2. Reaction of Carbon Nucleophile with Carbonyl Group

1. 2. Reaction of Carbon Nucleophile with Carbonyl Group Introduction: aldol and Claisen condensation, Robinson annulation Wittig reaction, and related olefination methods 2.1 Aldol Addition and Condensation Reactions 2.1.1. The General Mechanism Prototypical aldol addition reaction is the acid- or base-catalyzed dimerization of ketone and aldehyde,

5. The equilibrium constant for the dehydration phase is usually favorable, because of the conjugated a,b-unsaturated carbonyl system that is formed. 2.1.2 Mixed Aldol condensation with Aromatic Aldehyde One of the most general mixed aldol condensation inovolves the use of aromatic aldehyde with alkyl ketones or aldehyde. Non-enolizable Claisen-Schmidt Condensation

7. Pronounced preference for the formation of a trans double bond in the Claisen-Schmidt condensation of methyl ketones.

8. Base-catalyzed dehydration is slow relative to the reverse of the addition phase for the branched-chain isomer. In base, the straight-chain ketol is the only intermediate which is dehydrated. The branched chain ketol reverts to starting material. Under acid condition, both intermediates are dehydrated, however, the branched-chain ketol is formed most rapidly, because of the preference for acid-catalyzed enolization to give the more substituted enol.

9. Under acid condition, Both intermediates are dehydrated, however, the branched-chain ketol is formed most rapidly, because of the preference for acid-catalyzed enolization to give the more substituted enol forms rapidly major Base catalysis favors reaction at a methyl position over a methylene group, whereas acid catalysis gives the opposite preference.

10. 2.1.3. Control of Regiochemistry and Stereochemistry of Mixed Aldol Reactions of Aliphatic Aldehyde and Ketones 2.1.3.1. Lithium Enolates Directed Aldol Reaction Kinetic controlled conditions

13. Cyclic Transition State Anti-ketol E-enolate

14. The enolate formed from 2,2-dimethyl-3-pentanone under kinetically controlled conditions is the Z-isomer. Reaction with benzaldehyde gives syn aldol. When alkyl substituent of ketone is bulky, Z-enolate is formed. And syn- aldol product is formed. Order: t-butyl>i-propyl>ethyl

16. The enolate of cyclohexanone reacts with benzaldehyde are necessarily E-isomers. Anti-isomer is major. Because the aldol reaction is reversible, it is possible to adjust reaction conditions so that the two stereoisomeric aldol products equilibriate.

17. 1) Z-enolate  syn aldol; E-enolate  anti aldol 2) When the enolate has no bulky substituents, stereselectivity is low 3) Z-enolates are more stereoselctive than E-enolates. Ref. Table 2.1 For synthetic efficiency, it is useful to add MgBr2. The greater stability of the anti-isomer is attributed to the pseudoequitorial position of the methyl group in the chair-like chelate. With larger substituent groups, the thermodynamic preference for the anti-isomer is still greater.

19. Ketones with one tertiary alkyl substituent give mainly the Z-enolate. However, less highly substituted ketones usually give mixtures of E- and Z- Enolates. Control of stereochemistry of aldol reaction • Control of enolate stereochemistry • enhancement of the stereoselectivity in the addition step.

20. For simple ester, the E-enolate is preferred under kinetic conditions using a strong base such as LDA in THF. But Inclusion of a strong cation sovating co-solvent, such as HMPA favors the Z-enolate.

21. With LDA/THF conditions, cyclic transition state, an open transition state in the presence of an aprotic dipolar solvent If R= bulky, selectivity is increased Simple alkyl esters show rather low stereoselectivity. Highly hindered esters provide the anti-stereoisomers. See Table 2.2. HMPA Z-enolate Syn-major

25. a-alkoxy ester: higher stereoselectivity in some cases: it can be explained In terms of a chelated ester enolate. The aldehyde R group avoids being between the a-alkoxy and the methyl group in the ester enolate. When the ester alkyl group R becomes very bulky, the stereoselectivity is reversed. The allylic stabilization of the c-deprotonation product can lead to kinetic selectivity in the deprotomation.

26. 2.1.3.2. Boron Enolates The stereoselctivity is higher than for lithium enolates, since the O-B bond distances are shorter than the O-Li bond in the lithium enolates, and this leads to a more compact transition state. Trifluoromethanesulfonate = triflate Z-isomer Syn-isomer

27. E-boron enolate Anti-isomer Use of boron triflates with a more hindered amine favors the Z-enolate. The E-boron enolates of some ketone can be preferentially obtained with the use of dialkylboron chlorides.

30. Cyclic mechanism for hydride transfer Z-enolate E-boron enolate Anti-aldol product Boron enolates parallel lithium enolates in their stereoselectivity but show enhanced stereoselectivity. (ref. table 2.3)

31. 2.1.3.3. Titanium, Tin, Zirconium Enolates: intermediate between Li+ and covalent boron enolate. Z-enolate Syn-aldol Cyclic transition state N-acyloxazolidinone

32. catalytic

33. Tin enolates Syn-selective N-acylthiazolinethiones E-enolates

34. (Cp)2ZrCl2 with lithium enolate

35. Addition of silyl enol ethers can be catalyzed by (Cp)2Zr2+ species. The order of stereoselectivity is Bu2B>(Cp)2Zr>Li. These results are consistent With reactions proceeding through a cyclic transition state.

36. 2.1.3.4 The Mukaiyama Reaction: Lewis-acid-catalyzed aldol addition reactions of enol derivatives. Not a strong enough nucleophile, but with Lewis acid the reaction proceeds through an acyclic transition state.

37. For a-substituted aldehyde show a preference for a syn relationship between the a-substituent and hydroxy group. This is consistence with a Felkin-Ahn Transition state.

41. 2.1.3.5. Control of Enantioselectivity The combined interactions of chiral centers in both the aldehyde and the enolate determine the stereoselectivity. The result is called double stereodifferentiation.

43. The oxazolinone substituents R’ direct the approach of the aldehyde.

45. 2.1.4. Intramolecular Aldol Reaction and the Robinson Annulation Robinson Annulation is a procedure which construct a new 6-membered ring from a ketone. Originally thermodynamic controlled reaction is required.

46. The role of the trimethylsilyl group is to stabilize the enol formed in the conjugate addition. The silyl group is then removed during the dehydration step. It can be used under aprotic conditions.

47. The s-enantiomer of the product is obtained in high enantiomeric excess with L-proline,. L-proline participates in the proton-transfer step.

48. 2.2. Addition reactions of Imines and Iminium Ions. The reactivity order is C=NR<C=O<[C=NR2]+<[C=OH]+. 2.2.1. the Mannich Reaction: the condensation of an enolizable carbonyl compound with an iminium ion. The reaction is usually limited to secondary amines, because dialkylation can occur with primary amines.

49. The dialkylation reaction can be used in ring closure.

50. Synthesis of Mannich base Bis(methylamino)methane N,N-Dimethylmethyleneammonium idode “Eschenmoser’s salt”