1. 1 Chapter 5 Formatio of carbon-carbon bonds: the use of stabilized carbanions and related nucleophiles 5.1Carbanions stabilized by two –M groups 5.2Carbanions stabilized by one –M groups 5.3Carbanions stabilized by neibouring phosphorous or sulfur 5.4Nucleophilic acylation

2. 2 5.1Carbanions stabilized by two –M groups 5.1.1Alkylation 5.1.2Hydrolysis of the alkylated products: a route to carboxylic acids and ketones 5.1.3Acylation 5.1.4Condensation reaction 5.1.5The Michael reaction

3. 3

4. 4 5.1.1Alkylation Monoalkylation –Appropriate base

5. 5

6. 6

7. 7 Dialkylation –If the two alkyl groups are identical, ‘one pot’ reaction may be a choice.

8. 8

9. 9 Dialkylation –If two different alkyl groups, they may be introduced in stepwise manner: Smaller group first, then bulky group. The group having lesser electron-repelling effect first.

10. 10

11. 11 5.1.2Hydrolysis of the alkylated products: a route to carboxylic acids and ketones

12. 12 A method for the conversion of halides into carboxylic acids or ketones

13. 13

14. 14

15. 15 5.1.3Acylation A method for the conversion of RCOCl to RCOCH 3

16. 16

17. 17 Preparation of ß-keto-ester

18. 18 5.1.4Condensation reaction Knoevenagel condensations Addition of a catalytic amount of organic acid or an ammonium salt (usually the acetate) used as catalyst increase the yield.

19. 19 Aldehyde

20. 20 Ketone

21. 21 Variant of Knoevenagel condensations E-isomer is usually formed

22. 22

23. 23 5.1.5The Michael reaction

24. 24

25. 25

26. 26 α,β-unsaturated aldehydes may undergo a Knoevenagel-type condensation or a Michael reaction or (in some cases) both.

27. 27 5.2Carbanions stabilized by one –M group 5.2.1Alkylation 5.2.2Acylation 5.2.3Indirect routes to α-alkylated aldehydes and ketones 5.2.4Condensation reaction 5.2.5The Michael reaction

28. 28 5.2.1Alkylation Where the stabilizing –M group is a cyano or an ester group, the reactions are staightforward.

29. 29 Where the stabilizing –M group is ketonic or aldehydic, serious complications may arise. –For aldehydes or ketones having only one type α-hydrogen, the problem can be solved experimently.solved experimently

30. 30 Choice of experimental conditions: in an aprotic solvent, by slow addition of the ketone or aldehyde to a solution of the base (i.e. the base is always in excess) and then an excess (up to tenfold) of the alkylating agent must be added rapidly (i.e. so that alkylation is kinetically the most favoured process).

31. 31 For ketones possessing α-hydrogens on both sides of carbonyl group, indirect routes may be a good choice.

32. 32 Nitroalkanes usually react at oxygen rather than at carbon.

33. 33 5.2.2Acylation Claisen ester condensation

34. 34

35. 35

36. 36 –The reaction is fail with esters of the type R 2 CHCO 2 R 1.

37. 37 –Unsymmetrical ketones with α-hydrogenon both sides of the carbonyl group are acylated, almost exclusively, at the less-substituted carbon

38. 38 5.2.3Indirect routes to α-alkylated aldehydes and ketones 5.2.3.1Routes to α-alkylated aldehydes –Making use of immines

39. 39 – Making use of dihydro-1,3-oxazines

40. 40 5.2.3.2 Routes to α-alkylated ketones: ‘specific enolates Ketone may be converted to α,β-keto-aldehyde. β -keto-ester used as starting material

41. 41 α,β-unsaturated ketone as starting material

42. 42 5.2.4Condensation reactions 5.2.4.1Self-condensation of aldehydes and ketones

43. 43

44. 44

45. 45 5.2.4.2Mixed condensation

46. 46 One method one of the reactants contains the most acidic hydrogen and the other contains the most electrophilic carbonyl group. Order of electrophilicity of carbonyl compounds: aldehyde > ketone > ester alkyl-CO- > aryl-CO- Order of the acidity of α-hydrogens is inverse.

47. 47 Making use of compounds having no α-hydrogen as one of the reactant. Aromatic (and heteroaromatic) aldehydes are particularly useful. Another methods

48. 48

49. 49 Some indirect methods to prepare R 2 C=CHCHO or R 2 C=C(R 1 )CHO –Making use of imminesMaking use of immines –Making use of dihydro-1,3-oxazinesMaking use of dihydro-1,3-oxazines –Making use of ethoxyethyne

50. 50  Making use of ethoxyethyne

51. 51 5.3Carbanions stabillized by neighbouring phosphorus or sulfur 5.3.1 Phosphonium ylides (the Wittig reaction)

52. 52 –Non-stabilized ylides (R, R 1 = hydrogen or simply alkyl, a mixture of E- and Z-isomers)

53. 53 Stabilized ylides (R 1 = -M group, e.g. an ester. E-isomer usually predominates.

54. 54 5.3.1.3 Steric control in the Wittig reaction The ‘salt-Free’ wittig reaction of non-stabilized ylides gives the Z-alkene as the major product. –If the aldehyde contains α-substituents, Z-isomer increase. –Replacement of one of the P-pheny groups by isopropyl, can alter the steroselectivity, gives the E-isomer as the major product. Wittig reaction of non-stabilized ylides may also be modified to yield predominantely E-alkene.

55. 55 In this modification, the ylide is prepared by using PhLi and the addition to the aldehyde is carried out at –78 o C. Then a second mol. PhLi is added.

56. 56 5.3.2Sulfonium ylides

57. 57 5.4Nucleophilic acylation 5.4.1 The benzoin reaction (condensation) –KCN or NaCN as the catalyst. –Catalysed by N-substituted thiazolium salts.

58. 58 Summary  1,3-Dicarbony compounds undergo essentially complete monodeprotonation at C-2 using bases such as sodium alkoxides. The resulting carbanions, stablized by both electron-accepting (-M) groups, readily undergo alkylation and acylation.  Hydrolysis of β-keto-esters and malonate esters may be followed by decarboxylation, so that, for example, diethyl malonate and ethyl acetoacetate are synthetic equivalents of the synthons – CH 2 CO 2 H and – CH 2 COCH 3, respectively.

59. 59  Alkylation and acylation of carbanions require stoichiometric quantities of the base, whereas condensation reaction require the base only as a catalyst. A weaker base may be used for condensations and for conjugate additions (Michael addition) than for alkylations or acylations.  The formation of carbanions stabilized by only one –M group requires the use of much stronger bases. Deprotonation jof unsymmetrical ketones may give a mixture of two carbanions (enolates), but methods for the generation of specific enolates have been divised. Alkylation and acylation of these carbanions is achievable;

60. 60 The mechanism of the acylation process (Claisen acylation) permits the use of a weaker base (a sodium alkoxide) than is predicted in terms of the pK a of the ketone. α-alkylate aldehydes are best prepared by indirect methods, since self- condensation of aldehydes occurs readily in basic media. ‘Mixed’ condensations are synthetically useful only where one reactant contains the most reactive electrophile in the system and the other contains the most acidic hydrogen  The wittig reaction, involving the reaction of and aldehyde with a triphenyphosphonium ylide (or phosphorane), gives an alkene and triphenyphosphine oxide. The stereoselectivety in this reaction can be manipulated by variation of the reaction conditions.

61. 61  Sulonium ylides react in a different way with aldehydes and ketones, the products being oxiranes (epoxide).  Aldehydes and ketones are readily convertible into 1,3-dithianes, the carbanions derived from these may then be alkylated and hydrolysis of the alkylated species regenerates the carbonyl group. This sequence involves the Umpolung (reversal of polarity) of the C=O carbon and the process is one of nucleophilic acylation. Nucleophilic acylating agents are also involved in the dimerization of aromatic aldehydes to acyloins and in the Stetter reaction.

62. 62  Enols, enamines, arenes and heteroarenes also react as nucleophiles: the electrophiles with which they react include aldehydes, ketones, carbenes and iminium salts.  Some rules for the disconnection of target molecules, tabulated lists of synthetic equivalents for various synthons and some worked examples are included at the end of the chapter.