Lecture7: 123.312

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Told you that this was the important one. This weeks reagents include more enolates and then reactions with the C=O group including the such classics as the Wittig reaction.

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Lecture7: 123.312

  1. 1. FUNCTIONALGROUP 123.312 INTERCONVERSIONS LECTURE7
  2. 2. issue seven more c-c bond formation
  3. 3. chapter one the return of enolate chemistry
  4. 4. previously...
  5. 5. competing addition Li Li O Bu O Li O Bu H H
  6. 6. ? the solution
  7. 7. lithium diisopropylamide N Li Bu H pKa = 36 pKa = 48-51 (conjugate acid)
  8. 8. lithium diisopropylamide N Li Bu N H Bu H Li
  9. 9. lithium diisopropylamide LDA N N Li Li non-nucleophilic
  10. 10. what about...? ? Li O NiPr2 H
  11. 11. look at pKa... O N Li > H pKa = 36 pKa = 26.5 therefore...
  12. 12. deprotonation and no nucleophilic attack Li Li O NiPr2 O N H H
  13. 13. a second solution
  14. 14. Silyl enol ethers SiR3 O act like enolates
  15. 15. allow the use of weak bases O SiR3 O R3Si Cl H H Et3N: SiR3 O
  16. 16. reactions of enolates
  17. 17. enolates as nucleophiles Li O O R X Li X R
  18. 18. reactions of silyl enol ethers
  19. 19. silyl enol ethers & strong electrophiles SiR3 Cl AlCl3 O O AlCl4 Cl SiR3 SiR3 O O
  20. 20. silyl enol ethers & weak electrophiles SiR3 MeLi O O R X R SiR3 Me SiR3 Li O O Li Me R X
  21. 21. what about ? regioselectivity
  22. 22. unsymmetrical ketones can give two products O R O LDA and / or R X O R
  23. 23. how can we control ? regioselectivity
  24. 24. O O O O OEt OEt OEt H X R O O OEt method 1: Activated starting material R
  25. 25. ...then remove activating group O O O O NaOH OEt O Na R R H H O O O R heat O CO2 R
  26. 26. method 2: selective enolate formation O O O O kinetic energy O thermo- dynamic O reaction progress
  27. 27. formation of thermodynamic enolate... O R3Si Cl SiR3 O NEt3 SiR3 SiR3 SiR3 O δ+ O δ+ O or H H δ+ NEt3 δ+ NEt 3
  28. 28. or... OH O OH minor major R3Si Cl SiR3 Et3N H SiR3 O O
  29. 29. then regenerate enolate SiR3 Li O MeLi O
  30. 30. kinetic enolate O O H H H • more accessible (use bulky base) • more acidic (strong base at low temperature)
  31. 31. chapter two some reactions of enolates
  32. 32. O LDA O O O OH
  33. 33. Text OH O vitamin E ©darwin bell@flickr
  34. 34. Enolate alkylation Cy(iPr)NLi HMPA / THF Li N N PhO2S O O PhO2S O O I O Xc O
  35. 35. chapter three other nucleophiles
  36. 36. what about...? R C C H H2N Na ?
  37. 37. look at pKa... H2N Na R C C H pKa = 35 > pKa = 26 therefore...
  38. 38. deprotonation and nucleophilic attack R C C H H2N Na R C C Br Ph R C C Ph
  39. 39. other nucleophiles: nitriles Na CN Ph Br Ph CN
  40. 40. other nucleophiles: nitriles N N C :base C Ph H H Ph H Br CN Ph
  41. 41. the use of nitriles... O OH R CN C R OH Ni / H2 R CN R NH2
  42. 42. chapter four additions to C=O
  43. 43. previously on C-C bond formation... SN1 Nuc R X Nuc R X SN2 substitution reactions
  44. 44. Now, attack on... O C
  45. 45. mechanism 1: carbonyl without leaving group O O Cnuc Cnuc 1 2 R 1 R 2 R R HO Cnuc R1 R2
  46. 46. mechanism 2: carbonyl with leaving group O O Cnuc Cnuc 1 R1 LG R LG HO Cnuc O Cnuc Cnuc O R1 Cnuc R1 Cnuc R1 Cnuc
  47. 47. chapter four and a bit “organometallics”
  48. 48. Grignard reagents O HO R c R c MgBr 1 2 R1 R2 R R O Rc H BrMg R1 R2
  49. 49. Grignard reagents O HO Rc R c MgBr R1 OR2 R1 Rc impossible to stop at ketone
  50. 50. organolithium reagents O HO Rc Rc Li 1 2 R 1 R 2 R R O HO Rc Rc Li 1 2 R 1 R c R OR similar to Grignards except more nucleophilic (& BAsic)
  51. 51. increased reactivity allows... O Me Li O Me Li O Li H O Li R1 O R1 O Li R1 Me H2O O OH R1 OH R1 Me Me
  52. 52. Cl OH Cl N N fenarimol antifungal ©bmooneyatwork@flickr
  53. 53. organometallic reagent in total synthesis Li Cl Cl N N OH Cl O Cl N N
  54. 54. big problem
  55. 55. Nucleophilicity versus basicity Li MeO H H MeO H O O OMe OMe
  56. 56. transmetallation Li can give a less basic derivative CeCl3 Cl2Ce MeO MeO OH O OMe OMe
  57. 57. chapter four and a bit more “the wittig reaction”
  58. 58. the wittig reaction (or at least one of them) O PPh3 R 2 R 1 R 1 2 R
  59. 59. formation of ylide PPh3 Ph3P: R 2 Br Br R2 H base PPh3 PPh3 R 2 R2
  60. 60. two possible mechanisms... PPh3 O PPh3 O betaine PPh3 O oxaphosphetane
  61. 61. second mechanism O PPh3 Ph3P R O R H H PPh3 O
  62. 62. Wittig normally gives Z-alkenes O PPh3 1 2 R R R 1 2 R
  63. 63. Wittig normally gives Z-alkenes O O PPh3 O EtO O OHC H H O O O O EtO O H H O
  64. 64. Reason: Sterics of addition O PPh3 1 2 R R R1 R 2 Ph3P H O PPh3 O R1 R 1 R 2 R2 H
  65. 65. Reason: Sterics of addition O PPh3 1 2 R R R1 R 2 Ph3P H O PPh3 O R1 R 1 R 2 R2 H
  66. 66. Stabilised ylides O O PPh3 PPh3 R2 R 2
  67. 67. Stabilised ylide normally gives E-alkenes PPh3 O 2 R R1 2 1 R R O
  68. 68. Stabilised ylide normally gives E-alkenes O PPh3 EtO EtO2C O OHC O O O
  69. 69. Reason: reversibility of addition O PPh3 slow R1 CO2Et R1 CO2Et O PPh3 R1 CO2Et O PPh3 fast R1 CO2Et R1 CO2Et

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