M-Bromoanisole

Timolol maleate a-Bromoacetophenone Nomifensine maleate Bromoacetyl bromide Bromazepam Cephapirin sodium Clonazepam Flunitrazepam 5-Bromoacetyl salicylamide Labetalol HCI m-Bromoanisole Tramadol HCI p-Bromoanisole Cyclofenil Bromobenzene... 

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. 

Phenyl n-propyl et.her. Phenyl n-butyl ether o-Cresyl methyl ether (1) m-Cresyl methyl ether. p-Cresyl methyl ether. o-Cresyl ethyl ether m-Cresyl ethyl ether p-Cresyl ethyl ether Benzyl methyl ether Benzyl ethyl ether Methyl a-naphthyl ether Methyl p-naphthyl ether Ethyl a-naphthyl ether Ethyl p-naphthyl ether Benzyl a-naphthyl ether Benzyl P-naphthyl ether o-Methoxydiphenyl p-Methoxydiphenyl. o-Chloroanisole. m-Chloroanisole. p-Chloroanisolc o-Bromoanisole m-Bromoanisole. p-Bromoanisole. o-Iodoanisole m-Iodoanisole p-Iodoanisole o-Nitroanisole... 

The isomeric o- or m-bromoanisole give only the oxonium monocations. Presumably, dialkylation is inhibited by unfavorable charge-charge repulsive effects in the m- or o-isomers. 

Methyl 3-amino-2-pyrazinecarboxylate (166) gave methyl 3-trimethylsily-lamino-2-pyrazinecarboxylate (167) (BuLi, THF, - 78°C then Me3SiCl [, - 78°C 98%), and thence 9-methoxypyrazino[2,3-/ ]quinolin-9(5//)-one (168) [3-methoxybenzyne (generated from m-bromoanisole in situ), lithiated (167), - 40°C, 10 min 31%].320... 

It is instructive to follow the evolution of the strategic principles with an example of the total synthesis of estrone 128 (Scheme 3.33), as it can be regarded historically as one of the trial cases used to evaluate the effectiveness of various synthetic approaches.The first total synthesis of estrone, reported in 1948 by Anner and Mischner, involved 18 steps with an overall yield of 0.1 % (based on the starting material, m-bromoanisole). In 1958, Johnson s group accomplished the synthesis in 10 steps with a 4.2% yield based on 2-methoxytetralone 129. Finally, in 1965, Torgov and co-workers carried out a six-step synthesis, also based on 129, but in 25% yield. 

Dimethyl sulfate (38.4 g., 0.30 mole) is added slowly [Caution— toxic substance) with stirring to a solution of 44 g. (0.26 mole) of 7B-bromophenol (p. 54) in 107 g. of a 10% aqueous solution of sodium hydroxide. Stirring is continued until the reaction mixture is neutral. The organic layer is separated by ether extraction, and the ethereal solution is dried. Distillation gives a colorless oil, b.p. 209-212°/752 mm. This is redistilled and 35 g. (73%) of m-bromoanisole is collected at 210-211 . 

LDA is a useful base for generating a benzyne from m-alkoxyaryl bromides. Thus the aryl and not the benzylic proton is removed from 46 to give 47 which, on warming, produces aryne 48. The m-alkoxy substituent is essential, since m-bromoanisole, but not the 0- or / -isomers, undergoes analogous chemistry. 

The synthesis is in this case also simple. It consists of the reaction between a Grignard reagent, derived from m-bromoanisole, and the Mannich base produced from dimethylamine, formaldehyde and cyclohexanone. 

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