Syntheses of monohydroxy benzyl ethers of polyols: Tri-O- benzylpentaerythritol and other highly benzylated derivatives of symmetrical polyols

Article abstract of DOI:10.1016/j.carres.2004.08.006

Symmetrical polyols can be converted into benzyl ethers with one free hydroxyl group in good yield by reaction of the monodibutylstannylene acetal with excess benzyl bromide in the presence of tetrabutylammonium bromide and diisopropylethylamine in xylene. The reaction pathway involves initial benzylation of the dibutylstannylene acetal to give benzyl and bromodibutylstannyl ethers; if a hydroxyl group remains unsubstituted, the latter ether ring closes and reacts further.

Full text of DOI:10.1016/j.carres.2004.08.006

Carbohydrate
RESEARCH
Carbohydrate Research 339 (2004) 2607–2610
Note
Syntheses of monohydroxy benzyl ethers of polyols:
tri-O-benzylpentaerythritol and other highly benzylated
derivatives of symmetrical polyols
Hussein Al-Mughaid and T. Bruce Grindley*
Department of Chemistry, Dalhousie University, Halifax, NS, Canada B3H 4J3
Received 3 June 2004; accepted 17 August 2004
Available online 18 September 2004
Abstract—Symmetrical polyols can be converted into benzyl ethers with one free hydroxyl group in good yield by reaction of the
monodibutylstannylene acetal with excess benzyl bromide in the presence of tetrabutylammonium bromide and diisopropylethylam-
ine in xylene. The reaction pathway involves initial benzylation of the dibutylstannylene acetal to give benzyl and bromodibutylstann-
yl ethers; if a hydroxyl group remains unsubstituted, the latter ether ring closes and reacts further.
ꢀ
2004 Elsevier Ltd. All rights reserved.
Keywords: Dibutylstannylene; Pentaerythritol; Tri-O-benzylpentaerythritol; Dipentaerythritol; Trihydroxymethylethane
General methods for the isolation of single hydroxyl
groups from symmetrical polyols are of considerable
interest because the products are amenable to further
selective conversions to a wide variety of products
utylstannylene) acetal of pentaerythritol can serve as an
2
2
intermediate for making the dibenzyl derivative. We
now show that the mono(dibutylstannylene) acetal of
pentaerythritol and other symmetrical polyols can be
used to produce polybenzylated derivatives with one
unsubstituted hydroxyl group.
1
–7
4
,8
5,6,9
10–12
including dendrimers,
clusters,
ligands,
and
1
3
liquid crystals. Benzyl groups are among the most
desirable protecting groups because of their persistence
under many reaction conditions and because highly
selective deprotection is facile.
Dibutylstannylene acetals have been shown to be use-
ful for selective functionalization and chemical manipul-
2
3
We are interested in developing the chemistry of
pentaerythritol (1), dipentaerythritol (2), and related
molecules as cores of clusters and dendritic wedges.
We now report that the tri-O-benzyl ether of 1 (4) is
obtained in good yield (73%) on treatment of its mono-
dibutylstannylene acetal with excess benzyl bromide
(16equiv), tetrabutylammonium bromide, and N,N-
diisopropylethylamine (DIEA) in o-xylene for 12h at
reflux (Scheme 1). These conditions evolved from an ini-
tial attempt to obtain the mono-O-benzyl ether by treat-
ment of the monodibutylstannylene acetal with 1equiv
of benzyl bromide with tetrabutylammonium bromide
1
4
1
5–17
ation of diols and polyols.
They can be prepared by
reaction of diols with dibutyltin oxide in refluxing
methanol or by refluxing in benzene or toluene with
azeotropic removal of water. They have served as con-
venient intermediates for the formation of monobenzyl
ethers from diols or polyols by reaction with benzyl
bromide either in benzene or toluene in the presence of
added nucleophiles, such as tetrabutylammonium
1
8
in toluene. Despite the 1:1 stoichiometry, this attempt
yielded a mixture of mono-, di-, and tri-O-benzyl ethers,
1
8,19
bromide,
of cesium fluoride
stituted products. David demonstrated that the bis(dib-
or in dimethylformamide in the presence
2
0,21
21
similar to results of Nagashima and Ohno in reactions
to give good yields of monosub-
with glycerol. Experiments conducted with excess benzyl
bromide at lower temperatures (e.g., at reflux in toluene)
and in the absence of base gave mixtures of the di- and
tri-O-benzyl ethers.
*
Corresponding author. Fax: +1 902 494 1310; e-mail: bruce.
grindley@dal.ca
0
008-6215/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.carres.2004.08.006

2608
H. Al-Mughaid, T. B. Grindley / Carbohydrate Research 339 (2004) 2607–2610
HO
HO
OH
OH
HO
HO
O
Sn
O
BnO
BnO
OH
OBn
i
Bu
Bu
ii, iii
1
4
2
Scheme 1. Synthesis of tri-O-benzylpentaerythritol. Reagents and conditions: (i) Bu SnO (1equiv), MeOH, reflux, 2h; (ii) benzyl bromide (16equiv),
o-xylene, tetrabutylammonium bromide (1equiv), reflux 2h; (iii) add diisopropylethylamine (4equiv), reflux 12h, 73%.
Bu
OH OH
OH
OH OBn
OBn
Bu Bu
Sn
Bu
Bn
i, ii
Br
Sn
PhCH -Br
2
O
O
O
O
5
3
ROH C CH OH
ROH
2
C CH
2
OH
Scheme 3. Synthesis of 2,2-bis(benzyloxymethyl)-1-propanol. Rea-
gents and conditions: (i) Bu SnO (1equiv), MeOH, reflux, 2h; (ii)
2
2
Bn Bn
O
O
2
Bn
benzyl bromide (6equiv), o-xylene, tetrabutylammonium bromide
O
Bu
Sn
O
O
PhCH
2
-Br
(1equiv), diisopropylethylamine (6.5equiv), reflux 12h, 72%.
ROH C
ROH C
Bu
2
2
Bu
O
+
HBr
+
HBr
Dipentaerythritol (2) contains two pentaerythritol
units separated by an anhydro bridge. Exposure of the
bisdibutylstannylene acetal of 2 to the same conditions
as for the monodibutylstannylene acetal of 1 gave
Sn
Bu
Br
Scheme 2. Probable reaction pathway for multiple benzylation of
pentaerythritol.
2
(
,2,6,6-tetrakis(benzyloxymethyl)-4-oxa-1,7-heptanediol
6) and 2,2,6-tris(benzyloxymethyl)-4-oxa-1,7-heptane-
diol (7) in yields of 53% and 18.3%, respectively (Scheme
4). Presumably, steric hindrance slows the last substitu-
tion. The observation that only the symmetrical tetrakis
derivative was formed suggests either that stannylene
acetals do not form across oxygen atoms from the two
halves of dipentaerythritol, a span that would require
a 10-membered ring, or that such acetals are less
reactive.
Symmetrical polyols can be converted into benzyl
ethers with one free hydroxyl group in good yield by
reaction of the monodibutylstannylene acetal with
excess benzyl bromide in the presence of tetrabutylam-
monium bromide and diisopropylethylamine in xylene.
The reaction is thought to proceed in stepwise fashion
through reaction with the dibutylstannylene acetal
followed by ring closure of the resulting bromodibutyl-
stannyl ether with a remaining free hydroxyl group.
Non-symmetrical polyols give mixtures of regioisomers
under these conditions.
A probable reaction pathway is shown in Scheme 2. It
is well established that dibutylhalostannyl ethers are
intermediates in the reactions of stannylene acetals.
2
4,25
Multiple substitution occurs here because, as long as a
free hydroxyl group remains, the intermediate from
the initial benzylation, the bromodibutylstannyl ether,
can undergo an intramolecular nucleophilic displace-
ment of bromide to give another reactive stannylene
acetal. The base (DIEA) is necessary to ensure complete
conversion, presumably because it removes hydrogen
bromide. As with other reactions of stannylene ace-
1
7,26
tals,
there is a strong preference for reaction with
the cyclic stannylene acetal rather than the product
bromodibutylstannyl ether. After workup, this results
in products in which one hydroxyl remains unsubsti-
tuted. It appears that the second substitution is faster
than the first, while the third is slower than the second,
probably for steric reasons. Nagashima and Ohno
reported that benzylation of glycerol in DMF with
1
as catalyst gave about equal amounts of the mono and
equiv of the benzylating agent using cesium fluoride
1. Experimental
2
1
disubstituted products,
observations.
in agreement with our
1.1. General methods
9
Liu and Roy have reported the isolation of
compound 4 in lower yield from the reaction of penta-
erythritol with substoichiometric amounts of benzyl
bromide and sodium hydride in DMF followed by
chromatography.
1
13
H and C NMR spectra were recorded at 300K in
5mm NMR tubes on a Bruker AC-250MHz spectro-
meter operating at 250.13 and 62.9MHz, respectively.
Chemical shifts are given in parts per million (ppm)
(±0.01ppm) relative to that of tetramethylsilane
Other symmetrical polyols react in the same way. The
same conditions with 2,2-dihydroxymethyl-1-propanol
1
(TMS) (0.00ppm) in the case of H NMR spectra, and
to the central line of chloroform-d (d 77.23) for the
C NMR spectra. All assignments were confirmed by
(
(
3), gave a 72% yield of the di-O-benzyl derivative (5)
Scheme 3).
1
3

H. Al-Mughaid, T. B. Grindley / Carbohydrate Research 339 (2004) 2607–2610
2609
OH OH
O
OHOH
OH
OH
HO
O
OBn
OBn
OH OH OH OBn
BnO
BnO
+
i,ii,iii
BnO
O
OBn
6
7
OH
2
5
3%
18 %
Scheme 4. Reaction with dipentaerythritol. Reagents and conditions: (i) Bu
2
SnO (2equiv), MeOH, reflux, 2h; (ii) benzyl bromide (16equiv),
o-xylene, tetrabutylammonium bromide (2equiv); (iii) add diisopropylethylamine (6.5equiv), reflux 12h, 72%.
COSY, HETCOR, HMQC, or HMBC experiments. The
EI exact masses were measured on a CEC 21-110B mass
spectrometer using electron ionization (70eV). The ES
exact masses were measured by positive ion mode elec-
trospray ionization on a Micromass ZabSpec Hybrid
Sector-TOF mass spectrometer. The liquid carrier
NMR (62.1MHz, CDCl ): d 126.4–133.3 (PhC), 73.6
3
(3 · PhCH O), 70.8 (3 · CCH O), 65.8 (CH OH), 45.0
2
2
2
+
(Cquat). ESMS found m/z 429.2047 [M+Na ]. Calcd
for C H O Na 429.2042.
2
6
30
4
1.3. 2,2-Bis(benzyloxymethyl)-1-propanol (5)
(
MeOH) was infused into the electrospray source by
means of a Harvard syringe pump at a flow rate of
0lL/min. o-Xylene was dried by refluxing over calcium
A suspension of 2,2-bis(hydroxymethyl)-1-propanol (3)
(0.63g, 5.2mmol) and dibutyltin oxide (1.24g,
4.98mmol, 1.05equiv) in dry MeOH (150mL) was
boiled under reflux until a clear soln was obtained.
Reflux was then continued for 100min. Evaporation of
the solvent gave the crude stannylene derivative, which
was suspended in dry o-xylene (50mL). Benzyl bromide
(3.6mL, 30mmol), tetrabutylammonium bromide (1.6g,
5.0mmol), and freshly distilled diisopropylethylamine
(6.0mL, 34mmol) were added and the mixture was ref-
luxed for 12h in a Dean–Stark apparatus, then cooled to
room temperature, and stirred with water (100mL). The
1
hydride followed by distillation. MeOH was dried with
Mg/iodine, followed by distillation. N,N-Dimethylform-
˚
amide was stored over activated 4A molecular sieves for
7
2h. It was distilled under reduced pressure over freshly
˚
activated 4A molecular sieves. Compounds were visual-
ized by quenching of fluorescence or by spraying the
2
plate with a soln of 0.2% p-methoxyphenol in 1:1
7
EtOH–2N H SO and heating on a hot plate until color
2
4
developed. Other compounds were visualized by UV
where applicable and/or were located by spraying with
a soln of 2% ceric ammonium sulfate in 1M H SO fol-
organic layer was dried over MgSO and concentrated.
4
2
4
lowed by heating on a hot plate until color developed.
Compounds were purified on silica gel (TLC standard
grade, 230–400 mesh) by flash chromatography using
specified eluents.
Flash column chromatography of the residue on silica
gel with 1:4 EtOAc–hexanes as the eluent afforded the
1
title compound (5, 1.08g, 72%) as a syrup: H NMR
(250MHz, CDCl ): d 7.11–7.30 (m, 2 · PhH, 10H),
3
4
.59 (s, 2 · PhCH O, 4H), 3.71 (s, CH OH, 2H), 3.61
2
2
(AB quartet, J 8.85Hz, 4H, 2 · CCH O,), 1.06 (s,
2
1
.2. 2,2,2-Tris(benzyloxymethyl)ethanol (4)
13
CH , 3H); C NMR (62.1MHz, CDCl ): d 127.3–
3
3
1
38.3 (PhC), 74.2 (2 · PhCH O), 73.3 (2 · CCH O),
2
2
A suspension of pentaerythritol (1) (1.36g, 9.99mmol)
and dibutyltin oxide (2.50g, 10.0mmol, 1.01equiv) in
dry MeOH (300mL) was refluxed until a clear soln
was obtained. Reflux was continued for a further
68.2 (CH OH), 40.7 (Cquat), 17.4 (CH ). EIMS found
m/z 300.1730 [M ]. Calcd for C H O 300.1725.
2
3
+
1
9
24
3
1
00min. Evaporation of the solvent gave the crude
stannylene derivative to which was added o-xylene
250mL), benzyl bromide (19mL, 160mmol, 16equiv),
1.4. 2,2,6,6-Tetrakis(benzyloxymethyl)-4-oxa-1,7-hep-
tanediol (6) and 2,2,6-tris(benzyloxymethyl)-4-oxa-1,7-
heptanediol (7)
(
and tetrabutylammonium bromide (3.2g, 9.9mmol),
and the mixture was refluxed in a Dean–Stark apparatus
for 2h. Freshly distilled diisopropylethylamine (7.0mL,
A suspension of dipentaerythritol (2) (0.25g, 0.98mmol)
and dibutyltin oxide (0.54g, 2.2mmol, 2.2equiv) in dry
MeOH (400mL) was boiled under reflux until a clear
soln was obtained (2h). Evaporation of the solvent gave
the crude stannylene derivative, which was taken up in
o-xylene (250mL). Benzyl bromide (1.9mL, 15.7mmol,
16equiv) and tetrabutylammonium bromide (0.63g,
2.0mmol) were added and the mixture was refluxed in
a Dean–Stark apparatus for 2h. Freshly distilled diiso-
propylethylamine (0.7mL, 4mmol) was added and the
resulting soln was refluxed for 12h, then cooled to room
4
0mmol) was added and the resulting soln was refluxed
in a Dean–Stark apparatus for 12h, then cooled to room
temperature, and stirred with water (50mL). The org-
anic layer was dried over MgSO4 and concentrated.
The residue was purified by flash chromatography on sil-
ica gel (1:3 EtOAc–hexanes) to afford the title compound
1
(
2.92g, 73%) as a syrup: H NMR (250MHz, CDCl ): d
3
7
3
.11–7.60 (m, 3 · PhH, 15H), 4.60 (s, 3 · PhCH O, 6H),
2
13
.95 (s, CH OH, 2H), 3.72 (s, 3 · CCH O, 6H);
C
2
2

2610
H. Al-Mughaid, T. B. Grindley / Carbohydrate Research 339 (2004) 2607–2610
temperature, and stirred with water (175mL). The
organic layer was dried over MgSO and concentrated.
The residue was separated by flash column chromato-
graphy on silica gel (1:1 EtOAc–hexanes). First to elute
3. Farcy, N.; De Muynck, H.; Madder, A.; Hosten, N.; De
Clercq, P. J. Org. Lett. 2001, 3, 4299–4301.
4
4
. Lubineau, A.; Malleron, A.; Le Narvor, C. Tetrahedron
Lett. 2000, 41, 8887–8891.
5
. Calvo-Flores, F. G.; Isac-Garcia, J.; Hernandez-Mateo,
F.; Perez-Balderas, F.; Calvo-Asin, J. A.; Sanchez-Vaqu-
ero, E.; Santoyo-Gonzalez, F. Org. Lett. 2000, 2, 2499–
(
R 0.57, 1:1 EtOAc–hexanes) was compound 5 (0.32g,
f
1
5
7
3
3
3%), a syrup: H NMR (250MHz, CDCl ): d 7.25–
3
2
502.
.36 (m, 4 · PhH, 20H), 4.45 (s, 4 · PhCH O, 8H),
2
6
. Shchepinov, M. S.; Udalova, I. A.; Bridgman, A. J.;
Southern, E. M. Nucleic Acids Res. 1997, 25, 4447–4454.
. Martin, V. V.; Lex, L.; Keana, J. F. W. Org. Prep. Proced.
Int. 1995, 27, 117–120.
.67 (s, 2 · CH OH, 4H), 3.46 (s, 4 · CCH OBn, 8H),
2
2
1
3
.40 (s, CCH OCH C, 4H); C NMR (62.1MHz,
2
2
7
CDCl ): d 127.6–138.4 (4 · PhC), 73.7 (4 · PhCH O),
3
2
7
2.0 (CCH OCH C), 71.0 (4 · CCH OBn), 65.9
8. Padias, A. B.; Hall, H. K.; Tomalia, D. A.; McConnell,
J. R. J. Org. Chem. 1987, 52, 5305–5312.
9. Liu, B. C.; Roy, R. Chem. Commun. 2002, 594–595.
0. Seitz, T.; Muth, A.; Huttner, G.; Klein, T.; Walter, O.;
Fritz, M.; Zsolnai, L. J. Organomet. Chem. 1994, 469,
155–162.
2
2
2
(
2 · CH OH), 45.3 (2 · Cquat). ESMS found m/z
2
+
6
37.3148 [M+Na ]. Calcd for C H O Na 637.3141.
38 46 7
1
The second component (R 0.17, 1:1 EtOAc–hexanes)
f
was compound 6, which crystallized upon standing, mp
1
6
3
3
6
4–66ꢁC; H NMR (250MHz, CDCl ): d 7.25–7.30 (m,
11. Findeis, R. A.; Gade, L. H. Dalton Trans. 2003, 249–254.
3
1
2. Findeis, R. A.; Gade, L. H. Eur. J. Inorg. Chem. 2003, 99–
10.
3. Praefcke, K.; Psaras, P.; Eckert, A. Liq. Cryst. 1993, 13,
51–559.
· PhH, 15H), 4.45, 4.46 (s, 3 · PhCH O, 6H), 3.67,
2
1
.62 (s, 3 · CH OH, 6H), 3.47, 3.48 (s, 3 · CCH OBn,
2
2
1
1
H), 3.45, 3.46 (s, CCH OCH C, 4H); C NMR
3
2
2
5
(
62.1MHz, CDCl ): d 127.6–138.4 (3 · PhC), 73.8,
14. Wuts, P. G. M.; Greene, T. W. Protective Groups in
Organic Synthesis, 3rd ed.; Wiley: New York, 1999.
3
7
7
4
3.7 (3 · PhCH O, 72.5, 72.1 (CCH OCH C), 71.2,
2
2
2
1
5. David, S.; Hanessian, S. Tetrahedron 1985, 41, 643–663.
1.5 (3 · CCH OBn), 65.5, 64.8 (3 · CH OH), 45.2,
2
2
+
16. Grindley, T. B. In Synthetic Oligosaccharides: Indispensa-
ble Probes for the Life Sciences; Kov a´ c, P., Ed.; ACS:
Washington, 1994; pp 51–76.
5.3 (2 · Cquat). ESMS found m/z 547.2668 [M+Na ].
Calcd for C H O Na 547.2672.
3
1
40
7
1
1
1
2
2
7. Grindley, T. B. Adv. Carbohydr. Chem. Biochem. 1998, 53,
7–142.
8. David, S.; Thi e´ ffry, A.; Veyri e` res, A. J. Chem. Soc., Perkin
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Acknowledgements
We thank the Natural Sciences and Engineering
Research Council of Canada for financial support.
NMR spectra were recorded at the Atlantic Region
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1
08, 2486–2487.
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