Chemistry 206 Advanced Organic Chemistry Handout-23A Enolate Acylation Matthew d. shair Monday November 11. 2002
Chemistry 206 Advanced Organic Chemistry Handout–23A Enolate Acylation Matthew D. Shair Monday , November 11, 2002
D. A. Evans Enolate Acylation Acylation Carboxylation Chem 206 The Reaction: OM Deacylation: When an acyl residue is employed in the one of the illustrated bond constructions, it may then be removed by R nucleophilic deacylation: Several examples are provided R2 Deformylation Carboalkoxylation Situations where the reaction is employ i competitive ring cleavage not a problem due to more electrophilic formyl C=O a Acyl moiety is a constituent of the target structure Decarboxylation Alkyl-Oxygen Cleavage: tert-butyl esters R R2 CO2--Bu R-Br R OR3 R2 R2 L Acyl moiety employed in assisting bond construction but not part of the target structure ion in this system is a sigmatropic rearrangement involving +R-x presentative procedure: Henderson, Synthesis 1983, 996 a Alkyl-Oxygen Cleavage: Methyl esters → R COz-Me Co2-CO2 R=H leading references Tet let1990.31.14014 H23-01-Acylation Intro 11/5/008: 20 PM
Tet Let. 1990, 31, 1401-4 JOC. 1991, 56, 5301-7 D. A. Evans Enolate Acylation Acylation & Carboxylation Chem 206 The Reaction: Acylation + Carboalkoxylation + Situations where the reaction is employed: ■ Acyl moiety is a constituent of the target structure: + + (–) (+) (–) (+) ■ Acyl moiety employed in assisting bond construction but not part of the target structure: + R–X Deacylation: When an acyl residue is employed in the one of the illustrated bond constructions, it may then be removed by nucleophilic deacylation: Several examples are provided. Deformylation: HCO3 – competitive ring cleavage not a problem due to more electrophilic formyl C=O Decarboxylation in this system is a sigmatropic rearrangement involving C=O participation Decarboxylation: ■ Alkyl-Oxygen Cleavage: tert-butyl esters NaH, DMF R–Br CF3CO2H ∆ –CO2 representative procedure: Henderson, Synthesis 1983, 996 ■ Alkyl-Oxygen Cleavage: Methyl esters Li–I/H2O ∆ H3O+ CO2 R = H HO– Acylketene intermediate leading references OM R1 R2 X R3 O R2 R1 O R3 O O OR3 O R1 R2 O X OR3 R2 R1 OM R2 R1 OH OR3 O O OR3 O R1 R2 R2 R1 O X OR3 O O O OR3 O H R2 R1 X O R R H O O O O Me CO2Me CO2Me Me O Me R2 CO2Me R1 O OR3 O O Me Me Me Me O O Me CO2Me Me O CHO O Me Me Me Me O O CO2-t-Bu CO2-t-Bu O R R O O O O H H O R O CO2-Me Me N Me CO2 – O R O R O O– OR C O O H23-01-Acylation Intro 11/5/00 8:20 PM
D. A. Evans Claisen Condensation Related Processes Chem 206 Claisen Condensation: Condensation of 2 esters I Analysis of the two processes i Conventional Carbomethoxylation: Equilibrium achieved between all species oR+ COmE Intramolecular Variant: Dieckmann Condensation CO,Me RO Keg -10 MeoH COmE Me2CO3 ly speaking, the Claisen and Dieckmann condensations are defined as condensations discussion, we choose to liberalize the classifcation to include ketone enolates as well. I a Reaction Thermodynamics: Overall Keq -1 with aromatic ring disrupting the required planarity of the delo by peri-interaction Critical issue: Product enolate a is significantly destabi eater stability of B dictates the product. RO I Final enolization Step: Keq -10 COmE L This type of control is general rOH 2Et pKa 12 pKa 16 HCO2Et Me Me Reaction Control Elements: These reactions can be manipulated to give Meyers, JOC 1976, 41, 1976 either kinetic or thermodynamic control HCO2Et kinetic product Piers. Tet. Let 1968. 583 HCODEt hermodynamic MeO OM H23-02-Claisen Condensation 11/5/00 8: 17 PM
LDA D. A. Evans Claisen Condensation & Related Processes Chem 206 ■ Claisen Condensation: Condensation of 2 esters + RO– H3O+ ■ Intramolecular Variant: Dieckmann Condensation H3O+ RO– Strictly speaking, the Claisen and Dieckmann condensations are defined as condensations between ester enolates & ester electrophiles. In this discussion, we choose to liberalize the classifcation to include ketone enolates as well. ■ Reaction Thermodynamics: Overall Keq ~ 1 RO– + 2 + RO + – + ROH ■ Final enolization Step: Keq ~ 10+4 Contrary to popular belief, final enolization step does not render the process irreversible pKa 12 pKa 16 Reaction Control Elements: NaH kinetic product Thermodynamic product -78 °C 0 °C ■ Analysis of the two processes: Conventional Carbomethoxylation: Equilibrium achieved between all species Me2CO3 + MeO– + MeOH Keq ~ 10-2 Keq ~ 10+4 Me2CO3 Keq > 10+4 Critical issue: Product enolate A is significantly destabilized by peri-interaction with aromatic ring disrupting the required planarity of the delocalized enolate. Hence, the greater stability of B dictates the product. A B Keq >> 1 A B ■ This type of control is general: HCO2Et KOtBu Meyers, JOC 1976, 41, 1976 Piers, Tet. Let 1968, 583 MeO– HCO2Et benzene benzene HCO2Et MeO– JACS 1965, 87, 5728 These reactions can be manipulated to give either kinetic or thermodynamic control: CO2Me R Me CO2Me OR O O OR R O OR O R R O Me CO2Me R R O OR O R R O OR R O OR O O OR O– R R O NC OMe O O CO2Me O MeO OMe CO2Me O Me CO2Et O OH Me Me OH O CO2Et Me O– O CO2Me CO2Me O– O– CO2Me O O– CO2Me O– MeO O H CO2Me O– O Me O Me Me O Me O Me Me OH RO– H23-02-Claisen Condensation 11/5/00 8:17 PM
D. A. Evans Kinetic Enolate Acylation: The Mander Reagent Chem 206 a Kinetic Acylation: Methyl Cyanoformate (1): a The Tetrahedral Intermediate 2; Why is it so stable? 78°c Me 2 LCN Enolate acylation with 1 is fast Intermediate 2 breaks down to product Consider this in the broader context of elimination reactions more slowly than the acylation step of the elcb classification where Under these conditions, proton transfer ither c or some heteroatom from product to enolate does not occur X might ous leaving groups such as CN, OR etc. OMe slow +X les: o Co, Me 84% I Data is available for the case where x= CN, or&Y= carbanion Stirling, Chem. Commun. 1975. 940-941 CO2 Me 65% FG base CFG 一 FG COmE leaving grp pKa log OTMS Mander Tet. Lett. 1983. 24. 5425 Me-Li H CO,Me CMe Mander, SynLett. 1990, 169 Above data makes the point that CN is a poor LG but it also leads one to the faulty conclusion that 2 should partition to acyl cyanide rather than methyl ester! R2Cu(CN Hashimoto, chem Lett. 1989. 1063 R2 LICN H23-03-Mander Reagent 11/5/00 8: 21 PM
-78 °C fast D. A. Evans Kinetic Enolate Acylation: The Mander Reagent Chem 206 ■ Kinetic Acylation: Methyl Cyanoformate (1): + slow + LiCN 1 Enolate acylation with 1 is fast Intermediate 2 breaks down to product more slowly than the acylation step 2 Under these conditions, proton transfer from product to enolate does not occur. Mander Tet. Lett. 1983, 24, 5425 ■ Examples: LDA 1 84% 1 LDA 65% 75% LDA 1 1 Me-Li + isomer 7% Mander, SynLett. 1990, 169 1 R2Cu(CN)2Li2 82% Hashimoto, Chem. Lett. 1989, 1063 ■ The Tetrahedral Intermediate 2; Why is it so stable? 2 slow + LiCN Consider this process in the broader context of elimination reactions of the E1cb classification where: Y might be either C or some heteroatom X might be various leaving groups such as CN, OR etc. base – slow + X– + X slow – – base Data is available for the case where X = CN, OR & Y = carbanion: Stirling, Chem. Commun. 1975, 940-941 leaving grp (X) pKa H–X log kX kOPh –OPh 10 1 –CN 9.5 <-7 –C(Me)2-NO2 ~10 <-9 –OMe 16 -3.9 + LiOMe 2 + LiCN Above data makes the point that CN is a poor LG but it also leads one to the faulty conclusion that 2 should partition to acyl cyanide rather than methyl ester! O Li O CN R1 OMe R2 R2 O R1 OMe O X FG H R FG X FG X Y Y R Y H X R R R2 R R O R1 OMe O CN Li O R1 OMe O R R2 2 O R1 CN O O O NC OMe O R2 O R1 OMe O CN Li CO2Me Me OTMS Me CMe3 Me3C H R1 OLi R2 O R1 OMe O R2 Me O Me CO2Me O Me O CO2Me O Me Me O Me CO2Me O OTBS O CO2Me H23-03-Mander Reagent 11/5/00 8:21 PM
J. L Leighton, D. A. Evans Carbon Acylation with N-Methoxy-N-methylamides Chem 206 Acylating agents can be desiged where the tetrahedral intermediate exhibits exceptional stability (OMe)2 人人 THF/Et2O o-MeHgo OMe-110°cto0°C esen and c. Heathcock R凵 d or R-MgBr H3O Bn OMe THF,0°c M. Angelastro, N. Peet and P Be R= Me, n-Bu, or Ph; yields >90% Jorg.chem1989,54,3913 Weinreb Tet. Lett 1981. 22. 3815 Nucleophiles: Me R1-M RyMe-R制 H3O R1 R2 OMe Acceptable Unacceptable R-Li, R-Mgx R--Li(MgX) R-ZnX& other colalent metal alkyls Enolates and Metalloenamines J. Org. Chem.1991,56.2911-2 choli other colalent metal enolates THF,-78°c DIBAL LiAIH4 LiB(R)3H Weak hydride reagents: NaBH 47% In excellent review on all aspects of Weinreb amide chem THF.-78°ctoR.T M. Sibi, Organic Preparations and Procedures Int, 1993, 25(1), 15-40 J. Org. Chem.198954,4229 i Hydride Reductions Representative Organometals OMe OMe OMe TBSO OTBS OTBS N OMe DIBAl-H LOMe THF,7895% MeMgBr e OMe THF,0°C OMe OMe OMe TBsO Several other examples reported. Prasad and L Liebeskind Evans and s. mill g. Chem1993,58471 Me oMe MeMe Me H23-04 Weinreb Amides-1 11/5/008: 22 PM
Acylating agents can be desiged where the tetrahedral intermediate exhibits exceptional stability: Chem 206 D. Evans and S. Miller J. Org. Chem. 1993, 58, 471. 95% THF, -78 °C DIBAl-H M. Angelastro, N. Peet and P. Bey J. Org. Chem. 1989, 54, 3913. THF, -78 °C 73% P. Thiesen and C. Heathcock J. Org. Chem. 1988, 53, 2374. THF/Et2O -110 °C to -80 °C 62% Several other examples reported. J. Prasad and L. Liebeskind Tetrahedron Lett. 1987, 28, 1857. THF, 0 °C 99% MeMgBr R-Li or R-MgBr THF, 0 °C R = Me, n-Bu, or Ph; yields > 90% J. L. Leighton, D. A. Evans Carbon Acylation with N-MethoxyN-methylamides Nu(-) H3O+ Weinreb Tet. Lett. 1981, 22, 3815. Nucleophiles: R–Li, R–MgX Acceptable DIBAL LiAlH4 LiB(R)3H Weak hydride reagents: NaBH4 Unacceptable R–ZnX & other colalent metal alkyls other colalent metal enolates An excellent review on all aspects of Weinreb amide chemistry: M. Sibi, Organic Preparations and Procedures Int., 1993, 25 (1), 15-40. Representative Organometals: H3O+ Hydride Reductions: R1–M H3O+ H3O+ R2–M W. Wipple, H. Reich J. Org. Chem. 1991, 56, 2911-2. THF, -78 °C THF, -78 °C to R. T. J. Org. Chem. 1989, 54, 4229. Enolates and Metalloenamines: 83% 47% R Li(MgX) RO OLi R' N O Me OMe LiN R Li Ar S O R' R O O CH2Li BrMg OEt N OMe O N MeO Me OLi R Me N OMe O N O Li Nu R N O Me OMe R Me Me R Nu O N O Me OTBS N O OMe Me Ar N O Me OTBS Me O O R1 Ar MeO2C N Me OR O OMe MeO2C P(OMe)2 OR O O Li P(OMe)2 O CbzHN N Me Bn O OMe CbzHN OEt Bn O Me N OMe Me OMe Me TBSO Me O2N OMe OMe Me O OMe OMe Me H OMe Me OMe Me TBSO Me O2N OMe OMe Me O OMe O t-Bu OLi O O t-Bu O R1 R2 O N O Me OMe OLi Me O O Me H23-04 Weinreb Amides-1 11/5/00 8:22 PM