A Facile Conversion of Alcohols into p-Methoxybenzyl Ethers (PMB-ethers) Using p-Methoxybenzyl Alcohol-Yb(OTf)

Full text of DOI:10.1021/jo990563x

J . Org. Chem. 1999, 64, 8943-8944
8943
A F a cile Con ver sion of Alcoh ols in to
p-Meth oxyben zyl Eth er s (P MB-eth er s)
Usin g p-Meth oxyben zyl Alcoh ol-Yb(OTf)3
†
G.V. M. Sharma* and A.K. Mahalingam
Discovery Laboratory, Organic Chemistry Division III,
Indian Institute of Chemical Technology,
Hyderabad 500 007, India
Received March 30, 1999
The correct choice of an efficient protecting group1 is
often decisive for the completion of the successful syn-
thesis of a complex molecule, for which the strategy
should take into account the different requirements that
are present in the molecule. Protection of a hydroxyl
functionality as the benzyl ether is preferred as a
permanent protective group. However, the choice of
oxidation-labile benzyl groups, such as p-methoxybenzyl
(PMB) and 3,4-dimethoxybenzyl (DMB), proved its worth
as a result of the ease with which these groups undergo
deprotection under almost neutral conditions2 (DDQ,
aqueous dichloromethane). Conventionally, the PMB
protection is achieved under strongly basic conditions3,4
(PMB-halides, NaH, or NaOH), in which alkali-labile
protective groups are lost. Alternatively, PMB-trichloro
acetimidate5 has been developed, in which the substrate
is exposed to acids for a longer duration, and PMB-
diazomethane6 is not a desirable reagent of choice. Hence,
a better protocol is warranted for PMB protection, which
would preserve the integrity of both alkali- and acid-labile
protective groups. The unique potential of the PMB group
in organic synthesis, particularly in carbohydrate chem-
istry, prompted us to describe mild and potential reaction
conditions for PMB protection, using PMB alcohol-Yb-
(OTf)3 (eq 1).
F igu r e 1. Representative PMB ethers. All of the compounds
were characterized by 1H NMR. All of the reactions were
carried out using 5 mol % catalyst at room temperature, and
isolated yields are reported.
Ta ble 1
time yield
time yield
entry compd
(h)
(%)
entry compd
(h)
(%)
1
2
1
4
8
3
32
36
36
80
87
84
75
71
76
6
7
8
9
10
11
6
7
8
9
10
11
32
30
24
24
28
30
60
80
83
82
85
88
2
2a
3
3
4
5
4
5
a
10 mol % of yb(OTf)3 used.
of alcohols with PMB alcohol, whose oxidation potential
1/2
(E 1.22 V) would facilitate the generation of carbocation.
Initially, the reaction of 4-phenyl butanol with PMB
alcohol (2 equiv) in the presence of Yb(OTf)3 (5 mol %)
was carried out in different solvents such as CH3CN, CH3-
NO2, and CH2Cl2 independently to give the product in
42%, 59%, and 80% yield, respectively. The byproduct,
diPMB ether formed by dehydration, also was found to
react with alcohol to give the product, leaving behind 10-
15% of the dimer.
Having established the preferred reaction conditions,
PMB protection of several representative alcohols9 (Fig-
ure 1) was performed to demonstrate the versatility and
uniqueness of the present reaction conditions (Table 1).
Entry 2 depicts an acetylenic alcohol wherein rate
enhancement of the reaction was observed with 10 mol
% of catalyst, and entries 3 and 4 show the tolerance of
reaction conditions to both the THP and TBS ethers.
Entry 5 is a representative example for a benzoate ester,
in which the Bz group survives the reaction conditions,
and entry 6 depicts an example where the 1°,2° acetonide
Rare earth (III) salts such as triflates7 are advanta-
geously utilized as versatile Lewis acids in several
organic reactions. Our recent work8 on deprenylation
using Yb(OTf)3 through prenyl carbocation indicated it
to be the right catalyst for effecting the PMB protection
† IICT communication 4272.
(1) Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic
Synthesis, 2nd ed.; J ohn Wiley and Sons: New York, 1991.
(2) (a) Oikawa, Y.; Yoshioka, T.; Yonemitsu, O. Tetrahedron Lett.
1982, 23, 885-888.
(3) Macro, J . L.; Hueso-Rodriquez, J . A. Tetrahedron Lett. 1988, 29,
2459-2462.
(4) Takaku, H.; Kamaike, K.; Tsuchiya, H. J . Org. Chem. 1984, 49,
51-56.
(5) Nakajima, N.; Horita, K.; Abe, R.; Yonemitsu, O. Tetrahedron
Lett. 1988, 29, 4139-4142.
(6) Kamaike, K.; Tsuchiya, H.; Imai, K.; Takaku, H. Tetrahedron
1986, 42, 4701-4711.
(9) The starting materials for the preparation of compounds 1, 2, 7,
8, 10, and 11 are commercial samples. Compounds 6 and 9 were
prepared from the corresponding known aldehydes by Grignard
reaction with the respective bromides. Compounds 3-5 were prepared
by known methods from the commercially available diol.
(7) (a) Marshman, R. W. Aldrichimica Acta 1995, 28, 77-84. (b)
Kobayashi, S. Synlett 1994, 689-701.
(8) Sharma, G. V. M.; Ilangovan, A.; Mahalingam, A. K. J . Org.
Chem. 1998, 63, 9103-9104.
10.1021/jo990563x CCC: $18.00 © 1999 American Chemical Society
Published on Web 11/09/1999

8944 J . Org. Chem., Vol. 64, No. 24, 1999
Notes
Sp ectr a l Da ta for Selected Com p ou n d s. 1H NMR (200
MHz, CDCl3, TMS, δ in ppm): d a ta for 3, 1.30-1.90 (m, 14H),
3.30-3.50 (m, 4H), 3.75-3.88 (m, 5H), 4.40 (s, 2H), 4.55 (bs,
1H), 6.83 (d, 2H, J ) 4.34 Hz), 7.22 (d, 2H, J ) 4.34 Hz), MS
(EI) 237 (M+ - 85), HRMS calcd for C14H21O3 237.149070, obsd
237.149152; d a ta for 4, 0.9 (s, 9H), 1.30-1.43 (m, 4H), 1.48-
1.67 (m, 4H), 3.45 (t, 2H, J ) 3.52 Hz), 3.62 (t, 2H, J ) 3.52
Hz), 3.83 (s, 3H), 4.44 (s, 2H), 6.90 (d, 2H, J ) 4.70 Hz), 7.28 (d,
2H, J ) 4.70), MS (EI) 295 (M+ - 57), HRMS calcd for C15H27O3-
Si 295.172948, obsd 295.171520; d a ta for 5, 1.40-1.80 (m, 8H),
3.40 (t, 2H, J ) 2.47 Hz), 3.80 (s, 3H), 4.30 (t, 2H, J ) 2.47 Hz),
4.40 (s, 2H), 6.80 (d, 2H, J ) 3.45 Hz), 7.20 (d, 2H, J ) 3.45
Hz), 7.35-7.55 (m, 3H), 8.02 (d, 2H, J ) 2.96 Hz), MS (EI) 342
(M+), HRMS calcd for C21H26O4 342.183110, obsd 342.181705;
d a ta for 7, 0.80 (d, 3H, J ) 3.48 Hz), 0.85-1.10 (m, 11 H), 1.57-
1.70 (m, 2H), 1.90-2.00 (m, 1H), 2.10-2.25 (m, 1H), 3.40 (dt,
1H, J ) 5.18, 2.07), 3.80 (s, 3H), 4.45 (s, 2H), 6.85 (d, 2H, J )
4.41 Hz), 7.25 (d, 2H, J ) 4.41 Hz), MS (EI) 276 (M+), HRMS
calcd for C18H28O2 276.208930, obsd 276.207990; d a ta for 9, 1.28
(s, 3H), 1.47 (s, 3H), 3.85 (m, 4H), 4.15 (m, 2H), 4.35-4.65 (m,
5H), 5.28-5.38 (m, 2H), 5.63-5.80 (m, 1H), 5.95 (d, 1H, J )
1.91 Hz), 6.80 (d, 2H, J ) 4.03 Hz), 7.30-7.42 (m, 7H), FABMS
449 (M+ + Na); d a ta for 10, 1.31 (s, 6H), 1.45 (s, 3H), 1.53 (s,
3H), 3.50-3.63 (m, 2H), 3.80 (s, 3H), 3.90 (dt, 1H, J ) 2.40, 1.00
Hz), 4.20-4.30 (m, 2H), 4.48-4.58 (m, 3H), 5.50 (d, 1H, J ) 1.92
Hz), 6.85 (d, 2H, J ) 3.46 Hz), 7.35 (d, 2H, J ) 3.46 Hz), FABMS
379 (M+ - 1), HRMS calcd for C20H27O7 379.175679, obsd
379.176152; d a ta for 11, 0.80 (s, 3H), 1.10-1.67 (m, 8H), 1.73-
2.30 (m, 5H), 2.80 (m, 2H), 3.40 (m, 1H), 3.70 (s, 3H), 3.75 (s,
3H), 4.42 (s, 1H), 6.50 (s, 1H), 6.60 (d, 1H, J ) 4.39 Hz), 6.75 (d,
2H, J ) 4.40 Hz), 7.10 (d, 1H, J ) 3.96 Hz), 7.15 (d, 2H, J )
4.40 Hz), MS (EI) 406 (M+), HRMS calcd for C27H34O3 406.250795,
obsd 406.248844.
is intact. Entries 7 and 8 represent the terpenes, and
entries 9 and 10 represent carbohydrates in which allylic
as well as 1° alcohols were successfully protected without
effecting acetonides. Entry 11 represents an example of
a steroid. However, in the present reaction conditions,
tertiary alcohols were found to be unreacted. The results
of the present study, indicated in Table 1, amply dem-
onstrate the efficiency of PMB alcohol-Yb(OTf)3 in
effecting PMB protection under mild conditions on a wide
spectrum of compounds.
Thus, the merits of the present protocol are (a) com-
patibility to both the acid- and alkali-labile protecting
groups, (b) use of PMB alcohol rather the derivatives
(PMB-halide, PMB-trichloroacetimidate, PMB-diazo-
methane) for the first time, (c) use of Yb(OTf)3 as catalyst
(5 mol %), making this an environmentally friendly
protocol, and (d) tolerance of a wide variety of functional
groups and substrates. The present protocol for PMB
protection of hydroxy groups thus would find a wide
acceptability in organic synthesis, particularly in carbo-
hydrate chemistry.
Exp er im en ta l Section
Typ ica l P r oced u r e for P MB P r otection w ith Yb(OTf)3.
A solution of 4-phenylbutanol (150 mg, 1.0 mmol) and p-
methoxybenzyl alcohol (276 mg, 2.0 mmol) in CH2Cl2 (5 mL) was
treated with Yb(OTf)3 (31 mg, 0.05 mmol) and stirred at room
temperature. At the completion of the reaction (TLC analysis),
the reaction mixture was diluted with water (10 mL), and the
two layers were separated. The aqueous layer was extracted with
CHCl3 (3 × 5 mL), and the combined organic layers were washed
with water (2 × 5 mL), dried (Na2SO4), and evaporated under
reduced pressure. Purification of the crude residue by column
chromatography (silica gel, 1:9 ethyl acetate-hexane) gave 1-p-
methoxybenzyl 4-phenylbutanol (1) (216 mg) in 80% yield along
with di-p-methoxybenzyl ether (12%).
Ack n ow led gm en t. One of the authors, A. K. Ma-
halingam, is thankful to CSIR, New Delhi for financial
support.
J O990563X