Comparative intramolecular dehydrative lactonization of 4-oxocarboxylic acids

Reaction of 3-( p -toluoyl)propanoic acid, 1a (R = H) with refluxing acetic anhydride resulted quantitatively in 2 , a β , γ -unsaturated γ -lactone, which was then converted into 3a , an α , β - unsaturated lactone by isomerization with triethylamine. The methyl-substituted compound 1b (R = Me), an analogue of 1a , afforded the 2(5 H )-furanone 3b directly by heating with Ac 2 O. Similar reaction of the cycloalkane-containing oxocarboxylic acids ( 4 , 5 ) led in excellent yields to the fused furanones 6 and 7 , while treatment of 2-formyl-, 2-acetyl-and 2-( p -toluoyl)benzoic acids ( 8a-c ) with Ac 2 O gave the 3-acetoxy-1-(3 H )-isobenzofuranones, 9a-c .


Introduction
We recently described several cyclocondensation reactions of 4-and 5-oxocarboxylic acids with amines 1 and bifunctional amino derivatives, such as diamines, amino-alcohols and amino-thiols. 2urther studies of the reactivity of cis-and trans-cyclohexane-fused 4-oxocarboxylic acids with various dehydrating agents (H 2 SO 4 , PPA, H 3 PO 4 , AcCl, Ac 2 O, and DCC) led to formation of unsaturated lactones exclusively, instead of the expected saturated anthraquinone derivatives.These results prompted us to compare the reactivity of aromatic-, aliphatic-, and cycloalkanecondensed 4-oxocarboxylic acids with acetic anhydride as a mild and efficient reagent.

Results and Discussion
The typical reaction of 3-(p-toluoyl)propanoic acid, 1a (R = H) (Scheme 1) with an excess of refluxing acetic anhydride after 20 minutes resulted in the unsaturated lactone 2 in excellent yield (88 %), then it was isomerized to the 2(5H)-furanone 3a according to the method of Filler et al 12 in the presence of triethylamine in benzene at reflux for 15-18 hours.After purification by column chromatography on silica gel, 3a was obtained in poor yield.On the other hand, under similar conditions, the 2-methyl-substituted analogue (1b) afforded the α,β -unsaturated lactone directly in good yield.In the course of the lactonization process, unexpectedly the formation of the β,γ-isomer was not observed, so further examination was aimed at relating the substituent effect on the C-2 and C-3 carbon atom.Thus, cycloalkane anellation at these positions resulted in similar cyclization and α,β-unsaturation as in the oxocarboxylic acid 1b.When cis-2-(p-toluoyl)cyclopentane-and -cyclohexane carboxylic acids (4,5) were allowed to react in refluxing acetic anhydride the fused 2(5H)-furanones, 6 and 7, were obtained almost quantitatively (Scheme 2).It is known that five-or more-membered cycloalkanones and cycloalkyl ketones are readily enolizable, and therefore intramolecular cyclization by dehydrating agents usually takes place easily.On the other hand, lactonization in this way was unsuccessful in the case of the cyclobutane-and cyclopropane-skeleton oxocarboxylic acids, even under vigorous conditions, presumably owing to their strained and rigid cycloalkane-ring conformations.

Scheme 3
The structures of the compounds prepared were confirmed by their IR-, 1 H-and 13 C-NMR data.The structures were also studied by molecular modeling and the conformational protocol using ACD/3D ChemSketch (Version 4.01) software for compounds 2, 3a, 6 and 7 (Figure 1).Ab initio-and density functional-calculations on the ring-chain tautomerism of 4-oxocarboxylic acids were investigated recently. 15 relatively flexible conformation for the cyclohexene ring was observed for the lactone 7, contrary to the cyclopentane-condensed analogue 6, which was proved to be a rigid ring system by molecular modeling (Figure 1).The calculated structural parameters, such as distances and angles were also studied.The comparison of the computational results showed for compound 6 a relatively shorter distance between the anellation carbon atoms, and a slightly deformed furanone ring was observed on the basis of calculated bond angles.

Experimental Section
General Procedures.Melting points were determined using an Electrothermal block and are uncorrected.Infrared spectra were recorded for KBr discs or films with Perkin-Elmer 177 instrument.

Preparation of lactones 6, 7 and 9b, c (General procedure)
The 4-oxocarboxylic acid (4, 5, and 8b,c, (10 mmol) was dissolved in acetic anhydride (20 ml) then was heated at reflux for 2 h.After evaporation under reduced pressure a mixture of diethyl ether-n-hexane (15:5) was added to the residue.The mixture was kept in the refrigerator for 3-5 days and the precipitated crystals filtered off.
TMS) as internal standard, coupling constants (J values) are in Hz.Ascending TLC was performed on precoated plates of silica gel 60F 254 (Merck), and spots were visualized by using a UV lamp or iodine vapor.RT denotes room temperature.