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An efficient synthesis of β-ketoesters via transesterification and its applicationin Biginelli reaction under solvent-free, catalyst-free conditions

G.B. Dharma Rao, B.N. Acharya, M.P. Kaushik

PII: S0040-4039(13)01705-XDOI: http://dx.doi.org/10.1016/j.tetlet.2013.09.130Reference: TETL 43630

To appear in: Tetrahedron Letters

Please cite this article as: Dharma Rao, G.B., Acharya, B.N., Kaushik, M.P., An efficient synthesis of β-ketoestersvia transesterification and its application in Biginelli reaction under solvent-free, catalyst-free conditions,Tetrahedron Letters (2013), doi: http://dx.doi.org/10.1016/j.tetlet.2013.09.130

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Graphical Abstract

An efficient synthesis of β-ketoesters via transesterification and

its application in Biginelli reaction under solvent-free,

catalyst-free conditions

G. B. Dharma Rao, B. N. Acharya, M.P. Kaushik*

A simple and efficient transesterification process for the synthesis of β-ketoester derivatives has been achieved by the

reaction of methyl β-ketoester with higher alcohols at 110 °C under solvent-free, catalyst-free conditions and its

application in synthesis of 3,4-dihydropyrimidin-2(1H)-ones C-5 ester derivatives via Biginelli reaction has been described.

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An efficient synthesis of β-ketoesters via transesterification and its application in

Biginelli reaction under solvent-free, catalyst-free conditions

G. B. Dharma Rao, B. N. Acharya, M .P. Kaushik*

Discovery Centre, Process Technology Development Division, Defence R. & D. Establishment, Jhansi Road, Gwalior-474002, M. P.,

India.

Abstract— A simple and efficient transesterification process for the synthesis of β-ketoester derivatives has been achieved by the reaction of methyl β-

ketoester with higher alcohols at 110 °C under solvent-free, catalyst-free conditions and its application in synthesis of 3,4-dihydropyrimidin-2(1H)-ones C-5

ester derivatives via Biginelli reaction has been described. © 2013 Elsevier Science. All rights reserved.

The recent focus on the development of sustainable

chemical process has provided an emerging task to those

who applied chemistry in industry and academic research.

The construction of chemical compounds or protocols by

avoiding relatively volatile toxic solvents and hazardous

catalysts is the need in the present scenario for green

synthesis.1,2

Besides, it has been observed that the catalyst

employed protocols are not always environmentally benign,

and because of this several environmental solid mass

pollutants often results during the process of waste disposal.

These limitations prompted us to investigate the efficient,

viable and feasibility of solvent and catalyst-free reactions

under modified experimental conditions towards the

development of greener protocol for the synthesis of

diversified and functionalized cascade molecules.

In the current existence, transesterification

transformation have received considerable attention and

emerged as a most significant protocol in organic synthesis

(Scheme 1).3

Transesterification was one of the easiest

procedures for the synthesis of β-ketoesters, which are not

available commercially. β-Ketoesters serves as an

authoritative synthon which were used in synthesis of

polymers, drugs, biologically active compounds.4 Besides

this they are also used as building blocks in the synthesis of

complex natural products.5 β-Ketoesters have also proved to

be a superior synthon essentially because of the presence of

both electrophilic as well as nucleophilic centers.

______________________________________________

∗Corresponding author. Tel.:+91-751-2343972; fax: +91-751-

2340042. E-mail address: mpkaushik@rediffmail.com. (M. P.

Kaushik)

Keywords:- Transesterification; β-Ketoester; Alcohol; Biginelli reaction;

Dihydropyrimidinone; Green chemistry.

Transesterification reaction is also more advantageous than

the Claisen condensation or the reaction of diketene with

alcohols for the synthesis of β-ketoesters. Diketenes were

very difficult to handle due to corrosive and very reactive in

nature.

Scheme 1: General transesterification transformation

tert-Butyl β-ketoester readily underwent

transesterification transformation with alcohol to form the

corresponding β-ketoester in presence of toluene/xylene as

solvent under catalyst-free condition6 due to presence of

better leaving group and this protocol was only restricted to

tert-butyl β-ketoester. Toluene was found to be the best

solvent in comparison to other solvents. However, it was not

found to be environmental friendly. Transesterification is an

equilibrium driven process and it can be controlled by acidic

and basic catalysts7 in hydrocarbon solvents or usage of

excess of one of the precursor to get quantitative yield.

Literature survey revealed that, most of the reported

methods were developed either by the use of catalyst8 or

solvents.9

However, in spite of their potential utility, most of

these reported methods experienced from various

disadvantages such as drastic reaction conditions, modest

yields, requires special experimental apparatus and the use

of catalysts which are expensive, toxic, and air sensitive. To

the best of our knowledge, there are no reports for

transesterification of alcohol under solvent-free and catalyst-

free conditions using methyl β-ketoester as the

acetoacetylating agent.

Pergamon

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In continuation of our work on new synthetic

methodologies for the synthesis of various bioactive

compounds10

there was a need to synthesize various

functionalized β-ketoesters. Recently, we have developed a

protocol for transesterification of alcohols by using

ytterbium(III)triflate as catalyst under solvent-free

conditions.11

With an objective to develop greener protocol

of transesterification, the reaction (Scheme 1) was carried

out under solvent-free and catalyst-free conditions to obtain

a number of β-ketoesters by the simple and commonly used

method of transesterification from readily available methyl

β-ketoester. Herein, we report a realistic method for the

synthesis of β-ketoester using methyl β-ketoester with

different functionalized alcohols under solvent-free and

catalyst-free conditions at 110 Co.

With the intention of optimize the reaction conditions, we

initiated our investigation on transesterification of methyl β-

ketoester with cyclohexanol as a model substrate. The

cyclohexanol β-ketoester was obtained in moderate yield,

when methyl β-ketoester was reacted with an equilmolar

amount of cyclohexanol (1:1) in the absence of solvent and

catalyst after 3h at 110 °C. The methyl β-ketoester was

completely converted into cyclohexanol analogue, which

was obtained in 85% yield (Table 1, Entry 6). It also

revealed that the reaction proceeds under solvent-free and

catalyst-free conditions, when methyl β-ketoester and

cyclohexanol were used in a mole ratio of 1:1.5 (Figure 1).

Figure 1: Comparison of various mole ratio of cyclohexanol with methly β-ketoester in transesterification (GC yields).

The applicability of optimized reaction conditions were

further extended to the synthesis of more complex β-

ketoester with a wide range of structurally diverse and

functionalized alcohols. As expected, the rate of this

transformation also depends on steric hindrance and all the

results were appended in Table 1. The salient features of this

methodology are as follows, (i) methyl β-ketoester is

successfully transformed into synthetically useful higher

homologue of esters; even bulkier alcohols could be used for

transesterification (Table 1, Entry 7), (ii) the synthesis of

long chain esters which can be used as a precursors in the

polymer industry ( Table 1, Entry 4), (iii) the special features

of this protocol is that unsaturated alcohols (Table 1, Entries

13-15) smoothly underwent transesterification affording

unsaturated esters in high yields.

Table 1. Transesterification of methyl β-ketoester using various alcohols.

a,16

Entry ROH Time (h) Product %yieldb

1 3 9211

2 3

9011

3 3

85

4 3

8511

5 3 9011

6

3

8511

7

5.5

6011

8 3.5

8811

9 3

90

10

4

85

11 3

8311

12 4

80

13 3

8011

14 4 7611

15 3 7512

aReaction conditions: methyl β-ketoester (1.0 equiv.), and

alcohol (1.5 equiv.) at 110 ˚C under solvent- and catalyst-free conditions.

bIsolated yields.

β-Ketoester is one of the precursors, out of the three

building blocks in the Biginelli reaction13

to synthesize the

3,4-dihydropyrimidin-2(1H)-ones (DHPMs) which occupied

a prestigious position in medicinal chemistry due to their

pharmacological and biological activities such as calcium

channel blockers, mitotic kinesine inhibitor, adrenergic

receptor antagonist, antibacterial and antiviral activities.14,15

100

90

80

70

60

50

% c

on

ver

tio

n

1.51.41.31.21.11.0

mole ratio of cyclohexanol

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The β-ketoester can be varied to the largest extent by the

synthesis of non-commercial β-ketoester via

transesterification as mentioned above to achieve diversity at

C-5 position of DHPMs.

Recently, we have reported a Biginelli reaction10a

for

the construction of dihydropyrimidinones/thiones. The same

procedure was employed to Biginelli reaction under solvent-

free and catalyst-free conditions by using various types of β-

ketoesters which were synthesized via transesterification

transformation with constant arylaldehyde. From these

experiments, we found that tolerance of various β-ketoester

bearing diverse functionality underwent reaction smoothly

with p-methoxy benzaldehyde and urea to afford the

corresponding dihydropyrimidinone C-5 ester derivatives in

excellent yields and all the results are appended in Table 2.

Table 2: Synthesis of dihydropyrimidinones using non-

commercial β-ketoester under thermal conditionsa,17

Entry β-Ketoester Product M.P (°C) (%)Yield

1

196-198 9210a

2

172-174 90

3

190-192 92

4

178-180 92

5

200-202 90

6

140-142 89

7

152-154 90

8

128-130 87

9

194-196 85

10

158-160 82

aReaction conditions: β-ketoester (1.0 equiv.), arylaldehyde

(1.0 equiv.) and urea (1.2 equiv.) at 110 ˚C under solvent and catalyst free conditions.

bIsolated yields.

On the basis of above observations and the literature

reports, a plausible reaction pathway for the formation of

dihydropyrimidinone C-5 ester derivatives is depicted in

Scheme 2. Methyl β-ketoester is easily converted into

reactive acetylketene intermediate6 by the loss of relatively

volatile methyl alcohol at 110 °C followed by the

nucleophilic attack of the alcohol to form new β-ketoester

with corresponding alcohol. The resulting imine

intermediate10a

by the condensation of arylaldehyde and urea

undergo a cyclization with new β-ketoester furnish the

corresponding dihydropyrimidinone C-5 ester derivative

followed by the elimination of water molecule.

Scheme 2: Proposed mechanism for the synthesis of

dihydropyrimidinone C-5 ester derivatives.

In summary, we have developed and demonstrated a new

and highly efficient viable procedure for the synthesis of

non-commercial β-ketoester via transesterification

transformation and its function in synthesis of

dihydropyrimidinone C-5 ester derivatives through straight

forward Biginelli reaction under solvent-free, catalyst-free

conditions. The noteworthy merits of this protocol is the

simple operation, mild reaction conditions, easy work-up

procedure, no hazardous catalysts or corrosive, toxic

solvents. We believe that, this will be a better and more

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viable green methodology for solvent- and catalyst-free

reactions. Further research to widen the scope of this

enhanced protocol is in progress.

Acknowledgements:

We express special gratitude to the Director, DRDE,

Gwalior, for his keen interest and encouragement.

Supplementary data:

Supplementary data (Details experimental procedure and

characterization data of selected compounds and copies of 1H NMR and

13C NMR spectras are given in supplementary

material) associated with this article can be found.

References and note:

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16. Typical experimental procedure (transesterification

transfomation): A homogeneous mixture of an alcohol

(1.5 equiv.) and methylacetoacetate (1.0 equiv.) was

charged in a round bottomed flask and gently heated at

110 ˚C under solvent-free, catalyst-free conditions, for a

certain period of time as required. The progress of the

reaction was monitored by TLC. After completion, the

resulting desired product was distilled out directly or

separated by short column chromatography over silica

gel using light petroleum ether and ethylacetate (80:20)

to afford the pure product in 60-92% yield.

17. Typical Experimental Procedure (Biginelli reaction): A

25ml round bottom flask equipped with a reflux

condenser was charged with arylaldehyde (1.0 equiv.)

and urea (1.2 equiv.). Both precursors were finely

powdered and mixed together and allowed to stir for 30

min at room temperature. The β-ketoester (1.0 equiv.)

was subsequently added to above mixture. The resulting

reaction mixture was heated at 110 ˚C (oil bath) under

solvent- and catalyst-free conditions with constant

mechanical stirring for 3h. The progress of the reaction

was monitored by TLC (6 : 4, hexane : ethylacetate ).

After completion of the reaction as indicated on TLC, the

contents were cooled to room temperature and the crude

reaction mixture was crushed and washed with chilled

water (15ml x 3), filtered and dried under vacuum. For

analytically pure products, the final solid mass was

washed with diethyl ether (10ml x 2) to remove the un-

reacted reagents to afford the pure product in 82-92%

yield.