Evaporation Drying

A solution of 0.46 g of the diazoketone in 100 ml of chloroform is shaken with 22 ml of 48 % hydriodic acid for 1.5 min. After the addition of 400 ml of chloroform, the organic layer is washed successively with a saturated solution of potassium iodide, with a solution of sodium thiosulfate and with water. After drying, evaporation of the solvent yields 0.44 g of a product which is chromatographed over 10 g of alumina (diam. of column 1.0 cm). Elution with benzene (400 ml) and benzene-ether (9 1) (200 ml) gives 0.32 g of 3jS,5) ,19-trihydroxypregnan-20-one 3,19-diacetate (yield 76%) mp 96-99°. 

The mixture was then allowed to warm to room temperature in a nitrogen atmosphere during which process the ammonia evaporated. The reaction mixture was then acidified with 1 N aqueous hydrochloric acid, and the organic constituents extracted with ethyl acetate. The ethyl acetateextracts were combined, washed with water and dried. Evaporation of the ethyl acetate under reduced pressure yielded 1.4 g of crude dl-trans-3-(r,r-dimethylheptyl)-6,6a, 7,8,10,10a -hexahydro-1 -hydroxy-6,6-dimethyl-9H-dibenzo(b/J] pyran-9-one. The... 

In a dry evaporator the inlet expansion of refrigerant is controlled at a rate to have essentially no liquid in the unit. 

A stirred solution of the benzothiazepinone 2 (6.0 g, 33.9 mmol) in CH2C12 (200 mL) was treated with trimethyloxonium tetrafluoroborate (5.4 g, 36.5 mmol) and the mixture was stirred for 22 h. An excess of coned aq K2C03 was added, the mixture was filtered and the organic layer was separated and dried. Evaporation, followed by chromatography (silica gel, CH2C12) gave 6 as a yellow oil yield 5.8 g (89%). 

Tris(/m-butylsulfanyl)cyclopropeny]ium perchlorate (17 0.403 g, 1 mmol) in DMF (lOmL) was added dropwisc to a solution of benzene-1.2-diamine (0.216 g. 2 mmol) in DMF (20 mL). The mixture was stirred for 2 h and then poured into H20 (200 mL) containing NaCl. Extraction with Et20/hexane (1 1), followed by drying, evaporation in vacuo, chromatography (silica gel, Et20/hexane 1 2) and reerystallization (MeOH) gave the product yield 0.200 g (63%) pale-yellow crystals mp 136 C. 

The irradiation of 4-azido-3-methoxypyridazine (I, R = H 0.5 g, 6.6 mmol) was carried out as described above, except that only 1 cquiv of NaOMe was used. After the mixture had been evaporated the residue was dissolved in ice-cold pyridine (3 4 mL), AcCl (0.4 g, 5.1 mmol) was added, the solution was stirred at 20 C for 5-6 h then poured into ice-water (20 mL). The mixture was extracted with CH2C12 and the extract was washed successively with sat. aq NaHCOj and H20 and dried. Evaporation, followed by chromatography of the residue (alumina, 9% Et20,/CH2CI2) gave the product yield 0.34 g (26%) pale-yellow plates (hexane) mp 112-113LC. 

The sulfoxide in dry THF is added slowly to 1.2-1.5 equiv of LDA in THF at —I0°C and an intense orange-yellow color develops. After 20 min, benzaldehyde is added slowly until the color disappears. The mixture is allowed to warm 10 r.t. over 30 min. then 0.5 M sulfuric acid is added and the mixture extracted twice with EuO. The combined extracts arc washed with water and aq NaCl, then dried, evaporated and purified by chromatography (EtOAC/benzene 5 1). 

Olivetol 4.74 g (or equimolar amount of analog), 4.03 g (+) cis or trans p-methadien (2,8)-ol-l (the racemic compound can be used but yield will be one-half), 0.8 g p-toluenesulfonic acid in 250 ml benzene reflux two hours (or use 0.004 Moles trifluoracetic acid and reflux five hours). Cool, add ether, wash with NaHC03 and dry, evaporate in vacuum/to get about 9 g of mixture (can chromatograph on 3 50 g silica gel-benzene elutes the THC benzene ether 98 2 elutes an inactive product then benzene ether 1 1 elutes unreacted olivetol evaporate in vacuum to recover olivetol). 

Hydrolysis of benzopyrones (for synthesis see elsewhere here) will produce compounds of type (III) which will work in this synthesis. The hydrolysis proceeds as follows (JCS 926(1927)) Add lOg of the benzopyrone to 20g 30% NaOH, cool and shake 1 hour with 19 ml methylsulfate. Extract the oil with ether and dry, evaporate in... 

I). 4.5g(I), 150 ml benzene add dropwise to a solution prepared from 7.8 g Mg, 18 ml methyl iodide, and 90 ml ether. Reflux 20 hours and add 45 ml saturated NH4CI. Separate the organic layer and extract the aqueous phase with benzene. Combine the organic layer and benzene and dry, evaporate in vacuum to get the THC analog. 

Alternatively, to 150 ml ethylene diamine add portionwise with stirring at 110° C under Argon or N2, 5.3 g Li metal after one hour add dropwise 110 g (+) A3 carene. After one hour cool to 4° C and add water. Extract with ether, wash the ether five times with water and dry, evaporate in vacuum to get 100 g of a mix containing about 40% (+) A4 carene (can separate by fractional distillation). 

To 136 g A4 carene in 330 ml methylene chloride and 120 g anhydrous sodium acetate, add dropwise with vigorous stirring ir an ice bath, 167 g of 50% peracetic acid and continue stirring for ten hours. Heat to boiling for two hours, cool, wash with water, sodium carbonate, water, and dry, evaporate in vacuum the methylene chloride to get about 100 g p-menthadieneol. Apparently (CA... 

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. 

Dissolve 100 g malonic acid in 360 g dry pyridine and heat 48-52° C for forty hours with 100 g n-hexaldehyde (n-capronaldehyde) or homolog. Cool in ice bath and with good stirring add dropwise 150 ml ice cold concentrated sulfuric acid (keep temperature below 5° C). After addition add water to dissolve the precipitate and extract with ether two times. Dry, evaporate in vacuum the ether and distill (70/0.7 or 102/5) to get about 98 g 2-octenoic acid (I). 95 g (1) in 300 ml ether cool to -5° C and slowly add a solution of an excess of diazomethane in ether dried over KOH and let react for about one hour. Let stand twelve hours, evaporate in vacuum and distill (91/17) to get about 94 g clear methyl-2-octenoate (II). 

Add with stirring 22.5 g S0C12 in 100 ml ether in 20 ml portions to a solution of 15 g 3,5-dimethoxybenzyl alcohol, 1 ml pyridine and 200 ml ether. Let stand and wash with 2X100 ml cold water separate and dry, evaporate in vacuum the ether to get 16 g 3,5-dimethoxybenzyl chloride (I). Recrystallize from petroleum ether. 16 g (I), 300 ml ethanol, 30 g NaCN, 75 ml water reflux three hours and pour onto 400 g ice. After ice melts, filter and recrystallize precipitate from petroleum ether to get about 14 g 3,5-dimethoxybenzyl CN (II). 5 g 50% NaH in mineral oil wash three times with pentane or hexane fill flask with N2 or argon and add dimethoxyethane or dimethylformamide (freshly distilled from K if possible). Stir and add 9 ml methyl iodide. Carefully add 8 g (II) and stir twelve hours. Add ice water and neutralize with NaHC03 to pH 7-8. Extract with ether and dry, evaporate in vacuum the ether (can distill 170/0.1) to get about 9 g alpha, alpha-dimethyl-3,5-... 

Reflux 6.9 g triphenylphosphine and 6.6 g lauryl bromide (or equimolar amount of homolog) in 40 ml xylene for 60 hours. Remove solvent and wash residue with 5X20 ml ether (by decanting) to get 11 g lauryl triphenylphosphonium bromide (I). To a stirred suspension of 5.6 g (0.011M)(I) in 50 ml ether add 0.01M butyllithium solution (see Organic Reactions 8,258(1954) for preparation). Stir Vz hour at room temperature and slowly add 1.66 g 3,5-dimethoxybenzaldehyde (preparation given elsewhere here) in 10 ml ether over Vi hour. After 15 hours, filter, wash filtrate with water and dry, evaporate in vacuum. Dilute residue with pentane, filter and remove solvent. Dissolve the residual oil in 25 ml ethyl acetate and hydrogenate over O.lg Adams catalyst at one atmosphere and room temperature for 2 hours. Filter and evaporate in vacuum to get the 5-alkylresorcinol dimethyl ether which can be reciystallized from pentane and demethylated as described elsewhere here. 

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. -... 

---