Olefin Metathesis in Organic Synthesis Wendy Jen MacMillan Group Meeting January 17, 2001 I. Well-defined alkene metathesis catalysts II. Applications of Olefin Metathesis A. Ring closing metathesis B. Cross metathesis C. Ring opening metathesis Recent Reviews: Furstner, A. Angew. Chem. Int. Ed. 2000, 39, 3013. Grubbs, R. H.; Chang, S. Tetrahedron 1998, 54, 4413. Furstner, A. Topics in Organometallic Chemistry 1998, 1, 1. Schuster, M.; Blechert, S. Angew. Chem. Int. Ed. 1997, 36, 2036 Olefin Metathesis: Introduction 1 2 1 2 R R catalyst R R R1 R2 R1 R2 ! Chauvin-type mechanism: model proceeds through a metallacyclobutane intermediate R2 R2 R2 R2 R2 R2 [M] [M] [M] R1 R1 R1 ! Catalyst systems WCl6/ EtAlCl2/ EtOH i-Pr i-Pr ArO Re O / Al O / SnMe PCy3 2 7 2 3 4 Cl ArO Ta Ru N Cl (F3C)2MeCO ArO WCl6/ Me4Sn Ph Mo Ph PCy3 (F3C)2MeCO Ill-defined catalyst systems Well-defined catalyst systems Background: Metal Carbenes X ! Definition: Transition metal complex possessing a formal metal to carbon double bond ! LnM C X, Y = alkyl, aryl, H, or heteroatom (O, N, S, Halogen) Y ! Two types of metal carbenes: Fischer-type and Schrock-type OMe Me CH Fischer-type (OC)5W C Ta 2 Schrock-type Ph ! low oxidation state middle to late TM ! high oxidation state early TM ! Substituents (X & Y): at least one electronegative atom ! Substituents (X & Y) are H or alkyl ! Ligands are generally good ! acceptors ! Ligands are generally good " or ! donors ! Electrophilic carbenes: nucleophile attacks at Ccarbene ! Nucleophilic carbenes: electrophile attacks at Ccarbene ! Ccarbene is L-type ligand: Metal oxidation state unchanged ! Ccarbene is X2-type ligand: metal oxidation state changed by +2 Metal carbene (sp2) Metal carbene (sp) Schrock's Metathesis Catalyst ! Commercially available, as is synthetic precursor Mo(CHt-Bu)(NAr)(OTf)2(dme) ! Must be handled under Ar or N2 using dry solvents and substrates i-Pr i-Pr ! Relatively intolerant of protons on heteroatoms (RCOOH, RSH, ROH, etc.) and N Me some functionalities (eg. RCHO) (F3C)2MeCO Mo Ph (F C) MeCO Me ! Tolerant of S, P and nitrile functional groups 3 2 ! High reactivity Structural Features Ar Ar ! Electon deficient Mo(VI), 14 electron species N H2 N C H2 RO M CH2 RO C ! Pseudo-tetrahedral coordination sphere C M H CH2 2 C RO OR H2 ! NAr ligand, OR ligands, and initial alkylidene need to be bulky to allow for isolation. Trigonal bipyramidal Square planar ! Electron withdrawing alkoxides increase electrophilicity of metal center, hence increasing reactivity. Schrock's Catalyst: Influence of Ligand Set on Reactivity ! Two possible rotamers Ar Ar N N ka/s RO RO anti M M 1 syn H R C RO C RO ks/a R1 H Generally, syn isomer is more stable and anti isomer is more reactive ! Rate of interconversion between two rotamers is dependant on metal ligands and substrate L L NAr NAr -L ka/s -L RO M anti syn RO M H R k +L s/a +L OR R OR H anti CNO adduct syn CNO adduct Ar Ar Ar N N N o o H 90 H 90 R C C R R H electron withdrawing alkoxide substituents and bulky aryl groups decrease ks.a Schrock, R.R. Tetrahedron 1999, 55, 8141. Grubbs' Metathesis Catalyst ! Commercially available PCy3 Cl ! Reasonably stable toward H2O, O2, and minor impurities ease of handling Ru Cl Ph PCy3 ! Lower reactivity vs. Molybdenum imido alkylidene catalyst ! High functional group tolerance Mechanism: olefin binds cis to carbene and trans to Cl; formation of metallacycle believed to be rate determining PCy + Cy3P Cy3P H 3 - PCy3 PCy3 R Cl Cl Cl Ru Cl Ru Cl Ru products Cl Ru R + PCy Cl R R PCy3 3 R - Cl R R R Ligand Effect on Catalyst Activity: Halides: Catalyst activity increases from I < Br < Cl Trans influence I > Br > Cl olefin is bound tightest for Cl complex Cl is smallest large halogens disfavor olefin binding due to steric crowding Phosphines: Catalyst activity increases as cone angle and eletron donating ablilty increase As cone angle increases, dissociation of phosphine more facile for steric reasons More electon donating ligand labilizes trans ligand and stabilizes vacant orbital in 14 e- intermediate Dias, E. L.; Nguyen, S.T.; Grubbs, R.H. J. Am. Chem. Soc. 1997, 119, 3887. R R Ruthenium Catalysts Containing N-Heterocyclic N N Carbene (NHC) Ligands Arduengo et. al. JACS 1991, 113, 361 ! Sought to find more basic and sterically demanding ligand than PCy3; ! "Stable" imidazol-2-ylidene ligands (NHC) are such phoshine mimics Herrmann et al. Angew. Chem. Int. Ed. 1999, 38, 2416. PCy3 PCy3 Cl Ph PCy3 Cl Ph Grubbs et al. Org. Lett. 1999, 1, 953. Ru Cl Ru Cl Cl Ru Nolan et al. J. Am Chem. Soc. 1999, 121, 2674. R R Cl Ph R R N N R R N N N N Activity is significantly higher than parent Ru complex Orgin of increased reactivity: k1 k2 PCy Cy3P k3 Cy3P H 3 - PCy PCy3 + olefin 3 Cl Cl Cl Ru Cl Ru Cl Ru Cl Ru R + PCy3 Cl - olefin R R PCy3 R k Cl R -3 R k-1 k-2 High activity of NHC complex is due to improved selectivity for binding !-acidic olefinic substrates in the presence of "-donating free phosphine (decreasing k-1/k2). Sanford, M.S.; Ulman, M.; Grubbs, R.H. J. Am. Chem. Soc. 2001, ASAP Other Metathesis Catalyst Systems Hansen, S. M.; Rominger, F.; Metz, M.; Hofmann, P. Angew Me Me P Ru Cl OTf Chem. Int. Ed. 1999, 38, Al P Solv Ti 1273. Me Cl Me Tebbe, F. N.; Parshall, G.W.; Reddy, G.S. J. Am. Chem. Soc. 1978, 100, 3611 Me Ti CH2 Me Demonceau, A.; Noels, A. F.; Saive, E.; Hubert, Cl A. J. J. Mol. Catal. Ru 1992, 76, 123. Cy3P Cl R 87% R 2[Cp2Ti{P(OEt)3}2], Mg R SPh - [Cp2Ti(SPh)2 TiCp2 SPh Fujiwara, T.; Takeda, T. Synlett 1999, 354. Fundamental Olefin Metathesis Reactions RCM Ring Closing Metathesis (RCM) R2 Cross Metathesis (CM) CM R1 R2 R1 ROMP Ring Opening Metathesis Polymerization (ROMP) n ADMET Acyclic Diene Metathesis Polymerization (ADMET) n Ring Closing Metathesis (RCM) ! Intramolecular metathesis of a diene to form a cyclic olefin - ADMET H2C CH2 n M RCM M CH2 M n M ! Reaction pathway of diene depends on catalyst, dilution, ring size, and substrate (functional groups and sterics) Catalyst: O Re O /Al O -SnBu Si 2 7 2 3 4 Si ADMET Si Si + oligomers O dilute 14% 86% Schrock's catalyst 95% 5% concentrated Dilution: Intermolecular ADMET can generally be prevented by applying dilution principle Finkel'shstein et al. J. Mol. Cat. 1992, 76, 133. Forbes et al. J. Am. Chem. Soc. 1992, 114, 10978. RCM of Small Rings: Olefin Substitution ! Synthesis of 5-7 membered rings fairly facile; proper selection of catalyst depends on functional groups and steric demands of the substrate ! Typically ruthenium catalysts are preferred over molybdenum catalysts from a synthetic standpoint due to ease of handling and high function group tolerance of Ru catalyst. ! Choice of catalyst depends on olefin substitution of product Yield (%) using substrate product time 1 2 3 i-Pr i-Pr N Me (F3C)2MeCO Mo Ph (F3C)2MeCO Me 1 PCy3 Cl Ru Cl R PCy3 2 PCy Cl 3 Ph Ru Cl Mes Mes N N 3 Molybdenum and Ruthenium NHC catalysts are more effective for highly substitued olefins Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R.H Org. Lett 1999, 1, 953. PCy3 Cl Ph PCy3 Cl Ru 1 Ru Cl 2 RCM of Small Rings: Alcohols Cl Mes Mes R PCy3 N N ! Free alcohols: highly compatible with Ru based catalysts; Mo catalysts have low tolerance for ROH Exception: Me Me Me Me OH 2% Schrock's Me OH catalyst Me Schrock, R. R. Top. Organomet. Chem. 1998, 1, 1. ! Allylic Alcohols: compatible with Ru catalysts O O OH O O OH 1% 1 O N O N CH2Cl2 97% Bn Bn Crimmins, M.T.; King, B. W. J. Org. Chem. 1996, 61, 4192. Potential for isomerization of olefin if catalyst is not reactive enough OH OH OH O O 2 O 1 O O O O O O OH OH OH OH Ackermann, L.; Tom, D. E.; Furstner, A. Tetrahedron, 2000, 56, 2195. RCM of Small Rings: Ethers ! Allyl ethers and acetals: Both Mo and Ru catalysts tolerate these functionalities Me Ph Ph Ph O Grubbs' Schrock's catalyst Me Me O catalyst O O O Ph O (87%) 93% Me Me Fu, G.C.; Nguyen, S.T.; Grubbs, R.H. JACS 1993, 115, 9856. Fu, G.C.; Grubbs, R.H. JACS 1992, 114, 5426. [M] OR Caveat: allylic ethers have potential for decomposition R O R [M] ! Vinyl ethers: Mo catalyst used for the reaction/ formation of enol ethers; Ru is incompatible because resulting Ru carbene is unreactive OBn BnO O O 12% Schrock's O O O OBn catalyst (85%) OBn O Fujimura, O.; Fu, G.C.; Grubbs, R.H. J. Org. Chem. 1994, 59, 4029. RCM of Small Rings: Vinyl Ethers ! Tebbe reagent: carbonyl ester olefination and metathesis to form cyclic enol ether BnO Me Me BnO H O Ti Al H O Me Cl Me O O H 50% yield O H O 4 equiv H THF, reflux O H Nicolaou et al. J. Am. Chem. Soc. 1996, 118, 10335. ! Schrock's molybdenum and tungsten catalyst can also mediate olefin metathesis/ carbonyl olefination O 1.0 equiv Schrock's O(CH2)3Ph Mo catalyst O(CH2)3Ph 86% yield O R R [Mo] [Mo] O catalyst metathesizes olefins faster than it olefinates ketones Fu, G.C.; Grubbs, R.H.