Arylaminomethylenemalonates, cyclization

Thermal cyclization of the arylaminomethylenemalonate afforded quinoline 3-carboxylate 630 whose reaction with 1,1-dibromoethane gave oxazolo[5,4,3-(/]quinoline 631. Acid hydrolysis and reaction with N-methylpiperazine gave 632 whose bactericidal activity is superior to that of pipemidic acid (82JAPK57203085) (Scheme 108). 

The thermal ring closure of Af-(het)arylaminomethylenemalonates gave bi- or polycondensed 4-hydroxypyridine-3-carboxy lates. This type of reaction is named the Gould-Jacobs reaction. (The reaction is illustrated in Scheme 40). The cyclized products may exhibit oxo-enol tautomerism. In this review, the hydroxy form is generally depicted. This type of tautomerism was discussed in an excellent review (76MI1). 

In the cyclization of 7V-(het)arylaminomethylenemalonates, a wide variety of acidic agents have been used. Under such circumstances, not only iV-mono but also N /V-disubstituted derivatives could readily be cyclized. 

The cyclization of arylaminomethylenemalonates (701) on the action of phosphorus pentoxide in nitrobenzene gave quinoline-3-carboxylates (702) in 16-85% yields (74JMC137). Polyphosphoric acid proved to be a more effective cyclization agent than the phosphorus pentoxide-nitrobenzene system. For example, a chloro derivative (701, R = Et, R1 = Cl, R2 = R3 = R4 = H) gave quinoline-3-carboxylate (702, R = Et, R1 = Cl, R2 = R3 = R4 = H) in 46% yield on the action of polyphosphoric acid, whereas the yield was only 16% in the phosphorus pentoxide-nitrobenzene system. 

Nakagome and co-workers effected the successful cyclization of N-ethyl-N-arylaminomethylenemalonates (749) in poly phosphoric acid, prepared from orthophosphoric acid and phosphorus pentoxide in polyphosphate ester (PPE), prepared from phosphorus pentoxide and anhydrous diethyl ether in chloroform in phosphoryl chloride on the action of boron trifluoride etherate on the action of acetic anhydride and concentrated sulfuric acid or on the action of phosphorus pentoxide in benzene [71GEP2033971, 71JHC357 76JAP(K) 18440]. Depending on the work-up process, l-ethyl-4-oxoquinoline-3-carboxylates (750, R1 = Et), l-ethyl-4-oxoquinoline-3-carboxylic acids (750, R2 = H) and 3-ethoxycarbonyl-4-chloroquinolinium iodides (751) were obtained. Only the cyclization of... 

V-(3-trifluoromethylphenyl)aminomethylenemalonate (749, R = 3-CF3) proved unsuccessful in boiling phosphoryl chloride. The thermal cycliza-tion of ZV-ethyl-N-arylaminomethylenemalonates (749) and their ring closure in acetic acid, in acetic anhydride with zinc chloride, or in a melt of aluminium chloride were likewise unsuccessful (71JHC357). The corresponding quinoline was not obtained in a one-pot version when N-ethylani-line and EMME were reacted in polyphosphoric acid. Table V shows the yields of quinoline-3-carboxylic acid derivatives obtained from /V-ethyl-N-phenyl- and iV-ethyl-7V-(3,4-methylenedioxyphenyl)aminomethylene-malonates (749, R = H and 3,4-0CH20) under various acidic cyclization conditions. 

The thermal cyclization of arylaminomethylenemalonates (977, R = H, X = CH, N) and their N-methyl derivatives (R = Me) in Dowtherm A at 250°C for 15 min afforded the angular tricyclic derivatives (978) in excellent yields (87CCC2918 88MI11 89CCC713). 

---