Mannich reaction limitations

An important extension of these reactions is the Mannich reaction, in which aminomethyl-ation is achieved by the combination of formaldehyde, a secondary amine and acetic acid (Scheme 24). The intermediate immonium ion generated from formaldehyde, dimethyl-amine and acetic acid is not sufficiently reactive to aminomethylate furan, but it will form substitution products with alkylfurans. The Mannich reaction appears to be still more limited in its application to thiophene chemistry, although 2-aminomethylthiophene has been prepared by reaction of thiophene with formaldehyde and ammonium chloride. The use of A,iV-dimethyf (methylene) ammonium chloride (Me2N=CH2 CF) has been recommended for the iV,iV-dimethylaminomethylation of thiophenes (83S73). 

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... 

Regardless of how it does take place, the fact that this addition is irreversible certainly imparts a clear advantage. In the classical Mannich, the reversibility of the final step limits the number of cases where the yields are synthetically useful. By comparison, the Boronic Acid Mannich Reaction permits a much broader scope of conversions to be carried out. 

In CHEC-II(1996) the detailed discussion of thiophenes as intermediates was, somewhat arbitrarily, limited to photochemical and electrocyclic processes. Additionally, reactions were included which destroy the aromatic thiophene skeleton to give rise to open chain molecules. In this scheme very recent applications of thiophenes such as thiophene-based amide linkers in solid-phase synthesis <2006JOC6734> or V-(2-thienyl)sulfonyl aldimins in chiral Mannich reactions <2006OL2977> did not be fit in. 

The vast and steadily increasing volume of research into Mannich reactions makes it impossible to exhaustively review here the papers published on the topic with the same thoroughness that characterized previous publications that dealt with the literature up to the 1970s. Hence, we limit ourselves to a synthetical survey of the type of substrates employed in Mannich synthesis, with particular emphasis on the applications of the reaction. Updated references, however, enable the reader to search the literature to retrieve more comprehensive information on individual topics. 

Some comparisons between the yields of the Mannich reaction of enol silanes using in situ methods for preparation of the iminium salt and non in situ methods are shown in Table 9. Higher yields (20-30%) of P-amino ketones using in situ methods are seen in entries 2 and 4 but not in entry 1. Although a clear advantage of the in situ methods is not evident in these limited examples, in situ methods may be preferred from the standpoint of convenience. With aldehyde enol silanes (entry 3), the in situ method of Miyano et al is less practical due to elimination of the amino group, presumably caused by the strongly basic N,/V,/V, N -tetramethyl(methylene)diamine present in solution. 

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. 

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