Ethoxymethylenemalonate cyclizations derivatives

Addition of pyrrolyl potassium 194 to ethoxymethylenemalonic acid derivatives 195 gives the A -vinylpyrroles 196 with elimination of ethanol. Cyclization of 196 (R = CN, = Ph) with the aid of tetrafluoroboric acid or aqueous hydrochloric acid gives the amino pyrrolizidine salt 197 (82CB714). Exposure of (1-pyrrolylmethylene) acid 196 (R = CO2H, R = H), prepared in a different way, to phosphorus pentachloride gives the pyrrolizidine 198, Scheme 52 (82CB706). 

The 4-hydroxypyridine (or 4-pyridone) derivatives are obtained by the use of ethoxymethylenemalonate and acetoacetate (59NKZ534) or acetylenedicarboxylate (78USP4130649). In analogy to these reactions, cyclizations starting from 5-aminotropolone ethers (83USP4382088) or 2-aminotropones (83USP4381304) were claimed. 

Attempts to prepare tricyclic homologues of the naphthyridines have been partially successful. 4-Amino-1,5-naphthyridine (109) reacts under Skraup conditions to give 4,5,9-triazaphenanthrene (110), and 1,8,9-triazaanthracene derivatives (111) can be isolated from the mixtures of products obtained by treatment of 2-amino-l,8-naphthyridin-7-one and its derivatives with ethyl ethoxymethylenemalonate, acetylacetone and alkyl /3-oxoglutarates (72JHC801) (see also earlier papers in that series). However, 2-amino-1,8-naphthyridine (112 R = H) reacts under Skraup conditions to give the 2-oxo derivative (113 R = H) instead of a 1,8,9-triazaanthracene, and 2-amino-1,6-naphthyridine behaves similarly (75MI21103). Under non-hydrolytic conditions, naphthyridines (112 R = Aik, Ar, H) cyclize... 

A few extensions of the Conrad-Limpach synthesis have been applied to the synthesis of 4,7-phenanthrolines. Unlike o-phenylenediamine, which gives a quinoxaline derivative, p-phenylenediamine reacts with excess of ethyl ethoxalylpropionate to give an intermediate bisanil, which cyclizes in hot diphenyl ether to afford 3,8-dicarboethoxy-l,10-dihydroxy-2,9-dimethyl-4,7-phenanthroline in high yield.237 With diethyl ethoxymethylenemalonate as condensing agent, 6-amino-8-methoxy-quinoline has been converted into 2-carboethoxy-l-hydroxy-6-methoxy-4,7-phenanthroline.238 A related condensation affording 1-... 

A suspension of the diazonium salt in toluene was gradually heated and kept at 120°C (bath temp.) for 30 minutes with stirring. After evaporation of the solvent under reduced pressure, the residue was made alkaline with 10% sodium carbonate and then extracted with chloroform. The chloroform extract was dried over anhydrous potassium carbonate. After evaporation of the solvent, the crystalline residue was recrystallized from ethyl acetate to give 6-acetylamino-2-(4-ethoxycarbonyl-l-piperazinyl)-3-fluoropyridine (mp 132°-133°C). The 3-fluoro derivative was hydrolyzed with a mixture of 15% hydrochloric acid and methanol (1 2 v/v) to give 6-amino-2-(4-ethoxycarbonyl-l-piperazinyl)-3-fluoropyridine. This compound was treated with diethyl ethoxymethylenemalonate at 130°-140°C to give N-[2-(4-ethoxycarbonyl-l-piperazinyl)-3-fluoro-6-pyridinyl]aminomethylenemalonate (mp 144°-145°C) and then the product was cyclized by heating at 255°C to give ethyl 7-(4-ethoxycarbonyl-l-piperazinyl)-6-fluoro-l,4-dihydro-4-oxo-l,8-naphthyridine-3-carboxylate (mp 279°-281°C). 

Cyclizations of the type (156) - (151) include the conversion of (a) carboxylic acids (218 X = O, S) into diones (219) (34% yield) under acidic conditions <74MI 715-01) (b) pyridine derivative (220) into the pyrano[3,2-c]pyridine (221) (72% yield) via an intramolecular Grignard reaction <82JCS(P1)93> and (c) a 1 1 mixture of diastereoisomers (222) into a 1 1 mixture of diastereoisomeric pyranopyrans (223) via a HSnBu3-mediated free radical cyclization <93LA629>. The diethyl ethoxymethylenemalonate (EMME) synthesis of 3-ethoxycarbonyl-4-naphthyridone derivatives has been discussed in CHEC-I <84CHEC-i(2)58i>. 

Pyrido[2,3-< ]pyrimidines are usually synthesized by thermal cyclization (the Gould-Jacobs reaction) of enaminones derived from 6-aminopyrimi-dines and diethyl ethoxymethylenemalonate. The cyclization is generally carried out in Dowtherm or diphenyl ether at elevated temperature and affords overall good yields (Table VI, entry 1). 

The ethyl 6-(trifluoromethyl)-2-pyrone-3-carboxylate (61) was prepared by condensation of trifluoroacetone with diethyl ethoxymethylenemalonate, followed by cyclization of intermediate diethyl p-acylethylidenemalonate. This pyrone was used for the preparation of cage derivatives to explore their usefulness as antiviral agents. Reaction of 61 with ethylene at high pressure afforded ester 62. Hydrogenation of 62 yielded the corresponding alkyl bicyclo[2.2.2]octane-l-carboxylate, which was hydrolyzed to 63. The latter was converted into bicyclo[2.2.2]octan-l-amine hydrochloride 64 via the Schmidt reaction [29] (Scheme 21). 

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