Chem 206D. A. Evans 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 a73 Carbene Structure & Electronics a73 Methods for Generating Carbenes a73 Simmons-Smith Reactiona73 Carbene-Olefin Insertions a73 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 CO2EtCH 3 O O NH3C EtO2C CO2Me CO2Me MeO2C CO2Me O N O N2 CO2EtCH 3 CO2MeMeO2C OON CH3EtO2C 1. Rh2(OAc)4 2.MeO2C CO2Me JACS 1990 2037 O H OHN 2 150?C (71%) Useful References to the Carbene Literature Lecture 09A Simmons-Smith Reaction: Enantioselective VariantsLecture 26B Synthetic Applications of α-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 α-diazocarbonyl 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 Chem 206Carbenes: An IntroductionD. A. Evans 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 HH Carbenes: Electronic Structure Triplet (two unpaired e-) Singlet (all e- paired) p σ σ p a73 Carbene Configuration: Triplet vs. Singlet Often has radical-like character Often has electrophilic or nucleophilic character: A-type (Ambiphilic) p Energ y σ Due to electron repulsion, there is an energy cost in pairing both electrons in the σ orbital. If a small energy difference between the σ and p orbitals exists, the electrons will remain unpaired (triplet). If a large gap exists between the σ and p orbitals theelectrons will pair in the σ orbital (singlet). singlet 1.078 ? 133.8? 8–10 kcal/mol T1 S1 a73 Carbene Configuration: Triplet vs. Singlet p σ triplet a73 the History of the Singlet-Triplet Gap Method HCH Angle S–T Splittingkcal/molAuthorYear Qual. 90-100° ––Muliken1932 Grnd State singlet Thermochem 180° smallWalsh1947 triplet 160° 30Gallup1957 tripletQual. QM 138° >33Harrison1969 tripletAb initio –– 8–9Hase1971 tripletKinetics 19Pople1971 tripletSCF 132° 8.7Dewar1974 tripletMINDO 134° 19.5Lineberger1976 tripletExpt 138° 19.7Schaeffer1976 tripletAn Initio ––– 8.1Zare1978 tripletExpt ––– 8.5Haydon1982 tripletExpt ––– (Wentrup) a73 Nitrene R N Singlet (all e- paired) empty filled filled R N H empty filled a73 Nitrenium ion H Chem 206Carbenes: Structure and Generation C Cl Cl Cl H CClCl C C ORR Me MeMe N N Ts H Me MeMe N N Me MeMe N N Me MeMe H Ts MeMe Me a73 Alkyl Halides: heat or hν R2C + a73 ketenes a73 Bamford-Stevens Reaction: See Lecture 28 on HydrazonesShapiro Org. Rxns. 1976, 23, 405. -Ts R1 R2 N N R1 R2 N N R1C R2 R1 R2 N N Rh RhO O Me Rh Rh O O Me R1 R2 N N Rh RhO O Me a73 diazo compounds hν or heat R1 R2 Rh RhO O Me + N2 R1 R2 N N R2 R1 a73 metal-catalyzed decomposition Doyle Chem Rev. 1988, 86, 919. diazirines hν or heat Chem. Soc. Rev. 1982, 11, 127. carbenoid (ligands omitted forclarity)C R R Cl H CRR 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 σ orbital energetically favorable. As a result, these carbenes are often in the singlet state. CClCl Heteroatom-Substituted Carbenes: Singlets p tripletcarbene σ Energy donor porbital pi-donorheteroatomHeteroatom-substitutedcarbene Examples: Singlet CHC 6H5 Singlet M. Shair, D. A. Evans CO OH OR -N2 Rh2(OAc)4 -N2OH Chem 206M. Shair, D. A. Evans Carbenes: Structure and Generation N N H N N N N N N N N NaH, THF cat. tBuOK a73 "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 RH2C R R a73 Cyclopropanation The Skell Rule: H2C R R +1 R R 3 a73 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 NMe Me Au F F F FF 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) CH2I2 "Stable Carbenes–Illusion or reality"? Regitz, M. Angew. Chem. Int. Ed. Engl. 1991, 30, 674 Cl ISC ISC CH2 CH2 CH2I2 Zn(Cu) Chem 206M. Shair, D. A. Evans The Simmons-Smith Reaction 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 OBnOBn HOOMe Me O Me OBnOBn HOOMe Me a73 Hydroxyl directivity is a powerful atribute of the S–S Rxn Charette, A. B. JACS 1991, 113, 8166. a73 The Furakawa Simmons-Smith Variant Furukawa, J.; Kawabata, N.; Nishimura, J. Tetrahedron, 1968, 24, 53 Et2Zn, CH2I2 Solvent PhEt2Zn, PhCHI2ether, 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 OHR3R2 R1 OHR3R2 R1NHSO2R NHSO2R(0.12 eq.) ZnEt2, CH2I2 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. a73 Catalytic Asymmetric Cyclopropanation: Me R O N O OH OH N HNO O NH O R = Me MeR = Charrette, A. B.; J. Am. Chem. Soc.1996, 118, 10327. Falck J. Am. Chem. Soc.1996, 118, 6096. Barrett, JOC, 1996, 61, 3280. a73 Applications in Synthesis no diastereoselectivity >99:1 diastereoselectivity O O Me Cl OOH OMe HMeMeO O MeO NHOMe Me O H Calipeltoside A Et2ZnCF3COOH CH2I2 Cl OO Cl OO 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) CH2I2 Zn(Cu) CH2I2 Zn(Cu) Zn(Cu) CH2I2 Et2Zn CH2I2 H FR-900848U-106305 Chem 206Carbenoids: Cyclopropanation TBSO Me OO N2 TBSO O H Me O H H TBSO OMe O H H TBSO OMe OH H H HOMe 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 OH H O OMe OMe O2N OMe Me O N 2 a73 Buchner Reaction OMe OMe O2N cat. confertin CO2H OMe Me (84%) a73 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 a73 Synthetic Applications 130?C, Xylenes CuLi prostaglandins2 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 Chem 206D. A. Evans Carbenes: Enantioselective Cyclopropanation N2 CO2Et Ph Ph N2 CO2BHT Ph CO2BHT CO2Et Ph N O N OMe Me Me3C CMe3 Rh2(OAc)4 cat. For a detailed mechanistic study which provides supportingevidence for the intermediacy of a Rh carbene, see: Kodakek, Science, 1992, 256, 1544. a73 Catalytic Asymmetric Variants:Chiral Cu(I) Complexes L* L* = 99% ee94:6 trans/cis Evans, et al. J. Am. Chem. Soc. 1991, 113, 726. ** RR R EtO 2C N2 R CO2Etent-6b a, R = Ph, >99% ee b, R = Me, >99% ee + a73 Mechanism There is no definitive evidence for metal-catalyzed cyclopropanation and the possibility that metallacyclobutane intermediates are involved cannot be ruled out. N ON O Me MeCu Me3C Me3C N ON O Me MeCu Me3C Me3CCO 2R R R+ + + R ReductiveElimination H HR HCO2RRH H N ON O Me MeCu Me3C Me3CCO 2R H H O O N2 nPr O O nPrH HH Rh Rh O N NPh O CO2MeH (5 mol %) 95% eeDoyle et al. Tetrahedron Lett. 1995, 36, 7579. a73 Catalytic Asymmetric Variants:Chiral Rh(II) Complexes How do these complexes really work?? CuOTf CuOTf N2CHCO2R –OTf –OTf –OTf -N2 CH2Cl2 Chem 206D. A. Evans Carbenes: Enantioselective Cyclopropanation a73 The Carbene Complex O O N2 nPr O O nPrH HH Rh RhO N NPh O CO2MeH (5 mol %) 95% eeDoyle et al. Tetrahedron Lett. 1995, 36, 7579. a73 Catalytic Asymmetric Variants:Chiral Rh(II) Complexes CO2Me Doyle, JACS 1993, 115, 9968 Rh Rh O N NO HCO 2Me CO2MeH ONH ON H MeO2C Note N–O trans influence Rh N O O N12 34 Numbers designate increasing steric hindrance in each quadrant 27B favored by 3 kcal/mol CO2Me Rh Rh O N NO HCO 2Me CO2MeH ONH ON H MeO2C C H CO2Me CO2Me HPh H styrene CO2Me HH Ph48%ee 86%ee variable ligand CH2Cl2 27A Chem 206Carbenes: Rearrangements H HH C BrBr C C13 a73 Carbene-Carbene Rearrangements Wu, Tetrahedron Lett. 1973, 3903. C13 [1,2] a73 Skattebol Rearrangement Tetrahedron Lett. 1973, 2283. a73 Other Rearrangements Schecter, J. Am. Chem. Soc. 1971, 93, 5940. O H OH O O N2 O O N2 N OTBS TIPS Teoc Br BrO O Ph Ph N OTBS TIPS Sammes, Chem. Comm. 1975, 328. Teoc 150?C O O a73 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⊕ M. Shair, D. A. Evans 200?C O O BuLi Chem 206Carbenes: Rearrangements a73 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 SO 2Ar 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 OH Me H Me MeH Me O Me MeH Me H H capnellene 620?C P(OEt)2 N2 OH BuLi –78 °C C NR H N CRHR C C H P(OEt)2 N2 O R OLi H MeO O MeMe O P(OEt)2 N2 OH –78 °C KO-t-Bu OO Me Me Me68%Gilbert, JOC 1983, 48, 5251 Me Me OH Me H H 620?C Me Me OH Me H H carbene intermediates are accessible at high temperatures, more later! CH insertion M. Shair, D. A. Evans vinylidenecarbene K2CO3 MeOH OTf NaSO2Ar RCHO –N2 Chem 206Carbenes: Rearrangements a73 C–H Insertions continued... Me O N2 CO2Me O CO2Me Me N CO2Me N2 O O N CO2Me O OH O O N 2 O OH HRh RhO N NPh O CO2MeH (83%) (75%) Stork Tetrahedron Lett. 1988, 29, 2283. Electrophilic carbenes are very sensitive to electronic effects 99%, 97% ee Sulikowski, J. Org. Chem. 1995, 60, 2326. (5 mol %) Enantioselective C-H Insertion Doyle, JACS 1994, 116, 4507 H H N H O Me H HO O CO2PNB N H O Me H HO O CO2PNB N H O Me H HO S CO2 NH3 thienamycin Salzmann, JACS, 1980, 102, 6163. a73 N–H Insertions are also possible... N–H H O Me H HO CO2PNBO N2 HR2 R1 R3 A B HR2 R1 R3 A B Insertions (X-H): Stereochemical outcome R2 R1 R3 B A H Taber JACS, 1996, 107, 196. O CO2Me Me PhMe Ph MeO2C O N2 H M. Shair, D. A. Evans δ+δ+ δ+δ+ Retention Chiral DirhodiumCarboxamidates: Catalysts for Highly Enantioselective Syntheses of Lactones and Lactams, Aldrichchimica Acta. 1996, 29, 3 Rh2(OAc)4 CuOTf CH2Cl2 Rh2(OAc)4 Rh2(OAc)4 Chem 206Carbenes: Rearrangements hν R O H H N2O R O H H C O H R CO2Et OHH N S CO2Me H O O N2 N S CO2Me H O N H O Me Me O N2 Me OMe (88% hν Tetrahedron Lett. 1990, 31, 6589. iPr2NH Moore et al. J. Org. Chem. 1983, 48, 3365. Ring Contraction Ring Opening Wolff-[2+2] hν J. Org. Chem. 1980, 45, 2708. (74%) (81%) N2 Li TMS Br N2 TMSR TMSR TMS R [1,2]-Rearrangements Aoyama Chem. Pharm. Bull. 1989, 37, 2261. Me Me Me N2O Cu(I)MeOH Me Me CO2Me Vinylolgous Wolff Rearrangement Doyle pp520-521 Me Me Me Me O Me Me CMe O H Me Me C OH δ + M. Shair, D. A. Evans EtOH HOEt Rh2(OPIV)4 CuOTf