Patent GB-646829-A (GB)
Title: A process for the preparation of hetercyclic compounds
Filed: 1948-05-19
Abstract: Bicyclic heterocyclic compounds containing the structure <FORM:0646829/IV (b)/1> (wherein the spare valencies are satisfied by hydrogen or by organic radicals, e.g. alkyl, alkenyl, cycloalkyl, cycloalkenyl, aromatic or heterocyclic radicals, of which many are specified, or substitution products thereof, which radicals may be attached directly or through an atom of an element other than carbon, e.g. oxygen or sulphur) are manufactured by subjecting a derivative of 3 : 4-dihydro-1 : 2-pyran gearing in the 2-position a carboxyl group or a methanol group (in which one or both of the hydrogen atoms attached to the carbon atom may be replaced by a univalent substituent group, e.g. an alkyl, aryl, alkaryl, aralkyl, alkoxy, aryloxy or acyloxy group) for a sufficient time to conditions of temperature or acidity or both which favour the necessary cyclization reaction.  The process in the absence of acid may be effected at about 35-200 DEG  C., preferably about 35-125 DEG  C. in the case of the carboxy compounds or about 50-125 DEG  C. in the case of the methanol compounds, whilst lower temperatures (e.g. about 0-75 DEG C.) may be employed in the presence of an acid-reacting substance, e.g. a strong mineral acid (preferred), acetic acid, p-toluenesulphonic acid, chloracetic acid, sodium bisulphate, zinc chloride, aluminium sulphate or potassium dihydrogen phosphate. In examples: (1) the ethyl ester of 3 : 4 - dihydro - 1 : 2 - pyran - 2 - carboxylic acid is saponified and the free acid is heated to produce 7-keto-6 : 8-dioxabicyclo-[3.2.1]-octane; (2) 2 : 5 - dimethyl - 3 : 4 - dihydro - 1 : 2 - pyran-2-carboxylic acid is heated with dilute hydrochloric acid to give 1 : 4-dimethyl-7-keto-6 : 8-dioxabicyclo - [3.2.1] - octane; (3) 2 - methyl - 3 : 4 - dihydro - 1 : 2 - pyran - 2 - carboxylic acid similarly yields 1 - methyl - 7 - keto - 6 : 8 - di-oxabicyclo - [3.2.1] - octane; (4) and (5) 2 : 5 - dimethyl-3 : 4-dihydro-1 : 2-pyran-2-methanol is treated with methanolic hydrochloric acid at 40-50 DEG  C. or with aqueous acetic and hydrochloric acids at 90-95 DEG  C., to form 1 : 4-dimethyl - 6 : 8 - dioxabicyclo - [3.2.1] - octane; (6) 2 : 5 - dimethyl - 3 : 4 - dihydro - 1 : 2 - pyran-2-aldehyde is treated with methanolic hydrochloric acid, and the product, which is probably the methyl hemi-acetal of the aldehyde, is heated to produce 7-methoxy-1 : 4-dimethyl-6 : 8-dioxabicyclo-[3.2.1]-octane.  3 : 4-Dihydro-1 : 2-pyran-2-methanols and 2-carboxylic acids are obtainable by reduction and oxidation respectively from the corresponding aldehydes obtained by the action of heat, in the presence of a polymerization inhibitor and a solvent, on one or more a  : b -unsaturated aldehydes, e.g. acrolein, methacrolein or a -ethylacrolein.  In examples, the cyclic dimer of methacroelin or the cyclic co-dimer of acrolein and methacrolein is subjected to the Canizzaro reaction with sodium hydroxide solution, the 2-methanol compound is extracted from the reaction mixture by means of ether and the residue is acidified with hydrochloric acid to liberate the carboxylic acid.  Reduction with catalytically-activated hydrogen or with an alcohol and an aluminium alcoholate is also referred to.