Reactions of the Carbonyl Group O-Li+ MeLi Enolisation CH3CHO Me O-Li+ Addition to carbonyl Me H ! Protons on the α-carbon are, in principle, acidic, and a non-nucleophilic base can deprotonate the carbon. ! A prerequisite for deprotonation is a correct conformation! Enolate Chemistry – The Beginning CLAISEN-SCHMIDT CONDENSATION O NaOH, EtOH O O CHO O Schmidt, J.G. Ber. Dtsch. Chem. Ges. 1880, 13, 2341; 1881, 14, 1459. Claisen, L.; Claparède, A. Ber. Dtsch. Chem. Ges.1881, 14, 349. Claisen, L. Ber. Dtsch. Chem. Ges. 1887, 20, 655. Claisen, L. Justus Liebigs Ann. Chem. 1899, 306, 322. ACETOACETIC ESTER CONDENSATION O O 1. NaH, Et2O CO2Et + OEt 2. H3O Geuther, A. Arch. Pharm. (Weinheim) 1863, 106, 97. Claisen, L.; Claparède, A. Ber. Dtsch. Chem. Ges. 1881, 14, 2460. Claisen, L.; Lowman, O. Ber. Dtsch. Chem. Ges. 1887, 20, 651. Enolate Chemistry – The Beginning REFORMATSKY REACTION OZn, Me2CO OH O Cl OEt benzene OEt Reformatsky, S. Ber. Dtsch. Chem. Ges. 1887, 20, 1210. J. Russ. Phys. Chem. Soc. 1890, 22, 44. PERKIN REACTION CHO Ac2O ONa O O Perkin, W.H. J. Chem. Soc. 1868, 21, 53, 181; 1877, 31, 388. Enolates ! The term enolate first appeared in 1907, when Hans Stobbe discussed the FeCl3 color test for enols in terms of ‘das violette Eisenenolat’. The term was first applied to describe C=C-O- species in 1920, when Scheibler and Voβ described the preparation of several ester enolates. The first explicit formulation of a delocalized enolate was by Ingold, Shoppee and Thorpe in 1926, who represented base-catalyzed tautomerisms as shown below. The authors did not, however, use the term ‘enolate’, not even thirty years later! B HCCO CCO CCOH ! The ambident nucleophilic nature of enolates was established by 1937, when Hauser accurately described the base-promoted enolisation in the mechanism of acetoacetic ester condensation. ! In the early days, the enolates were generated in the presence of the electrophile. It was only in the ‘50’s that Hauser first reported the use of a preformed enolate to obtain cross-coupling products of esters and aldehydes. O OH O LiNH2, NH3 Ph O Me t-BuO t-BuO Ph 76 % Enolates ! The first important base of reduced nucleophilicity was BMDA (bromomagnesium di- isopropylamide), which was first used by Hauser in 1949 as a catalyst for acetoacetic ester condensation. The first useful, nowadays perhaps the most popular base, was LDA (lithium di- isopropylamide), used originally by Levine for the same purpose in 1950 [Hamell, M.; Levine, R. J. Org. Chem. 1950, 15, 162; Levine, R. Chem. Rev. 1954, 54, 467.] However, it took another decade until Wittig employed LDA for the deprotonation of aldimines in the ‘Wittig directed aldol condensation’. LDA, ether O 25 ºC, 15 min EtO CO2Et O Hauser, 1950 47 % LDA, THF Ph2C=O H H3O+ Ph NLi ON N Ph CHO Ph Ph Wittig, 1963 Enolates ! Hydrophobic strong bases (triphenylmethylsodium, -potassium, and -lithium) were developed in the ‘50’s and ‘60’s as reagents soluble in most common organic solvents and basic enough to deprotonate ketones and esters. Furthermore, they are highly colored, and can thus serve as indicators - this is their principal use nowadays. Early examples of stoichiometric enolisation from normal ketones originated from the laboratories of Herbert O. House. OOLiOLi LDA, DME -78 ºC + 99 % 1 % O OLi OLi H H LDA, DME -78 ºC + H H H 98 % 2 % Kinetic and thermodynamic control Kinetic vs. thermodynamic control R R R -O O -O Thermodynamically favored Kinetically favored More stable Forms faster Kinetic and thermodynamic control -O Me O Me -O Me CH Me Me H3CMe Me AB 3 H 1H ! A tetrasubstituted alkene A is more stable ! If A and B can equilibrate, and [A] > [B] – A is the thermodynamic enolate ! If equilibration is not possible (e.g. large, strong base, which only ‘sees’ the methyl group), a kinetically controlled product mixture is formed; – B is the kinetic enolate Kinetic and thermodynamic control t-BuOK O t-BuOH, ∆ O 86-94 % Br O OLi 65 ºC LDA, THF, Br hexane, -72 ºC 77-84 % House, H.O.; Sayer, T.S.B.; Yau, C.-C. J. Org. Chem. 1978, 43, 2153. Kinetic and thermodynamic control Enolaatti Ketoni Termodynaaminen Kineettinen - O O O- Ph3CLi 28 72 tasapain. 94 6 - O O O- LDA 1 99 tasapain. 78 22 - O O O- H H H H H Ph3CLi 13 87 tasapain. 53 47 Kinetic and thermodynamic control O- O Me MeI Ainoa tuote! H H Aksiaalinen H Me MeI O Me H O- O O- House, H. J. Org. Chem. 1979, 44, 2400. Regioselective Enolate Formation 1. Use of Activating Groups R R Overall O O HCO2Et Acid or base NaOEt ∆ R R R O - O O CHO CHO CHO O Baisted, J. Chem. Soc. 1965, 2340. Johnson, J. Am. Chem. Soc. 1960, 82, 614. R R base O -O SPh SPh Coates, Tetrahedron Lett. 1974, 1955. Regioselective Enolate Formation 2. Use of Blocking Groups R R R HCO2Et O O O CHO CHOH TsS STs KOAc R O SS Removal: RaNi Woodward J. Chem. Soc. 1957, 1131. Regioselective Enolate Formation 3. Use of Enamines R R R H+ cat. + R'2NH > - H2O O R'2N R'2N E = 0 rel Erel = 1.6 kcal/mol Augustine Org. Synth Coll Vol V 1973, 869. Regioselective Enolate Formation 3. Use of Enamines - Robinson type R R R R'2N R'2N R'2N - O -O O R R '- R'2NH' R'2N O O Augustine Org. Synth Coll Vol V 1973, 869. Regioselective Enolate Formation 4. Thermodynamic vs. Kinetic Control R R R -O O -O Thermodynamically preferred Kinetically preferred More stable More rapidly formed Regioselective Enolate Formation THERMODYNAMIC ENOLATE FORMATION: ! less than stoichiometric amount of base ! weak, sterically non-hindered base ! protic solvents KINETIC ENOLATE FORMATION: ! at least stoichiometric amount of base ! strong, bulky base ! polar aprotic solvents House J. Org. Chem. 1971, 36, 2361. Stork J. Org. Chem. 1974, 39, 3459. Regioselective Enolate Formation 5. Enones as Enolate Precursors Et3Si Li, NH3 O t O BuOH -OO Boeckman J. Am. Chem. Soc. 1974, 96, 6179. Stork, J. Am. Chem. Soc. 1974, 96, 6181. Et Si Me3 Me Me2CuLi O O -OO Boeckman J. Am. Chem. Soc. 1973, 95, 6867. Regioselective Enolate Formation 6. Enol Derivatives a) Enol acetates RR R R OHO AcO AcO Favored Erel = 0 R R Me Me -O -O O Me2CO Erel = 2.3 kcal/mol House J. Org. Chem. 1965, 30, 1341, 2502. Regioselective Enolate Formation 6. Enol Derivatives b) Silyl enolates TMSCl, Et3N + DMF TMSO TMSO 991: (80 %) O 1) LDA 99: 1 (74 %) 2) TMSCl Stork, G. J. Am. Chem. Soc. 1968, 90, 4462. House, H.O. J. Org. Chem. 1969, 34, 2324. 1) Li/NH3 2) TMSCl O TMSO Stork, G. J. Am. Chem. Soc. 1974, 96, 7114. Regioselective Enolate Formation 1) Me2CuLi > 90 % O 2) TMSCl TMSO Boeckman J. Am. Chem. Soc. 1974, 96, 6179. SiEt3 MeLi O etc. TMSO -O O > 80 % Stork, G. J. Am. Chem. Soc. 1973, 95, 6152. Enolates n-BuLi [conditions unknown] LOBA N N H Li O 2-hexanone, THF, Me3SiCl, SiCl, THF, Me3 Bu -78 ºC -78 ºC Me OSiMe3 OSiMe3 OSiMe3 OSiMe3 C H C H 4 9 4 9 Bu Bu Me Me 97.5 % 2.5 % 97 % 3 % Corey, E.J.; Gross, A.E. Tetrahedron Lett. 1984, 25, 495. Corey, E.J.; Gross, A.G. Org. Synth. 1987, 65, 166. Regioselective Enolization O 1. LDA, DME, -78ºC (92:8 selectivity in enolisation*) MeO 2. hexanal 3. H2O, HCl Me3SiO OOH MeO Me3SiO (rac)-[6]-gingerol (57 %) *LiHMDS in place of LDA gave only 75:25 selectivity in enolisation Denniff, P.; Whiting, D.A. J. Chem. Soc., Chem. Commun. 1976, 712. Denniff, P.;Macleod, I.; Whiting, D.A. J. Chem. Soc. Perkin I 1981, 82. Regioselective Enolization t-BuOK O t-BuOH, ∆ O 86-94 % Br O OLi 65 ºC LDA, THF, Br hexane, -72 ºC 77-84 % House, H.O.; Sayer, T.S.B.; Yau, C.-C. J. Org. Chem. 1978, 43, 2153. Regioselective Enolization LICA, THF -78 ºC MeI H H LiO O kinetic enolate 85 % H t-BuOK, t-BuOH, ∆ O HOAc H H KO O thermodynamic enolate N Li LICA = Lee, R.A.; McAndrews, C.; Patel, K.M.; Reusch, W. Tetrahedron Lett. 1973, 965. Lithium i-propykcyclohexylamide Ringold, J.; Malhotra, S.K. Tetrahedron Lett. 1972, 669. Regioselective Enolization O 1. LDA, THF 1. LiAlH4 2. CH2=CHCH2Br 2. H2O O O 80 % Stork, G.; Danheiser, R.L. J. Org. Chem. 1973, 38, 1775. O LDA 1. MeLi Cl O THF-HMPA Cl 2. H3O+ OEt OEt O β-vetivone Stork, G.; Danheiser, R.L.; Ganem, B. J. Am. Chem. Soc. 1973, 95, 3414. Regioselective Enolization Me 1. Li, NH3, t-BuOH Me 2. CH2O, ether, -78 ºC HO O O 64 % H H Me HO O 1. Li, NH3, PhNH2 Me 2. CH2O, ether, -78ºC O 60 % H HO Stork, G.; d'Angelo, J. J. Am. Chem. Soc. 1974, 96, 7114. Regioselective Enolization R1 O O R1 OH O R2 OEt R2 OEt R3 R4 R3 R4 O O H H X X COOH 2 XC (COOEt) XCC COOEt C 2 5 ka 10 % enol % enol Neat CCl4 Neat CCl4 H H C 2 C 5,56 68 91 Me H HC C 1,95 40 66 78 89 Me H C C 0,73 17 30 30 44 Me Me 2,2 26 50 5 5 H2C C Me Me 1,1 HC C 15 28 5 5 Gelin, S.; Gelin, R.