The Selective Activation of Alternative Reaction Sites in Substrates

13 THE SELECTIVE ACTIVATION OF ALTERNATIVE REACTION SITES IN SUBSTRATES 

More thoughtful analysis revealed additional opportunities hidden in the structure of acetoacetic ester. In fact, the non-equivalence of the two a-positions to the carbonyl group suggests an alternative mode of selectivity based on preferential attack at the C-1 carbon. This idea seems to be paradoxical, but in 

The presence of two negative charges in close proximity makes this new reagent 174 extremely reactive. Its carbanionic sites, at C-1 and C-3, however, differ sharply in their nucleophilicity and reactivity. The different surroundings of the carbanionic centers in this system makes the carbanion at C-3 better stabilized than at C-1. Therefore, electrophilic attack should be directed primarily at C-1. In fact, the addition of one equivalent of an electrophile to a solution of 174 leads to a highly selective attack at the terminal carbon atom. The product of this reaction, 175, still retains a carbanionic center and with the addition of another electrophile the formation of a second bond occurs selectively at C-2. In this manner, the dianion 174 is an excellent three-carbon building block for the synthesis of ketones of type 176 or four-carbon building block for the synthesis of esters of the type 177. 

Many synthetic problems requiring a reverse in the traditional mode of selectivity have been solved by the application of these and other polyanions. It is worthwhile to note that this novel aspect of carbanion utilization was brought to light owing to the elaboration of the conditions (strong bases, polar aprotic solvents) which secured completeness in carbanionic species generation. 

The selective monoalkylation of ketones at the a-position had no general solution for a long time. A classical approach to this problem, based upon the selective activation of this site via the introduction of additional electron withdrawing substituents e.g. alkoxycarbonyl group), is applicable only for symmetrical ketones. Non-symmetrical compounds react non-selectively in this auxiliary step. The synthetic importance of this problem triggered a thorough study of enolate chemistry in the 1960s and, as a result, at present the selective substitution at any of the a-positions of carbonyl compounds can be achieved via a number of routes. 

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