Anisole synthesis

Clegg W, Dale SH, Drummond AM et al (2006) Afkali-metal-mediated zincation of anisole synthesis and structures of three instructive ortho-zincated complexes. J Am Chem Soc 128 7434-7435. doi 10.1021/ja061898g... 

Wnte equations showing how you could prepare each of the following from anisole and any necessary organic or inorganic reagents If an ortho para mixture is formed in any step of your synthesis assume that you can separate the two isomers... 

Picolyl ethers are prepared from their chlorides by a Williamson ether synthesis (68-83% yield). Some selectivity for primary versus secondary alcohols can be achieved (ratios = 4.3-4.6 1). They are cleaved electrolytically ( — 1.4 V, 0.5 M HBF4, MeOH, 70% yield). Since picolyl chlorides are unstable as the free base, they must be generated from the hydrochloride prior to use. These derivatives are relatively stable to acid (CF3CO2H, HF/anisole). Cleavage can also be effected by hydrogenolysis in acetic acid. ... 

During the synthesis of peptides that contain 4-methoxybenzyl-protected cysteine residues, sulfoxide formation may occur. These sulfoxides, when treated with HF/ anisole, form thiophenyl ethers that cannot be deprotected therefore, the peptides should be subjected to a reduction step prior to deprotection. ... 

The first synthesis of p-methoxyphenyllead triacetate by direct plumbation was reported by Harvey and Morman, who obtained the compound in 2418 yield by heating anisole and lead tetraacetate in acetic acid at SO C for 4... 

An example of this is found in the synthesis of a crown containing a mefa-xylylene unit (see also Sect. 3.5) and a convergent methoxyl group. 4-Methyl-2,6-bishydroxymethyl-anisole was treated with pentaethylene glycol and sodium hydride in THF solution to afford the crown (mp 71—73°) shown in Eq. (3.52) in 59% yield. 

Anisole.—The prepaiation of anisole fiom phenol is analogous to Williamson s synthesis of the ethers (see p. 236), luit the etheis of phenol cannot be obtained by the action of tire alcohol on the phenol in presence of sulphuric acid. This reaction c.an, howet er, be effected In the case of the naphthdls (see p 316). 

The selective bromination of a ketone in the presence of another susceptible functional group was achieved in a diterpene synthesis 240). A competing bromination of an anisole ring could be avoided here through the use of a pyrrolidine enamine derivative for activation of the methylene group adjacent to the carbonyl function. 

The Phacm group is stable to the following conditions DIEA-CH2CI2, TFA-CH2CI2, piperidine-DMF, 0.1 M TBAF-DMF, and DBU-DMF for 24 h at It to HF-anisole or / -cresol (9 1) at 0° for 1 h and to TFA-scavengers (phenol, HSCH2CH2SH, p-cresol, anisole) for 2 h at 25°. It is partially stable (>80%) to TFMSA-TFA-/ -cresol for 2 h at 25°. These stability characteristics make the group compatible with BOC- or Fmoc-based peptide synthesis. ... 

The methoxy group of methoxythiophenes shows a reactivity which, in many respects, differs appreciably from the reactivity of the corresponding anisoles. Thus, in an attempted Hoesch synthesis with 5-methoxy-2-thenylcyanide (167) and phloroglucinol, the methoxy group reacted instead and 5-(2, 4, 6 -trihydroxyphenyl)-2-thenyl cyanide (168) was obtained. 2-Thenyl cyanide reacts normally in the Hoesch synthesis, Likewise, upon acid hydrolysis of the reaction product of 5-methoxy-2-thienyllithium with benzophenone, (169) was obtained instead of the expected substituted methoxythiophene. No defined products could be isolated from the attempted Claisen rear-... 

Anisole and mixtures of diethyl ether with aromatic hydrocarbons have both been widely employed as solvents for these reactions. Ethers other than diethyl ether and anisole have also been successfully used (cf. refs. 14-17). Hcxamethylphosphorotriamide has recently been used as a solvent for indole Grignard reactions. Young and Mizianty have recently described the use of an aromatic magnesium halide (phenylmagnesium bromide) for the synthesis of indole magnesium bromide. 

Oddo and Sessa claimed that 1-carboxyindole (375) was obtained on treatment of indole magnesium iodide with gaseous carbon dioxide. Majima and Kotake later reported that 3-carboxyindole (376) and not 375 was the main product obtained in this reaction improved yields of 376 were obtained when the reaction was carried out in anisole instead of ether.Subsequently, several workers have employed essentially this procedure, for the synthesis of 376. It has recently been shown, however, that both the acids 375 and 376 are formed in approximately equal amounts by the carbonation of the indole Grignard reagent (Kasparek and Hea-cook ). 

Dichlorodibenzo-p-dioxin was prepared from isotopic potassium 2,4-dichlorophenate uniformly labeled with Ullman conditions gave a 20.5% yield. Small amounts of dichlorophenoxy chlorophenol were removed from the product by extraction with sodium hydroxide before purification by fractional sublimation and recrystallization from anisole. Chlorination of 2,7-dichlorodibenzo-p-dioxin in chloroform solution containing trace amounts of FeCls and 12 yielded a mixture of tri-, tetra-, and pentachloro substitution products. Purification by digestion in boiling chloroform, fractional sublimation, and recrystallization from anisole was effective in refining this product to 92% 2,3,7,8-tetrachloro isomer, which also contained 7% of the tri- and 1% of the penta-substituted dibenzo-p-dioxin. Mass spectroscopy was used exclusively to monitor the quality of the products during the synthesis. 

At stage 1 of the synthesis, m-bromoanisole [1] and n-butyUithium are converted via bromo/lithium exchange in order to obtain m-lithium anisole [2] and n-bromobutane. At stage 11, the reaction mixture is treated with dimethylformamide, and then the reaction is quenched using 3 M hydrochloric acid. Tetrahydrofurane is used as solvent at both synthetic stages. 

A New Improved Synthesis of Tricycle Thienobenzazepines Apphcation of chemistry recently developed by Knochel" combined with the well-described halogen dance (HD) reaction, allowed preparation of our key intermediate A in only three synthetic transformations (Scheme 6.4). In this respect, treatment of 2-bromo-5-methylthiophene with hthium diisopropylamide followed by dimethylformamide afforded aldehyde 11 in good yield, lodo-magnesium exchange with conunercial 4-iodo-3-nitro anisole followed by reaction with 11 afforded the thiophene catbinol 12. Dehydroxylation of 12 provided our key intermediate A which presented the requisite functionality to examine our approach to the construction of the seven-member ring system. 

Scheme 11.2 shows some representative halogenation reactions. Entries 1 and 2 involve Lewis acid-catalyzed chlorination. Entry 3 is an acid-catalyzed chlorination using NCS as the reagent. Entry 4 shows a high-yield chlorination of acetanilide by i-butyl hypochlorite. This seems to be an especially facile reaction, since anisole is not chlorinated under these conditions, and may involve the A-chloroamide as an intermediate. Entry 5 describes a large-scale chlorination done with NCS. The product was used for the synthesis of sulamserod, a drug candidate. 

To seek further evidence for a bromonium ion-mediated dioxabicyclization and to investigate the regioselectivity of ring closure, we studied reactions with 3,4-dibromocyclohexyl hydroperoxides411. We developed a synthesis of 3-cyclohexenyl hydroperoxide based on oxidation of the corresponding N-tosylhydrazine by the procedure of Caglioti et al.42). Anisole was the starting material and the full reaction sequence is shown in Eq. 29. 

Diathiadiphosphetane disulfides are probably the most studied and the most thermally and hydrolytically stable of all the phosphorus-chalcogen heterocycles. They contain a central four membered P2S2 ring and can be prepared from heating phosphorus pentasulfide with aromatic compounds. The most well-known of these is Lawesson s reagent (43), which is made from anisole and phosphorus pentasulfide,92 and is used extensively in organic synthesis procedures (see Section 5.4.1). Other dithiadiphosphetane disulfides of note are 44 and 45, formed from the reaction of phosphorus pentasulfide with ferrocene or 1 -bromonaphthalene respectively.93... 

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