Rapid and simple method of monoacylation of polyols by β-ketoesters using microwave irradiation

Article abstract of DOI:10.1081/SCC-200054750

Polyols undergo rapid selective transesterification with β-ketoesters upon microwave irradiation in solvent-free and catalyst-free conditions to form monoesters. Copyright Taylor & Francis, Inc.

Full text of DOI:10.1081/SCC-200054750

This article was downloaded by: [North West University]
On: 21 December 2014, At: 11:23
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954
Registered office: Mortimer House, 37-41 Mortimer Street, London W1T 3JH,
UK
Synthetic Communications: An
International Journal for Rapid
Communication of Synthetic
Organic Chemistry
Publication details, including instructions for
authors and subscription information:
http://www.tandfonline.com/loi/lsyc20
Rapid and Simple Method of
Monoacylation of Polyols by
β‐Ketoesters Using Microwave
Irradiation
Sanjib Kumar Karmee a & Anju Chadha a
a Laboratory of Bioorganic Chemistry,
Department of Biotechnology , Indian Institute of
Technology—Madras , Chennai, 600036, India
Published online: 16 Aug 2006.
To cite this article: Sanjib Kumar Karmee & Anju Chadha (2005) Rapid and Simple
Method of Monoacylation of Polyols by β‐Ketoesters Using Microwave Irradiation,
Synthetic Communications: An International Journal for Rapid Communication of
Synthetic Organic Chemistry, 35:9, 1151-1160, DOI: 10.1081/SCC-200054750
To link to this article: http://dx.doi.org/10.1081/SCC-200054750
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the
information (the “Content”) contained in the publications on our platform.
However, Taylor & Francis, our agents, and our licensors make no
representations or warranties whatsoever as to the accuracy, completeness,
or suitability for any purpose of the Content. Any opinions and views
expressed in this publication are the opinions and views of the authors, and
are not the views of or endorsed by Taylor & Francis. The accuracy of the
Content should not be relied upon and should be independently verified with

primary sources of information. Taylor and Francis shall not be liable for any
losses, actions, claims, proceedings, demands, costs, expenses, damages,
and other liabilities whatsoever or howsoever caused arising directly or
indirectly in connection with, in relation to or arising out of the use of the
Content.
This article may be used for research, teaching, and private study purposes.
Any substantial or systematic reproduction, redistribution, reselling, loan,
sub-licensing, systematic supply, or distribution in any form to anyone is
expressly forbidden. Terms & Conditions of access and use can be found at
http://www.tandfonline.com/page/terms-and-conditions

Synthetic Communicationsw, 35: 1151–1160, 2005
Copyright # Taylor & Francis, Inc.
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1081/SCC-200054750
Rapid and Simple Method of Monoacylation
of Polyols by b-Ketoesters Using
Microwave Irradiation
Sanjib Kumar Karmee and Anju Chadha
Laboratory of Bioorganic Chemistry, Department of Biotechnology,
Indian Institute of Technology—Madras, Chennai, India
Abstract: Polyols undergo rapid selective transesterification with b-ketoesters upon
microwave irradiation in solvent-free and catalyst-free conditions to form monoesters.
Keywords: b-Ketoesters, microwaves, monoesters, polyols, solvent- and catalyst-free
reactions
INTRODUCTION
Fatty acid monoglycerides (MG) find widespread use in the food, cosmetic,
agro and pharmaceutical industries.[1,2] These molecules are used as emulsi-
fiers[1] and as starting materials for numerous synthetic applications,[2]
for example, in the synthesis of phospholipids, defined triacylglycerols, and
glycolipids. Other monoesters of glycerol, more specifically esters of b-keto
esters, have been shown to promote absorption of insulin and inulin[3a,3b] in
rabbits and enhance drug absorption in the intestine.[3c,3d]
Esters of alcohols can be formed by esterification or more conveniently by
transesterification.[4] The monoesterification of 1, n-diols can be achieved by
careful control of reaction conditions,[5] continuous extraction,[6] the use of
alumina as a support,[7] phase-transfer catalyst,[8] inorganic polymer
Received in India December 13, 2004
Address correspondence to Anju Chadha, Laboratory of Bioorganic Chemistry,
Department of Biotechnology, Indian Institute of Technology—Madras, Chennai
600036, India. E-mail: anjuc@iitm.ac.in

1152
S. K. Karmee and A. Chadha
supports,[9] or via the formation of cyclic compounds.[10,11] The other methods
for selective acylation of polyols include the use of catalysts such as metal
sulfates supported on silica gel,[12,13] silica gel,[14] Al2O3/MeSO3H,[15,16]
and organotin reagents.[17,18] The esters used in these studies were ethyl pro-
pionate, ethyl ethanoate, methyl butanoate, methyl pentanoate,[12,13] and
alkenyl ester.[18]
Numerous methods for transesterification of b-ketoesters have been
reported[19] but selective monoacylation of polyols with b-ketoesters still
remains a challenge. 2-Mercaptoethanol and 2-amino-2-methyl-1,3-propane-
diol show selective transesterification with b-ketoesters in the presence of
NBS (N–Bromo Succinimide)[19a] and Yttria–Zirconia-based Lewis acid
catalyst[20] to form the corresponding ester and amide. However, no selectivity
was observed when b-ketoesters were transesterified with ethylene glycol in
the presence of NBS, which yielded only the diester, while Yttria–Zirconia-
based monoacylation of 1, 2-propanediol does not address the question of
selectivity at all. The reaction of ethyl acetoacetate with glycerol in the
presence of natural kaolinitic clay[19b] yields only the diacylated product
(55%). Even though aromatic b-ketoesters could be transesterified in the
presence of Hb-zeolite,[19c] the reaction occurs only at the secondary
alcohol and not at the primary alcohol group. Commercially available
neutral chromatographic alumina[19d–g]-mediated transesterification of
b-ketoesters with 1,2- or 1,3-diols fails to give the monoacylated product.
All these methods use “green catalysts” (viz. kaolinitic clay, Hb-zeolite,
alumina) for the acylation of glycerol and diols, but none of them are
selective for the monoacylated product. Clearly there was a need to develop
a method for the selective monoacylation of glycerol with b-keto esters.
This article reports the monoacylation of glycerol with a wide range of
b-ketoesters using microwave irradiation.[21]
EXPERIMENTAL
A domestic microwave (980 Watt) oven was used (Batliboi Eddy, India) and
1
operated at Power 4 of total power 9. H NMR spectra were recorded using
Bruker 400 MHz and 13C NMR spectra were recorded using a Bruker
100 MHz Instrument. Mass spectra were recorded using micromass Quadru-
pole Time-of-fight (Q-tof) mass spectrometer.
b-ketoesters were purchased from Sigma-Aldrich Co., USA. Polyols and
solvents were purchased locally and all solvents were distilled before use.
General Procedure of Synthesis of Compounds
15 mmol of glycerol (1.38 g) and 3 mmol (390 mg) of ethyl acetoacetate was
put in a test tube, placed in an Al2O3 bath, and irradiated by Microwave

Monoacylation of Polyols
1153
Irradiation (MW). The progress of the reaction was followed by TLC. After the
completion of the reaction, the reaction mixture was dissolved in ethyl acetate
and washed with saturated brine. Solvent was evaporated and the product was
purified by column chromatography. The monoacyl glycerol of acetoacetic acid
was obtained as a colorless oily liquid. Yield 80% (425 mg). 1H NMR (DMSO-
d6, 400 MHz) d (ppm) 2.22 (s, 3H), 3.33–3.36 (m, 2H), 3.59 (s, 2H), 3.63–3.65
(m, 1H), 3.92–3.96(dd, 1H), 4.07–4.11(dd, 1H), 4.67–4.70 (t, 1H), 4.93–4.95
(d, 1H). 13C NMR (DMSO-d6, 400 MHz) d (ppm) 29.9, 49.7, 62.4, 66.1, 69.1,
167.2, 201.6. EIMS (m/z ¼ 199.14 (M þ Na)þ, 100%).
RESULTS AND DISCUSSION
In a typical experimental procedure, when b-keto esters were treated with
polyols under microwave irradiation, the corresponding monoesterified
product was obtained in good to excellent yields (63–92%) (Scheme 1). The
reaction proceeded smoothly under microwave irradiation probably because
of the efficient absorption of microwave energy by the polar reactants that
promote the reaction. Diacylglycerol is the minor product (5–15%). Trans-
esterification of ethyl acetoacetate with glycerol was taken as a model
reaction. The molar ratio of ethyl acetoacetate–glycerol affects product distri-
bution and can be controlled to maximize the yield of monoacyl glycerol
(80%). For a molar ratio of 1:1 (glycerol–ethyl acetoacetate), 60% of the cor-
responding monoglyceride and 25–27% of the 1,3-diglyceride were obtained.
When the molar ratio was increased to 1:5 (ethyl acetoacetate–glycerol), the
Scheme 1.

1154
S. K. Karmee and A. Chadha
formation of monoacyl product increased to 80% and only 5% of diacyl
glycerol was obtained. No further improvement in the conversion to mono-
acylglycerol was seen upon increasing the ethyl acetoacetate to glycerol
ratio. Complete elimination of the diacylglycerol formation was difficult
even by additional optimization of power and time of the reaction. This
could be because the concentration of the monoacyl glycerol increases with
time as compared to glycerol and it starts getting diacylated. The minor
amount of diacylated product was removed by column chromatography.
Acyl migration has been reported in the regioselective acylation of
polyhydroxy compounds and it is believed that the acyl migration rate of
1,3-diacylglycerol is lower than that of 1-monoacylglycerol, the latter being
more prone to acyl migration.[22] In the case of 1-monoacylglycerols
reported here, this trend of acyl migration was observed as indicated by
1H NMR and TLC. The acyl migration of pure 1-monoglycerides is more pro-
nounced in the slightly acidic CDCl3-TMS than in DMSO-d6.
In the cases of ethyl acetoacetate (Table 1, entry 5), methyl acetoacetate
(Table 1, entry 4), and ethyl-4-nitrobenzoyl acetate (Table 1, entry 3), good
yields (75–80%) of the corresponding monoacyl glycerol were obtained
within 4 min. However, ethyl-4-methoxybezoyl acetate (Table 1, entry 2)
and ethyl benzoyl acetate (Table 1, entry 1) required a marginal increase in
the reaction time (5 min) for yields of 73–75%. When iso-propyl acetoacetate
(Table 1, entry 6) and tert-butyl acetoacetate (Table 1, entry 7) were trans-
esterified with glycerol, the reaction time was 6 and 7 min respectively and
the yields were only 63–65%. It is important to note that in uncatalyzed trans-
acetoacetylation, tert-butyl acetoacetate does not react with diols and triols to
give the monoacylated product.[19d]
Ethylene glycol reacts with various b-ketoesters (Table 1, entries 8–11)
to form the corresponding monoesters in excellent yields (82–92%) in
8–14 min. Significantly, the NBS-catalyzed transesterification of b-ketoesters
with ethylene glycol did not result in any monoacylated product.[19a]
b-Ketoesters undergo selective transesterification with diethylene glycol
(Table 1, entries 12–16) to give the corresponding monoester in excellent
yields (80–92%), suggesting that the presence of the oxygen atom in diethy-
lene glycol has no bearing on the monoacylation. However, a decrease in
reaction time was observed during the transesterification of b-ketoesters
with diethylene glycol as compared to ethylene glycol, and the yields were
nearly the same for the monoacylated products of both ethylene glycol and
diethylene glycol. 1,4-Butenediol (Table 1, entry 19) undergoes monoesterifi-
cation with benzoyl acetoacetate in 8 min with 85% yield whereas 1,4-butane
diol (Table 1, entry 17) and 1,5-pentane diol (Table 1, entry 18) were trans-
esterified with benzoyl acetoacetate to form the corresponding monoacylated
products in 7 min. Thus, this method is potentially applicable for selective
acylation of both saturated and unsaturated diols.

Table 1. Microwave-assisted synthesis of monoacyl polyols
Time
(min)
Isolated
yield (%)b
Entry
1
Esters
Triol and diols
Producta
5
5
75
73
2
3
4
78
4
5
4
4
75
80
(continued)

Table 1. Continued
Time
(min)
Isolated
yield (%)b
Entry
6
Esters
Triol and diols
Producta
6
63
7
8
9
7
10
8
65
89
92
10
12
85
11
12
14
9
82
90

13
14
15
8
8
89
92
84
10
16
17
12
7
80
85
18
19
7
8
88
85
1
aAll the products were characterized by H, 13C-NMR, and mass spectrometry.
bIsolated yield (after column chromatography).

1158
S. K. Karmee and A. Chadha
To ascertain the role of the keto group in this reaction, ethyl butanoate
was used as the ester instead of the b-keto ester. No transesterified product
was seen in this case. Aryl saturated and unsaturated esters viz. ethyl
cinnamate and ethyl hydrocinnamate did not give the transesterified product
with glycerol (P-4; 4 min). The reactions did not work even on increasing
the reaction time to 10 min. These observations indicate that transesterification
of b-ketoesters with glycerol is due to the b-keto functionality. The impor-
tance of the position of the keto group in the ester for this selective
acylation of glycerol was determined by using 2- (or a-) oxo-4-phenyl-
butyric acid ethyl ester as a substrate for transesterification under the pre-
viously mentioned reaction conditions. No transesterified product was seen
even after 10 min, suggesting that the keto functionality at b position is
essential for this transesterification. This could be because only b-hydroxy
esters have the possibility of forming an internal hydrogen bond between
the 22OH (enol form) and C55O, giving a six-membered ring facilitating
the transesterification reaction.[23] A plausible explanation for the rapid trans-
esterification in the reactions reported in this work could be the evaporation of
the alcohols (viz. methanol, ethanol, iso-propanol, and tert-butanol) formed in
the reaction because of the high final temperature (100–130 8C), thereby
shifting the equilibrium in the forward direction.
In conclusion, we have demonstrated that b-ketoesters undergo selective
transesterification with polyols under solvent- and catalyst-free conditions
with microwave irradiation.
ACKNOWLEDGMENT
Financial support from MNES (Ministry of Non-conventional Energy),
Government of India, is gratefully acknowledged.
REFERENCES
1. (a) Sonntag, N. O. V. Glycerolysis of fats and methyl esters: Status, review and
critique. J. Am. Oil Chem. Soc. 1982, 59, 795; (b) Baumann, H.; Buhler, M.;
Fochem, H.; Hirsinger, F.; Zoebelin, H.; Falbe, J. Natural fats and oils:
Renewable raw materials for the chemical industry. Angew. Chem., Int. Ed.
Engl. 1988, 100, 41.
2. (a) Wehrli, H. P.; Pomeranz, Y. Synthesis of galactosyl glycerides and related
lipids. Chem. Phys. Lipids 1969, 3, 357; (b) Van Deenen, L. L. M.; De
Haas, G. H. The substrate specificity of phospholipase. Biochim. Biophys. Acta.
1963, 70, 538; (c) Ahmed, F. U. Efficient synthesis of fatty monoglyceride
sulfates from fatty acids and fatty acid methyl esters. J. Am. Oil Chem. Soc.
1990, 67, 8.

Monoacylation of Polyols
1159
3. (a) Nishihata, T.; Kim, S.; Morishita, S.; Kamada, A.; Yata, N.; Higuchi, T.
Adjuvant effects of glyceryl esters of acetoacetic acid on rectal absorption of
insulin and inulin in rabbits. J. Pharm. Sci. 1983, 72, 280; (b) Acceleration of
drug absorption in the intestine by diketones. Patent No. JP 55113723, Sawai Phar-
maceuticals Co., Ltd, Japan, 1980; (c) Miyake, M.; Nishihata, T.; Wada, N.;
Takeshima, E.; Kamada, A. Rectal absorption of lysozyme and heparin in
rabbits in the presence of non-surfactant adjuvants. Chem. Pharm. Bull. 1984,
32, 2020; (d) Akira, K. Adjuvant for promoting absorption of therapeutically
active substances through the digestive tract, pharmaceutical composition com-
prising said adjuvant and enamine derivatives. EP 9609 19800416, Eur. Pat. Appl.
4. Otera, J. Transesterification. Chem Rev. 1993, 93, 1449.
5. Wilkinson, S. G. Stoddart, J. F., Ed.; Comprehensive Organic Chemistry.
Pergamon: Oxford, 1979; Vol. 1.
6. Babler, J. H.; Coghlan, M. J. A facile method for monoacetylation of symmetrical
diols: Application to the total synthesis of Z-8-dodecenyl acetate, the sex attractant
of the oriental fruit moth. Tetrahedron Lett. 1979, 22, 1971.
7. (a) Ogawa, H.; Chihara, T.; Taya, K. Selective monomethyl esterification of dicar-
boxylic acids by use of monocarboxylate chemisorption on alumina. J. Am. Chem.
Soc. 1985, 107, 1365; (b) Ogawa, H.; Ichimura, Y.; Chihara, T.; Teratani, S.;
Taya, K. Methylation of alcohols, phenols, and carboxylic acids, and selective
monomethylation of diols and dicarboxylic acids with dimethyl sulfate by use of
alumina. Bull. Chem. Soc. Jpn. 1986, 59, 2481; (c) Ogawa, H.; Chihara, T.;
Teratani, S.; Taya, K. Selective monoesterification of the longer carbon chain in
a mixture of dicarboxylic acids by adsorbing and aligning the acids on alumina.
J. Chem. Soc. Chem. Commun. 1986, 1337.
8. Zerda, J. D. L.; Barak, G.; Sasson, Y. Selective monoeterification and monoester-
ification of diols and diacids under phase transfer conditions. Tetrahedron Lett.
1989, 45, 1533.
9. Leznoff, C. C. The use of insoluble polymer supports in general organic synthesis.
Acc. Chem. Res. 1978, 11, 327.
10. Murahashi, S.; Oda, Y.; Naota, T. Ruthenium-catalyzed oxidation of cyclic acetals
with tert-butyl hydroperoxide: A facile synthesis of glycol monoesters. Chem. Lett.
1992, 11, 2237.
11. Wu, Z.; Stanly, R. R.; Pittman, C. U. Selective diesterification of diols through
cyclic ketene acetal intermediates. J. Org. Chem. 1999, 64, 8386.
12. Nishiguchi, T.; Kawamine, K.; Ohtsuka, T. Highly selective monoacylation of
symmetrical diols catalysed by metal sulfates supported on silica gel. J. Org.
Chem. 1992, 57, 312.
13. Nishiguchi, T.; Fugisaki, S.; Ishii, Y.; Yano, Y.; Nishida, A. Convenient mono-
acylation of 1,n-diols catalyzed by ion exchange resins. J. Org. Chem. 1994, 59,
1191.
14. Ogawa, H.; Amano, M.; Chihara, T. J. Facile and highly selective monoacylation
of symmetric diols adsorbed on silica gel with acetyl chloride. J. Chem. Soc.,
Chem. Commun. 1998, 495.
15. Sharghi, H.; Sarvari, M. H. Al2O3/MeSO3H(AMA) as a new reagent with high
selective ability for monoesterification of diols. Tetrahedron 2003, 59, 3627.
16. Sharghi, H.; Sarvari, M. H. Highly selective methodology for the direct conversion
of aromatic aldehydes to glycol monoesters. J. Org. Chem. 2003, 68, 4096.

1160
S. K. Karmee and A. Chadha
17. Reginato, G.; Ricci, A.; Roelens, S.; Scapecchi, S. Organotin-mediated monoacy-
lation of diols with reversed chemoselectivity: A convinient synthetic method.
J. Org. Chem. 1990, 55, 5132.
18. Orita, A.; Mitsutome, A.; Otera, J. Distannoxane-catalyzed highly selective
acylation of alcohols. J. Chem. Soc., Chem. Commun. 1998, 2420.
19. (a) Bandgar, B. P.; Uppalla, L. S.; Sadavarte, V. S. Chemoselective transesterifica-
tion of b-keto esters under neutral conditions using NBS as a catalyst. Synlett 2001,
11, 1715; (b) Ponde, D. E.; Deshpande, V. H.; Bulbule, V. J.; Sudalai, A.;
Gajare, A. S. Selective catalytic transesterification, transthioesterification and pro-
tection of carbonyl compounds over natural kaolinitic clay. J. Org. Chem. 1998,
63, 1058; (c) Balaji, B. S.; Sasidharan, M.; Kumar, R.; Chanda, B. A facile and
selective synthesis of b-keto esters via zeolite catalyzed transesterification.
J. Chem. Soc., Chem. Commun. 1996, 707; (d) Witzeman, J. S.;
Nottingham, W. D. Transacetoacetylation with tert-butyl acetoacetate: synthetic
applications. J. Org. Chem. 1991, 56, 1713; (e) Posner, G. H.; Oda, M. Organic
reactions at alumina surfaces: An extremely simple, convenient and selective
method for acetylating primary alcohols in the presence of secondary alcohols.
Tetrahedron Lett. 1981, 22, 5003; (f) Rana, S. S.; Barlow, J. J.; Matta, K. L.
The selective acetylation of primary alcohols in the presence of secondary
alcohols in carbohydrates. Tetrahedron Lett. 1981, 22, 5007; (g) Posner, G. H.;
Okada, S. S.; Babiak, K. A.; Miura, K.; Rose, R. K. Organic reactions at
alumina surfaces: An extremely simple, mild and convenient method for acetylat-
ing primary alcohols. Synthesis 1981, 11, 789.
20. Kumar, P.; Pandey, R. K. A facile and selective procedure for transesterification of
b-keto esters promoted by Yttria–Zirconia based Lewis acid catalyst. Synlett
2000, 2, 251 and references cited therein.
21. Loupy, A. Microwaves in organic synthesis. Wiley-VCH: Weinheim, 2002.
22. Halldorsson, A.; Magnusson, C. D.; Haraldsson, G. G. Chemoenzymatic synthesis
of structured triacylglycerols by highly regioselective acylation. Tetrahedron
2003, 59, 9101.
23. Padhi, S. K.; Chadha, A. Sodium borohydride reduction and selective transesteri-
fication of b-keto esters in a one pot reaction under mild conditions. Synlett 2003,
5, 639.