Mannich reagent

Reactions of aromatic and heteroaromatic rings are usually only found with highly reactive compounds containing strongly electron donating substituents or hetero atoms (e.g. phenols, anilines, pyrroles, indoles). Such molecules can be substituted by weak electrophiles, and the reagent of choice in nature as well as in the laboratory is usually a Mannich reagent or... 

The condensation of 2,5-diunsubstituted pyrroles with formic acid20 is a viable method to produce porphyrins. However, the most common procedure21 22 involves the heating of the corresponding pyrroles 1 with aldehydes and aldehyde derivatives like imines or a Mannich reagent in the presence of acid. The reaction is initiated by electrophilic attack of the aldehyde (or aldehyde derivative) to the pyrrole 1. The formed (hydroxyalkyl)pyrrole 3 then undergoes electrophilic substitution with another pyrrole to form a dipyrrylmethane 4. Repeated addition of aldehyde and pyrrole finally forms a tetrameric (hydroxyalkyl)bilane 5. 

In recent years a number of methods have been developed for the preparation of dialkyl(methylene)ammonium salts (Mannich reagents)and their use in Mannich-type condensation reactions under anhydrous conditions has improved the scope and efficiency of this important synthetic process. However, the orientation of the Mannich reaction may nevertheless be difficult to control. Apart from the work of the submitters, the preparation of isomer-ically pure Mannich bases has only been achieved by indircci... 

Calculations of simple model Mannich reactions have focused on the role of iminium salt as potential Mannich reagent. ... 

Hydroxythiocoumarins are, of course, enolic and react as acetoacetate analogues. Electrophiles such as Mannich reagents, aromatic aldehydes and enones react readily (Scheme 22), while acylation can be direct, or via a Fries-type rearrangement of 4-acyloxy precursors. 

Aube and co-workers have found that enolizable ketones react with benzyl azide in triflic acid to yield /V-(phenylamino)-methylated products [Eq. (5.354)]. The transformation is an aza-Mannich reaction interpreted with the involvement of the Mannich reagent A -phenyl iminium ion 295 formed in situ in a Schmidt rearrangement. Cyclic tertiary alcohols react with alkyl azides in triflic acid to yield N-alkylamines (296, 297)983 [Eq. (5.355)]. The Schmidt rearrangement was used to transform Merrifield resin into amino-polystyrene resin by reacting the azido derivative in excess triflic acid (CH2CI2, 0°C).984... 

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]. 

The imines 12 (X = 4-CH3-QH4-SO2 (Ts), Ar, C02R, COR, etc.) preformed or generated in situ from N,0- or N,N-acetals or hemiacetals are another important class of Mannich reagents frequently used for diastereo- and/or enantioselective aminoalkylation reactions catalyzed by chiral Lewis acids (usually copper or palladium BINAP complexes such as 13). Among other things excellent results were obtained in the aminoalkylation of silyl enol ethers or ketene acetals [24], A typical example is the synthesis of Mannich bases 14 depicted in Scheme 5 [24b], Because of their comparatively high electrophilicity imines 12 could even be used successfully for the asymmetric aminoalkylation of unactivated alkenes 15 (ene reactions, see Scheme 5) [24h, 25], and the diastereo- and/or enantioselective aminoalkyla-... 

The Mannich reaction with dihydrocodeinone 203 gave not the expected 7-dimethylaminomethyl Mannich base, nor the corresponding 7-methylene elimination product (93), but a dimer to which the symmetrical structure 95 was initially assigned. A reinvestigation 204 of the reaction with a milder Mannich reagent, N,JV,N, N -tetramethylmethanediamine 205 confirmed that the only isolatable product was a dimer, but H and 13C nmr characteristics suggested a nonsymmetrical dimer of structure, 94. The dimer arises from a... 

The crosslinking action performed by Mannich bases or Mannich reagents relates to three main types of reactions of notable practical interest. 

The sulfonic group present in anthraquinonc dyes is readily replaced by the Mannich reagent, as has been mentioned previously (see 10 in Sec. A. I) in particular, 1 -amino-and l-hydroxy-2-anthraquinone-sulfonic acids may occasionally be involved in the production of cyclic Mannich bases. Finally, the methyl group of dimelhylsulfite (CH,)2SOj may be similarly replaced by the dimethylaminomcthyl group giving OjS—CH —... 

Curulli, A.. Giardi. M. 1 ., and SIciter, G., Electrophilic heteroaromatic substitutions. VI. The reaction of some. 3,4,5-tri- and I,.3,4,5-tetrasubstitmed 2-methylpyrrolcs with Mannich reagents, Gazz, Chim. Iial., 113, 115, 1983. 

The amine-oxide (316) reacts with trifluoroacetic anhydride in the manner depicted in Scheme 13. The iminium ion (317) has the properties of a Mannich reagent, and alkylates a second steroid molecule in the enamine form (318) to give the 2-methylene-3-ketone (31-9) after hydrolysis. The demethylated amine was formed at the same time. Different behaviour of the A -unsaturated amine oxide (320) results from participation of the olefinic bond in a novel type of Grob... 

The ideal approach for the preparation of conjugated carbonyl compounds having an exo-methylene group would be via a mixed aldol condensation of an enolizable carbonyl substrate with formaldehyde as the electrophilic partner. However, formaldehyde is a very powerful electrophile and tends to react more than once with enols and enolates. This shortcoming can be circumvented by converting the formaldehyde to an iminium ion (Mannich reagent) by reaction with a secondary amine, usually dimethy-lamine, and a catalytic amount of HCl. 

As mentioned above, the capacity of the intermediate iminium ion (2) to condense with its counterion is a crucial product-determining step. This is illustrated by the reaction of trimethylamine A -oxide with acetic and trifluoroacetic anhydride (Scheme 2). With acetic anhydride the iV-demethylated product di-methylacetamide is formed in high yield, whereas with trifluoroacetic anhydride under similar conditions the iminium ion (9), a synthetically useful Mannich reagent, is generated in nearly quantitative yield. ... 

Li, Y., Xiao, H., Wu, J. The study on the mechanism of iminium salts as potential Mannich reagents. Part 2. Ethylene as pseudo-acid component. THEOCHEM A995, 333, 165-170. 

Li, Y. M., Xiao, H. M. Studies on the mechanism of Mannich reaction involving iminium salt as potential Mannich reagent. III. Furan as pseudo acid component, tnt. J. Quantum Chem. 1995, 54, 293-297. 

The methyleneammonium salt (2) is a highly reactive Mannich reagent. It has been used to introduce a methyl group into the corrin nucleus. Thus stirring a solution of the corrin (3) in dichloromethane with (2) gives the pure 15-(dimethylamino)methyl derivative (4) in 85 % yield. This product (4) was converted into the 15-methylcorrin derivative (5) by catalytic hydrogenation.1... 

MANNICH REAGENT Dimethyl(methyl-ene)ammonium iodide. 

The reaction of trifluoroacetic anhydride on the A(-oxides of 3)5-dimethytamino-steroids (51) (e.g., iV-methyl-5a-dihydroparavallarine) leads to the immonium salts (52) and (53), which can be hydrolysed to the 3-keto- or the 3-methylamino-steroid, respectively. " This reaction is generally applicable to other amines trimethylamine oxide is converted into iViV-dimethylformaldimmonium tri-fluoroacetate (54), which is an excellent Mannich reagent. ... 

Mannich reagent. French chemists reported that use of trifluoroacetic anhydride rather than acetic anhydride in the Polonovski reaction resulted in improved yields (2, 7, 8). They1 now find that the reaction of trifluoroacetic anhydride with the N-oxide of trimethylamine leads to the trifluoroacetate of N,N-dimethylformaldimmonium (1). This ion is considered to be the actual reagent in... 

In addition to the very important palladium-catalysed reactions, boronic acids undergo a number of useful reactions that do not require transition-metal catalysis, particularly those involving electrophilic ipso-substitutions by carbon electrophiles. The Petasis reaction involves ip,y(9-replacement of boron under Mannich-like conditions and is successful with electron-rich heterocyclic boronic acids. A variety of quinolines and isoquinolines, activated by ethyl pyrocarbonate, have been used as the Mannich reagent . A Petasis reaction on indole 3-boronic acids under standard conditions was an efficient route to very high de a-indolylglycines. " ... 

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