Mannich reaction (1)
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The Mannich reaction involves the condensation of an enolizable carbonyl compound, an aldehyde such as formaldehyde, and a primary or secondary amine. This results in an aminoalkylation and formation of a β-aminocarbonyl compound known as a Mannich base. Modifications using preformed Mannich bases and reactive substrates extend the scope and selectivity of the reaction. The Mannich reaction has wide applications in organic synthesis and for producing natural and medicinal compounds.
Mannich reaction (1)
- 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)