An efficient method for para-methoxybenzyl ether formation with lanthanum triflate

Article abstract of DOI:10.1016/S0040-4039(03)00282-X

PMB ethers of alcohols are prepared in high yields and short reaction times using the trichloroacetimidate of PMB alcohol and lanthanum triflate. The mild conditions allow protection of acid-sensitive alcohols.

Full text of DOI:10.1016/S0040-4039(03)00282-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 2267–2269
An efficient method for para-methoxybenzyl ether formation
with lanthanum triflate
Anand Narain Rai and Amit Basu*
Department of Chemistry, Brown University, Providence, RI 02912, USA
Received 8 January 2003; revised 29 January 2003; accepted 30 January 2003
Abstract—PMB ethers of alcohols are prepared in high yields and short reaction times using the trichloroacetimidate of PMB
alcohol and lanthanum triflate. The mild conditions allow protection of acid-sensitive alcohols. © 2003 Elsevier Science Ltd. All
rights reserved.
The para-methoxybenzyl (PMB) group has found
application in organic synthesis as a protecting group
for alcohols due to the robustness of its ether linkage to
basic, nucleophilic, and mildly acidic conditions.1
Deprotection of the PMB group can be accomplished
under oxidative, reductive or acidic conditions.1,2 For
substrates which are not base sensitive, the most com-
mon method for installation of the protecting group
involves treatment of the alcohol with a base such as
sodium hydride in the presence of a para-methoxybenz-
yl halide.1 However, for substrates which are not
stable under these basic conditions, protection can be
effected by reaction of the alcohol with the
trichloroacetimidate of para-methoxybenzyl alcohol
(PMBTCA, 2) in the presence of Brønsted acids such as
para-toluenesulfonic acid, triflic acid, or camphorsul-
fonic acid.3 Lewis acids such as BF3·OEt2, TrBF4,
TMSOTf, Sn(OTf)2, and TrClO4 have also been used as
catalysts.3b,4 While other methods for formation of
PMB ethers have been reported,5 the trichloroacetimi-
date continues to find extensive use due to its ease of
preparation.4a
flates, especially the lanthanide triflates, are highly
effective in catalyzing the desired transformation. We
began by examining the protection of (−)-menthol
under various conditions (Table 1). A variety of magne-
sium, copper, and zinc salts were screened, and each of
Table 1. Reaction of (−)-menthol and PMBTCA with
various catalysts/solvents
Entry
Catalyst
Solvent
Time
Conversion (%)a
1
2
3
4
Mg(OTf)2
Cu(OTf)2
Zn(OTf)2
MgBr2
Cu(OTf)2
CuSO4
Yb(OTf)3
Sc(OTf)3
La(OTf)3
La(OTf)3
La(OTf)3
La(OTf)3
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
Toluene
Toluene
Toluene
Toluene
Toluene
CH3CN
Toluene
Toluene
4 h
2 h
2 h
72 h
30 min
72 h
B5 min
B5 min
B5 min
B5 min
B5 min
B5 min
89 (64)
74 (67)
58
55
97
21
79
96
98 (85)
92
5
6b
7
We recently found that attempts at protection of a
multifunctional alcohol using PMBTCA along with
several commonly used promoters resulted in either
recovery of the starting material or decomposition of
the reagents to an intractable mixture (vide infra).
Prompted by these failures, we sought to identify milder
conditions for installation of the PMB ether using the
trichloroacetimidate. We now report that metal tri-
8
9
10
11c
12d
85
81
a Conversion was determined by GC analysis of the crude reaction
mixtures and refers to the ratio of product to alcohol starting
material. Numbers in parentheses refer to isolated yields.
b Anhydrous copper sulfate was used.
Keywords: protecting group; trichloroacetimidate; etherification.
c The toluene was saturated with water prior to use.
d 1.0 equiv. of PMBTCA was used.
* Corresponding author. Fax: 253-540-0698; e-mail: amit basu@
–
brown.edu
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00282-X

2268
A. N. Rai, A. Basu / Tetrahedron Letters 44 (2003) 2267–2269
Table 2. Formation of PMB ether by reaction of alcohols
with PMBTCA and La(OTf)3
the salts afforded product within a few hours in
dichloromethane (entries 1–4). Of these salts, copper
triflate was the most effective, and changing the reac-
tion solvent from dichloromethane to toluene resulted
in a four-fold increase in the rate of the reaction, which
was complete in thirty minutes. Even copper sulfate
was somewhat effective in toluene, providing 21% con-
version to product after 72 h.
We next examined a series of lanthanide triflates as
possible promoters (entries 7–9). Lanthanum triflate
and scandium triflate were excellent catalysts, providing
essentially quantitative formation of product within
minutes of their addition (entries 8 and 9). Lanthanide
triflates are known to be effective Lewis acids in polar
and aqueous solutions.6 In our studies, this characteris-
tic was borne out by reactions which proceeded with
high conversions in acetonitrile as well as toluene which
had been saturated with water (entries 10 and 11).7 A
reaction using one equivalent of PMBTCA also pro-
ceeded with high conversion, albeit not to completion
(entry 12).
For preparative reactions with La(OTf)3 we used tolu-
ene as the reaction solvent, with 1.5 equivalents of
PMBTCA as the PMB donor. We then examined the
scope of the reaction with a variety of alcohols (Table
2). In each case examined, the reaction was complete in
approximately 5 min, as monitored by TLC.8 The
b-hydroxy ketones 4 and 5 both underwent reaction
smoothly to provide the corresponding ethers without
any evidence of dehydration, even for the tertiary alco-
hol 5. The glucose derivatives 6 and 7 were protected in
91 and 93% isolated yields, respectively. The carbamate
and acetamide protected threonine esters 8 and 9 were
also protected efficiently as their PMB ethers.
The utility of the lanthanides as promoters was illus-
trated by the successful etherification of the alcohols 10
and 11. The differentially protected triol 10 provided
the PMB ether in 89% isolated yield.9 Previous attempts
to etherify 10 with the imidate 2 using boron trifluoride,
triflic acid, or para-toluenesulfonic acid either resulted
in no reaction or decomposition of the alcohol. Nota-
bly, the use of lanthanum triflate allows the etherifica-
tion of the acid sensitive epoxy alcohol 11 derived from
cinnamyl alcohol. Etherification of 11 under our stan-
dard conditions (5 mol% La(OTf)3, toluene, rt) resulted
in rapid decomposition of the alcohol, and no desired
product was isolated. However, when the reaction was
carried out at −78°C, the alcohol was consumed within
5 min, and the epoxy ether was isolated in 34% yield.
The use of boron trifluoride under these low tempera-
ture conditions resulted in an 8% yield of the PMB
ether. We speculated that the poor yield was due to
cation induced decomposition of the styryl epoxide
moiety. Inclusion of the carbocation scavenger thio-
anisole in the reaction mixture increased the yield of the
ether to 61%, consistent with this hypothesis.
The rapid reaction times, even at −78°C, low catalyst
loading, along with the ease of handling and moisture
tolerance of La(OTf)3 should render this a useful
method for the preparation of PMB ethers.
Acknowledgements
This work was supported by Brown University and the
NIH Rhode Island Biomedical Research Infrastructure
Network (Pilot Study Grant). We thank Dr. Hormuzd
Mulla for providing compounds 6 and 7.
In summary, the reaction of alcohols with PMBTCA in
the presence of catalytic amounts of La(OTf)3 rapidly
affords the corresponding PMB ethers in high yields.

A. N. Rai, A. Basu / Tetrahedron Letters 44 (2003) 2267–2269
2269
References
J=9.7); 13C NMR (100 MHz) l 25.5, 32.5, 54.5, 55.3,
63.6, 74.7, 113.8, 128.8, 131.3, 158.9, 208.2; HRMS calcd
for [C14H20O3+Na]+ 259.1310, obsd. 259.1302.
1. Green, T. W.; Wuts, P. G. M. Protective Groups in
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6. Kobayashi, S.; Sugiura, M.; Kitagawa, H.; Lam, W. W.-L.
Chem. Rev. 2002, 102, 2227–2302. Lanthanide triflates
have been used for the activation of glycosyl trichloroace-
timidates. See—Adinolfi, M.; Barone, G.; Iadonisi, A.;
Mangoni, L.; Schiattarella, M. Tetrahedron Lett. 2001, 42,
5967–5969.
7. When the reaction was carried out in wet toluene using
para-methoxybenzyl alcohol in place of the imidate 2, no
product was observed, indicating that etherification in
entry 11 proceeded via the imidate and hydrolysis of 2 was
not significant under the reaction conditions.
8. Representative procedure for PMB protection using
La(OTf)3: PMBTCA was prepared via the method of
Audia et al. (Ref. 4a). All PMB ethers with the exception
of that derived from 11 were prepared using the represen-
tative procedure described below. A solution of menthol
(20 mg, 0.128 mmol) and p-methoxybenzyl trichloroace-
timidate (54 mg, 0.192 mmol) in toluene (3 ml) was treated
with La(OTf)3 (4 mg, 0.006 mmol) at room temperature.
After completion of the reaction (<5 min), the reaction
mixture was concentrated and purified by column chro-
matography (1:9 ethyl acetate:hexane) to afford 30 mg
(85%) of 3.
Compound 6: Rf=0.6 (ethyl acetate/hexane, 1/4); 1H
NMR (300 MHz) l 3.40 (s, 3H), 3.53 (dd, 1H, J=9.2,
3.4), 3.57 (t, 1H, J=9.5), 3.69 (t, 1H, J=10), 3.78 (s, 3H),
3.82 (dt, 1H, J=8.1, 4.5), 4.02 (t, 1H, J=9.2), 4.26 (dd,
1H, J=9.8, 4.5), 4.58 (d, 1H, J=3.6), 4.67–4.87 (ab, 2H,
J=12.1), 4.74–4.85 (ab, 2H, J=10.8), 5.54 (s, 1H), 6.82 (d,
2H, J=8.5), 7.25–7.50 (m, 12 H); 13C NMR (100 MHz) l
55.1, 55.2, 62.2, 68.9, 73.6, 74.9, 78.2, 79.1, 82.0, 99.2,
101.1, 113.6, 125.9, 127.8, 128.0, 128.1, 128.4, 128.8, 129.6,
130.8, 137.4, 138.1, 159.1; HRMS calcd for [C29H32O7+H]+
493.2226, obsd. 493.2246.
Compound 7: Rf=0.7 (ethyl acetate/hexane, 1/1); 1H
NMR (300 MHz) l 2.02 (s, 3H), 2.07 (s, 6H), 3.37 (s, 3H),
3.60 (t, 1H, J=9.2), 3.80 (s, 3H), 3.88 (ddd, 1H, J=9.9,
4.1, 2.3), 4.23 (dd, 1H, J=12, 4.2), 4.31 (dd, 1H, J=12,
2.3), 4.44–4.56 (ab, 2H, J=10.8), 4.82–4.86 (m, 2H), 5.51–
5.58 (m, 1H), 6.85–6.88 (m, 2H), 7.17–7.19 (m, 2H); 13C
NMR (100 MHz) l 20.7, 20.8, 20.9, 55.2, 55.3, 62.6, 68.3,
71.2, 72.2, 74.1, 75.3, 96.8, 113.9, 129.3, 129.8, 159.5,
169.8, 170.4, 171.6; HRMS calcd for [C21H28O10+Na]+
463.1580, obsd. 463.1579.
Compound 8: Rf=0.5 (ethyl acetate/hexane, 9/1); 1H
NMR (300 MHz) l 1.21 (d, 3H, J=6.3), 3.76 (s, 3H), 4.12
(dq, 1H, J=6.3, 2.1), 4.17–4.41 (ab, 2H, J=11.5), 4.37–
4.41 (dd, 1H, J=9.5, 2.2), 5.06–5.17 (ab, 2H, J=13), 5.12
(s, 2H), 5.37 (d, 1H, J=9.6), 6.78–6.82 (m, 2H), 7.05–7.08
(m, 2H), 7.23–7.36 (m, 10H); 13C NMR (100 MHz) l 16.3,
55.2, 58.8, 67.0, 67.2, 70.4, 73.8, 113.7, 127.9, 128.1, 128.3,
128.4, 128.49, 128.54, 129.2, 129.8, 135.3, 136.3, 156.8,
159.2, 170.7; HRMS calcd for [C27H29NO6+Na]+ 486.1893,
obsd. 486.1893.
Compound 9: Rf=0.5 (ethyl acetate/hexane, 8/2); 1H
NMR (300 MHz) l 1.19 (d, 3H, J=6.3), 2.06 (s, 3H), 3.67
(s, 3H), 3.80 (s, 3H), 4.10 (dq, 1H, J=6.3, 2.2), 4.28–4.51
(ab, 2H, J=11.4), 4.66 (dd, 2H, J=9.3 2.2), 6.16 (d, 1H,
J=8.7), 6.85–6.89 (m, 2H), 7.16–7.19 (m, 2H); 13C NMR
(100 MHz) l 16.3, 23.2, 52.3, 55.3, 56.6, 70.5, 73.8, 113.8,
129.4, 129.8, 159.3, 170.5, 171.2; HRMS calcd for
[C15H21NO5+Na]+ 318.1317 obsd. 318.1312.
Compound 10: Rf=0.3 (ethyl acetate/hexane, 7/93); 1H
NMR (300 MHz) l 0.09 (s, 6H), 0.90 (s, 9H), 3.58–3.63
(m, 1H), 3.75–3.84 (m, 2H), 3.80 (s, 3H), 3.86–3.92 (m,
1H), 4.43–4.54 (m, 2H), 4.56–4.74 (ab, 2H, J=11.1), 6.86
(d, 2H, J=8.6), 7.2 (d, 2H, J=8.3), 7.44–7.49 (m, 2H),
7.57–7.62 (m, 1H), 8.02–8.04 (m, 2H); 13C NMR (100
MHz) l −5.56, −5.53, 18.1, 25.8, 55.2, 62.9, 63.7, 63.8,
72.7, 75.2, 113.8, 128.4, 129.6, 129.7, 129.8, 133.6, 159.4,
166.2; HRMS calcd for [C25H35O5Si+Na]+ 508.2244, obsd.
508.2258.
Characterization data for PMB ethers of 1, 4–11:
Compound 1: Rf=0.5 (ethyl acetate/hexane, 1/9); 1H
NMR, HRMS—Reported in J. Org. Chem. 1999, 64, 8943;
13C NMR: (100 MHz) l 15.7, 20.7, 22.0, 22.9, 25.1, 31.2,
34.2, 39.9, 47.9, 54.9, 69.7, 78.0, 113.3, 129.0, 130.9, 158.7.
Compound 4: Rf=0.4 (ethyl acetate/hexane, 15/85); 1H
NMR (300 MHz) l 2.16 (s, 3H), 2.69 (t, 2H, J=6.2 Hz),
3.70 (t, 2H, J=6.4), 3.0 (s, 3H), 4.43 (s, 2H), 6.87 (d, 2H,
J=8.5), 7.24 (d, 2H, J=8.6); 13C NMR (100 MHz) l 30.4,
43.8, 55.3, 64.9, 72.9, 113.8, 129.3, 130.1, 159.2; HRMS
calcd for [C12H16O3+Na]+ 231.0997, obsd. 231.1002.
Compound 5: Rf=0.5 (ethyl acetate/hexane, 1/9); 1H
NMR (300 MHz) l 1.35 (s, 6H), 2.19 (s, 3H), 2.66 (s, 2H),
3.79 (s, 3H), 4.39 (s, 2H), 6.86 (d, 2H, J=8.4), 7.24 (d, 2H,
Compound 11: Rf=0.5 (ethyl acetate/hexane, 15/85); 1H
NMR (300 MHz) l 3.21–3.25 (m, 1H), 3.60 (dd, 1H,
J=11.5, 5.2 Hz), 3.76–3.78 (m, 1H), 3.80 (s, 3H), 3.82 (dd,
1H, J=11.5, 3.1), 4.56 (d, 2H, J=2.6), 6.88 (d, 2H, J=8.6
Hz), 7.26–7.36 (m, 7H); 13C NMR (100 MHz) l 55.3, 55.9,
61.2, 69.6, 73.1, 113.8, 125.7, 128.1, 128.2, 129.4, 129.9,
136.9, 159.3; HRMS calcd for [C17H18O3+Na]+ 293.1154,
obsd. 293.1163.
9. Compound 10 was prepared from the corresponding azi-
dotriol via benzoylation of the dibutylstannylene ketal
followed by silylation. Full experimental details will be
published elsewhere.