Patent GB-543363-A (GB)
Title: Manufacture of tetrahydro-dibenzopyran derivatives
IPC: C07D311/80
Filed: 1940-08-13
Abstract: 543,363. Dibenzopyran -derivatives. ROCHE PRODUCTS, Ltd., TODD, A. R., WILKINSON, S., and GHOSH, R. Aug. 13, 1940, Nos. 12965 and 14026. [Class 2 (iii)] 2 : 2 - Dialkyl - 31 : 4<SP>1</SP> : 5<SP>1</SP> : 6<SP>1</SP> - tetrahydrodibenzopyrans which may be substituted in the benzene ring bv hydroxy and alkyl groups, and may also be substituted in the cyclohexene ring by one or more alkyl groups are prepared by re-acting 3 4-cyclohexeno-coumarins with excess of Grignard re-agents. The compounds so produced may then be de-hydrogenated preferably by palladized charcoal to the corresponding dibenzopyran compound. Other dehydrogenating agents which may be used include sulphur and selenium. An alternative procedure is to de-hydrogenate the parent 3 : 4-cyclohexeno-coumarin to 3 : 4-benzocoumarin before applying the Grignard reagent. Hydroxy coumarins are usually employed in the form of their acetates. In examples (1) 6-Hydroxy-3 : 4-cyclohexenocoumarin prepared by the condensation of hydroquinone with ethyl cyclohexanone-2- carboxylate in the presence of concentrated sulpnuric acid is acetylated and re-acted with magnesium methyl iodide in anisole solution to give 5<SP>11</SP>-hydroxy-2 : 2-dimethyl-3<SP>1</SP> : 4<SP>1</SP> : 5<SP>1</SP> : 6<SP>1</SP>- tetrahydrodibenzopyran. (2) 5-Hydroxy-5<SP>1</SP>- methyl - 7 - n - amyl - 3 : 4 - cyclohexenocoumarin prepared by condensing olivetol monohydrate with ethyl methylcyclohexan-3- one-4-carboxylate in the presence of strong sulphuric acid is acetylated and then re-acted with magnesium methyl iodide in anisole solution to give 6<SP>11</SP>-bydroxy-2 : 2 : 51-trimethyl- 4<SP>11</SP>-n-amyl-3<SP>1</SP> : 4<SP>1</SP> : 5<SP>1</SP> : 6<SP>1</SP>-tetrahydrodibenzopyran. The corresponding 6<SP>11</SP>-hydroxy-2:2:5<SP>1</SP>- trimetbyl-4<SP>11</SP>-n-amyl-dibenzopyran(Cannabinol) may be prepared either by de-hydrogenation of the tetrahydro compound by palladized charcoal, or it may be formed by tne alternative process of first de-hydrogenating 5-acetoxy-5<SP>1</SP>- methyl-7-n-amyl-3 4-cyclohexenocoumarin with palladized charcoal followed by the Grignard re-action. (3) 5-Hydroxy-5<SP>1</SP>-methyl- 7-ethyl-3 : 4-cyclohexenocoumarin, prepared by condensation of ethyl resorcinol with ethyl methylcyclohexan-3-one-4-carboxylate in the presence of strong sulphuric acid, is acetylated and submitted to a Grignard re-action to give 6<SP>11</SP> - hydroxy - 2 : 2 : 51 - trimethyl - 4<SP>11</SP> - ethyl - 3<SP>1</SP> : 4<SP>1</SP> : 51 : 6<SP>1</SP> - tetrahydrodibenzopyran. (4) 5 - Hydroxy - 5<SP>1</SP> - methyl - 7 - isohexyl - 3 : 4 - cyclohexenocoumarin, prepared by. the sulphuric acid condensation of isohexyl-resorcinol and ethyl-methylcyclohexan-3-one-4-carboxylate, is treated as in the previous examples to give 6<SP>11</SP> - nydroxy - 2 : 2 : 5<SP>1</SP> - trimethyl - 4<SP>11</SP> - isohexyl - 3<SP>1</SP> : 4<SP>1</SP> : 5<SP>1</SP> : 6<SP>1</SP> - tetrahydrodibenzopyran. (5) 5 - Hydroxy - 5<SP>1</SP> - methyl - 7 - n - heptyl - 3 : 4 cyclohexenocoumarin prepared as in example (4) using heptyl resorcinol is treated as above to give 6<SP>11</SP>-hydroxy-2 : 2 : 51- trimethyl - 4<SP>11</SP> - n - heptyl - 3<SP>1</SP> : 4<SP>1</SP> : 5<SP>1</SP> : 6<SP>1</SP>-tetrahydrodibenzopyran. (6) 5-Hydroxy-5<SP>1</SP>:7-dimethyl - 3 : 4-cyclohexenocoumarin is treated with butyl magnesium bromide in benzene solution to give 6<SP>11</SP>-hydroxy-5<SP>1</SP> - 4<SP>11</SP>-dimethyl- 2 : 2 - dibutyl - 3<SP>1</SP> : 41 : 5<SP>1</SP> : 6<SP>1</SP> - tetrahydrodibenzopyran. (7) 5 - Acetoxy - 7 - methyl 3 : 4 - cyclohexenocoumarin is treated with a Grignard re-agent to give 6<SP>11</SP>-hydroxy-2 : 2 : 4<SP>11</SP>-trimethyl- 3<SP>1</SP> : 4<SP>1</SP> : 5<SP>1</SP> : 6<SP>1</SP>-tetrahydrodibenzopyran. (8) 7- Hydroxy-3 : 4-benzocoumarin is acetylated and treated with a Grignard re-agent to give 4<SP>11</SP>- hydroxy-2 : 2-dimethyldibenzopyran. The parent 7-hydroxy-3 : 4-benzocoumarin may be prepared from 7-hydroxy-3 : 4-cyclohexenocoumarin in one of the three ways, (a) by heating at 300‹-320‹ C. with selenium for 36 hours, (b) by heating the acetylated starting material with palladized charcoal, (c) by esterification with dimethyl sulphate to give 2<SP>1</SP> : 4' - dimethoxyphenyl - #<SP>1</SP> - cyclohexene - 21-carboxylic acid.