Pyrano pyridine synthesis

An intramolecular variant of this cycloaddition process is combined with a Knoevenagel reaction in a total synthesis of the insectan leporin A, a pyrano[3,2-c]pyridine derivative <96JOC2839>. 

INAC reactions have also led to enantioselective syntheses of key intermediates in the synthesis of antibiotic l 3-Methylcarbapenem (724), to optically pure derivatives of tetrahydropyrano[2,3] cyclohexane (725a) to novel terahydro-isoxazolo-fused pyrano 2,3-/ quinolines (725b) and to a novel heterocyclic system, isoxazolo[3,4-d]thieno[2,3-b]pyridine (Scheme 2.229) (221). 

Heterocycles (167) and (168) react with sodium hydride yielding the pyrano[2,3-/>]pyridines (130) <92JOC1930> and 1,8-naphthyridine derivatives (111) <92JMC518> respectively a related synthesis of tetrahydropyrano[2,3-6]pyridines has been reported <71JCS(B)279>. Under acidic conditions, the diester (169) affords heterocycle (170) (44% yield) <93H(35)93>. The sulfone (171) reacts with LDA giving an intermediate (172) which cyclizes yielding the sulfone (173) (Scheme 1) <84JOC5l36>. 

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>. 

The compound (102.3), used in the synthesis of a fused pyridine in Section II. I, may also be cyclized to pyrano- or thiopyrano-pyrazole by heating with phosphorus pentoxide-PPA or phosphorus pentasulphide. The presence of ethanol or acetic acid retards the reaction. 

As part of a general study of the synthesis of 2,2-dimethylpyrano-derivatives, a convenient synthesis of the acridone alkaloid, acronycine (31 R = R = Me) was devised. Heating a solution of 1,3-dihydroxyacridone and 4,4-dimethoxy-2-methylbutan-2-ol in pyridine afforded a mixture of linear and angular pyrano derivatives. The angular product (31 R = R = H), which predominated, is itself a natural compound and was converted by methylation into acronycine. 

Many methods for the synthesis of pyrano[3,2-c]pyridine derivatives (96CHEC-II(8)345, 02505(15)285, 08CHEC-III(7)217) are known. 

The l-fiT-pyrano[3,4-c]pyridine nucleus is found extensively amongst alkaloids and a short photochemical synthesis has been reported, starting from readily available 4-acetoxy- or 4-alkoxy-2-pyridones (54). Under photochemical stimulation, these compounds react with the diethyl acetal of acrolein. Treatment of the head-to-tail adducts (55) with a base gives the cyclobuta[c]pyridone derivative (56), which rearranges (upon heating in acid) to produce the H-pyrano[3,4-c]pyridone (57). The method is claimed to be general. 

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