Oxidative ortho-acylation

SCHEME 23.22 Rh-catalyzed oxidative ortho-C-H acylation with aldehydes. 

The effect of a substituent may be substantially modified by fast, concurrent, reversible addition of the nucleophile to an electrophilic center in the substituent. Ortho- and para-CS.0 and pam-CN groups have been found by Miller and co-workers to have a much reduced activating effect on the displacement of halogen in 2-nitrohaloben-zenes with methoxide ion [reversible formation of hemiacetal (143) and imido ester anions (144)] than with azide ion (less interaction) or thiocyanate (little, if any, interaction). Formation of 0-acyl derivatives of 0x0 derivatives or of A-oxides, hydrogen bonding to these moieties, and ionization of substituents are other examples of reversible and often relatively complete modifications under reaction conditions. If the interaction is irreversible, such as hydrolysis of a... 

Synthesis of the remaining half of the molecule starts with the formation of the monomethyl ether (9) from orcinol (8). The carbon atom that is to serve as the bridge is introduced as an aldehyde by formylation with zinc cyanide and hydrochloric acid (10). The phenol is then protected as the acetate. Successive oxidation and treatment with thionyl chloride affords the protected acid chloride (11). Acylation of the free phenol group in 7 by means of 11 affords the ester, 12. The ester is then rearranged by an ortho-Fries reaction (catalyzed by either titanium... 

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 starting acyl chloride has lost the elements of HC1 in the formation of A. Because A forms benzene-1,2-dicarboxylic acid on oxidation, it must have two carbon substituents ortho to each other. 

It is better to acylate aniline before nitration to prevent oxidation or over-nitration and reduce the proportion of ortho-nitration. The yield of 45 is after separation from the ortho isomer.10 Notice that in the last step nitrogen, like oxygen, prefers to attack the acyl rather than the alkyl chloride. 

Neither pyridine nor pyridine /V-oxide can be alkylated or acylated (but see 67MI1(I62) for early reports]. 2-Pyridone and 3-hydroxypyridine can be carboxylated ortho and para to the hydroxy group under basic conditions (24CB1161 54CA1337i, 54JOC510). 

Previously, the most widely used method for preparation of 4-alkyl-benzoyl chlorides on a laboratory scale has been from the benzoic acids obtained by oxidation of aromatic ketones, usually 4-alkylacetophe-nones. 14 The latter are usually prepared by acylating alkylbenzenes. Although this sequence gives high yields, it is lengthy (three completely separate steps) and the scale is restricted in the second step because of the large volumes required. The submitters state that they were unable to repeat the reported alkylation of toluic acid.15 Methods that lead to formation of ortho and para isomeric intermediates are inconvenient since they require that the isomers be separated.16"19... 

In a Study of the formation of benzimidazoles by the peroxy acid-catalyzed cyclization of o-acylamino-iV,lV-dialkylaniIines, it has been demonstrated that the reaction proceeds via an iV-oxide intermediate, since it has proved possible to synthesize this N-oxide and cyclize it under the reaction conditions (B-73MI40800). Both ortho-N-acylated and -N-... 

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