Highly regioselective preparation of 1,3-Dioxolane-4-methanol derivatives from glycerol using phosphomolybdic acid

Article abstract of DOI:10.1055/s-0028-1083319

Phosphomolybdic acid (PMA) forms a blue-colored complex with glycerol in a 1:10 molar ratio. The glycerolato complex catalyzes conversion of glycerol into 1,3-dioxolane-4-meth-anol derivatives with complete regiospecificity in high yields (>95%) and the catalyst can be recycled up to ten times without loss of activity or regiospecificity. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0028-1083319

PAPER
557
Highly Regioselective Preparation of 1,3-Dioxolane-4-methanol Derivatives
from Glycerol Using Phosphomolybdic Acid
P
reparation of 1,3-
i
D
ioxol
t
ane-4-m
i
etha
n
n
ol
D
erivatives from
W
G
lycerol asantrao Fadnavis,* Gowri Sankar Reddipalli, Gadupudi Ramakrishna, Mithilesh Kumar Mishra,
Gurrala Sheelu
Biotransformations Laboratory, Discovery Block, Indian Institute of Chemical Technology, Uppal Road, Habsiguda, Hyderabad 500007,
India
Fax +91(40)27160512; E-mail: fadnavis@iict.res.in; E-mail: fadnavisnw@yahoo.com
Received 12 September 2008
phosphomolybdic acid (>95%)
Abstract: Phosphomolybdic acid (PMA) forms a blue-colored
complex with glycerol in a 1:10 molar ratio. The glycerolato com-
1
O
6
O1
OH
R1
R2
R1
R2
5
plex catalyzes conversion of glycerol into 1,3-dioxolane-4-meth-
anol derivatives with complete regiospecificity in high yields
(>95%) and the catalyst can be recycled up to ten times without loss
of activity or regiospecificity.
5
PTSA
H+
R1
R2
+
OH
+
HO
3
O
HO
2
3
2
4
O
1 50–90%
OH
42 10–40%
O
X
Key words: glycerol, phosphomolybdic acid, complexation, re-
giospecificity, 1,3-dioxolane-4-methanol
phosphomolybdic acid
Scheme 1 Ketalization of glycerol with various ketones in presence
of an acid catalyst (PTSA) vs phosphomolybdic acid
Glycerol is the main byproduct obtained during the pro-
duction of biodiesel from vegetable oils and about 10 wt%
of glycerol is produced during the transesterification pro-
cess. Increasing biodiesel production around the world is
causing a substantial glut in the market for glycerol. Value
addition by developing new processes/product lines from
glycerol would help the biodiesel industry. Several prod-
ucts, such as surfactants, fuel additives, acrolein, glycerol
carbonate, etc., are being produced using glycerol as a
platform chemical.1,2 These are, however, low-value
products. Products such as 2,2-dimethyl-1,3-dioxolane-4-
methanol (1a, solketal) are of relatively high value and are
useful as plasticizers, solubilizing and suspending agents
in pharmaceutical preparations, lubricants,3 and fuel addi-
tives.4 Enantiomerically pure forms of 1,3-dioxolane-4-
methanol compounds are used in the synthesis of b-block-
ers, glycerophospholipids, PAF (platelet aggregating fac-
tor), (aryloxy)propanolamines, and other products used in
the treatment of epilepsy and hypertension.5 Preparation
of such derivatives directly from glycerol is traditionally
carried out using a homogeneous acid catalyst (H2SO4 or
PTSA) and the ketone in large excess.6 However, glycerol
is a triol and its ketalization leads to a mixture of two
products, a compound ketalized between positions 1 and
2 (product 1) and a compound ketalized between positions
1 and 3 (product 2), which is difficult to separate
(Scheme 1).7 In addition, recovery of the product from the
homogeneous catalyst increases costs and produces un-
necessary effluent. A reusable, solid acid heterogeneous
catalyst with high regiospecificity would be highly desir-
able for such a reaction.
Heteropoly acids, such as phosphomolybdic acid (PMA),
are commercially inexpensive and environmentally
friendly catalysts that exhibit high activity and selectivi-
ty.8 It has been reported that heteropoly acids are several
times more active than sulfuric acid, 4-toluenesulfonic
acid, boron trifluoride–diethyl ether complex, and zinc
chloride9 and, they can be supported on a solid matrix
such as silica gel and recycled several times.10 Silica gel
supported phosphomolybdic acid has been used as an acid
catalyst for the chemoselective hydrolysis of acetonides
of carbohydrates.10e Herein, we report on the feasibility of
preparing 1,3-dioxolane derivatives directly from glycer-
ol and ketones using phosphomolybdic acid as a catalyst.
The reactions proceed smoothly to give only the five-
membered 1,3-dioxolane derivative 1 without side prod-
ucts. All the unconsumed reagents are easily recovered
and recycled, the catalyst can be reused several times
without loss of activity or regiospecificity, and the overall
process is highly environmentally friendly producing very
little effluent (Scheme 1).
Phosphomolybdic acid is sparingly soluble in most sol-
vents including water. However, it was found to dissolve
in glycerol on heating and form a deep blue complex. The
formation of glycerolato complexes between glycerol and
metal ions such as zinc, cobalt, and nickel has been previ-
ously reported.11 However, they have been reported to be
insoluble in most solvents and have, indeed, been crystal-
lized from water. The glycerol–phosphomolybdic acid
complex is found to be fairly soluble in excess glycerol.
Elemental analysis of the isolated glycerol–phosphomo-
lybdic acid complex indicates complexation of ten glycer-
ol molecules with one phosphomolybdic acid molecule
along with two molecules of water. The infra red spectrum
of commercial phosphomolybdic acid exhibits bands in
the range 3200–3400 cm–1 due to n(O–H) and n(H–O–H)
SYNTHESIS 2009, No. 4, pp 0557–0560
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x
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x
x
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0
0
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Advanced online publication: 09.01.2009
DOI: 10.1055/s-0028-1083319; Art ID: P09808SS
© Georg Thieme Verlag Stuttgart · New York

558
N. W. Fadnavis et al.
PAPER
for water of crystallization and constitutional water ene. Removal of toluene gave the ketal in 93–95% yield
present in the heteropoly acid. The other major peaks at (based on glycerol). The ketals 1a–f were then further pu-
1064, 960, and 783 cm–1 are due to (P–Oi–Mo), (Mo–Ot), rified by flash chromatography over silica gel for charac-
and (Mo–Ob–Mo), where Oi, Ot, and Ob are the inner, ter- terization.
minal, and bridging oxygen atoms, respectively, in the
The structure of the product was determined from the 1H
Keggin framework. These bands are shifted to 1090, 980,
NMR and 13C NMR spectra. The signals in 1H NMR spec-
and 827 cm–1 due to complexation with glycerol. The UV-
tra mostly appear as multiplets due to partial merging of
visible spectrum of the glycerol–phosphomolybdic acid
complex in acetonitrile shows absorption maxima at 288
the signals due to the a- and b-isomers that are present in
approximately equal concentrations. Similarly, in the 13C
and 302 nm due to ligand-to-metal charge-transfer transi-
NMR spectra, two closely spaced signals are obtained for
tions associated with the octahedrally coordinated Mo6+
the same carbon atom. In spite of this, it was easy to dis-
unit and a broad shoulder at 700 nm.12 Thermogravimetric
tinguish between the five- and six-membered ring prod-
analysis of the complex shows a loss of 1% in weight up
to 110 °C, a major weight loss of 12.9% up to 260 °C, and
a further weight loss of 8.5% between 260 °C and 380 °C.
This behavior is consistent with loss of water of hydration
ucts. In 1H NMR, H4 of the five-membered 1a (Scheme 1)
resonates as a multiplet at d = 4.18 while H5 of the six-
membered 2a resonates at d = 3.55. Integration of the pro-
ton resonating at d = 4.18 gave the concentration of five-
(1.3%) and carbon (13%).
membered ketal 1a as 100%. In 13C NMR spectra of the
Direct ketalization of glycerol by various ketones, such as ketals 1a–f, C4 of the five-membered acetonide resonated
acetone, butan-2-one, cyclopentanone, and cyclohex- around d = 75–76 while C5 in the six-membered ring res-
anone, catalyzed by 4-toluenesulfonic acid gave the de- onated at d = 64 (between the signals of CH2OH and C5
sired five-membered dioxolanes 1a–d with 80–90% carbon). Absence of the signal at d = 64 in the 13C NMR
selectivity along with 20–10% of six-membered dioxane spectra of all the compounds 1a–f confirmed that phos-
2a–f as a side product. In the case of acetophenone, 1e was phomolybdic acid catalyzed ketalization is regiospecific
formed with only 50% selectivity. Several other products and gives exclusively the five-membered ketals. The re-
were also formed in this case and isolation of the desired sults are summarized in Table 1.
product was quite tedious. In comparison, preparation of
The catalyst residue obtained after product extraction with
the dioxolanes using glycerol–phosphomolybdic acid
toluene consisted mainly of the catalyst and some unreact-
complex as catalyst gave dioxolane derivatives 1a–f with
ed glycerol, which was recycled without isolation or puri-
fication with a fresh batch of glycerol and the ketone in the
complete regiospecificity.
In a typical experiment, phosphomolybdic acid (0.92 g, same pot. In the case of solketal 1a, recycle studies for ten
0.5 mmol) and commercial glycerol (11 g, 85% purity, 0.1 recycles on a 100-gram product scale showed that the cat-
mol) were placed in a two-necked round-bottomed flask alyst can be reused at least ten times without loss of activ-
fitted with a magnetic stirrer and Dean–Stark assembly. ity or regioselectivity.
Toluene (100 mL) was added and the reaction mixture
In conclusion, phosphomolybdic acid can be used as an
was refluxed with stirring. Water present in the glycerol
efficient regiospecific catalyst for the preparation of ket-
was removed as an azeotrope over two hours. The glycer-
als of glycerol in high yields. A molar ratio of 1:200 of
ol–phosphomolybdic acid complex was formed in the
catalyst to substrate is enough to carry out the reaction
flask as a deep blue complex. In case of high boiling ke-
within 6–20 hours depending on the ketone. Additionally,
tones such as acetophenone, the ketone (0.1 mol) was then
it is not necessary to support the catalyst on a solid sur-
added to the reaction flask and the contents were further
face. At the end of reaction, the toluene soluble product is
refluxed with simultaneous azeotropic removal of water.
separated from insoluble heavy catalyst by simple decan-
The conversion of ketone into the ketal was followed by
tation and the catalyst is reused for several recycles with-
GC analysis. After complete conversion, the reactants
out removal from the reactor or any purification.
were cooled to room temperature and the clear toluene
layer containing the product was decanted. The insoluble
Commercially available chemicals were reagent grade and were re-
viscous catalyst layer was washed with toluene (2 × 10
mL) and the combined toluene layers were concentrated
distilled before use. 1H NMR spectra were recorded with a Bruker
Avance DPX 300 spectrometer at 300 MHz using TMS as an inter-
on a rotavapor. The ketal was obtained as an oil (>97%
pure by GC analysis, yield 96% based on ketone). In the
case of relatively low boiling ketones such as acetone and
butan-2-one, toluene was decanted after azeotropic re-
moval of excess water from the glycerol–phosphomolyb-
dic acid mixture, and the ketone itself was used as a
solvent. Water formed during ketalization was removed
via a soxhlet extractor loosely packed with 4 Å molecular
sieves. After completion of the reaction (followed by GC),
the low boiling solvent was recovered by distillation and
the product was extracted from the oily catalyst with tolu-
nal standard. 13C NMR spectra were recorded on the same instru-
ment at 75 MHz and are referenced against the central line of the
solvent signal (CDCl3 triplet at d = 77.0). IR spectra were obtained
with a Bio-Rad FTS 3000MX. Mass spectra were recorded with a
Finnigan Mat 1210 spectrometer. Elemental analyses (C, H, N)
were performed with a Perkin Elmer 2400 Series II CHNS/O Ana-
lyzer. GC analysis was carried out on Shimadzu 2010 GC unit using
DB-5 capillary column (J & W Scientific, 30 m, 0.25 mm ID). Anal-
ysis conditions were as follows: injector temperature: 300 °C; de-
tector temp. 310 °C, column pressure 100 kPa. Analysis program:
inject 100 °C, hold 1 min, ramping 5 °C/min up to 150 °C; hold 2
min; ramping 10 °C/min up to 250 °C, hold for 7 min.
Synthesis 2009, No. 4, 557–560 © Thieme Stuttgart · New York

PAPER
Preparation of 1,3-Dioxolane-4-methanol Derivatives from Glycerol
559
Table 1 Phosphomolybdic Acid Catalyzed Preparation of 1,3-Dioxolane-4-methanol Derivatives from Glycerol and Ketones
Substrate
acetone
Product
Solvent
acetone
Time (h)
6
Isolated yield (%)
95
HO
HO
O
O
1a
O
O
butan-2-one
1b
1c
butan-2-one
toluene
6
6
94
93
HO
HO
O
cyclopentanone
O
O
cyclohexanone
1d
toluene
6
95
O
HO
HO
O
acetophenone
benzophenone
1e
1f
toluene
toluene
18
18
96
96
O
Ph
O
Ph
O
Ph
2,2-Dimethyl-1,3-dioxolane-4-methanol (1a); Typical Proce-
dure
2-Ethyl-2-methyl-1,3-dioxolane-4-methanol (1b)
GC: tR = 4.0 (1b), 3.26 (2b) min.
Phosphomolybdic acid (PMA) (9.2 g, 5 mmol) and commercial
glycerol (110 g, 1 mol based on 85% purity) were placed in a 2-L 2-
necked round-bottomed flask fitted with a mechanical stirrer and
Dean–Stark assembly. Toluene (300 mL) was added and the mix-
ture was refluxed with stirring at 100 rpm. H2O present in glycerol
was removed as an azeotrope over 2 h. The glycerol–PMA complex
was formed in the flask as a deep blue viscous slurry. The flask was
cooled to r.t. and toluene was decanted. The side arm of the Dean–
Stark assembly was loosely packed with 4 Å molecular sieves, ace-
tone (1 L) was then added, and the mixture was refluxed with stir-
ring. The reaction was followed by GC analysis of the acetone layer.
When the reaction was complete (6–8 h), acetone was recovered by
distillation and collected from the side arm. Toluene (200 mL) was
added, the contents were stirred for 5 min, the layers were allowed
to separate, and the toluene layer was decanted. The procedure was
repeated twice to extract the product into the toluene layer. Removal
of toluene gave the acetonide 1a. The catalyst slurry was reused for
the next cycle without removing it from the flask. The catalyst was
recycled 10 times without losing activity or selectivity. In each run
105–110 g of product (93–95% yield based on 85% pure glycerol)
was obtained; GC: tR = 3.02 (1a), 3.17 (2a) min.
IR (CHCl3): 3434 (br), 2977, 2937, 2885, 1378, 1338, 1191, 1135,
1077, 936, 877 cm–1.
1H NMR (300 MHz, CDCl3): d = 4.28–4.11 (m, 1 H), 4.05–3.95 (m,
1 H), 3.85–3.70 (m, 2 H), 3.51–3.61 (m, 1 H), 1.85 (br s, 1 H), 1.76–
1.60 (m, 2 H), 1.30 and 1.36 (2 s, 3 H), 1.0–0.90 (m, 3 H).
13C NMR (75 MHz, CDCl3): d = 111.53 and 111.21 (C2), 76.53 and
75.84 (C4), 65.8 (C5), 63.08 and 62.90 (CH2OH), 32.51 and 31.59
(CH2CH3), 24. 13 and 23.08 (Me), 8.42 and 8.15 (CH3CH2).
MS: m/z =147 (M + 1).
1,4-Dioxaspiro[4.4]nonane-2-methanol (1c)
GC: tR = 7.34 (1c), 7.89 (2c) min.
IR (CHCl3): 3438 (br), 2957, 2877, 1336, 1204, 1107, 1041, 973,
860 cm–1.
1H NMR (300 MHz, CDCl3): d = 4.19–4.10 (m, 1 H), 3.98–3.92 (m,
1 H), 3.78–3.66 (m, 3 H), 3.60–3.52 (m, 1 H), 1.90–1.70 (m, 8 H).
13C NMR (75 MHz, CDCl3): d = 110.4 (C2), 72.42 (C4), 65.31 (C5),
62.99 (CH2OH), 38.34 and 23.21 (cyclopentyl).
MS: m/z = 159 (M + 1).
IR (CHCl3): 3430 (br), 2986, 2937, 2887, 2363, 1376, 1254, 1214,
1156, 1051, 973, 843 cm–1.
1H NMR (300 MHz, CDCl3): d = 4.18 (m, 1 H), 4.00 (dd, J = 8.31,
6.80 Hz, 1 H), 3.76 (dd, J = 8.31, 6.80 Hz, 1 H), 3.68 (dd, J = 11.33,
3.78 Hz, 1 H), 3.54 (dd, J = 11.33, 5.29 Hz, 1 H), 1.80 (br s, 1 H),
1.38 (s, 3 H), 1.20 (s, 3 H).
1,4-Dioxaspiro[4.5]decane-2-methanol (1d)
GC: tR = 9.25 (1d), 10.22 (2d) min.
IR (CHCl3): 3443 (br), 2935, 2862, 1161, 1103, 1043, 932 cm–1.
1H NMR (300 MHz, CDCl3): d = 4.23–4.13 (m, 1 H), 4.04–3.96 (m,
1 H), 3.78–3.64 (m, 2 H), 3.58–3.45 (m, 1 H), 2.10 (br s, 1 H), 1.66–
1.20 (m, 10 H).
13C NMR (75 MHz, CDCl3): d = 109.93 (C2), 75.71 (C4), 65.33
(C5), 63.08 (CH2OH), 36.35, 34.72, 25.06, 23.94, 23.71 (cyclohex-
yl).
13C NMR (75 MHz, CDCl3): d = 109.28 (C2), 76.11 (C4), 65.66
(C5), 62.86 (CH2OH), 26.54 and 25.11 (Me).
MS: m/z = 133 (M + 1).
Synthesis 2009, No. 4, 557–560 © Thieme Stuttgart · New York

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N. W. Fadnavis et al.
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MS: m/z = 173 (M + 1).
References
(1) (a) Pagliaro, M.; Ciriminna, R.; Kimura, H.; Rossi, M.; Pina,
C. D. Angew. Chem. Int. Ed. 2007, 46, 4434. (b)Corma,A.;
Iborra, S.; Velty, A. Chem. Rev. 2007, 107, 2411.
(c) Armaroli, N.; Balzani, V. Angew. Chem. Int. Ed. 2007,
46, 52. (d) Chheda, J. N.; Huber, G. W.; Dumesic, J. A.
Angew. Chem. Int. Ed. 2007, 46, 7164.
(2) (a) Klepacova, K.; Mravec, D.; Kaszonyi, A.; Bajus, M.
Appl. Catal., A 2007, 328, 1. (b) Ott, L.; Bicker, M.; Vogel,
H. Green Chem. 2006, 8, 214. (c) Chai, S.-H.; Wang, H.-P.;
Liang, Y.; Xu, B.-Q. Green Chem. 2007, 9, 1130.
(3) Walsh, R. H. US 5268007, 1993.
2-Methyl-2-phenyl-1,3-dioxolane-4-methanol (1e)
GC: tR = 12.42 and 12.56 (1e), 16.06 and 16.22 (2e) min.
IR (CHCl3): 3358 (br), 2925, 2358, 1216, 1042 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.49–7.22 (m, 5 H), 4.39–4.29 (m,
1 H), 4.20–4.01 (m, 1 H), 3.90–3.55 (m, 3 H), 1.80 (br s, 1 H), 1.60
and 1.65 (2 s, 3 H).
13C NMR(75 MHz, CDCl3): d = 142.98, 128.20, 127.88, 125.21
(CPh), 109.63 (C2), 75.96 (C4), 66.19 and 65.69 (C5), 63.35 and
62.82 (CH2OH), 28.09 and 27.95 (CH3).
MS: m/z = 195 (M + 1).
(4) Seemuth, P. D. US 4457763, 1984.
(5) Jurczac, J.; Pikul, S.; Bauer, T. Tetrahedron 1986, 42, 447.
(6) He, D. Y.; Li, Z. J.; Liu, Y. Q.; Qiu, D. X.; Cai, M. S. Synth.
Commun. 1992, 22, 2653.
(7) (a) Kazumasa, H.; Furukawa, Y. US 6143908, 2000.
(b) Kazumasa, H.; Furukawa, Y. US 6124479, 2000.
(8) (a) Kozhevnikow, I. V. Chem. Rev. 1998, 98, 171.
(b) Mizuno, N.; Misono, M. Chem. Rev. 1998, 98, 199.
(c) Misono, M.; Ono, K.; Aoshima, G. A. Pure Appl. Chem.
2000, 72, 1305.
2,2-Diphenyl-1,3-dioxolane-4-methanol (1f)
IR (CHCl3): 3436 (br), 3059, 2939, 2888, 1262, 1207, 1088, 1027,
995 cm–1.
1H NMR (300 MHz, CDCl3): d = 7.56–7.23 (m, 10 H), 4.37–4.27
(m, 1 H), 4.06–3.96 (m, 2 H), 3.84–3.76 (m, 1 H), 3.68–3.58 (m, 1
H), 1.80–1.75 (m, 1 H).
13C NMR (75 MHz, CDCl3): d = 141.94, 128.17, 126.18, 125.97
(CPh), 110.04 (C2), 76.36 (C4), 66.19 (C5), 63.08 (CH2OH).
(9) Kitamura, M.; Isobe, M.; Ichikawa, Y.; Goto, T. J. Am.
Chem. Soc. 1984, 106, 3252.
MS: m/z = 257 (M + 1).
(10) (a) Izumi, Y.; Hasebe, R.; Urabe, K. J. Catal. 1983, 84, 402.
(b) Yadav, J. S.; Satyanarayana, M.; Balanarsaiah, E.;
Raghavendra, S. Tetrahedron Lett. 2006, 47, 6095.
(c) Nagaiah, K.; Sreenu, D.; Srinivasa Rao, R.; Vashishta,
G.; Yadav, J. S. Tetrahedron Lett. 2006, 47, 4409.
(d) Abd El-Wahab, M. M. M.; Said, A. A. J Mol. Catal. A:
Chem. 2005, 240, 109. (e) Yadav, J. S.; Raghavendra, S.;
Satyanarayana, M.; Balanarsaiah, E. Synlett 2005, 2461.
(11) (a) Radoslovich, E. W.; Raupach, M.; Slade, P. G.; Taylor,
R. M. Aust. J. Chem. 1970, 23, 1963. (b) Taylor, R. M.;
Brock, A. J. US 4544761, 1985.
PMA–Glycerol Complex
The dark blue PMA–glycerol complex recovered after the reaction
with acetone was washed with a large excess of boiling acetone (2
×) and the blue-black powder was dried under vacuum at 60 °C for
12 h (13 g, 95%). Elemental analysis indicates complexation of 10
glycerol molecules and 2 H2O molecules with one PMA molecule.
Anal. Calcd for C30H67Mo12O72P: C, 13.03; H, 2.42; Mo, 41.71; P,
1.12. Found: C, 13.01; H, 2.51; Mo, 35.3; P, 1.14.
Due to inherent nature of heteropoly acids, the phosphorus/molyb-
denum ratio is not exact.
(12) Tsigdinos, G. A.; Hallada, C. J. Inorg. Chem. 1968, 7, 437.
Acknowledgment
We thank the Council of Scientific and Industrial Research (CSIR),
New Delhi and the University Grants Commission (UGC) for finan-
cial support.
Synthesis 2009, No. 4, 557–560 © Thieme Stuttgart · New York