M.C. White, Chem 153 了- allyl chemistry375 Week of december 9. 2002 oT- Trimethylenemethane cyclization Provide a mechanism for the following transformation toluene,Δ SiMe mixture of stereoisomers SiMe L,Pd(o Ph LnPd山 LnPd山 团 Pd(o Trost JACS1980(102)6359,ACS1983(105)2326
M.C. White, Chem 153 π-allyl chemistry -375- Week of December 9, 2002 π-Trimethylenemethane cyclization O O Ph AcO SiMe3 (Ph3P)4Pd O O Ph H H Provide a mechanism for the following transformation. mixture of stereoisomers + toluene, ∆ LnPd Ph (0) AcO SiMe3 Ph SiMe3 OAc Ph LnPd(II) LnPd(II) O O Ph Pd(II)Ln O O Ph Pd(II)Ln O O Ph H H Pd(0)Ln O O Ph H H Pd(0) H Trost JACS 1980 (102) 6359, JACS 1983 (105) 2326
M.C. White, Chem 153 Metal alkylidenes 376 Week of december 9. 2002 Metal carbenes Fischer Carbenes(formally derived from a singlet carbene) Schrock Carbenes(formally derived from a triplet carbene) carbene RV O alkyl(or H) The presence of strong 8+6 I-acceptor ligands on the ts competes LM=CR I-donation from the metal P orbital weak inlet extreme nmr transfered to the C(p,) orbital LnM=CR alkyl (or H) High oxidation state, early metals tal-carbon bonds are more Low oxidation state. late metals carbenes Non-a acceptor ligands on the metal than t -backbonding (often I-donor ligands such as Cp or CI) nature and highly polarized alkyl (or H)substituents on the carbene resulting in a partial negative T-donar substituents on the carbene C resulting in a partial positive charge on the the carbene c arlene carbon likened to a carbonyl: 8 80Me PapA (CO)sCr (CO)4C 18e. Ph (BUcH)3Ta note: that the formal charge for the carbene unit is zero. the # highly oxophilic, early metal of electrons donated is 2 CrCO)+ (CO)4C (A-BucH3Ta 人 (A-BuCH3Ta Ph ome Fischer Chem. Ber. 1972(105)3966 Schrock jACS1974(96)6796,1976(98)5399
M.C. White, Chem 153 Metal alkylidenes -376- Week of December 9, 2002 Metal Carbenes singlet carbene M C X sp2 pz R' R O C LnM=CR2 δ+ δ- Fischer Carbenes (formally derived from a singlet carbene) (CO)5Cr0 OMe Ph OR (CO)5CrII Ph OMe OR (CO)5CrII Ph OMe OR CO Ph RO OMe Cr0(CO)6 Fischer Chem. Ber. 1972 (105) 3966. · Low oxidation state, late metals · π-acceptor ligands on the metal · π-donar substituents on the carbene C δ+ δ- + · electrophilic carbenes · σ-donation is stronger than π-backbonding resulting in a partial positive charge on the carbene carbon note: that the formal charge for the carbene unit is zero, the # of electrons donated is 2. π-donation from the carbene substituents competes w/ π-donation from the metal The presence of strong π-acceptor ligands on the metal renders π-backbonding into the empty carbene p orbital weak. R' X = heteroatoms likened to a carbonyl: O OMe Me δ+ δ- 18 etriplet carbene Schrock Carbenes (formally derived from a triplet carbene) M C R sp2 pz R · The metal-carbon bonds are more covalent in nature and highly polarized towards C resulting in a partial negative charge on the carbene C. alkyl (or H) X R' R' LnM=CR2 δ- δ+ · High oxidation state, early metals · Non- π acceptor ligands on the metal (often π-donor ligands such as Cp or Cl) · alkyl (or H) substituents on the carbene. · nucleophilic carbenes The first characterized Schrock carbene: Ta V t-Bu t-Bu t-Bu t-Bu δ δ+ - + likened to a phosphorus ylide: Ph3P t-Bu δ- δ+ O pentane/N2 O2 and moisture sensitive -2 charge/ 4 electron donor 10 e- (t-BuCH2)3Ta V t-Bu O (t-BuCH2)3Ta V O t-Bu highly oxophilic, early metal (t-BuCH2)3Ta V O t-Bu + 85% Schrock JACS 1974 (96) 6796, 1976 (98) 5399. M C R sp2 pz R alkyl (or H) X R' R' extreme π-backbonding: where the 2e- in the M(dπ) orbital are transfered to the C(pz) orbital
M.C. White, Chem 153 Metal alkylidenes-377 Week of december 9. 2002 The first isolated and characterized Schrock carbenes The first characterized Schrock carbene a-agostic Interaction w/extra electron density (t-BuCH2)( ciTa CI -Bu 2eqA-BuCH)Li (-BuCH2k( CI)Ta ([-BuCH2hTa (- BuCH2)Ta≌ 10 LiCI LiCI steric conjestion induces direct a-proton abstraction by one of the neopentane ligands resulting in the metal alkylidene Schrock JACS 1974(96)6796, Acc Chem. Res 1979(12)98 solated Schrock carbene B +C(Ph CH MeC(Ph) 16e- Schrock Jacs1975(97)657706579 is suggestive of a significant amount of db character
M.C. White, Chem 153 Metal alkylidenes -377- Week of December 9, 2002 The first isolated and characterized Schrock carbenes The first isolated Schrock carbene: TaV Me Me Me 18 eC(Ph)3 BF4 MeC(Ph)3 TaV Me CH2 16 eH BF4 base TaV Me CH2 18 eSchrock JACS 1975 (97) 6577, 6579. 2.026 Å 2.246Å ~ 10 % shorter Ta-C bond is suggestive of a significant amount of db character The first characterized Schrock carbene: (t-BuCH2)2(Cl)Ta V t-Bu Cl H 10 e- complex α-agostic interaction provides the metal w/extra electron density 2 eq t-BuCH2Li (t-BuCH2)2(Cl)Ta V t-Bu H t-Bu steric conjestion induces direct α-proton abstraction by one of the neopentane ligands resulting in the metal alkylidene. (t-BuCH2)2TaV t-Bu Cl CMe4 (t-BuCH2)3Ta V t-Bu LiCl LiCl Schrock JACS 1974 (96) 6796, Acc. Chem. Res. 1979 (12) 98
M.C. White, Chem 153 Metal alkylidenes-378- Week of december 9. 2002 Carbonyl methylenation: Tebbe's reagent Tebbe's reagent: Tebbe JACS 1978(100)3611 Ti.aiMe CH2 stoichiometric toluene AMe toluene,-15°C 2 AlMe 65% 16e AlMe,CI Tebbe's reagent 0.5M soln 100 mL/S363 In situ prep: Grubbs JOC 1985(50)2386 (Aldrich 2001) i\AlMy R Synthetic applications OTBS OBn oTBs O OTBS OBn OTBS 2TICH, CIAIMe? Eto,C tol-THF-Py, Eto,C 8Cto-15°C otBs OBI otbs otbs OBI otbs Schreiber JAcs 1990(112)9657 key intermediate in the total synth of Hikizimycin CpTiCH2CIAIMe2 THF, rt, Ih Nicolaou ACIEE1994(33.,2184,2187,2190 key intermediate in the total synthesis of Zaragozic acid
M.C. White, Chem 153 Metal alkylidenes -378- Week of December 9, 2002 Carbonyl methylenation: Tebbe’s reagent TiIV Cl Cl 16 e- + 2 AlMe3 toluene rt TiIV Cl 16 eAlMe2 CH4, AlMe2Cl Tebbe's reagent: Tebbe JACS 1978 (100) 3611. Tebbe's reagent 0.5M soln 100 mL/$363 (Aldrich 2001) TiIV Cl AlMe2 TiIV O TiIV O R R CH2 16 eTiIV Cl AlMe2 stoichiometric toluene, -15 o C 65% Synthetic applications: EtO2C O OTBS OTBS OBn OBn OTBS OTBS Cp2TiCH2ClAlMe2 tol-THF-Py, -78oC to -15o C 82% EtO2C OTBS OTBS OBn OBn OTBS OTBS key intermediate in the total synthesis of Hikizimycin Schreiber JACS 1990 (112) 9657. OR O O O Cp2TiCH2ClAlMe2 THF, rt, 1h 85% O OR O Nicolaou ACIEE 1994 (33), 2184, 2187, 2190 key intermediate in the total synthesis of Zaragozic acid In situ prep: Grubbs JOC 1985 (50) 2386
M.C. White, Chem 153 Metal alkylidenes- 379 Week of december 9. 2002 Tebbe's reagent Tebbe's reagent reacts with olefins to give metallocyclobutanes AICIMe Grubbs OM 1982(1)1658 Titanium metallocyclobutane I reacts with acid chlorides to form Ti enolates OTiCICp2 PhCHO CI tol, -20C to 0%C Ph Grubbs JACS 1983(105)1665
M.C. White, Chem 153 Metal alkylidenes -379- Week of December 9, 2002 Tebbe’s reagent TiIV Cl AlMe2 TiIV 16 e- + AlClMe2 TiIV TiIV Tebbe's reagent reacts with olefins to give metallocyclobutanes: Titanium metallocyclobutane 1 reacts with acid chlorides to form Ti enolates. 1 Grubbs OM 1982 (1) 1658. O Cl Ph tol, -20oC to 0o C OTiClCp2 Ph PhCHO O Ph OH Ph 69% TiIV TiIV O Cl Ph O Cl Ph Grubbs JACS 1983 (105) 1665
M.C. White, Chem 153 Metal alkylidenes- 380- Week of december 9. 2002 Olefin metathesis: Tebbe's reagent Tebbe's reagent reacts with olefins to give titanacyclobutanes AlMe? AICIMe Titanacyclobutanes are effective catalysts for a-olefin metathesis First application of olefin metathesis to synthesis Cp2 TICHCIAIMe L. cat t-Bu DMAP. benzene D t-BuO《 t-Bu eTiC Cp2Ti(O)t-BuO t-Buo TSOH ie<D 81 Grubbs JACS 1982(104)7491 Grubbs JACS 1986(108)855
M.C. White, Chem 153 Metal alkylidenes -380- Week of December 9, 2002 Olefin metathesis: Tebbe’s reagent TiIV Cl AlMe2 TiIV 16 e- + t-Bu AlClMe2 TiIV t-Bu Tebbe's reagent reacts with olefins to give titanacyclobutanes: 1 D D D t-Bu t-Bu TiIV t-Bu D t-Bu D t-Bu D TiIV D D D t-Bu t-Bu TiIV D D D t-Bu TiIV t-Bu D D D TiIV t-Bu D D TiIV t-Bu D D t-Bu t-Bu D t-Bu t-Bu D t-Bu D + 1, cat + Titanacyclobutanes are effective catalysts for α-olefin metathesis . Grubbs JACS 1982 (104) 7491. O t-BuO O t-BuO TiCp2 O t-BuO TiCp2 t-BuO HO OH O O H H H Cp2TiCH2ClAlMe2 DMAP, benzene 25oC 90oC p-TsOH 81% overall yield Cp2Ti(O) (±)-Capnellene First application of olefin metathesis to synthesis: Grubbs JACS 1986 (108) 855
M.C. White, Chem 153 Metal alkylidenes- 381- Week of december 9. 2002 Carbonyl methylenation: Petasis reagent Difficulties with the Tebbe and Grubbs Ti-mediated olefinations include the high cost of Ti reagent, long preparation times, short shelf life, and the need for special techniques due to sensitivity to air and water. Many of these difficulties are overcome with Petasis procedure which uses dimethyltitanocene. Petasis JACS 1990112 639 aldehydes Cp,TiM CpTiMe 2 0-3eg-H3C 0 60-65C 62% 60-65"C 83% hemoselectivity for ketones in the presence of esters o Cp TiMe2 CpTiMez OCH toluene OCH3 60-65 60-65" Petasis JACS 1990 112639 Based on deuterium labelling studies, Petasis originally proposed a mechanism i Hughes finds that in the reaction with C-13 labelled ethyl acetate shown below, involving initial carbonyl complexation to Cp2 TiMez followed by methyl scrambling of the label only occurs if trifluoroacetic acid is present and proposes that this transfer and subsequent loss of methane and titanocene oxide scrambling is due to an acid-catalyzed, degenerate[ 1, 31-hydrogen shift. He proposes that i the scrambling observed by Petasis was likely due to adventitious acid present on all acid-washed glassware. To support this argument, Hughes repeated the deuterium ware that HC、O OTiCp2 CD3 H3C、(O-50% CpTi(CI iCp2 H3 C H H3G/LO <1%incorporation ofc deuterium detected at C-3 Hughes uses these experiments in conjunction with detailed kinetic studies to provide O=iCp Tic riCe oTIC H Petasis JACS 19901126392 Hughes OM 199615 663
M.C. White, Chem 153 Metal alkylidenes -381- Week of December 9, 2002 Carbonyl methylenation: Petasis reagent O O H H3C Me O O H3C O H3C O H3C O OTiCp2CD3 H3C CD3 H H3C Me O D3C H3C O H3C H3C O D D O OCH3 O OCH3 O 8 8 62 % 83 % aldehydes ketones esters chemoselectivity for ketones in the presence of esters 80 % 60 % Cp2TiMe 2 3 eq. toluene 60-65 o C Cp2TiMe 2 3 eq. toluene 60-65 o C Cp2TiMe 2 3 eq. toluene 60-65 o C Cp2TiMe 2 1 eq. toluene 60-65 o C Based on deuterium labelling studies, Petasis originally proposed a mechanism involving initial carbonyl complexation to Cp2TiMe2 followed by methyl transfer and subsequent loss of methane and titanocene oxide. Petasis JACS 1990 112 6392. Difficulties with the Tebbe and Grubbs' Ti-mediated olefinations include the high cost of Ti reagent, long preparation times, short shelf life, and the need for special techniques due to sensitivity to air and water. Many of these difficulties are overcome with Petasis' procedure which uses dimethyltitanocene. Petasis JACS 1990 112 6392. 11 Cp2Ti(CD3)2 11 ? 11 11 ~50% "significant amount of deuterium detected at C-3." H313C O H3C O O TiCp2 H313 C EtO H313 C H3C O <1% incorporation of 13C label into methylene position Hughes finds that in the reaction with C-13 labelled ethyl acetate shown below, scrambling of the label only occurs if trifluoroacetic acid is present and proposes that this scrambling is due to an acid-catalyzed, degenerate [1,3]-hydrogen shift. He proposes that the scrambling observed by Petasis was likely due to adventitious acid present on all acid-washed glassware. To support this argument, Hughes repeated the deuterium labelling experiments reported by Petasis using glassware that was not acid washed and, contrary to Petasis, observed no scrambling of the label. O Me TiCp2 Me O Cp2 Ti C H2 H CH3 CH2 O TiCp2 Petasis JACS 1990 112 6392. Me TiCp2 Me O TiCp2 O TiCp2 CH2 O TiCp2 Hughes uses these experiments in conjunction with detailed kinetic studies to provide strong support for a mechanism involving a titanium carbene. Hughes OM 1996 15 663. 1 2 3 1 2 3
M.C. White, Chem 153 Metal alkylidenes- 382 Week of december 9. 2002 Olefin metathesis The first reports of olefin cross metathesis(heterogeneous cat) by Banks The first report of ROMP (ring opening metathesis polymerzation 个 Mo(COk supported on Al MXn= TICl4 50°C,30am ZrCl4, Mocks, Banks Ind and Eng. Chem.(Product Res and Derelopment) 1964(3)170 Natta Makromol. Chem. 1963(69)163 Haines Chemt. Soc. Rev. 1975(4)155 Natta ACIEE 1964 (3)723 Well-defined W and Mo olefin cross metathesis and ROMP catalysts: Wittig-type chemistry ith aldehydes>>ketones (slow rates HIc F3C 12e CH CH3 Schrock JACS1990(112)3875,8378, Schrock JACS 1986(108)2771 1991(113) Olefin cross metathesis: ROMP (Ring opening metathesis polymerization) Often called a"living polymerizatio ermination only occurs upon Grubbs Science 1989(243)907
M.C. White, Chem 153 Metal alkylidenes -382- Week of December 9, 2002 Olefin metathesis The first reports of olefin cross metathesis (heterogeneous cat) by Banks: 2 Mo(CO)6 supported on Al 150oC, 30 atm. + Banks Ind. and Eng. Chem. (Product Res. and Development) 1964 (3) 170. Haines Chem. Soc. Rev. 1975 (4) 155. The first report of ROMP (ring opening metathesis polymerzation): MXn + Al(Et)3 MXn = TiCl4, n ZrCl4, MoCl5, WCl6 Natta Makromol. Chem. 1963 (69) 163. Natta ACIEE 1964 (3) 723. Well-defined WVI and MoVI olefin cross metathesis and ROMP catalysts: WVI N t-Bu O O F3C H3C F3C F3C F3C CH3 i-Pr i-Pr MoVI N t-Bu O O F3C H3C F3C F3C F3C CH3 i-Pr i-Pr · Wittig-type chemistry with aldehydes> ketones>> and esters (slow rates). · Wittig-type chemistry with aldehydes>>ketones (slow rates). Schrock JACS 1986 (108) 2771. Schrock JACS 1990 (112) 3875, 8378; 1991 (113) 6899. Olefin cross metathesis: Mn t-Bu 12 e- 12 eMn t-Bu Mn Mn Mn Mn ROMP (Ring opening metathesis polymerization) Mn R M R Mn R Mn R Mn R m propagation PhCHO Ph R m termination + Mn=O initiation Often called a "living polymerization" because termination only occurs upon addition of a capping unit (often aldehyde). Grubbs Science 1989 (243) 907
M.C. White, Chem 153 Metal alkylidenes- 383- Week of december 9. 2002 Mo-mediated ring closing metathesis(RCM of acyclic diene ethers 5-membered ring formation dihydrofurans Tri-and tetrasubstituted olefins 1. 5 mol% i-Pr benzene. rt 15 min 93 yield membered ring formation dihydropyrans 7-membered heterocycles benzene. rt benzene. rt 92% vield 75 yield Grubbs JACS 1992(114)5426 General mechanism Evaporative loss of the low molecular weight acyclic olefin generated and the thought to be tw favoring the RCM pathway L.Mo' VIMol LoMo of RCM 1,12mol% Sophora compound I
M.C. White, Chem 153 Metal alkylidenes -383- Week of December 9, 2002 Mo-mediated ring closing metathesis (RCM) of acyclic diene ethers O Ph O Ph Me benzene, rt 15 min 92 % yield O Ph Me O Me Ph 92 % yield benzene, rt 15 min O O Me O BnO OBn Me O O O BnO OBn O O O HO OH Me O Me Ph Me O Ph Me Me benzene, rt 3 h Me 93 % yield O Ph Et Me O Ph benzene, rt 4 h 75 % yield 1, 5 mol% 1, 5 mol% 1, 5 mol% 1, 5 mol% MoV I N O O i-Pr i-Pr Me Me Ph CF3 F3C Me Me F3C CF3 1 Grubbs JACS 1992 (114) 5426. 1, 12 mol% 85 % 95 % Sophora compound I Grubbs JOC 1994 (59) 4029. H2, Pd-C Grubbs recognized the potential for applying olefin metathesis towards a productive synthetic pathway: RCM (Ring Closing Metathesis) General mechanism: X LnMoVI R LnMoVI X VI MoLn X R R X LnMoVI X LnMoVI X 5-membered ring formation: dihydrofurans Tri-and tetrasubstituted olefins: 6-membered ring formation: dihydropyrans 7-membered heterocycles R Evaporative loss of the low molecular weight acyclic olefin generated and the entropic gain of generating 2 molecules from 1 are thought to be two factors favoring the RCM pathway. An early synthetic application of RCM:
M.C. White. Chem 153 Metal alkylidenes-384- Week of december 9. 2002 Mo-mediated rCm of acyclic diene amines and amides 1. 4 mol% 1. 4 mol% benzene. rt benzene. rt 83%yield 6-membered rings 7-membered ring -lactam formation 1. 4 mol% 1. 4 mol% I h 6% yield 90% vield Grubbs JACS 1992114 5426 Formation of 5-and 6-membered lactams via RCM of acyclic diene-amides is hindered by formation of stable chelate intermediates. This may be due to the Lewis acidic properties of the formally 12 e- Mo alkylidene - Mo stable This problem can be averted by directing the catalytic cycle with appropriate olefin substitution pattens. Because metathesis of monosubstituted olefins by 1 is faster than that of disubstituted olefins, the initial Mo alkylidene preferentially forms at the less substituted olefin where intramolecular chelate formation with the amide carbonyl is not favored 1. 10 mol%Bn 50℃ Et Grubbs JACS 1992(114)7324, see also Schrock OM1989(8)2260
M.C. White, Chem 153 Metal alkylidenes -384- Week of December 9, 2002 Mo-mediated RCM of acyclic diene amines and amides N Me Bn N Me Bn N O R N Me Bn N O R Mo N Bn Me MoVI N O O i-Pr i-Pr Me Me Ph CF3 F3C Me Me F3C CF3 N O R N F3C O N Bn O N F3C O N Bn O benzene, rt 3 h 93 % yield 86 % yield benzene, rt 1 h benzene, rt 15 min 83 % yield benzene, rt 1.5 h 90 % yield 1, 4 mol% 1, 4 mol% 1, 4 mol% 1, 4 mol% 1 Grubbs JACS 1992 114 5426. Formation of 5- and 6-membered lactams via RCM of acyclic diene-amides is hindered by formation of stable chelate intermediates. This may be due to the Lewis acidic properties of the formally 12 e- Mo alkylidene. 1 N O R 1 N O R Mo N O R N O Bn Me N O Bn Mo Me N O Bn stable chelate stable chelate N O Bn N O Bn Et Mo N O 1, 10 mol% Bn benzene 50 o C 1.5 h 74 % yield Et 80 % yield 1, 10 mol% benzene 50 o C 1.5 h This problem can be averted by directing the catalytic cycle with appropriate olefin substitution patterns. Because metathesis of monosubstituted olefins by 1 is faster than that of disubstituted olefins, the initial Mo alkylidene preferentially forms at the less substituted olefin where intramolecular chelate formation with the amide carbonyl is not favored. Grubbs JACS 1992 (114) 7324, see also Schrock OM 1989 (8) 2260. 5-membered rings 6-membered rings 7-membered ring - lactam formation 12e-