Alkylidene Aminomethylenemalonates

The heating of cycloalkylidene phenylaminomethylenemalonates (1163) in the melt at 245°C, in Dowtherm A between 175-245°C, in dibenzyl ether at 250°C, or in boiling nitrobenzene for a few minutes, gave 4-hydroxyquinolines (1164) [e.g., 69BRP1147760 87T4803 88JAP(K)-239269]. 

When (3-substituted phenyl)aminomethylenemaIonate (1163, 3-R = H) was applied, a mixture of 5-substituted and 7-substituted 4-hydroxyquino-lines (1164, 5-R + H and 7-R + H) was obtained. For example, the thermal cyclization of (3-nitrophenyl)aminomethylenemalonate in dibenzyl ether at 250°C afforded a 3 1 mixture of 7-nitro- and 5-nitro-4-hydroxy-quinolines (1164, R = 7-N02 and 5-NO ). 4-Hydroxyquinolines (1164) could also be prepared when a mixture of anilines, triethyl orthoformate, and isopropylidene malonate was slowly heated to 100°C in Dowtherm A, stirred over a period of 30 minutes, and then raised to a temperature of 

The cyclization of isopropylidene l-(phenylamino)alkylidenemalonates (1165) in diphenyl ether at 25Q-260°C under nitrogen, or in boiling Dowtherm A, gave 2-substituted 4-hydroxyquinolines (1166) in 63-96% yields (69BRP1147760 87S482). 

When the reaction mixture of 4-chloroaniline, triethyl orthoformate, and isopropylidene methylmalonate in Dowtherm A was heated slowly, stirred to reflux, and maintained at reflux for 3 minutes, 6-chloro-4-hydroxy-3-methylquinoline (1167) was obtained (69BRP1147760). 

The thermal cyclization of isopropylidene 3-pyridylaminomethylene-malonate (1181) afforded 4-hydroxy-1,5-naphthyridine (1182), while that of isopropylidene 3-quinolinylaminomethylenemalonate (1183) gave l-hydroxybenzo(/)-l,7-naphthyridine (1184) (69BRP1147760). 

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Because of the higher CH acidity (by 7-8 pKa units) of alkylidene malonates (441), as compared with that of dialkyl malonates (87JA809), one-pot syntheses of alkylidene aminomethylenemalonates (442) could be carried out readily with a wide variety of primary and secondary aliphatic and cycloaliphatic amines, anilines, naphthylamines and heterocyclic amines, trialkyl orthoformate, and alkylidene malonates (83MI1 86MI9). It was proposed that the higher CH acidity of alkylidene malonates was a consequence of the electrostatic (dipole-dipole) repulsion effects... 

Anilines, bis(2-amino-4-chlorophenyl)disulfide, naphthylamine, 2- and 3-aminopyridines, 2-aminopyrimidines, 2-, 3-, 5-, 6-, 7-, and 8-aminoquino-lines, 6-aminocoumarin, and 2-aminopyrazine were reacted in the absence or presence of a solvent (ethanol, toluene) with ethyl orthoformate and isopropylidene or 4-heptylidene malonates to give alkylidene (het)aryl-aminomethylenemalonates (442, R = R2 = Me, Pr) in 32-100% yields [69BRP1147759 75USP3907798 88JAP(K)239269]. p-Toluenesulfonic acid monohydrate was sometimes applied as catayst. 

Alkylidene 5-acylmalonates were reacted with O-substituted hydroxyl-amine to give aminomethylenemalonates (451) [82JAP(K)62274], However, when 7/3-amino-ceph-3-em-4-carboxylic acids (452) were first reacted with A,0-bis(trimethyIsilyl)acetamide in THF and then with isopropylidene 5-acylmalonate (449, R1 = R2 = Me), instead of the corresponding aminomethylenemalonate, 7/3-acylamido-ceph-3-em-4-carboxylic acids (453) were obtained (83EUP54970). 

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