Structural Elucidation of Z- and E- Isomers of 5-Alkyl-4ethoxycarbonyl-5-(4`-chlorophenyl)-3-oxa-4-pentenoic Acids

Z- and E-isomers of 5-alkyl-4-ethoxycarbonyl-5-(4`-chlorophenyl)-3-oxa-4-pentenoic acids were prepared via the condensation of p-chloroacetophenone and/or pchloropropiophenone with diethyl-2,2`-oxydiacetate in the presence of sodium hydride as a basic catalyst. The Z-isomers of 2a and 2b were found to be predominant. The behaviour of the corresponding anhydrides towards the action of hydrazine, phenylhydrazine, primary aromatic amines, hydrocarbons and ethanolysis has also been investigated. The structures and configurations of the products have been elucidated by chemical and spectroscopic means.


Results and Discussion
The condensation of p-chloroacetophenone and p-chloropropiophenone with diethyl-2,2`oxydiacetate in the presence of sodium hydride [5] afforded in each case a mixture of the expected stereoisomeric E-and Z-alkenes.The E-isomers 1a and 1b could be isolated in pure crystalline form, the remainder being an oily fraction whose composition was revealed by saponification.The Z-hemiesters 2a and 2b were obtained in 40% and 42% yields, respectively (vide infra).The predominance of this configuration can be interpreted in terms of the mechanism involving the formation of the diastereoisomeric δ-lactonic intermediates I and II.The steric course of the condensation will be controlled by the initial attack by the ester carbanion on the ketone.Out of the possible diastereomeric condensate anions III and IV, III is expected to be more easily formed owing to the transoid orientation of the p-chlorophenyl group and ester groups (larger effective bulk than OCH 2 COOC 2 H 5 ).Cyclisation of III to I was also expected to be enhanced by the diequatorial accommodation of the bulky aryl and ester groups when I approaches a chair-like conformation during cyclization.The easier formation of I reasonably explains the higher yields of the Z-hemiesters.Furthermore, the predominance of this configuration in the two investigated ketones, indicates that the ratio of isomers is almost solely controlled by the conformational factor, and is almost independent of the polar effect of substituents.

Structure and Configuration of the Hemiesters
The crystalline E-hemiesters 1a and 1b exhibited strong bands at 1712 and 1686 cm -1 for α,βunsaturated ester and non-conjugated carboxyl groups, respectively [6].Saponification of the crystalline E-hemiester of 1a and 1b gave the corresponding E-diacids 1c and 1d.The oily Z-hemiester 2a and 2b gave fairly high yields of the Z-diacids 2c and 2d in pure crystalline state.The dibasic acids 1c, 1d, 2c and 2d were converted to the corresponding cyclic anhydrides 3a-d by the use of N,N`dicyclohexylcarbodiimide (DCC) as dehydrating agent.The anhydrides 3a-d exhibited the expected carbonyl coupling bands [6].
The configuration of the E-hemiesters 1a and 1b was confirmed from cyclization of the derived anhydrides 3a and 3b with anhydrous aluminium chloride to the corresponding oxoindenyl acids 4a and 4b in good yields.Similar treatment of the Z-anhydrides 3c and 3d gave the corresponding dibasic acids 2c and 2d as the sole acidic products.
Beside elementary analyses, solubility in sodium carbonate solution, yellow colour, and formation of 2,4-dinitrophenylhydrazones, each of the indenyl acids 4a and 4b showed two bands for ν C=O .The position of the maxima in the electronic spectra (λ max 253 and 296; ε max 18500 and 16500), closely resemble those of 2-carboxymethyl analogues [7].
Treatment of the anhydrides 3a and 3b with hydrazine hydrate and phenylhydrazine in refluxing ethanol [2,3] led to cleavage at the non-conjugated carbonyl and gave the hydrazide derivatives 5a-d.
Amidation of the E-anhydrides 3a and 3b with aromatic amines, namely, aniline, p-toluidine, αnaphthylamine and benzylamine at 170 o C afforded the 5-alkyl-N-aryl-4-carboxy-5 On the other hand, the anhydride 3b was subjected to reactions with aromatic hydrocarbons such as benzene, toluene, cumene and anisole in the presence of anhydrous aluminium chloride under Friedel-Crafts' reaction conditions and gave the 2-aroyl-methoxy-3-(p-chlorophenyl)-pent-2-enoic acids 7a-d.The carboxy hemiesters 1e, 1f, 2e and 2f were obtained through ethanolysis of the anhydrides 3a-d in ca 80% yield.The presence of non-conjugated ester and α,β-unsaturated carbonyl groups was shown by the ν C=O at 1745 and 1700 cm -1 , thus providing additional proof for the position of unsaturation in the original hemiesters.

General
All elemental analyses gave satisfactory results : C ± 0.36, H ± 0.16, N ± 0.31, Cl ± 0.42.IR (KBr disks) and U.V. spectra were measured with Unicam SP 1400 and SP1800 spectrophotometers, re-spectively.The 1 H-NMR spectra were measured on a Varian EM-390 at 90 MHz using TMS as the internal lock and reference compound.

Saponification of the hemiesters
The hemiesters were hydrolyzed by refluxing with 10% aqueous sodium hydroxide (10 ml of alkali solution/1g of the hemiester) for 3 hrs.The pure crystalline hemiesters 1a, 1b gave the corresponding diacids 1c and 1d in ca.80% yield.The oily hemiester (13.6g) from p-chloroacetophenone gave an acidic product (12.1g)which was digested with ether to give (i) the above E-diacid 1c (1.3g) as insoluble fraction and (ii) the Z-diacid 2c as soluble fraction (10.7g).

Formation of hydrazide derivatives 5a-d
A solution of 3 (0.01 mol) and hydrazine hydrate and/or phenylhydrazine (0.05 mol) in 50 mL etha-nol was refluxed for 2 hrs.Evaporation of alcohol left a solid product which crystallised from a suitable solvent to give 5 (cf.Table 2).