Quinazolines. Part XVIII. A second stereospecific cis-addition of the elements of nitromethane across a tetrasubstituted ethylenic double bond. A concerted mechanism for the reaction of nitroacetic acid with enamines

Abstract

The reaction of ethyl 3,4,5,6-tetrahydroanthranilate with nitroacetic acid gave, stereospecifically, ethyl cis-2-amino-trans-2-nitromethylcyclohexanecarboxylate (7) in 70% yield. The stereochemistry was deduced by the following sequence of reactions: (7)→ ethyl cis-2-amino-trans-2-aminomethylcyclohexanecarboxylate (8)→ 3a-amino-trans-perhydroisoindol-1-one (9)→ 3a-(N′-phenylureido)-trans-perhydroisoindol-1-one (10)→ 8a-aminomethyl-3-phenyl-cis-perhydroquinazoline-2,4-dione hydrochloride (18)→ 8a-bromomethyl-3-phenyl-cis-perhydroquinazoline-2,4-dione (19)→ 8a-methyl-3-phenyl-cis-perhydroquinazoline-2,4-dione (20), in which the configuration at the asymmetric centres was preserved. Compound (20) was prepared from authentic methyl trans-2-methyl-cis-2-(N′-phenylureido)cyclohexanecarboxylate (22) by cyclisation with methanolic sodium hydroxide. Although this cyclisation in a deuteriated medium proceeded with complete exchange of the 4a-proton in the dione (20), it was shown to occur with retention of configuration by reduction with sodium dihydrobis-(2-methoxyethoxy)aluminate to cis-2-anilinomethyl-1,N-dimethylcyclohexylamine (25) and then to 1,8a-dimethyl-3-phenyl-cis-perhydroquinazoline (26), whose 1H n.m.r. spectrum was unambiguous.The trans stereochemistry of the isoindolone (9) was confirmed by reduction to 3a-amino-trans-perhydroisoindole (14) whose 1H n.m.r. spectrum was similar to that of 3a-methylanalogue (15) but different from that of 3a-methyl-cis-perhydroisoindole (16).This second observation of a stereospecific cis-addition of the elements of nitromethane strongly supports a concerted mechanism for the reaction of nitroacetic acid with enamines. Further evidence is reported from experiments in [2H3]nitromethane which show that no deuterium was incorporated into the nitromethane adducts.N.m.r. spectra of various compounds are discussed in connection with the generality of application of the principle that the protons in the alicyclic six-membered rings of reduced six–five, six–six and six–seven membered fused ring systems give a narrow band envelope for cis ring fusion and a wide band envelope for trans ring fusion.