Aminomethylation Mannich reaction

A mixture of formaldehyde with ammonia or a primary or secondary amine can be used to replace mobile hydrogen by an aminomethyl or (substituted amino)methyl group. This reaction, which was systematically explored by Mannich,698 can be formulated as  

The carbonyl component has been almost exclusively formaldehyde, in aqueous solution or as paraformaldehyde, and only rarely other aldehydes such as acetaldehyde.699 

The amine component may be ammonia or a primary or secondary amine, generally presented as hydrochloride. In reactions of ammonia or a primary amine, further condensation has been observed as a side reaction  

Blicke, Org. Reactions, 1, 303 (1942) H. Hellmann and G. Opitz, Angew. Chem., 68, 265 (1956) B. Reichert, Die Mannich-Reaktion, Springer-Verlag, Berlin, 1959. 

For the preparation of primary amines by Mannich reaction it is useful to start from dibenzylamine as the two benzyl groups can be removed later by catalytic hydrogenation. 

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The side-chain cyanoethylation of alkyl thienyl ketones with acrylonitrile has been studied " and used for the preparation of 8-oxonitriles and S-oxoacids. Aminomethylation (Mannich reaction) of 2-acetylthiophene followed by steam distillation yielded 50% of 2-thienyl vinyl ketone, and has also been used for the synthesis of compounds of biological interest. ... 

Without additional reagents Aminomethylation-Mannich reaction... 

The desired pyridylamine was obtained in 69 % overall yield by monomethylation of 2-(aminomethyl)pyridine following a literature procedure (Scheme 4.14). First amine 4.48 was converted into formamide 4.49, through reaction with the in situ prepared mixed anhydride of acetic acid and formic acid. Reduction of 4.49 with borane dimethyl sulfide complex produced diamine 4.50. This compound could be used successfully in the Mannich reaction with 4.39, affording crude 4.51 in 92 % yield (Scheme 4.15). Analogous to 4.44, 4.51 also coordinates to copper(II) in water, as indicated by a shift of the UV-absorption maximum from 296 nm to 308 nm. 

Mannich Reaction. Aminomethylation of polyacrylamide with formaldehyde [50-00-0] and a secondary amine to produce a Mannich polyacrjiamide has been extensively studied (40). 

The yields of this reaction are typically 40—80%. C-nmr studies (41) indicate that the reaction is a second-order process between polyacrylamide and dim ethyl am in om eth an ol, which is one of the equiUbrium products formed in the reaction between formaldehyde and dimethylamine [124-40-3] C2H2N. The Mannich reaction is reversible. Extensive dialysis of Mannich polyacrylamides removes all of the dimethyl aminomethyl substituents (42). 

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). 

N-Unsubstituted pyrazoles and imidazoles add to unsaturated compounds in Michael reactions, for example acetylenecarboxylic esters and acrylonitrile readily form the expected addition products. Styrene oxide gives rise, for example, to 1-styrylimidazoles (76JCS(P1)545). Benzimidazole reacts with formaldehyde and secondary amines in the Mannich reaction to give 1-aminomethyl products. 

A generally applicable reaction scheme naturally cannot be given. The reaction mechanism of one particular carbinolamine with a particular reagent can depend on the reaction conditions in nonpolar solvents, the nondissociated carbinolamine obviously reacts (Sj 2 mechanism). In polar solvents, on the other hand, the mesomeric cation reacts (S l mechanism). Formally all these reactions belong to the general class of aminomethylation. The reaction products can be considered to be Mannich bases. ... 

Reaction of 2-amino-4/f-pyrido[l,2-n]pyrimidin-4-ones 143 with HNMei -HCl and paraformaldehyde in Dowtherm A afforded a mixture of 3-(A,A-dimethylamino)methyl derivatives 144 and bis-compounds 145 (93FES1225). Mannich reaction of 9-hydroxy-2-methyl-4//-pyri-dor],2-nlpyrimidin-4-one (146) yielded 8-aminomethyl derivatives 147 (94KFZ(10)23). 

The derivative from an isomeric fused system has been described as a sedative-hypnotic compound. The synthesis starts by condensation of the aminopicoline 32 with the haloketone 33. The resulting pyrrolo[l,2-a]pyridine 34 then undergoes a Mannich reaction with formaldehyde and dimethylamine to give the aminomethylated derivative 35. After quatemization of the di-methylamino group in 35 with methyl iodide, the ammonium group is displaced by cyanide to... 

Table 3 Highly substituted 2-pyridones were aminomethylated by utilizing a microwave-assisted Mannich reaction...

Phenols, secondary and tertiary aromatic amines, pyrroles, and indoles can be aminomethylated by treatment with formaldehyde and a secondary amine. Other aldehydes have sometimes been employed. Aminoalkylation is a special case of the Mannich reaction (16-15). When phenols and other activated aromatic compounds are treated withA-hydroxymethylchloroacetamide, amidomethylation takes place " ... 

The Mannich reaction has been applied to the synthesis of a wide array of iV-aminomethyl-l,2,4-trialozethiones. For example, 1,2,4- triazolo-3-thione 52 reacts with iV-phenylpiperidine in the presence of 40% formalin to give the corresponding N-substituted l,2,4-triazolo-3-thione 53 in 77% yield (Equation 16) <2005PS(180)537, 2000PS(164)67>. 

Vainilavicius and co-workers studied the Mannich reaction of oxadiazolethiones in detail and reported several examples pointing to the importance of starting reagent stmctures and the reaction conditions on the course of the reaction <2002M 173, 2003CHE1364>. For example, aminomethylation and acylation of 5-(4,6-diphenyl-2-pyrimidinyl)-... 

The reaction of 2,5-dimercapto-l,3,4-thiadiazolidine 34 with dialkylamines under Mannich reaction conditions gave N,S-aminomethylated thiadiazoles in 69-70% yields (Equation 24) <1998CHE1431>. With urea, thiourea, semicarbi-zide, or thiosemicarbazide, thiadiazolidine 34 gave N,N-aminomethylated thiadiazoles in 89-98% yields (Equation 25). 

A The Mannich reaction proceeds through the intervention of the N,A dimethylmethyleniininium cation [Me N =CHJ, This is insufficiently electrophilic to react with the benzene ring under the mild reaction conditions. Similarly, were the electrophile to react with the carbonyl oxygen atom of the heterocycle, this reaction would be reversible, as an aminomethyl ether is relatively unstable in acidic media. Thus, it seems plausible that the chromone utilizes enol or enolate character to trap the electrophile at C-3, followed by deprotonation of the adduct to reform the chromone ring system ( heme 5.9). 

Regioselective aminomethylation and subsequent cyclization of methyl 2,4-dihydroxybenzoate 517 was accomplished through a Mannich reaction with formaldehyde and primary amines in methanol to yield 3-substituted-3,4-dihydro-2/7-l,3-benzoxazine derivatives 518 (Equation 60). Simultaneous mixing of the reactants resulted in poor yields, but good yields were achieved by the pretreatment of paraformaldehye with a primary amine to form a Schiff base, followed by the addition of compound 517 <2001TL7273>. 

There are cases in which appropriate modification of one unsaturated oxazolone yields a new unsaturated oxazolone analogue. Most of the examples described in the literature involve modification of the substituent on the exocyclic double bond. For example, a series of 4-[2-hydroxy-3-(aminomethyl)benzylidene]-5(4//)-oxazo-lones 382 that were evaluated for bactericidal and fungicidal activities were obtained from Mannich reaction of 4-(2-hydroxybenzylidene)-5(4//)-oxazolones 381 (Scheme 7.123). ... 

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