C-C linkage by replacement of hydroxyl by carbon 955Hydroxyalkylation occurs when certain compounds containing active
protons are treated with higher aldehydes: e.g., the copper chelate of glycine
reacting with aldehydes affords <%-amino-/?-hydroxy acids:
693'
694RCHO + NH 2 CH 2 COOH • R—CH—CH—COOHHO NH 2Diethyl chloromalonate and acetaldehyde give diethyl <%-chloro-<%-(l-hydroxy-
ethyl)malonate analogously.
695- Aminomethylation (Mannich reaction)
1060
'6966973A 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,
698can be formulated as:
RH + CH 2 O + R
/2 NH 2 +Cr > RCH 2 NHR
/
2+Cl- + H 2 O
It has been widely employed in synthesis. Many groups of workers have devoted
an extremely large number of papers to its application to the most varied
types of compound containing acidic CH groups. The frequent use of this
reaction is due to the simplicity of the technique and the far-ranging applic-
ability of the so-called Mannich bases in syntheses of very varied type. Several
reviewers have collected the available material;
696an excellent oversight,
including the synthetic applications of Mannich bases, is given in a book by
Hellmann and Opitz.
697aThe CH-acidic compounds used include acetylenes,
nitriles, ketones, both cyclic and open-chain, alkyl aryl and diaryl ketones,
oxo acids, dicarboxylic acids, aldehydes, iV,iV-dialkylarylamines, phenols,
aromatic compounds with activated side chains, ^-aromatic compounds such
as azulenes, aliphatic nitro compounds, and heterocycles such as furan,
pyrrole, indole, and pyrazolone. For the reaction with hydrogen cyanide
see page 519.
The carbonyl component has been almost exclusively formaldehyde, in
aqueous solution or as paraformaldehyde, and only rarely other aldehydes
such as acetaldehyde.
699The 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:
NH 3 • RCH 2 NH 2 > (RCH 2 )NH > (RCH 2 ) 3 N693 x. T. Otani and M. Winitz, Arch. Biochem. Biophys., 102, 464 (1963); H. Mix and
F. W. Wilcke, Z. Physiol. Chem., 337, 40 (1964).(^694) H. Mix, Z. Physiol. Chem., 327, 41 (1961).
(^695) H. Gault and P. Bouvier, C. R. Hebd. Seances Acad. Set, 254, 2179 (1962).
(^696) F. F. Blicke, Org. Reactions, 1, 303 (1942); H. Hellmann and G. Opitz, Angew. Chem.,
68, 697 265 (1956); B. Reichert, "Die Mannich-Reaktion," Springer-Verlag, Berlin, 1959.
H. Hellmann and G. Opitz, (a) "A-Aminoalkylierung," Verlag Chemie, Weinheim/
Bergstrafie, 698 1960, (b) p. 218, (c) pp. 251, 256, 263.
C. Mannich and co-workers, Arch. Pharm., 250, 647 (1912); 264, 65, 164 (1926);
265, 684 (1927); Ber. Deut. Chem. Ges., 55, 3510 (1922); 53, 1874 (1920).
(^699) C. Mannich and P. Mohs, Ber. Deut. Chem. Ges., 63, 608 (1930), P. Petrenko-Krit-
schenko, Ber. Deut. Chem. Ges., 42, 3683 (1909).