Chemistry 206 Advanced Organic Chemistry Handout-35B The Synthetic Applications of Carbonyl Ylides avid m. barnes Evans group seminars, March 16, 1993 Monday Matthew d. shair December 16. 2002
Chemistry 206 Advanced Organic Chemistry Handout–35B The Synthetic Applications of Carbonyl Ylides Matthew D. Shair Monday , December 16, 2002 David M. Barnes Evans Group Seminars, March 16, 1993
The Synthetic Applications of Carbonyl Ylides Stabilized(Isolable) Carbonyl Ylides °Push-Pu" Stabilization David M. Barnes Evans Group Seminars, March 16, 1993 Arduengo, A.J., Ill; Janulis, E P, Jr. J. Am. Chem. Soc. 1983 iIsomunchnons Hamaguchi, M; Ibata, T. Tetrahedron Lett. 1974, 4475-4476. Isomunchnons cycloadd to dipolarophiles mEws·Ydes A: Hornbuckle S F. Chem. Rev. C6H4NO2 M. P Acc. Chem. Res. 1986. 19. 348. M.P.chem.Rev.1986,86,919939. PhH. reflux Hamaguchi, M; Ibata, T. Chem. Lett. 1975, 499-502. 35B-01 Ylides12/17991207PM
- + : The Synthetic Applications of Carbonyl Ylides David M. Barnes Evans Group Seminars, March 16, 1993 Reviews - Ylides Padwa, A.; Hornbuckle, S. F. Chem. Rev. 1991, 91, 263-309. Padwa, A.; Krumpe, K. E. Tetrahedron. 1992, 48, 5385-5483. Padwa, A. Acc. Chem. Res. 1991, 24, 22-28. Carbenes Doyle, M. P. Acc. Chem. Res. 1986, 19, 348-356. Doyle, M. P. Chem. Rev. 1986, 86, 919-939. "Push-Pull" Stabilization Stabilized (Isolable) Carbonyl Ylides Cu(acac)2 - + - + PhH, 80 °C Hamaguchi, M.; Ibata, T. Tetrahedron Lett. 1974, 4475-4476. X = H, Br, OMe - + Hamaguchi, M.; Ibata, T. Chem. Lett. 1975, 499-502. hν + - Arduengo, A. J., III; Janulis, E. P., Jr. J. Am. Chem. Soc. 1983, 105, 5929-5930 "Isomünchnons" Isomünchnons cycloadd to dipolarophiles PhH, reflux quantitative 87% R1 R2 O R1 O R2 A B A B R1 O R2 N N2 O O X O2N CH3 N O O CH3 O2N X N O O CH3 O2N X N O O CH3 N O2N CH3O2C CO2CH3 N O O CH3 Ph C6H4NO2 O O CH3 Ph C6H4NO2 CO2CH3 CO2CH3 NPh O O NPh O O H3C N N CH3 O CH3 CH3 CF3 F3C CF3 F3C N2 CF3 F3C CF3 F3C O NMe2 Me2N 35B-01 Ylides 12/17/99 12:07 PM
Equivalence of Oxirane Ring-Opening Intermediate to Generation of Carbonyl Ylides via the Ring-opening Carbene-Carbonyl Lone Pair Interaction Intermediates of epoxides isooctane A H3CO2C HcHO k2 125°C,15min HoC cOaCH Ratios CO2CH3 n 40(9,175) 125℃c,10da HcHO 40(10.5.230 - c(co,CH3 C(CO2 CH3)2 bach, W: Brokatzky, J; Fritz, H. Angew. Chem. Int. Ed. Engl. 1980, 19, 47-48. atzky, J: Eberbach, W. Tetrahedron Letf. 1980, 21, 4909-4912 Ratio k2 lk2 3 Photochemical ring-openings gave a complex mixture of products was due in part to a scrambling of the ylide Huisgen, R; de March, P J. J. Am. Chem. Soc. 1982, 104, 4952, 4953. See Brokatzky-Geiger, J. Eberbach, W. Heterocycles. 1983, 20, 1519-1524 Tetrahedron Lett. 1 35B-02Ydes3/16/933:23PM
Photochemical ring-openings gave a complex mixture of products in overall low yields. This was due in part to a scrambling of the ylide substituents. See Brokatzky-Geiger, J.; Eberbach, W. Heterocycles. 1983, 20, 1519-1524. Tetrahedron Lett. 1984, 25, 1137-1140. Eberbach, W.; Brokatzky, J.; Fritz, H. Angew. Chem. Int. Ed. Engl. 1980, 19, 47-48. Brokatzky, J.; Eberbach, W. Tetrahedron Lett. 1980, 21, 4909-4912. 91 34 11 66 100 89 100 100 9 75 30 97 57 73 75 isooctane 40 (9, 175) 30 (9, 175) 72 (5, 170) 58 (7, 215) 55 (8, 240) 40 (10.5, 230) Ratios H CO2Me R 1 2 1 3 5 10 n conversion (hours, °C) yield A B C C A B Generation of Carbonyl Ylides Via the Ring-Opening of Epoxides + - - + - + (CH3O2C)2C-N2 + C6H5-CHO Oxirane 3.3 3.0 Ratio k2 / k2 Huisgen, R.; de March, P. J. J. Am. Chem. Soc. 1982, 104, 4952, 4953. PhCHO PhCHO Equivalence of Oxirane Ring-Opening Intermediate to Carbene-Carbonyl Lone Pair Interaction Intermediates + - 125 °C, 15 min. 125 °C, 10 days Starting material k2' k2 C6H5 O CO2CH3 H CO2CH3 O C(CO2CH3)2 C6H5 H C(CO2CH3)2 H O H CO2CH3 H3CO2C H C6H5 CH3O2C CO2CH3 CH3O OCH3 N2 O O O C(CO2CH3)2 H O H C6H5 C6H5 O ( )n Ph CN O O ( )n O Ph CN O ( )n O Ph CN O Ph H R O Ph H R R CN CN O Ph R H CN O O ( )n Ph CN R R R H H H H H 35B-02 Ylides 3/16/93 3:23 PM
Cycloadditions with Oxidopyrylium Ylides Photochemical Ring-Openings of Epoxides to Generate Ylides AEB Br2, MeOH 1)H3O° 150°ccH3CN,16h 12+2] cat HOAC/CH3CN Feldman, KS: Tetrahedron Lett. 1983, 24, 5585-5586. Sammes, P. G: Street, L.J. J. Chem. Soc., Chem. Commun. 1982. 1056- 35B-03 Ylides3/179311:16AM
[2+2] • • hν PhH, pyrex Photochemical Ring-Openings of Epoxides to Generate Ylides PhH, pyrex hν 65% 34% 35% Feldman, K. S.; Tetrahedron Lett. 1983, 24, 5585-5586. Cycloadditions with Oxidopyrylium Ylides + - Br2, MeOH -45 °C 1) H3O+ 2) Ac2O / pyr 80% from furfuraldehyde 150 °C, CH3CN, 16h 61% DBN, CH2Cl2, RT 75% Me2CuLi (n = 1) pyrolysis cat. HOAc / CH3CN 150 °C, 16h 52% Sammes, P. G.; Street, L. J. J. Chem. Soc., Chem. Commun. 1982, 1056-1057 n = 1 O O CH3 O O O O O O CH3 O O O O O O O O O O A B A B O ( )n OH O OH R MeO OMe O O ( )n AcO O O ( )n AcO ( )n O H O O O AcO O H O Me O O O O OH O O 35B-03 Ylides 3/17/93 11:16 AM
Intermolecular Trapping of Oxidopyrylium Ylides Applications of FMO Theory for the Rationalization of Product Regio- and stereochemistries Orbital Theory of Dipolar-Dipolarophile Cycloadditions Carbonyl Ylides have very small HOMO-LUMO gaps 30-135°C Hendrickson, J. B; Farina, J.A. J. Org. Chem. 1980, 45, 3359-3361. herefore, either raising the dipolarophile HOMo (electron-donating substituents)or lowering the LUMO (electron-withdrawing)will accelerate LUMO EtN RT R= Ph 5 Endo product as a result of secondary orbital overlap Sammes, P. G: Street, L J. J. Chem. Soc., Perkin Trans. I. 1983, 1261-1265 35B-04 Ylides3/16/934:40PM
- - + Intermolecular Trapping of Oxidopyrylium Ylides: Applications of FMO Theory for the Rationalization of Product Regio- and Stereochemistries Endo product as a result of secondary orbital overlap , Et3N, RT R = Ph, OEt Sammes, P. G.; Street, L. J. J. Chem. Soc., Perkin Trans. I. 1983, 1261-1265. 130-135 °C 69% 4:1 exo:endo Generally low yields with electron-poor olefins. Hendrickson, J. B.; Farina, J. A. J. Org. Chem. 1980, 45, 3359-3361. R = OEt; 56% R = Ph; 65% LUMO HOMO HOMO LUMO Orbital Theory of Dipolar-Dipolarophile Cycloadditions Carbonyl Ylides have very small HOMO-LUMO gaps Energy ylide dipolarophile Therefore, either raising the dipolarophile HOMO (electron-donating substituents) or lowering the LUMO (electron-withdrawing) will accelerate the reaction. O O O O R AcO R O O O O O O O H O O O O H O EtO 35B-04 Ylides 3/16/93 4:40 PM
Cycloadditions with Oxidopyrylium Ylides-Syntheses Cycloadditions with Oxidopyrylium Ylides-Syntheses Cryptofauronol Fauronyl Acetate 阝 Bulnes 50°C,24h 150°C,20h 1)Pd/C, EtoH 2) Ac20 l pyr CHCN CH3CN 2) MeAl TiCl4 Na, Et20 84% CrO3-pyr 46%(3sep5 Ac2O, NaOAc△ 83% smn:0mxP门1 Sammes. P.G. Street L J. J. Chem. Soc. Chem. Commun. 1983. 666-668 ammes, P G: Street, L J: Whitby, R.J. J. Chem. Soc. Perkin Trans. I. 1986, 281-289 35B-05 Ylides3/16/934:43PM
Cycloadditions with Oxidopyrylium Ylides - Syntheses 150 °C, 24 h CH3CN 1) 1 O2-MeOH then PPh3 2) Ac2O / pyr. Cryptofauronol Fauronyl Acetate 1) iPrMgI, CuBr•Me2S 2) MeMgI TiCl4 Ac2O, NaOAc, ∆ 46% (3 steps) 84% 83% + Sammes, P. G.; Street, L. J. J. Chem. Soc. Chem. Commun. 1983, 666-668. Sammes, P. G.; Street, L. J.; Whitby, R. J. J. Chem. Soc. Perkin Trans. I. 1986, 281-289. Sammes, P. G.; Street, L. J. J. Chem. Soc. Chem. Commun. 1983, 666-668. Sammes, P. G.; Street, L. J.; Whitby, R. J. J. Chem. Soc. Perkin Trans. I. 1986, 281-289. Me2C=PPh3 Na, Et CrO3-pyr 2O 1) Pd / C, EtOH 2) MeMgI 3)SOCl2 150 °C, 20 h CH3CN 1:5 β:α-Me β-Bulnesene Cycloadditions with Oxidopyrylium Ylides - Syntheses H CH3 O O AcO O H O CH3 Me H O CH3 Cl H HO CH3 H O CH3 H CH3 O O AcO H H OH O O OH O H3C O OH H3C O CH3 CH3 CH3 OH O CH3 CH3 OAc O H H OAc O O H3C O CH3 TiCl3 CH3 O CH3 iPr 35B-05 Ylides 3/16/93 4:43 PM
Phorbol 1-The Oxidopyrylium Approach Cyclizations with 5-Hydroxy-4-Pyrones A=8 Phorbol 1)PhH, reflux, 12 h 2:1 erythro: threo DBU, RT 1)CH3CN, reflux, 60 h t-BuLi nder, et. al. J. Am. Chem nder. et. al. J. Am. chem 7-8958 Phorbol 35B-06 Ylides3/16/934:45PM
Garst, M. E.; McBride, B. J.; Douglass, J. G. III. Tetrahedron Lett. 1983, 24, 1675-1678. n = 1 : 70% n = 2 : 65% Z = CO2Me 1) heat 2) acetylation 42% 55% 1) CH3CN,reflux, 60 h 2) acetylation 1) PhH, reflux, 12 h 2) acetylation Cyclizations with 5-Hydroxy-4-Pyrones * * 92% Phorbol 1 - The Oxidopyrylium Approach Phorbol 2:1 erythro : threo 2:1 epimers DBU, RT t-BuLi Phorbol Wender, et. al. J. Am. Chem. Soc. 1989, 111, 8954-8957. Wender, et. al. J. Am. Chem. Soc. 1989, 111, 8957-8958. - + OH OH H OH OH OH H O O O OAc OTBS OAc O H OAc O OTBS OAc H OTBS O O O I O O H O H O O OPiv OH O H O H OH O OH O A B O O OH A B O O OH N O O O OH N O O N O O OAc H O N O O OAc O O OH ( )n Z Z O ( )n Z O OAc Z H 35B-06 Ylides 3/16/93 4:45 PM
Phorbol 3-A Kinder, Gentler Cyclization Phorbol 2 -The Hydroxypyrone Approach PhCH3200℃C,3da TBSO. Phorbol HcHS3,200°C,3days TBSO OTBS PhcH3,200°c Activation allows milder conditions TBSO TBSO CH2Cl2/DMF 18SO. Meotf 71% Wender, P A McDonald. F E. J Am. Chem. Soc. 1990. 112, 4956-4958 Wender, P. A: Mascarenas, J. L. J. Org. Chem. 1991, 56, Tetrahedron Lett. 1992, 33, 2115-2118.(Intermolecular t 35B-07 Ylides3/16/934:47PM
Activation allows milder conditions: Phorbol 3 - A Kinder, Gentler Cyclization PhCH3, 200 °C, 3 days 74% only trace amounts (isomerization) PhCH3, 200 °C, 3 days TfO- + MeOTf CH2Cl2 CsF CH2Cl2 / DMF RT 3.8 : 1 84% 82% 3.8 : 1 RT MeOTf CH2Cl2 + TfOH Wender, P. A.; Mascareñas, J. L. J. Org. Chem. 1991, 56, 6267-6269. Tetrahedron Lett. 1992, 33, 2115-2118. (Intermolecular trapping) Phorbol 2 - The Hydroxypyrone Approach Phorbol - + PhCH3, 200 °C 71% Wender, P. A.; McDonald, F. E. J. Am. Chem. Soc. 1990, 112, 4956-4958 OH OH H OH OH OH H O O OTBS O TBSO O H O OTBS O H OTBS O TBSO O t-BuMe2Si O OTBS O O H O O OTBS O TBSO OTBS O TBSO O O OTBS O TBSO OTBS O TBSO O O OBz O TBSO O OBz MeO TBSO OTBS O TBSO O O OBz O HO O OBz MeO HO OTBS O MeO O N 35B-07 Ylides 3/16/93 4:47 PM
The Synthesis of Enol Ethers Ylide formation by the Interaction of Carbenoids with Carbonyl Lone Pairs 人 33584 Bien, S: Gillon, A; Kohen, S. J. Chem. Soc. Perkin Trans. 1. 1976. 489-492 he carbene precursor of choice is a Rh2(pfb)4 CHat-Bu insertion Nt-BU PhH, reflux most common method involves catalytic amounts of etals, such as copper or rhodium. CH2-Bu 16-H transfer Doyle, M. P. Taunton, J ; Pho. H. Q. Tetrahedron Lett. 1989. 30, 5397 35B-08 Ylides3/179311:17AM
- Generally, the carbene precursor of choice is a diazoalkane or, more frequently, an α-diazocarbonyl. These can be decomposed via thermolysis or photolysis. However, the most common method involves catalytic amounts of transition metals, such as copper or rhodium. + Ylide Formation by the Interaction of Carbeneoids with Carbonyl Lone Pairs pfb = perfluorobutyrate Doyle, M. P., et al. J. Org. Chem. 1991, 56, 820-829. Doyle, M. P.; Taunton, J.; Pho, H. Q. Tetrahedron Lett. 1989, 30, 5397. 1,6-H transfer + insertion products - + Rh2(pfb)4 PhH, reflux The Synthesis of Enol Ethers + - Bien, S.; Gillon, A.; Kohen, S. J. Chem. Soc. Perkin Trans. I. 1976, 489-492 catalyst 1 2 catalyst Temp (°C) %1 %2 Pd2Cl2(C3H5)2 Cu(PhCOCHCOMe)2 (MeO)3PCuI Rh2(OAc)4 None RT 80 RT RT 80 53 50 3 1 15 3 13 35 58 54 H+ R1 R2 O R1 O R2 M EtO CHN2 O O EtO O O MLn O EtO2C O O EtO O O EtO O OEt O H3C N t-Bu O O N2 CO2Et O N O O EtO O N O O EtO CH2t-Bu CH2t-Bu L4Rh2 O N OH O EtO CH2t-Bu 35B-08 Ylides 3/17/93 11:17 AM
The Synthesis of Furans The Synthesis of Furans ll CO2Et Intermolecular addition to a B-unsaturated carbonyls 60° O CHN2 160° hydrolysis --m 29% CO- CH Methyl vinhaticoate Storm, D L: Spencer, T.A. Tetrahedron Lett. 1967, 1865-1867 Spencer, T.A., et al. J. Am. Chem. Soc. 1967, 89, 5497-5499 Tandem intramolecular addition to alkynes-cyclization Cu(acac)2 Rh2(oAc)4 85% COCH3 Rh2(oAc)4 Padwa, A, et al. J. Org. Chem. 1990, 55, 414-416. CHO Tdebrandt, K: Debaerdemaeker, T; Friedrichsen, W. Tetrahedron Lett. 1988, 29, 2045-2046 35B-09 Ylides3/179311:18AM
The Synthesis of Furans + - CuSO4 160 °C 29% 2-methoxymethylenecholestanone-3 1) -OH 2) -CO2 Storm, D. L.; Spencer, T. A. Tetrahedron Lett. 1967, 1865-1867. Intermolecular addition to α,β-unsaturated carbonyls Tandem intramolecular addition to alkynes - cyclization Rh2(OAc)4 : 85% •• Rh2(OAc)4 Padwa, A., et al. J. Org. Chem. 1990, 55, 414-416. 52% Methyl vinhaticoate hydrolysis decarboxylation ~30% CuSO4 160 °C The Synthesis of Furans II Spencer, T. A., et. al. J. Am. Chem. Soc. 1967, 89, 5497-5499. Cu(acac)2 Hildebrandt, K.; Debaerdemaeker, T.; Friedrichsen, W. Tetrahedron Lett. 1988, 29, 2045-2046. 89% OMe O OMe O O EtO2C EtO2C Et O CHN2 O O O N2 Et Et O O Et O N2 O O O O O O O O O CHOCH3 H3C CO2CH3 H3C CO2CH3 EtO CHN2 O O CO2Et H3C CO2CH3 O CO2CH3 O O O O N2 CH3O O O O O CO2CH3 CH3O CO2CH3 O O O CH3O O CO2CH3 O O O CH3O HO 35B-09 Ylides 3/17/93 11:18 AM