.85 (each 2H, d,
Jϭ8.8 Hz), 6.91 and 7.34 (each 2H, d, Jϭ8.5 Hz). UV lmax (MeOH) nm (e):
282 (1380), 222 (10500). LR-MS (EI) m/z: 230 (Mϩ). HR-MS (EI) m/z:
230.0939 (Calcd for C14H14O3: 230.0943). Anal. Calcd for C14H14O3·
1/3H2O: C, 71.17; H, 6.26. Found: C, 71.30; H, 6.07.
Hydroqinone (5)22): UV lmax (EtOH) nm (e): 293 (2900), 224 (5300).
Boc–Tyr(Bn)–Tyr(MPM)–OMe (6) To a solution of Boc–Tyr(Bn)–OH
(37.1 mg, 0.1 mmol)22) and diphenylphosphorylazide (DPPA, 22.6 ml, 0.11
mmol) in DMF (0.25 ml) a solution of H–Tyr(MPM)–OMe 16 (32.7 mg,
0.1 mmol) in DMF (0.25 ml) was added dropwise at 0 °C. The mixture was
stirred at rt for 12 h and then poured into ice-cooled phosphate buffer solu-
tion (pH 7.0, 10 ml). The resulting mixture was extracted with AcOEt
(10 ml) and the organic layer was washed with H2O (10 ml) and brine
(10 ml) and dried over Na2SO4. After concentration in vacuo, the residue
was purified by flash silica gel column chromatography (CHCl3), providing
6 (63.5 mg, 95%): mp 164—165 °C. 1H-NMR (270 MHz) d: 1.39 (9H, s),
2.89—3.04 (4H, m), 3.67 and 3.81 (each 3H, s), 4.23—4.38 and 4.72—4.80
(each 1H, m), 4.93 (2H, d, Jϭ3.4 Hz), 5.02 (2H, s), 6.29 (1H, br), 6.83—
6.92 (8H, m), 7.09 (2H, dd, Jϭ8.3, 6.4 Hz), 7.31—7.42 (7H, m). LR-MS
(FAB) m/z: 669 (Mϩϩ1). Anal. Calcd for C39H44N2O8: C, 70.04; H, 6.63; N,
4.19. Found: C, 69.81; H, 6.58; N, 4.21.
General Procedure for the Chemoselective Hydrogenation of 3d, 6, 9,
11, 13 and 15 Using a Pd/C–Pyridine System (the Preparation of Com-
pounds 4d, 7, 10, 12, 14 and 16, Chart 1 and Table 2) After two vac-
uum/H2 cycles to remove air from the reaction tube, the stirred mixture of
the substrate (0.1 mmol), 5% Pd/C(en) (10% of the weight of the substrate)
and pyridine (4 ml, 0.05 mmol, 0.5 eq of the substrate) in MeOH (1.0 ml),
MeOH (0.5 ml)ϩdioxane (0.5 ml) or DMF (1.0 ml) depending on the solu-
bility of the substrate was hydrogenated at ordinary pressure (balloon) and
temperature (ca. 20 °C) for the appropriate time (see Chart 2 and Table 2).
The reaction mixture was filtered using a membrane filter (Millipore Dimex-
13, 0.22 mm) and the filtrate was concentrated in vacuo. The resulting prod-
uct was purified by flash silica gel column chromatography, if necessary.
Boc–Tyr–Tyr(MPM)–OMe (7): NMR (270 MHz) d: 1.42 (9H, s), 2.92—
3.00 (4H, m), 3.68 and 3.82 (each 3H, s), 4.20—4.36 and 4.68—4.82 (each
1H, m), 4.95 (2H, s), 6.21 (1H, br), 6.71 (2H, d, Jϭ8.3 Hz), 6.82—6.93 (6H,
m), 7.02 (2H, d, Jϭ7.3 Hz), 7.35 (2H, d, Jϭ8.3 Hz). LR-MS (FAB) m/z: 579
(Mϩϩ1). HR-MS (FAB) m/z: 579.2724 (Calcd for C32H39N2O8: 579.2706).
4-(4-Methoxybenzyloxy)cinnamic Acid Methyl Ester (9)12) To
a
stirred mixture of 4-hydroxycinnamic acid methyl ester (1.78 g, 10.00 mmol)
and NaH (60% w/w in mineral oil, 0.44 g, 11.00 mmol) in anhydrous DMF
1
4-(4-Methoxybenzyloxy)dihydrocinnamic Acid Methyl Ether (10)12): H-

324
Vol. 51, No. 3
3) Sajiki H., Hirota K., J. Synth. Org. Chem., Jpn., 59, 109—120 (2001).
4) Greene T. W., Wuts P. G. M., “Protective Groups in Organic Synthe-
sis,” 3rd ed., John Wiley & Sons, New York, 1999, pp. 76—86.
5) Bindra J. S., Grodski A., J. Org. Chem., 16, 3240—3241 (1978).
6) Czech B. P., Bartsh R. A., J. Org. Chem., 49, 4076—4078 (1984).
7) Ghosh A., Krishnan K., Tetrahedron Lett., 39, 947—948 (1998).
8) Gaunt M. J., Yu J., Spencer J. B., J. Org. Chem., 63, 4172—4173
(1998).
9) Sajiki H., Tetrahedron Lett., 36, 3465—3468 (1995).
10) Sajiki H., Kuno H., Hirota K., Tetrahedron Lett., 39, 7127—7130
(1998).
11) Sajiki H., Hirota K., Tetrahedron, 54, 13981—13996 (1998).
12) We also found that a Pd/C catalyst formed an isolable complex with
the ethylenediamine employed as catalytic poison, selectively catalyz-
ing the hydrogenation of various functional groups without the hy-
drogenolysis of the O-benzyl protective group even in phenolic benzyl
ethers, see: Sajiki H., Hattori K., Hirota K., J. Org. Chem., 63, 7990—
7992 (1998).
NMR (270 MHz) d: 2.60 and 2.89 (each 2H, t, Jϭ7.7 Hz), 3.67 and 3.82
(each 3H, s), 496 (2H, s), 6.89, 6.91, 7.11 and 7.35 (each 2H, d, Jϭ8.8 Hz).
LR-MS (EI) m/z: 298 (Mϩ), HR-MS (EI) m/z: 300.1356 (Calcd for C18H20O4
300.1362).
4-Amino-4Ј-(4-methoxybenzyloxy)biphenyl (12): 1H-NMR (270 MHz) d:
3.68 (2H, br), 3.82 (3H, s), 5.02 (2H, s), 6.74 (2H, d, Jϭ8.8 Hz), 6.92 (2H, d,
Jϭ8.3 Hz), 7.00 (2H, d, Jϭ8.8 Hz), 7.36 (2H, d, Jϭ8.3 Hz), 7.38 (2H, d,
Jϭ8.8 Hz), 7.45 (2H, d, Jϭ8.3 Hz). LR-MS (EI) m/z: 305 (Mϩ). HR-MS
(EI) m/z: 305.1425 (Calcd for C20H19NO2: 305.1416).
Boc–Tyr(MPM)–OH (14): 1H-NMR (400 MHz) d: 1.42 (9H, s), 2.98—
3.19 (2H, m), 3.81 (3H, s), 4.50—4.58 (1H, m), 4.96 (2H, s), 6.72 (1H, br),
6.90 (2H, d, Jϭ7.6 Hz), 6.91 (2H, d, Jϭ8.5 Hz), 7.00 (1H, br), 7.09 (2H, d,
Jϭ7.6 Hz), 7.34 (2H, d, Jϭ8.5 Hz). LR-MS (FAB) m/z: 402 (Mϩϩ1). HR-
MS (FAB) m/z: 402.1911 (Calcd for C22H28NO6: 402.1917).
Tyr(MPM)–OMe (16): 1H-NMR (400 MHz) d: 2.79 (1H, dd, Jϭ13.7,
7.8 Hz), 3.00 (1H, dd, Jϭ13.7, 5.4 Hz), 3.58—3.70 (1H, m), 3.69 and 3.79
(each 3H, s), 4.94 (2H, s), 6.88 (2H, d, Jϭ8.3 Hz), 6.89 (2H, d, Jϭ8.8 Hz),
7.08 (2H, d, Jϭ8.3 Hz), 7.32 (2H, d, Jϭ8.8 Hz). LR-MS (EI) m/z: 315 (Mϩ).
HR-MS (EI) m/z: 315.1459 (Calcd for C18H21NO4: 315.1471).
Boc–Tyr–Tyr–OMe (8) After two vacuum/H2 cycles to remove air from
the reaction tube, the stirred mixture of Boc–Tyr(Bn)–Tyr(MPM)–OMe 6
(67 mg, 0.1 mmol), 5% Pd/C(en) (7 mg) and pyridine (4 ml, 0.05 mmol) in
MeOH (1.0 ml) and dioxane (1.0 ml) was hydrogenated at ordinary pressure
(balloon) and temperature (ca. 20 °C) for 24 h. The reaction mixture was fil-
tered using a membrane filter (Millipore Dimex-13, 0.22 mm) and the filtrate
was concentrated in vacuo. The residue was purified by flash silica gel col-
umn chromatography (CHCl3 : MeOHϭ50 : 1), providing analytically pure 8
(36 mg, 78%): 1H-NMR (270 MHz) d: 1.42 (9H, s), 2.87—2.93 (4H, m),
3.69 (3H, s), 4.20—4.35 (1H, m), 4.68—4.82 (1H, m), 5.22 (1H, br), 6.67
(1H, br), 6.53—6.91 (8H, m). LR-MS (FAB) m/z: 459 (Mϩϩ1). HR-MS
(FAB) m/z: 459.2125 (Calcd for C24H31N2O7: 459.2131).
13) For preliminary communication, see: Sajiki H., Kuno H., Hirota K.,
Tetrahedron Lett., 38, 399—402 (1997).
14) Davis R., Muchowski J. M., Synthesis, 1982, 987—988 (1982).
15) Greene T. W., Wuts P. G. M., “Protective Groups in Organic Synthe-
sis,” 3rd ed., John Wiley & Sons, New York, 1999, pp. 86—91.
16) The deprotection method for the 2,4,6-trimethylbenzyl group is ex-
tremely limited to the use of TFA. See: Young S. D., Tamburini P. P., J.
Am. Chem. Soc., 111, 1933—1934 (1989).
17) Horita K., Yoshioka T., Tanaka T., Oikawa Y., Yonemitsu O., Tetrahe-
dron, 42, 3021—3028 (1986) and references cited therein.
18) White J. D., Amedio J. C., J. Org. Chem., 54, 736—738 (1989).
19) Srikrishna A., Viswajanani R., Sattigeri J. A., Vijaykumar D., J. Org.
Chem., 60, 5961—5962 (1995).
20) Horita et al. reported17) that the selective removal of an aliphatic O-
benzyl protection in the presence of a MPM protective group for
aliphatic hydroxyl functions was achieved with hydrogenolysis over
W-4 Raney nickel, although a large excess amount of catalyst was re-
quired to complete the reaction.
References and Notes
1) Rylander P. N., “Hydrogenation Methods,” Academic Press, New
York, 1985, pp. 157—163.
2) Nishimura S., “Handbook of Heterogeneous Catalytic Hydrogenation
for Organic Synthesis,” Wiley-Interscience, New York, 2001, pp.
583—597.
21) Still W. C., Kahn M., Mitra A., J. Org. Chem., 43, 2923—2925 (1978).
22) Commercially available.