Reaktion #344382
ord-43ae62c510ee4581989c7f7c45849097
Reagenzien
Lösungsmittel
Reaktionsbedingungen
Vorschrift
The thieno[2,3-b]pyran compounds of this invention are prepared according to Scheme 2. As can be seen from the reaction sequence, 2-methoxythiophene (11) prepared from 2-bromothiophene [Arkiv. Kemi., 1958, 12, 239] is treated with bromine in an inert solvent such as methylene chloride, chloroform or THF at 0° to about 25° C. for about 1-24 h to give the 2,5-disubstituted thiophene (12). Compound 12 is then treated with a 3,3-disubstituted acryloyl chloride and a Lewis acid catalyst such as tin ##STR9## (IV) chloride, ferric chloride, zinc chloride or the like in an inert solvent such as methylene chloride, chloroform or THF at about 0° to 25° C. for about 1-24 h to give the unsaturated ketone derivative (13). The bromine is cleaved by the action of agents such as trialkyltin hydrides [Synthesis, 1970, 10, 499] either neat or in an inert solvent such as ether, benzene or bromobenzene to give 14. The methoxy group is cleaved by the action of agents such as boron trifluoride, boron tribromide, boron trichloride, pyridinium hydrochloride or trimethylsilyl iodide in an inert solvent such as methylene chloride or chloroform at about -20° to 20° C. to give the 2-hydroxy-3-substituted thiophene which is not isolated, generally, but is treated with protic acids such as p-toluenesulfonic acid in an inert solvent such as benzene, toluene or the like at about 0° to 200° C. to give the 3,3-disubstituted thieno[2,3-b]pyran-5-one (15). Using reaction conditions essentially as described in Scheme 1, reduction of the ketone (15) by reducing agents forms alcohol 16. Dehydration of 16 gives the olefin 17. Alternatively, the ketone 15 may be reduced and the crude, unisolated alcohol 16 may be directly converted to 17 under similar conditions. Conversion of 17 to bromohydrin 18 is accomplished by the action of N-bromosuccinimide and water in polar solvents. The bromohydrin is generally used without isolation and treated with bases to form the unstable epoxide 19. Anions of amine or amide derivatives are prepared in situ by treating various amines such as pyrrolidine or piperidine or amides such as pyrrolidinone, piperidinone, caprolactam, benzamide and substituted benzamides such as p-nitrobenzamide with sodium hydride. Epoxide 19 is treated with the thus-formed amine or amide anions to form 20 (R1R2 =H). Reaction of 20 with electrophiles such as bromine or nitric acid or the like gives the substituted compound (20) wherein R1R2 =bromine or nitro, for example. When the electrophile is an acylating agent such as acetyl chloride or acetic anhydride and the reaction is carried out in the presence of a Lewis acid or protic acid catalyst at about -20° to 20° C. for 1 hour to 6 days, the product is the acyloxy derivative 21 (R1R2 =H). Further reaction under similar conditions produces the acyl acetate 21 (R1 or R2 =acyl, for example, acetyl). Reaction of 21 with methanolic sodium hydroxide or sodium carbonate at about 0°-25° C. for 1-24 hours yields the acyl compound (20) (R1 or R2 =acyl, for example, acetyl).