Silver(I)-Catalyzed deprotection of p -methoxybenzyl ethers: A mild and chemoselective method

Article abstract of DOI:10.1021/jo301787v

The p-methoxybenzyl protecting group (PMB) on various alcohols and an acid was efficiently and selectively cleaved by the action of a catalytic amount of silver(I) hexafluoroantimonate combined with 0.5 equiv of 1,3,5- trimethoxybenzene in dichloromethane at 40 °C.

Full text of DOI:10.1021/jo301787v

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Article
Silver(I)-Catalyzed Deprotection of para-Methoxybenzyl
Ethers: A Mild and Chemoselective Method
Nicolas Kern, Thomas Dombray, Aurélien Blanc, Jean-Marc Weibel, and Patrick Pale
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 24 Sep 2012
Downloaded from http://pubs.acs.org on September 28, 2012
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Silver(I)ꢀCatalyzed Deprotection of paraꢀ
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Methoxybenzyl Ethers: A Mild and Chemoselective
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Method
Nicolas Kern, Thomas Dombray, Aurélien Blanc*, JeanꢀMarc Weibel and Patrick Pale*
Laboratoire de Synthèse et Réactivité Organiques
UMR 7177 associé au CNRS, Institut de Chimie, Université de Strasbourg
4 rue Blaise Pascal, 67070 Strasbourg, France
ablanc@unistra.fr, ppale@unistra.fr
RECEIVED DATE (to be automatically inserted after your manuscript is accepted if
required according to the journal that you are submitting your paper to)
paraꢀMethoxylbenzyl protecting group (PMB) of various alcohols were efficiently and
selectively cleaved by action of a catalytic amount of silver(I) hexafluoroantimonate
combined with 0.5 equiv of 1,3,5ꢀtrimethoxybenzene in dichloromethane at 40°C.
Introduction
The syntheses of complex molecules, e.g. natural products, is still a challenge despite the
tremendous progress made in the last 20 years.1 Most of these syntheses still require many
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protection and deprotection steps, although achieving syntheses without protecting groups is
becoming another current challenge2 within the Green Chemistry revolution.3
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In response to the increasing complexity of the molecular structures synthesized, numerous
protecting groups have been developed, as well as methods for their introduction and their
deprotection.4 Nevertheless, new and more selective protecting groups are still required,5
while milder and more selective conditions are actively pursued.6
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Among protecting groups, benzyl derivatives occupy a unique position due to their
deprotection conditions being orthogonal to other protecting and functional groups, and due to
their broad applications, including the protection of alcohols, thiols, amines and carboxylic
acids.7 Methoxyꢀsubstituted benzyl derivatives are even more interesting due to the very
specific oxidative conditions8 used to deprotect them, and are thus widely used. So far,
dichlorodicyanoquinone (DDQ) is the reagent of choice, usually applied in dichloromethane
in the presence of water (Scheme 1, top).9 However, this reagent must be used at least in
stoichiometric amount and leads to sideꢀproducts, anisaldehyde and acidic hydroquinone.
There is thus a need to replace this reagent with a milder, greener, catalytic method. Acting by
two successive single electron transfers (SET), DDQ could be replaced by species also prone
to SET, but in a more selective way. Interestingly, a version catalytic in DDQ has been
developed using Fe3+ or Mn3+ as an electron relay.10 Various conditions based on
cerium(III/IV) salts have also been reported11, however only cerium(IV) ammonium nitrate
(CAN) seems to be regularly used (Scheme 1, middle). Cerium(III) versions proceed with
variable amounts of catalyst in nitromethane at reflux and seem to be water dependent.11d,12
Stronger Lewis acids such as AlCl3, SnCl2, MgBr2.Et2O and ZrCl4 are also known to promote
PMB cleavage.13 However, these methods suffer from drawbacks such as the use of
stoichiometric reagents, their association with nucleophiles or purification problems.
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A few examples of PMB deprotection by protic acid are also known.14 Among them, a few
reported the simultaneous use of sulfonamides14c and 1,3ꢀdimethoxybenzene14d as trapping
agents. Recently, Jung et al. proposed an approach using triflic acid14e, with or without 1,3ꢀ
dimethoxybenzene as stoichiometric trapping reagent, despite some limitations notably for
allylic and propargylic alcohols and the inherent problem of orthogonality with the other
acidic sensitive protecting groups (Scheme 1).
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This context led us to explore the role of coinage metal salts in the selective deprotection of
PMB protecting groups (Scheme 1, bottom). Coinage metals, mostly copper and silver, are
well known not only for their redox properties,15 but also for their Lewis acid character.16
Combining both would facilitate the cleavage of redoxꢀactive protecting groups. Herein, we
describe a new Agꢀcatalyzed mild and chemoselective method for the removal of such
protecting groups.
Scheme 1. Known deprotection of methoxybenzyl ethers (R' = H or OMe) and a proposed
coinage metalꢀcatalyzed deprotection.
Results and Discussion
Catalyst and condition survey. In order to find the best conditions for the deprotection of
methoxybenzyl ethers, the most common paraꢀmethoxybenzyl (PMB) derivatives were
considered. We looked for a simple compound, but one heavy enough for easy handling and
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quantification of the formed product(s). The PMB 3ꢀphenylpropyl ether 1a was thus selected.
It was readily obtained from the commercially available alcohol 2a by deprotonation with
NaH and alkylation with the PMB iodide prepared in situ.17
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This PMB ether was submitted to various common salts of coinage metals under various
conditions (Table 1). Copper salts did not give any significant transformation, whatever their
oxidation states; modifying the solvent and reaction temperature made no difference (entries
1ꢀ4). In contrast, silver salts gave interesting results that were dependent on the nature of their
counterion. Silver chloride did not give any transformation, probably for solubility reasons,
even in polar and coordinating solvents and at high temperatures (entries 5ꢀ6). More soluble
in common organic solvents, silver triflate and hexafluoroantimonate gave mixtures of
products, among which was the desired deprotected alcohol. At room temperature, the former
gave the expected alcohol 2a in modest yield and after a long reaction time (entry 7).
Surprisingly, a major sideꢀproduct could be isolated and spectroscopic investigations revealed
its symmetrical acetal structure 3a. With silver hexafluoroantimonate, the same results were
observed but with a higher overall yield and with a higher alcoholꢀacetal ratio in favor of the
required alcohol (5.5:1 vs 2:1 respectively; entry 8 vs 7). Upon warming, the reaction became
quantitative within a few hours, giving 68% and 15% of respectively 2a and 3a (i.e. 98% of
the mass balance, entry 9).
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The unexpected formation of the acetal 3a suggested the intervention of the solvent,
dichloromethane, as a possible source of the extra carbon of this acetal. Therefore, we further
screened other solvents with silver hexafluoroantimonate as catalyst to improve the reaction,
while minimizing the acetal formation. Dichloroethane and chloroform gave similar
conversions as dichloromethane, but with some variation in the alcoholꢀacetal ratio (5.1:1 and
1.4:1 vs 4.5:1, respectively (entries 10ꢀ11 vs 9). The fact that dichlorethane provided the same
mixture of 2a and 3a products excluded the CH2Cl2 origin of the acetal carbon (entry 10). In
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sharp contrast, less polar as well as more polar solvents either led to rapid degradation upon
warming (entry 12) or to almost no transformation (entry 13ꢀ15).
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Gold chloride provided similar results but in a faster reaction and with an increase of the ratio
in favor of the acetal (3.5:1 vs 5.5:1 respectively; entry 16 vs 9). The more cationic
Ph3PAuNTf2 proved less effective than AuCl presumably due to degradation of the catalyst
after 5h (gold mirror formation, entry 16 vs 17). Gold trichloride did not improve the reaction
yield and nor the alcohol:acetal ratio (entry 18 vs 16).
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Table 1. Condition screening for PMB ether 1a deprotection.a
Time
(h)
4
20
4
20
1
20
20
20
4
Yieldb
1a (%)
100
”
Yieldc
2a (%)
Yieldb,d
3a (%)
Entry
Catalyst
Conditions
CH2Cl2
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
CuCl
CuCl
CuCl2
CuCl2
AgCl
AgCl
AgOTf
AgSbF6
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
rt→rfx
rt→rfx
rt→rfx
rt→rfx
rt→rfx
rt→rfx
rt
rt
rfx
rfx
CH3CN
CH2Cl2
CH3CN
CH2Cl2
CH3CN
CH2Cl2
CH2Cl2
CH2Cl2
Cl(CH2)2Cl
CHCl3
”
”
”
”
ꢀ
ꢀ
trace
trace
ꢀ
ꢀ
ꢀ
30
55
68
67
39
deg.
trace
ꢀ
15
10
15
13
27
deg.
trace
ꢀ
”
”
”
”
”
”
”
1
6
rt→rfx
rt→rfx
rt→rfx
rt→rfx
rt→rfx
r.t.
PhMe
THF
20
20
20
20
5
ꢀ
97
100
100
ꢀ
CH3CN
CH3NO2
CH2Cl2
CH2Cl2
CH2Cl2
ꢀ
ꢀ
13
9
AuCl
PPh3AuNTf2
AuCl3
46
21
39
r.t.
r.t.
5
1
49e
ꢀ
15
Reaction conditions: C = 0.1 mol/L in solvent, 5 mol% catalyst; b Estimated yield based on
a
1
c
d
the H NMR of the crude mixture; Yields of isolated pure product; Reported yields were
e
based on the stoichiometry of the reaction; No evolution of the conversion was observed
after 5h of reaction.
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Mechanistic hypothesis and condition optimization. During these catalyst screening
studies, we noticed in all reactions the presence of numerous sideꢀproducts, notably the bis(4ꢀ
methoxyphenyl)methane. The latter clearly derived from the PMB part of the starting
materials. These observations suggested a purely Lewis acid mechanism and another origin of
the acetal extra carbon coming from the PMB motif itself.11d Indeed, taking into account the
lack of reactivity with Cu(I) or Cu(II) and the strong Lewis acidity of AuCl and AuCl3 (Table
1, entries 1ꢀ4,16 and 18), a nonꢀredox mechanism seemed more pertinent for the present PMB
deprotection. Such a mechanism would thus produce a very reactive electrophilic methylene
quinone intermediate, which could react with any nucleophile including the methoxyphenyl
moiety of the starting material leading to Friedel–Crafts products (Scheme 2). Moreover, the
formation of isolated byꢀproducts could also be explained by the condensation of the
protected alcohol 1 on the postulated methylene quinone. The resulting intermediate adduct
would lead after rearrangement to the bis(4ꢀmethoxyphenyl)methane and the methylene
oxonium of the alcohol, which could be trapped by deprotected alcohol, forming the
symmetric acetal 3. It is noteworthy that presence of trace of water, or protons coming from
the rearomatization of FriedelꢀCrafts adducts, could easily explain the hydrolysis of silver
alcoholate.
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Scheme 2. Proposed mechanism for the silver–catalyzed deprotection of PMB ethers and the
formation of acetal 3.
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O
O
OMe
R
R
MeO
3
R
O
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+
O
+
MeO
R
O
Me
1
O
Me
R
OMe
Ag+
O
R
R
R
H2O or H+
Friedel-Crafts
by-products
O
O Ag+
+
O
H
Ag+
2
MeO
Ag+
In order to diminish the production of byꢀproducts, but also to support this hypothesis, we ran
the deprotection reaction in the presence of water or a better nucleophile than the
methoxyphenyl group, i.e. the 1,3,5ꢀtrimethoxybenzene (TMB), to trap the putative pꢀ
methoxybenzyl cation (Table 2).
Expecting some in situ deacetalization, the model PMB ether 1a was thus submitted to the
best conditions we had found (AgSbF6 in dichloromethane at 40°C) but in the presence of
water. However, only slight improvement was achieved using 1 equivalent of H2O with a
better ratio in favor of the alcohol, while an excess of water blocked the catalytic activity
(entries 2ꢀ3 vs 1).
Switching to one equivalent of TMB as additive, the Agꢀcatalyzed deprotection efficiently
proceeded within mostly the same reaction time and rewardingly, without the formation of
acetal 3a as expected (Table 2, entry 4 vs 1). Moreover, the purification was considerably
simplified as a series of new apolar aromatic derivatives were produced along with some
remaining TMB. Their isolation and characterization revealed that they resulted from addition
of PMB moieties to the added TMB. Three TMB derivatives containing one, two and three
PMB units (4a-c in Scheme 3) were isolated, indicating that TMB was able to react up to
three times. Therefore, oneꢀthird equivalent of TMB should have been sufficient, but
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experiments showed that half an equivalent was the best compromise. Indeed, under such
conditions, the deprotection was still quantitative and TMB was fully consumed, leading to
the 4a-c mixture, in which the bisꢀadduct 4b was the major one (entry 5 vs 4). It is worth
noting that such results corroborated our mechanistic hypothesis (Scheme 2).
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A rapid screening showed that under these updated conditions, silver hexafluoroantimonate
was still the best catalyst. Nevertheless, the corresponding triflimide was almost as efficient,
requiring a slightly longer reaction time (entry 6 vs 5). Silver triflate and tetrafluoroborate
were also very efficient catalysts, but they drastically lowered the reaction rate (entries 7ꢀ8 vs
5). Other salts gave either only slow deprotection, such as the hexafluorophosphate (entry 7 vs
5), or no reaction, such as the nitrate and chloride (entries 8ꢀ9).
Table 2. Effect of water and aromatic donors and conditions on PMB ether deprotectiona
Time
(h)
5
5
20
5
5
7
24
”
”
Yield
2a (%)
68
75
ꢀ
100
100
99
97
96
Yieldb
3a (%)
15
12
ꢀ
Ratioc
Entry
Catalyst
Additive
TMBd-4a-4b-4c (%)
1
2
3
4
5
6
7
8
9
AgSbF6
”
ꢀ
H2O 1 eq.
H2O 10 eq.
TMB 1 eq.
TMB 0.5 eq.
”
”
”
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
27ꢀ46ꢀ26ꢀ1
0ꢀ38ꢀ52ꢀ10
AgNTf2
AgOTf
AgBF4
AgPF6
AgNO3
AgCl
”
”
”
”
”
”
32
0
0
10
11
”
”
a
b
Reaction conditions: C = 0.1 mol/L in CH2Cl2 at 40°C, 5 mol% catalyst; Estimated yield
1
c
from the H NMR of the crude mixture; Ratio relative to TMB, estimated from NMR
analysis; d TMB = 1,3,5ꢀtrimethoxybenzene.
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Scheme 3. Structures of the aromatic sideꢀproducts derived from trimethoxybenzene (TMB)
4
5
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used as a trap during deprotection of PMB ethers.
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Scope and limitation. Having compared the efficiency of various catalysts and established
optimum conditions, we looked at the scope and limitation of this novel silverꢀcatalyzed
deprotection reaction. We thus screened a series of PMB ethers derived from representative
alcohols (Table 3).
PMB ethers derived from primary aliphatic alcohols readily reacted, quantitatively yielding
the corresponding alcohols after 5ꢀ7 h (entries 1ꢀ2). Secondary alcohols were as reactive and
no epimerization occurred with chiral alcohols (entries 3ꢀ4). Unexpectedly, PMB ethers
derived from allylic alcohols led to complex mixtures of products from which traces (entry 5)
or small amounts (entry 6) of the corresponding alcohol could be isolated. It is noteworthy
that the allylic alcohols themselves are unstable under our conditions probably due to the
formation of allyl cation. Once in a nonꢀallylic position, an alkene function was fully
compatible with the reaction conditions (entries 4 and 7). In sharp contrast to allyl ethers,
PMB ethers derived from propargylic alcohols proved very reactive toward this Agꢀcatalyzed
deprotection and the corresponding alcohol was rapidly obtained in high yield (entry 8).
Phenol PMB ethers could be deprotected without problems in good to excellent yields (entry
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9ꢀ11 vs 1ꢀ3). Finally, even the 4ꢀmethoxybenzyl ester 1l could be cleaved using our smooth
4
5
6
conditions affording palmitic acid in a quantitative yield (entry 12).
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Table 3. Scope of the Agꢀcatalyzed PMB ether deprotection.
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Entry
1
2
Substrate
Time (h)
Yield (%)
100
99
5
7
1a
1b
2a
2b
3
4
2.5
10
93
85
1c
2c
1d
2d
5
6
2
2a
1e
1f
2e
2f
20
10a
7
8
5
2
99
85
1g
1h
2g
2h
9
8
8
72
95
1i
1j
2i
2j
10
11
6
8
93
99
1k
1l
2k
2l
12
a Decomposition occurs.
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The tolerance of the deprotection conditions towards other protecting and functional groups
was also explored (Table 4). To look at protecting group compatibility, a series of butanꢀ1,4ꢀ
diol derivatives and a few derivatives of the Zꢀbutenꢀ1,4ꢀdiol were prepared and submitted to
the Agꢀcatalyzed deprotection conditions. These diols were monoprotected with PMB
bromide using standard conditions, and then further protected with various groups.
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Ester groups, including carbonate, were fully stable under the Agꢀcatalyzed deprotection
conditions and the PMB ether were selectively cleaved in high yields (Table 4, entries 1ꢀ2).
Interestingly, the benzyl protecting group was also fully compatible with such conditions
(entries 3ꢀ4). Despite the disappointing results gained with allylic PMB ethers (Table 3), the
PMB and benzyl ether of Zꢀbutenꢀ1,4ꢀdiol was surprisingly readily deprotected, in a fast,
clean and quantitative reaction (entry 4).
However, silyl groups such as triisopropylsilyl (TIPS) gave rise to an unexpected sideꢀ
reaction. Although the PMB group was readily cleaved, a silyl transfer occurred, leading to
the corresponding bisꢀsilylated diol. The latter was isolated with 16 % yield (entry 5).
Acetal cleavage has been reported in the presence of various Lewis acids, even at room
temperature.4 It was therefore gratifying that the present Agꢀcatalyzed deprotection proved to
be compatible with acetal groups (entries 6 and 7). Simple THPꢀPMB protected diol could be
selectively deprotected and the corresponding THP alcohol was isolated with a modest yield
(entry 6). Interestingly, the PMB ether derived from a ribose diacetal proved even more
compatible as good yield of the selective PMB cleavage product could be achieved (entry 7).
Protected aminoalcohols gave different results depending on the nature of the protecting
group on the nitrogen atom (entries 8ꢀ10). tertꢀButyloxycarbonyl group seemed to preclude
any deprotection (entry 8). Surprisingly, no NꢀBoc deprotection occurred and the starting
materials were mostly recovered, suggesting that NꢀBoc could act as ligand toward the AgI
catalyst. In order to check this hypothesis, the PMB ether derived from 5ꢀphthalimidopentanꢀ
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1ꢀol was prepared and submitted to the deprotection conditions. The reaction readily and
rapidly occurred, selectively giving the expected 5ꢀphthalimidopentanꢀ1ꢀol in high yield
(entry 9).
9
In order to look at some selectivity between Nꢀ and OꢀPMB, we prepared the Nꢀtosyl, Nꢀ and
OꢀPMB derivative from 5ꢀaminopentanꢀ1ꢀol and submitted it to the Agꢀcatalyzed
deprotection conditions. Interestingly, a high selectivity was observed in favor of the
deprotection of the OꢀPMB ether, and only after a long reaction time did some NꢀPMB
deprotection occur (entry 10).
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These examples clearly show that the Agꢀcatalyzed PMB deprotections are compatible with a
large variety of functional groups, including other protecting groups.
Table 4. Compatibility of the Agꢀcatalyzed PMB ether deprotection with other protecting and
functional groups
Entry
1
Substrate
Time (h)
17
Yield (%)
94
1m
1n
2m
2n
2
5
99
3
4
5
6
23
4
93
99
1o
1p
1q
1r
2o
2p
2q
2r
11
21
54a
58
7
8
2
75
ꢀb
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1t
2s
2t
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82
1u
1v
2u
2v
10
16
80c
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a The bisꢀsilylated diol was isolated (16%); b No conversion; c The Nꢀtosyl aminoalcohol was
also isolated (10%).
Conclusion
In the present work, we have reported that silver(I) salts catalyzed the smooth deprotection of
PMB ethers in the presence of an external nucleophile, i.e. trimethoxybenzene. These
conditions were compatible with various functions. Moreover, the orthogonality with different
protecting groups, notably the benzyl group, was demonstrated. Further studies on the
application of this procedure to other methoxybenzyl ethers and their extension to the
protection of acids and ketones are ongoing in our laboratory.
Experimental Section
General Information: Proton (1H NMR) and carbon (13C NMR) nuclear magnetic resonance
spectra were recorded on 300, 400 or 500 MHz instruments. Chemical shifts are given in part
per million (ppm) on the delta scale. Solvent peaks were used as reference values, with CDCl3
1
at 7.26 ppm for H NMR and 77.23 ppm for 13C NMR. Data are presented as followed:
chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, quint = quintet, m
= multiplet), integration and coupling constants (J in Hz). Assignments were determined on
the basis of either unambiguous chemical shifts or coupling patterns, and of COSY, HMQC,
HMBC, ROESY experiments when required. Infrared spectra were recorded neat.
Wavelengths of maximum absorbance (νmax) are quoted in wave numbers (cmꢀ1). High
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Resolution Mass Spectra (HRMS) data were recorded on a microTOF spectrometer equipped
with orthogonal ElectroSpray Interface (ESI). The parent ions [M+H]+, [M+Na]+ or [M+Li]+
are quoted. Analytical Thin Layer Chromatographies (TLC) were carried out on silica gel 60
F254 plates with visualization by ultraviolet light, potassium permanganate or Ceric
Ammonium Molybdate (CAM) dip. Flash column chromatography was carried out using
silica gel 60 (40ꢀ63 ꢁm) using cyclohexane and EtOAc as eluent and the procedure included
the subsequent evaporation of solvents in vacuo. Reagents and solvents were purified using
standard means. Dichloromethane (CH2Cl2) and acetonitrile (CH3CN) were distilled from
CaH2 under an argon atmosphere; THF was distilled from sodium metal/benzophenone.
AgSbF6 (98%), AgOTf (99%), AgBF4 (99%), AgNO3 (99%+) and AgCl (99.9%) were
purchased from STREM Chemicals. AgNTf2 was prepared from commercially available
HNTf2 and Ag2CO3.18 Alcohols, phenols or acids 2a-l were commercially available. All other
chemicals were used as received. All other extractive procedures were performed using
technical solvents and all aqueous solutions used were saturated.
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General procedure 1 for the formation of p-methoxybenzyl ethers from alcohols
To a solution of alcohol (4 mmol) in anhydrous THF (20 mL) cooled to 0°C was added
sodium hydride (57% in mineral oil, 4.8 mmol) in several portions. The suspension was
stirred for 20 minutes at 0°C, pꢀmethoxybenzyl chloride and tetrabutylammonium iodide were
then added. The mixture was stirred at room temperature until completion. An aqueous
solution of ammonium chloride was added to the reaction mixture. The aqueous layer was
extracted with ethyl acetate (3 × 30 mL). The combined organic layers were washed with
water, brine, dried over anhydrous sodium sulfate and evaporated. The crude residue was
purified by flash chromatography (cyclohexane/EtOAc).
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1-(4-Methoxybenzyloxy)-3-phenylpropane (1a)19: According to general procedure 1, 3ꢀ
4
5
6
1
phenylpropanꢀ1ꢀol 2a (545 mg, 4 mmol) gave 1a (882 mg, 86 %) as a colorless oil. H NMR
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(300 MHz, CDCl3) δ 7.32ꢀ7.22 (m, 4 H), 7.21ꢀ7.14 (m, 3 H), 6.90 (d, J = 8.7 Hz, 2 H), 4.45
(s, 2 H), 3.82 (s, 3 H), 3.47 (t, J = 6.4 Hz, 2 H), 2.71 (t, J = 7.7 Hz, 2 H), 2.00ꢀ1.87 (m, 2 H);
13C NMR (75 MHz, CDCl3) δ 159.2, 142.1, 130.7, 129.3, 128.5, 128.3, 125.8, 113.8, 72.6,
69.2, 55.3, 32.4, 31.4.
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4-Methoxybenzyloxyoctane (1b)13e: According to general procedure 1, octanꢀ1ꢀol 2b (521
1
mg, 4 mmol) gave 1b (832 mg, 83 %) as a colorless oil. H NMR (300 MHz, CDCl3) δ 7.26
(d, J = 8.6 Hz, 2 H), 6.88 (d, J = 8.6 Hz, 2 H), 4.43 (s, 2 H), 3.80 (s, 3 H), 3.43 (t, J = 6.7 Hz,
2 H), 1.59 (tt, J = 6.7, 7.3 Hz, 2 H), 1.42ꢀ1.18 (m, 10 H), 0.88 (t, J = 6.8 Hz, 3 H); 13C NMR
(75 MHz, CDCl3) δ 159.1, 130.8, 129.2, 113.7, 72.5, 70.3, 55.3, 31.7, 29.8, 29.5, 29.3, 26.2,
22.7.
(-)-4-Methoxybenzyloxymenthyle (1c)14e: According to general procedure 1, (ꢀ)ꢀmenthol 2c
1
(625 mg, 4 mmol) gave 1c (718 mg, 65 %) as a colorless oil. H NMR (300 MHz, CDCl3) δ
7.27 (d, J = 8.7 Hz, 2 H), 6.87 (d, J = 8.7 Hz, 2 H), 4.59 (d, J = 11 Hz, 1 H), 4.33 (d, J = 11
Hz, 1 H), 3.80 (s, 3 H), 3.15 (dt, J = 10.6, 4.2, Hz, 1 H), 2.80 (dhept, J = 6.8, 2.8 Hz, 1 H),
2.22ꢀ2.13 (m, 1 H), 1.72ꢀ1.56 (m, 3 H), 1.44ꢀ1.18 (m, 2 H), 1.15ꢀ0.76 (m, 10 H), 0.70 (d, J =
7 Hz, 3 H); 13C NMR (75 MHz, CDCl3) δ 159.1, 131.3, 129.4, 113.7, 78.2, 70.1, 55.3, 48.3,
40.4, 34.6, 31.6, 25.5, 23.3, 22.4, 21.1, 16.1.
Cholesterol 4-methoxybenzyl ether (1d)14e: To a solution of cholesterol 2d (600 mg, 1.55
mmol) in dry tolene (15 mL) was added 4ꢀmethoxybenzyl tricholoracetimidate (0.48 mL, 2.32
mmol) and Sc(OTf)3 (38 mg, 0.077 mmol). The reaction mixture was maintained for 2 h at
reflux. After cooling to room temperature, the mixture was concentrated and the residue was
treated with acetone to precipitate the PMB ether 1d. The precipitate was filtered off, washed
with acetone and dried (235 mg, 30 %). 1H NMR (500 MHz, CDCl3) δ 7.27 (d, J = 8.6 Hz, 2
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H), 6.86 (d, J = 8.6 Hz, 2 H), 5.35ꢀ5.33 (m, 2 H), 4.49 (ab, Jab = 11.6 Hz, 2 H), 3.80 s, 3 H),
3.28ꢀ3.23 (m, 1 H), 2.42ꢀ2.38 (m, 1 H), 2.29ꢀ2.23 (m, 1 H), 2.04ꢀ1.79 (m, 5 H), 1.60ꢀ0.94 (m,
25 H), 0.91 (d, J = 6.5 Hz, 3 H), 0.87 (d, J = 6.6 Hz, 3 H), 0.86 (d, J = 6.5 Hz, 3 H), 0.68 (s, 3
H); 13C NMR (125 MHz, CDCl3) δ 159.1, 141.1, 131.3, 129.1, 121.5, 113.8, 78.3, 69.6, 56.8,
56.2, 55.3, 50.2, 42.4, 39.8, 39.5, 39.2, 37.3, 36.9, 36.2, 35.8, 32.0, 31.9, 28.5, 28.2, 28.0,
24.3, 23.8, 22.8, 22.6, 21.1, 19.4, 18.7, 11.9.
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1-(4-Methoxybenzyloxy)-3-phenylprop-2-ene (1e)20: According to general procedure 1,
1
cinnamyl alcohol 2e (537 mg, 4 mmol) gave 1e (865 mg, 85 %) as a colorless oil. H NMR
(300 MHz, CDCl3) δ 7.44ꢀ7.20 (m, 7 H), 6.90 (d, J = 8.7 Hz, 2 H), 6.62 (td, J = 1.5, 15.8 Hz,
1 H), 6.33 (td, J = 6.0, 15.8 Hz, 1 H), 4.51 (s, 2 H), 4.18 (dd, J = 1.5, 6.0 Hz, 2 H), 3.61 (s, 3
H); 13C NMR (75 MHz, CDCl3) δ 159.2, 136.8, 132.5, 130.4, 129.5, 128.6, 127.7, 126.5,
126.2, 113.9, 71.9, 70.5, 55.3.
1-(4-Methoxybenzyloxy)-cyclohex-2-ene (1f)21: According to general procedure 1,
1
cyclohexꢀ2ꢀenꢀ1ꢀol 2f (300 mg, 3.05 mmol) gave 1f (426 mg, 65%) as a colorless oil. H
NMR (300 MHz, CDCl3) δ 7.29 (d, J = 8.6 Hz, 2 H), 6.88 (d, J = 8.6 Hz, 2 H), 5.94ꢀ5.70 (m,
2 H), 4.53 (d, J = 11.6 Hz, 1 H), 4.47 (d, J = 11.6 Hz, 1 H), 4.00ꢀ3.87 (m, 1 H), 3.79 (s, 3 H),
2.16ꢀ1.44 (m, 6 H); 13C NMR (75 MHz, CDCl3) δ 159.0, 131.1, 130.7, 129.1, 127.9, 113.7,
71.8, 69.6, 55.2, 28.4, 25.2, 19.3.
1-(4-Methoxybenzyloxy)-undec-10-ene (1g)22: According to general procedure 1, undecꢀ10ꢀ
1
enꢀ1ꢀol 2g (1 g, 5.87 mmol) gave 1g as a yellow oil (1.05 g, 62%). H NMR (300 MHz,
CDCl3) δ 7.26 (d, J = 8.6 Hz, 2 H), 6.88 (d, J = 8.6 Hz, 2 H), 5.88ꢀ5.75 (m, 1 H), 4.99 (dq, J =
17.1, 1.7 Hz, 1 H), 4.93 (dquint, J = 10.3, 1.1 Hz, 1 H), 4.48 (s, 2H), 3.80 (s, 3 H), 3.43 (t, J =
6.8 Hz, 2 H), 2.04 (dt, J = 7.8, 6.8 Hz, 2 H), 1.64ꢀ1.51 (m, 2 H), 1.44ꢀ1.31 (m, 4 H), 1.31ꢀ1.23
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(m, 8 H); C NMR (75 MHz, CDCl3) δ 159.1, 139.3, 130.1, 129.2, 114.1, 113.8, 72.5, 70.3,
55.3, 33.8, 29.8, 29.6, 29.5, 29.2, 29.0, 26.2.
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1-(4-Methoxybenzyloxy)-hept-2-yne (1h): According to general procedure 1, heptꢀ2ꢀynꢀ1ꢀol
2h (450 mg, 4 mmol) gave 1h (808 mg, 87 %) as a colorless oil. 1H NMR (300 MHz, CDCl3)
δ 7.27 (d, J = 8.7 Hz, 2 H), 6.87 (d, J = 8.7 Hz, 2 H), 4.51 (s, 2 H), 4.11 (t, J = 2.2 Hz, 2 H),
3.80 (s, 3 H), 2.24 (tt, J = 6.8, 2.2 Hz, 2 H), 1.57ꢀ1.35 (m, 4 H), 0.91 (t, J = 7.2 Hz, 3 H); 13C
NMR (75 MHz, CDCl3) δ 159.6, 130.1, 114.1, 113.8, 87.5, 76.2, 71.3, 57.7, 55.6, 31.1, 22.3,
18.8, 13.9; IR (neat) νmax 2955, 2931, 2857, 2281, 2220, 1979, 1611, 1585, 1511, 1464, 1441,
1381, 1352, 1301, 1246, 1172, 1133, 1069, 1034, 941, 922, 898, 819, 757, 723, 637 cmꢀ1; HRꢀ
MS 255.1355 (C15H20O2+Na calcd 255.1361).
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4’-Methoxybenzyloxybenzene (1i)23: To a solution of phenol 2i (600 mg, 6.35 mmol) in
anhydrous THF were added tetraꢀbutylammonium iodide (236 mg, 0.64 mmol, 10 mol%),
potassium carbonate (2.64 g, 19.1 mmol) and pꢀmethoxybenzyl chloride (0.9 mL, 6.7 mmol).
The reaction mixture was heated at reflux for 20 h, cooled at room temperature and quenched
with a saturated aqueous solution of ammonium chloride. The aqueous layer was extracted
with dichloromethane. The organic layer was washed with brine, dried over anhydrous
sodium sulfate and evaporated. The crude residue was purified by flash chromatography to
afford 1i as a white solid (1.31 g, 97 %). 1H NMR (300 MHz, CDCl3) δ 7.35 (d, J = 9.0 Hz, 2
H), 7.26 (t, J = 7.2 Hz, 1 H), 7.03ꢀ6.88 (m, 6 H), 5.00 (s, 2 H), 3.82 (s, 3 H); 13C NMR (75
MHz, CDCl3) δ 158.8, 137.1, 129.5, 128.6, 127.9, 127.5, 120.9, 114.8, 69.9.
4’-Methoxybenzyloxy-4-nitrobenzene (1j)11e: To a solution of 4ꢀnitrophenol 2j (667 mg,
4.79 mmol) in anhydrous THF were added tetraꢀbutylammonium iodide (177 mg, 0.48 mmol,
10 mol%), potassium carbonate (1.32 g, 9.58 mmol) and pꢀmethoxybenzyl chloride (0.65 mL,
4.79 mmol). The reaction mixture was heated to reflux for 4 h, cooled at room temperature
and quenched with a saturated aqueous solution of ammonium chloride. The aqueous layer
was extracted with dichloromethane. The organic layer was washed with brine, dried over
anhydrous sodium sulfate and evaporated. The crude residue was purified by flash
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chromatography (cyclohexane/EtOAc) to afford 1j (1.12 g, 90 %) as a white solid. H NMR
(500 MHz, CDCl3) δ 8.20 (d, J = 9.3 Hz, 2 H), 7.35 (d, J = 8.6 Hz, 2 H), 7.01 (d, J = 9.3 Hz,
2 H), 6.94 (d, J = 8.6 Hz, 2 H), 5.08 (s, 2 H), 3.82 (s, 3 H); 13C NMR (125 MHz, CDCl3) δ
163.8, 159.9, 141.6, 129.3, 127.5, 125.9, 114.9, 114.2, 70.6, 55.3.
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(R,R,R)-α-Tocopherol 4-methoxybenzyl ether (1k): According to general procedure 1,
(R,R,R)ꢀαꢀtocopherol 2k (1 g, 2.32 mmol) gave the title compound 1k (1.2 g, 95 %) as a pale
yellow oil. 1H NMR (300 MHz, CDCl3) δ 7.43 (d, J = 8.5 Hz, 2 H), 6.94 (d, J = 8.7 Hz, 2 H),
4.64 (s, 2 H), 3.84 (s, 3 H), 3.61 (t, J = 6.6 Hz, 2 H), 2.23 (s, 3 H), 2.18 (s, 3 H), 2.12 (s, 3 H),
1.88ꢀ1.76 (m, 2 H), 1.60ꢀ1.02 (m, 32 H), 0.90ꢀ0.86 (m, 15 H); 13C NMR (125 MHz, CDCl3) δ
159.4, 148.2, 147.9, 130.3, 129.4, 128.0, 126.0, 122.9, 117.5, 113.9, 74.8, 74.5, 55.3, 40.1,
39.4, 37.6, 37.4, 37.3, 32.8, 32.7, 31.4, 31.3, 28.0, 24.8, 24.5, 23.9, 22.7, 22.6, 21.0, 20.7,
19.8, 19.7, 12.9, 12.0, 11.8; HRꢀMS 573.4302 (C37H58O3+Na calcd 573.4284).
4’-Methoxybenzyl hexadecanoate (1l)24: Palmitic acid 2l (2 g, 7 mmol) was dissolved in Nꢀ
methylꢀ2ꢀpyrrolidone (25 mL). Diisopropylamine (1.2 mL, 7 mmol), sodium iodide (3.5
mmol) and 4ꢀmethoxybenzyl chloride (0.95 mL, 7 mmol) were then added. The resulting
mixture was heated to 80°C for 1 h. The reaction was cooled down and poured into 100 mL of
water. After extraction with dichloromethane, the combined organic layers were washed with
water, brine and dried over MgSO4. After flash chromatography (cyclohexane/EtOAc), 1.58 g
1
(60 %) of 1l was obtained as a colorless powder. H NMR (300 MHz, CDCl3) δ 7.26 (d, J =
8.6 Hz, 2 H), 6.88 (d, J = 8.7 Hz, 2 H), 5.04 (s, 2 H), 3.81 (s, 3 H), 2.31 (t, J = 7.4 Hz, 2 H),
13
1.62 (quint, J = 7.3 Hz, 2 H), 1.34ꢀ1.21 (m, 24 H), 0.88 (t, J = 6.9 Hz, 3 H); C NMR (125
MHz, CDCl3) δ 173.8, 159.6, 130.0, 128.3, 113.9, 65.9, 55.3, 34.4, 31.9, 29.7, 29.7, 29.6,
29.6, 29.5, 29.4, 29.3, 29.1, 25.0, 22.7, 14.1.
4-(4-Methoxybenzyloxy)butan-1-ol (I)25: According to general procedure 1, butanꢀ1,4ꢀdiol
1
(1 g, 11 mmol) gave the title compound I (1.28 g, 55 %) as a colorless oil. H NMR (300
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H), 3.63 (t, J = 5.9 Hz, 2 H), 3.49 (t, J = 5.9 Hz, 2 H), 2.39 (s, 1 H), 1.76ꢀ1.62 (m, 4 H); C
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NMR (75 MHz, CDCl3) δ 159.0, 130.0, 129.2, 113.7, 72.7, 70.0, 62.7, 55.3, 30.3, 26.8.
4-(4-Methoxybenzyloxy)butyl acetate (1m): To a solution of I (315 mg, 1.5 mmol) in
dichloromethane were added acetic anhydride (0.24 mL, 2.5 mmol) and pyridine (0.25 mL, 3
mmol). The reaction was stirred for 2 hours and then quenched with a saturated aqueous
solution of sodium hydrogencarbonate. After extraction with ethyl acetate, the combined
organic layers were washed with brine and evaporated in vacuo. The crude residue was
purified by flash chromatography (cyclohexane/EtOAc) to afford 1m (360 mg, 95%) as a
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colorless oil. H NMR (300 MHz, CDCl3) δ 7.25 (d, J = 8.7 Hz, 2 H), 6.87 (d, J = 8.7 Hz, 2
H), 4.43 (s, 2 H), 4.07 (t, J = 6.5 Hz, 2 H), 3.80 (s, 3 H), 3.46 (t, J = 6.0 Hz, 2 H), 2.03 (s, 3
H), 1.80ꢀ1.59 (m, 4 H); 13C NMR (75 MHz, CDCl3) δ 170.8, 158.7, 130.1, 128.8, 113.3, 72.2,
69.0, 63.9, 54.8, 25.8, 25.1, 20.6; IR (neat) νmax 2936, 2854, 1743, 1611, 1585, 1512, 1464,
1364, 1301, 1238, 1172, 1092, 1033, 955, 818, 757, 708, 636, 606 cmꢀ1; HRꢀMS 275.1266
(C14H20O4+Na calcd 275.1259).
4-(3-(4-Methoxybenzyloxy)prop-1-ynyl)-4-methyl-1,3-dioxolan-2-one (1n): A solution of
2ꢀmethylbutꢀ1ꢀenꢀ3ꢀyne (661 mg, 10 mmol) in THF (25 mL) was cooled to ꢀ78°C, then a
solution of nBuLi in hexanes (6.9 mL, 1.6 M) was added dropwise. The mixture was stirred at
ꢀ78°C for 30 minutes then pꢀformaldehyde (348 mg, 11 mmol) was added in one portion. The
reaction mixture was allowed to warm at room temperature then poured in a separatory funnel
containing a saturated aqueous solution of ammonium chloride (30 mL). After extraction with
diethyl ether, the combined organic layers were washed with brine, dried over anhydrous
magnesium sulfate and evaporated in vacuo. The crude residue was purified by filtration
through a small pad of silica with pentane/ether (4:1) as an eluent to give 4ꢀmethylpentꢀ4ꢀenꢀ
1
2ꢀynꢀ1ꢀol as a pale yellow oil (896 mg, 93%). H NMR (300 MHz, CDCl3) δ 5.30 (s, 1 H),
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5.27ꢀ5.20 (m, 1 H), 4.39 (s, 2 H), 1.91ꢀ1.87 (m, 3 H); 13C NMR (75 MHz, CDCl3) δ 126.2,
122.3, 86.8, 86.3, 51.4, 23.3.
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A solution of 4ꢀmethylpentꢀ4ꢀenꢀ2ꢀynꢀ1ꢀol (890 mg, 9.3 mmol) in anhydrous THF (20 mL)
was cooled to 0°C. Sodium hydride (424 mg, 9.7 mmol, 57% suspension in mineral oil) was
added in one portion. The solution was stirred at 0°C for 20 min. Tetrabutylammonium iodide
(342 mg, 0.9 mmol) and pꢀmethoxybenzyl chloride (1.6g, 10.2 mmol) were then added. The
reaction was stirred at room temperature for 1 hour then heated to reflux for 30 minutes. The
reaction was quenched with a saturated aqueous solution of ammonium chloride (25 mL).
After extraction with ethyl acetate, the combined organic layers were washed with water,
brine, and then dried over anhydrous sodium sulfate and evaporated in vacuo. The crude
residue was purified by flash chromatography (cyclohexane/EtOAc) to give 4ꢀ
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methoxybenzyloxy(4ꢀmethylpentꢀ4ꢀenꢀ2ꢀyne) (1.7 g, 84%) as a pale yellow oil. H NMR (300
MHz, CDCl3) δ 7.34 (d, J = 8.7 Hz, 2 H), 6.89 (d, J = 8.7 Hz, 2 H), 5.35 (s, 1 H), 5.30ꢀ5.22
(m, 1 H), 4.57 (s, 2 H), 4.27 (s, 2 H), 3.83 (s, 3 H), 1.91ꢀ1.89 (m, 3 H). 13C NMR (75 MHz,
CDCl3) δ 159.4, 129.8, 129.5, 122.2, 113.8, 87.6, 84.2, 71.2, 57.4, 55.3, 23.4.
To a solution of 4ꢀmethoxybenzyloxy(4ꢀmethylpentꢀ4ꢀenꢀ2ꢀyne) (1.43 g, 6.6 mmol) in a
acetone/water (4/1) (20 mL) mixture was added Nꢀmethylmorpholine oxide (1.55 g, 13.2
mmol). The reaction mixture was cooled to 0°C. An osmium tetroxide solution (0.83 mL,
0.08M, 0.132 mmol, 1 mol%) was then added dropwise. The solution was stirred for 17 hours
then the reaction was quenched with a saturated aqueous solution of sodium bisulfate. The
aqueous layer was saturated with sodium chloride and extracted with ethyl acetate. The
combined organic layers were washed with brine, dried over anhydrous sodium sulfate and
evaporated in vacuo. The crude residue was purified by flash chromatography to give 5ꢀ(4ꢀ
1
methoxybenzyloxy)ꢀ2ꢀmethylpentꢀ3ꢀyneꢀ1,2ꢀdiol as a colorless oil (1.24 g, 75%). H NMR
(300 MHz, CDCl3) δ 7.26 (d, J = 8.7 Hz, 2 H), 6.87 (d, J = 8.7 Hz, 2 H), 4.50 (s, 2 H), 4.14
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(s, 2 H), 3.78 (s, 3 H), 3.62 (d, J = 11.2 Hz, 1 H), 3.59 (s, 2 H), 3.47 (d, J = 11.2 Hz, 1 H),
1.44 (s, 3 H); 13C NMR (75 MHz, CDCl3) 159.8, 130.2, 129.6, 114.3, 88.6, 80.5, 71.9, 70.9,
68.9, 57.4, 55.7, 25.6.
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To a solution of 5ꢀ(4ꢀmethoxybenzyloxy)ꢀ2ꢀmethylpentꢀ3ꢀyneꢀ1,2ꢀdiol 2n (411 mg, 1.86
mmol) in anhydrous dichloromethane (5 mL) was added pyridine (0.75 mL, 9.3 mmol, 5 eq.).
The reaction mixture was cooled to 0°C, then trisphosgene (1.1g, 3.72 mmol, 2 eq.) was
added in one portion. The reaction mixture was stirred for 15 minutes then a saturated
aqueous solution of copper sulfate was added. The mixture was vigorously stirred for 1h.
After extraction with dichloromethane, the combined organic layers were washed with brine,
dried over anhydrous sodium sulfate and evaporated in vacuo. The crude residue was purified
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by flash chromatography to give 1n (411 mg, 90%) as a colorless oil. H NMR (300 MHz,
CDCl3) δ 7.25 (d, J = 8.7 Hz, 2 H), 6.87 (d, J = 8.7 Hz, 2 H), 4.49 (s, 2 H), 4.48 (d, J = 8.2
Hz, 1 H), 4.21 (d, J = 8.2 Hz, 1 H), 4.16 (s, 2 H), 3.79 (s, 3 H), 1.77 (s, 3 H). 13C NMR (75
MHz, CDCl3) δ 159.8, 153.7, 130.0, 129.1, 114.1, 84.8, 83.2, 75.8, 75.5, 72.0, 56.9, 55.5,
26.8; IR (neat) νmax 2839, 1797, 1611, 1585, 1512, 1465, 1442, 1386, 1372, 1354, 1282, 1236,
1174, 1146, 1086, 1060, 1031, 945, 819, 768, 711, 621 cmꢀ1; HRꢀMS 299.0887
(C15H16O5+Na calcd 299.0895).
1-Benzyloxy-4-(4-methoxybenzyloxy)-butane (1o)14e: According to general procedure 1
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using benzyl chloride, I (315 mg, 1.5 mmol) gave 1o (432 mg, 95 %) as a colorless oil. H
NMR (300 MHz, CDCl3) δ 7.31ꢀ7.15 (m, 7 H), 6.80 (d, J = 8.7 Hz, 2 H), 4.43 (s, 2 H), 4.36
13
(s, 2 H), 3.75 (s, 3 H), 3.49ꢀ3.34 (m, 4 H), 1.78ꢀ1.57 (m, 4 H); C NMR (75 MHz, CDCl3) δ
159.1, 138.6, 130.7, 129.2, 128.3, 127.6, 127.5, 113.8, 72.9, 72.5, 70.2, 69.8, 55.3, 26.5.
(Z)-1-Benzyloxy-4-(4-methoxybenzyloxy)-but-2-ene (1p)11e
:
According to general
procedure 1, (Z)ꢀ4ꢀ(benzyloxy)butꢀ2ꢀenꢀ1ꢀol26 2p (833 mg, 4 mmol) gave 1p (432 mg, 65 %)
as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 7.30ꢀ7.11 (m, 7 H), 6.78 (d, J = 8.7 Hz, 2 H),
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5.75ꢀ5.64 (m, 2 H), 4.40 (s, 2 H), 4.33 (s, 2 H), 3.96 (dd, J = 8.6, 4.4 Hz, 4 H), 3.71 (s, 3 H).
13C NMR (75 MHz, CDCl3) δ 158.8, 137.7, 129.8, 129.4, 129.3, 129.0, 128.0, 127.4, 127.3,
113.4, 71.9, 71.5, 65.4, 65.0, 54.9.
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1-Triisopropylsilyloxy-4-(4-methoxybenzyloxy)-butane (1q): According to general
procedure 1, 4ꢀ(triisopropylsilyloxy)ꢀbutanꢀ1ꢀol27 2q (493 mg, 2 mmol) gave 1q (594 mg,
81%) as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 7.25 (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), 3.69 (t, J = 6.3 Hz, 2 H), 3.47 (t, J = 6.3 Hz, 2 H),
1.74ꢀ1.53 (m, 4 H), 1.14ꢀ0.97 (m, 21 H); 13C NMR (75 MHz, CDCl3) δ 159.1, 130.8, 129.2,
113.7, 72.5, 70.1, 63.2, 55.3, 29.7, 26.3, 18.0, 12.0; IR (neat) νmax 2940, 2863, 1612, 1586,
1512, 1462, 1382, 1362, 1301, 1245, 1205, 1171, 1102, 1037, 1012, 995, 918, 881, 819, 784,
722, 678, 657, 638 cmꢀ1; HRꢀMS 389.2480 (C21H38O3Si+Na calcd 389.2488).
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1-Tetrahydropyranyloxy-4-(4-methoxybenzyloxy)-butane (1r)28 : To a solution of I (315
mg, 1.5 mmol) in dichloromethane were added 2,3ꢀdihydropyrane (168 g, 2 mmol) and
camphorsulfonic acid (10 mol%). The reaction was then stirred for 16 hours. The mixture was
partitioned between water and ethyl acetate. After extraction, the combined organic layers
were washed with brine, dried over anhydrous sodium sulfate and evaporated in vacuo. The
crude residue was purified by flash chromatography (cyclohexane/EtOAc) to afford 1r (357
mg, 81%) as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 7.26 (d, J = 8.7 Hz, 2 H), 6.87 (d,
J = 8.7 Hz, 2 H), 4.60ꢀ4.53 (m, 1 H), 4.43 (s, 2 H), 3.93ꢀ3.67 (m, 5 H), 3.57ꢀ3.34 (m, 4 H),
1.90ꢀ1.42 (m, 10 H); 13C NMR (75 MHz, CDCl3) δ 159.1, 130.7, 129.2, 113.7, 98.8, 72.5,
69.9, 67.3, 62.2, 55.3, 30.7, 26.6, 26.5, 25.5, 19.6.
5-(4-Methoxybenzyloxy-methyl-2,3-O-isopropylidene-β-D-ribofuranoside (1s): According
to general procedure 1, methylꢀ2,3ꢀOꢀisopropylideneꢀβꢀDꢀribofuranoside29 2s (408 mg, 2
1
mmol) gave 1s (550 mg, 85%) as a colorless oil. H NMR (300 MHz, CDCl3) δ 7.26 (d, J =
8.7 Hz, 2 H), 6.87 (d, J = 8.7 Hz, 2 H), 4.95 (s, 1 H), 4.65 (dd, J = 0.7, 6.0 Hz, 1 H), 4.55 (d,
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J = 6.0 Hz, 1 H), 4.47 (s, 2 H), 4.39ꢀ4.30 (m, 1 H), 3.79 (s, 3 H), 3.48 (dd, J = 6.4, 9.7 Hz, 1
H), 3.41 (dd, J = 8.1, 9.7 Hz, 1 H), 3.28 (s, 3 H), 1.47 (s, 3 H), 1.30 (s, 3 H); 13C NMR (75
MHz, CDCl3) δ 159.2, 130.1, 129.3, 113.8, 112.3, 109.2, 85.1, 82.1, 72.9, 70.8, 55.2, 54.8,
26.4, 25.0; IR (neat) νmax 2989, 2936, 2835, 1612, 1585, 1512, 1464, 1372, 1302, 1245, 1208,
1193, 1173, 1161, 1086, 1048, 960, 868, 848, 817, 759, 735, 703 cmꢀ1; HRꢀMS 347.1455
(C17H24O6+Na calcd 347.1471).
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tert-Butyl(3-((4-methoxybenzyl)oxy)propyl)carbamate (1t)8: According to general
procedure 1, tertꢀbutyl (3ꢀhydroxypropyl)carbamate 2t (500 mg, 2.86 mmol) gave 1t (758 mg,
90%) as a colorless oil. 1H NMR (300 MHz, CDCl3)
δ 7.25 (d, J = 8.6 Hz, 2 H), 6.88 (d, J =
8.6 Hz, 2 H), 4.70ꢀ5.05 (broad s), 4.43 (s, 2 H), 3.80 (s, 3 H), 3.51 (t, J = 6.0 Hz, 2 H), 3.22
(q, J = 6.0 Hz, 2 H), 1.77 (tt, J = 6.3, 6.3 Hz, 2 H), 1.43 (s, 9 H); 13C NMR (75 MHz, CDCl3)
159.2, 156.0, 130.4, 129.3, 113.8, 79.0, 72.7, 68.4, 55.3, 38.8, 29.7, 28.5.
3-(4-Methoxybenzyloxy)-1-phthalimidopropane (1u): According to general procedure 1,
3ꢀphthalimidopropanꢀ1ꢀol30 2u (800 mg, 3.42 mmol) gave 1u (350 mg, 30%) as a yellow oil.
1H NMR (300 MHz, CDCl3) δ 7.82 (dd, J = 3.2, 5.4 Hz, 2 H), 7.69 (dd, J = 3.2, 5.4 Hz, 2 H),
7.21 (d, J = 8.4 Hz, 2 H), 6.82 (d, J = 8.4 Hz, 2 H), 4.39 (s, 2 H), 3.82 (t, J = 6.1 Hz, 2 H),
3.79 (s, 3 H), 3.51 (t, J = 6.1 Hz, 2 H), 2.03ꢀ1.94 (m, 2 H); 13C NMR (75 MHz, CDCl3) δ
168.4, 159.1, 133.8, 132.2, 130.4, 129.3, 123.1, 113.7, 72.7, 67.7, 55.3, 35.7, 28.7; IR (neat)
νmax 2858, 1697, 1635, 1606, 1509, 1395, 1371, 1241, 1176, 1143, 1036, 901, 851; HRꢀMS
348.1215 (C19H19NO4+Na calcd 348.1212).
N-(4-Methoxybenzyl)-N-(5-(4-methoxybenzyloxy)pentyl)-4-methylbenzenesulfonamide
(1v): According to general procedure 1, NꢀTosylꢀ5ꢀaminopentanolꢀ131 (500 mg, 1.95 mmol)
gave 1v (280 mg, 29%) as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 7.71 (d, J = 8.2 Hz, 2
H), 7.30 (d, J = 8.3 Hz, 2 H), 7.23 (d, J = 8.6 Hz, 2 H), 7.18 (d, J = 8.6 Hz, 2 H), 6.87 (d, J =
8.6 Hz, 2 H), 6.82 (d, J = 8.6 Hz, 2 H), 4.37 (s, 2 H), 4.24 (s, 2 H), 3.80 (s, 3 H), 3.78 (s, 3 H),
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3.30 (t, J = 6.5 Hz, 2 H), 3.05 (dd, J = 7.6, 7.6 Hz, 2 H), 2.43 (s, 3 H), 1.48ꢀ1.37 (m, 2 H),
1.37ꢀ1.25 (m, 2 H), 1.24ꢀ1.10 (m, 2 H); 13C NMR (75 MHz, CDCl3) δ 159.6, 159.5, 143.5,
137.6, 131.0, 130.1, 130.0, 129.6, 128.8, 127.6, 114.3, 114.2, 73.0, 70.2, 55.7, 51.8, 48.2,
29.6, 28.3, 27.3, 23.7, 21.9; IR (neat) νmax 2931, 2852, 1690, 1612, 1512, 1392, 1247, 1169,
1092, 1034, 820; HRꢀMS 520.2129 (C28H35NO5S+Na calcd 520.2134).
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General procedure 2 for the cleavage of p-methoxybenzyl ethers
A mixture of pꢀmethoxybenzyl ether (0.4 mmol) and 1,3,5ꢀtrimethoxybenzene (33.6 mg, 0.2
mmol) in anhydrous dichloromethane (3 mL) was added via a cannula to a solution of silver
hexafluoroantimonate (6,9 mg, 20 ꢁmol, 5 mol%) in anhydrous dichloromethane (1 mL). The
reaction mixture was heated to reflux until completion, and filtered through a small pad of
Celite with dichloromethane as eluent. Solvents were removed in vacuum and the crude
residue was purified by flash chromatography (cyclohexane/EtOAc).
4-(Acyloxy)butan-1-ol (2m)32: According to general procedure 2, 1m (101 mg, 0.4 mmol)
gave 2m (71.3 mg, 94 %) as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 4.04 (t, J = 6.4 Hz,
2 H), 3.61 (t, J = 6.4 Hz, 2 H), 2.12 (s, 1 H), 1.99 (s, 3 H), 1.76ꢀ1.49 (m, 4 H); 13C NMR (75
MHz, CDCl3) δ 171.3, 64.3, 62.1, 29.0, 25.0, 20.9.
4-(3-Hydroxyprop-1-yn-1-yl)-4-methyl-1,3-dioxolan-2-one (2n): According to general
procedure 2, 1n (110.5 mg, 0.4 mmol) gave 2n (62 mg, 99%) as a colorless oil. 1H NMR (300
MHz, CDCl3) δ 4.52 (d, Jab = 8. 4 Hz, 1 H), 4.27 (s, 2 H), 4.24 (d, Jab = 8.4 Hz, 1 H), 2.83 (s,
ꢀOH, 1 H), 1.74 (s, 3 H); 13C NMR (75 MHz, CDCl3) δ 154.1, 86.8, 81.9, 76.1, 75.5, 50.4,
26.4; IR (neat) νmax 3406, 2919, 1784, 1544, 1478, 1388, 1375, 1282, 1232, 1148, 1092, 1050,
1007, 949, 858, 769, 711, 611 cmꢀ1; HRꢀMS 179.0310 (C7H8O4+Na calcd 179.0320).
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4-(Benzyloxy)butan-1-ol33 (2o): According to general procedure 2, 1o (120.2 mg, 4 mmol)
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gave 2k (67 mg, 93 %) as a colorless oil. H NMR (300 MHz, CDCl3) δ 7.31ꢀ7.18 (m, 5 H),
4.42 (s, 2 H), 3.53 (t, J = 5.9 Hz, 2 H), 3.42 (t, J = 5.9 Hz, 3 H), 1.70ꢀ1.48 (m, 4 H); 13C
NMR (75 MHz, CDCl3) δ 138.6, 128.8, 128.2, 128.1, 73.5, 70.8, 63.1, 30.5, 27.1.
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(Z)-4-(Benzyloxy)but-2-en-1-ol (2p)26: According to general procedure 2, 1p (119.3 mg, 0.4
1
mmol) gave 2p (71.3 mg, 100 %) as a colorless oil. H NMR (300 MHz, CDCl3) δ 7.39ꢀ7.26
(m, 5 H), 5.87ꢀ5.78 (m, 1 H), 5.78ꢀ5.68 (m, 1 H), 4.53 (s, 2 H), 4.16 (d, J = 6.2 Hz, 2 H), 4.09
(d, J = 6.2 Hz, 2 H); 13C NMR (75 MHz, CDCl3) δ 132.4, 128.5, 128.2, 127.9, 127.8, 72.5,
65.7, 58.7.
4-(Triisopropylsilyloxy)-butan-1-ol (2q)27: According to general procedure 2, 1q (134.6
mg, 0.4 mmol) gave 2q (53.2 mg, 54%) as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 3.75
(t, J = 5.5 Hz, 2 H), 3.66 (t, J = 5.5 Hz, 2 H), 1.77ꢀ1.57 (m, 4 H), 1.20ꢀ0.96 (m, 21 H); 13C
NMR (75 MHz, CDCl3) δ 63.2, 62.4, 30.0, 29.7, 17.6, 11.5.
4-Tetrahydropyranyloxy-butan-1-ol (2r)34: According to general procedure 2, 1r (117.8
mg, 0.4 mmol) gave 2r (53.2 mg, 54%) as a colorless oil. 1H NMR (300 MHz, CDCl3) δ 4.56
(t, J = 3.5 Hz, 1 H), 3.82 (m, 1 H), 3,74 (dt, J = 9.8, 5.8 Hz, 1 H), 3.60 (m, 2 H), 3.47 (m, 1
H), 3.38 (dt, J = 9.8, 5.6 Hz, 1 H), 2.78 (s, ꢀOH, 1 H), 1.77 (m, 1 H), 1.61ꢀ1.67 (m, 5 H), 1.38ꢀ
1.54 (m, 4 H); 13C NMR (75 MHz, CDCl3)
19.4.
δ 98.7, 67.4, 62.3, 62.1, 30.5, 29.8, 26.3 25.3,
Methyl-2,3-O-isopropylidene-β-D-ribofuranoside (2s)29: According to general procedure
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2, 1s (150 mg, 0.46 mmol) gave 2s (70 mg, 75%) as a colorless oil. H NMR (300 MHz,
CDCl3) δ 4.97 (s, 1 H), 4.83 (d, J = 6.0 Hz, 1 H), 4.59 (d, J = 6.0 Hz, 1 H), 4.43 (t, J = 2.8 Hz,
1 H), 3.76ꢀ3.53 (m, 2 H), 3.43 (s, 3 H), 3.31ꢀ3.12 (m, 1 H), 1.48 (s, 3 H), 1.32 (s, 3 H); 13C
NMR (75 MHz, CDCl3) δ 125.8, 112.1, 110.0, 88.8, 86.2, 81.9, 64.4, 55.9, 26.7, 25.0.
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3-Phthalimidopropan-1-ol (2u)30: According to general procedure 2, 1u (130 mg, 0.4
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mmol) gave 2u (76 mg, 82%) as a colorless oil. H NMR (300 MHz, CDCl3) δ 7.85 (dd, J =
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5.4, 3.2 Hz, 2 H), 7.73 (dd, J = 5.4, 3.2 Hz, 2 H), 3.86 (t, J = 6.4 Hz, 2 H), 3.62 (q, J = 6.1
Hz, 2 H), 2.47 (t, J = 6.6 Hz, 1 H), 1.88 (quint, J = 6.1 Hz, 2 H); 13C NMR (75 MHz, CDCl3)
δ 169.0, 134.1, 132.0, 123.4, 59.0, 34.2, 31.4.
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N-(5-Hydroxypentyl)-N-(4-methoxybenzyl)-4-methylbenzenesulfonamide (2v): According
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to general procedure 2, 1v (50 mg, 0.1 mmol) gave 2v (30 mg, 80%) as a colorless oil. H
NMR (300 MHz, CDCl3)
δ 7.72 (d, J = 8.2 Hz, 2 H), 7.31 (d, J = 8.2 Hz, 2 H), 7.18 (d, J =
8.6 Hz, 2 H), 6.83 (d, J = 8.6 Hz, 2 H), 4.24 (s, 2 H), 3.80 (s, 3 H), 3.51 (t, J = 6.5 Hz, 2 H),
3.06 (t, J = 7.5 Hz, 2 H), 2.44 (s, 3 H), 1.44ꢀ1.30 (m, 4 H), 1.21ꢀ1.13 (m, 2 H); 13C NMR (75
MHz, CDCl3) 159.3, 143.1, 137.1, 129.7, 129.6, 128.5, 127.2, 114.0, 62.6, 55.3, 51.6, 47.8,
32.1, 27.9, 22.8, 21.5. IR (neat) υmax 3295, 2933, 1611, 1511, 1454, 1328, 1245, 1153, 1089,
1031, 813, 745, 655, 547; HRꢀMS 400.1539 (C20H27NSO4+Na calcd 400.1558).
Bis(3-phenylpropoxy)methane (3a)35: 1H NMR (300 MHz, CDCl3) δ 7.30ꢀ7.14 (m, 10 H),
4.69 (s, 2 H), 3.56 (t, J = 6.4 Hz, 4 H), 3.69 (dd, J = 7.6, 7.6 Hz, 4 H), 1.94ꢀ1.84 (m, 4 H); 13C
NMR (75 MHz, CDCl3) δ 141.9, 128.5, 128.4, 125.8, 95.4, 67.2, 32.5, 31.4.
1
1,3,5-Trimethoxy-2-(4-methoxybenzyl)benzene (4a)36: H NMR (300 MHz, CDCl3) δ 7.15
(d, J = 8.7 Hz, 2 H), 6.76 (d, J = 8.7 Hz, 2 H), 6.15 (s, 2 H); 3.87 (s, 2 H), 3.80 (s, 3 H), 3.79
(s, 6 H), 3.75 (s, 3 H); 13C NMR (75 MHz, CDCl3) δ 159.8, 159.0, 157.6, 134.7, 129.5, 113.6,
111.0, 90.9, 55.9, 55.5, 55.4, 27.6.
1
1,3,5-Trimethoxy-2,4-bis(4-methoxybenzyl)benzene (4b): White solid; mp 102ꢀ103°C; H
NMR (300 MHz, CDCl3)
δ 7.11 (d, J = 8.5 Hz, 2 H), 6.76 (d, J = 8.5 Hz, 2 H), 6.35 (s, 1 H),
3.92 (s, 4 H), 3.78 (s, 6 H), 3.75 (s, 6 H), 3.47 (s, 3 H); 13C NMR (75 MHz, CDCl3) 158.3,
157.5, 157.4, 134.2, 129.1, 115.3, 113.5, 92.1, 61.9, 55.8, 55.2, 28.4; IR (neat) υmax 3000,
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2939, 2834, 1597, 1507, 1463, 1238, 1199, 1169, 1092, 1033, 799, 558, 526; HRꢀMS
431.1821 (C25H28O5+Na calcd 431.1834).
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1,3,5-Trimethoxy-2,4,6-tris(4-methoxybenzyl)benzene (4c)37: 1H NMR (300 MHz, CDCl3)
δ 7.11 (d, J = 8.8 Hz, 6 H), 6.80 (d, J = 8.7 Hz, 6 H), 3.99 (s, 6 H), 3.77 (s, 9 H), 3.50 (s, 9 H);
13C NMR (75 MHz, CDCl3) δ 157.6, 157.1, 133.6, 129.0, 124.3, 113.6, 61.6, 55.2, 29.4.
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Acknowledgment. We gratefully acknowledge the CNRS and the French Ministry of
Research for financial support. NK and TD thank the French Ministry of Research for a PhD
fellowship.
1
Supporting information. H and 13C NMR spectra for all new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org/.
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