And Mannich reactions

Michael-type addition, hydroxymethylation and Mannich reaction take place at nitrogen to give the corresponding 2-substituted 4-hydroxyphthalazin-l(2/f)-ones. 

Pyrazoles and imidazoles exist partly as anions (e.g. 108 and 109) in neutral and basic solution. Under these conditions they react with electrophilic reagents almost as readily as phenol, undergoing diazo coupling, nitrosation and Mannich reactions (note the increased reactivity of pyrrole anions over the neutral pyrrole species). 

Taking into account the close relationship to pyridines one would expect 2-pyridones to express similar type of reactivities, but in fact they are quite different. 2-Pyridones are much less basic than pyridines (pKa 0.8 and 5.2, respectively) and have more in common with electron-rich aromatics. They undergo halogenations (a. Scheme 10) [67] and other electrophilic reactions like Vilsmeier formylation (b. Scheme 10) [68,69] and Mannich reactions quite easily [70,71], with the 3 and 5 positions being favored. N-unsubstituted 2-pyridones are acidic and can be deprotonated (pJCa 11) and alkylated at nitrogen as well as oxygen, depending on the electrophile and the reaction conditions [24-26], and they have also been shown to react in Mitsonobu reactions (c. Scheme 10) [27]. 

Similar organocatalytic species to those successfully used for the Strecker reaction were used for the asymmetric Mannich reaction. Catalyst structure/ enantioselectivity profiles for the asymmetric Strecker and Mannich reactions were compared by the Jacobsen group [160]. The efficient thiourea... 

After the initial two reports of Rh- and Co-catalyzed reductive aldol couplings, further studies did not appear in the literature until the late 1990s. Beyond 1998, several stereoselective and enantioselective reductive aldol reactions were developed, which are catalyzed by a remarkably diverse range of metal complexes, including those based upon Pd, Cu, Ir, and In. In this chapter, transition metal-catalyzed aldol, Michael, and Mannich reactions that proceed via transition metal hydride-promoted conjugate reduction are reviewed. 

Nishiyama H, Shiomi T (2007) Reductive Aldol, Michael, and Mannich Reactions. 279 105-137... 

It should be noted that the demarcation between metal complex catalysis of the Henry (454-458) and Mannich reactions is arbitrary, and that the catalyzed process is sometimes called the Mannich reaction (see, e.g., Ref. 456). 

Actually, the reactions of AN with bases produce reversibly carbanions A, which are the major intermediates in the classical reactions of AN (Henry, Michael, and Mannich reactions). The reactions of AN with acids afford iminium cations B (also reversibly), which are the key intermediates in the Nef reaction... 

Sodeoka and co-workers have reported enantioselective aldol and Mannich reactions (Equations (106) and (J07)) 464,464a 464e Involvement of palladium enolates was confirmed by 111 NMR and ESI-MS spectrometry. /3-Keto esters (pronucleophiles) directly add to imines with high selectivity without preformation of silicon enolates (Equation (108)). 

Electrophilic attack at carbon is a well-documented reaction which occurs regioselectively at the C-3 position. It was illustrated by numerous examples, including nitrations, halogenations, acylations, and Mannich reactions in CHEC(1984) and CHEC-II(1996) <1996CHEC-II(8)249>. Table 1 reports some additional recent examples. It should be noted that all these synthetic transformations were carried out in the field of medicinal chemistry. 

Conversion of Graft Polyacrylamide to Amines via the Hofmann and Mannich Reactions... 

Scheme 23 Transition states in aldol and Mannich reactions...

Enamine nucleophiles react readily with soft conjugated electrophiles, such as a, 3-unsaturated carbonyl, nitro, and sulfonyl compounds [20-22], Both aldehydes and ketones can be used as donors (Schemes 27 and 28). These Michael-type reactions are highly useful for the construction of carbon skeletons and often the yields are very high. The problem, however, is the enantioselectivity of the process. Unlike the aldol and Mannich reactions, where even simple proline catalyst can effectively direct the addition to the C = O or C = N bond by its carboxylic acid moiety, in conjugate additions the charge develops further away from the catalyst (Scheme 26) ... 

Odedra A, Seeberger PH (2009) 5-(Pyrrolidin-2yl)tetrazole-catalyzed aldol and Mannich reactions acceleration and lower catalyst loading in a continuous-flow reactor. Angew Chem Int Edit 48(15) 2699-2702... 

Dyatkin, A. B. Rivero, R. A. The Solid Phase Synthesis of Complex Propargylamines Using the Combination of Sonogashira and Mannich Reactions, Tetrahedron Lett. 1998,39, 3647-3650. 

Multi-functional enantioselective catalysts for direct aldol and Mannich reactions have been prepared from (.S )-proline and 2,2/-diaminoBINAP.117... 

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