Polyalkylation of 2,2-bis(hydroxymethyl)-1-alkanols with tert-butyl bromoacetate

Article abstract of DOI:10.1081/SCC-100104039

A series of 2,2-bis(hydroxymethyl)-1-alkanols was poly-O-alkylated in satisfactory yields with the tert-butyl bromoacetate by phase transfer catalysis. The resulting pure polyesters were converted in polyacids in quantitative yields.

Full text of DOI:10.1081/SCC-100104039

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POLYALKYLATION OF 2,2-
BIS(HYDROXYMETHYL)-1-
ALKANOLS WITH TERT-BUTYL
BROMOACETATE
Claude Dupuy a , Romain Viguier a & Agnes Dupraz
a
a Université Joseph Fourier , Laboratoire d'Etudes
Dynamiques et Structurales de la, Sélectivité
(LEDSS 4) UMR CNRS 5616, BP 53, Grenoble, Cedex
9, F-38041, France
Published online: 09 Nov 2006.
To cite this article: Claude Dupuy , Romain Viguier & Agnes Dupraz (2001)
POLYALKYLATION OF 2,2-BIS(HYDROXYMETHYL)-1-ALKANOLS WITH TERT-BUTYL
BROMOACETATE, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 31:9, 1307-1313, DOI: 10.1081/
SCC-100104039
To link to this article: http://dx.doi.org/10.1081/SCC-100104039
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SYNTHETIC COMMUNICATIONS, 31(9), 1307–1313 (2001)
POLYALKYLATION OF
2,2-BIS(HYDROXYMETHYL)-1-ALKANOLS
WITH TERT-BUTYL BROMOACETATE
ClaudeDupuy, * Romain Viguier, and Agnes Dupraz
Laboratoire d’Etudes Dynamiques et Structurales de la
Selectivite (LEDSS 4), UMR CNRS 5616, Universite
Joseph Fourier, BP 53, F-38041 Grenoble Cedex 9, France
ABSTRACT
A series of 2,2-bis(hydroxymethyl)-1-alkanols was poly-O-
alkylated in satisfactory yields with the tert-butyl bromo-
acetate by phase transfer catalysis. The resulting pure
polyesters were converted in polyacids in quantitative yields.
The synthesis of tripodal triether acid compounds has been investigated
to prepare dendrimers,1,2 non-macrocyclic receptors for transition metal or
lanthanide ions,3,4,5 or polypodal ligands as phase transfer catalysts.
The O-alkylation of some primary polyols with ethyl diazoacetate has
been described,6 but it gives product mixtures and is not compatible with
functional groups such as amino groups. With tert-butyl bromoacetate,
examples of diol O-alkylations7–9 are reported in the literature. These
O-alkylation procedures applied to primary polyols like the triols 1-5 and
the pentaerythritol 6 gave unsatisfactory low yields. Particularly, the
classical Williamson synthesis using deprotonation with sodium hydride in
* Corresponding author. E-mail: claude.dupuy@ujf-grenoble.fr
1307
Copyright & 2001 by Marcel Dekker, Inc.
www.dekker.com

1308
DUPUY, VIGUIER, AND DUPRAZ
DMF or DMSO and addition of tert-butyl bromoacetate resulted in
complex product mixtures, including side products with more tert-butyl
groups than expected (1H NMR). Their formation is probably due to the
presence of excess base, leading to further alkylation of the acidic a-position
of the a-oxy-substituted esters present in the products.
A phase transfer catalysis procedure has been described by Nouguier10
for the etherification of pentaerythritol 6 and trimethylolpropane 1 with
alkyl halides. With tert-butyl bromoacetate, this method also gave low
yields.
In this communication, it is shown that the 2,2-bis(hydroxymethyl)-1-
alkanols 1-6 can be conveniently alkylated by tert-butyl bromoacetate in
acceptable yields under phase transfer catalysis (PTC). The results of our
O-alkylation experiments are collected in Table 1 for polyols 1-5. The
reported yields are for isolated products.
Two secondary products, tert-butyl fumarate and tert-butyl di-
glycolate, are also obtained in variable yields that depend on the reaction
temperature (the fumarate quantities increase greatly if this temperature is
Table 1.
R
Yield
1
2
3
4
5
CH3
C2H5
n-C10H23
C6H5
N(CH2Ph)2
48%
59
38
65
17%
36
23
15
53
—

2,2-BIS(HYDROXYMETHYL)-1-ALKANOLS
1309
above 20ꢀC), and on whether an excess of tert-butyl bromoactetate is used.
These two compounds are formed exclusively from tert-butyl bromoacetate.
The tert-butyl fumarate formation results from the acidic methylene group
of tert-butyl bromoacetate: a self-condensation, followed by an hydrobro-
mation elimination. The nucleophilic substitution of the bromide by the
hydroxyl anion, followed by the alcoolate formation explains the expected
production of tert-butyl diglycolate ether.11
The monoethers of polyols 1-5 were never isolated. The absence of
formation of monoalkylated products can be rationalized by the fact that
the mono(tetra-butylammonio)-triol salts are not transported into the
organic phase.10
The phase transfer catalyst is usually the tert-butyl ammonium
bromide, but the iodide or hydrogenosulfate salts give similar results.
Conversely, with the tetra-octyl ammonium bromide, regarded as a good
transfer reagent11 for O-alkylation by PTC, the yields of alkylated products
are slightly lower.
After optimization, it appeared that the reaction time was an import-
ant factor and should be less than 3 h.
The extension of the same experimental procedure to the very hydro-
philic primary polyols such as pentaerythritol 6 and tris(hydroxymethyl)-
aminomethane 7 (TRIS) lead to O-alkylated products with less that 5%
yields. By reacting 6 with saturated solution of potassium hydroxide
(70%) instead of sodium hydroxide (50%), two alkylated products were
obtained (Scheme 1). Tert-Butyl fumarate and tert-butyl diglycolate are
also isolated in a nearly 60% yield from tert-butyl bromoacetate.
Scheme 1.
With these experimental conditions, the tris(hydroxymethyl)amino-
methane 7 always gives less than 5% of the tri O-alkylated product. This
result may be explained by the fact that the tri(tetra-butylammonium) salt is
not conveniently transported into the organic phase.
The new tri-tert-butyl esters were obtained from polyols 1-5 and the
tetra-tert-butyl ester from 6 were easily hydrolyzed in quantitative yields by
formic acid.

1310
DUPUY, VIGUIER, AND DUPRAZ
In conclusion, this study reveals several features necessary to achieve
the polyol O-alkylation with tert-butyl bromoacetate. Classical Williamson
procedures fail with these primary polyols 1-6. The PTCetherifications
afford better results, particularly with more lipophilic polyols. The observed
poly O-alkylations and the absence of monoalkylation products agree with
Nouguier’s results.10 The secondary reactions of tert-butyl bromoacetate
should be slower than the polyol O-alkylation rates to prevent the side
products being formed in excess.
EXPERIMENTAL
Materials and Instrumentation
NMR spectra were recorded on a Bruker AC200 spectrometer
(1H: 200.13 MHz, 13C: 50.32 MHz) using CDCl3 or D2O (polyacids) as a
solvent. Melting points are uncorrected. All compounds have IR, 1H,
13CNMR spectra and mass spectra consistent with their assigned structures.
All IR spectra of tert-butyl polyesters show a very strong ꢀ C ¼ O band
between 1745 and 1750 cmÀ1. The polyols 1, 2, 6, and 7 are commercially
available. The compounds 3 (12), 4 (12), and 5 (2) were prepared as per the
procedures reported in the literature.
Typical Procedure for Phase Transfer Catalysis
In a chilled sodium hydroxide solution (50%, 6 g, 150 mmol in 6 mL),
polyol (5 mmol), H2CCl2 (6 mL), and phase transfer catalyst (0.75 mmol)
were stirred together, maintaining the temperature between 10ꢀ and 20ꢀC.
Tert-butyl bromoacetate (16 mmol) was added dropwise and stirred for 3 h.
The temperature of the reaction mixture was maintained below 20ꢀC . HO
2
(10 mL) and pentane (40 mL) were added and stirred for 10 min. The
organic layer was washed with brine, dried (Na2SO4), and evaporated.
The residual oil was purified by chromatography using silica gel (40 g,
Merck 60, 0.2 mm, cyclohexane/ethyl acetate gradient from 10:0 to 8:2).
The elution order was: tert-butyl fumarate, tert-butyl diglycolate, tri- or
tetra- tert-butyl esters, and poly tert-butyl esters-alcohol.
H3C–C(CH2OCH2CO2t-Bu)3
Transparent viscous oil. 1H: 1.04 (s, 3H, CH3C), 1.47 (s, 27H,
C(CH3)3), 3.46 (s, 6H, CCH2O), 3.95 (s, 6H, OCH2CO2tBu). 13C: 17.09

2,2-BIS(HYDROXYMETHYL)-1-ALKANOLS
1311
(CH3-C), 28.10 (C(CH3)3), 40.94 (CH3C), 69.46 and 74.34
(CCH2OCH2CO2tBu), 81.26 (C(CH3)3), 169.89 (CO2tBu). MS: m/z 463
(MHþ). Anal. Calc. for C23H42O9: C, 59.7; H, 9.2. Found: C, 59.5; H, 9.1.
H3C ꢀ CðCH2OCH2CO2t ꢀ BuÞ2
j
CH2OH
Transparent viscous oil. 1H: 0.95 (s, 3H, CH3C), 1.48 (s, 18H,
C(CH3)3), 3.46 (s, 4H, CCH2O), 3.54 (d, 2H, J ¼ 6.6 Hz, CH2OH), 3.71
(t, 1H, J ¼ 6.6 Hz, CH2OH), 3.95 (s, 4H, OCH2CO2tBu). 13C: 17.09 (CH3-
C), 28.10 (C(CH3)3), 40.94 (CH3C), 68.45 (CH2OH), 74.31 and 69.43
(CCH2OCH2CO2tBu), 81.26 (C(CH3)3), 169.88 (CO2tBu). MS: m/z 349
(MHþ). Anal. Calc. for C17H32O7: C, 58.6; H, 9.3. Found: C, 58.5; H, 9.5.
C6H5—C(CH2OCH2CO2t-Bu)3
M.p. 60ꢀ–62ꢀC 1H: 1.47 (s, 27H, C(CH3)3), 3.93 (s, 6H, CCH2O), 3.96
(s, 6H, OCH2CO2tBu), 7.3–7.6 (m, 5H, C6H5). 13C: 28.13 (C(CH3)3), 48.40
(C6H5C), 69.71 and 73.87 (CCH2OCH2CO2tBu), 81.33 (C(CH3)3), 126.62,
127.40, 128.14, 140.98 (C6H5), 169.77 (CO2tBu). MS: m/z 542 (MþNHþ4 ).
Anal. calc. for C28H44O9: C, 64.1; H, 8.5. Found: C, 63.9; H, 8.6.
C6H5 ꢀ CðCH2OCH2CO2t ꢀ BuÞ2
j
CH2OH
Transparent viscous oil. 1H: 1.47 (s, 18H, C(CH3)3), 3.85 (d, 2H,
CH2OH), 3.96 (s, 8H, CH2OCH2), 4.10 (t, 1H, CH2OH), 7.3–7.6 (m, 5H,
C6H5). 13C: 27.98 (C(CH3)3), 48.63 (C6H5C), 65.69, 68.70 and 74.10
(CCH2OCH2CO2tBu and CH2OH), 81.89 (C(CH3)3), 126.57, 126.93,
128.20, 140.77 (C6H5), 170.27 (CO2tBu). MS: m/z 411 (MHþ). Anal. calc.
for C22H34O7: C, 64.4; H, 8.3. Found: C, 64.0; H, 8.7.
(PhH2C)2N—C(CH2OCH2CO2t-Bu)3
Transparent viscous oil. 1H: 1.46 (s, 27H, C(CH3)3), 3.75 (s, 6H,
CCH2O), 3.85 (s, 6H, OCH2CO2tBu), 4.05 (s, 4H, CH2Ph), 7.05–7.19
(m, 10H, C6H5). 13C: 28.10 (C(CH3)3), 54.72 (NCCH2O), 64.39
(NCH2Ph), 69.43 and 72.24 (CCH2OCH2CO2tBu), 81.20 (C(CH3)3),
125.99, 127.55, 128.41, 142.34 (C6H5), 169.65 (CO2tBu). MS: m/z 644

1312
DUPUY, VIGUIER, AND DUPRAZ
(MHþ). Anal. calc. for C36H53O9: C, 57.72; H, 8.84. Found: C, 57.62;
H, 8.86.
C(CH2OCH2CO2t-Bu)4
M.p. 93ꢀ–94ꢀC. 1H: 1.46 (s, 36H, C(CH3)3), 3.63 (s, 8H, CCH2O), 3.96
(s, 8H, OCH2CO2tBu). 13C: 28.01 (C(CH3)3, 45.20 (C(CH2)4), 69.42 and
70.75 (CCH2OCH2CO2tBu), 81.08 (C(CH3)3, 169.70 (CO2tBu). MS: m/z
593 (MHþ). Anal. calc. for C29H52O10: C, 58.78; H, 8.84. Found: C,
58.90; H, 8.72.
CðCH2OCH2CO2t ꢀ BuÞ2
j
CH2OH
1
Transparent very viscous oil. H: 1.47 (s, 27H, C(CH3)3), 2.35 (s, 1H,
CH2OH), 3.59 (s, 6H, CCH2O), 3.71 (s, 2H, CH2OH), 3.95 (s, 6H,
OCH2CO2tBu). 13C: 28.04 (C(CH3)3), 45.00 (C(CH2)4), 63.00 (CH2OH),
68.95 and 71.23 (CCH2OCH2CO2tBu), 81.64 (C(CH3)3), 170.00 (CO2tBu).
MS: m/z 479 (MHþ). Anal. calc. for C23H42O10: C, 57.72; H, 8.84. Found:
C, 57.62; H, 8.86.
ACKNOWLEDGMENTS
The authors thank Dr. R. Nouguier (Universite d’Aix-Marseille 3) for
such fruitful discussions.
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Received in the UK May 22, 2000