N. Barroca-Aubry et al. / Tetrahedron Letters 54 (2013) 5118–5121
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Table 3
Formation of PMB ethers: comparison between PMB-NPTFA 1a and PMB-TCA 1b
a.
NaH, DCM, 0°C to rt, 2h, 89% by crystallization
Scheme 1. Preparation of PMB-NPTFA 1a.
Entry
Alcohols
Reagent
PMB ether
Yield (%)
1
2
3
4
2
2
6
6
PMB-TCA 1b
PMB-NPTFA 1a
PMB-TCA 1b
PMB-NPTFA 1a
3
3
7
7
92a
98b
90a
95b
Table 1
Reaction of alcohol 2 and PMB-NPTFA 1a with catalytic amounts of rare earth metal or
bismuth triflates
Reaction conditions: 1a or 1b (1.3 equiv), Bi(OTf)3 (3 mol %), conventional 4 Å MS,
[ROH] = 0.1 mol LÀ1, toluene, rt.
a
PMB ethers 3 and 7 were contaminated by TCA-NH2, even after two purifica-
tions by flash-chromatography. Respective PMB ethers and TCA-NH2 amounts were
estimated using 1H NMR.
Entry
Catalyst
(mol %)
T (°C)
Time (h)
Yielda (%)
b
Isolated yields.
1
2
3
4
5
6
7
Sm(OTf)3
Nd(OTf)3
Nd(OTf)3
In(OTf)3
Sc(OTf)3
Yb(OTf)3
Bi(OTf)3
5
5
10
3
3
3
rt
rt
rt
10
10
10
10
1
1
3
1
1
1
1
25
15
98
79
83
93
93
the replacement of conventional 4 Å MS by AW300 had a detri-
mental effect on the formation of PMB ether 3 (entries 2 and 4 vs
1 and 3). Partial decomposition of PMB-NPTFA 1a was observed
when AW300 was used, suggesting that the proton scavenging
capacity of conventional 4 Å MS is beneficial to the reaction.
Next, to determine if the new PMB-NPTFA reagent 1a offered an
added value over the previously described PMB-TCA 1b,4d–g we
investigated the etherification of primary and secondary alcohols
2 and 615 with either imidates 1a or 1b. If both reagents allowed
reaching full conversion of both substrates, consistently higher iso-
lated yields were obtained with 1a (Table 3). Indeed, when 1b was
used, two purifications by chromatography on silica gel were not
sufficient to obtain ethers 3 and 7 exempt of residual trichloroace-
tamide by product. In contrast, the low polarity of the UV active N-
phenyl-2,2,2-trifluoroacetamide produced in the reaction with
PMB-NPTFA 1a, greatly facilitated the isolation of PMB ethers 3
and 7 in pure form after a single flash-chromatography.
3
Reaction conditions: PMB-NPTFA 1a (1.2 equiv), [ROH] = 0.1 mol LÀ1
.
Yields were determined using 1H NMR of the crude reaction mixtures.
a
Table 2
Influence of solvent and MS nature on the Bi(OTf)3 catalyzed etherification with PMB-
NPTFA 1a
Entry
Alcohol
Solvent
MS
Time
Yielda (%)
Then to probe the compatibility of the optimized etherification
procedure with acid labile protecting groups, acetonide 8, dime-
thoxytrityl derivative 10, and N-Boc amino-acid 1818 were used
as substrates. As shown in Table 4, entries 1 and 6, 1,2-O-isopropyl-
idene and N-Boc moieties proved to be fully stable under the reac-
tion conditions, leading to the corresponding PMB ethers in
respective 77% and 92% isolated yields.19 With the DMTr ether
10, the reaction was quenched after 4 h giving compound 11 in
50% yield along with 45% of unreacted 10 (entry 2), indicating that
DMTr ethers are also stable under the reaction conditions. Not sur-
prisingly, benzyl and allyl ethers were fully stable as shown by the
isolation of ether 13 in 80% yield (entry 3). Gratifyingly, the base
sensitive substrates 14 and 16, containing respectively an acetate
or a uronate moiety, were converted in their respective PMB ethers
in good yields as expected (entries 4 and 5). Taken together, these
data demonstrate the versatility and broad substrate compatibility
of Bi(OTf)3 catalyzed etherification reaction with imidate 1a.
Finally, we used 1,2-diol furanose 20a and 1,3-diol pyranose
22a, to evaluate the potentiality of PMB-NPTFA 1a for regioselec-
tive etherification of primary versus secondary alcohols. A first
set of experiments was performed on diol 20a (Bi(OTf)3, 3 mol %)
and, as expected, the primary position reacted faster, leading to
6-O-PMB ether 20b20 in the highest proportions (Table 5, entries
1 and 4). Depending on the reaction conditions, various propor-
tions of 5-O-PMB regioisomer 20c20 and 5,6-di-O-PMB ether 20d
were formed: changing DCM to toluene resulted in a small increase
from 12% to 16% of the 5-O-PMB ether 20c along with the enhance-
ment of the proportion for 20b from 56% to 62% (entries 1 and 3).
Such result suggested that toluene favored the mono etherification
on diol 20a. Lowering the temperature from À10° to À40° reduced
1
2
3
4
5
6
2
2
2
2
4
4
DCM
DCM
Toluene
Toluene
DCM
4 Åb
1 h
1 h
1 h
1 h
2 h
15 min
92
76
98
80
52
81
AW300c
4 Åb
AW300c
4 Åb
Toluene
4 Åb
Reaction
conditions:
PMB-NPTFA
1a
(1.3 equiv),
Bi(OTf)3
(3 mol %),
[ROH] = 0.1 mol LÀ1, rt.
a
Isolated yields.
Conventional 4 Å MS.
AW300 (4 Å acid-washed MS).
b
c
for further evaluation of the scope and limitations of the use of imi-
date 1a for the preparation of PMB ethers.
Toluene and acid-washed MS have been reported to have ben-
eficial effect on glycoside acetimidates or PMB-TCA 1b activation
leading to enhancement of reaction rates.4f,14a,16 Thus, we next
examined the influence of solvent and MS nature on the outcome
of the reaction. In order to determine whether primary and second-
ary alcohols would react in the same way, alcohols 2 and 4 were
both used as substrates with 1a (1.3 equiv), Bi(OTf)3 (3 mol %),
either in DCM or toluene and with conventional or acid washed
4 Å MS (AW300). Primary alcohol 2 reacted faster in DCM than sec-
ondary alcohol 4 (Table 2, entries 1 and 5). Gratifyingly, with the
later substrate, we observed an impressive increase in the reaction
rate when DCM was replaced by toluene (entries 5 and 6). Indeed,
with toluene as the solvent, ether 5 was isolated in 81% yield after
only 15 min reaction at rt.17 In contrast to the results reported with
NPTFA glycoside donors14a,16 and irrespective of the solvent used,