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 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. h ν + - Arduengo, A. J., III; Janulis, E. P., Jr. J. Am. Chem. Soc . 1983 , 105 , 5929-5930 "Isomünchnons"Isomünchnons cycloadd to dipolarophiles quantitative PhH, reflux 87% R 1 R 2 O R 1 O R 2 AB AB O R 1 R 2 N N 2 OO X O 2 N CH 3 N O OC H 3 X O 2 N N O OC H 3 X O 2 N N O OC H 3 N O 2 N CH 3 O 2 C CO 2 CH 3 N O O CH 3 Ph C 6 H 4 NO 2 O O CH 3 Ph C 6 H 4 NO 2 CO 2 CH 3 CO 2 CH 3 NPh O O NPh O O H 3 C NN CH 3 O CH 3 CH 3 CF 3 CF 3 F 3 C F 3 C N 2 CF 3 CF 3 F 3 C F 3 C O NMe 2 Me 2 N 35B-01 Ylides 12/17/99 12:07 PM Photochemical ring-openings gave a complex mixture of productsin overall low yields. This was due in part to a scrambling of the ylidesubstituents.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 3411 66100 89100100 9 753097577375 isooctane 40 (9, 175)30 (9, 175)72 (5, 170)58 (7, 215)55 (8, 240)40 (10.5, 230) Ratios HCO 2 Me R 1213510 C B A yield conversion (hours, °C) n C B A Generation of Carbonyl Ylides Via the Ring-Openingof Epoxides + -- + - + (CH 3 O 2 C) 2 C-N 2 + C 6 H 5 -CHO Oxirane 3.33.0 Ratio k 2 / k 2 Huisgen, R.; de March, P. J. J. Am. Chem. Soc . 1982 , 104 , 4952, 4953. PhCHO PhCHO Equivalence of Oxirane Ring-Opening Intermediate toCarbene-Carbonyl Lone Pair Interaction Intermediates + - 125 °C, 15 min. 125 °C, 10 days Starting material k 2' k 2 C 6 H 5 OC O 2 CH 3 CO 2 CH 3 H O C(CO 2 CH 3 ) 2 C 6 H 5 H C(CO 2 CH 3 ) 2 O H CO 2 CH 3 H H H 3 CO 2 C C 6 H 5 CH 3 O 2 C CO 2 CH 3 CH 3 O OCH 3 N 2 OO O C(CO 2 CH 3 ) 2 O H H C 6 H 5 C 6 H 5 ( )n O Ph CN O O ( )n O Ph CN O ( )n O Ph CN OP h R H OP h R H R CN CN OP h H R CN O O ( )n Ph CN R R R H H H H H 35B-02 Ylides 3/16/93 3:23 PM [2+2] ? ? h ν PhH, pyrex Photochemical Ring-Openings of Epoxides to Generate Ylides PhH, pyrex h ν 65% 34% 35% Feldman, K. S.; Tetrahedron Lett . 1983 , 24 , 5585-5586. Cycloadditions with Oxidopyrylium Ylides + - Br 2 , MeOH -45 °C 1) H 3 O + 2) Ac 2 O / pyr 80% from furfuraldehyde 150 °C, CH 3 CN, 16h 61% DBN, CH 2 Cl 2 , RT 75% Me 2 CuLi (n = 1) pyrolysis cat. HOAc / CH 3 CN 150 °C, 16h 52% Sammes, P. G.; Street, L. J. J. Chem. Soc., Chem. Commun . 1982 , 1056-1057 n = 1 O O CH 3 O O O O O O CH 3 O O O O O O O O O O B A AB O ( )n OH O OH R OMe MeO 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 Rationalizationof Product Regio- and Stereochemistries Endo product as a result of secondary orbital overlap , Et 3 N, 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 yieldswith electron-poorolefins. 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-donatingsubstituents) or lowering the LUMO (electron-withdrawing) will acceleratethe 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 150 °C, 24 hCH 3 CN 1) 1 O 2 -MeOH then PPh 3 2) Ac 2 O / pyr. Cryptofauronol Fauronyl Acetate 1) iPrMgI, CuBr?Me 2 S 2) MeMgI TiCl 4 Ac 2 O, NaOAc, ? 84% 46% (3 steps) 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. Me 2 C=PPh 3 CrO 3 -pyr Na, Et 2 O 1) Pd / C, EtOH2) MeMgI3)SOCl 2 150 °C, 20 hCH 3 CN 1:5 β:α -Me β -Bulnesene Cycloadditions with Oxidopyrylium Ylides - Syntheses H CH 3 O O AcO O H O CH 3 Me H O CH 3 Cl H HO CH 3 H O CH 3 H CH 3 O O AcO HH OH O O OH O H 3 C O OH H 3 C O CH 3 CH 3 CH 3 OH O CH 3 CH 3 OAc O HH OAc O O H 3 C O CH 3 TiCl 3 CH 3 O CH 3 iPr 35B-05 Ylides 3/16/93 4:43 PM Garst, M. E.; McBride, B. J.; Douglass, J. G. III. Tetrahedron Lett. 1983 , 24, 1675-1678. n = 1 : 70%n = 2 : 65% Z = CO 2 Me 1) heat2) acetylation 42% 55% 1) CH 3 CN,reflux, 60 h 2) acetylation 1) PhH, reflux, 12 h2) 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 AB O O OH B A O O OH N O O O OH N O O N O O OAcHO 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 Activation allows milder conditions: Phorbol 3 - A Kinder, Gentler Cyclization PhCH 3 , 200 °C, 3 days 74% only trace amounts(isomerization) PhCH 3 , 200 °C, 3 days TfO - + MeOTfCH 2 Cl 2 CsFCH 2 Cl 2 / DMF RT 3.8 : 1 84%82% 3.8 : 1 RT MeOTfCH 2 Cl 2 + TfO - H Wender, P. A.; Mascare?as, J. L. J. Org. Chem . 1991 , 56 , 6267-6269. Tetrahedron Lett . 1992 , 33 , 2115-2118. (Intermolecular trapping) Phorbol 2 - The Hydroxypyrone Approach Phorbol - + PhCH 3 , 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 H O OTBS O O TBSO t-BuMe 2 Si O OTBS O O H O O OTBS O TBSO OTBS O O TBSO O OTBS O TBSO OTBS O O TBSO O OBz O TBSO O OBz MeO TBSO OTBS O O TBSO O OBz O HO O OBz MeO HO OTBS O O MeO N 35B-07 Ylides 3/16/93 4:47 PM - Generally, the carbene precursor of choice is a diazoalkane or, morefrequently, an α -diazocarbonyl. These can be decomposed via thermolysis or photolysis.However, the most common method involves catalytic amounts oftransition metals, such as copper or rhodium. + Ylide Formation by the Interaction of Carbeneoids withCarbonyl 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 + insertionproducts - + Rh 2 (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 Pd 2 Cl 2 (C 3 H 5 ) 2 Cu(PhCOCHCOMe) 2 (MeO) 3 PCuI Rh 2 (OAc) 4 None RT80RTRT80 53503115 313355854 H + R 1 R 2 O R 1 O R 2 M EtO CHN 2 OO EtO OO ML n O EtO 2 C O O EtO O O EtO O OEt O H 3 C N t-Bu OO N 2 CO 2 Et O N O OEtO O N O O EtO CH 2 t-Bu CH 2 t-Bu L 4 Rh 2 O N O OHEtO CH 2 t-Bu 35B-08 Ylides 3/17/93 11:17 AM The Synthesis of Furans + - CuSO 4 160 °C 29% 2-methoxymethylenecholestanone-3 1) - OH 2) -CO 2 Storm, D. L.; Spencer, T. A. Tetrahedron Lett . 1967 , 1865-1867. Intermolecular addition to α,β -unsaturated carbonyls Tandem intramolecular addition to alkynes - cyclization Rh 2 (OAc) 4 : 85% ?? Rh 2 (OAc) 4 Padwa, A., et al . J. Org. Chem . 1990 , 55 , 414-416. 52% Methyl vinhaticoate hydrolysisdecarboxylation ~30% CuSO 4 160 °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% OMeO OMeO O EtO 2 C EtO 2 C Et O CHN 2 O O O N 2 Et Et O O Et O N 2 O O O O O O O O O CHOCH 3 H 3 C CO 2 CH 3 H 3 C CO 2 CH 3 EtO CHN 2 O O CO 2 Et H 3 C CO 2 CH 3 O CO 2 CH 3 O O O ON 2 CH 3 O O O O O CO 2 CH 3 CH 3 O CO 2 CH 3 O O O CH 3 O O CO 2 CH 3 O O O CH 3 O HO 35B-09 Ylides 3/17/93 11:18 AM