Chem 206D. A. Evans Matthew D. Shair Monday, December 16 , 2002 http://www.courses.fas.harvard.edu/~chem206/ Reading Assignment for this Lecture: Introduction to Carbenes & Carbenoids-2 Recent Review Article:Chemistry of Diazocarbonyls: McKervey et al. Chem Rev. 1994, 94, 1091. Carbenes and Nitrenes in "Reactive Molecules: The Neutral Reactive Intermediates in Organic Chemistry", Wentrup, C. W. 1984, Wiley, p. 162. Rearrangements of Carbenes and Nitrenes in Rearrangements in Ground & Excited States, Academic Press, DeMayo ed., Jones, W. M. 1980, p. 95. Carbene Chemistry, 2nd ed. Academic Press, Kirmse, W., 1971. Books:Modern Catalytic methods for Organic Synthesis with Diazo Compounds; M. P. Doyle, Wiley, 1998. Carey & Sundberg, Advanced Organic Chemistry, 4th Ed. Part B Chapter 10, "Reactiona Involving Highly Reactive Electron-Deficient Intermediates", 263-350 . Useful References to the Carbene Literature Lecture 09A Simmons-Smith Reaction: Enantioselective VariantsLecture 26B Synthetic Applications of α-Diazocarbonyl Compounds Lecture 35A The Use of Fischer Carbenes in Organic SynthesisLecture 35B The Synthetic Applications of Carbonyl Ylides Chemistry 206 Advanced Organic Chemistry Lecture Number 35 Introduction to Carbenes & Carbenoids-2 a73 Thermally Induced Carbene Rearrangementsa73 Carbonyl Ylides and their Reactions R C R R R O R O R R R R O R R Ra73 Oxonium & Sulfonium Ylides and their Reactions R C R RX R RX RCR R ?? ?? The Automerization of Naphthalene (The Cume Question from Hell!) α–13C-labeled C10H8 is isomerized into β–13C-labeled C10H8 at 1035 °C ?Rationalize Scott, L.T., et. al., JACS 113 7082 (1991) Corannulene 10%≤ 10-4 Torr1000° C Provide a Mechanism for this Transformation L. T. Scott, JACS 1991, 113, 9692. Chem 206D. A. Evans, D. Guterman Carbenes are Accessible via Sigmatropic Rearrangement O H O H H H O O O O O O O O O O O O O O Karpf, M., Dreiding, A.S., Helv. Chim. Acta. 67 1963 (1984) Clovene80% (+ 19% isomers) 14 TorrN 2 , 1 Hr 620° CMe Me OH H Me Me Me a73 [1,2] Shifts: Alpha-Alkynone Cyclizations Karpf, M., Dreiding, A., Helv. Chim. Acta. 65 13 (1982) Conditions: 620° C, 12-16 Torr, Quartz filled Quartz Tube [1,2] ? ? 90%892_ Recovery 89%_4654 78%13_87 80% 182260 _ 1°2°3°S.M. The Automerization of Naphthalene (The Cume Question from Hell!) α–13C-labeled C10H8 is isomerized into β–13C-labeled C10H8 at 1035 °C ? σ2s + σ2api2s + pi2a pi2s + pi2aσ2s + σ2a a73 For the azulene–naphthalene Isomerization: ?G° = –30.7 kcal/mol (298K)a73 The Activation energy for the isomerization: ?G± = +86 kcal/mol H H a73 Mechanism-1: L. T. Scott, JACS 1977, 99, 4506; a73 Mechanism-2,3: L. T. Scott, JACS 1991, 113, 9692. HH?? H H HH?? H H ?? HH H H X X B A?(HB–HA) = –3.4 kcal/mol (MNDO) BF BF B A+900 °C 21% 79%+ Rationalize Thermal Generation of Carbene Intermediates Option–2 Option–3O C-Hinsertion H ? Chem 206Thermal Generation of Carbene Intermediates Scott, L.T., et. al., JACS 113 7082 (1991) Corannulene 10%≤ 10-4 Torr1000° C Provide a Mechanism for this Transformation Internal Ring: 6 e–External Ring: 14 e– CC ≤ 10-4 Torr 1000° CH H H H ???? C–H Insertion Carbenes: Reaction with Heteroatoms Suggested Reading Houk and Wu J. Org. Chem. 1991, 56, 5657. Review Articles Padwa and Hornbuckle Chem. Rev. 1991, 91, 263. Padwa and Krumpe Tetrahedron 1992, 48, 5385.Hoffman, R. W. Angew. Chem. Int. Ed. Engl. 1979, 18, 563. McKervey et al. Chem. Rev. 1994, 94, 1091. R R R R O R O R R R Generally, the carbene precursor of choice is a diazoalkane or, more frequently, an α-diazocarbonyl reagent. 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 Carbeneoidswith Carbonyl Lone Pairs ?? R O RR R R O R R R X Y R O RR RX Y Dipolar Cycloaddition D. A. Evans, D. Guterman H H Chem 206Carbonyl Ylids: Dipolar CycloadditionD. A. Evans, D. Barnes OCHN 2 O O O R R O NPh R O O O H H O CO2CH3 CO2CH3 R O O N CO 2Et R O O O R N C CO2Et R O NPh H O O Tandem Intramolecular Cyclization–Intermolecular Cycloaddition O O HOMO LUMO Dipolar-Dipolarophile Cycloadditions: HOMO–LUMO Energies 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 accelerate the reaction. Reactions of Diazoimides: [3+2] addition 74% Et3SiH / BF3?Et2O CH2Cl2 68% Maier, M. E.; Evertz, K. Tetrahedron Lett. 1988, 29, 1677-1680. ON OBn H CH3 N MeH MeOH H O Bn O N Me O O O N2Bn ON OBn COMe H Me Me PhCH3, 110 °C O N OBn COMe Padwa et. al. Tetrahedron Lett. 1992, 33, 4731-4734. "high yield" Rh2(OAc)4 PhH, refluxN Me O O O N2 N O Me H H O O N ON Me O O N2 N N OMe O O H H H 88% Me Me O RCHO DMAD Rh2(OAc)4 Rh 2(OAc)4 –N2 Chem 206D. A. Evans, K. Beaver HH Dipolar Cycloadditions: Carbonyl Ylides O CO2Et N2O HH H OAc MeMe H H O O CO2Et H AcO Me Me H H O CO2EtO MeMeAcO H Dauben, JOC 1993 7635 Tigilane Skeleton (86%) N N OMeO Me O N2 O Bz NBz O N MeO2C OM Me NBz NOMeO2C O Me H HRh2(pfb)4 N N O EtMe CO 2Me ON N O EtMe CO 2Me O O N O O CO 2Me N2Et NMe (95%) Padwa, JOC 1995 6258 Padwa, JOC 1995 2704 Lysergic Acid Skeleton Vindoline Skeleton (93%) N ZN 2 OO R2 R2R1 Me N O O R1 R2 R2 Me Z ON O Me Z R1 R2 R2 O Z R1 R2 R2 N Me O O O N2 N O CO2Me COCH3 MeO2C O MeO Padwa, A.; Hertzog, D. L.; Chinn, R. L. Tetrahedron Lett. 1989, 30, 4077-4080. 85% Rh2(OAc)4, PhH, 80 °C Maier, M. E.; Sch?ffling, B. Chem. Ber. 1989, 122, 1081-1087. Yields = 44-63%R 1 = H, OBnR2 = H, Me Z = COMe, CO2Me Rh2(OAc)4 PhCH3, 110 °C – Me–N=C=O –+ Reactions of Diazoimides: [3+2] addition – [4+2] retroaddition CO2MeMeO2C N O O Me O N O O Me OCO2Me MeO2C O CO2Me MeO2C OHMe N CO2Me Carbonyl Ylids: Dipolar Cycloaddition–2 O O Rh2(OAc)4 Rh2(OAc)4 MeOH H MeOH Chem 206D. A. Evans, D. Barnes N CHN 2OMe O N O O HCO 2MeMeHC C CO2CH3 The Carbonyl Ylide - Azomethine "Dipole Cascade" Padwa, A.; Dean, D. C.; Zhi, L. J. Am. Chem. Soc. 1989, 111, 6451-6452.Padwa, A.; Dean, D. C.; Zhi, L. J. Am. Chem. Soc. 1992, 114, 593-601. The 1,3-proton shift is catalyzed by trace amounts of water. Azomethine ylide formation requires a proton at the tertiary center. N O O Me N O O Me MeO2C N O O Me N Me CO2Me O O H H N Me CO2Me OH O not observed HC C CO2CH3 Intermolecular addition to α,β-unsaturated carbonyls Spencer Tetrahedron Lett. 1967, 1865-1867. 2-methoxymethylenecholestanone-3 29% CuSO4 160 °C The Synthesis of Furans OMe O OMe O OEtO2C EtO2C Et O CHN2O Cu(acac)2 Hildebrandt, Tetrahedron Lett. 1988, 29, 2045-2046. 89% CO2CH3 O OO O N2CH3O CO2CH3 O OO CH3O HO Can you propose a rational mechanism for this transformation? O O OO CO2CH3CH3O CO2CH3 O OO CH3O O Methyl vinhaticoate hydrolysisdecarboxylation ~30% CuSO4 160 °C Spencer, T. A., et. al. JACS 1967, 89, 5497. O CHOCH 3 Me CO2CH3 Me Me Me CO2CH3 Me Me EtO CHN2 O O CO2Et Me CO2CH3 Me Me O The Synthesis of Furans rearrange Carbonyl Ylids: Dipolar Cycloaddition (and More!)–3 Rh2(OAc)4 Chem 206D. A. Evans, D. Barnes Carbonyl Ylids: Dipolar Cycloaddition (and More!)–3 O R O MeO2C N2 TMSO O R O MeO2C TMSO O R O MeO2C Merck, TL 1994 9185 TMSO (66%) Zaragozic Acid Skeleton H O OO OH HO2CHO 2C OH CO2H Ph OAc Me Ph OMe Application of Carbonyl Ylids to the Synthesis of Zaragozic acid: H RO OO R OH HO2CHO 2C OH CO2H H RO OO R OH HO2CHO 2C OH CO2H C=O Ylid Transforms H RO OO R OH HO2CHO 2C OH CO2H H RO OHOH R OH HO2CHO 2C OH CO2H O OHO2C O R OHH ORH OH AHO2C H A = CO2H OHO2C O R OHH ORH OH AHO2C H Hodgson et al. J. Chem. Soc. Perkin Trans I, 2000, 3432 ORO2C O R OROR N2RO2C O OR OR R O CHO–CO2R N2EtO2C O OTBSOTBS MeO Rh(II) ORO2C O R OTBSOTBS Ot-BuO2CH OEtO2C O R OTBSH OTBSHOt-BuO2C H 58% yield Rh2(OAc)4 If you are anxious for over-exposure,to prepublication disclosure, to good food and good drink,without leisure to think, try IUPAC symposia." Sir John Cornforth: Chem 206 Ylid Formation versus Cyclopropanation D. A. Evans, D. Barnes 313 3558 54 5350 31 15 RT80 RTRT 80 Pd2Cl2(C3H5)2Cu(PhCOCHCOMe) 2(MeO) 3PCuIRh 2(OAc)4None %2%1Temp (°C)catalyst 2 1 catalyst Bien, S.; Gillon, A.; Kohen, S. J. Chem. Soc. Perkin Trans. I. 1976, 489-492 EtO CHN2 O O EtO O O ML n OEtO 2C O OEtO O OEtO O OEtO it is evident that these are reactions of metal carbenoids Rh2(pfb)4 PhH, reflux - + insertionproducts H transfer 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. pfb = perfluorobutyrate Me N t-Bu O O N2 CO2Et O N O Me O EtO O N OMe O EtO CH2t-Bu CH2t-BuL 4Rh2 O N O Me OH EtO CH2t-Bu+ Carbene Heteroatom Transformations: Ylid Formation Tandem O-H Insertion/Claisen Rearrangement Me OMe O N2 O Me OH+ Me OCH3 HO O O Me Wood, JACS 1997 9641 98% ee 95% ee OO X Me CO2MeMe [3,3] OO XMe CO2MeMe slow fast (66%) Wood, JACS 1999, 121, 1748 Me OCH3 HO O O Me Me OMe O O O Me PhH, ?, 20 min OMeHO CO2MeMe PhH, ?, 18 hrs Z-Enol Transition State E-Enol Transition State 47% ee (75%) The opposite enantiomer is observed! Merck Thienamycin Process NH HMe OH H N2 O O O NO2 O Rh2(oct)4 N HMe OH H O OH CO2p-NBPhH, 80 °C100% N HOH H O S CO2 NH3 Salzmann, JACS 1980 6161 Thienamycin X = H, Rh(II) ?? H H+ Rh2(OAc)4 Chem 206M. Shair, K. Beaver Ylide Formation R N2 OEt O catalyst R X OEt O R R X is generally S, O or N and can be sp2 or sp3 hybridizedYlides often undergo sigmatropic rearrangements or cycloadditions Reviews: Barnes, Evening Seminar, March 16, 1993 Padwa, Chem. Rev. 1991 263Padwa, Chem. Rev. 1996 223 [2,3]-Sigmatropic rearrangement: Stevens Rearrangement ([1,2] alkyl shift): R2 N N2 R1 O Rh2(OAc)4 N O R1 R2 N O R2 R1 West, JACS 1993 1177 OMe SPh O N2 O S Ph OE SPhE OAcorenone B Kido and Kato, JCS Perkins 1 1992 229 Vedejs, JACS 1989, 111, 8430 Methynolide has been synthesized by Vedejsusing this ring-expansion methodology 72% 72% 50% Methods based on sulfur ylides: (review) Vedejs, Accts. Chem. Res. 1984, 17, 358 Ring expansion reactions have been investigated S N 2 CO2Et S CO 2Et S CO2Et S S Et O MeO TfO CO2Et S EtO2CMe Me OHHO Me O Carbene Heteroatom Transformations: Sulfonium & Oxonium Ylids OMe ClMeO CO2MeO N2O MeMe OMe ClMeO O Me CO2MeO OMe ClMeO O O O OH Me griseofulvin Pirrung et al JACS, 1991, 113, 8561. Me Cu(I) OH AcO H Me O N2 OAcOMe O OAcOMe O Cu(I)or Rh(II) Clark et al. Tetrahedron Lett. 1996, 37, 5605. R2X Rh2(OAc)4 DBU KOt-Bu Rh2(OAc)4