C-C - C-C BOND FORMATION 72 Carbon- Carbon Bond Formation...

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Unformatted text preview: C-C BOND FORMATION 72 Carbon- Carbon Bond Formation 1. Alkylation of enolates, enamines and hydrazones C&S: Chapt. 1, 2.1, 2.2 problems Ch 1: 1; 2; 3, 7; 8a-d; 9; 14 Ch. 2: 1; 2; 4) Smith: Chapt. 9 2. Alkylation of heteroatom stabilized anions C&S :Chapt. 2.4 - 2.6) 3. Umpolung Smith: Chapt. 8.6 4. Organometallic Reagents C&S: Chapt. 7, 8, 9 problems ch 7: 1; 2; 3, 6; 13 Ch. 8: 1; 2 Smith: Chapt. 8 5. Sigmatropic Rearrangements . C&S Chapt. 6.5, 6.6, 6.7 # 1e,f,h,op Smith Chapt. 11.12, 11.13 Enolates Comprehensive Organic Synthesis 1991 , vol. 2, 99.- -deprotonation of a ketone, aldehyde or ester by treatment with a strong non- nucleophillic base.- carbonyl group stabilizes the resulting negative charge. R O H H H B: R O H H- R O - H H- Base is chosen so as to favor enolate formation. Acidity of C-H bond must be greater (lower pK a value) than that of the conjugate acid of the base (C&S table 1.1, pg 3) H 3 C CH 3 O pK a = 20 MeO- pK a = 15 tBuO- pK a = 19 unfavorable enolate concentration H 3 C CH 2 O OEt O pK a = 10 more favorable enolate concentration- Common bases: NaH, EtONa, tBuOK, NaNH 2 , LiNiPr 2 , M N(SiMe 3 ) 2 , Na CH 2 S(O)CH 3 Enolate Formation:- H + Catalyzed (thermodynamic) O H + OH- Base induced (thermodynamic or kinetic) O H :B O - + B:H Regioselective Enolate Formation Tetrahedron 1976 , 32 , 2979.- Kinetic enolate- deprotonation of the most accessable proton (relative rates of deprotonation). Reaction done under essentially irreversible conditions. O LDA, THF, -78C O - Li + C-C BOND FORMATION 73 typical conditions: strong hindered (non-nucleophilic) base such as LDA R 2 NH pKa= ~30 N Li Ester Enolates- Esters are susceptible to substitution by the base, even LDA can be problematic. Use very hindered non-nucleophillic base (Li isopropylcyclohexyl amide) R O OR' LDA, THF, -78C E + R O N R O OR' THF, -78C N Li O- Li + OR' R- Thermodynamic Enolate- Reversible deprotonation to give the most stable enolate: more highly substituted C=C of the enol form O tBuO- K + , tBuOH O - K + O - K + kinetic thermodynamic typical conditions: RO- M + in ROH , protic solvent allows reversible enolate formation. Enolate in small concentration (pKa of ROH= 15-18 range)- note: the kinetic and thermodynamic enolate in some cases may be the same- for , -unsaturated ketones O thermodynamic site kinetic site Trapping of Kinetic Enolates- enol acetates Ph O 1) NaH, DME 2) Ac 2 O kinetic Ph O O Ph O O + isolatable separate & purify CH 3 Li, THF CH 3 Li, THF Ph O- Li + Ph O- Li + Regiochemically C-C BOND FORMATION 73 typical conditions: strong hindered (non-nucleophilic) base such as LDA R 2 NH pKa= ~30 N Li Ester Enolates- Esters are susceptible to substitution by the base, even LDA can be problematic. Use very hindered non-nucleophillic base (Li isopropylcyclohexyl amide) R O OR' LDA, THF, -78C E + R O N R O OR' THF, -78C N Li O- Li + OR' R- Thermodynamic Enolate- Reversible deprotonation to give the most stable enolate: more highly substituted C=C of the enol form...
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C-C - C-C BOND FORMATION 72 Carbon- Carbon Bond Formation...

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