Olivetol dimethyl ether

Reduce 3,5-dimethoxybenzoic acid with lithium aluminum hydride to 3,5-dimethoxybenzyl alcohol (I), to 10.5 g (I) in 100 ml methylene chloride at 0° C add 15 g PBr3 warm to room temperature and stir for one hour. Add a little ice water and then more methylene chloride. Separate and then dry, evaporate in vacuum the methylene chloride. Add petroleum ether to precipitate about 11.5 g of the benzyl bromide (II). To 9.25 g (II), 15 g Cul, 800 ml ether at 0° C, add butyl (or other alkyl)-Li (16% in hexane), and stir for four hours at 0° C. Add saturated NH4C1 and extract with ether. Dry and evaporate in vacuum the ether (can distill 100/0.001) to get about 4.5 g olivetol dimethyl ether (HI) or analog. Distill water from a mixture of 90 ml pyridine, 100 ml concentrated HC1 until temperature is 210° C. Cool to 140 0 C and add 4.4 g (III) reflux two hours under N2. Cool and pour into water. Extract with ether and wash with NaHC03. Make pH 7 and dry, evaporate in vacuum to get 3.8 g olivetol which can be chromatographed on 200 g silica gel (elute with CHC13) or distill (130/0.001) to purify. 

To a stirred solution of 45g 3,5-dimethoxybenzoyl chloride and 17.4g thiophen in 300 ml benzene at 0° C, add dropwise 10.5g freshly distilled stannic chloride. Stir one hour at room temperature and add 200 ml 3% aqueous HC1. Separate the benzene layer and wash the aqueous layer with benzene. Dry and evaporate in vacuum the combined benzene layers and distill the red residue (250° C bath/4.5) to get 45g 2-(3,5-dimethoxybenzoyl) thiophen(I). Recrystallize from petroleum ether. Add a solution of 21 g AICI3 in 160 ml ether to a stirred suspension of 6.1 g lithium aluminum hydride in 140 ml ether. After 5 minutes add a solution of 39g(I) in 300 ml ether at a rate giving a gentle reflux. Reflux and stir 1 hour cool in an ice bath and treat dropwise with 50 ml water, then 50 ml 6N aqueous sulfuric acid. Separate the layers, extract the aqueous layer with 3X100 ml ether and dry, evaporate in vacuum the combined ether layers. Can distill the residue (230° C bath/5mm) to get 27g oily 2-(3,5-dimethoxybenzyl) thiophen (II). Recrystallize from petroleum ether. Reflux a solution of 5g (II) in 700 ml ethanol with W-7 Raney Nickel prepared from Ni-Al alloy (see Org. Synthesis Coll. Vol 111,176(1955)) for 6 hours. Filter, evaporate in vacuum and can distill (140/0.01) to get about 2.2g oily olivetol dimethyl ether which can be reduced to olivetol as described elsewhere here. -... 

Olivetol. (5-Alkyl Resourcinol) BER 69, 1644 (1936). Mix 25 g of ethyl-3,4,5-trimethoxy benzoyl acetate and 2.0 g of clean sodium in 100 ml ethanol and warm to react. Add 2 g n-propyl iodide (this may be replaced with n-amyl iodide) and heat on a steam bath for 12 hours, then neutralize and remove the ethanol by distillation. Extract the residue with ether, dry, and evaporate in vacuo to get 30 g of the alkyl acetate. Heat 22 g of this acetate in 5% KOH ethanolic solution for 1 hour at 50° and let stand to precipitate 14 g of 3,4,5-trimethoxyvalerophenone. Mix 11 g of the above product with 60 g of sodium in 600 ml ethanol. Warm and after dissolving the sodium add 2 liters of water. M e acidic with HCl acid and remove the ethanol by distillation. Extract with ether, dry, and evaporate the ether in vacuo to get if. g olivetol dimethyl ether. To demethylate this ether add it to 70 ml of hydrogen iodide and heat to boiling and reflux for two hours. Distill and keep the fraction at 160°-170° with 3-4 mm of vacuum applied to the distillation set-up. Yield about 6 g. 

Olivetol. 3,5-Dimethoxybenzyl alcohol. (This can be made by reducing 3,5-dimethoxybenzoic acid, or it can be purchased.) (10 g) in 100 ml of methylene chloride is cooled to 0° and 15 g of PBrs is added. Warm to room temp and stir for 1 hour, then add a little ice water followed by more methylene chloride. Add petroleum ether to precipitate the benzyl bromide, which is separated off. 9.3 g of the benzyl bromide is put in a flask with 800 ml of dry ether and then add 15 g of copper iodine at 0°. Add butyl lithium (16% in hexane) and stir for four hours at 0°. Add saturated NH4CI and extract with ether. The ether is removed by evaporating in vacuo to give the olivetol dimethyl ether which must be demethylated by one of the methods given in the above formulas. Yield A little over 4 g. Taken from HCA, 52, 1132. 

The above methyloctane is demethylated as follows. Mix 40 g of the above product with 100 ml of 48% hydrogen bromide and 320 ml of glacial acetic acid. Heat under reflux for 4 hours, and pour onto ice. Add portions of 10 N sodium hydroxide to the mixture until you get a pH of 4 to 5, then extract with ether. The ether extracts are combined, and extracted with three 150 ml portions of 2 N NaOH. These extracts are combined and acidified with acetic acid, which is then extracted with ether. Dry the combined ether extracts with MgSC 4 and evaporate under reduced pressure (vacuum) to remove the ether. Distill the residue, collecting the fraction boiling at 158-160° at 0.1 mm vacuo to get 20 g of dimetbyl-heptyl resorcinol. Tins demetbylation may be used on olivetol dimethyl ether to demethylate. 

Aiylation with a homocuprate. A key step in a synthesis of the cannabis constituent 4 is the reaction of 1 with the homocuprate derived from olivetol dimethyl ether (2) hy regiospecific lithiation followed by reaction with CuBr. The cuprate does not react with 1 in the absence of a Lewis acid, but in the presence of BF, etherate (3.5 equiv.) ( —)-3 is obtained in 78% yield with high regio- and stereospecificity. The dihydrobromide of... 

II), 600 ml ethanol, 60 g Na warm and after Na is dissolved, add 2 L water. Acidify with HCl, distill df the ethanol and extract with ether. Dry, evaporate in vacuum the ether to get 7.8 g olivetol dimethyl ether (or analog) (HI). 7.2 g (HI), 70 ml hydrogen iodide boil two hours and distill (164/760) to get olivetol. 

Olivetol dimethyl ether, 185 Oppenauer oxidation, 69, 107 Ornithine, 79... 

Oxidative decarboxyiation of dihydroaromatic acids. Some years ago Birch mentioned that 1-substituted 1,4-dihydrobenzoic acids are decarboxylated to arenes by LTA. The starting materials are readily available by a one-step Birch reduction (Li-NHo) and alkylation from benzoic acids. Birch and Slobbe have now extended the early work and shown that this process is useful synthetically. One example is the synthesis of olivetol dimethyl ether (equation I), liquation II formulates the synthesis of a useful intermediate to dihydrojasmone. 

Birch AJ, Slobbe J (1976) Oxidative decarboxylation of dihydroaromatic acids with lead tetraacetate a synthesis of olivetol dimethyl ether and of rosefuran. Tetrahedron Let 2079-2082... 

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