Chemistry 206 Advanced Organic Chemistry Handout 25A The asymmetric Baylis-Hillman Reaction An Evans group Afternoon Seminar Jake Janey March 29th. 2001 EWG cat base EWG RR EWG Matthew d. shair Friday, November 15. 2002
Matthew D. Shair Friday, November 15, 2002 Chemistry 206 Advanced Organic Chemistry Handout 25A The Asymmetric Baylis-Hillman Reaction An Evans Group Afternoon Seminar Jake Janey March 29th, 2001 EWG + cat. base XH EWG X R R' R R' * EWG –
J. Janey The Asymmetric Baylis-Hillman Reaction Chem 206 An Evans Group Afternoon Seminar An anti propionate aldol equivalent March 29th. 2001 REWG Rh(),H2 EWG EWG EWG Early Synthetic Examples 10 years after the Baylis-Hillman German patent. used in a C1o integeminecic acid synthesis: Leading References cO2Et DABCO Langer, P Angew. Chem. Int Ed Engl. 2000, 39, 3049-3052 MecHo Ciganek, E. Org. React. 1997, 51, 201-350 257"Me HO2C M Basavaiah. D et a Tetrahedron 1996 52. 8001-8062 94%o yield Drewes,S E: Roos, G.H. P. Tetrahedron. 1988. 44. 4653-4670 Drewes. S.E. J. Chem. Soc.. Perkin Trans. 1 1982. 2079-2083 Baylis-Hillman Reaction Scope Shortly thereafter, a more extensive, published study: EWG cat. base EWG COmE 15% DABCO cOmE 25°c,0.5to7d X=O, NTs, NCO2R, NPPh2, NSO2Ph EWG= CO2R, CN, POEt2, 94% yield COR, SO2Ph, SO3Ph R=H, alkyl, EWG All reactions run neat in a sealed tube with 1.5-2 equivalents of acrylate Hoffmann, H M. R. Rabe, J Angew. Chem. Int Ed. Engl. 1983, 22, 795-797. 3-hydroxyquinuclidine(3-QDL) DABCo quinuclidine 25A-0111/9/01106PM
J. Janey The Asymmetric Baylis-Hillman Reaction Chem 206 Leading References: Langer, P. Angew. Chem. Int. Ed. Engl. 2000, 39, 3049-3052. Ciganek, E. Org. React. 1997, 51, 201-350. Basavaiah, D.; et. al. Tetrahedron, 1996, 52, 8001-8062. Drewes, S. E.; Roos, G. H. P. Tetrahedron, 1988, 44, 4653-4670. An Evans Group Afternoon Seminar Jake Janey March 29th, 2001 EWG + cat. base XH EWG X R R' R R' * EWG – Baylis-Hillman Reaction Scope R1 X EWG R2 X = O, NTs, NCO2R, NPPh2, NSO2Ph R1 = alkyl, aryl R2 = H, alkyl, EWG EWG = CO2R, CN, POEt2, CHO, COR, SO2Ph, SO3Ph + cat. base EWG R1 R2 XH R OH EWG Rh(I), H2 R EWG OH An anti propionate aldol equivalent... N N N N OH cat. bases: 3-hydroxyquinuclidine (3-QDL) DABCO quinuclidine n-Bu3P: Early Synthetic Examples CO2Et MeCHO 5% DABCO 25 °C, 7d Me OH CO2Et 94% yield HO2C Me Me CO2H Me OH + Drewes, S. E. J. Chem. Soc., Perkin Trans. 1 1982, 2079-2083. 10 years after the Baylis-Hillman German patent...used in a C10 integerrinecic acid synthesis: Shortly thereafter, a more extensive, published study: CO2Me RCHO 15% DABCO 25 °C, 0.5 to 7d R OH CO2Me 94% yield + Hoffmann, H. M. R.; Rabe, J. Angew. Chem. Int. Ed. Engl. 1983, 22, 795-797. • All reactions run neat in a sealed tube with 1.5-2 equivalents of acrylate. R = alkyl or aromatic 25A-01 11/9/01 1:06 PM
J. Janey The Asymmetric Baylis-Hillman Reaction Chem 206 J.S.: Isaacs, N. S.J. Phys. Org. Chem. 1990, 3. Sal 5614: Bode, M L. Tetrahedron Let. 1991, 32 Evidence for an Intermediate Drewes, SE; et al. Syn. Comm. 1993, 23, 2807-2815 EWG Coumarin Salt 1 eq DABco CH2Cl2, rt, 2.5 h EWG E2 elimination RCHO CH2Cl2 EWG Effects of Acrylate Ester Substituent initially formed eliminates 13% DABCO E1cB is also possible 1.3 eq eq pseudo-second order if amine-constant addition to aldehyde is r.d. s. because the dipole s R increased by further charge seperation Et enolate geometry not considered relation between o values and reactivity was ethereal solvent inhibits reaction whereas alcohols observed pecially diols)accelerate reaction huge volume of activation: AV* of-79 cm mor'(the 2-adamanty 62 40 Diels-Alder is-35 cm mor' found by plotting Inkohsvs CH CHaF The products undergo retro Baylis-Hillman, Le P. 5000 bar increases rate by 1. x 105 CH2CH2Br ir the reaction is reversible Reaction is reversible (i.e. a Grob type CH2 CF 15h 58 fragmentation), thus mechanism could be ternary, with CH2CH2OMe 89 no discrete enolate intermediate(supported by AV+ and CH2CH2 NMe2 (CH2)6CI Caubere. P: et al. Tetrahedron 1992. 48. 6371-6384 25A-0211/9/01
The Asymmetric Baylis-Hillman Reaction Chem 206 EWG R3N + EWG R3N – + R'CHO EWG R3N O R' + EWG R' OH NR3 H H Hα EWG O + R' NR3 H H Hα EWG + O E2 elimination... initially formed eliminates • rate = Kobs[aldehyde][alkene][amine] • pseudo-second order if [amine]≈constant • addition to aldehyde is r.d.s. because the dipole is increased by further charge seperation • acrylonitrile and methyl acrylate studied • enolate geometry not considered • ethereal solvent inhibits reaction whereas alcohols (especially diols) accelerate reaction • huge volume of activation: ∆ V‡ of -79 cm3 mol-1 (the Diels-Alder is -35 cm3 mol-1) found by plotting lnkobs vs. P. 5000 bar increases rate by 1.1 x 106 • Reaction is reversible (i.e. a Grob type fragmentation), thus mechanism could be ternary, with no discrete enolate intermediate (supported by ∆ V‡ and temperature effects). Hill, J. S.; Isaacs, N. S. J. Phys. Org. Chem. 1990, 3, 285-288. Kaye, P. T.; Bode, M. L. Tetrahedron Lett. 1991, 32, 5611-5614. :B – – – E1cB is also possible Evidence for an Intermediate O O O 1 eq DABCO CH2Cl2, r.t., 2.5 h O O N N + Cl X-ray 81% yield Coumarin Salt Drewes: "...the counter ion was chloride (presumably originating from the dichloromethane...)." O OH + Cl O O OH + OMe O 1 eq DABCO CH2Cl2, 0 °C O O N N + Cl Or... 40% yield Drewes, S. E.; et. al. Syn. Comm. 1993, 23, 2807-2815. H H H – – Effects of Acrylate Ester Substituent CO2R + 13% DABCO neat, r.t 1.3 eq 1.0 eq Ph OH O OR PhCHO R Me Et Bn n-C10 H21 t-Bu 2-adamantyl CH2CH2F CH2CH2Br CH2CF3 CH2CH2OMe CH2CH2NMe2 (CH2)6Cl time (days) 6 7 2 14 65 62 3 2 15 h 4 8 15 yield (%) 89 79 88 75 65 40 81 NR 58 89 82 NR Caubere, P.; et. al. Tetrahedron 1992, 48, 6371-6384. • For aryl substituted benzyl ethers, no clear relation between σ values and reactivity was observed. • Trends hold for furfural. • The products undergo retro Baylis-Hillman, i.e. the reaction is reversible. J. Janey 25A-02 11/9/01 1:07 PM
J. Janey The Asymmetric Baylis-Hillman Reaction Chem 206 Bases for Catalysis Reaction is accelerated for a wide variety of aldehydes when conducted atoC pKa H2O (DMSO) · Author conclude folate must react faster than another (i.e. a kinetic versus a thermodynamic ∠N cOmE 3-Hydroxyqinui sine (3-QDL) 2.97, 8.82(2.97 109(980) NMe2 NMe2 人 Which enolate is more stable and which is more reactive Leahy, J. W; Rafel, S.J. Org. Chem. 1997, 62, 1521-1522. 3-Acetoxyquinuclidil 3-Quinuclidone Proton 120(7.50) Stencs also important Enolate Geometr Me2NH> Me2NEt > MeNEt2> NEt3 10.75(9.00) Many, many phosphines screened. the winner: n-Bu3P-9 O、OMe n-Bu3P is only a slightly better catalyst than DABCO mediate, as any charge seperation more charge separation will accelerat less stable Inreactive enolate twists out of plane by PM3 Temperature Effects 0.1 mol% DABcO Q:0 4πe MecHo HOMO 2M in dioxane 25°1week 0°c8 hours! better conjugation intoσ 25A-0311/9011:07PM
The Asymmetric Baylis-Hillman Reaction Chem 206 Bases for Catalysis N N DABCO 2.97, 8.82 (2.97, 8.93) N Quinuclidine 10.9 (9.80) N 3-Hydroxyquinuclidine (3-QDL) 9.5 (~8.5) OH > >>> N 3-Acetoxyquinuclidine OAc N 3-Quinuclidone 6.9 O or O OR N O H ...or could accelerate protonation of intermediate, as any alcohol additive will accelerate reaction NMe2 NMe2 Proton sponge 12.0 (7.50) N N DBU (~12) Sterics also important: Me2NH > Me2NEt > MeNEt2 > NEt3 10.75 (9.00) Many, many phosphines screened...the winner: n-Bu3P ~9 P P unreactive • n-Bu3P is only a slightly better catalyst than DABCO. pKa H2O (DMSO) – >> Temperature Effects CO2Me + MeCHO 0.1 mol% DABCO 2M in dioxane Me OH CO2Me 25 °C 1 week 0 °C 8 hours! 74% yield • Reaction is accelerated for a wide variety of aldehydes when conducted at 0 °C • Temperature effect not seen with acrylonitrile (cannot form enolate) • Author concludes that one enolate must react faster than another (i.e. a kinetic versus a thermodynamic enolate). NR3 O OMe + R3N O – + E CO2Me R3N + Z Which enolate is more stable and which is more reactive? Leahy, J. W.; Rafel, S. J. Org. Chem. 1997, 62, 1521-1522. – OMe Enolate Geometry NR3 O OMe R3N O + + – E R3N + Z Thermodynamic Kinetic • less charge seperation • less reactive • more charge separation • less stable • enolate twists out of plane by PM3 O OMe + R3N O OMe O MeO NR3 σ* 4π eHOMO + MeO O NR3 σ* + better conjugation into σ* OMe – – – J. Janey 25A-03 11/9/01 1:07 PM
J. Janey The Asymmetric Baylis-Hillman Reaction Chem 206 Salt Additive Lewis Acid Catalysis cO2t-Bu 1 eq DABCO coMMe. PhCHO 5% DABCO co2t-Bu MecN. rt 1 d E2,0°C,201 5 mol% ligand, 5 mol% metal 1.2 eq )eg ICIO4(mol%) yield (% trace Sc(oTf)3 Yb(oTf) 12 128 (+)diethyl tartrate 7.3 2(812 OMe 25 Stablize enolate? (+) (+)hydrobenzoin 16.2 5.8 (+)triphenylethaned a 15 mol% DABCO was used (+)TADDOL 4.5 ethylene glycol Ether was found to be optimal from solvent screenr triethanolamine 465 10.8 General for a variety of alkenes and aldehydes Kobayashi, S; Kawamura, M. Tetrahedron Lett. 1999, 40, 1539-1542 N-methylephedrine DABCO loading dropped to <10 mol% with(+r-BINOL ac-BINOL showed no rate acceleration Aggarwal, V. K; et al. Chem. Coml 96,27132 Aggarwal, V. K; et al. J. Org. Che 63,718 25A-0411/9011:07PM
The Asymmetric Baylis-Hillman Reaction Chem 206 Salt Additive CO2Me + PhCHO 5% DABCO Et2O, 0 °C, 20 h Ph OH CO2Me LiClO4 (mol%) 0 5 10 50 70 100 200 500 yield (%) trace 12 40 63 72 (81)a 25 12 trace 1.2 eq 1.0 eq a 15 mol% DABCO was used. • Ether was found to be optimal from solvent screening. • General for a variety of alkenes and aldehydes. R3N O + Li ClO4 Stablize enolate? Kobayashi, S.; Kawamura, M. Tetrahedron Lett. 1999, 40, 1539-1542. – OMe Lewis Acid Catalysis CO2t-Bu + PhCHO 1 eq DABCO MeCN, r.t., 1 d Ph OH CO2t-Bu ligand none (+)BINOL (+)diethyl tartrate (+)diisopropyl tartrate (+)TMTDA (+)hydrobenzoin (+)triphenylethanediol (+)TADDOL ethylene glycol triethanolamine salen box N-methylephedrine Sc(OTf)3 3.3 9.4 5.2 3.5 4.1 3.5 3.2 2.9 3.3 4.65 2.31 3.6 2.87 Yb(OTf)3 3.6 14.4 9.7 9.5 8.0 16.2 5.2 4.5 6.3 5.8 Eu(OTf)3 3.5 12.8 5.5 4.6 3.6 5.8 2.2 3.8 5.2 3.2 La(OTf)3 4.7 14.6 7.3 8.1 4.0 5.3 5.9 4.7 10.8 4.0 4.4 5 mol% ligand, 5 mol% metal Relative Reaction Rates • no enantioselectivity observed • DABCO loading dropped to <10 mol% with (+)-BINOL • rac -BINOL showed no rate acceleration Aggarwal, V. K.; et. al. Chem. Commun. 1996, 2713-2714. Aggarwal, V. K.; et. al. J. Org. Chem. 1998, 63, 7183-7189. J. Janey 25A-04 11/9/01 1:07 PM