Thermische Lactonisierung von Estern γ‐Brom‐α, β‐ungesättigter Carbonsäuren zu Δα‐Butenoliden. Direkte γ‐Bromierung von α, β‐ungesättigten Säuren

Abstract

AbstractBy heating with iron powder at 120–150° some γ‐bromo‐α, β‐unsaturated carboxylic methyl esters, and, less smothly, the corresponding acids, were lactonized to Δ7alpha;‐butenolides with elimination of methyl bromide. The following conversions have thus been made: methyl γ‐bromocrotonate (1c) and the corresponding acid (1d) to Δα‐butenolide (8a), methyl γ‐bromotiglate (3c) and the corresponding acid (3d) to α‐methyl‐Δα‐butenolide (8b), a mixture of methyl trans‐ and cis‐γ‐bromosenecioate (7c and 7e) and a mixture of the corresponding acids (7d and 7f) to β‐methyl‐Δα‐butenolide (8c). The procedure did not work with methyl trans‐γ‐bromo‐Δα‐pentenoate (5c) nor with its acid (5d).Most of the γ‐bromo‐α, β‐unsaturated carboxylic esters (1c, 7c, 7e and 5c) are available by direct N‐bromosuccinimide bromination of the α, β‐unsaturated esters 1a, 7a and 5a; methyl γ‐bromotiglate (3c) is obtained from both methyl tiglate (3a) and methyl angelate (4a), but has to be separated from a structural isomer. The γ‐bromo‐α, β‐unsaturated esters are shown by NMR. to have the indicated configurations which are independent of the configuration of the α, β‐unsaturated esters used; the bromination always leads to the more stable configuration, usually the one with the bromine‐carrying carbon anti to the carboxylic ester group; an exception is methyl γ‐bromo‐senecioate, for which the two isomers (cis, 7e, and trans, 7d) have about the same stability.The N‐bromosuccinimide bromination of the α,β‐unsaturated carboxylic acids 1b, 3b, 4b, 5b and 7b is shown to give results entirely analogous to those with the corresponding esters. In this way γ‐bromocrotonic acid (1 d), γ‐bromotiglic acid (3 d), trans‐ and cis‐γ‐bromosenecioic acid (7d and 7f) as well as trans‐γ‐bromo‐Δα‐pentenoic acid (5d) have been prepared.Iron powder seems to catalyze the lactonization by facilitating both the elimination of methyl bromide (or, less smoothly, hydrogen bromide) and the rotation about the double bond.α‐Methyl‐Δα‐butenolide (8b) was converted to 1‐benzyl‐(9a), 1‐cyclohexyl‐(9b), and 1‐(4′‐picoly1)‐3‐methyl‐Δα‐pyrrolin‐2‐one (9 c) by heating at 180° with benzylamine, cyclohexylamine, and 4‐picolylamine.The butenolide 8b showed cytostatic and even cytocidal activity; in preliminary tests, no carcinogenicity was observed. Both 8b and 9c exhibited little toxicity.