Synthesis of 3-Carbethoxycoumarin

Synthesis of 3-Carbethoxycoumarin

Timikeyi Egbuson

11/14/2013

Chemistry 213. 101

Michael Banales

Synthetic FFR 1

Introduction

Coumarins, a class of heterocyclic compounds, derived its name from “Coumarou”, the vernacular name of the tonka bean (DipteryxodorotaWilld.,Fabacae), from which coumarin itself was isolated in 1820. 1Coumarins are found in fruits (e.g bilberry), cinnamon bark oil, cassia leaf oil and consist primarily of four sub types: the simple coumarins, furanocoumarins, pyranocoumarins and the pyrone-susbstitute coumarins.2Coumarins are used in agrochemicals, perfumes, food additives and also have widespread biological significance based on their cytotoxic, anticoagulant, anxiolytic and antioxidant properties.3Carbonyl condensation reactions take place in various metabolic pathways and effectively synthesize various useful macromolecules. The formation of carbon-carbon bonds in carbonyl condensation reactions explains its use as a precursor for the formation of large compounds due to the ability of carbonyl compounds to act as both the electrophile and nucleophile. Aldol condensation reactions combine two carbonyl compounds by forming a bond between the α carbon of one of the molecules and the carbonyl carbon of the other i.e a combination of nucleophilic addition and α substitution. The dehydration of aldol products give rise to conjugated enones both in acidic and basic conditions. In acidic conditions, the formation of enols occur and water acts as a good leaving group based on elimination reactions. In basic conditions, the formation of an enolate ion leads to the expulsion of the hydroxyl group based on the unimolecular elimination of the conjugate base mechanism. 3-carbethoxycoumarin, a simple coumarin derivative, was synthesized via base catalyzed trans esterification, followed by an aldol condensation reaction of salicylaldehyde and diethylmalonate.The relatively easy accessibility of esters account for their convenientuse as starting materials in transesterification reactions.Not only is transesterification vastly used in pure organic synthesis, it plays a role in polymerization and ring opening of cyclic compounds. A drying tube filled with Drierite was used to keep atmospheric moisture from the reaction. Alternatively, 3-carbethoxycoumarin can be synthesized from the conjugated addition of lithium and magnesium derivatives of o-carboranes.4 It is also used as a precursor in the synthesis of more complex coumarin derivatives such as ethyl 4-phenyl-3,4-dihydro-3-coumarincarboxylate.5

Scheme 1.Mechanism showing synthesis of 3-carbethoxycoumarin from salicyladehyde , and diethylmalonate via transesterification and aldol condensation.

Due to the relatively low pka (≃13) of the diethyl malonate in comparison to that of the aldehyde (pka≃17), the acidic alpha hydrogen is easily deprotonated by the non-nucleophilic pyridine base to form the nucleophilic enolate ion intermediatewhich attacks the electrophiliccarbonyl of salicylaldehyde. The resulting alkoxide picks up the acidic proton on the ethanol solvent and the hydroxide formed attacks an intermolecular hydride ion to form water (a good leaving group). Dehydration occurs, thus, forming the stable conjugated enone while the phenol attacks the carboxyl group in an intramolecular fashioneventually causing the ether group to leave. The displaced ether group, which is the conjugate base of ethanol, is highly nucleophilic and attacks the acidic proton on the carboxylic acid and upon tautomerization, 3 carbethoxycoumarin is adequately formed.

Coumarins, and its derivatives, are widely utilized in agriculture and biology, explaining the purpose of the synthesis of 3 carbethoxycoumarin via transesterification and aldolcondensation of diethyl malonate and salicyladehyde. The reaction progress was monitored using thin layer chromatography based on spot intensities and retardation values while recrystallization was employed for the purification of the crude product. Percent yield and recovery calculations were determined while melting point analysis was taken to determine purity of product. Infrared and nuclear magnetic resonance spectroscopy confirmed formation of desired product and showed no starting materials or intermediates present.

Experimental

Salicylaldehyde (1.1 mL), diethyl malonate (1.7mL), ethanol (4mL), piperidine (20 drops) and glacial acetic acid (4 drops)were added to 25-mL round bottom flask and refluxed for two hours, while stirring. The reaction was monitored by thin layer chromatography (40%EtoAc/hexane). Upon cooling, crude crystals were isolated by vacuum filtration, using Buchner funnel. Dry crude crystals were recrystallized using 95% ethanol and upon vacuum filtration, white clear crystals evolved.

Results and Discussion

The use of piperidine , rather than hydroxide, as base in the transesterification is due to its relatively low nucleophilicity, but yet high solubulity in organic compounds. As a result, it tends to interact with specific functional groups of interest in compounds with multiple functional group based on its selective nature. Two thin layer chromatography plates were spotted while the reaction was being refluxed. At about 60 min,

1 | Egbuson