59-331/333 Product Elements as Keys for Retrosynthetic Analysis 1. Base Catalyzed (‘Thermodynamic’) Aldol Condensation O O O 1 _ R R + 1 R H R ααα,α,,,ββββ- unsaturated carbonyl 2. Kinetic Aldol Condensation O OH O O 1 _ + R R R H R1 βββ-hydroxy carbonyl 3. Claisen Condensation/Dieckmann Condensation O O O O 1 _ + R R R EtO R1 1,3-dicarbonyl β (ββ-oxo carbonyl) 4. Darzens’ (Glycidic Ester) Condensation O O O O OEt Cl + R R OEt H H R O one carbon extension of aldehyde/ketone 5. Stobbe Condensation – not taught 2012 R R _ CO2Et CO2Et + R R O CO2Et CO2H 6. Enolate Alkylation/β-Keto Ester Alkylation-Decarboxylation O _ 3 1 + R X O R 2 R3 R R1 O R2 O _ CO Et CO Et R1 2 3 R1 2 + R X R2 R3 R2 7. Enolate O-Alkylation/Acylation/Silylation R3 _ O O 2 2 + 3 R 1 R R X R1 R enol ether/ester/silane 8. Enamine Alkylation O O + 3 R2 R3 R X 1 R1 N R R2 R1 ααα- alkylation of ketone 2 R 9. Imine Alkylation O Ph N Ph N O R3 2 1 R3 _ + R3 X R R R1 R1 R1 2 R R2 R2 ααα- alkylation of ketone 10. Michael Reaction O O O O + CO2Et R1 R R1 _ R or 1,5-dicarbonyl O O + 1 EtO2C R _ R 11. Robinson Ring Annulation (and its variants) 1 R R1 R2 O R2 O R2 O R1 O + _ O R3 R3 R3 fusion of cyclohexenone 12. Acid Catalyzed Halogenation O O Br + Br + H+ R1 R1 2 R2 R2 ααα-bromo ketone 13. Iodoform Reaction O O - + HO + I2 R OH R CH3 Carboxylic acid 14. Acid Catalyzed Aldol O O O + + H+ R1 R1 R H R ααα,α,,,ββββ-unsaturated carbonyl 15. Lewis Acid Mediated Aldol OSiMe O OH 3 O + + Lewis acid R1 R1 R H R ααα-hydroxy carbonyl 16. Mannich Reaction O O NR2 + 2 + CH2=O + HNR2 + H 1 R R1 R R2 βββ -Amino ketone 17. Elimination of Mannich Base O O NR2 ∆∆∆ - + CH3I; or HO R1 R1 R2 R2 ααα,α,,,ββββ-unsaturated carbonyl 18. Tertiary Alkylation of Silyl Enol Ethers – not taught 2012 O OSiMe3 1 + Me3C-X + TiCl4 R R1 2 R 2 R 19. Addition of Organometallics to CO 2 O RM + CO2 R OH Carboxylic acid 20. Addition of Organometallics to Aldehyde/Ketone OH O R3 M + R1 R2 R1 R3 R2 21. Di-addition of Organometallics to Esters OH O + 2 R2-M R1 R2 1 R2 R OEt 3o alcohol, 2 identical groups 22. Addition of Organometallics to Nitriles O R1 N + R2-M R1 R2 Ketone 23. Addition of Cuprates to Acid Chlorides O O + R2-M R1 R2 R1 Cl Ketone 24. Addition of Organometallics to Weinreb Amides O O 2 1 OMe + R -M R1 R2 R N Ketone CH3 25. 1,4-(Conjugate) Addition of Cuprates 2 1 R1 2 R R + (R )2CuLi O O βββ-Alkyl/Aryl Carbonyl 26. Addition of Organometallics to Epoxides R1 O 1 2 R2 R + R -M OH 27. Addition of Allylsilanes to Aldehydes/Ketones – not taught in 2012 O OH + SiMe3 + Lewis acid H R1 R1 28. Reformatsky Reaction – not taught in 2012 O O OH O + + Zno Br H R1 EtO R1 EtO βββ-Hydroxy Ester 29. Hydrogenation of Alkynes R1 R2 + H2/Lindlar R1 R2 (Z)- Alkene 30. Hydrogenation of Alkenes R2 R2 1 + H2/Catalyst R1 R Alkane 31. Hydrogenation of Ketones/Aldehydes O OH + H2/Catalyst R1 R2 R1 R2 1o or 2o Alcohol 32. Hydroboration-Oxidation of Alkenes OH 1 + BH ;H O /HO- R1 R 3 2 2 Alcohol (anti-Markovnikov) 33. Hydroboration-Protonation R2 R2 1 + BH3; CH3CO2H R1 R Alkane 34. Hydroboration of Aldehydes/Ketones O OH + + BH3;H3O R1 R2 R1 R2 1o or 2o Alcohol 35. Hydroboration of Carboxylic Acids O OH + + BH3;H3O R1 OH R1 1o Alcohol 36. Hydride Attack on Aldehydes/Ketones OH O + "H-" 1 2 R R R1 R2 1o/2o Alcohol 37. Hydride Attack on Esters/Acids OH O + "H-" 1 R R1 OR2 1o Alcohol 38. Clemmensen/Wolff-Kischner/Dithioacetal Reduction O + Zn/Hg, HCl or H2N-NH2/KOH/ethylene glycol, 1 2 1 2 R R R R or HSCH2CH2SH/BF3, then H2/Ni Alkane 39. Birch Reduction 1,4-cyclohexadiene 40. Metal-Acid reduction O O or O 1 2 1 2 R R R R R1 R2 Alkanone X 41. Acyloin Condensation O O R1 + Nao R1 R1 OEt OH ααα-Hydroxy ketone 42. Oxidation of Alcohols to Aldehydes/Ketones O OH R1 R2 R1 R2 Ketone/Aldehyde 43. Oxidation of 1 o Alcohols/Aldehydes to Acids O OH O + 1 R1 OH R R1 H Acid 44. MnO 2 Oxidation O OH R2 R1 R2 R1 ααα,α,,,ββββ-Unsaturated Aldehyde/Ketone 45. Peracids Oxidation of Alkenes O R2 3 1 + R CO3H R1 R2 R Epoxide 46. Nucleophilic Ring Opening of Epoxides (see # 26 ) OH O R2 + Nu R1 R1 R2 Nu βββ-"Nu" Alcohol 47. Baeyer-Villiger Oxidation O O 2 1 R R O R1 R2 Ester/Lactone 48. Epoxidation of Unsaturated Ketones O O - O + H2O2, HO R2 R2 R1 R1 Epoxy Ketone 49. Osmylation of Alkenes OH R2 R2 R1 R2 + OsO4 OH 1,2-Diol 50. Periodate Oxidation of Vicinal Diols OH O O R3 + + NaIO R1 R2 4 R1 H R2 R3 OH 51. Ozonolysis (Reductive Workup) O O R2 + O ; Me S + R2 3 2 R1 H R2 R3 R3 Aldehyde or Ketone (2 molecules) 52. Ozonolysis (Oxidative Workup) O O R2 + O ;H O + R1 3 2 2 1 R2 R3 R OH R3 Acid or Ketone (2 molecules) 53. Wittig Reaction PPh3 R2 O R2 R1 + R1 R3 R3 Alkene 54. Horner-Wadsworth-Emmons Reaction 2 1 2 EtO _ R R R R1 + EtO P 3 3 R O R O O O ααα,α,,,ββββ-Unsaturated Carbonyl 55. Diels-Alder Reaction EWG EWG + Cyclohexene/Cyclohexadiene 56. Curtius Rearrangement O O 1 - R NH2 1 + N3 R N3 R1 Cl Amine with 1C less 57. Beckmann Rearrangement HO O N O 2 + H2N-OH 1 R R N R1 R2 1 2 H R R Amide/Lactam 58. Arndt Eistert Synthesis O O O 1 + CH2N2 R R1 CHN OH 2 R1 Cl Acid with 1C more 59. Protection/Deprotection of Ketone/Aldehyde O RO OR + 2 ROH + H+ R1 R2 R1 R2 Ketone/Aldehyde Acetal 60. Protection/Deprotection of Alcohols + R1 + + H R1 OH O O O Alcohol THP ether .