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
D.A. Evans Design of Soft Enolization Systems Chem 206 Strategy Lithium enolates Choose Lewis Acid( LA) which can reversibly associate with amine base(B Roush Masamune Tet. Lett. 1984. 25. 2183-2186 B Horner-Wadsworth-Emmons Reaction This system has the potential to enolize carbonyl functional groups LiCL, 1.2 equiv ∠LA Base, 1.0equiv (Eto)2P B-H CHO. 1 e0 R CH2-H 1.2 equ Mecn pKa 19.2(DMSO), K counterion Base Dbu 5 min. 99%>50: 1 E: Z pKa 12.2(Diglyme), Li counterion Base= diPea, 7h, 97%, >50: 1 E Z Isefullewis Acid airs Complexation -OT =-OSO2 CF3 MgBr2 NEt3 Re NHCbz CHo using DIPEg NHCbz O Li-X Nr3 Reversible Sn(oTi)2+ NR3 Reversible(Et3N, EtNi-Pr2) 24 h. rt R2B-OTf NR3 Reversible(Et3N, EtNi-Pr2) 85%+ 10% recovered aldehyde R2BCI NR3 Reversible(Et3N, EtNi-PT2 Conventional methods of deprotonation (NaH)resulted in epimerization PhBCl2+ NR3 Reversible(Et3N, EtNi-Pr2 (Overman JACS 1978, 5179) TICl4 NR3 Irreversible(Et3N, EtNi-Pr2) i-PrOTiCl3 Nr Reversible(Et3N, EtNi-Pr2 Rathke, Nowak J. Org. Chem. 1985, 50, 2624-2626 i-Pro)2TiCl2 NR3 Reversible(Et3N, EtNi-Pr2 (Et3N, EtNi-Pr2) MgBr2, 1.2 equiv All of the above systems will enolize simple ketones to some extent EtN, 1.1 equiv OEt THF. rt R= i-Pr, 40% yield 100% enolization for B Sn. ti partial enolization for Li, Mg
Choose Lewis Acid (LA) which can reversibly associate with amine base (B:). This system has the potential to enolize carbonyl functional groups: R CH2–H O LA O LA R CH2 Useful Lewis Acid Pairs All of the above systems will enolize simple ketones to some extent. O + R CH3 LA B B: B: LA B Me N Me B–H O OEt (EtO)2P O O OEt (EtO)2P O NHCbz CHO Me R CH3 O O RS CH3 PhO CH3 O O EtO CH3 R2N CH3 O Me NHCbz OEt O R OEt O OEt O Me Me Lithium Enolates Rathke, Nowak J. Org. Chem. 1985, 50, 2624-2626. MgBr2, 1.2 equiv Et3N, 1.1 equiv 1 equiv R= i-Pr, 40% yield R= n-C6H13, 100% yield Conventional methods of deprotonation (NaH) resulted in epimerization (Overman JACS 1978, 5179). 85% + 10% recovered aldehyde Above conditions using DIPEA 24 h, rt Base = DBU, 5 min, 99%, >50:1 E:Z Base = DIPEA, 7 h, 97%, >50:1 E:Z Horner-Wadsworth-Emmons Reaction. 1.2 equiv LiCl, 1.2 equiv Base, 1.0 equiv i-PrCHO, 1 equiv MeCN rt pKa 19.2 (DMSO), K+ counterion pKa 12.2 (Diglyme), Li+ counterion D.A. Evans Design of Soft Enolization Systems Chem 206 Strategy LA + (–) (+) + LA + + (+) (–) (+) Complexation MgBr2 + NEt3 Reversible Li–X + NR3 Reversible Sn(OTf)2 + NR3 Reversible (Et3N, EtNi-Pr2) -OTf = - OSO2CF3 R2B-OTf + NR3 Reversible (Et3N, EtNi-Pr2) R2BCl + NR3 Reversible (Et3N, EtNi-Pr2 ) PhBCl2 + NR3 Reversible (Et3N, EtNi-Pr2) TiCl4 + NR3 Irreversible (Et3N, EtNi-Pr2 ) i-PrOTiCl3 + NR3 Reversible (Et3N, EtNi-Pr2) (i-PrO)2TiCl2 + NR3 Reversible (Et3N, EtNi-Pr2) (i-PrO)3TiCl + NR3 Reversible (Et3N, EtNi-Pr2) 100% enolization for B, Sn, Ti partial enolization for Li, Mg RCHO, 1 equiv THF, rt Roush & Masamune, Tet. Lett. 1984, 25, 2183-2186
D.A. Evans A Survey of Soft' Enolization Techniques Chem 206 Magnesium Enolates Titanium Enolates Rathke J. org. Chem. 1985,, 4877-4879 The Early Literature Syn. Comm1986,16,1133-1139 Lehnert, W. Tetrahedron lett. 1970. 4723-4724 Dieth MgCl2, 1 equiv EtN, 2 equiv OEt Et 85% yield Ketone Carboxylation gcl2, equiv Harrison, C R. Tetrahedron Lett. 1987, 28, 4135-4138 Nal, 2 equiv Et N, 4 equiv COOH TiCl4 cO, MeCN 7%y 30 min Ketone and aldehyde combined followed 91% yield MgCl2, 2 equiv by sequential addn of TiCl4 and then amine 95: 5 syn/anti EtoH -cO 2 CTICl4 Michael reaction CO2 Me COmE Et Brocchini. Eberle, Lawton J. Am. Chem. Soc. 1988. 110. 5211-5212 CH2Ch2,0° 73% yield, 93: 7 diastereomer ratio OH Et3N-H 10-15:1ZE Deuterium quench indicates 25% enolization of N-propionyloxazolidinone
O O EtO O OEt O O N Bn O Me O CO2Me O Me N O Bn O Mg Brn Et3N–H Me O Cl O O O Mg EtOH -CO2 MVK O COOH O Me N O Bn O CO2Me OEt O EtO O O Me O Me O O Me Ph TiCl4 NO2 O S OH O EtO OEt O Ph Me O Ph H O PhCHO Et Et O CHO Ph Me O Ph Ph O Me OH S O NO2 OH O Ph H TiCl4 O EtO OEt O Et Et + + + + The Early Literature 10-15:1 Z/E TiCl4 DIPEA THF -40° C Brocchini, Eberle, Lawton J. Am. Chem. Soc. 1988, 110, 5211-5212. 91% yield 95:5 syn/anti TiCl4 Et3N CH2Cl2, 0° C 30 min + Ketone and aldehyde combined followed by sequential addn of TiCl4 and then amine Harrison, C. R. Tetrahedron Lett. 1987, 28, 4135-4138. 75% yield TiCl4 Pyridine THF Lehnert, W. Tetrahedron Lett. 1970, 4723-4724. + Michael reaction Rathke Evans, Bilodeau unpublished results. 73% yield, 93:7 diastereomer ratio Magnesium Enolates Deuterium quench indicates 25% enolization of N-propionyloxazolidinone MgBr2•OEt2 Et3N CH2Cl2, 0° C 75% yield MgCl2, 2 equiv Et3N, 4 equiv +CO2 MeCN rt 70 % yield MgCl2, 2 equiv NaI, 2 equiv Et3N, 4 equiv Ketone Carboxylation 85% yield MgCl2, 1 equiv Et3N, 2 equiv MeCN, rt Diethylmalonate acylations J. Org. Chem. 1985, 50, 2622-2624. J. Org. Chem. 1985, 50, 4877-4879. Syn. Comm. 1986, 16, 1133-1139. D.A. Evans A Survey of 'Soft' Enolization Techniques Chem 206 Titanium Enolates CO2, MeCN rt
M. Bilodeau, d.A. evans A Survey of Soft Enolization Techniques Chem 206 Titanium Enolates Reactions with Representative Electrophiles C Cl4 CI-t-Cl 00 H2OBn TICl4 le R3N Me9%.991 CH,SPh a Enolization process not responsive to tertiary amine structur BOMCI 93%,973 I DIPEA, Et3N, N-Ethylpiperidine all suitable bases 78%.982 PhSCHCI L DBU and tetramethylguanidine do not provide enolate CH2 Cl2 is the only suitable solvent for these enolizations N-Propionyloxazolidone(1) Ethylisopropylketone (CH2)2COEt CICH2NHCOPh CH2 NHCOPh Lewis acid 88%,>99:1 89%,973 TICL4'2THF 80 i-PrO)TIC HC(OMe)3 MeOCH2NHCbz (APrO)2TiCl2 70 (A-PrO3TICl 10 I Order of addition of reagents is important for Ticl4 CH2 NHCBZ CH(OMe)2 RaN-Ticl4 Irreversible Complexation 91%.96:4 IOrder of addition of reagents is not important for A-ProTiCl3 or(A-PrO)2TiCl 99%.>99:1 R3N APrOTiCk R3N-TICl(OPr Reversible Complexation JAm.Chem.Soc.1990,112,82158216;Jorg.chem.1991,56,57505752 Enolizable substrates 1. cI SUbstrates Which present problems: self condensation self condensation Evans, Clark, Metternich, Novack, Sheppard J. Am. Chem. Soc. 1990, 112, 866
R3N R3N O Me N O Bn O R O Me TiCl4 i-PrOTiCl3 TiCl4 •2THF (i-PrO)3TiCl (i-PrO)2TiCl2 TiCl4 i-PrOTiCl3 O t-Bu Me TiCl4 i-Pr Me O O N Bn O Me O Ti Cl Cl Cl Cl R3N-TiCl4 TiCl4 i-PrOTiCl3 R3N (i-PrO)2TiCl2 MeO OMe O Me O Me Me O Me N O Bn O Ti Cl4 PhS Me O Xp (CH2)2COEt O Me Bn O N O O Me O Me OMe O Me O Xp Me O CH(OMe)2 Xp HC(OMe)3 Et O BOMCl Xp CH2OBn O Me Xp CH2OH O Me O Me N O Bn O Ti Cln O O O MeO O Me O R Me O PhSCH2Cl ClCH2NHCOPh MeOCH2NHCbz Me O O N O O Bn Me Me OH Me Me O CH2SPh Xp Me O CH2NHCBz Xp Xp CH2NHCOPh O Me 86% yield, >99:1 Evans, Clark, Metternich, Novack, Sheppard J. Am. Chem. Soc. 1990, 112, 866. 1. TiCl4 DIPEA 2. i-PrCHO 99%, >99:1 93%, 97:3 89%, 97:3 91%, 96:4 93%, 99:1 99%, >99:1 88%, >99:1 78%, 98:2 H2C=CHCO2Me J. Am. Chem. Soc. 1990, 112, 8215-8216.; J. Org. Chem. 1991, 56, 5750-5752. Reactions with Representative Electrophiles self condensation self condensation 1 50 80 100 Lewis Acid % Enolization Ethylisopropylketone 80 ~10 70 100 100 Lewis Acid % Enolization N-Propionyloxazolidone (1) R Reversible Complexation 3N-TiCl3(OiPr) + - + ■ Order of addition of reagents is not important for i-PrOTiCl3 or (i-PrO)2TiCl2. ■ Enolization process not responsive to tertiary amine structure ■ DIPEA, Et3N, N-Ethylpiperidine all suitable bases. ■ DBU and tetramethylguanidine do not provide enolate. ■ CH2Cl2 is the only suitable solvent for these enolizations. ■ Order of addition of reagents is important for TiCl4 . + + - Irreversible Complexation Titanium Enolates ■ Enolizable substrates: ■ Substrates Which present problems: R=Ar, R<i-Pr M. Bilodeau, D.A. Evans A Survey of 'Soft' Enolization Techniques Chem 206
D.A. Evans A Survey of Soft'Enolization Techniques: Boron Enolates-1 Chem 206 Dialkylboron Triflates B-X R3N Di-n-buty boron triflate Mukaiyama, Inoue Chem. Lett. 1976, 559-562. Bull. Chem. Soc. Jpn. 1980, 53, 174-178 ratio 97: 3 Enolizes ketones with 2.6-lutidine or dipea in ethereal solvents Cy2B-Cl, Et3N ratio 21: 79 Diastereoselective Aldol Reactions of Boron Enolates Bu 2B-OTf, Et N ratio-97: 3 Evans, Vogel, Nelson J. Am. Chem. Soc. 1979, 101, 612 Borane and lutidine or DIPEA form 1: 1 complex with L-B-OTf Evans, Nelson, Vogel, Taber J. Am. Chem. Soc. 1981, 103, 3099-3111 Complexation reversible as enolization will occur upon addition of vans. Bartroli. Shih J. Am. Chem. Soc. 1981. 103. 212 ketone. Less hindered nitrogen bases-pyridine, Dabco, DBU Masamune.S. et. al. Tetrahedron Lett. 1979. 2225. 2229. 3937. irreversibly complex with L2B-oTf Masamune. S et al. J. Am chem. Soc. 1981. 103. 1566-1568 The Ketone-Boron Complexes as enolate precursors: Chiral dialky boron triflates Masamune. Sato, Kim Wollmann J.Am.chem.Soc.1986,108,82798281.TfoB Paterson. l. et. al. Tetrahedron1990,46,4663-4684 charged Tetrahedron Lett. 1989. 30. 997-1000 Tetrahedron Lett. 1986. 27. 4787-4790 BOT ()(pc)2BoTf Enolate Stereochemistry Evans, Nelson, Vogel, Taber J. Am. Chem. Soc. 1981, 103, 3099-3111 Goodman. Tetrahedron Lett. 1992. 33. 7219 NrY Enolization Model: Paterson, Tetrahedron Lett. 1992. 33. 7223 小BL20Tf Me R2B-x, R3n Me Cy2BCl-ketone complex may deprotonate through syn complex 9-BBN-OTf, Et3N rato~88:12 Cy2B-Cl, Et3N R2BOTf-ketone complex may deprotonate through charged complex () preference Brown, J. Org. Chem. 1993, 58, 147-153
R R -X– -X– H Me H O BL2OTf +X– H Me H +X– O O BL2X Me Me Me Me Me O BR2 Me TfOB Me Me Me O BR2 Me Mr Me BOTf Me Me R O B X R R Me Me O OBL2 R Me O B R R Me R O BR2 Me Me B R Me R O R R OBL2 Me Mr Me O BR2 Me R O B X R R R2BOTf-ketone complex may deprotonate through charged complex with (Z) preference charged Cy2BCl-ketone complex may deprotonate through syn complex + + syn + + anti The Ketone-Boron Complexes as enolate precursors: Bu2B-OTf, Et3N ratio ~97: 3 9-BBN-OTf, Et3N ratio ~97: 3 R2B-X, R3N Cy2B-Cl, Et3N ratio 21:79 Brown, J. Org. Chem. 1993, 58, 147-153 Cy2B-Cl, Et3N ratio ~ 3: 97 R2B-X, R3N ratio ~ 88: 12 Enolization Model: Paterson, Tetrahedron Lett. 1992, 33, 7223. Goodman, Tetrahedron Lett. 1992, 33, 7219. A Survey of 'Soft' Enolization Techniques: Boron Enolates-1 Borane and lutidine or DIPEA form 1:1 complex with L2B-OTf. Complexation reversible as enolization will occur upon addition of ketone. Less hindered nitrogen bases - pyridine, Dabco, DBU, irreversibly complex with L2B-OTf. 9-BBN-OTf, Et3N Evans, Nelson, Vogel, Taber J. Am. Chem. Soc. 1981, 103, 3099-3111. + + - - NR'3 NR'3 (-)-(Ipc)2BOTf Chiral dialkylboron triflates Masamune, S. et. al. Tetrahedron Lett. 1979, 2225, 2229, 3937. Masamune, S. et. al. J. Am Chem. Soc. 1981, 103, 1566-1568. Diastereoselective Aldol Reactions of Boron Enolates. Di-n-butylboron triflate Evans, Vogel, Nelson J. Am. Chem. Soc. 1979, 101, 6120. Evans, Nelson, Vogel, Taber J. Am. Chem. Soc. 1981, 103, 3099-3111. Evans, Bartroli, Shih J. Am. Chem. Soc. 1981, 103, 2127. Dialkylboron Triflates Enolizes ketones with 2,6-lutidine or DIPEA in ethereal solvents. Mukaiyama, Inoue Chem. Lett. 1976, 559-562. Bull. Chem. Soc. Jpn. 1980, 53, 174-178. Masamune, Sato, Kim, Wollmann J. Am. Chem. Soc. 1986, 108, 8279-8281. Tetrahedron 1990, 46, 4663-4684. Tetrahedron Lett. 1989, 30, 997-1000. Tetrahedron Lett. 1986, 27, 4787-4790. D.A. Evans Chem 206 Enolate Stereochemistry Paterson, I. et. al. anti syn
D. A. Evans Enolate Structures from X-ray diffraction Chem 206 Ab initio calculations(Spartan)indicate M Metal Tautomerism that the partial negative charge on the alpha carbon is-0. 22 for the Li enolate Me S/H M=Li For alkali metal enolates(M= Li, Na, Ketc ) the o-metal tautomer is strongly favored. This generalization holds for most alkaline earth enolates(Mg) as well. These are the generally useful enolate nucleophiles For certain metal enolates from heavy metals such as M=Hg"the C-metal tautomer is sometimes favored Resonance Structures 0" resonance C resonance structure structure ince enolates some interest to ed contributing ray crystal ructures of a r One would predict that as the relative importance of the C structure J.Am.Chem.Soc.1985,107,5403 does hold, but the net change in 130- would lengthen increases the c-o bond would shorten and the c-c bond The prediction stated above 135A the C-C bond length is <2 %! 132A~134A CMea In solution and in the solid state metal enolates have a strong tendency to aggregate into dimers and tetramers to satisfy metal solvation requirements o-Ma
Mg N O Li Li O M H Me H O R M R R R O O Li H R H Br Mg OEt2 O Me CMe3 H H R H O Me M OR RO M O O R M M Me O O CMe3 H Li N Me2 Me2 N Mg Br M M M O M R O R O R R O M R R O R M R R O M R O M ● ● 1.35 Å 1.34 Å + In solution and in the solid state metal enolates have a strong tendency to aggregate into dimers and tetramers to satisfy metal solvation requirements. Crystallized as the dimer Crystallized as the dimer Seebach & co-workers, J. Am. Chem. Soc. 1985,107, 5403. For certain metal enolates from heavy metals such as M = Hg+2 the C-metal tautomer is sometimes favored. The prediction stated above does hold, but the net change in the C–C bond length is < 2 % ! 1.36 Å 1.32 Å One would predict that as the relative importance of the C– structure increases, the C–O bond would shorten and the C–C bond would lengthen. Since enolates usually function as carbon nucleophiles, it is therefore of some interest to assess the relative importance of the illustrated contributing polar resonance structures. Within the last decade good X-ray crystal structures of a number of metal enolates have been obtained. C – resonance structure O – resonance structure For alkali metal enolates (M = Li, Na, K etc.) the O-metal tautomer is strongly favored. This generalization holds for most alkaline earth enolates (Mg+2) as well. These are the generally useful enolate nucleophiles Metal Tautomerism Resonance Structures D. A. Evans Enolate Structures from X-ray Diffraction Chem 206 d– Ab initio calculations (Spartan) indicate that the partial negatilve charge on the alpha carbon is ~ – 0.22 for the Li enolate M = H M = Li – 0.19 – 0.22