Mannich bases deamination

Fig. 81) may occur on either the substrate (a) or the amine (b) side, thus affording deaminomethylation or deamination, respectively. Although the possibility of simultaneous reaction exists, one process usually prevails over the other, - depending on the chemical nature of the base. In general, C-Mannich bases, particularly the kctonic ones, arc more stable toward deaminomethylation, the reverse occurring with X-Mannich bases. There are, however, important exceptions to this behavior. 

Unsaturated Products Given by Deamination Reaction of Mannich Bases ... 

A reaction occurring during Mannich thesis. H deamination of the free Mannich base or the add ammonium sail (hydrochloride, etc.)- C deamination of the tetraallgdammonium salt of the... 

In several deamination reactions, formation of the hydroxymethyl derivatives 243 (Fig. 90) is frequently reported instead of the expected unsaturated product. Thus, deamination of para-aminomethyl phenols (242, R = p-hydroxyphenyl) produces an intermediate methylenequinonc, which then evolves to hydroxymethyl phenol by reaction with water, - whereas deamination of aminome-thane sulfonates (242, R = SO Na) proceeds through an Sn2 attack by water on the zwit-terionie form of the Mannich base to yield the hydroxylated derivative. - "... 

Although characterized by a quite complex mechanism, the deamination of acetylenic Mannich bases by lithium-alkyF yields interesting substituted acroleins R—CH=CH—CHO, that is, the isomeric form of the corresponding acetylenic hydroxymethyl derivatives R—C C—CH2OH, as a consequence of alkync metallation followed by hydrolysis. 

The hydrogenolysis product of the Mannich base is also obtained through the formation of a suitable intermediate, in some cases not isolated or purified, which is subsequently subjected to hydrogenation. This may be an unsaturated derivative (R=CH2) produced by deamination of Mannich base, - - or the R—CH2—X (X = 0-Acyl or S-Alkyl -) product deriving from amino group replacement. 

Inversely, vinylogous Mannich bases give the adducts 334 by reaction with dieno-philes such as maleic anhydride or with a vinyl group of their deamination product, thus... 

Five-membered O-heterocycIic derivatives of the type dihydrobenzofuran (352 in Fig. 137) are formed by reaction with diazomethane or analogous reagents. It is to be stressed, in partieular, that the deamination of a Mannich base may be favored by the formation of amine N-oxide, instead of the corresponding quaternary ammonium salt, as is usually required. 

Finally, phenolic Mannich bases may provide heterodiene formation at the ortho-mcthylencquinone moiety originated by deamination (Fig. 139 sec also Fig. 134) this... 

When a Mannich reaction is carried out between a substrate containing at least two active hydrogen atoms and a primary or a bis-secondary amine, a polycondensation takes place with production of a polymeric derivative. Fhe polycondensation can also occur when both an NH group and one active hydrogen atom arc present in the same molecule. The reaction product is thus characterized by the presence of the methylene moiety, whieh is derived from the formaldehyde, and forms the polymer backbone, with the consequent possibility of polymer degradation by deamination or dcaminomethy-lation both of these reactions are typical of Mannich bases (Chap. II, A). 

The above monomers are obtained mainly by deamination or deaminodccarboxy-lation of carboxylic Mannich bases. Acrylic monomers have also been obtained by addition of alkenc Mannich bases to acrylonitrile and vinyl monomers by deamination of the Mannich bases of alkylpyridines and alkylquinolines. - ... 

Replacement of the amino group in the Mannich base is also applied to alkaloid synthesis. Thus, ellipticinc alkaloids are prepared by deamination of the intermediate indole Mannich base 457 (Fig. 174), which allows ring closure to the hcxa-atomic cycle evolving. subsequently toward the phenolic moiety (458) through the occurrence of tautomeric equilibria. 

Steroidal aminomethyl derivatives have been subjected to some of the reactions typical of Mannich bases, described in Chap. II, usually with the aim of introducing structural modifications of the molecule by means, in particular, of deamination and hydrogen-olysis. The formation of a quaternary ammonium salt (mainly iodomethylatc) by N-alkylation of the base - is also performed to the same end in order to obtain unsaturated deaminated products. ... 

Deamination is the most commonly performed reaction of steroid Mannich bases. It is usually carried out by heating the base in the presence of acetic acid/acctic anhydride, - by column chromatography on silica gel, by heat decomposition of the corresponding hydrochloride or iodomethylate, or under suitably modified reaction conditions leading directly to the unsaturated final pnxluct starting from the usual Mannich reactants (Chap. II, A.2). 

Fig. 175. Deamination reaction of vinylogous Mannich bases of steroid derivatives.

The repotted observations of the cleavage (dcaminomethylation and deamination sec Chap. II, A. I and 2) as well as the /ra 5-aminomethylation reactions (see 32f-h in Table 5 and Ref. 283) of Mannich bases also give useful support to this argument. 

Except in rare cases, the deamination reaction (Fig. 85) is peculiar to C-Mannich bases and involves the elimination of a primary or secondary amine from 231 or of a tertiary amine from the quaternary ammonium salt 232. The presence of a hydrogen atom in the P position with respect to the amino group is not essential, as other groups, such as the carboxyl group of P-amino acids 233 may also be eliminated in conjunction with the amine. 

Several different deamination procedures are reported in Table 23, as the reaction may take place alternatively by modification of Mannich synthesis (A), by suitable treatment of a Mannich base (B), or by conversion of the base into the corresponding quaternary ammonium salt, which is more easily decompo,sable (C). Due probably to steric reasons, some particular amines, such as diethylamine, are more suited to the deamination process. - - - ... 

Fig. S6. Deamination of cyclohexanone Mannich bases leading to a phenol derivative.

Acetylenic Mannich bases, upon deamination, tend to produce isomerized derivatives such as allenes or compounds of type 239, bearing the alkyne moiety as an end group, These compounds are cKcasionally found in the presenee of vinyl acetylenes... 

Ring closure with concomitant amino group elimination is actually a replacement reaction, as depicted below, strictly connected with the replacement reaction described in Sec. B. Similarly, the cyclization mechanism may or may not involve the formation of a vinyl intermediate (vinylketone, methylcnequinone, etc.), originated by the deamination of the initial Mannich base, which then undergoes addition. 

Finally, acyl-qxjxides 347 may be produced in appreciable quantity by deamination of the iodomethyl derivative of Mannich ketobasc in the presence of hydrogen per-oxide, and cyclic sulfoncs 348 are yielded by reaction of sodium hydroxymethane sulfmate, HOCH2SC>2Na, with the Mannich base of CS-diphenyl-pentanedionc. ... 

Phenolic Mannich bases afford cyclic derivatives as the result of deamination, O-heterocycles being prepared to a larger extent than N-heterocycles, although an interesting example of homocycle synthc.sis (Fig. 135) from para-aminomethylated phenolic Mannich bases is worth mentioning. ... 

N-Alkylation—Secondary Mannich bases can give the corresponding tertiary derivatives by treatment with particular alkylation agents, such as epoxides (affording P-ami-noalcohols) and acrylic derivatives. Tertiary Mannich bases, mostly, are submitted to N-alkylation in order to produce stable quaternary ammonium salts to be subsequently subjected to deamination (Sec. A.2). However, different quaternary ammonium byproducts can be readily given by the reaction. " For instance, a base-catalyzed rearrangement is afforded by allyl ammonium salts 365 (Fig. 144), obtained by N-alkylation of acetylenic Mannich bases with ally] halides. " In the presence of sodium hydride, the compounds 365 yield a wide range of 3-amino-5-hexen-l-yne derivatives 366. 

In addition to the side reactions mentioned above, deamination of Mannich bases can occur, especially at elevated temperature, to give a,p-unsaturated derivatives. This route of decomposition of Mannich bases has been exploited as a means of in situ generation of a,p-unsaturated ketones in the Michael reaction and for the direct synthesis of a,3-unsaturated ketones several reviews of the Mannich reaction have discussed aspects of these applications.Recently, a direct one-pot synthesis of a-methylene ketones has been reported involving condensation of ketones with formaldehyde and A -methylaniline tri-fluoroacetate in aptotic solvents. Also, a less direct method has been described in which Mannich bases prepared from 3-keto esters, formaldehyde and dimethylamine are subjected to quatemarization and thermal fragmentation to yield a-methylene ketones.This method is particularly useful for the regios-pecific synthesis of a-methylene ketones because the aminomethylation reaction always takes place at the most activated position flanked by the ketone and ester groups. 

Some preparative importance attaches also to reductive deamination of tertiary Mannich bases, which are accessible by condensation of a CH-acidic compound with formaldehyde and a secondary aliphatic amine. By this route... 

The pyrrolizidine nucleus is characteristic of this group of alkaloids. The a is either L-omithine or l-arginine, and the p is a biogenic amine, the putrescine. Oxidative deamination by the enzyme NAD" converts two molecules of putrescine into the imine (oxidative deamination, Schift-base formation, oxidative reaction again, and the intramolecular Mannich reaction. 

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