D A Evans and P H. Carter Intramolecular Enolate Acylation-Dieckmann Condensation Chem 206 The Dieckmann Condensation Regioselectivity Reviews: Schaefer, Bloomfield, Organic Reactions 1967, 15, 1 Eto2C、A∠CO2Eac6 CO2Et Davis& Garratt, Comprehensive Organic Synthesis 1991, 2, 806-829 Kinetic Control? CO2RCO2R NaoEt/EtOH √ EtO2C\CH2CO2Et Eto2C CO2Et Thermodynamic Accesible Ring Sizes CO2Et ONa CO2R CO2R NaOT/EtOH Eto2C、 COrI ot observed CO2R Explanation B2 not viable excellent excellent acceptable situation dependent i Enolization at (A)preferred on basis of inductive effects. Hence Path a preferred in kinetically controlled situatie The individual steps Enolates(B1)and(B2) both more stable than enolate(A) Enolization: Under equilibrating conditions(B1) appears to be preferred over(B2) The effect of beta heteroatoms: classical kinetic vs thermodynamic contr of bases may be considered for the enolization step hilic base such as nah are comn Choice of base can be important(Vide infra) KOtBu /PhH CO2Et Ring Closure Keq(enoliz N、co2Et oEt CO2Et CO2Et R.H. Schlessinger, et al. Heterocycles 1987, 25, 315. CO2Et Statements claiming that the final enolization step renders the process irreversible are simply incorrect H23-07 Dieckmann-1115/008:29PMUnder equilibrating conditions (B1) appears to be preferred over (B2) Not observed Enolates (B1) and (B2) both more stable than enolate (A) Enolization at (A) preferred on basis of inductive effects. Hence, Path A preferred in kinetically controlled situation Explanation: Thermodynamic Control? Kinetic Control? B B2 NaOEt/EtOH NaOEt/EtOH A NaH/C6H6 Davis & Garratt, Comprehensive Organic Synthesis 1991, 2, 806-829 A B1 ( )n Reviews: The Dieckmann Condensation Regioselectivity: D. A. Evans and P.H. Carter Intramolecular Enolate Acylation–Dieckmann Condensation Chem 206 Schaefer, Bloomfield, Organic Reactions 1967, 15, 1. ( )n not viable excellent excellent acceptable situation dependent high dilution required Accesible Ring Sizes The individual steps: + EtO– Enolization: + base + base-H A variety of bases may be considered for the enolization step. Either alkoxide or a non-nucleophilic base such as NaH are commonly used. Choice of base can be important (Vide infra). Ring Closure: + EtOH Keq (enoliz) Keq (cycliz) ~ 1 Keq (enoliz) ~ 10+4 Statements claiming that the final enolization step renders the process irreversible are simply incorrect. NaOEt EtOH ∆ KOtBu / PhH R.H. Schlessinger, et al. Heterocycles 1987, 25, 315. NaOEt / EtOH The effect of beta heteroatoms: classical kinetic vs. thermodynamic control ∆ ∆ EtO2C CH2CO2Et ONa N ONa CO2Et MeO MeO CO2Et CO2Et N CO2Et OH N OH CO2Et EtO O – OEt O O OEt O – EtO O – O CO2R O CO2R O CO2R O CO2R O CO2R CO2R O CO2RCO2R CO2Et EtO2C CO2Et CO2Et ONa CO2Et CO2Et EtO2C O OEt O EtO2C EtO CO2Et O CO2Et CO2Et H23-07-Dieckmann-1 11/5/00 8:29 PM