1. Rahul Patel
M.S. IInd sem.
Department of medicinal chemistry

2.  Background
 Reaction
 Mechanism
 Limitations
 Modifications
 Applications
 Conclusions

3. Carl Ulrich Franz Mannich (March 8, 1877 in Breslau-March
5, 1947 in Karlsruhe) was a German Chemist
From 1927 to 1943 he was Professor for pharmaceutical
chemistry at the University of Berlin
His areas of expertise were Keto bases, Alcohol
bases, Piperidine-Derivatives, Papaverine, Lactone and also
Digitalis-Glycoside

4. The Mannich reaction is the aminoalkylation reaction, involving the
condensation of an enolizable carbonyl compound with a nonenolizable
aldehyde (like formaldehyde) and ammonia, or a primary or a secondary
amine to furnish a β-aminocarbonyl compound, also known as Mannich
base
Li, J.J. Name Reactions. 2. Springer 2003.

5. Li, J.J. Name Reactions. 2. Springer 2003.

6. O-
O
O Enolate R1
R2 R
R1 N R2
R2 f ormation
R R1
H R
N
R
B:
Li, J.J. Name Reactions. 2. Springer 2003.

7. Thus the range of application is limited (e.g. confined to
aminomethylation)
In many cases undesired side products are formed
The ability to control regio- and stereoselectivity is generally
unsatisfactory

8. Preformed Mannich reagents
Higher concentration of the electrophile, leading to lower
reaction temperatures and much shorter reaction times
Many undesired side reactions, which so often cause
problems in the Mannich reaction, are avoided, even with
sensitive substrates
Carbonyl component can be replaced with much more
reactive synthetic equivalents such as enolates
Extended spectrum of application for the reaction

9. Preformed Mannich reagents
NR R 2N NR 2 R 2O NR 2
R1 R1 R1
Imines Aminals N,O-acetals
N
N
N NR2
NR 2 R1 X
R1
benzotriazole aminals Iminium Salts
Angew. Chem. Int. Ed. 1998, 37, 1044-1070.

10.  Carbonyl Compounds (With Iminium salts)
O
H 2C NMe 2 Cl O
Ph
Ph NMe2 HCl
 Enolates (With N,O acetals)
OLi
O N
O N
+ N +
Ph
Ph
Ph OTiCl3
anti : syn = 78:22
Angew. Chem. Int. Ed. 1998, 37, 1044-1070.

11. Boron enol ethers (With aminals)
OBBu2 O NMe 2 O NMe 2
Me2 N
Ph + Ph Ph +
Ph NMe2 Ph Ph
anti syn
Silyl enol ethers (With methelene iminium salts)
OSiMe3 OSiMe3 O
NMe 2 1) HCl
CH 2 I 2) OH-
NMe2 HI NMe2
Angew. Chem. Int. Ed. 1998, 37, 1044-1070.

12. Angew. Chem. Int. Ed. 1998, 37, 1044-1070.

13. O
OH R
N R1 NR 2
R1
R
N
TMSO O
N
Chem. Ber. 1979, 112, 1913.
Tet.Lett. 1980, 21, 805.

14. Angew. Chem. Int. Ed. 1998, 37. 1044-1070
Angew. Chem. Int. Ed. 2004, 43. 5138-5175

15. Org. Lett. 2010, 12, 708-711.

16. J. Pharm. Sci. 1996, 4, 715-733.

17. O
O
R1
R1 HN N
HN HN HCHO
R2
R2 O N
O N H
H
N HN
O O
HCHO F
Me2NH O F
HCl F
fluoxetin
O
O O
N
(CH 2O) n/AcOH N HCL
N HCl
H HO
Tramadol
Chem. Pharm. Bull. 1994, 8, 1676-1685.
J. Med. Chem. 1976, 19, 345-350.
J. Org. Chem. 1959, 24, 1069-1076.

18. Bn Bn
N N Cl
O
COCl COOMe
HOOC 2 N
N
Bn COOMe
COMe Epibatidine
H
Bn N
O N
COMe
COCl
2
HOOC N
COOMe MeOOC Ferruginine
Bn
O Bn
N O H O
COCl N
HOOC N
2
n
Bn
Anatoxin
Angew. Chem. Int. Ed. 1998, 37, 1044-1070.

19. Angew. Chem. Int. Ed. 1998, 37, 1044-1070.

20. Nucleophilic addition of an enol to an iminium ion formed by the reaction of formaldehyde with
a secondary amine
Multi-component condensation
Amino-methylation
Modifications like preformed mannich bases and use of different reagents like enolate s, silyl
enol ethers etc. gives wide range of the synthesis and amino-alkylation
Wide synthetic applications
organic synthesis of natural compounds such
as peptides, nucleotides, antibiotics, and alkaloids (e.g. tropinone)
Agro chemicals such as plant growth regulators, paint- and polymer chemistry, catalysts and
crosslinking
Medicinal compounds
e.g. rolitetracycline (Antibiotic), fluoxetine (antidepressant), tramadol, and tolmetin (anti-
inflammatory drug)