Chemistry 206 Advanced Organic Chemistry Handout-22A A Survey of"Soft Enolization"Techniques Mark bilodeau Evans Group seminar, March 10, 1993 Matthew d. shair Friday November 8. 2002
Chemistry 206 Advanced Organic Chemistry Handout–22A A Survey of "Soft Enolization" Techniques Mark Bilodeau Evans Group Seminar, March 10, 1993 Matthew D. Shair Friday November 8, 2002
M. Bilodeau. D.A. Evans A Survey of Soft Enolization Techniques Chem 115 Alkoxides of lanthanum and yttrium A Survey of Soft Enolization Techniques Sasai. Suzuki. Arai. Arai. Shibasaki J. Am. Chem. Soc. 1992. 114. 4418-4420 PhCHO CI THE Lay(ot-Bu)g(3. 3 mol%), -72 C, 30 h, 74% yield Metal alkoxides Zr(ot-Bu)4( 140 mol%), -50 C, 2.5 h, 86% yield Ti(Ot-Bu)4-No coupling product I. Lewis acid/ amine base enolizations A. Horner-Emmons reactions a Catalytic Enantioselective Aldol Reactions of Nitroalkanes B. Glycine Enolates C Methods for General Carbonyl Substrates Laa(0t-Bu)(3.3 mol%) THE MeNO2, 10 equi D Boron Enolates-Enolate Stereochemistry (S)-Binaphthol (15 mol%) LiCL 20 mol% H 'H NMR shows absence of a t-Butoxy group on the catalys R=C-C6H11, 91% yiel ee Mark bilodeau Evans Group Meeting 3/10/93 Tetrahedron Lett. 1993. 34. 851-854 0 -Naphto 50 equiv -50°c,60h Catalyst prepared from: LaCl 7H20(10 mol%) 80% yield (R)(+)bi de(10m%) H20(10 mol%) 22A-01 Ketone Acidity 11/1/01 3: 41 PM
Sasai, Suzuki, Arai, Arai, Shibasaki J. Am. Chem. Soc. 1992, 114, 4418-4420. PhCHO + Catalyst THF Ti(Ot-Bu)4 - No coupling product La3(Ot-Bu)9 (3.3 mol%), -72° C, 30 h, 74% yield Y3(Ot-Bu)8Cl (3.3 mol%), -43° C, 3.5 h, 50% yield Zr(Ot-Bu)4 (140 mol%), -50° C, 2.5 h, 86% yield La3(Ot-Bu)9 (3.3 mol%) (S)-Binaphthol (15 mol%) + THF, rt 2 h 1H NMR shows absence of a t-Butoxy group on the catalyst RCHO, 1 equiv MeNO2, 10 equiv LiCl, 20 mol% H2O, 1 equiv R = c-C6H11, 91% yield, 90% ee R = i-Pr, 80% yield, 85% ee R = PhCH2CH2CHO, 79% yield, 73% ee ■ Catalytic Enantioselective Aldol Reactions of Nitroalkanes Sasai, Itoh, Suzuki, Shibasaki Tetrahedron Lett. 1993, 34, 855-858. Tetrahedron Lett. 1993, 34, 851-854. 1 equiv + MeNO2 50 equiv Catalyst -50° C, 60 h LaCl3•7H2O (10 mol%) (R)-(+)-binaphthoxide (10 mol%) NaOt-Bu (10 mol%) H2O (10 mol%) Catalyst prepared from: 80% yield 92% ee Alkoxides of Lanthanum and Yttrium Mark Bilodeau Evans Group Meeting 3/10/93 A Survey of 'Soft' Enolization Techniques D. Boron Enolates - Enolate Stereochemistry I. Metal Alkoxides II. Lewis Acid/ Amine Base Enolizations A. Horner-Emmons Reactions B. Glycine Enolates C. Methods for General Carbonyl Substrates M. Bilodeau, D.A. Evans A Survey of 'Soft' Enolization Techniques Chem 115 O Me Cl Me O Ph HO Cl NO2 R HO α−NaphtO NO2 OH α−NaphtO CHO 22A-01 Ketone Acidity 11/1/01 3:41 PM
M. Bilodeau. D.A. Evans A Survey of Soft Enolization techniques Chem 115 Horner-Wadsworth -Emmons reaction Lewis Acid -Tertiary Amine Enolizations i-PrCHO, 1 equiv oEt MecN 1.2 equiv 了 pKa 19.2( DMSO), K,counterion Base= DIPEA, 7 h, 97%, >50: 1E:Z pKa 12.2( Diglyme), Li counterion R'3N-MLn NHCbz NHCbz 85%+ 10% recovered aldehyde a Acidity of a-protons enhanced by coordination of Lewis acid Conventional methods of deprotonation(NaH)resulted in epimerization I This allows the use of mild bases to depronate substrate I A critical issue in the success of procedure of enolization is the Rathke, Nowak J. Org. Chem. 1985, 50, 2624-2626 reversible Lewis acid/amine base association R3N MLn R3NLn a Many reactions surveyed here dont rely on complete enolization of the carbonyl substrate. If the electrophile can withstand the reaction conditions it can access an equilibrium concentration of the enolate R= i-Pr, 40% yield R= n-CaH13, 100% yield 22A-02 Ketone Acidity 11/1/01 3: 41 PM
R3N MLn R3N + MLn ■ Many reactions surveyed here don't rely on complete enolization of the carbonyl substrate. If the electrophile can withstand the reaction conditions it can access an equilibrium concentration of the enolate. pKa 19.2 (DMSO), K+ counterion pKa 12.2 (Diglyme), Li+ counterion LiCl, 1.2 equiv Base, 1.0 equiv i-PrCHO, 1 equiv MeCN 1.2 equiv rt Horner-Wadsworth-Emmons Reaction. Base = DBU, 5 min, 99%, >50:1 E:Z Base = DIPEA, 7 h, 97%, >50:1 E:Z Above conditions using DIPEA 24 h, rt 85% + 10% recovered aldehyde Conventional methods of deprotonation (NaH) resulted in epimerization (Overman JACS 1978, 5179). R= i-Pr, 40% yield R= n-C6H13, 100% yield 1 equiv MgBr2, 1.2 equiv Et3N, 1.1 equiv RCHO, 1 equiv THF rt Rathke, Nowak J. Org. Chem. 1985, 50, 2624-2626. El+ ■ Acidity of a-protons enhanced by coordination of Lewis acid. ■ This allows the use of mild bases to depronate substrate. ■ A critical issue in the success of procedure of enolization is the reversible Lewis acid/amine base association. Lewis Acid - Tertiary Amine Enolizations + MLn R'3N R'3N-MLn R'3N - + M. Bilodeau, D.A. Evans A Survey of 'Soft' Enolization Techniques Chem 115 R O Me Me O R MLn O MLn-1 R Me O R Me El O OEt (EtO)2P O R OEt O O OEt (EtO)2P O OEt O Me Me NHCbz CHO Me Me NHCbz OEt O 22A-02 Ketone Acidity 11/1/01 3:41 PM
M. Bilodeau. d.A. evans A Survey of Soft Enolization Techniques Chem 115 Formation of Glycine Enolate h、∠N、CO2Me co Me Elan, 1 equiv CO2R Kanemasa, Yoshioka J. Org. Chem. 1988 anemasa,Uchida, Wada. Org. Chem. 1990, CH2Cl, rt Co-Me LiBr, 1.5 equiv 1.2: 1 R=Me/R: Et3N, 1.2 equiv COmE Note: Regiochemistry of addition opposite to that above lequiv THF. rt Glycine Enolate CuCl. 5 mol% cN、CO2Me+RcHo EtN. 5 mol% Et2, Znl2, EtAICl employed in related reactions Ito tet. lett. 1985. 5781 869874) R= Me, 100% yield, 2: 1 trans/cis LiBr, 1.1 equiv R=Et2CH, 75% yield, trans only DBU, 1.0 equ When only EtN is employed -complex mixtures, low yields COmE THF. rt 77% yield, single isomer Ito, Sawamura, Hayashi J. Am. Chem. Soc., 1986, 108, 6405-6406. Grigg et al Tetrahedron198844557570;1989,4546494668 Tetrahedron lett.1989,30,4727-4730,1990,31,65696572 ,西 CO, Me [Au(c-HexNC)2) 'BF4/1(1 mol%) iPrCHO +CN OMe COmE Meo cH2Cl225°c ZnBr2, THF, 90% yield, 1: 2.7 99% yield, 98: 2 trans/cis AgOAc, THF, 90% yield, 1:>9 Related reactions have been conducted with MnBr2, MgBr2OEt, TINO3, CoCh the basis of Cu()'s strong preference for N coordination. Ago has recently been optimised to provide moderate-to-good enantioselectivity Hayashi, Ito et al. Tet Lett. 1991, 32, 2799-2802 22A-03 Ketone Acidity 11/1/01 3: 41 PM
M. Bilodeau, D.A. Evans A Survey of 'Soft' Enolization Techniques Chem 115 77% yield, single isomer 1 equiv 1 equiv + LiBr, 1.1 equiv DBU, 1.0 equiv THF, rt NaI, MgBr2•OEt2, ZnI2, Et2AlCl employed in related reactions (Bull. Chem. Soc. Jpn. 1989, 62, 869-874). 82% yield AgOAc, THF, 90% yield, 1:>9 ZnBr2, THF, 90% yield, 1:2.7 Formation of Glycine Enolates. Tsuge, Kanemasa, Yoshioka J. Org. Chem. 1988, 53, 1384-1391. Kanemasa, Tatsukawa, Wada, Tsuge Chem. Lett. 1989, 1301-1304. Kanemasa, Uchida, Wada J. Org. Chem. 1990, 55, 4411-4417. LiBr, 1.5 equiv Et3N, 1.2 equiv THF, rt + + Grigg et al Tetrahedron 1988, 44, 557-570; 1989, 45, 4649-4668. Tetrahedron Lett. 1989, 30, 4727-4730; 1990, 31, 6569-6572. 1 equiv 1 equiv 1 equiv 2 equiv Ti(Oi-Pr)3Cl, 1.5 equiv Et3N, 1 equiv CH2Cl2, rt 80% yield 1.2:1 R=Me/R=i-Pr Note: Regiochemistry of addition opposite to that above. + + Lewis Acid Et3N Solvent rt LiBr, MeCN, 89% yield, 1:6 Related reactions have been conducted with MnBr2, MgBr2•OEt2, TlNO3, CoCl2 • Cu(I) catalyzes the reaction but with no enantioselectivity. This has been rationalized on the basis of Cu(I)'s strong preference for N coordination. • Ag(I) has recently been optimised to provide moderate-to-good enantioselectivity . Hayashi, Ito et. al. Tet. Lett. 1991, 32, 2799-2802. CH2Cl2, 25 °C [Au(c-HexNC)2]+BF4- / 1 (1 mol%) i-PrCHO + 1a : R=Et 1b : R=Me Ito, Sawamura, Hayashi J. Am. Chem. Soc., 1986, 108, 6405-6406. (R)-(S) Ito Tet. Lett. 1985, 5781. + RCHO CuCl, 5 mol% Et3N, 5 mol% THF, RT • When only Et3N is employed - complex mixtures, low yields R= Me, 100% yield, 2:1 trans/cis R=Et2CH, 75% yield, trans only 99% yield, 98:2 trans/cis 92% ee Glycine Enolates Ph N CO2Me CO2Me H Ph CO N 2Me MeO2C N O OMe O Li MeO Ph CO2Me N CO2Me Ph N CO2Me CO2Me Ph CO2R H N Ph Me CO2Me MeO2C MeO2C Ph CO2Me H N H Ph CO N 2Me CO2Me MeO2C CO2Me Me Me Me Me Me N Me t-Bu CO2Me CO2Me Me CO2Me t-Bu N CO2Me CN O Fe OMe O PPh2 N PPh2 NCH2CH2NR2 Me H Me i-Pr CO2Me CN CO2Me O N R CO2Me 22A-03 Ketone Acidity 11/1/01 3:41 PM
M. Bilodeau. D.A. Evans A Survey of Soft Enolization Techniques Chem 115 Lithium halide enolizations Magnesium Enolates Kelleher, McKervey, Vibuljan Chem Comm. 1980, 486-488 1986.16.1133-1139 Diethylmalonate acylation C.1 R= n-CBH11, 85% CI MeCN. rt TMSCL, Et3N 85% yield Et20, reflux Reaction can be brought about with less than 1 equiv of Lil. COOH Kaiser. Fohlisch He/. Chim. Acta. 1990. 73. 1504-1514 70% yield 人 MgCh, 2 equiv Et3N, 4 equiv EtOH 75% yield Evans, Bilodeau unpublished results Harmata. Elahmad Tetrahedron lett. 1993. 34. 789-792 MgBr2.0Et2 3M LICIO4 Et2O 16: 1 ratio of isomers Deuterium quench indicates 25% enolization of N-propionyloxazolidinone 22A-04 Ketone Acidity 11/1/01 3: 42 PM
Rathke M. Bilodeau, D.A. Evans A Survey of 'Soft' Enolization Techniques Chem 115 16:1 ratio of isomers 3M LiClO4 Et3N Et2O Harmata, Elahmad Tetrahedron Lett. 1993, 34, 789-792. 70% yield + LiClO4 Et3N Et2O Kaiser, Fohlisch Helv. Chim. Acta. 1990, 73, 1504-1514. "Reaction can be brought about with less than 1 equiv of LiI." 76%, 60:40 ratio of diastereomers LiI TMSCl, Et3N Et2O, reflux PhCHO R= Ph, 77% R= n-C6H11, 85% slow addn of: RCHO Et2O reflux 4 equiv + LiI 1 equiv Lithium Halide Enolizations Kelleher, McKervey, Vibuljan Chem. Comm. 1980, 486-488. - 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 MVK EtOH MgCl2, 2 equiv Et3N, 4 equiv CO2 MeCN rt 70 % yield MgCl2, 2 equiv NaI, 2 equiv Et3N, 4 equiv CO2 MeCN rt 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. Me O Me Me O R Me O Me Me O Me Ph OH O O Cl Cl Cl O O O O Cl O O Cl O O O EtO O OEt Me O Cl OEt O EtO O O Me O O COOH O O O O Mg O Me O O N Bn O Me O CO2Me O Me N O Bn O CO2Me 22A-04 Ketone Acidity 11/1/01 3:42 PM