A practical method for p -methoxybenzylation of hydroxy groups using 2,4,6-tris(p -methoxybenzyloxy)-1,3,5-triazine (TriBOT-PM)

Article abstract of DOI:10.1055/s-0033-1339713

A new acid-catalyzed p-methoxybenzylating reagent, 2,4,6-tris(p- methoxybenzyloxy)-1,3,5-triazine (TriBOT-PM), has been developed. The reaction of acid- and alkali-labile alcohols with TriBOT-PM in the presence of a catalytic amount of various acids (TfOH, BF₃·OEt₂, CSA, etc.) afforded the corresponding p-methoxybenzyl ethers in good yields. Since TriBOT-PM is an air-stable crystalline solid and can be prepared from inexpensive materials, i.e. cyanuric chloride and anisyl alcohol, this route is of practical use. Georg Thieme Verlag Stuttgart, New York.

Full text of DOI:10.1055/s-0033-1339713

PAPER
▌2989
paper
A Practical Method for p-Methoxybenzylation of Hydroxy Groups Using
2,4,6-Tris(p-methoxybenzyloxy)-1,3,5-triazine (TriBOT-PM)
p-Methoxybenzylation of Hydroxy Groups Using TriBOT-PM
Kohei Yamada, Hikaru Fujita, Masanori Kitamura, Munetaka Kunishima*
Faculty of Pharmaceutical Sciences, Institute of Medical, Pharmaceutical, and Health Sciences, Kanazawa University, Kakuma-machi,
Kanazawa 920-1192, Japan
Fax +81(76)2646201; E-mail: kunisima@p.kanazawa-u.ac.jp
Received: 07.07.2013; Accepted after revision: 13.08.2013
Recently, we reported a novel acid-catalyzed benzylating
reagent, 2,4,6-tris(benzyloxy)-1,3,5-triazine (TriBOT),
the formal trimer of the smallest unit of benzyl imidate
(Scheme 1).7 The key advantages of TriBOT are its reac-
Abstract: A new acid-catalyzed p-methoxybenzylating reagent,
2,4,6-tris(p-methoxybenzyloxy)-1,3,5-triazine (TriBOT-PM), has
been developed. The reaction of acid- and alkali-labile alcohols
with TriBOT-PM in the presence of a catalytic amount of various
acids (TfOH, BF3·OEt2, CSA, etc.) afforded the corresponding p- tivity, stability, cost, and excellent atom economy. We
methoxybenzyl ethers in good yields. Since TriBOT-PM is an air-
stable crystalline solid and can be prepared from inexpensive mate-
rials, i.e. cyanuric chloride and anisyl alcohol, this route is of prac-
could act as a reagent for p-methoxybenzylation and it
tical use.
strongly believed that a PMB analogue of TriBOT, 2,4,6-
tris(p-methoxybenzyloxy)-1,3,5-triazine (TriBOT-PM),
would have the aforementioned advantages.8 In this study,
we report the development of TriBOT-PM as a reagent for
p-methoxybenzylation.
Key words: benzylation, protecting groups, cations, ethers, alkyla-
tion
TriBOT-PM was easily synthesized from anisyl alcohol
and cyanuric chloride in the presence of sodium hydride
As p-methoxybenzyl (PMB) ethers can be selectively de-
in 89% yield (Scheme 2). Similar to TriBOT, TriBOT-PM
protected by oxidative cleavage using 2,3-dichloro-5,6-
is a nonhygroscopic crystalline solid without irritating or
dicyano-1,4-benzoquinone (DDQ) in the presence of es-
allergenic properties, and it is stable in air at room temper-
ters, silyl ethers, and acetals,1 the PMB group is a versatile
ature for one year.
protecting group for hydroxy groups.2 It can be tolerated
under various chemical transforming conditions, such as
hydrolysis, of these functional groups. Hydroxy groups
are most commonly transformed into p-methoxybenzyl-
oxy groups by using either a PMB halide and a strong
OMe
Cl
O
N
N
NaH
base, such as sodium hydride (the Williamson ether syn-
thesis),1 or PMB 2,2,2-trichloroacetimidate (PMBTCAI)
and catalytic acid, such as trifluoromethanesulfonic acid.3
However, these reagents are not convenient for use and
long-term storage because they are sensitive to moisture
and heat. Therefore, a number of alternative methods us-
ing stable imidate-surrogate-type reagents,4 anisyl alco-
hol,5 and other reagents6 have been developed.
MeO
N
N
THF
0 °C to r.t.
3 h
Cl
N
Cl
O
N
O
89%
OH
MeO
OMe
Scheme 2 Synthesis of TriBOT-PM
This work
Previous work
OMe
O
N
O
O
N
N
·stable
·non-irritating
·low cost
·high atom economy
·easy purification
N
N
N
MeO
N
N
O
O
O
N
O
O
O
OMe
formal trimerization of
the smallest unit of benzyl imidate
TriBOT
TriBOT-PM
Scheme 1 The concept and design of TriBOT-PM
SYNTHESIS 2013, 45, 2989–2997
Advanced online publication: 10.09.2013
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0033-1339713; Art ID: SS-2013-F0464-OP
© Georg Thieme Verlag Stuttgart · New York

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K. Yamada et al.
PAPER
Upon treatment of 3-phenylpropan-1-ol (1a, 0.5 mmol) was added dropwise to the reaction mixture over three
with TriBOT-PM (0.4 equiv) and trifluoromethanesulfon- minutes (initial concentration of 1a: 0.4 M, final concen-
ic acid (1 mol%) in 1,4-dioxane (0.2 M) at room tempera- tration: 0.2 M), and the resulting mixture was quenched
ture, the p-methoxybenzylation of 1a afforded the after two minutes (total reaction time: 5 min). As a result,
corresponding PMB ether 2a in 68% yield (Table 1, entry the yield of 2a increased to 91% and the formation of 3 de-
1).
creased to 11% (entry 2). Interestingly, a prolonged reac-
tion time (dropwise addition time: 7 min; total reaction
time: 15 min) resulted in a decrease in the yield of 2a (en-
try 3, 73%) and production of symmetric acetal 4 (Figure
1) in 16% yield. Kern et al. reported that the reaction of
the PMB ethers with Lewis acids furnished the symmetric
In this reaction, N-(p-methoxybenzyl)isocyanuric acid (3,
Figure 1) was formed as a byproduct (65% yield based on
TriBOT-PM). The reaction of 1a with 3 under the same
conditions did not produce 2a. Therefore, the competing
formation of 3 would be responsible for the moderate
yield. We assumed that 3 was mainly generated by the N-
p-methoxybenzylation of TriBOT-PM,9 not that of isocy-
anuric acid, because if the p-methoxybenzylation of iso-
cyanuric acid takes place, it should occur at the carbonyl
oxygens rather than the nitrogen atoms.10 Therefore,
keeping a low concentration of TriBOT-PM during the re-
action would be effective to suppress the production of 3.
For this purpose, a solution of TriBOT-PM in 1,4-dioxane
acetal through methyleneoxonium intermediate
5
(Scheme 3).11 Symmetric acetal 4 would be generated
through a similar reaction pathway. In comparison with
TriBOT, which requires relatively a large amount of tri-
fluoromethanesulfonic acid (as much as 20 mol%) for O-
benzylation, TriBOT-PM was more reactive, and under-
went O-p-methoxybenzylation of alcohols in the presence
of only 0.1 mol% of trifluoromethanesulfonic acid (entry
4, 90%). Solvents that exhibit Lewis basic properties (do-
Table 1 Screening of Solvent and Acid Conditions
TriBOT-PM
acid
Ph
OH
Ph
OPMB
solvent
time, r.t.
1a
2a
Entry
Solvent
TriBOT-PM
(equiv)
Acid
(mol%)
Dropwise addition Additional reaction Yielda
time
time
(%) of 2a
c
1
1,4-dioxane
0.4
0.4
0.4
0.4
0.4
0.4
0.4
0.4
0.4
0.4
0.7
0.65
0.65
TfOH (1)
–
5 min
72 (68b)
91
2d
TfOH (1)
3 min
2 min
8 min
30 min
5 min
5 min
5 min
15 min
10 min
10 min
5 h
3d
TfOH (1)
7 min
30 min
10 min
10 min
10 min
10 min
10 min
10 min
73
4d
TfOH (0.1)
TfOH (0.3)
TfOH (0.3)
TfOH (0.3)
TfOH (1)
90
5d
CH2Cl2
66
6d
CH2Cl2–Et2O (1:1)
EtOAc
90
7d
94
8d,e,f
9d,e
10d,e
11f
12g
13g
DME
95
Sc(OTf)3 (5)
BF3·OEt2 (5)
BF3·OEt2 (0.1)
CSA (15)
91
92
c
THF
–
95
c
–
10 h
99
c
TsOH (15)
–
5.5 h
99
a Yields (%) were determined by 1H NMR based on 1a using an internal standard.
b Isolated yield.
c TriBOT-PM was added in one portion.
d TriBOT-PM solution was prepared in the same solvent as the reaction mixture.
e Powdered molecular sieves 5A were added.
f The reaction was conducted at 0 °C.
g The reaction was conducted at reflux.
Synthesis 2013, 45, 2989–2997
© Georg Thieme Verlag Stuttgart · New York

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p-Methoxybenzylation of Hydroxy Groups Using TriBOT-PM
2991
nor properties) appear to be suitable for this reaction. The
reaction using dichloromethane as a solvent afforded 2a in
66% yield (entry 5) due to the competing Friedel–Crafts
reaction,7 whereas changing the solvent to a dichloro-
methane–diethyl ether mixture improved the yield of 2a
(entry 6, 90%). The use of ethyl acetate or 1,2-dimethoxy-
ethane as the solvent also produced 2a in good yields (en-
tries 7 and 8, 94% and 95%, respectively). We previously
reported that O-benzylation with TriBOT proceeds
through a benzyl cation intermediate7 that can be generat-
ed by using very strong acids such as trifluoromethanesul-
fonic acid or trimethylsilyl trifluoromethanesulfonate. If
the p-methoxybenzylation using TriBOT-PM involves a
similar cationic species (PMB cation), the reaction can be
catalyzed by acids weaker than trifluoromethanesulfonic
acid because a PMB cation is more stable than a benzyl
cation.12 As expected, upon treatment of 1a with Lewis
acids, such as scandium(III) trifluoromethanesulfonate
and boron trifluoride–diethyl ether complex, the reaction
proceeded to give 2a in 91% and 92% yields, respectively
(entries 9 and 10).
O
O
PMB
O
PMB
O
PMB
O
HN
N
N
N
O
N
H
3
N
H
6
Ph
O
O
Ph
4
Figure 1 Byproducts in p-methoxybenzylation
+
O
2a
Ph
5
1a or 2a
Ph
O
O
Ph
4
Scheme 3 Formation of 4 through methyleneoxonium intermediate 5
We developed a method for the p-methoxybenzylation by
dropwise addition of a solution of 0.4 equivalents of Tri-
BOT-PM (equal to 1.2 equiv of the PMB group) to the re-
action mixture in the presence of very small amount
(minimum 0.1 mol%) of trifluoromethanesulfonic acid.
yield presumably due to decomposition of 1b and 2b by
trifluoromethanesulfonic acid. The yield of 2b increased
by changing the acid catalyst to (+)-10-camphorsulfonic
acid (entry 3). Therefore, (+)-10-camphorsulfonic acid
seems to be a suitable catalyst for acid-labile substrates.
Moreover, 2-(trimethylsilyl)ethanol (1c) and tertiary alco-
hol 1d were also converted into 2c and 2d in good yields
(entries 4–6). The reactions of β-hydroxy ketone 1e (entry
7) and β-hydroxy ester 1f (entries 8 and 9), which are
prone to undergo retro-aldol reaction and/or β-elimina-
tion, afforded 2e and 2f in good to excellent yields. No ra-
cemization occurred during the reactions of 1f, ethyl
lactate 1g (entry 10), and serine derivative 1h (entry 11).
The protecting groups such as Boc, TBS, and acetonide in
1h–j (entries 11–13) were tolerated under the reaction
conditions. A highly polar sugar tetraol 1k (entry 14) is
soluble in tetrahydrofuran and was thus successfully con-
verted into the tetra-PMB sugar derivative 2k in 69%
yield. The reactions of phenol (1l, entry 15 and 16) result-
ed in poor yields under the conditions with (+)-10-cam-
phorsulfonic acid or boron trifluoride–diethyl ether
complex because of the competing Friedel–Crafts reac-
tion at the aromatic rings in both the substrate and the
product. In contrast, p-chlorophenol (1m, entry 17) gave
the PMB ether 2m in an excellent yield, indicating that the
electron-withdrawing p-chloro substituent would sup-
press the side reaction.
Although adjustments of the time for dropwise addition
and the additional reaction time are required, this method
can be considered as a high-atom-economy and time-
saving procedure. Further, we developed alternative con-
venient methods using excess TriBOT-PM (0.65 equiv or
more) and weaker acids without dropwise addition of the
TriBOT-PM solution. The reaction with TriBOT-PM and
boron trifluoride–diethyl ether complex (0.1 mol%) for
five hours at 0 °C provided 2a in excellent yield (entry 11,
95%). The reactions with (+)-10-camphorsulfonic acid
(15 mol%) or p-toluenesulfonic acid (15 mol%) in tetra-
hydrofuran under reflux gave almost quantitative yields
(99%, entries 12 and 13). In these cases, 4 was scarcely
produced (<0.1%), although the production of 3 increased
(38%, entry 12) and the N,N′-dibenzylated byproduct 6
(Figure 1, 12%, entry 12) was obtained.
We examined various alcohols for p-methoxybenzylation
using TriBOT-PM (Table 2). The p-methoxybenzylation
of 1a on a gram scale using trifluoromethanesulfonic acid
was achieved to give 2a in an excellent yield (entry 1).
However, the reaction of cinnamyl alcohol 1b (entry 2)
with trifluoromethanesulfonic acid resulted in a moderate
© Georg Thieme Verlag Stuttgart · New York
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K. Yamada et al.
PAPER
Table 2 Scope and Limitations of Various Alcohols for p-Methoxybenzylation
TriBOT-PM
conditions
R-OH
R-OPMB
1
2
Entry
1a
Product
TriBOT-PM (equiv) Conditions
Yield (%) of 2
Ph
2a
Ph
2b
OPMB
OPMB
0.37
TfOH (0.3 mol%), EtOAc, r.t., 15 min
94
2a
3
0.4
0.65
0.4
TfOH (0.3 mol%), THF, r.t., 15 min
CSA (10 mol%), THF, reflux, 11 h
TfOH (0.3 mol%), EtOAc, r.t., 15 min
BF3·OEt2 (0.8 mol%), THF, 0 °C, 45 min
66
85
83
92
TMS
OPMB
4a
5
2c
0.6
Ph
OPMB
6
7
2.0
0.6
CSA (15 mol%), THF, reflux, 8 h
CSA (10 mol%), THF, reflux, 6 h
94
83
2d
O
OPMB
OPMB
2e
MeO
8
9a
0.6
0.4
1.1
CSA (15 mol%), THF, reflux, 11 h
TfOH (0.3 mol%), THF, r.t., 15 min
CSA (15 mol%), THF, reflux, 13 h
92
77
87
O
2f
EtO
O
OPMB
10
2g
OPMB
OMe
O
BocHN
11
12
1.0
0.7
CSA (15 mol%), THF, reflux, 9 h
CSA (15 mol%), THF, reflux, 12 h
77
84
2h
OPMB
TBSO
2i
O
O
O
O
H
13
14
1.1
4.8
CSA (15 mol%), THF, reflux, 7.5 h
CSA (60 mol%), THF, reflux, 30 h
90
69
PMBO
O
2j
OPMB
O
PMBO
PMBO
PMBO
OMe
2k
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p-Methoxybenzylation of Hydroxy Groups Using TriBOT-PM
2993
Table 2 Scope and Limitations of Various Alcohols for p-Methoxybenzylation (continued)
TriBOT-PM
conditions
R-OH
R-OPMB
1
2
Entry
15
Product
TriBOT-PM (equiv) Conditions
Yield (%) of 2
OPMB
0.6
BF3·OEt2 (0.5 mol%), THF, 0 °C, 2 h
15
2l
16
17
0.6
CSA (20 mol%), THF, reflux, 1.5 h
CSA (15 mol%), THF, reflux, 9 h
<1
94
Cl
OPMB
0.65
2m
a A solution of TriBOT-PM in the same solvent as the reaction mixture was added dropwise over 10 min for entries 1, 2, 4, and 9.
into H2O and cooled to 0 °C. After 1 h, the precipitate was filtered,
and washed with H2O (2 × 200 mL), hexane (2 × 100 mL), and H2O
(200 mL). The residue was recrystallized (CH2Cl2–MeOH) to give
2,4,6-tris(p-methoxybenzyloxy)-1,3,5-triazine (26.2 g, 89%) as col-
orless crystals; mp 101.5–102.2 °C.
In conclusion, we successfully developed a new reagent,
TriBOT-PM, for p-methoxybenzylation that is superior to
the conventional reagent (PMBTCAI) with respect to
atom economy, stability, and cost. Because TriBOT-PM
can be activated by not only trifluoromethanesulfonic acid
but also other weaker acids, such as boron trifluoride–
diethyl ether complex and (+)-10-camphorsulfonic acid,
various alcohols possessing alkali-labile or acid-labile
functional groups are converted into PMB ethers in good
yields. In addition, common ethereal solvents (1,4-diox-
ane, DME, and THF) and ethyl acetate can be utilized for
the reaction; therefore, various combinations of the sol-
vents and acids are available depending on the require-
ments of the substrate.
IR (KBr): 2956, 2835, 1614, 1558, 1429, 1340, 1248, 1120, 820
cm–1.
1H NMR (CDCl3): δ = 7.37 (d, J = 8.7 Hz, 6 H), 6.89 (d, J = 8.7 Hz,
6 H), 5.38 (s, 6 H), 3.81 (s, 9 H).
13C NMR (100 MHz, CDCl3): δ = 173.0, 159.8, 130.2, 127.5, 113.9,
69.7, 55.3.
HRMS (FAB): m/z [M + H]+ calcd for C27H28N3O6: 490.1978;
found: 490.1984.
Anal. Calcd for C27H27N3O6: C, 66.25; H, 5.56; N, 8.58. Found: C,
66.05; H, 5.63; N, 8.48.
N-(p-Methoxybenzyl)isocyanuric Acid (3)
NMR spectra were determined on a Jeol JNM-ECS400 spectrome-
ter [1H NMR (400 MHz), 13C NMR (100 MHz)] or a Jeol JNM-
ECA600 [13C NMR (150 MHz)], relative to TMS (1H) as the inter-
nal standard or TMS or residual solvents (13C, CDCl3: δ = 77.0,
DMSO-d6: δ = 39.5) as the internal standard. IR spectra were re-
corded on a Horiba FT-720 FREEXACT-II spectrophotometer.
Mass spectra were measured on a Micromass Zq2000 spectrometer
(ESI-MS), JMS-SX102A (FAB and EI). Analytical TLC was per-
formed on Merck precoated analytical plates, 0.25 mm, silica gel 60
Colorless crystals; mp 256.5–258.0 °C.
IR (KBr): 3224, 3093, 2964, 2837, 2789, 1772, 1684, 1469, 1254,
1034 cm–1.
1H NMR (DMSO-d6): δ = 11.47 (br s, 2 H), 7.24 (d, J = 8.7 Hz, 2
H), 6.87 (d, J = 8.7 Hz, 2 H), 4.75 (s, 2 H), 3.72 (s, 3 H).
13C NMR (100 MHz, DMSO-d6): δ = 158.5, 149.9, 148.6, 129.1,
128.8, 113.7, 55.1, 43.0.
HRMS (FAB): m/z [M]+ calcd for C11H11N3O4: 249.0750; found:
F254. Preparative TLC separations were performed on Merck analyt-
ical plates (0.50 mm) precoated with silica gel 60 F254. Flash chro-
matography separations were performed on Kanto Chemical Silica
Gel 60 N (spherical, neutral, 40–100 mesh) unless otherwise noted.
Recycling preparative HPLC was performed with Japan Analytical
Industry LC-928 equipped with GPC columns Jaigel-1H and 2H.
Reagents were commercial grades and were used without any puri-
fication unless otherwise noted. Anhyd Et2O, 1,4-dioxane, THF,
and CH2Cl2 were purchased from commercial sources. DME and
EtOAc were purchased from commercial sources and distilled be-
fore use. All reactions sensitive to O2 or moisture were conducted
under a N2 atmosphere.
249.0753.
Anal. Calcd for C11H11N3O4: C, 53.01; H, 4.45; N, 16.86. Found: C,
53.03; H, 4.43; N, 16.79.
N,N′-Bis(p-methoxybenzyl)isocyanuric Acid (6)
Colorless crystals; mp 183.5–186.2 °C.
IR (KBr): 3203, 3076, 2966, 2839, 1724, 1685, 1454, 1252, 1034
cm–1.
1H NMR (CDCl3): δ = 8.04 (br s, 1 H), 7.41 (d, J = 8.7 Hz, 4 H),
6.85 (d, J = 8.7 Hz, 4 H), 4.94 (s, 4 H), 3.79 (s, 6 H).
13C NMR (100 MHz, CDCl3): δ = 159.5, 149.7, 148.3, 130.8, 127.7,
113.9, 55.3, 45.1.
HRMS (FAB): m/z [M + H]+ calcd for C19H20N3O5: 370.1397;
found: 370.1410.
2,4,6-Tris(p-methoxybenzyloxy)-1,3,5-triazine (TriBOT-PM)8a
To a suspension of NaH (60%) (8.64 g, 216 mmol) in THF (360
mL), anisyl alcohol (24.4 mL, 198 mmol) was added dropwise at
0 °C. The mixture was warmed to r.t., stirred for 50 min, and then
cooled to 0 °C. Cyanuric chloride (11.07 g, 60.0 mmol) in THF (120
mL) was added dropwise over 30 min. The mixture was stirred for
an additional 30 min at 0 °C and 3 h at r.t., the mixture was poured
Anal. Calcd for C19H19N3O5: C, 61.78; H, 5.18; N, 11.38. Found: C,
61.73; H, 5.19; N, 11.17.
© Georg Thieme Verlag Stuttgart · New York
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p-Methoxybenzyl 3-Phenylpropyl Ether (2a)11
HRMS (FAB): m/z [M]+ calcd for C17H18O2: 254.1307; found:
254.1311.
To a solution of 3-phenylpropan-1-ol (613 μL, 4.50 mmol) in
EtOAc (9.2 mL), the dropwise addition of TriBOT-PM (815.1 mg,
1.67 mmol) in EtOAc (12.0 mL, prepared in a test tube) over 10 min
was started at r.t. and then TfOH (0.3 mol%) in EtOAc (300 mM,
45.0 μL) was added immediately. After the dropwise addition was
complete, the residual TriBOT-PM in the test tube was rinsed with
EtOAc (1.3 mL) into the mixture over 1 min. The mixture was
stirred for a total of 15 min and washed with sat. NaHCO3 (15 mL),
H2O (15 mL), and brine (15 mL). The organic layer was dried
(MgSO4), filtered, and concentrated under reduced pressure. The
residue was purified by column chromatography (hexane–toluene,
1:1 to hexane to hexane–EtOAc, 19:1) to afford 2a (1.09 g, 94%) as
a clear colorless oil.
Anal. Calcd for C17H18O2: C, 80.28; H, 7.13. Found: C, 80.35; H,
7.11.
(2-Trimethylsilyl)ethyl p-Methoxybenzyl Ether (2c)
High-Atom-Economy Method: To a solution of 2-(trimethylsi-
lyl)ethanol (142 μL, 1.00 mmol) in EtOAc (2.25 mL), the dropwise
addition of TriBOT-PM (195.8 mg, 0.400 mmol) in EtOAc (2.20
mL, prepared in a test tube) over 10 min was started at r.t. and then
TfOH (0.3 mol%) in EtOAc (100 mM, 30.0 μL) was added imme-
diately. When the dropwise addition was complete, the residual Tri-
BOT-PM in the test tube was rinsed with EtOAc (0.30 mL) into the
mixture over 1 min. The mixture was stirred for a total of 15 min
and washed with sat. NaHCO3 (5 mL), H2O (5 mL), and brine (5
mL). The organic layer was dried (MgSO4), filtered, and concen-
trated under reduced pressure. The residue was purified by column
chromatography (hexane–toluene–CHCl3, 2:1:1 to 1:1:1) to afford
2c (198.3 mg, 83%).
IR (CHCl3): 3062, 2937, 2862, 1612, 1508, 1099 cm–1.
1H NMR (CDCl3): δ = 7.30–7.23 (m, 4 H), 7.20–7.14 (m, 3 H), 6.88
(d, J = 8.7 Hz, 2 H), 4.43 (s, 2 H), 3.80 (s, 3 H), 3.46 (t, J = 6.4 Hz,
2 H), 2.70 (t, J = 7.8 Hz, 2 H), 1.92 (tt, J = 6.4, 7.8 Hz, 2 H).
13C NMR (100 MHz, CDCl3): δ = 159.1, 142.0, 130.7, 129.3, 128.5,
128.3, 125.7, 113.8, 72.6, 69.2, 55.3, 32.4, 31.4.
HRMS (FAB): m/z [M]+ calcd for C17H20O2: 256.1463; found:
256.1467.
Convenient Method: To a solution of 2-(trimethylsilyl)ethanol (142
μL, 1.00 mmol) and TriBOT-PM (293.7 mg, 0.600 mmol) in THF
(5.00 mL), BF3·OEt2 in THF (200 mM, 40.0 μL) was added at 0 °C.
After 45 min, the mixture was diluted with Et2O (20 mL) and
washed with 2% Na2CO3 (100 mL), H2O (100 mL), and brine (20
mL). The organic layer was dried (Na2SO4), filtered, and concen-
trated under reduced pressure. The residue was purified by column
chromatography (hexane–EtOAc, 19:1) to afford 2b (218.9 mg,
92%) as a clear colorless oil.
Anal. Calcd for C17H20O2: C, 79.65; H, 7.86. Found: C, 79.45; H,
7.90.
Bis(3-phenylpropyloxy)methane (4)11
1H NMR (CDCl3): δ = 7.31–7.24 (m, 4 H), 7.22–7.15 (m, 6 H), 4.69
(s, 2 H), 3.56 (t, J = 6.4 Hz, 4 H), 2.69 (t, J = 7.8 Hz, 4 H), 1.91 (m,
4 H).
IR (CHCl3): 2956, 2860, 1614, 1510, 1074 cm–1.
1H NMR (CDCl3): δ = 7.26 (d, J = 8.7 Hz, 2 H), 6.87 (d, J = 8.7 Hz,
2 H), 4.42 (s, 2 H), 3.81 (s, 3 H), 3.58–3.51 (m, 2 H), 1.02–0.94 (m,
2 H), 0.01 (s, 9 H).
13C NMR (100 MHz, CDCl3): δ = 141.9, 128.4, 128.3, 125.8, 95.4,
67.1, 32.4, 31.4.
LRMS (ESI): m/z = 307 ([M + Na]+).
13C NMR (100 MHz, CDCl3): δ = 159.0, 130.8, 129.2, 113.7, 72.0,
67.3, 55.2, 18.2, –1.4.
HRMS (FAB): m/z [M]+ calcd for C13H22O2Si: 238.1389; found:
238.1397.
Cinnamyl p-Methoxybenzyl Ether (2b)13
High-Atom-Economy Method: To a solution of cinnamyl alcohol
(129 μL, 1.00 mmol) in THF (2.50 mL), the dropwise addition of
TriBOT-PM (195.8 mg, 0.400 mmol) in THF (2.25 mL, prepared in
a test tube) over 10 min was started at r.t. and then TfOH (0.3 mol%)
in EtOAc (100 mM, 30.0 μL) was added immediately. After the
dropwise addition was complete, the residual TriBOT-PM in the
test tube was rinsed with THF (0.25 mL) into the mixture over 1
min. The mixture was stirred for a total of 15 min, diluted with Et2O
(5 mL), washed with sat. NaHCO3 (5 mL), H2O (50 mL), and brine
(5 mL). The organic layer was dried (MgSO4), filtered, and concen-
trated under reduced pressure. The residue was purified by column
chromatography (hexane–EtOAc, 19:1) to afford 2b (167.0 mg,
66%) as colorless crystals.
Anal. Calcd for C13H22O2Si: C, 65.50; H, 9.30. Found: C, 65.20; H,
9.49.
p-Methoxybenzyl 2-Methyl-4-phenylbutan-2-yl Ether (2d)14
To a solution of 2-methyl-4-phenylbutan-2-ol (74.0 mg, 0.451
mmol) and TriBOT-PM (441.1 mg, 0.901 mmol) in THF (1.50 mL),
CSA (15.7 mg, 0.0676 mmol) was added at r.t. The mixture was
heated to reflux and additional TriBOT-PM was added after 1.5 h
(132.3 mg, 0.270 mmol), 3 h (66.2 mg, 0.135 mmol), 4.5 h (66.2
mg, 0.135 mmol), and 6 h (44.1 mg, 0.0901 mmol), respectively.
The mixture was stirred for an additional 2 h, and then it was cooled
to r.t. and diluted with Et2O (10 mL), washed with H2O (23 mL),
10% K2CO3 (3 × 10 mL), and brine (10 mL). The organic layer was
dried (Na2SO4), filtered, and concentrated under reduced pressure.
The residue was purified by column chromatography (hexane–
EtOAc, 40:1 to 19:1) to afford 2d (107.9 mg, 94%) as a clear color-
less oil.
Convenient Method: To a solution of cinnamyl alcohol (77.1 μL,
0.600 mmol) and TriBOT-PM (190.9 mg, 0.390 mmol) in THF
(2.00 mL), CSA (13.9 mg, 0.0598 mmol) was added at r.t. The mix-
ture was heated to reflux for 11 h. After cooling to r.t., the mixture
was diluted with Et2O (20 mL), washed with H2O (40 mL), 10%
K2CO3 (3 × 20 mL), and brine (20 mL). The organic layer was dried
(Na2SO4), filtered, and concentrated under reduced pressure. The
residue was purified by column chromatography (hexane–EtOAc,
19:1) to afford 2b (129.5 mg, 85%) as colorless crystals; mp 38.1–
40.1 °C.
IR (CHCl3): 3060, 2937, 2867, 1614, 1466, 1257 cm–1.
1H NMR (CDCl3): δ = 7.32–7.24 (m, 4 H), 7.23–7.15 (m, 3 H), 6.88
(d, J = 8.7 Hz, 2 H), 4.40 (s, 2 H), 3.80 (s, 3 H), 2.76–2.68 (m, 2 H),
1.92–1.84 (m, 2 H), 1.32 (s, 6 H).
13C NMR (100 MHz, CDCl3): δ = 158.8, 142.9, 131.8, 128.8,
128.34, 128.31, 125.6, 113.7, 74.8, 63.4, 55.3, 42.3, 30.4, 25.8.
HRMS (FAB): m/z [M]+ calcd for C19H24O2: 284.1776; found:
284.1777.
IR (CHCl3): 3062, 2997, 2839, 1612, 1506, 1466, 1111, 1076 cm–1.
1H NMR (CDCl3): δ = 7.42–7.37 (m, 2 H), 7.35–7.21 (m, 5 H), 6.89
(d, J = 8.7 Hz, 2 H), 6.62 (dd, J = 1.4, 15.6 Hz, 1 H), 6.32 (dt, J =
15.6, 6.0 Hz, 1 H), 4.51 (s, 2 H), 4.17 (dd, J = 1.4, 6.0 Hz, 2 H), 3.80
(s, 3 H).
Anal. Calcd for C19H24O2: C, 80.24; H, 8.51. Found: C, 80.19; H,
8.36.
13C NMR (100 MHz, CDCl3): δ = 159.2, 136.7, 132.5, 130.3, 129.5,
128.5, 127.6, 126.5, 126.2, 113.8, 71.8, 70.5, 55.3.
Synthesis 2013, 45, 2989–2997
© Georg Thieme Verlag Stuttgart · New York

PAPER
p-Methoxybenzylation of Hydroxy Groups Using TriBOT-PM
2995
4-(p-Methoxybenzyloxy)butan-2-one (2e)15
1H NMR (CDCl3): δ = 7.29 (d, J = 8.7 Hz, 2 H), 6.88 (d, J = 8.7 Hz,
2 H), 4.63 (d, J = 11.3 Hz, 1 H), 4.39 (d, J = 11.3 Hz, 1 H), 4.23 (dq,
J = 10.8, 7.1 Hz, 1 H), 4.19 (dq, J = 10.8, 7.1 Hz, 1 H), 4.03 (q, J =
6.9 Hz, 1 H), 3.80 (s, 3 H), 1.43 (d, J = 6.9 Hz, 3 H), 1.30 (t, J = 7.1
Hz, 3 H).
13C NMR (150 MHz, CDCl3): δ = 173.4, 159.4, 129.67, 129.66,
113.8, 73.7, 71.6, 60.8, 55.3, 18.7, 14.3.
To a solution of 4-hydroxybutan-2-one (86.4 μL, 1.00 mmol) and
TriBOT-PM (342.7 mg, 0.700 mmol) in THF (3.33 mL), CSA (23.2
mg, 0.100 mmol) was added at r.t. The mixture was heated to reflux
for 6 h. After cooling to r.t., the mixture was diluted with Et2O (33
mL), washed with H2O (67 mL), 10% K2CO3 (3 × 33 mL), and brine
(33 mL). The organic layer was dried (Na2SO4), filtered, and con-
centrated under reduced pressure. The residue was purified by col-
umn chromatography (hexane–EtOAc, 19:1 to 9:1) to afford 2e
(174.3 mg, 83%) as a clear colorless oil.
LRMS (ESI): m/z = 261 ([M + Na]+).
Boc-L-Ser(OPMB)-OMe (2h)
IR (CHCl3): 2866, 1716, 1612, 1363, 1101 cm–1.
To a solution of Boc-L-Ser-OMe (232.0 mg, 1.06 mmol) and
TriBOT-PM (521.9 mg, 0.107 mmol) in THF (3.52 mL), CSA (36.9
mg, 0.159 mmol) was added at r.t. The mixture was heated to reflux
and additional TriBOT-PM was added after 2 h (33.7 mg, 0.0688
mmol), 3 h (33.7 mg, 0.0688 mmol), 4 h (50.5 mg, 0.103 mmol), 6.5
h (33.7 mg, 0.0688 mmol), and 8 h (33.7 mg, 0.0688 mmol), respec-
tively. The mixture was stirred for an additional 1 h, then it was
cooled to r.t., diluted (hexane–EtOAc, 1:1; 53 mL), and washed
with H2O (80 mL), sat. NaHCO3 (2 × 30 mL), and brine (30 mL).
The organic layer was dried (Na2SO4), filtered, and concentrated
under reduced pressure. The residue was purified by column chro-
matography (hexane–EtOAc, 9:1 to 6:1 to 4:1) followed by recy-
cling preparative HPLC to afford 2h (276.9 mg, 77%) as a clear
colorless oil.
1H NMR (CDCl3): δ = 7.25 (d, J = 8.7 Hz, 2 H), 6.88 (d, J = 8.7 Hz,
2 H), 4.44 (s, 2 H), 3.80 (s, 3 H), 3.71 (t, J = 6.2 Hz, 2 H), 2.70 (t,
J = 6.2 Hz, 2 H), 2.17 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 207.3, 159.2, 130.1, 129.3, 113.8,
72.9, 64.9, 55.3, 43.8, 30.5.
HRMS (FAB): m/z [M]+ calcd for C12H16O3: 208.1099; found:
208.1101.
Anal. Calcd for C12H16O3: C, 69.21; H, 7.74. Found: C, 68.92; H,
7.46.
Methyl (R)-3-(p-Methoxybenzyloxy)-2-methylpropanoate (2f)16
High-Atom-Economy Method: To a solution of methyl (R)-3-hy-
droxy-2-methylpropanoate (110 μL, 1.00 mmol) in THF (2.50 mL),
the dropwise addition of TriBOT-PM (195.8 mg, 0.400 mmol) in
THF (2.30 mL, prepared in a test tube) over 10 min was started at
r.t. and then TfOH (0.3 mol%) in THF (150 mM, 20.0 μL) was add-
ed immediately. When the dropwise addition was complete, the re-
sidual TriBOT-PM in the test tube was rinsed with THF (0.20 mL)
into the mixture over 1 min. The mixture was stirred for a total of
15 min, diluted with Et2O (15 mL), washed with H2O (50 mL), sat.
NaHCO3 (5 mL), and brine (5 mL). The organic layer was dried
(Na2SO4), filtered, and concentrated under reduced pressure. The
residue was purified by column chromatography (hexane–EtOAc,
19:1 to 9:1) to afford 2f (183.9 mg, 77%) as a clear colorless oil.
IR (CHCl3): 3442, 2956, 2871, 1749, 1709, 1512, 1173 cm–1.
1H NMR (CDCl3): δ = 7.20 (d, J = 8.7 Hz, 2 H), 6.87 (d, J = 8.7 Hz,
2 H), 5.37 (br d, J = 8.3 Hz, 1 H), 4.47 (d, J = 11.9 Hz, 1 H), 4.42
(d, J = 11.9 Hz, 1 H), 4.42 (ddd, J = 8.3, 9.2, 9.2 Hz, 1 H), 3.83 (dd,
J = 3.2, 9.2 Hz, 1 H), 3.81 (s, 3 H), 3.74 (s, 3 H), 3.65 (dd, J = 3.2,
9.2 Hz, 1 H), 1.45 (s, 9 H).
13C NMR (100 MHz, CDCl3): δ = 171.2, 159.3, 155.5, 129.6, 129.3,
113.8, 79.9, 72.9, 69.6, 55.3, 54.0, 52.4, 28.3.
HRMS (FAB): m/z [M + H]+ calcd for C17H26NO6: 340.1755;
found: 340.1762.
Anal. Calcd for C17H25NO6: C, 60.16; H, 7.42; N, 4.13. Found: C,
60.42; H, 7.64; N, 4.12.
Convenient Method: To a solution of methyl (R)-3-hydroxy-2-
methylpropanoate (99.4 μL, 0.900 mmol) and TriBOT-PM (264.3
mg, 0.540 mmol) in THF (3.00 mL), CSA (31.4 mg, 0.135 mmol)
was added at r.t. The mixture was heated to reflux for 11 h. After
cooling to r.t., the mixture was diluted with Et2O (9 mL), washed
with H2O (45 mL), sat. NaHCO3 (9 mL), and brine (9 mL). The or-
ganic layer was dried (Na2SO4), filtered, and concentrated under
reduced pressure. The residue was purified by column chromato-
graphy (hexane–EtOAc, 24:1 to 12:1) to afford 2f (197.3 mg, 92%)
as a clear colorless oil.
1H NMR (CDCl3): δ = 7.24 (d, J = 8.7 Hz, 2 H), 6.87 (d, J = 8.7 Hz,
2 H), 4.46 (d, J = 11.9 Hz, 1 H), 4.44 (d, J = 11.9 Hz, 1 H), 3.80 (s,
3 H), 3.69 (s, 3 H), 3.63 (dd, J = 7.3, 9.2 Hz, 1 H), 3.46 (dd, J = 6.0,
9.2 Hz, 1 H), 2.82–2.72 (m, 1 H), 1.17 (d, J = 7.4 Hz, 3 H).
6-(tert-Butyldimethylsilyloxy)hexyl p-Methoxybenzyl Ether
(2i)5f
To a solution of methyl (6-tert-butyldimethylsilyloxy)hexan-1-ol
(139.5 mg, 0.600 mmol) and TriBOT-PM (205.6 mg, 0.420 mmol)
in THF (2.00 mL), CSA (20.9 mg, 0.0900 mmol) was added at r.t.
The mixture was heated to reflux for 12 h. After cooling to r.t., the
mixture was diluted with Et2O (6 mL) and washed with H2O (30
mL), 10% K2CO3 (3 × 6 mL), and brine (6 mL). The organic layer
was dried (Na2SO4), filtered, and concentrated under reduced pres-
sure. The residue was purified by column chromatography (hexane–
EtOAc, 38:1 to 19:1) to afford 2i (173.8 mg, 84%) as a clear color-
less oil.
1H NMR (CDCl3): δ = 7.26 (d, J = 8.7 Hz, 2 H), 6.87 (d, J = 8.7 Hz,
2 H), 4.43 (s, 2 H), 3.80 (s, 3 H), 3.59 (t, J = 6.4 Hz, 2 H), 3.43 (t,
J = 6.4 Hz, 2 H), 1.66–1.57 (m, 2 H), 1.57–1.45 (m, 2 H), 1.42–1.26
(m, 4 H), 0.89 (s, 9 H), 0.04 (s, 6 H).
13C NMR (100 MHz, CDCl3): δ = 175.3, 159.1, 130.2, 129.2, 113.7,
72.7, 71.6, 55.2, 51.7, 40.1, 14.0.
LRMS (ESI): m/z = 261 ([M + Na]+).
13C NMR (100 MHz, CDCl3): δ = 159.1, 130.8, 129.2, 113.7, 72.5,
70.1, 63.2, 55.2, 32.8, 29.8, 26.02, 25.98, 25.7, 18.4, –5.3.
LRMS (ESI): m/z = 375 ([M + Na]+).
Ethyl (S)-2-(p-Methoxybenzyloxy)propanoate (2g)17
To a solution of ethyl (S)-lactate (102 μL, 0.898 mmol) and Tri-
BOT-PM (264.3 mg, 0.540 mmol) in THF (3.33 mL), CSA (31.4
mg, 0.135 mmol) was added at r.t. The mixture was heated to reflux
and additional TriBOT-PM was added after 6 h (176.2 mg, 0.360
mmol) and 10 h (44.1 mg, 0.0901 mmol), respectively. The mixture
was stirred for an additional 3 h, then it was cooled to r.t. and diluted
(hexane–EtOAc, 1:1; 53 mL), washed with H2O (80 mL), sat.
NaHCO3 (2 × 30 mL), and brine (30 mL). The organic layer was
dried (Na2SO4), filtered, and concentrated under reduced pressure.
The residue was purified by column chromatography (hexane–
EtOAc, 25:1 to 12:1) to afford 2g (185.4 mg, 87%) as a clear color-
less oil.
1,2:5,6-Di-O-isopropylidene-3-O-(p-methoxybenzyl)-α-D-gluco-
furanose (2j)9,11,18
To a solution of 1,2:5,6-di-O-isopropylidene-α-D-glucofuranose
(104.1 mg, 0.400 mmol) and TriBOT-PM (117.5 mg, 0.240 mmol)
in THF (1.33 mL), CSA (13.9 mg, 0.0598 mmol) was added at r.t.
The mixture was heated to reflux and additional TriBOT-PM was
added after 3.5 h (78.3 mg, 0.160 mmol) and 6.5 h (19.6 mg, 0.0400
mmol), respectively. The mixture was stirred for an additional 1 h,
the mixture was cooled to r.t., diluted with Et2O (25 mL), and
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 2989–2997

2996
K. Yamada et al.
PAPER
washed with H2O (40 mL), 10% K2CO3 (2 × 27 mL), and brine (27
mL). The organic layer was dried (Na2SO4), filtered, and concen-
trated under reduced pressure. The residue was purified by column
chromatography (hexane–EtOAc, 19:1 to 14:1 to 9:1) to afford 2j
(137.4 mg, 90%) as a clear colorless oil.
1H NMR (CDCl3): δ = 7.27 (d, J = 8.7 Hz, 2 H), 6.88 (d, J = 8.7 Hz,
2 H), 5.89 (d, J = 3.7 Hz, 1 H), 4.61 (d, J = 11.4 Hz, 1 H), 4.57 (d,
J = 11.4 Hz, 1 H), 4.56 (d, J = 3.7 Hz, 1 H), 4.34 (ddd, J = 7.6, 8.7,
8.7 Hz, 1 H), 4.14 (dd, J = 3.0, 7.6 Hz, 1 H), 4.10 (d, J = 6.0, 8.7 Hz,
1 H), 4.00 (d, J = 3.0 Hz, 1 H), 3.99 (d, J = 6.0, 8.7 Hz, 1 H), 3.81
(s, 3 H), 1.49 (s, 3 H), 1.43 (s, 3 H), 1.38 (s, 3 H), 1.31 (s, 3 H).
LRMS (EI): 214 ([M]+).
p-Chlorophenyl p-Methoxybenzyl Ether (2m)21
To a solution of p-chlorophenol (119.3 mg, 0.928 mmol) and Tri-
BOT-PM (340.7 mg, 0.603 mmol) in THF (3.10 mL), CSA (32.3
mg, 0.139 mmol) was added at r.t. The mixture was heated to reflux
and additional TriBOT-PM was added after 1 h (90.9 mg, 0.186
mmol), 2 h (45.4 mg, 0.0927 mmol), and 5 h (22.7 mg, 0.0464
mmol), respectively. The mixture was stirred for an additional 4 h,
and it was cooled to r.t., diluted with Et2O (9 mL), and washed with
H2O (47 mL), 10% K2CO3 (3 × 9 mL), and brine (9 mL). The organ-
ic layer was dried (Na2SO4), filtered, and concentrated under re-
duced pressure. The residue was purified by column
chromatography (hexane–CHCl3, 1:1) to afford 2m (216.6 mg,
94%) as colorless crystals; mp 106.0–107.0 °C.
13C NMR (150 MHz, CDCl3): δ = 159.4, 129.7, 129.4, 113.8, 111.8,
109.0, 105.3, 82.7, 81.32, 81.31, 72.6, 72.1, 67.4, 55.3, 26.9, 26.8,
26.3, 25.5.
1H NMR (CDCl3): δ = 7.34 (d, J = 8.7 Hz, 2 H), 7.23 (d, J = 9.0 Hz,
2 H), 6.91 (d, J = 8.7 Hz, 2 H), 6.89 (d, J = 8.9 Hz, 2 H), 4.95 (s, 2
H), 3.81 (s, 3 H).
LRMS (ESI): m/z = 403 ([M + Na]+).
Methyl 2,3,4,6-Tetrakis-O-(p-methoxybenzyl)-α-D-glucopyran-
oside (2k)
13C NMR (100 MHz, CDCl3): δ = 159.5, 157.4, 129.29, 129.22,
To a solution of methyl α-D-glucopyranoside (58.3 mg, 0.300
mmol) and TriBOT-PM (235.0 mg, 0.480 mmol) in THF (4.00 mL),
CSA (41.8 mg, 0.180 mmol) was added at r.t. The mixture was heat-
ed to reflux and additional TriBOT-PM was added after 1 h (117.5
mg, 0.240 mmol), 5.5 h (33.7 mg, 0.0688 mmol), 12.5 h (58.7 mg,
0.120 mmol), 17 h (58.7 mg, 0.120 mmol), and 21 h (117.5 mg,
0.240 mmol), respectively. The mixture was stirred for an addition-
al 9 h, the mixture was cooled to r.t., diluted with Et2O (12 mL), and
washed with H2O (60 mL), 10% K2CO3 (3 × 12 mL), and brine (12
mL). The organic layer was dried (Na2SO4), filtered, and concen-
trated under reduced pressure. The residue was purified by column
chromatography (hexane–EtOAc, 4:1 to 3:1 to 2:1) followed by re-
cycling preparative HPLC to afford 2k (139.1 mg, 69%) as a clear
pale yellow oil.
128.5, 125.7, 116.1, 114.0, 70.1, 55.3.
LRMS (EI): m/z = 248 ([M]+).
Acknowledgment
This study was financially supported in part by a Grant-in-Aid for
Young Scientists (B) (23790009) from the Ministry of Education,
Culture, Sports, Science, and Technology of Japan, and by Adap-
table and Seamless Technology Transfer Program through Target-
driven R&D (Development of eco-, and user-friendly acid-catalyzed
alkylating reagents) from Japan Science and Technology Agency.
H.F. acknowledges the Grant-in-Aid for JSPS Fellows.
IR (CHCl3): 3003, 2937, 2839, 1612, 1510, 1259, 1053 cm–1.
1H NMR (CDCl3): δ = 7.28 (d, J = 8.7 Hz, 2 H), 7.28 (d, J = 8.7 Hz,
2 H), 7.24 (d, J = 8.7 Hz, 2 H), 7.01 (d, J = 8.7 Hz, 2 H), 6.86 (d, J =
8.7 Hz, 2 H), 6.85 (d, J = 8.7 Hz, 2 H), 6.84 (d, J = 8.7 Hz, 2 H),
6.80 (d, J = 8.7 Hz, 2 H), 4.88 (d, J = 10.5 Hz, 1 H), 4.74 (d, J = 10.5
Hz, 1 H), 4.73 (d, J = 11.4 Hz, 1 H), 4.72 (d, J = 10.1 Hz, 1 H), 4.58
(d, J = 11.4 Hz, 1 H), 4.56 (d, J = 11.9 Hz, 1 H), 4.54 (d, J = 3.7 Hz,
1 H), 4.39 (d, J = 11.9 Hz, 1 H), 4.33 (d, J = 10.1 Hz, 1 H), 3.91 (dd,
J = 9.2, 9.6 Hz, 1 H), 3.80 (s, 3 H), 3.80 (s, 3 H), 3.78 (s, 3 H), 3.76
(s, 3 H), 3.71–3.63 (m, 2 H), 3.60–3.52 (m, 2 H), 3.50 (dd, J = 3.7,
9.6 Hz, 1 H), 3.35 (s, 3 H).
13C NMR (150 MHz, CDCl3): δ = 159.4, 159.24, 159.18, 159.1,
131.1, 130.5, 130.3, 130.0, 129.8, 129.62, 129.60, 129.5, 113.83,
113.79, 113.74, 113.72, 98.3, 81.9, 79.5, 77.4, 75.4, 74.6, 73.05,
73.03, 70.0, 68.0, 55.28, 55.28, 55.27, 55.2, 55.1.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis.SnoIufproi
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References
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HRMS (FAB): m/z [M + H]+ calcd for C39H47O10: 675.3169; found:
675.3178.
Anal. Calcd for C39H46O10: C, 69.42; H, 6.87. Found: C, 69.63; H,
7.10.
p-Methoxybenzyl Phenyl Ether (2l)19,20
To a solution of phenol (28.2 mg, 0.300 mmol) and TriBOT-PM
(88.1 mg, 0.180 mmol) in THF (1.50 mL), BF3·OEt2 in THF (100
mM, 15.0 μL) was added at 0 °C. The mixture was stirred for 2 h,
and it was quenched by solid NaHCO3, filtered through silica gel,
and concentrated under reduced pressure. The residue was purified
by preparative TLC (hexane–CHCl3, 1:1) to afford 2l (9.6 mg, 15%)
as colorless crystals; mp 90.8–93.0 °C.
(b) Chavan, S. P.; Harale, K. R. Tetrahedron Lett. 2012, 53,
4683. (c) Bhaskar, G.; Solomon, M.; Babu, G.;
1H NMR (CDCl3): δ = 7.36 (d, J = 8.7 Hz, 2 H), 7.32–7.26 (m, 2 H),
7.00–6.93 (m, 3 H), 6.92 (d, J = 8.7 Hz, 2 H), 4.99 (s, 2 H), 3.82 (s,
3 H).
13C NMR (100 MHz, CDCl3): δ = 159.4, 158.8, 129.5, 129.2, 129.1,
120.8, 114.8, 114.0, 69.7, 55.3.
Muralidharan, D.; Perumal, P. T. Indian J. Chem., Sect. B:
Org. Chem. Incl. Med. Chem. 2010, 49, 795. (d) Yadav, J.
S.; Bhunia, D. C.; Krishna, K. V.; Srihari, P. Tetrahedron
Lett. 2007, 48, 8306. (e) Krishna, P. R.; Lavanya, B.;
Mahalingam, A. K.; Reddy, V. V. R.; Sharma, G. V. M. Lett.
Synthesis 2013, 45, 2989–2997
© Georg Thieme Verlag Stuttgart · New York

PAPER
Org. Chem. 2005, 2, 360. (f) Sharma, G. V. M.;
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(7) Yamada, K.; Fujita, H.; Kunishima, M. Org. Lett. 2012, 14,
5026.
(8) Although TriBOT-PM has been investigated for several
applications, it has not been investigated as a p-methoxy-
benzylating reagent: (a) Srinivas, K.; Sitha, S.; Rao, V. J.;
Bhanuprakash, K.; Ravikumar, K. J. Mater. Chem. 2006, 16,
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(9) Other intermediates, 4,6-bis(p-methoxybenzyloxy)-1,3,5-
triazin-2(1H)-one and 6-(p-methoxybenzyloxy)-1,3,5-
triazine-2,4(1H,3H)-dione could also undergo N-p-meth-
oxybenzylation, which leads to the formation of 3 (Figure 2).
p-Methoxybenzylation of Hydroxy Groups Using TriBOT-PM
2997
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(18) Kurita, T.; Hattori, K.; Seki, S.; Mizumoto, T.; Aoki, F.;
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(19) Dai, H.-L.; Liu, W.-Q.; Xu, H.; Yang, L.-M.; Lv, M.; Zheng,
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O
O
N
NH
OPMB
(20) Kuwano, R.; Kusano, H. Org. Lett. 2008, 10, 1979.
(21) Anderson, K. W.; Ikawa, T.; Tundel, R. E.; Buchwald, S. L.
J. Am. Chem. Soc. 2006, 128, 10694.
HN
NH
OPMB
PMBO
N
O
N
Figure 2 Other intermediates for N-p-methoxybenzylation
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2013, 45, 2989–2997