Ethers, dimethoxybenzyl synthesis

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. -... 

Methyl 4-0-(4-methoxybenzyl)2,3-di-0-methyl-oc-D-glucopyranoside has been prepared [371] by Liptak s procedure (see Sect. 2.6). This lithium aluminium hydride — aluminium trichloride method was also used in the synthesis of 4-hydroxy-3-methoxy-benzyl [372], 4-hydroxy-3,5-dimethoxybenzyl [372], and 1-phenylethyl [373] ethers from the 4,6-acetals derived from vanillin, syringealdehyde, and acetophenone. Various vinylbenzyl ethers were prepared by the reaction of carbohydrates with vinylbenzyl chloride, and copolymerized with styrene [374]. 

The synthesis of bufotenine itself followed closely upon the proof of its structure. Hoshino and Shimodaira reduced the ethyl ester of 5-ethoxy-indole-3-acetic acid by the Bouveault-Blanc procedure to the corresponding primary alcohol, which was treated with phosphorus tribromide and then dimethylamine, to give the ethyl ether of bufotenine, which was demethylated with aluminum chloride (130). In a later synthesis, 2,5-dimethoxybenzyl cyanide (XXIII) was alkylated by Eisleb s method with dimethylaminoethyl chloride in the presence of sodamide to give l-(2,5-dimethoxyphenyl)-3-dimethylaminopropyl cyanide (XXIV), which was then hydrogenated over Haney nickel to yield 2-(2,5-di-methoxyphenyl)-4-dimethylaminobutylamine (XXV R = Me). De-methylation of this with hydrobromic acid, followed by oxidation of the product (XXV R = H) with potassium ferricyanide yielded bufotenine (XIX) via the related quinone (109). 

A synthesis of the protein phosphatase inhibitor Tautomycin by the Oikawa group155 employed the superior hydrolytic lability of the 3.4-dimethoxybenzyli-dene acetal group in a synthesis of the maleate side chain [Scheme 3.84]. Thus treatment of the 3,4-dimethoxybenzyl ether 84.1 with DDQ effected oxidative... 

There is sufficient latitude in the rates for selective removal of a 3,4-dimethoxy-benzyl ether in the presence of an adjacent p-methoxybenzyl ether as illustrated in Scheme 4T74, taken from Smith s synthesis of Zampanolide,247 324 For other examples of the beneficial lability of 3,4-dimethoxybenzyl ethers, see Smith s synthesis of Phorboxazole131 and Nicolaou s synthesis of Apoptoli-dine.325... 

With 3,5-dimethoxybenzoyl chloride used in the monoacylation of cyclohexanone to produce finally the same (MeO ArC synthon, an alternative synthesis of cardol 8(Z)-monene was developed [138]. Fig( 4)-49, Persoonol dimethyl ether (5-[(Z)-undec-3-enyl]resorcinol dimethyl ether) was synthesised from 3,5-dimethoxybenzyl alcohol [149], This same reactant has been employed for a range of 5-substituted resorcinols although its application to unsaturated phenolic lipids was not discussed [228]. Acetylenic methods have proved valuable for deriving phenolic lipidic double bonds in the Z-configurations and with advances in boration methodology [229] the corresponding E-isomers are accessible. 

The chemistry of brazilin (21) and hematoxylin (22) has been reviewed by Robinson (62, 63) and Donnelly (20). In the first successful approach to a synthesis of brazilin the trimethyl ether (79) of an-hydrobrazilin (deoxybrazilone) (78) was prepared by treating 7-methoxy-3(3,4-dimethoxybenzyl)chroman-4-one (77) with phosphoric anhydride (16). The hydroxyl group at C-6a was introduced by a series of transformations (63). Later Kirkiacharian (41) found that hydration of the double bond can be achieved more directly by sequential treatment with diborane and alkaline hydrogen peroxide. The brazilin and hematoxylin derivatives obtained in this fashion were identical with products of earlier experiments. The course of the hydroboration reaction established the cis-fusion of rings B and C. 

The synthesis of papaveraldine (CXVI), which can be transformed into papaverine by reduction has also been studied. Its 3,4-dihydro derivative (CXVIII) [(mp 190°-191°) B-HCl (mp 183°)] has been prepared in one step by condensation of homoveratrylamine with the isonitroso derivative of acetoveratrone (CXVII) under the action of 85 % phosphoric acid (184). Papaveraldine itself (CXVI) can be obtained, although in low jdeld (8%), by condensing the ketone (CXIX) with aminoethyldiethylacetal (CXXX) to the A-(a-veratrylveratrylidene)-aminoacetal (CXXI). This is cyclized without further purification to papaveraldine (CXVI) by the action of 72 % sulfuric acid (185). A better yield was obtained by Popp and McEwen (186), who condensed the lithium salt of the known Reissert compound CXXII at — 20° in ether-dioxane solution with 1 mole of veratraldehyde. On alkaline hydrolysis the condensation product yielded papaverinol (CXXIII) in 67 % yield. When an excess of veratraldehyde is used it acts as an oxidant and 67 % of papaveraldine (CXVI) is produced. The Reissert compound (CXXII) can also be condensed with 3,4-dimethoxybenzyl chloride and the product formed affords papaverine (CIII) in 22% yield on alkaline hydrolysis. 

The imidate can be prepared from the sodium alkoxide ion of benzyl alcohol and trichloroacetonitrile according to procedures based on those developed by Cramer in the late 1950s. Substituted benzyl ethers have also been prepared this way, for example using 4-methoxybenzyl trichloroacetimidate, 3,4-dimethoxybenzyl trichloroacetimidate, and 2,6-dichlorobenzyl trichloroacetimidate, and the method has also been applied for the synthesis of allyl and r-butyl ethers, as well as for 2-phenylisopropyl esters for peptide synthesis. The benzyl and 4-methoxybenzyl 2,2,2-trichloroacetimidates are available commercially. 

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