Secondary Mannich reaction

The Mannich Reaction involves the condensation of formaldehyde with ammonia or a primary or secondary amine and with a third compound containing a reactive methylene group these compounds are most frequently those in which the methylene group is activated by a neighbouring keto group. Thus when acetophenone is boiled in ethanolic solution with paraformaldehyde and dimethylamine hydrochloride, condensation occurs readily with the formation of... 

There also exists an acidregioselective condensation of the aldol type, namely the Mannich reaction (B. Reichert, 1959 H. Hellmann, 1960 see also p. 291f.). The condensation of secondary amines with aldehydes yields Immonium salts, which react with ketones to give 3-amino ketones (=Mannich bases). Ketones with two enolizable CHj-groupings may form 1,5-diamino-3-pentanones, but monosubstitution products can always be obtained in high yield. Unsymmetrical ketones react preferentially at the most highly substituted carbon atom. Sterical hindrance can reverse this regioselectivity. Thermal elimination of amines leads to the a,)3-unsaturated ketone. Another efficient pathway to vinyl ketones starts with the addition of terminal alkynes to immonium salts. On mercury(ll) catalyzed hydration the product is converted to the Mannich base (H. Smith, 1964). 

The Mannich reaction can be realized with formaldehyde and secondary amines. 

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

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. 

Mannich reaction is the condensation between formaldehyde, ammonia, or a primary or secondary amine (preferably as the hydrochloride), and a compound containing at least one active hydrogen atom... 

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 " ... 

A particularly useful variation of this reaction uses cyanide rather than HCN. a-Amino nitriles can be prepared in one step by the treatment of an aldehyde or ketone with NaCN and NH4CI. This is called the Strecker synthesisand it is a special case of the Mannich reaction (16-15). Since the CN is easily hydrolyzed to the acid, this is a convenient method for the preparation of a-amino acids. The reaction has also been carried out with NH3-I-HCN and with NH4CN. Salts of primary and secondary amines can be used instead of NH to obtain N-substituted and N,N-disubstituted a-amino nitriles. Unlike 16-51, the Strecker synthesis is useful for aromatic as well as aliphatic ketones. As in 16-51, the Me3SiCN method has been used 64 is converted to the product with ammonia or an amine. ... 

The thioxotetrazinoquinazoline 7 was reacted with paraformaldehyde and secondary amines, namely diethylamine and piperidine (Mannich reaction), to afford the corresponding derivatives (Equation 2) <1999IJB850>. 

It is obvious that the Mannich reaction pathway and the immonium ion mechanism may occur simultaneously, especially at conditions of room temperature or greater. Formaldehyde-facilitated crosslinking reactions between molecules that both contain nucleophiles probably occur primarily by the immonium ion pathway, since the Mannich reaction proceeds at a slower rate. In addition, the Mannich reaction will cause nondescript polymerization between molecules that possess both active hydrogens and amine groups. It is best to utilize the Mannich reaction only when one of the molecules contains no nucleophilic groups but at least one active hydrogen, and the other molecule contains a primary or secondary amine. 

In its simplest form, the Mannich reaction consists of the condensation of formaldehyde (or sometimes another aldehyde) with ammonia, in the form of its salt, and another compound containing an active hydrogen. Instead of using ammonia, however, this reaction can be done with primary or secondary amines, or even with amides. An example is illustrated in the condensation of acetophenone, formaldehyde, and a secondary amine salt (the active hydrogens are shown underlined) ... 

The group of Leadbeater reported a different type of Mannich reaction, which involved condensation of an aldehyde (1.5 equivalents) with a secondary amine and a terminal alkyne, in the presence of copper(I) chloride (10 mol%) to activate the... 

In the framework of this concept a series of new mixed P/N ligands was prepared, employing the phosphorus-analogous Mannich reaction (Scheme 9). This transformation permits the substitution of primary or secondary amines by methylenephos-phine residues -CH2PRR (R, R = alkyl, aryl) through reaction with a secondary phosphine and formaldehyde (46). Based on the... 

SOLID-PHASE MANNICH REACTIONS OF A RESIN-IMMOBILIZED SECONDARY AMINE... 

The Mannich reaction of secondary amines R NH (dibenzylamine, piperidine, morpholine, etc.), aldehydes R2CHO (R2 = alkyl, Ph or 2-furyl) and thiols R3SH (R3 = alkyl, Ph or benzyl) results in a-amino sulphides, which react with Grignard compounds to give tertiary amines in good yields (equation 47)136. 

The Mannich reaction of secondary amines with paraformaldehyde and vinylboronic acids gives excellent yields of pure (E)-allylamines, e.g. equation 63181. 

This MCR chemistry began in 1850 when the Strecker reaction S-3CR of ammonia, aldehydes, and hydrogen cyanide was introduced. Since 1912 the Mannich reaction M-3CR of secondary amines, formaldehyde, and (3-protonated ketones is used. 

Primary and secondary nitroalkanes, dinitromethane, and terminal em-dinitroaliphatic compounds like 1,1-dinitroethane, all contain acidic protons and have been used to generate Mannich products. Formaldehyde is commonly used in these reactions although the use of other aliphatic aldehydes has been reported. The nitroalkane component is frequently generated in situ from its methylol derivative, a reaction which also generates formaldehyde. Ammonia, " aliphatic amines, " hydrazine, and even urea have been used as the amine component of Mannich reactions. 

The use of primary nitramines in Mannich reactions is an important route to numerous secondary nitramines. However, a far more common route to such nitramines involves the Mannich condensation of a terminal gem-dinitroalkane, formaldehyde, and an amine, followed by IV-nitration of the resulting polynitroalkylamine. The preformed methylol derivative of the gem-dinitroalkane is often used in these reactions and so formaldehyde can be omitted. This route has been used to synthesize explosives like (92) and (209). ... 

Highly enantioselective organocatalytic Mannich reactions of aldehydes and ketones have been extensively stndied with chiral secondary amine catalysts. These secondary amines employ chiral prolines, pyrrolidines, and imidazoles to generate a highly active enamine or imininm intermediate species [44], Cinchona alkaloids were previonsly shown to be active catalysts in malonate additions. The conjngate addition of malonates and other 1,3-dicarbonyls to imines, however, is relatively nnexplored. Snbseqnently, Schans et al. [45] employed the nse of Cinchona alkaloids in the conjngate addition of P-ketoesters to iV-acyl aldimines. Highly enantioselective mnltifnnctional secondary amine prodncts were obtained with 10 mol% cinchonine (Scheme 5). 

The Mannich reaction consists on the condensation of a CH-activated compound with a primary or a secondary amine and a non-enolizable aldehyde or ketone to afford p-aminocarbonyl derivatives known as Mannich bases (Scheme 20). This sequence is of great use for the constmction of heterocyclic targets, as illustrated for example by the Robinson-Schopf synthesis of tropinone in 1937 or by the preparation of some azabicyclo[3.3.1]nonanones or pyranocoumarine derivatives (Fig. 1) [100]. In the following, representative recent examples of the formation of five- to seven-membered ring heterocycles will be presented. 

A Mannich reaction is the reaction of formaldehyde with a primary or secondary amine and a compound with an active hydrogen atom. The product, an amine with a y-carbonyl, is called a Mannich base, useful in a number of synthesis reactions. An example is in Figure 15-23, and the mechanism is in Figure 15-24. 

Finally, Ramsh and co-workers methylated 133 and isolated a 3 1 mixture of 135 and 136 albeit, in only 35% combined yield. The Russian authors offered a much different mechanistic rationale to account for these results than earlier work. Mannich reactions of 68 lead to markedly different results depending on the amine component (Schemes 6.36 6.37). For example, 137 was isolated in poor yield after refluxing a mixture of 68, benzylamine, paraformaldehyde, and acetic acid in methanol.The same material was also prepared from 138 under similar conditions. In a continuation of this work, Ramsh and co-workers investigated reactions using other primary and secondary amines. When 68 was treated with an excess of formalin and a secondary amine either 139 or 140 was isolated, albeit in fair to modest yield. However, some primary amines gave rise to the oxa-zolo[3,2-fl]l,3,5-triazines 141a-d, whereas other primary amines led to the... 

In a closely related example, a Mannich reaction of the somewhat more complex phenol (20-1) with formaldehyde and fert-butylamine gives the aminomethylated product (20-2). Hydrolysis of the acetamide protecting group then affords the corresponding aniline (20-3). Alkylation with the quinoline (17-6) in this case also proceeds on aniline nitrogen. The selectivity over the more basic secondary side nitrogen can probably be ascribed to steric hindrance about the latter. There is thus obtained tebuquine (20-4) [22]. 

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