Anisole meta-acylation

The meta acylation of anisole, using a carbonyl anion equivalent as the nucleophile, illustrates the unique regioselectivity available with the Cr(CO)3 activation (equation 31). 

With arenes bearing a single resonance donor substituent (NR2, OMe, F), the addition is strongly preferred at the meta position, with small amounts of ortho substitution (0-10%). " The meta acylation of anisole, using a carbonyl anion equivalent as the nucleophile, illustrates the unique regioselectivity available with the Cr(CO)3 activation (equation 115). ... 

The combination of ortho metallation and meta nucleophilic acylation was used to prepare a key intermediate in a synthesis of deoxyfrenolicin (42), as outlined in Scheme 11. The complex of anisole is orf/io-metallated with n-butyllithium and quenched with chlorotrimethylsilane the resulting [(o-(tri-methylsilyl)anisole)Cr(CO)3] (43) is then metallated again, converted to the arylcuprate, and coupled with ( )-2-hexenyl bromide to give the complex of l-trimethylsilyl-2-methoxy-3-(2-hexenyl)benzene (44). Addition of the carbanion from the cyanohydrin acetal of 4-pentenal, followed by the standard iodine oxidation and subsequent hydrolysis of the cyanohydrin acetal to regenerate the carbonyl group... 

The acylation of anisole with C2 - C12 acids was carried out under the same conditions as that of toluene, except a shorter reaction time (5 h). The acylated anisole formed as the major product para/ortho = 59 1 - 96 1 and no meta isomers) together with esterification products - methyl esters of carboxylic acids and phenol. No phenyl esters formed. The selectivity to esters increases from acetic to dodecanoic acid, reaching 40% for the latter. The acylation of anisole, in contrast to that of toluene, is most efficient with C2 - C6 acids, giving a 62 - 65% yield of acylated products and only 2 - 6% of methyl esters. 

One of the first eye-catching synthetic applications of arene-chromium chemistry was the synthesis of the sp/ro-sesquiterpenes ( )-acorenone and ( )-acorenone B (rac-7) disclosed by Semmelhack and Yamashita in 1980 [14]. These authors twice exploited the meta-selective nucleophile addition to anisole-Cr(CO)3 derivatives (Scheme 1). Starting from complex rac-1, such a reaction is first used for the regioselective introduction of an acyl sidechain to give 2 after oxidative workup. A few steps later, the nitrile rac-4 (obtained from rac-3 by complexation and separation of the diastereomeric products by preparative HPLC) is deprotonated to form the spiro addition product rac-5, from which the enone rac-6 is obtained after protonation and hydrolysis of the initially formed dienol ether. The final conversion of rac-6 into acorenone B (rac-7) efficiently proceeds over five steps and involves a diastereoselective hydrogenation of an exo-methylene group. 

All the syntheses of tricyclic ketones in Scheme 8 described so far have been carried out from comparatively poorly accessible meta-substituted anisoles. Consequently, the possibility of using themore accessible para-substituted anisoles as starting materials offered considerable interest [219]. The acylation of anisole (82) with glutaric anhydride, esterification, the Stobbe reaction, and hydrolysis led to the triacid (87). 

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