Zinc mediated transesterification of β-ketoesters and coumarin synthesis

Article abstract of DOI:10.1016/S0040-4039(02)02006-3

The transesterification of ketoesters using zinc and iodine is described. The reaction has been done on a variety of alcohols and phenols. Alcohols furnish transesterified products whereas phenols gave 4-methylcoumarins. The method is highly promising compared with existing methods.

Full text of DOI:10.1016/S0040-4039(02)02006-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 8583–8586
Zinc mediated transesterification of b-ketoesters and
coumarin synthesis
Subhash P. Chavan,* K. Shivasankar, R. Sivappa and Ramesh Kale
Division of Organic Chemistry Technology, National Chemical Laboratory, Pune 411 008, India
Received 22 July 2002; revised 29 August 2002; accepted 13 September 2002
Abstract—The transesterification of ketoesters using zinc and iodine is described. The reaction has been done on a variety of
alcohols and phenols. Alcohols furnish transesterified products whereas phenols gave 4-methylcoumarins. The method is highly
promising compared with existing methods. © 2002 Elsevier Science Ltd. All rights reserved.
of AF4,13 and the synthesis of benzhydrols14 to name a
few.
The electrophilic and nucleophilic sites of b-ketoesters
are valuable tools in synthesis. Facile reactions on the
two electrophilic carbonyls and the two nucleophilic
carbons1 have made b-ketoesters popular synthons.
Many biologically active systems are accessible from
b-ketoesters of different alcohols.1b Usually, b-
ketoesters can be readily prepared from the reactions of
diketene with alcohols to furnish the desired esters.
However, diketene poses practical problems due to its
reactivity, corrosiveness and handling difficulties.
Methyl or ethyl acetoacetates are commercially avail-
able and are stable. Although tert-butyl acetoacetate
can be readily transformed to the corresponding esters
in the absence of any catalyst,2 this method is restricted
to tert-butyl esters, which in turn are not readily avail-
able. A great deal of attention has been given to effect
transesterification of methyl or ethyl acetoacetate
employing homogeneous catalysts like DMAP,3 DBU,4
titanium tetraoxide5 and p-TSA.6,7 We were the first to
describe the utility of a heterogeneous catalyst viz.
S-SnO2 as an efficient heterogeneous catalyst in effect-
ing transesterification8a as well as deprotection of
crotyl, cinnamoyl and dimethylallyl esters.8b After our
publication several other catalysts were also shown to
be effective.9 We have also shown commercially avail-
able Amberlyst-15 to be an efficient catalyst10 for
transesterification.
In this communication we report the use of zinc as an
efficient mediator for transesterification reactions. The
reaction has been performed on a standard substrate,
namely methyl acetoacetate with various alcohols
(Scheme 1).
The results are summarized in Table 1. The use of
activated zinc15 and the conditions used for the reaction
are some of the highlights. A noteworthy feature of the
present protocol is that benzyl, allyl and propargyl,
esters (entries 3, 5 and 7, respectively) become readily
accessible. The allyl and propargyl esters are known to
be difficult to prepare as they readily undergo the
Carroll rearrangement.3 From Table 1, it is evident that
both primary as well as secondary alcohols participate
well in the reaction. However a tertiary alcohol i.e.
tert-butanol, did not lead to the formation of the
corresponding tert-butyl ester.
In a typical example, zinc (1.10 g, 16.95 mmol) was
taken in a round bottom flask attached to a reflux and
a distillation condenser. Methyl acetoacetate (1 g, 8.47
mmol) in toluene (10 ml) was added followed by the
addition of cyclohexanol (0.93 g, 9.32 mmol) in toluene
(5 ml). A catalytic amount of iodine was added and the
reaction was heated under reflux for 5 h whilst being
The use of zinc has gained popularity of late in effect-
ing synthetically useful transformations like the ene
cyclization,11 the Diels–Alder reaction,12 the synthesis
Keywords: zinc; iodine; transesterification; coumarins.
* Corresponding author. Tel./fax: 00 91 20 589 3614; e-mail:
spchavan@dalton.ncl.res.in
Scheme 1.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02006-3

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S. P. Cha6an et al. / Tetrahedron Letters 43 (2002) 8583–8586
Table 1.
monitored by TLC. The reaction was quenched with
dil. HCl (20 ml) or with saturated aqueous NH4Cl,
filtered, and the compound was extracted in ether and
purified by chromatography using silica gel (60–120
mesh).
industrially important coumarins like 7-hydroxy-4-
methylcoumarin (coumarin 47 or coumarin 460)16b and
7-diethylamino-4-methylcoumarin (umbelliferon-47).16b
The synthesis of 4-methylcoumarin has been mainly
reported via the Pechmann condensation using various
catalyst like H2SO4-microwave,21 montmorillonite
clay22 and PPA.23 In this communication we describe a
protocol to effect a Pechmann condensation using zinc
and iodine (Scheme 2).
Having obtained encouraging results in the formation
of ketoesters, it was decided to study the reactivity of
phenols in the transesterification reaction. The same
protocol with a slight modification was used for the
phenols. It was found that under the reaction condi-
tions, coumarins were efficiently formed. Coumarins
form an elite class of compounds, occupying a special
place in nature as they form sub-units of many natural
compounds.16b They exhibit a broad spectrum of bio-
logical activity profiles such as anthelmintic, anticoagu-
lants, hypnotic and insecticidal properties.16 Coumarins
have been synthesized using various reactions condi-
tions such as the Pechmann condensation,17 the Knoev-
enagal condensation,18 the Wittig reaction19 and by
flash-vacuum pyrolysis.20
The use of 0.5 equiv. of iodine in the reaction leading to
the coumarins was arrived at after considerable experi-
mentation, during which it was also observed that the
use of an excess of iodine did not increase the yield.
In the class of coumarins, 4-methylcoumarins have
enjoyed a special status as they form the core of
Scheme 2.

S. P. Cha6an et al. / Tetrahedron Letters 43 (2002) 8583–8586
8585
Table 2. Synthesis of 4-methylcoumarins
offers both coumarin synthesis as well as
transesterificaiton.
A wide variety of phenols were subjected to the condi-
tions and the results obtained are tabulated in Table 2.
It was observed that the reaction goes better with
cresols. However with o-chlorophenol, no correspond-
ing coumarin was obtained.
Acknowledgements
We (K.S., R.S., R.K.) thank the CSIR, New Delhi
(India) for the award of fellowships. Funding under the
YSA (SPC) scheme from CSIR, India is gratefully
acknowledged. We are also thankful to Dr. M. K.
Gurjar, Head and Dr. T. Ravindranathan, Ex. Head,
Division of Organic Chemistry Technology, National
Chemical Laboratory, Pune 411 008, India for
encouragement.
In a typical procedure, ethyl acetoacetate in toluene
was added zinc (2 equiv.). a-Naphthol was added fol-
lowed by the addition of iodine (0.5 equiv.). The reac-
tion mixture was refluxed for 5 h and monitored by
TLC. The reaction was worked up using either dil. HCl
(10%) or using saturated aqueous NH4Cl. The com-
pound was extracted with ethyl acetate. The solvent
was then concentrated under reduced pressure and the
residue thus obtained was precipitated using pet. ether.
The compound was then filtered and dried to furnish
the corresponding coumarin (see entry 8).
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