Page 168 - Advanced Organic Chemistry Part B - Reactions & Synthesis

140 2.2.1. The Mannich Reaction

CHAPTER 2 The Mannich reaction is the condensation of an enolizable carbonyl compound
Reactions of Carbon with an iminium ion. 180 It is usually done using formaldehyde and introduces an
Nucleophiles with -dialkylaminomethyl substituent.
Carbonyl Compounds
O O
CR′ + CH O + HN(CH ) (CH ) NCH CHCR′
RCH 2 2 3 2 3 2 2
R

The electrophile is often generated in situ from the amine and formaldehyde.

H + +
CH 2 O + HN(CH ) HOCH N(CH ) CH 2 N(CH )
3 2
3 2
2
3 2
The reaction is normally limited to secondary amines, because dialkylation can occur
with primary amines. The dialkylation reaction can be used to advantage in ring
closures.
O
CH CH 2 O CH CH 3 C H C H
2 5
3
2 5
2
CH O CCH C CHCO CH 3 +CH 2 O +CH NH 2 CH O C CO CH 3
3
2
2
3
3
2
2
N
CH 3
Ref. 181
Scheme 2.12 shows some representative Mannich reactions. Entries 1 and 2
show the preparation of typical “Mannich bases” from a ketone, formaldehyde, and
a dialkylamine following the classical procedure. Alternatively, formaldehyde equiva-
lents may be used, such as bis-(dimethylamino)methane in Entry 3. On treatment with
trifluoroacetic acid, this aminal generates the iminium trifluoroacetate as a reactive
electrophile. N,N-(Dimethyl)methylene ammonium iodide is commercially available
and is known as Eschenmoser’s salt. 182 This compound is sufficiently electrophilic to
react directly with silyl enol ethers in neutral solution. 183 The reagent can be added to
a solution of an enolate or enolate precursor, which permits the reaction to be carried
out under nonacidic conditions. Entries 4 and 5 illustrate the preparation of Mannich
bases using Eschenmoser’s salt in reactions with preformed enolates.
The dialkylaminomethyl ketones formed in the Mannich reaction are useful
synthetic intermediates. 184 Thermal elimination of the amines or the derived quaternary
salts provides -methylene carbonyl compounds.
180
F. F. Blicke, Org. React., 1, 303 (1942); J. H. Brewster and E. L. Eliel, Org. React., 7, 99 (1953);
M. Tramontini and L. Angiolini, Tetrahedron, 46, 1791 (1990); M. Tramontini and L. Angiolini,
Mannich Bases: Chemistry and Uses, CRC Press, Boca Raton, FL, 1994; M. Ahrend, B. Westerman,
and N. Risch, Angew. Chem. Int. Ed. Engl., 37, 1045 (1998).
181 C. Mannich and P. Schumann, Chem. Ber., 69, 2299 (1936).
182
J. Schreiber, H. Maag, N. Hashimoto, and A. Eschenmoser, Angew. Chem. Int. Ed. Engl., 10, 330
(1971).
183 S. Danishefsky, T. Kitahara, R. McKee, and P. F. Schuda, J. Am. Chem. Soc., 98, 6715 (1976).
184
G. A. Gevorgyan, A. G. Agababyan, and O. L. Mndzhoyan, Russ. Chem. Rev. (Engl. Transl.), 54, 495
(1985).