Mannich reaction (1)


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Mannich reaction (1)

  1. 1. Rahul Patel M.S. IInd sem.Department of medicinal chemistry
  2. 2.  Background Reaction Mechanism Limitations Modifications Applications Conclusions
  3. 3. Carl Ulrich Franz Mannich (March 8, 1877 in Breslau-March5, 1947 in Karlsruhe) was a German ChemistFrom 1927 to 1943 he was Professor for pharmaceuticalchemistry at the University of BerlinHis areas of expertise were Keto bases, Alcoholbases, Piperidine-Derivatives, Papaverine, Lactone and alsoDigitalis-Glycoside
  4. 4. The Mannich reaction is the aminoalkylation reaction, involving thecondensation of an enolizable carbonyl compound with a nonenolizablealdehyde (like formaldehyde) and ammonia, or a primary or a secondaryamine to furnish a β-aminocarbonyl compound, also known as MannichbaseLi, J.J. Name Reactions. 2. Springer 2003.
  5. 5. Li, J.J. Name Reactions. 2. Springer 2003.
  6. 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. 7. Thus the range of application is limited (e.g. confined toaminomethylation)In many cases undesired side products are formedThe ability to control regio- and stereoselectivity is generallyunsatisfactory
  8. 8. Preformed Mannich reagentsHigher concentration of the electrophile, leading to lowerreaction temperatures and much shorter reaction timesMany undesired side reactions, which so often causeproblems in the Mannich reaction, are avoided, even withsensitive substratesCarbonyl component can be replaced with much morereactive synthetic equivalents such as enolatesExtended spectrum of application for the reaction
  9. 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 SaltsAngew. Chem. Int. Ed. 1998, 37, 1044-1070.
  10. 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 = 78:22Angew. Chem. Int. Ed. 1998, 37, 1044-1070.
  11. 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 NMe2Angew. Chem. Int. Ed. 1998, 37, 1044-1070.
  12. 12. Angew. Chem. Int. Ed. 1998, 37, 1044-1070.
  13. 13. O OH R N R1 NR 2 R1 R N TMSO O NChem. Ber. 1979, 112, 1913.Tet.Lett. 1980, 21, 805.
  14. 14. Angew. Chem. Int. Ed. 1998, 37. 1044-1070Angew. Chem. Int. Ed. 2004, 43. 5138-5175
  15. 15. Org. Lett. 2010, 12, 708-711.
  16. 16. J. Pharm. Sci. 1996, 4, 715-733.
  17. 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 TramadolChem. Pharm. Bull. 1994, 8, 1676-1685.J. Med. Chem. 1976, 19, 345-350.J. Org. Chem. 1959, 24, 1069-1076.
  18. 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 AnatoxinAngew. Chem. Int. Ed. 1998, 37, 1044-1070.
  19. 19. Angew. Chem. Int. Ed. 1998, 37, 1044-1070.
  20. 20. Nucleophilic addition of an enol to an iminium ion formed by the reaction of formaldehyde witha secondary amineMulti-component condensationAmino-methylationModifications like preformed mannich bases and use of different reagents like enolate s, silylenol ethers etc. gives wide range of the synthesis and amino-alkylationWide synthetic applicationsorganic synthesis of natural compounds suchas peptides, nucleotides, antibiotics, and alkaloids (e.g. tropinone)Agro chemicals such as plant growth regulators, paint- and polymer chemistry, catalysts andcrosslinkingMedicinal compoundse.g. rolitetracycline (Antibiotic), fluoxetine (antidepressant), tramadol, and tolmetin (anti-inflammatory drug)