Malonic acids Mannich bases

Malonic acid, 489, 490 Malononitrile, 428, 434 Mandelic acid, 754, 774 Manganous oxide catalyst, 339 Mannich bases, 910, 911 Mannich reaction, 910, 911, 912, 1012, 1013... 

The Mannich bases investigated are acctoacetic and malonic acid derivatives, Y-carboxyglutamic acid included. - Compounds having the lactone structure give preferably decarboxylation of the ester groups not involved in the lactone ring. - ... 

Acdve methylene compounds ranging in acidity from -keto esters, malonates and nitroalkanes pK = 9-13) to ketones (pATa = 16-20) can be used in the Mannich reaction. The lack of examples using simple unactivated esters (p/iTa = 25) appears to be due to their weaker acidity or to transamination and/or hydrolysis side reactions. Enolizable aldehydes have also been used in certain instances however, side products arising from subsequent aldol condensation of the resulting -amino aldehyde often occur. Best results are achieved with a-branched aldehydes, which produce Mannich bases without enolizable protons. 

Reactions using highly acidic active methylene compounds (pAa = 9-13) comprise nearly all the early examples of imine condensation reactions, some of which date back to the turn of the century. Reviews by Layer and Harada have summarized many of these reactions and include examples using diethyl malonate, ethyl cyanoacetate, ethyl malonamide, acetoacetic acid, benzoylacetic esters and nitroalkanes. Conditions of these reactions vary they have been performed both in protic and aptotic solvents, neat, and with and without catalysts. Elevated temperatures are generally required. Reactions with malonates have useful applications for the synthesis of 3-amino acids. For example, hydrobenzamide (87), a trimeric form of the benzaldehyde-ammonia Schiff base, and malonic acid condense with concomitant decarboxylation to produce p-phenylalanine (88) in high yield (equation 14). This is one of the few examples of a Mannich reaction in which a primary Mannich base is produced in a direct manner but is apparently limited to aromatic imines. 

Mannich condensation of [Cu(en)2]2+ with methanal and di(m)ethyl-malonate forms [ 6,6,13,13-tetrakis(carbo(m)ethoxy)-cyclam copper(II)]2+ (97), in approximately 10% yield in methanol,92 approximately 20% in DMF,93 with lower yield for the reaction with Ni11 (Scheme 25). The ester functions are hydrolyzed in base to form the tetrakis(carboxyl)-substituted cation (98), which readily decarboxylates in acid to form the trans- 6,13-bis(carboxyl)-substituted cation (99).92 The carboxyl groups of (99) have been converted to carbomethoxyl, carbamoyl, (m)ethylcarbamoyl, and hydrazinocarbonyl functions.94... 

Ishihara et al. developed a Mg(ii)-binaphthonate catalysed highly enantioselective direct Mannich-type reaction between aldimines 3 and malonates 4 to form adducts 5 (Scheme 3.1). It was speculated that the cooperative acid-base Mg(ii)-BINOL catalyst activates both the aldimine and malonate, and the divalent Mg(ii) centre would be firmly bound to both BINOL and malonate through ionic and coordinate bonds. Indeed, the Mg(ii)-BINOL catalyst prepared in situ from BINOL and dibutylmagnesium under anhydrous conditions could efficiently promote the reaction in excellent yields (up to 99%) and enantioselectivities (up to 99% ee). 

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