Benzene 2.5- dimethoxy-1 - -, preparation

A solution of 50 grams of N-(a-methylhomoveratryl)-3-methoxy-4-ethoxyphenylacetamide, prepared as set out above, in 200 cc of benzene, is treated with 8 cc of phosphorus oxychloride. The mixture is refluxed for about 3 hours, cooled and then is shaken with a solution composed of 15 grams of sodium hydroxide dissolved in 60 cc of water. The aqueous layer is removed, and the benzene solution is washed with water. The washed benzene solution is dried over anhydrous magnesium sulfate, filtered and evaporated to dryness. The low-melting solid residue is 6,7-dimethoxy-3-methyl-1-(3 -methoxy-4 -ethoxybenzyl)-dihydroisoquinoline base. 

The (R)-(+)-chiral 1,4-diol 17b was easily prepared from L-(+)-dimethyl tartrate. Dimethyl tartrate was converted to the corresponding phenylethylidene derivative by treatment with 1,1-dimethoxy-l-phenylethane and cat. p-toluenesulfonic acid in refluxing benzene, followed by conversion to the diol 17b with excess phenylmagnesium bromide. The diol was purified by column chromatography on silica gel (hexane ethyl acetate =5 1), and recrystalization from a mixture of hexane and 2-propanol. 

The first synthesis of a derivative of 2,8-phenanthroline was reported by Merz, Weidlich, and Fink13 in 1964. They prepared 5,6-dimethoxy-2,8-phenanthroline (34) (isolated as the dipicrate) in very low yield by conducting a double Pomeranz-Fritsch isoquinoline synthesis on 4,5-dimethoxyisophthalaldehyde. The parent compound was prepared 2 years later12 in 25-35% yield, along with 1,9-phenanthroline (4%), by the photocyclization of trans-1 (3-pyridyl)-2-(4-pyridyl)ethylene in benzene. This reaction was used by Hiinig and his colleagues15 to prepare an N,N -dimethyl diquaternary salt of 2,8-phenanthroline by methylating the crude product from the irradiation reaction. 

Various 3-methylcoumarilic acids substituted in the benzene ring by alkyl or methoxyl groups have been thus prepared, then decarboxylated to the corresponding benzofurans,10 208 e.g., 3-methyl-4,7-dimethoxy-benzofuran 2-naphthol233 leads to 3-methylnaphtho[2,l-6]furan (79), guaiacol to ethyl 7-methoxy-3-methyl coumarilate.234... 

Protection of aldehydes and ketones.1 Bis-o-nitrobenzyl acetals or ketals are removable in 85-95% yield on irradiation at 350 nm in benzene. The acetals or ketals are easily prepared from 1 by an exchange reaction using 2,2-dimethoxy-propane (1, 268-269) catalyzed by an arenesulfonic acid. In the case of hindered ketones (17-keto steroids), the glycol o-N02C6H4CH(OH)CH2OH (2) can be used. 

SYNTHESIS In 50 mL of benzene there was dissolved 31.6 g 2,5-dimethoxy-4-methylbenzaldehyde (see recipe for 2C-D for its preparation), 20.2 mL 1-nitropropane, and 6 mL cyclohexylamine. This solution was held at reflux in a Dean Stark apparatus for 24 h, effectively removing the water of reaction. Upon cooling, there was deposited 19.6 g of 1 -(2,5-dimethoxy-4-methylphenyl)-2-nitro-1 -butene as brilliant orange crystals. The mp, after recrystallization from MeOH, was 114-115 °C and a second recrystallization increased the mp another 2 °C. Anal. 

When 1,3-dimethoxybenzene is heated in benzene with la-acetyl-l-phthalamido-la,6b-dihydro-benzofuro[2,3-fo]az.irine as a source of phthalimidonitrene, 2,4-dimethoxy-7-phthalimido-3//-azepine is isolated in modest yield <95JCS(PI )809>. If the reaction is carried out over a shorter time period (5h instead of 18h), it is the 2//-azepine which is isolated in 18% yield. A number of other analogues have been prepared and the X-ray structure of 5,7-dimethoxy-3-methyl-2-phthalimido-27/-azepine has been determined. 

Zinc enolates can be prepared in solvents of greatly different polarity, including THF, DME, Et20, 1,4-dioxane, benzene, toluene, dimethoxy-methane, DMF, B(OMe)3, DMSO, and mixtures thereof, just to mention the most frequently used ones.1-3 Reformatsky reactions in the absence of a solvent have also been described.7 The reagent is dimeric in the crystal state and in solution except for the most polar media.5,8... 

Dimethoxy-2-(3-nitro-1,2,4-triazol-1 -yl)benzene and 1,1,4-trimethoxy-4-(3-nitro-l,2,4-triazol-l-yl)cyclohexane-2,5-diene have been prepared by indirect electrochemical method [598],... 

The following alkoxypyrazines have been prepared from the corresponding dichloropyrazines and alkoxide ions 2,3-dimethoxy-5,6-dimethyl(and diphenyl) (797) 2,3-dibenzyloxy (sodium benzyl oxide in benzyl alcohol at reflux for 24 hours (883)] [but 23-dichloropyrazine with sodium hydride and benzyl alcohol in xylene gave l,4-dibenzyl-2,3-dioxo-l,2,3,4-tetrahydropyrazine)(988)] 2-chloro-5-methoxy (838) 2,5-diethoxy-3,6-dimethyl (872) 2methanolic sodium methoxide refluxed for 2 h) 2,5-dimethoxy-3-phenyl (817) 2-chloro-5-methoxy(and ethoxy)-3,6-diphenyl (817) 2,5-dimethoxy-3,6-dimethyl (and diisopropyl) (844) 2,5-dimethoxy-3-isopropyl-6-methyl (methanolic potassium methoxide at reflux for 6 days) (844) 2(5)-s-butyl-3-chloro-6-ethoxy-5(2)-isobutyl (93) 2-chloro-6-methoxy (838, 883) 2,6-dimethoxy (reflux for 8h) (832) 2,6-diethoxy (reflux for 14 h) (883) 2-benzyloxy-6-chloro (1 equiv. of sodium hydride and benzyl alcohol in benzene at reflux) (832) 2,6-dibenzyloxy (5 equiv. of sodium benzyloxide in benzene at reflux gave 70%) (832) and 3,5-dimethoxy-2-methyl (535). 

Preparation of l-Hydroxy-2,6-dimethoxy-4-(tertiary alkyl)benzene... 

Perhydropyrido[l,2-c][l,3]oxazin-l-ones were prepared in the reaction of the appropriate 2-(2-piperidyl)ethanols and ethyl chloroformate (63AP38) in the presence of sodium ethylate in boiling benzene, or when 2-(2-piperidyl)ethanol was reacted with dimethyl carbonate in the presence of sodium methylate (91X1311). l-Hydroxymethyl-9,10-dimethoxy-l,2,4,6,7,llb-hexahydro-[l,3]oxazino[4,3-fl]isoquinoline-4-oneand 4-thione were prepared from l-[bis(hydroxymethyl)methyl]-6,7-dimethoxy-l,2,3,4-tetrahydroisoquinoline with ethyl chloroformate in the presence of sodium methylate, and thiophosgene in the presence of NEts, respectively... 

Further examples of synthetic application of the para-alkoxylation reaction include the preparation of dimethoxy ketal 231, which is an essential precursor in the enantioselective synthesis of the potent antifungal agent (-)-jesterone [297], the synthesis of various dimethoxy ketals of para- and ort/to-benzoquinones [298] and the methoxylation of various phenolic substrates, such as 232, using (diacetoxyiodo)benzene in methanol (Scheme 3.95) [299-301]. 

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