Preparation of pyrimido[2,1-a]phthalazines and an aminopyrimido[2,1-a]isoindole by retro Diels–Alder reaction

Abstract

The reactions of cis-2-p-toluoylcyclohexanecarboxylic acid 1 with endo,endo- or exo,exo-3-aminobicyclo[2.2.1]heptane- and -hept-5-ene-2-carbohydrazides 2, 4 and 3, 5 yielded partly saturated methylene-bridged phthalazino[1,2-b]quinazolinone diastereomers 6a–6b, 7a–7b, 8a–8b and 9a–9b, and phthalazino[1,2-b]quinazolinediones 10–13 containing a trans-condensed cyclohexane ring. After separation of the products, the structures were established by means of NMR methods. The diastereomers 6–9 differ in the configurations of the annelational carbons: the hydrogens attached to them lie either on the same side (a) or in pairs on opposite sides (b) of the ring skeleton. On heating, the mixtures of diastereomeric norbornene derivatives 8 and 9 underwent retrodiene decomposition: cyclopentadiene split off to yield the pyrimido[2,1-a]phthalazine 14 containing a cis-fused cycloalkane ring. The reaction of 4 with the aroylbenzoic acid 15 furnished the benzologue 19 directly, while, after isolation from the reaction mixture of 1 and 5, and on heating, 20 resulted in 21 containing a saturated trans-condensed isoindole moiety by cycloreversion.