The Mannich reaction starts with the
nucleophilic addition of an amine to a carbonyl group followed by dehydration to the
Schiff base. The Schiff base is an
electrophile which reacts in a second step in an
electrophilic addition with an enol formed from a carbonyl compound containing an acidic alpha-proton. The Mannich reaction is a
condensation reaction.[4]: 140
In the Mannich reaction, primary or secondary
amines or ammonia react with formaldehyde to form a Schiff base. Tertiary amines lack an N–H proton and so do not react. The Schiff base can react with α-CH-acidic compounds (
nucleophiles) that include carbonyl compounds,
nitriles,
acetylenes, aliphatic
nitro compounds, α-alkyl-
pyridines or
imines. It is also possible to use activated
phenyl groups and electron-rich heterocycles such as
furan,
pyrrole, and
thiophene.
Indole is a particularly active substrate; the reaction provides
gramine derivatives.
The Mannich reaction can be considered to involve a mixed-
aldol reaction, dehydration of the alcohol, and conjugate addition of an amine (
Michael reaction) all happening in "
one-pot". Double Mannich reactions can also occur.
Reaction mechanism
The mechanism of the Mannich reaction starts with the formation of an
iminium ion from the amine and formaldehyde.[4]: 140
The compound with the carbonyl functional group (in this case a
ketone) will
tautomerize to the enol form, after which it attacks the iminium ion.
On methyl ketones, the enolization and the Mannich addition can occur twice, followed by an β-elimination to yield β-amino enone derivatives.[5][6]
Asymmetric Mannich reactions
(S)-prolinecatalyzes a chiral Mannich reaction. It diastereoselects the
syn adduct, with greater effect for larger aldehyde substituents; and enantioselects the (S, S) adduct.[7] A substituted proline can instead catalyze the (R, S) anti adduct.[8]
Applications
The Mannich reaction is used in many areas of organic chemistry, Examples include:
^
abcCarey, Francis A.; Sundberg, Richard J. (2007). Advanced Organic Chemistry: Part B: Reactions and Synthesis (5th ed.). New York: Springer. pp. 140–142.
ISBN978-0387683546.
^Cromwell, Norman H.; Soriano, David S.; Doomes, Earl (November 1980). "Mobile keto allyl systems. 18. Synthesis and chemistry of N-substituted and N,N-disubstituted 2-benzoyl-1-amino-3-propenes". The Journal of Organic Chemistry. 45 (24): 4983–4985.
doi:
10.1021/jo01312a034.
^Girreser, Ulrich; Heber, Dieter; Schütt, Martin (May 1998). "A Facile One-Pot Synthesis of 1-Aryl-2-(dimethylaminomethyl)prop-2-en-1-ones from Aryl Methyl Ketones". Synthesis. 1998 (5): 715–717.
doi:
10.1055/s-1998-2056.