Bases Lithium diisopropylamide-Hexamethylphosphoric triamide

This important synthetic problem has been satisfactorily solved with the introduction of lithium dialkylamide bases. Lithium diisopropylamide (LDA, Creger s base ) has already been mentioned for the a-alkylation of acids by means of their dianions1. This method has been further improved through the use of hexamethylphosphoric triamide (HMPA)2 and then extended to the a-alkylation of esters3. Generally, LDA became the most widely used base for the preparation of lactone enolates. In some cases lithium amides of other secondary amines like cyclo-hexylisopropylamine, diethylamine or hexamethyldisilazane have been used. The sodium or potassium salts of the latter have also been used but only as exceptions (vide infra). Other methods for the preparation of y-Iactone enolates. e.g., in a tetrahydrofuran solution of potassium, containing K anions and K+ cations complexed by 18-crown-6, and their alkylation have been successfully demonstrated (yields 80 95 %)4 but they probably cannot compete with the simplicity and proven reliability of the lithium amide method. 

The regioselectivity of the latter reaction is strongly dependent on the base used for deprotonation. Thus, reaction with lithium diisopropylamide in tetrahydrofuran/hexamethylphosphoric triamide results in selective endo metalation23 and leads to the bicyclic product 10. 

Synthesis of ketones. Stork and Maldonado6 have disclosed a new synthesis of ketones from aldehydes RCHO-> RCOR. The aldehyde is first converted into the cyanohydrin and then the hydroxyl group is protected by reaction with ethyl vinyl ether to give (1). This is then converted into the anion by reaction with lithium diisopropylamide under carefully controlled conditions, The base is generated from butyl-lithium and diisopropylamine in THF and then (1) in hexamethylphosphoric triamide... 

The formation of ( )-enolates is favored in tetrahydrofuran alone, whereas addition of metalchelating solvents such as hexamethylphosphoric triamide, A,A, /V, Ar-tetranncthylcthylenedi-amine or l,4-dimethyltetrahydro-2(l//)-pyrimidinone reverses the enolate configuration to the (Z)-product. The best seleetivities were obtained with 45% l,3-dimethyltetrahydro-2(l//)-pyrimidinone. In comparison to lithium diisopropylamide in 23% hexamethylphosphoric triamide. slightly bulkier bases, i.e., lithium hexamethyldisilanazide, have proved to be more E selective256. 

---