Mannich reaction general

The benzo[6] heterocycles are generally less reactive than their monocyclic counterparts. Thus benzo[6]thiophene unlike thiophene does not undergo Vilsmeier formylation or the Mannich reaction. 

Intramolecular Mannich reactions of iminium 1 and acyliminium ions (see Section D.1.4.5.) with electron-rich double bonds are important reactions in the synthesis of naturally occurring alkaloids. In general, the iminium ions are not isolated but produced as intermediates. 

Recent efforts in the development of efficient routes to highly substituted yS-ami-no acids based on asymmetric Mannich reactions with enantiopure sulfmyl imine are worthy of mention. Following the pioneering work of Davis on p-tolu-enesulfmyl imines [116], Ellman and coworkers have recently developed a new and efficient approach to enantiomerically pure N-tert-butanesulfmyl imines and have reported their use as versatile intermediates for the asymmetric synthesis of amines [91]. Addition of titanium enolates to tert-butane sulfmyl aldimines and ketimines 31 proceeds in high yields and diastereoselectivities, thus providing general access to yS -amino acids 32 (Scheme 2.5)... 

The condensation of nitro compounds and imines, the so-called aza-Henry or nitro-Mannich reaction, has recently emerged as a powerful tool for the enantioselective synthesis of 1,2-diamines through the intermediate /3-amino nitro compounds. The method is based on the addition of a nitronate ion (a-nitro carbanion), generated from nitroalkanes, to an imine. The addition of a nitronate ion to an imine is thermodynamically disfavored, so that the presence of a protic species or a Lewis acid is required, to activate the imine and/or to quench the adduct. The acidic medium is compatible with the existence of the nitronate anion, as acetic acid and nitromethane have comparable acidities. Moreover, the products are often unstable, either for the reversibility of the addition or for the possible /3-elimination of the nitro group, and the crude products are generally reduced, avoiding purification to give the desired 1,2-diamines. Hence, the nitronate ion is an equivalent of an a-amino carbanion. 

The procedure described is an example of a general reaction,1-2 the Mannich reaction, a review of which, from the experimental point of view, has recently been published. ... 

Bifunctional thiourea-catalysed enantioselective Michael reaction has been achieved. The thiourea moiety and an amino group of the catalyst activated a nitroolefin and a 1,3-dicarbonyl compound, respectively afford the Michael adduct with high enantioselectivity.177,178 Thioureas work as one of the most effective and general enantioselective nitro-Mannich reaction and carbonyl cyanation catalyst.179,180... 

This is a fairly general reaction, and requires an amine plus an aldehyde (usually, but not necessarily, formaldehyde) together with an enolizable ketone, which together generate a P-aminoketone via an iminium system. The Mannich reaction is surprisingly... 

The amine-catalyzed Mannich reaction has also been a subject of special reviews [243, 244]. In general, yields and enantioselectivities of proline-catalyzed Mannich reactions are very high. Initially, the reactions were restricted to imines bearing an aromatic A-substituent, such as the p-methoxyphenyl (PMP) group. This restriction considerably limited the usefulness of the protocol, because relatively... 

Alkylation of acetylacetone chelates is generally unsuccessful, but carbon—methylene bonds can be formed by chloromethylation,279 reaction with ethyl diazoacetate,287 reaction with thioacetals288 (equations 64, 65 and 66) and by the Mannich reaction (Scheme 73).279 The Mannich base can be quatemized with methyl iodide and converted by cyanide ion into a cyanomethyl-substituted chelate. 

Nevertheless, the use of chirally modified Lewis acids as catalysts for enantioselective aminoalkylation reactions proved to be an extraordinary fertile research area [3b-d, 16]. Meanwhile, numerous publications demonstrate their exceptional potential for the activation and chiral modification of Mannich reagents (generally imino compounds). In this way, not only HCN or its synthetic equivalents but also various other nucleophiles could be ami-noalkylated asymmetrically (e.g., trimethylsilyl enol ethers derived from esters or ketones, alkenes, allyltributylstannane, allyltrimethylsilanes, and ketones). This way efficient routes for the enantioselective synthesis of a variety of valuable synthetic building blocks were created (e.g., a-amino nitriles, a- or //-amino acid derivatives, homoallylic amines or //-amino ketones) [3b-d]. 

For example, N-(2-hydroxyphenyl)imines 9 (R = alkyl, aryl) together with chiral zirconium catalysts generated in situ from binaphthol derived ligands were used for the asymmetric synthesis of a-amino nitriles [17], the diastereo- and/or enantioselective synthesis of homoallylic amines [18], the enantioselective synthesis of simple //-amino acid derivatives [19], the diastereo- and enantioselective preparation of a-hydroxy-//-amino acid derivatives [20] or aminoalkyl butenolides (aminoalkylation of triisopropylsilyloxyfurans, a vinylogous variant of the Mannich reaction) [21]. A good example for the potential of the general approach is the diastereo- and enantioselective synthesis of (2R,3S)-3-phenylisoserine hydrochloride (10)... 

S)-proline-catalyzed reaction using propionaldehyde as donor and the results showed that the imine reactivity was approximately sevenfold higher than that of the aldehyde [83]. Under basic conditions, it is generally accepted that nucleophilic addition to an aldehyde is typically faster than addition to an aldimine, but nucleophilic addition to an aldimine is faster than addition to an aldehyde when protonation of the imine nitrogen occurs [83]. In the (S)-proline-catalyzed three-component Mannich reactions in the absence of arylaldehyde, self-Mannich products were obtained with moderate to high diastereo- and enantioselectivities (Scheme 2.19) [71b, 82]. 

General Procedure for Direct Mannich Reaction of Aldehydes and Preformed Imines [10] (p. 39)... 

General Procedures for Three-Component Mannich Reactions (p. 46)... 

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