D.A. Evans Enolates Metalloenamines-1 Chem 206 Assigned Journal Articles http://www.courses.fasharvardedu/-chem206/ Structure and Reactivity of Lithium Enolates. From Pinacolone to kylations of Peptides. Difficulties and Chemistry 206 Afforded by Complex Structures D Seebach Angew. Chem. Int Ed Engl, 27, 1624(1983).(handout) Advanced organic Chemistry Stereoselective Alkylation Reactions of chiral Metal Enol D. A Evans Asymmetric Synthesis, 3, 1 (1984).(hand Lecture number 22 Other Useful references Recent Advances in Dianion Chemistry". C M. Thompson and D L C. Green Enolates metalloenamines-1 Tetrahedron,47,4223(1991 The Reactions of Dianions of Carboxylic Acids and Ester Enolates"N Petragnani and M. Yonashiro Synthesis, 521( 1982) Generation of Simple Enols in Solution ". Capon, Guo, Kwok, Siddhanta, and Zucco Acc. Chem. Res 21, 121(1988) Keto-Enol Equilibrium Constants of Simple Monofunctional Aldehydes and Ketones in Aqueous Solution". Keeffe, Kresge, and Schepp JACS, 112, 4862 Tautomerism in C=O and C=NR Systems (1990) c=O Enolization with Metal Amide bases pKa and Keto-Enol Equilibrium Constant of Acetone in Aqueous Solution C=O Enolization Kinetic Acidities Mild Methods for Enolate Generation Enolate Structure: A Survey of X-ray Structures a Rationalize why metalloenamine B is more stable than A. Metallo-Enamine X-ray Structures L Reading Assignment for this Week Carey& Sundberg: Part A; Chapter 7 pKa(DMSO) BuLi Carbanions Other Nucleophilic Carbon Species more stable Carey Sundberg Part B: chapter 2 Reactions of Carbon Nucleophiles with Carbonyl Compounds Friday E November 8. 2002 minor(<5%) major(<95%)
http://www.courses.fas.harvard.edu/~chem206/ R R O M R R N M R N R BuLi A N R Li N R El N Li R B N R El D. A. Evans Chem 206 Matthew D. Shair Friday, November 8, 2002 ■ Reading Assignment for this Week: Carey & Sundberg: Part A; Chapter 7 Carbanions & Other Nucleophilic Carbon Species Enolates & Metalloenamines-1 Carey & Sundberg: Part B; Chapter 2 Reactions of Carbon Nucleophiles with Carbonyl Compounds ■ Assigned Journal Articles ■ Rationalize why metalloenamine B is more stable than A. Chemistry 206 Advanced Organic Chemistry Lecture Number 22 Enolates & Metalloenamines-1 ■ Tautomerism in C=O and C=NR Systems ■ C=O Enolization with Metal Amide Bases ■ C=O Enolization: Kinetic Acidities ■ Mild Methods for Enolate Generation ■ Enolate Structure: A Survey of X-ray Structures ■ Metallo-Enamine X-ray Structures "Structure and Reactivity of Lithium Enolates. From Pinacolone to Selective C-Alkylations of Peptides. Difficulties and Opportunities Afforded by Complex Structures". D. Seebach Angew. Chem. Int. Ed. Engl., 27, 1624 (1983). (handout) "Stereoselective Alkylation Reactions of Chiral Metal Enolates". D. A. Evans Asymmetric Synthesis, 3, 1 (1984). (handout) ■ Other Useful References "Recent Advances in Dianion Chemistry". C. M. Thompson and D. L. C. Green Tetrahedron, 47, 4223 (1991). The Reactions of Dianions of Carboxylic Acids and Ester Enolates". N. Petragnani and M. Yonashiro Synthesis, 521 (1982). "Generation of Simple Enols in Solution". Capon, Guo, Kwok, Siddhanta, and Zucco Acc. Chem. Res. 21, 121 (1988). "Keto-Enol Equilibrium Constants of Simple Monofunctional Aldehydes and Ketones in Aqueous Solution". Keeffe, Kresge, and Schepp JACS, 112, 4862 (1990). "pKa and Keto-Enol Equilibrium Constant of Acetone in Aqueous Solution". Chiang, Kresge, and Tang JACS 106, 460 (1984). more stable pKa (DMSO) ~30 (El+) minor (<5%) major (<95%)
D. A. Evans Enolates Metalloenamines: Introduction Chem 206 Important References Tautomers: Structural isomers generated as a consequence of the 1, 3-shift of a proton adjacent to a X=Y bond. for example cA时 Icture and Reactivity of Lithium Enolates. From Pinacolone to Selective lkylations of Peptides. Difficulties and Opportunities Afforded by Complex H Structures D Seebach Angew. Chem. Int Ed. Engl, 27, 1624(1983) Stereoselective Alkylation Reactions of Chiral Metal Enolates".D. A. Evans Asymmetric Synthesis, 3, 1(1984) Keto-Enol Tautomers: Tautomerism may be catalyzed by either acids Generation of Simple Enols in Solution". B. Capon, B.-Z.Guo, F C Kwok, A. K or bases Siddhanta, and C Zucco Acc. Chem. Res 21, 121 (1988) pKa and Keto-Enol Equilibrium Constant of Acetone in Aqueous Solution.Y. Chiang, A J. Kresge, and Y. S. Tang J. Am. Chem. Soc. 106, 460 (1984) base catalysis Enols Enolates are the most important nucleophiles in organic biological chemistry E+) Rb Ra Acidity of Keto and Enol Tautomers: Consider Acetone Enamines metalloenamines, their nitrogen counterparts, are H3C CH3 H a。O、分DK=822( measured Ra Rb pK =1916(calculated) 3C Kresge, JACS 1984, 106, 460 metalloenamine
D. A. Evans Enolates & Metalloenamines: Introduction Chem 206 "Structure and Reactivity of Lithium Enolates. From Pinacolone to Selective C-Alkylations of Peptides. Difficulties and Opportunities Afforded by Complex Structures". D. Seebach Angew. Chem. Int. Ed. Engl., 27, 1624 (1983). "Stereoselective Alkylation Reactions of Chiral Metal Enolates". D. A. Evans Asymmetric Synthesis, 3, 1 (1984). "Generation of Simple Enols in Solution". B. Capon, B.-Z. Guo, F. C. Kwok, A. K. Siddhanta, and C. Zucco Acc. Chem. Res. 21, 121 (1988). "pKa and Keto-Enol Equilibrium Constant of Acetone in Aqueous Solution". Y. Chiang, A. J. Kresge, and Y. S. Tang J. Am. Chem. Soc. 106, 460 (1984). Important References Ra O Rb Ra OH Rb Ra O – Rb El(+) El(+) Ra O Rb El Enols & Enolates are the most important nucleophiles in organic & biological chemistry. H + base Ra N Rb El(+) El(+) H + base Enamines & metalloenamines, their nitrogen counterparts, are equally important. R Ra N Rb R M Ra N Rb R H Ra N Rb R El Tautomers: Structural isomers generated as a consequence of the 1,3-shift of a proton adjacent to a X=Y bond. for example: + H + pK = 19.16 (calculated) + H pK = 10.94 (measured) + pK = 8.22 (measured) Acidity of Keto and Enol Tautomers: Consider Acetone: + H + – H + – H + + H + Keto-Enol Tautomers: Tautomerism may be catalyzed by either acids or bases: acid catalysis: + base catalysis: R CH3 O O – R H H H R OH R OH R H H CH3 O H H Z O R CH3 X Y Z X Y H H C O H3C CH3 C OH H3C C H H C H H H3C C O – C H H H3C C OH H3C C CH3 O C O – H3C C H H Kresge, JACS 1984, 106, 460 On the origin of the acidity of enols: Wiberg, JACS 1996, 118, 8291-8299 enamine metalloenamine
D. A. Evans Enolization with metal amides bases Chem 206 Tautomeric Equilibria: Ketones vs Imines Stereochemist LM-NR (E) M ase R-Substituent Ratio, ( E): (2) MeNH2 H2O LDA(THF) -OMe, o-t-Bu 95: 5 DA(THF) Keg >10 The enamine interpart. above, ring n now stabilizes the enamine tautomer as the LDA (THF) -NEt 0:100 Enolization: Amide Bases S-BuLi (THF) -net2 H a Solvent Base R-Substituent Ratio. (E):(4) (E)Ge .(THF) 95:5 LM-NR2 LDA(THF, HMPA)-OMe H Base Structure Masamune(. Am. Chem. Soc. 1982, 104, 5526) (Z) Geometry The Ireland Model (J. Am. Chem. Soc. 1976, 98, 2868) Narula. Tetrahedron Lett. 1981. 22. 4119 THF,-78°C more recent study: Ireland, JOC 1991, 56, 650 For the latest word on this subject see: Xie, JOC 1997, 62, 7516-9 (E)Geometry (Z) Geometry Stereoelectronic Requirements: The a-C-H bond must be able to overlap with Base R=Et, (E): 4 R=Cy,(E: (4) Ha *C-0 C-O Hc\,Hb Li-N(SiMe3)2 15:85 Li-N(SIEt3)2 1:99 LiN(SiMe2Ph)2 0:100 0:100 at equilibrium 16:84
N R R H H R Li O Me N R R H Me R Li O H O OH R O Me N Me N Me H MeNH2 –H2O R O Me OLi R Me R Me OLi O Me R Hc Hb Ha R C O Hc Hb R O – s-BuLi (THF) Li–N(SiMe2Ph)2 Li–N(SiEt3)2 Li–N(SiMe3)2 Li–N(i-Pr)2 LiNR2 -OMe -OMe -NEt2 -NEt2 -S-t-Bu -CMe3 -CHMe2 -C6H5 Me R OLi OLi R Me OLi Me R R Me OLi D. A. Evans Enolization with Metal Amides bases Chem 206 Tautomeric Equilibria: Ketones vs. Imines Keq ~ 10–3 Keq > 10 The enamine content in an analogous imine is invariably higher than its carbonyl counterpart. In the case above, ring conjugation now stabilizes the enamine tautomer as the major tautomer in solution. Enolization: Amide Bases LM–NR2 ‡ (E) Geometry (Z) Geometry The Ireland Model (J. Am. Chem. Soc. 1976, 98, 2868) Narula, Tetrahedron Lett. 1981, 22, 4119 more recent study: Ireland, JOC 1991, 56, 650 For the latest word on this subject see: Xie, JOC 1997, 62, 7516-9 R-Substituent Ratio, (E):(Z) 95 : 5 Base LDA (THF) LDA (THF, HMPA) 16 : 84 ■ Solvent 25 : 75 LDA (THF) 95 : 5 LDA (THF) 0 : 100 LDA (THF) 0 : 100 LDA (THF) 0 : 100 LDA (THF) 40 : 60 LDA (THF) -Et 77 : 23 LDA (THF) Base -OMe, O-t-Bu 95 : 5 R-Substituent Ratio, (E):(Z) LM–NR2 (E) (Z) + 39 : 61 15 : 85 4 : 96 0 : 100 R = Cy, (E):(Z) 0 : 100 1 : 99 30 : 70 THF, -78 °C R = Et, (E):(Z) 70 : 30 Base ■ Base Structure Masamune (J. Am. Chem. Soc. 1982, 104, 5526) + (E) Geometry (Z) Geometry at equilibrium 16 : 84 Stereoelectronic Requirements: The a-C-H bond must be able to overlap with p* C–O – Ha + base ■ Stereochemistry p* C–O Can you rationalize these differences?
D.A. Evan Enolization with metal amides bases Chem 206 Base Structure Corey&Co-workers, Tetrahedron Lett.1984,25,491,495 Regioselective Enolization LiNR2 M-base THF,-78°c B (E)Geometry (4) Geometry Base temp control Ratio(A: B) LiN(-Pr)2 LDA)77:23 N(SiMe3)2-78 kinetic 955 Phc- kinetic 90:10 MeLi Me Ph3C-Li thermo LTMP)86:14 1090 Na-H thermo 26:74 thermo 38 A: Alkyl groups stabilize metal enolate Lithium Halide Effects Collum(J Am. Chem. Soc. 1991, 113, 9572) A: as m-o bond becomes more ionic a is attenuated Collum(J. Am. Chem. Soc. 1991, 113, 9575) Kinetic Selection sensitive to structure Collum(J Am. Chem. Soc. 1991, 113, 5053 LiNR M-base THF,78°C Ratio, (E): 2 ato:99:1 2Ph (25 LITMP 10% B pKeq est: 7(10") Unsaturated Ketones For the latest in the series of Column papers see: JACS 2000, 122, 2452-2458 N(i-Pr) kinetic enolate thermodynamic eno ee kinetic acidity handout for an extensive compilation of cases
Et Me O LiNR2 O Me Et N Li Me Me Me Me LiNR2 Li–N(i-Pr)2 OLi Et Me Me Et OLi LiTMP Me Me Me Me Me3C Me N Li Et Me OLi OLi Me Et KO Me O Ph K–H Na–H O Me Ph3C–Li Ph3C–Li LiN(i-Pr)2 LiN(SiMe3 )2 t-BuOH O Ph O Me A A A OLi Ph OLi Me LiN(i-Pr)2 B B B OLi Ph OLi Me LiO Me D. A. Evans Chem 206 Ratio, (E):(Z) LiTMP, 10% LiBr 98 : 2 86 : 14 THF, -78 °C + Collum (J. Am. Chem. Soc. 1991, 113, 5053) Collum (J. Am. Chem. Soc. 1991, 113, 9575) Lithium Halide Effects Collum (J. Am. Chem. Soc. 1991, 113, 9572) (LiTMP) 86 : 14 (LOBA) 98 : 2 (LDA) 77 : 23 (E) Geometry (Z) Geometry + Base Structure Corey & Co-workers, Tetrahedron Lett. 1984, 25, 491, 495 THF, -78 °C M–base + Base temp control Ratio (A:B) –78 ° kinetic 99:1 –78 ° kinetic 95:5 –78 ° kinetic 90:10 heat thermo 10:90 heat thermo 26:74 heat thermo 38:62 Regioselective Enolization A: Alkyl groups stabilize metal enolate A: As M–O bond becomes more ionic A is attenuated M–base + Kinetic Selection sensitive to structure ratio: 99:1 estimated pKa's (Bordwell) (25) (18) Unsaturated Ketones kinetic enolate KOt–Bu thermodynamic enolate see kinetic acidity handout for an extensive compilation of cases. Enolization with Metal Amides bases pKeq est: 7 (10+7) For the latest in the series of Column papers see: JACS 2000, 122, 2452-2458
D.A. Evans Enolization with metal amides bases Chem 206 Kinetic Selection sensitive to structure Kinetic Selection in Enolization of Unsaturated Ketones LDA oLi 71:29 LDA only enolate CH2 LDA only enolate CH2 14:86 OLi only enolate DA 85:15 LDA only enolate 90:10 only enolate LDA 83:17
Me Me O Me Me O Me Ph Me O Ph O O Me N O Et MeO O MeO OLi N OLi Et OLi Me Ph OLi Me CH2 OLi Me Ph CH2 OLi Me CH2 OLi MeO OLi N OLi Et OLi Me Ph OLi Me Me OLi Me Ph Me OLi Me Me OLi O Me Me O O Me O O Me O Me Me Me OLi Me Me LiO OLi Me OLi Me O OLi Me Me Me D. A. Evans Enolization with Metal Amides bases Chem 206 Kinetic Selection sensitive to structure LDA 71:29 LDA 99:1 LDA 14:86 LDA 99:1 LDA ~90:10 LDA ~83:17 LDA 85:15 LDA only enolate LDA only enolate LDA only enolate LDA only enolate LDA only enolate Kinetic Selection in Enolization of Unsaturated Ketones