Improved routes for the preparation of pentaerythritol mono-O-benzyl ether

Article abstract of DOI:10.1080/00397910600764006

Two new efficient routes for the synthesis of pentaerythritol monobenzyl ether are described. In one route, the known mono-O-benzylidenepentaerythritol (5) is selectively benzylated via its dibutylstannylene acetal and then the benzylidene acetal is hydro

Full text of DOI:10.1080/00397910600764006

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Improved Routes for the Preparation of Pentaerythritol
Mono‐O‐benzyl Ether
Hussein Al‐Mughaid a & T. Bruce Grindley a
a Department of Chemistry , Dalhousie University , Halifax, Nova Scotia, Canada
Published online: 16 Feb 2007.
To cite this article: Hussein Al‐Mughaid & T. Bruce Grindley (2006) Improved Routes for the Preparation of Pentaerythritol
Mono‐O‐benzyl Ether, Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic
Chemistry, 36:18, 2569-2575, DOI: 10.1080/00397910600764006
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Synthetic Communicationsw, 36: 2569–2575, 2006
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910600764006
Improved Routes for the Preparation of
Pentaerythritol Mono-O-benzyl Ether
Hussein Al-Mughaid and T. Bruce Grindley
Department of Chemistry, Dalhousie University, Halifax,
Nova Scotia, Canada
Abstract: Two new efficient routes for the synthesis of pentaerythritol monobenzyl
ether are described. In one route, the known mono-O-benzylidenepentaerythritol (5)
is selectively benzylated via its dibutylstannylene acetal and then the benzylidene
acetal is hydrolized. In the other route, compound 5 is reduced directly to the mono-
benzyl ether using EtAlCl2-Et3SiH.
Keywords: Dibutylstannylene acetal, ethylaluminum dichloride, mono-O-benzylpen-
taerythritol, pentaerythritol, selective reduction
INTRODUCTION
There has been intense interest recently in the use of pentaerythritol (1) and its
derivatives as scaffolds for the construction of a wide range of clusters and
dendrimers.[1–13] Monosubstituted derivatives are highly useful because
they can act as branching points in dendrimer synthesis; the three hydroxyls
can be transformed into branches and the original substituent can be
removed or reacted further to allow extension of the growing dendrimer in
the inward direction.
Monosubstituted derivatives of pentaerythritol can be prepared directly in
good yields[14,15] based on the reagent employed if 0.5 equiv or less of the
reagent is used, particularly if the reagent employed is hindered, such as
t-butyldimethylsilyl chloride.[14] Direct reaction with greater amounts of
reagent leads to mixtures.[16] One general approach is available to
Received in the USA March 14, 2006
Address correspondence to T. Bruce Grindley, Department of Chemistry, Dalhousie
University, Halifax, Nova Scotia, B3H 4J3, Canada. E-mail: bruce.grindley@dal.ca
2569

2570
H. Al-Mughaid and T. B. Grindley
[17]
Scheme 1. Synthesis of pentaerythritol mono-O-benzyl ether via the orthoester.
monosubstituted derivatives. As shown in Scheme 1, Dunn et al.[17] formed
pentaerythritol orthoacetate (2), which can be converted into any other mono-
substituted derivative by the appropriate reaction followed by acid hydroly-
sis.[18–20] However, orthoester 2 is quite acid labile,[21] is also known to
polymerize rapidly at higher temperatures,[20] and is therefore difficult to
store or purify.
We now introduce two efficient alternative routes to pentaerythritol
mono-O-benzyl ether (4) that avoid the use of orthoester (2).
RESULTS AND DISCUSSION
Mono-O-benzylidenepentaerythritol (5) can be prepared conveniently on a
very large scale.[22] Dibutylstannylene acetals are formed readily from diols
and are known to have a high preference for the formation of monoalkyl
derivatives.[23–25] In the case of mono-O-benzylidenepentaerythritol (5),
reaction with 1 equiv of dibutyltin oxide in refluxing methanol for 2 h,
followed by methanol removal and treatment of the resulting product with
benzyl bromide and tetrabutylammonium bromide in toluene, gave a
mixture of the diasteroisomeric mono-O-benzyl ethers 6a and 6b in 73%
yield as a 3:2 ratio of cis/trans isomers (Scheme 2). These isomers were
separated by column chromatography on silica gel.
The structures of the isomers were assigned from their NMR spectra. It is
1
well-known that in 1,3-dioxanes, the H NMR signals of methyl and alkyl
groups at the C-5 position are more deshielded if the group is axial than if
it is equatorial,[26–30] unlike the situation for cyclohexane substituents. We
have shown that for 13C NMR chemical shifts the situation is reversed;
Scheme 2. Formation of the mono-O-benzylpentaerythritol via selective
monobenzylation.

Pentaerythritol Monobenzyl Ether
2571
equatorial carbons attached to the C-5 position are more deshielded than those
of their axial counterparts.[31] On this basis, the major isomer, compound 6a
(62.8 ppm, CH2OH), was assigned the structure that had the phenyl and hydro-
xymethyl groups cis, and the minor isomer, compound 6b (65.2 ppm,
CH2OH), was assigned the structure with the phenyl and hydroxymethyl
1
groups trans (see Scheme 2). The H NMR chemical shifts were entirely in
accord with these assignments; the signal of the CH2 in the CH2OH group
was less shielded when it was axial in 6a (4.04 ppm) than when it was equa-
torial in 6b (3.41 ppm); that of the CH2 in the CH2OBn group was more
shielded when it was equatorial in 6a (3.31 ppm) than when it was axial in
6b (3.88 ppm); even the benzyl CH2s fit this trend (4.49 ppm for 6a,
4.54 ppm for 6b), although the difference is small. It should be noted that
substitution on the equatorial oxygen atom was preferred slightly over
substitution on the axial oxygen atom (3/2).
Benzylidene acetals can be removed by acid hydrolysis or by hydroge-
nolysis.[32,33] The most commonly used conditions for acid hydrolysis are
reflux in 80% aqueous AcOH,[34] stirring with 90% aqueous CF3CO2H
acid in CH2Cl2 at room temperature,[35] and reaction with 1% I2 in
CH3OH (w/v) at room temperature or at reflux.[36] Unfortunately, none of
these methods work efficiently for the hydrolysis of the diasteroisomeric
mixture 6a and 6b. However, it was found that treatment the diastero-
isomeric mixture 6a and 6b with conc. HCl in 80% aqueous MeOH at
reflux for 8 h furnished the desired mono-O-benzyl ether 4 in 74% yield
(Scheme 2).
The second route for the production of pentaerythritol monobenzyl ether
(4) is to partially reduce mono-O-benzylidenepentaerythritol (5). Benzylidene
acetals can be transformed into the mono-O-benzyl ethers of the corresponding
diols by various reducing agents, most commonly LiAlH4-AlCl3,[37]
[40]
NaCNBH3-HCl,[38] Et3SiH-TFA,[39] Et3SiH-BF3 Et2O,
and DIBAL.[41]
.
Most of these methods are ineffective if hydroxyl groups are present in the
substrate being reduced. It was found here that ethylaluminum dichloride,
a Lewis acid recently introduced for this type of reaction,[42] was quite
effective for 5 with Et3SiH as a reducing agent, giving the mono-O-benzyl
ether 4 in 85% yield after column chromatography (Scheme 3). This method
is shorter and has the advantages of ease of reaction, high yield, and the
use of the easily prepared and stable mono-O-benzylidenepentaerythritol.
However, for large-scale preparations, ethylaluminium dichloride is costly.
Scheme 3. Formation of mono-O-benzyl ether 4 via reductive cleavage of acetal 5.

2572
H. Al-Mughaid and T. B. Grindley
EXPERIMENTAL
Melting points were determined with a Fisher-Johns melting-point apparatus
1
and are uncorrected. H and 13C NMR spectra were recorded at 300 K in
5-mm NMR tubes on Bruker AC 250-MHz or Avance 500 NMR spec-
trometers operating at 250.13 or 500.13 and 62.9 or 125.76 MHz, respectively,
on solutions in chloroform-d. Chemical shifts are given in parts per million
(ppm) (+0.01 ppm) relative to that of tetramethylsilane (TMS) (0.00 ppm)
in the case of 1H NMR spectra and to the central line of chloroform-d
(77.16 ppm) for the 13C NMR spectra. All assignments were confirmed by
1
1H-1H and H-13C correlation spectroscopy, heteronuclear multiple quantum
correlation, or heteronuclear multiple bond correlation experiments. Exact
masses were measured on a CEC 21-110B mass spectrometer using electron
impact ionization (70 eV). MeOH was dried by distillation from magnesium
turnings. Dichloromethane was first dried with calcium chloride and then
refluxed over calcium hydride for 1 h, followed by distillation. Toluene was
dried by refluxing over calcium hydride, followed by distillation. Benzylidene
acetals were visualized on TLC by quenching of fluoresence or by spraying the
plate with a solution of 0.2% p-methoxyphenol in ethanol/2 N H2SO4 (1/1,
v/v)[43] and heating until color developed. Other compounds were visualized
by quenching of fluoresence where applicable and/or were located by spraying
with a solution of 2% ceric sulfate in 1 M sulfuric acid followed by heating
until color developed. Compounds were purified on silica gel TLC standard
grade (230–400 mesh) by flash chromatography using specified eluents.
Trans-5-Benzyloxymethyl-cis-5-hydroxymethyl-2-phenyl-1,3-
dioxane and cis-5-Benzyloxymethyl-trans-5-hydroxymethyl-2-
phenyl-1,3-dioxane (6a and 6b, respectively)
A suspension of mono-O-benzylidenepentaerythritol (5)[22] (1.5 g, 6.7 mmol)
and dibutyltin oxide (1.66 g, 6.7 mmol, 1 eq) in methanol (350 mL) was
refluxed until a clear solution was obtained. Reflux was then continued for
2 h. The solution was concentrated, and the residue was suspended in dry
toluene (250 mL). Benzyl bromide (1.2 mL, 10 mmol, 1.5 eq) and tetrabuty-
lammonium bromide (2.16 g, 6.7 mmol, 1 eq), were added, and the mixture
was refluxed for 12 h, then cooled to room temperature, and stirred with
water (250 mL). The organic layer was dried (MgSO4) and concentrated to
dryness. The oily residue was fractionated by flash column chromatography
on silica gel (EtOAc–hexanes, 1:5). First to elute was compound 6a as a
colorless syrup (930 mg, 44.2%); RF ¼ 0.24 (EtOAc–hexanes, 1:4); 1H
NMR 7.46–7.27 (m, 10H, PhH), 5.42 (s, 1H, acetal H), 4.49 (s, 2H,
PhCH2O), 4.16, 3.79 (AB q, 4H, J ¼ 12.5 Hz, 2 dioxane CH2), 4.04 (d, 2H,
J ¼ 7.5 Hz, CH2OH), 3.31 (s, 2H, CH2OBn), 2.22 (t, 1H, OH); 13C NMR
138.2–126.1 (PhC), 101.8 (acetal C), 73.6 (PhCH2O), 71.4 (CH2OBn), 69.8

Pentaerythritol Monobenzyl Ether
2573
(C-4 and C-6, dioxane), 62.7 (CH2OH), 38.9 (C quat). EI HRMS calcd. for
C19H22O4: 314.1518. Found: 314.1514.
The second component, 6b, was also a colorless syrup (600 mg. 28.5%):
1
RF ¼ 0.18 (EtOAc–hexanes, 1:4); H NMR7.42–7.25 (m, 10H, PhH), 5.35
(s, 1H, acetal H), 4.54 (s, 2H, PhCH2O), 4.11, 3.69 (AB q, 4H, J ¼ 12.5 Hz,
2 dioxane CH2), 3.41 (d, 2H, J ¼ 5 Hz, CH2OH), 3.88 (s, 2H, CH2OBn),
2.73 (t, 1H, OH); 13C NMR 138.2–126.1 (PhC), 101.9 (acetal C), 73.6
(PhCH2O),71.3 (CH2OBn), 70.2 (C-4 and C-6, dioxane), 65.1 (CH2OH),
38.6 (qC). EI HRMS calcd. for C19H22O4: 314.1518. Found: 314.1505.
2-(Benzyloxymethyl)-2-(hydroxymethyl)-1,3-propanediol (4)[17]
Method A
The oily mixture of compounds 6a and 6b obtained prior to chromatographic
separation (0.13 g, 0.41 mmol) was dissolved in CH3OH (35 mL) and treated
with concentrated HCl (6 ml) and H2O (8 mL). The resulting reaction mixture
was stirred at reflux temperature for 8 h. After being cooled to room tempera-
ture, MeOH was removed by evaporation, and the resulting residue was
dissolved in CH2Cl2 (25 mL) and washed with saturated NaHCO3 (50 mL).
The organic layer was separated, and the aqueous layer was extracted with
CH2Cl2 (6 Â 50 mL). The combined organic extracts were dried over MgSO4
and concentrated. Purification by flash column chromatography using EtOAc
as eluant gave the title compound as a colorless viscous oil (70 mg, 75%);
1
RF ¼ 0.22 (EtOAc); H and 13C NMR chemical shifts agreed with literature
values[17] (average differences +0.09 ppm and +0.6 ppm, respectively).
Method B
To a stirred solution of mono-O-benzylidenepentaerythritol (5)[22] (0.30 g,
1.34 mmol, dried by co-evaporation with dry toluene) in dry dichloromethane
(30 mL), Et3SiH (1.56 mmol, 1.2 eq, 0.25 mL) was added, and the solution
was cooled to 2788C. EtAlCl2 (1.8 M in toluene, 4.3 mmol, 3.3 eq, 2.4 mL)
was added dropwise, and the reaction mixture was stirred at 2788C for
40 min under nitrogen. It was quenched with saturated NaHCO3 (80 mL)
and extracted with dichloromethane (5 Â 35 mL). The combined organic
extracts were dried (MgSO4) and concentrated to a residue that was purified
as in method A, yield 0.25 g, 85%.
ACKNOWLEDGMENTS
We thank the Natural Sciences and Engineering Research Council of Canada
for support and the Atlantic Region Magnetic Resonance Centre for NMR time.

2574
H. Al-Mughaid and T. B. Grindley
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