D A. Evans Introduction to carbenes Carbenoids-2 Chem 206 http:/www.courses.fasharvardedu/-chem206/ Useful References to the Carbene Literature Chemistry 206 Recent Review Article Chemistry of Diazocar McKervey et al. Chem Rev. 1994, 94, 1091 Advanced Organic Chemistry Books Modern Catalytic methods for Organic Synthesis with Diazo Compounds M. P. Doyle, Wiley, 1998 Lecture Number 35 Carbenes and Nitrenes in"Reactive molecules: The neutral reactive Intermediates in Organic Chemistry, Wentrup, C W. 1984, Wiley, p. 162 Introduction to Carbenes Carbenoids-2 Rearrangements of Carbenes and Nitrenes in Rearrangements in Ground Excited States, Academic Press, DeMayo ed, Jones, W. M. 1980, p. 95 a Thermally Induced Carbene Rearrangements Carbonyl Ylides and their reactions Carbene Chemistry, 2nd ed. Academic Press, Kirmse, W, 1971 R 0⑨ Oxonium Sulfonium Ylides and their reactions The Automerization of Naphthalene(The Cume Question from Helli) Rationaliz ○Q=0Q Reading Assignment for this Lecture: 13C-labeled C,ohg is isomerized into B-13C-labeled C1oh8 at 1035.C Carey Sundberg, Advanced Organic Chemistry, 4th Ed Part B Chapter 10, "Reactiona Involving Highly Reactive L.T.scot,JAcs1991,13,9692 Electron-Deficient Intermediates".263-350 Lecture 09A Simmons-Smith Reaction: Enantioselective variants Lecture 26B Synthetic Applications of a-Diazocarbonyl Compounds Provide a mechanism for this transformation Lecture 35A The Use of Fischer Carbenes in Organic Synthesis Lecture 35B The Synthetic Applications of Carbonyl Ylides 1000°c Corannulene 10% Matthew d shair Monday, December 16. 2002 Scott, L T, et aL., JACS 113 7082(1991)
D. A. Evans Chem 206 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 Variants Lecture 26B Synthetic Applications of a-Diazocarbonyl Compounds Lecture 35A The Use of Fischer Carbenes in Organic Synthesis Lecture 35B The Synthetic Applications of Carbonyl Ylides Chemistry 206 Advanced Organic Chemistry Lecture Number 35 Introduction to Carbenes & Carbenoids-2 ■ Thermally Induced Carbene Rearrangements ■ Carbonyl Ylides and their Reactions R C R R R O R O R R R R O R R R ■ Oxonium & Sulfonium Ylides and their Reactions R C R R X R R X R C R R •• •• The Automerization of Naphthalene (The Cume Question from Hell!) a– 13C-labeled C10H8 is isomerized into b– 13C-labeled C10H8 at 1035 °C D Rationalize Scott, L.T., et. al., JACS 113 7082 (1991) Corannulene 10% £ 10-4 Torr 1000° C Provide a Mechanism for this Transformation L. T. Scott, JACS 1991, 113, 9692
D A Evans. D. Guterman Thermal Generation of carbene Intermediates Chem 206 Carbenes are Accessible via Sigmatropic Rearrangement The Automerization of Naphthalene(The Cume Question from Hell!) [1, 2] Shifts: Alpha-Alkynone Cyclizations H72 1 C-labeled Canh, at1035°c Conditions: 620C. 12-16 Torr, Quartz filled quartz Tube i Mechanism-1: L. T Scott, JACS 1977. 99, 4506 2s+2a S M 3 18 +2a 12s+r2a 1378% a For the azulene-naphthalene Isomerization: AG=-30.7 kcal/mol(298K The Activation energy for the isomerization: AG =+86 kcal/mol 89% I Mechanism-2, 3: L. T. Scot, JACS 1991, 113, 969 90% rpf, M tion -3 Karpf, M, Dreiding, A s, He/v. Chim. Acta. 67 1963(1984) A(HB-HA)=-34 kcal/mol (MNDO)
D. A. Evans, D. Guterman Chem 206 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) Clovene 80% (+ 19% isomers) 14 Torr N2 , 1 Hr 620° C Me Me O H H Me Me Me ■ [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% 8 92 _ Recovery 54 46 _ 89% 78% 13 _ 87 80% 60 22 18 _ S.M. 3° 2° 1° The Automerization of Naphthalene (The Cume Question from Hell!) a– 13C-labeled C10H8 is isomerized into b– 13C-labeled C10H8 at 1035 °C D s 2s + s 2a p 2s + p 2a p 2s + p 2a s 2s + s 2a ■ For the azulene–naphthalene Isomerization: DG° = –30.7 kcal/mol (298K) ■ The Activation energy for the isomerization: DG ± = +86 kcal/mol H H ■ Mechanism-1: L. T. Scott, JACS 1977, 99, 4506; ■ Mechanism-2,3: L. T. Scott, JACS 1991, 113, 9692. H H •• H H H •• H H H •• H H H H X X B D(HB–HA) = –3.4 kcal/mol (MNDO) A BF BF B + A 900 °C 21%+ 79% Rationalize Thermal Generation of Carbene Intermediates Option–2 Option–3 O C-H insertion H D
D A Evans. D Guterman Thermal Generation of carbene intermediates Chem 206 Provide a mechanism for this transformation Carbenes: Reaction with Heteroatoms 1000°c ggested Readi Houk and Wu J. Org. Chem. 1991, 56, 5657 Padwa and Hombuckle Chem Rev. 1991. 91.263 Scott, L T, et aL., JACS 113 7082 (1991) Review articl Padwa and Krumpe Tetrahedron 1992, 48, 5385 Hoffman, R W. Angew. Chem. Int. Ed. Engl. 1979, 18, 563 cKervey et al. chem. Rev. 1994, 94, 1091 Ylide Formation by the Interaction of Carbenoids 仓 R⊙O、④ Internals External Ring: 14e Generally, the carbene precursor of choice is a diazoalkane or, more frequently. an a-diazocarbonyl reagent. These can be decomposed via thermolysis or 1000°c photolysis. However, the most common method involves catalytic amounts of transition metals, such as copper or rhodium Dipolar Cyclo -H insertio ROOR X-Y R
Thermal Generation of Carbene Intermediates Chem 206 Scott, L.T., et. al., JACS 113 7082 (1991) Corannulene 10% £ 10-4 Torr 1000° C Provide a Mechanism for this Transformation Internal Ring: 6 e – External Ring: 14 e – C C £ 10-4 Torr 1000° C H 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 a-diazocarbonyl reagent. 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 •• R O R R R R O R R R X Y R O R R R X Y Dipolar Cycloaddition D. A. Evans, D. Guterman H H
D. A. Evans. D. Barnes Carbonyl Ylids: Dipolar Cycloaddition Chem 206 Tandem Intramolecular Cyclization-Intermolecular Cycloaddition Reactions of Diazoimides: [3+2] addition R 2(oac)4 e NEC-COEt 00o RCHO DMAD O2CH3 Et SiH/BF3 Et2O Dipolar-Dipolarophile Cycloadditions: HOMO-LUMO Energies Carbonyl Ylides have very small HOMO-LUMO Maier, M. E: Evertz, K. Tetrahedron Lett. 1988. 29, 1677-1680 ylide dipolarophile Therefore, either raising the dipolarophile HOMo (electron-donating substituents )or lowering the LUMo (electron-withdrawing)will accelerat 000 the reaction LUMO HOMO Padwa et. al. Tetrahedron lett. 1992, 33, 4731-4734
D. A. Evans, D. Barnes Carbonyl Ylids: Dipolar Cycloaddition Chem 206 O CHN2 O O O R R O NPh R O O O H H O CO2CH3 CO2CH3 R O O N CO2Et 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-donating substituents) 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. O N Bn O H CH3 N Me H Me OH H O Bn O N Me O O O Bn N2 O N Bn O COMe H Me Me PhCH3 , 110 °C O N Bn O COMe Padwa et. al. Tetrahedron Lett. 1992, 33, 4731-4734. "high yield" Rh2 (OAc)4 PhH, reflux N Me O O O N2 N O Me H H O O N O N Me O O N2 N N Me O O O H H H 88% Me Me O RCHO DMAD Rh2 (OAc)4 Rh2 (OAc)4 –N2
D. A. Evans. K. Beaver Carbonyl Ylids: Dipolar Cycloaddition-2 Chem 206 Dipolar Cycloadditions: Carbonyl Ylides Reactions of Diazoimides: [3+2] addition-[4+2]retroaddit AcoMe N2Rh2(OAc). hCH3110°C CO2Et OCO,Et Me-N=C=o Dauben, JOC 1993 7635 Tigilane Skeleton 一 R=H OBI MeO2C Meo.c Me R2=H M Z= COMe, COmE N2 OMe Maier, M. E, Schoffling, B. Chem. Ber. 1989, 122, 1081-1087. Padwa. JOC 1995 2704 Lysergic Acid Skeleton Meoh H,80°c 85% CO2 Me 8-9 Me MeO.c Me MoC MeOH N-CO,Me Padwa. JOC 1995 6258 IPadwa,A; Hertzog, D L;Chinn, RL.Tetrahedron Lett.1989,30,4077-4080
D. A. Evans, K. Beaver Chem 206 H H Dipolar Cycloadditions: Carbonyl Ylides O CO2Et N2 O H H H OAcMe Me H H O O CO2Et H AcO Me Me H H O CO2Et O Me Me AcO H Dauben, JOC 1993 7635 Tigilane Skeleton (86%) N N O OMe Me O N2 O Bz N Bz O N MeO2C OM Me N Bz N O MeO2C O Me H H Rh2 (pfb)4 N N O Et Me CO2Me O N N O Et Me CO2Me O O N O O CO2Me N2 Et N Me (95%) Padwa, JOC 1995 6258 Padwa, JOC 1995 2704 Lysergic Acid Skeleton Vindoline Skeleton (93%) N Z N2 O O R 2 R 2 R 1 Me N O O R 1 R 2 R 2 Me Z O N Me O Z R 1 R 2 R 2 O Z R 1 R 2 R 2 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.; Schöffling, B. Chem. Ber. 1989, 122, 1081-1087. Yields = 44-63% R 1 = H, OBn R 2 = H, Me Z = COMe, CO2Me Rh2 (OAc)4 PhCH3 , 110 °C – Me–N=C=O + – Reactions of Diazoimides: [3+2] addition – [4+2] retroaddition MeO2C CO2Me N O O Me O N O O Me O CO2Me MeO2C O CO2Me MeO2C OH Me N CO2Me Carbonyl Ylids: Dipolar Cycloaddition–2 O O Rh2 (OAc)4 Rh2 (OAc)4 MeOH H MeOH
D. A. Evans. D. Barnes Carbonyl Ylids: Dipolar Cycloaddition (and More! ) -3 Chem 206 The Carbonyl Ylide- Azomethine"Dipole Cascade The Synthesis of Furan CHOCH °C HC三c-Co2CH o not observed rearrange I HCEC-CO2CH3 eOc Methyl vinhaticoate CO, CH3 Spencer, T.A, et al. JACS 1967, 89, 5497. Can you propose a rational mechanism for this transformation? CO Me Me Co/Me The 1, 3-proton shift is catalyzed by trace amounts of water. Azomethine ylide formation requires a proton at the tertiary center Padwa.A: Dean. D. C. Zhi L. J. Am. Chem. Soc. 1989. 111 6451 Cu(acac) cc.1992,114,59360 The Synthesis of Furans HO CO2 CH3 160° 2-methoxymethylenecholestanone-3 CHO CO2CH3 pencer Tetrahedron Let. 1967, 1865-1867. Hildebrandt, Tetrahedron Let. 1988. 29, 2045-2046
D. A. Evans, D. Barnes Chem 206 N CHN2 Me O O N O O H Me CO2Me HC 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 a,b-unsaturated carbonyls Spencer Tetrahedron Lett. 1967, 1865-1867. 2-methoxymethylenecholestanone-3 29% CuSO4 160 °C The Synthesis of Furans OMe O OMe O O EtO2C EtO2C Et O CHN2 O Cu(acac)2 Hildebrandt, Tetrahedron Lett. 1988, 29, 2045-2046. 89% CO2CH3 O O O O N2 CH3O CO2CH3 O O O CH3O HO Can you propose a rational mechanism for this transformation? O O O O CO2CH3 CH3O CO2CH3 O O O CH3O O Methyl vinhaticoate hydrolysis decarboxylation ~30% CuSO4 160 °C Spencer, T. A., et. al. JACS 1967, 89, 5497. O CHOCH3 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
D A Evans. D. Barnes Carbonyl Ylids: Dipolar Cycloaddition (and More! )-3 Chem 206 Application of Carbonyl Ylids to the Synthesis of Zaragozic acid TBS Rh(I) HO-C /+Buo,C-o C=o Ylid Transforms t-BuO,C -OTBs 58 HO C TMSO If you are anxious for over-exposure, Rh2 (oAc)4 Sir John Cornforth to good food and good drink, without leisure to think erck,719949185 Zaragozic Acid skeleton A= CO,H HOC HOC Hodgson et al. J. Chem. Soc. Perkin Trans 1, 2000, 3432 灬0 CHO-CO2R HOC ROC
D. A. Evans, D. Barnes Carbonyl Ylids: Dipolar Cycloaddition (and More!)–3 Chem 206 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 O O OH HO2C HO2C OH CO2H Ph OAc Me Ph O Me Application of Carbonyl Ylids to the Synthesis of Zaragozic acid: H RO O O R OH HO2C HO2C OH CO2H H RO O O R OH HO2C HO2C OH CO2H C=O Ylid Transforms H RO O O R OH HO2C HO2C OH CO2H H RO OH OH R OH HO2C HO2C OH CO2H O O HO2C O R OH H OR H OH A HO2C H A = CO2H O HO2C O R OH H OR H OH A HO2C H Hodgson et al. J. Chem. Soc. Perkin Trans I, 2000, 3432 RO2C O O R OR OR RO2C N2 O OR OR R O CHO–CO2R EtO2C N2 O OTBS OTBS Me O Rh(II) RO2C O O R OTBS OTBS O t-BuO2C H O EtO2C O R OTBS H OTBS H O t-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:
D.A. Evans. D. Barnes Carbene heteroatom transformations Ylid formation Chem 206 Ylid Formation versus Cyclopropanation Tandem O-H Insertion/Claisen Rearrangement EO2C、 Rh2oAc)e Me phh,△,20mn OCH catalyst Temp(C) Pd2CL2(C3H 53 COmE fast (PhCoCHCOMe)2 80 50 13 (MeO)3PCul RT Z-Eno transition state Jood JACS 1997 9641 Rh2(oAc Wood,JAcs199,121,1748 enantiomer is it is evident that these are reactions of metal carbenoids Bien. s: Gillon. A: Kohen. s. J. Chem. Soc. Perkin trans/ 1976. 489-492 PhH△,18hs|Ho 00 0 L CH2+-Bu E-Eno Transition state 479 CO2Et Merck Thienamycin Process PhH,80°C transfer hienamycin Doyle, M P, et al. J. Org. Chem. 1991, 56, 820-829 Doyle, M. P Taunton, J; Pho, H.Q. Tetr 1989,30,5397 Salzmann, JAcs 1980 6161
Chem 206 Ylid Formation versus Cyclopropanation D. A. Evans, D. Barnes 3 13 35 58 54 53 50 3 1 15 RT 80 RT RT 80 Pd2Cl2 (C3H5 )2 Cu(PhCOCHCOMe)2 (MeO)3PCuI Rh2 (OAc)4 None catalyst Temp (°C) %1 %2 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 MLn O EtO2C O EtO O O O EtO O O OEt it is evident that these are reactions of metal carbenoids Rh2 (pfb)4 PhH, reflux - + insertion products 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 O Me O EtO CH2 t-Bu CH2 t-Bu L4Rh2 O N O Me OH EtO CH2 t-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 O O X Me CO2Me Me [3,3] O O X Me CO2Me Me slow fast (66%) Wood, JACS 1999, 121, 1748 Me OCH3 HO O O Me Me OMe O O O Me PhH, D, 20 min O Me HO CO2Me Me PhH, D, 18 hrs Z-Enol Transition State E-Enol Transition State 47% ee (75%) The opposite enantiomer is observed! Merck Thienamycin Process NH H Me OH H N2 O O O NO2 O Rh2 (oct)4 N H Me OH H O OH CO2p-NB PhH, 80 °C 100% N H OH H O S CO2 NH3 Salzmann, JACS 1980 6161 Thienamycin X = H, Rh(II) ?? H H + Rh2 (OAc)4
M. Shair, K Beaver Carbene heteroatom Transformations: Sulfonium Oxonium Ylids Chem 206 Ring expansion reactions have been investigated Yide formation I Methods based on sulfur ylides: (review) Vedejs, Accts. Chem. Res. 1984, 17, 358 catalyst Cu(O) COEt Reviews: Padwa. Chem. Rev. 1991 263 Padwa. Chem. Rev. 1996 223 Bames, Evening Seminar, March 16, 1993 is generally S, O or N and can be sp? or sp hybridized Ylides often undergo sigmatropic rearrangements or cycloadditions EtO2C [2, 3]-sigmatropic rearrangement Vedejs, JACS 1989, 111, 8430 00 OMe Rh2(oAc)4 Kido and Kato, Jcs Perkins 1 1992 229 Pirrung et al JACS, 1991, 113, 8561. OMe Stevens Rearrangement ([1, 2] alkyl shift) h2(oAc) Cua) ⑥R2 West, JACS 19931177 1
M. Shair, K. Beaver Chem 206 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 hybridized Ylides often undergo sigmatropic rearrangements or cycloadditions Reviews: Barnes, Evening Seminar, March 16, 1993 Padwa, Chem. Rev. 1991 263 Padwa, 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 O E SPh E Acorenone B O Kido and Kato, JCS Perkins 1 1992 229 Vedejs, JACS 1989, 111, 8430 Methynolide has been synthesized by Vedejs using 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 N2 CO2Et S CO2Et S CO2Et S S Et O Me O TfO CO2Et S EtO2C Me Me OH HO Me O Carbene Heteroatom Transformations: Sulfonium & Oxonium Ylids OMe Cl MeO CO2Me O N2 O Me Me OMe Cl MeO O Me CO2Me O OMe Cl MeO O O O OH Me griseofulvin Pirrung et al JACS, 1991, 113, 8561. Me Cu(I) O H AcO H Me O N2 AcO O Me O AcO O Me O Cu(I) or Rh(II) Clark et al. Tetrahedron Lett. 1996, 37, 5605. R2X Rh2 (OAc)4 DBU KOt-Bu Rh2 (OAc)4
