D. A. Evans Introduction to carbenes Carbenoids-1 Chem 206 http://www.courses.fasharvardedul-chem206/ Useful references to the carbene literature Books. Chemistry 20 Modern Catalytic methods for Organic Synthesis with Diazo Co M. P. Doyle, Wiley, 1998 Advanced Organic Chemistry Carbene Chemistry, 2nd ed. Academic Press, Kirmse, W, 1971 Lecture Number 34 Introduction to Carbenes Carbenoids-1 Provide a mechanism for the following transformations Carbene Structure electronics a Methods for Generating Carbenes Simmons -Smith reaction CO, Me Carbene- olefin Insertions Carbene rearrangements Reading Assignment for this Lecture Carey Sundberg Advanced Organic Chemistry, 4th Ed Part B Chapter 9, C-C Bond Forming Rxns of Boron, Silicon &Tin",595-680 Carey Sundberg, Advanced Organic Chemistry, 4th Ed Part B Chapter 10, "Reactions Involving Highly Reactive Eto2C Lecture 09A Simmons-Smith Reaction: Enantioselective variants Meo,c co, Me igand Effects on the chemoselectivity of Transition Metal Cat Rxns of a- diazocarbonyl Compnds "Padwa et al. Angew Chem Int Ed. 1994, 33, 1797 Acs19902037 Chiral DirhodiumCarboxamidates: Catalysts for Highly Enantioselective Syntheses of cones and Lactams. Aldrichchimica Acta 1996 29.3 150°C Stable Carbenes-Ilusion or reality"? Regitz, M. Angew. Chem. Int Ed. Engl. 1991 Matthew D. shair Friday December 13. 2002
D. A. Evans Chem 206 Matthew D. Shair Friday, December 13 , 2002 http://www.courses.fas.harvard.edu/~chem206/ Reading Assignment for this Lecture: Introduction to Carbenes & Carbenoids-1 Chemistry 206 Advanced Organic Chemistry Lecture Number 34 Introduction to Carbenes & Carbenoids-1 ■ Carbene Structure & Electronics ■ Methods for Generating Carbenes ■ Simmons-Smith Reaction ■ Carbene-Olefin Insertions ■ Carbene Rearrangements Chiral DirhodiumCarboxamidates: Catalysts for Highly Enantioselective Syntheses of Lactones and Lactams, Aldrichchimica Acta. 1996, 29, 3 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, "Reactions Involving Highly Reactive Electron-Deficient Intermediates", 595–680. Provide a mechanism for the following transformations. O N O N2 CO2Et CH3 O O N H3C EtO2C CO2Me CO2Me MeO2C CO2Me O N O N2 CO2Et CH3 MeO2C CO2Me O O N CH3 EtO2C 1. Rh2 (OAc)4 2.MeO2C CO2Me JACS 1990 2037 O H O H N2 150˚C (71%) Useful References to the Carbene Literature Lecture 09A Simmons-Smith Reaction: Enantioselective Variants Lecture 26B Synthetic Applications of a-Diazocarbonyl Compounds Carey & Sundberg, Advanced Organic Chemistry, 4th Ed. Part B Chapter 9, " C–C Bond Forming Rxns of Boron, Silicon & Tin", 595–680. Ligand Effects on the Chemoselectivity of Transition Metal Catalyzed Rxns of adiazocarbonyl Compnds" Padwa et al.Angew Chem Int Ed. 1994, 33, 1797 "Stable Carbenes–Illusion or reality"? Regitz, M. Angew. Chem. Int. Ed. Engl. 1991, 30, 674 Rh2 (OAc)4
D. A. Evans Carbenes: An Introduction Chem 206 Mandatory Reading: i Carbene Configuration: Triplet vs Singlet Doyle, Chem Rev. 1988, 86, 919 Kodadek Science. 1992. 256 1544 Recent Review Article Chemistry of Diazocarbonyls: McKervey et al. Chem Rev. 1994, 94, 1091 8-10 kcalmol Books Modern Catalytic methods for Organic Synthesis with Diazo Compounds T1 tri 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& i Due to electron repulsion, there is an energy cost in pairing both electrons in the a orbital Excited States, Academic Press, DeMayo ed, Jones, W. M. 1980, p. 95 g and p orbitals exists, the electrons will remain unpaired (triplet). If a large gap exists between the g and p orbitals the electrons will pair in the o orbital(singlet) Carbene Chemistry, 2nd ed. Academic Press, Kirmse, W, 1971 a the History of the Singlet-Triplet Gap S-TSplitting Carbenes: Electronic Structure ear Method Author HCH Angle Grnd State kcal/mol Carbene Configuration: Triplet Vs Singlet /932 Qual. Muliken 90-100 singlet 1078A 1947 Thermochem Walsh triplet 1957aua. QM Gallup160° H 133.8 1969 Ab initio i 1971 Kinetics ase 8-9 Triplet( two unpaired e) ingle (all e paired) 1971 Often has radical-like character Often has electrophilic or nucleophilic character: Atype 1974 MINDO 134° 87 hilic ■ Nitrene empty 1976 Expt Lineberger 138 195 1976 An Initio Schaeffe i 1978 Expt Zare triplet Singlet(all e paired) 1982 E ■ Nitrenium ion
D. A. Evans Carbenes: An Introduction Chem 206 Mandatory Reading: Doyle, Chem Rev. 1988, 86, 919. Kodadek, Science, 1992, 256, 1544. 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. H H H H Carbenes: Electronic Structure Triplet (two unpaired e-) Singlet (all e- paired) p s s p ■ Carbene Configuration: Triplet vs. Singlet Often has radical-like character Often has electrophilic or nucleophilic character: A-type (Ambiphilic) p Energy s Due to electron repulsion, there is an energy cost in pairing both electrons in the s orbital. If a small energy difference between the s and p orbitals exists, the electrons will remain unpaired (triplet). If a large gap exists between the s and p orbitals the electrons will pair in the s orbital (singlet). singlet 1.078 Å 133.8˚ 8–10 kcal/mol T1 S1 ■ Carbene Configuration: Triplet vs. Singlet p s triplet ■ the History of the Singlet-Triplet Gap Method HCH Angle S–T Splitting Year Author kcal/mol 1932 Qual. Muliken 90-100° –– Grnd State singlet 1947 Thermochem Walsh 180° small triplet 1957 Gallup 160° 30 Qual. QM triplet 138° >33 Harrison 1969 Ab initio triplet –– 8–9 Hase 1971 Kinetics triplet 19 Pople 1971 SCF 132° triplet 1974 MINDO Dewar 134° triplet 8.7 1976 Expt Lineberger 138° triplet 19.5 1976 An Initio Schaeffer ––– triplet 19.7 1978 Expt Zare ––– triplet 8.1 1982 Expt Haydon ––– triplet 8.5 (Wentrup) ■ Nitrene R N Singlet (all e- paired) empty filled filled R N H empty filled ■ Nitrenium ion H
M. Shair. D. A. evans Carbenes: Structure and generation Chem 206 Heteroatom-Substituted Carbenes: Singlets i Bamford-Stevens Reaction: See Lecture 28 on Hydrazones hapiro Org. RXns. 1976, 23, 405 The p orbital of carbenes substituted with p-donor atoms(N, O, halogen) is raised high enough in energy to make the pairing of the electrons in the g orbital energetically favorable. As a result, these carbenes are often in the singlet state + Heteroatom- substituted heteroatom Cl ■ diazo compounds C diazirines Methods of Synthesis Chem. Soc. Rev. 1982. 11. 127 ■ Alkyl Halides: L metal-catalyzed decomposition Doyle Chem Rev. 1988, 86, 919 OH R Rh2(oAc)4 ligands omitted for 0N ■ ketenes R carbene heat or hy R2C:+ CO
Carbenes: Structure and Generation Chem 206 C Cl Cl Cl H C Cl Cl C C O R R Me Me Me N N Ts H Me Me Me N N Me Me Me N N Me Me Me H Ts Me Me Me ■ Alkyl Halides: heat or hn R2C + ■ ketenes ■ Bamford-Stevens Reaction: See Lecture 28 on Hydrazones Shapiro Org. Rxns. 1976, 23, 405. -Ts R1 R2 N N R1 R2 N N R1 C R2 R1 R2 N N Rh Rh O O Me Rh Rh O O Me R1 R2 N N Rh Rh O O Me ■ diazo compounds hn or heat R1 R2 Rh Rh O O Me + N2 R1 R2 N N R2 R1 ■ metal-catalyzed decomposition Doyle Chem Rev. 1988, 86, 919. diazirines hn or heat Chem. Soc. Rev. 1982, 11, 127. carbenoid (ligands omitted for clarity) C R R Cl H C R R Methods of Synthesis The p orbital of carbenes substituted with p-donor atoms (N, O, halogen) is raised high enough in energy to make the pairing of the electrons in the s orbital energetically favorable. As a result, these carbenes are often in the singlet state. C Cl Cl Heteroatom-Substituted Carbenes: Singlets p triplet carbene s Energy donor p orbital p-donor heteroatom Heteroatomsubstituted carbene Examples: Singlet C H C6H5 Singlet M. Shair, D. A. Evans CO OH OR -N2 Rh2 (OAc)4 -N2 OH
M. Shair. D. A. evans Carbenes: Structure and generation Chem 206 ■" Stable Carbenes Cyclopropanation The Skell Rule Regitz, M. Angew. Chem. Int. Ed. Engl 1991, 30, 674 cat. tBuOK Singlet carbenes add to olefins stereospecifically: Arduengo et al. J. Am. Chem. Soc. 1991, 113, 361: 1992, 114, 5530 R Arduengo et al. J. Am. Chem. Soc. 1994, 116, 6812, Neutron diffraction study H2C H2C, R Arduengo argues that these resonance structures are not players based on electron distribution from neutron diffraction R H2C R These are nucleophilic carbenes which display high stability Triplet carbenes add non-stereospecifically Regitz, M. Angew. Chem. Int. Ed. Engl. 1996, 35, 725. Regitz, M. Angew. Chem. Int. Ed Engl. 1991, 30, 674 Skell and Woodworth JACS. 1956. 78 4496 Simmons-Smith Cyclopropanation(See Tedrow handout 09B) X-ray Structure Simmons. H: Smith. R J. Am. Chem. Soc. 1958. 80. 5323 >99: 1 diastereoselectivity H G Raubenheimer Chem. Comm. 1990. 1722. CH2l2 150: 1 Cis: trans 75% yield Winstein Sonnenberg JACS 1961, 91, 3235
M. Shair, D. A. Evans Carbenes: Structure and Generation Chem 206 N N H N N N N N N N N NaH, THF cat. tBuOK ■ "Stable Carbenes" Arduengo et al. J. Am. Chem. Soc. 1991, 113, 361; 1992, 114, 5530. (89%) Arduengo et al. J. Am. Chem. Soc. 1994, 116, 6812, Neutron diffraction study: Arduengo argues that these resonance structures are not players based on electron distribution from neutron diffraction. For reviews on the subject, see: Regitz, M. Angew. Chem. Int. Ed. Engl. 1996, 35, 725. Regitz, M. Angew. Chem. Int. Ed. Engl. 1991, 30, 674. These are nucleophilic carbenes which display high stability. + R R R R R R H2C R R H2C R R R R H2C R R ■ Cyclopropanation The Skell Rule: H2C R R + 1 R R 3 ■ Simmons-Smith Cyclopropanation (See Tedrow hanndout 09B) OH Triplet carbenes add non-stereospecifically OH >99:1 diastereoselectivity Skell and Woodworth JACS, 1956, 78, 4496. S N Me Me Au F F F F F H. G. Raubenheimer Chem. Comm. 1990, 1722. X–ray Structure Singlet carbenes add to olefins stereospecifically; Simmons, H.; Smith, R. J. Am. Chem. Soc., 1958, 80, 5323. The intermediate organometallic reagent: I–CH2–Zn–I OH OH 150:1 cis : trans 75% yield Winstein & Sonnenberg, JACS 1961, 91, 3235 Zn(Cu) CH2 I2 "Stable Carbenes–Illusion or reality"? Regitz, M. Angew. Chem. Int. Ed. Engl. 1991, 30, 674 Cl ISC ISC CH2 CH2 CH2 I2 Zn(Cu)
M. Shair. D. A. Evans The Simmons-Smith Reaction Chem 206 The Furakawa Simmons-Smith Variant a Catalytic Asymmetric Cyclopropar For a recent general review of the ions-Smith reaction see: Charette Beauchemin, Organic Reactions, 58, 1-415(2001) ZnEt2, CH2l2 Et2Zn, CH2I2 △ NHSO2R Solvent (0.12eq) R1 NHSO2R 66-82% Et-Zn-Et 1-CHr= 2 -CH2-Zn-Et Kobayashi, et al. Tetrahedron Lett. 1994, 35, 7045 Furukawa. J: Kawabata. N. Nishimura, J. Tetrahedron. 1968. 24. 53 For a Lewis Acid catalyzed process in which the rate of the catalyzed process is Furukawa, J. Kawabata, N; Fujita, T. Tetrahedron, 1970, 26, 243 L Applications in Synthesis Et2Zn, PhCHI2 syn: anti New ss varian see Shi. Tet. Lett 1998. 39 ether, rt 69% 862 Hydroxyl directivity is a powerful atribute of the S-s Rxn CH2I2 O Me >99:1 CF3COOH Calipeltoside A CH2l2 diastereoselectivity i Meo with Burch org.Let2001,3.503 For an review of the directed Simmons-Smith see with A Hoveyda and G. Fu Chem. Rev. 1993, 93, 1307. Me EtZn OBn CH Charrette. A.B. J. Am. Chem. Soc Falck J. Am. chem Charette. A B. JACS 1991. 113 8166 >50: 1 diastereoselection 1996.118.10327 1996.118.6096 Barrett, JOC, 1996, 61
M. Shair, D. A. Evans The Simmons-Smith Reaction Chem 206 Me OH Me Me Me OH OMe OMe For an review of the directed Simmons-Smith, see: with A. Hoveyda and G. Fu Chem. Rev. 1993, 93, 1307. Me Me OH Me Me OH >99:1 diastereoselectivity >50 : 1 diastereoselection O Me OBn OBn HO O Me Me O Me OBn OBn HO O Me Me ■ Hydroxyl directivity is a powerful atribute of the S–S Rxn Charette, A. B. JACS 1991, 113, 8166. ■ The Furakawa Simmons-Smith Variant Furukawa, J.; Kawabata, N.; Nishimura, J. Tetrahedron, 1968, 24, 53 Et2Zn, CH2 I2 Solvent Ph Et2Zn, PhCHI2 ether, rt 69% syn : anti 94 : 6 Furukawa, J.; Kawabata, N.; Fujita, T. Tetrahedron, 1970, 26, 243 Et–Zn–Et + I–CH2–I 2 I–CH2–Zn–Et OH R3 R2 R1 OH R3 R2 R1 NHSO2R NHSO2R (0.12 eq.) ZnEt2 , CH2 I2 66-82 % ee Kobayashi, et al. Tetrahedron Lett. 1994, 35, 7045. For a Lewis Acid catalyzed process in which the rate of the catalyzed process is faster than the uncatalyzed, see: Charette, A. B. JACS 1995, 117, 11367. ■ Catalytic Asymmetric Cyclopropanation: Me R O N O OH OH N HN O O NH O R = Me Me R = Charrette, A. B.; J. Am. Chem. Soc. 1996, 118, 10327. Falck J. Am. Chem. Soc. 1996, 118, 6096. Barrett, JOC, 1996, 61, 3280. ■ Applications in Synthesis no diastereoselectivity >99:1 diastereoselectivity O O Me Cl O OH O Me H Me MeO O MeO NH Me O Me O H Calipeltoside A Et2Zn CF3COOH CH2 I2 Cl O O Cl O O 50:1 diastereoselectivity New SS variant: see Shi, Tet. Lett 1998, 39, 8621 with Burch Org. Lett. 2001, 3, 503 For a recent general review of the Simmons-Smith reaction see: Charette & Beauchemin, Organic Reactions, 58, 1-415 (2001) CH2 I2 Zn(Cu) CH2 I2 Zn(Cu) Zn(Cu) CH2 I2 Et2Zn CH2 I2 H FR-900848 U-106305
M. Shair D. A. evans Carbenoids: Cyclopropanation Chem 206 a Synthetic Applications ■ Buchner reaction Cu( cOmE cat. -COmE TBSO 1.Br2 ELAICI Rh2(oAc)4 2. DBU 1BSO' 1, 3-shift TBSO Corey Myers JACS 1985, 107, 5574 COmE 130.C, Xylenes Wolff Rearrangement OMe OMe O retention THPO THPO O2N AgOBz CO2H prostaglandins Evans et al. J Et,0,-12C org.chem.1993,58,471. (+)Macbecin THPO Corey and Fuchs JACS 1972, 94, 4014
Chem 206 Carbenoids: Cyclopropanation TBSO Me O O N2 TBSO O H Me O H H TBSO O Me O H H TBSO O Me O H H H HO Me OH CO2Me O O H 1. Br2 2. DBU Antheridic Acid Corey & Myers JACS 1985, 107, 5574. McKervey et al. JCS PTI, 1991, 2565. N2 CO2Me CO2Me Me AcO Me O N2 Me AcO Me O O Me Me OTBS H Me MeH O H H O OMe OMe O2N OMe Me O N2 ■ Buchner Reaction OMe OMe O2N cat. confertin CO2H OMe Me (84%) ■ Wolff Rearrangement Evans et al. J. Org. Chem. 1993, 58, 471. (+) Macbecin Cu(I) O THPO O N2 CO2Me THPO O CO2Me O THPO O CO2Me O Cu Powder ■ Synthetic Applications 130˚C, Xylenes CuLi 2 prostaglandins Et2O, -12˚C Corey and Fuchs JACS 1972, 94, 4014. CO2Me retention 1,3-shift M. Shair, D. A. Evans Et2AlCl Rh2 (OAc)4 AgOBz H2O
D.A. Evans Carbenes: Enantioselective Cyclopropanation Chem 206 ■ Mechanism Rh2(oAc)4 cat. i There is no definitive evidence for metal d cyclopropanation and the ossibility that metallacyclobutane intermediates are in annot be I ruled out. Me3C Me, c For a detailed mechanistic study which provides supporting Me N2CHCO2R CO2R Me evidence for the intermediacy of a Rh carbene, see Kodakek, Science. 1992. 256. 1544 Reductive a Catalytic Asymmetric Variants Chiral Cu() Complexes Merc CMes CuOTf i Catalytic Asymmetric Variants: Chiral Rh(I)Complexes 94: 6 trans/cis Cuotf CO2Et ent-6b H ar= Ph >99%ee H Evans et al. J. Am. chem. soc. 1991. 113 726 Doyle et al. Tetrahedron Lett. 1995, 36, 7579 low do these complexes really work??
D. A. Evans Carbenes: Enantioselective Cyclopropanation Chem 206 N2 CO2Et Ph Ph N2 CO2BHT Ph CO2BHT CO2Et Ph N O N O Me Me Me3C CMe3 Rh2 (OAc)4 cat. For a detailed mechanistic study which provides supporting evidence for the intermediacy of a Rh carbene, see: Kodakek, Science, 1992, 256, 1544. ■ Catalytic Asymmetric Variants: Chiral Cu(I) Complexes L * L * = 99% ee 94:6 trans/cis Evans, et al. J. Am. Chem. Soc. 1991, 113, 726. ** R R R EtO2C N2 R CO2Et ent-6b a, R = Ph, >99% ee b, R = Me, >99% ee + ■ Mechanism There is no definitive evidence for metal-catalyzed cyclopropanation and the possibility that metallacyclobutane intermediates are involved cannot be ruled out. N O N O Me Me Cu Me3C Me3C N O N O Me Me Cu Me3C Me3C CO2R R R + + + R Reductive Elimination H H R H CO2R R H H N O N O Me Me Cu Me3C Me3C CO2R H H O O N2 nPr O O H nPr H H Rh Rh O N Ph N O CO2Me H (5 mol %) Doyle et al. Tetrahedron Lett. 1995, 36, 7579. 95% ee ■ Catalytic Asymmetric Variants:Chiral Rh(II) Complexes How do these complexes really work?? CuOTf CuOTf N2CHCO2R –OTf –OTf –OTf -N2 CH2Cl2
D. A. Evans Carbenes: Enantioselective Cyclopropanation Chem 206 I Catalytic Asymmetric Variants: Chiral Rh()Complexes The Carbene Complex (5mo% favored by 3 kcal/mol CH2CL2 Doyle et al. Tetrahedron Lett. 1995, 36, 7579 varable ligand OMe 27A CO Me OaMe MeO2c hOmE MdcO, M Note n-o trans influence ene 2 o-Rh-N Numbers designate increasing steric hindrance in each quadrant Dye,JACS1993159984896 CO Me 27B
D. A. Evans Carbenes: Enantioselective Cyclopropanation Chem 206 ■ The Carbene Complex O O N2 nPr O O H nPr H H Rh Rh O N Ph N O CO2Me H (5 mol %) 95% ee Doyle et al. Tetrahedron Lett. 1995, 36, 7579. ■ Catalytic Asymmetric Variants:Chiral Rh(II) Complexes CO2Me Doyle, JACS 1993, 115, 9968 Rh Rh O N N O H CO2Me CO2Me H O N H O N H MeO2C Note N–O trans influence Rh N O O N 1 2 3 4 Numbers designate increasing steric hindrance in each quadrant 27B favored by 3 kcal/mol CO2Me Rh Rh O N N O H CO2Me CO2Me H O N H O N H MeO2C C H CO2Me CO2Me Ph H H styrene CO2Me H H Ph 48%ee 86%ee variable ligand CH2Cl2 27A
M. Shair. D. A. Evans Carbenes: Rearrangements Chem 206 Carbene-Carbene Rearrangements ■ Other Rearrangements (71%) Wu. Tetrahedron Lett. 1973. 3903 Schecter, J. Am. Chem. Soc. 1971. 93 5940 200c Skattebol Rearrangement Sammes, Chem. Comm. 1975, 328 a Vinylidenes Corey-Fuchs TIPS [12] Tetrahedron Lett. 1973. 2283 Ph 2 eq BuLi OTBS OTBS
Carbenes: Rearrangements Chem 206 H H H C Br Br C C 13 ■ Carbene-Carbene Rearrangements Wu, Tetrahedron Lett. 1973, 3903. C 13 [1,2] ■ Skattebol Rearrangement Tetrahedron Lett. 1973, 2283. ■ Other Rearrangements Schecter, J. Am. Chem. Soc. 1971, 93, 5940. O H O H O O N2 O O N2 N OTBS TIPS Teoc Br Br O O Ph Ph N OTBS TIPS Sammes, Chem. Comm. 1975, 328. Teoc 150˚C O O ■ Vinylidenes Ph Ph Corey-Fuchs: Danishefsky et al. J. Am. Chem. Soc. 1996, 118, 9509. 2 eq. BuLi -78˚C (81%) (71%) (92%) O H O H Å M. Shair, D. A. Evans 200˚C O O BuLi
M. Shair. D. A. Evans Carbenes: Rearrangements Chem 206 a Carbene Rearrangements houy, BaL SOaR IPh CH2Cl2, 20'C TPh N2 CENEN OaR (63%) OMOM Stang et al. J. Am. Chem. Soc. 1994, 116, 93 OMOM Meo,C carbene intermediates are accessible at high temperatures, more later! Meoh (83%) Bestman, et al. Synlett 1996, 521 620c KO-t-Bu (oEt)2 -78° Gilbert, JOC1983,48,5251
Carbenes: Rearrangements Chem 206 ■ Carbene Rearrangements 25˚C Me P(OEt)2 O N2 O CHO OMOM MeO2C OMOM MeO2C N O I+Ph N O I+Ph SO2Ar N O SO2Ar N O + (83%) Bestmann, et al. Synlett 1996, 521. (63%) CH2Cl2 , 20˚C -PhI Stang et al. J. Am. Chem. Soc. 1994, 116, 93. Me Me O H Me H Me MeH Me O Me MeH Me H H capnellene 620˚C P(OEt)2 N2 O H BuLi –78 °C C N R H N C R H R C C H P(OEt)2 N2 O R OLi H Me O O Me Me O P(OEt)2 N2 O H –78 °C KO-t-Bu O O Me Me Me 68% Gilbert, JOC 1983, 48, 5251 Me Me O H Me H H 620˚C Me Me O H Me H H carbene intermediates are accessible at high temperatures, more later! CH insertion M. Shair, D. A. Evans vinylidene carbene K2CO3 MeOH OTf NaSO2Ar RCHO –N2