Amide directing group

The development of facial selective addition reactions of cyclohexa-1,4-dienes 7 and 14 has greatly extended the value of the asymmetric Birch reduction-alkylation. For example, amide directed hydrogenation of 15 with the Crabtree catalyst system occurs with outstanding facial selectivity iyw to the amide carbonyl group to give 16 (Scheme 5)."... 

Even sulphonate esters 109 are powerful directing groups, competing well with tertiary amides. No substitution accompanies ortholithiation of ethyl or isopropyl benzene-sulphonate by BuLi. Hydrolysis and chlorination of the products 110 gives functionalized sulphonyl chlorides 111 (Scheme 48) °°. 

More powerful directing groups such as those based on amides and sulphonamides are successful with pyridines as with carboxylic rings, and will not be discussed separately. The enhanced acidity of pyridine ring protons makes the simple carboxylate substituent an ideal director of lithiation in pyridine systems . The pyridinecarboxylic acids 232-234 are deprotonated with BuLi and then lithiated with an excess of LiTMP all the substitution patterns are lithiated nicotinic acid 233 is lithiated in the 4-position (Scheme 113). The method provides a valuable way of introducing substituents into the picolinic, nicotinic and isonicotinic acid series. 

The usual directing groups such as secondary amides will also successfully direct lateral lithiation at the 2-methyl group of a pyrrole (Scheme 226/° . 

The preparation of amides directly from alkyl esters is also feasible but is usually too slow for preparative convenience. Entries 4 and 5 in Scheme 3.6 are successftd examples. The reactivity of ethyl cyanoacetate (entry 4) is higher than that of unsubstituted aliphatic esters because of the inductive effect of the cyano group. 

The application of new bis-substituted dtc ligands containing various polyether and amide spacer groups has lead to the constmction of a wide range of metal-directed assembled bimetallic macrocycles and cryptands (Scheme 5).48 Cryptands can be assembled through careful choice of a suitable octahedral stereochemical directing metal centre such as iron(III) and cobalt(III). 

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