Myers The Olefin Metathesis Reaction Chem 115 Reviews: Cross Metathesis (CM): Hoveyda, A. H.; Khan, R. K. M.; Torker, S.; Malcolmson, S. J. 2013 (We gratefully acknowledge Professor Hoveyda and co-workers for making this review available to us ahead of print). CM R2 + R4 R3 + R4 Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem., Int. Ed. Engl. 2005, 44, 4490–4527. R1 R3 R1 R2 Grubbs, R. H. Tetrahedron 2004, 60, 7117–7140. • Chatterjee, A. K.; Choi, T.-L.; Sanders, D. P.; Grubbs, R. H. Self-dimerization reactions of the more valuable alkene may be minimized by the use of J. Am. Chem. Soc. 2003, 125, 11360–11370. an excess of the more readily available alkene. Schrock, R. R.; Hoveyda, A. H. Angew. Chem. Int. Ed. 2003, 42, 4592–4633. Catalysts Connon, S. J.; Blechert, S. Angew. Chem., Int. Ed. Engl. 2003, 42, 1900–1923. Fürstner, A. Angew. Chem., Int. Ed. Engl. 2000, 39, 3012–3043. i-Pr i-Pr MesN NMes Ring-Opening Metathesis Polymerization (ROMP): P(c-Hex) P(c-Hex) N 3 3 CH Cl Ph Cl F3C 3 Ph Cl O Mo Ru Ph Ru Ph Ph Cl H Cl H Ru F3C CH3 P(c-Hex) P(c-Hex) Cl H ROMP n CH3 O 3 3 H P(c-Hex)3 F3C CH3 F3C 1-Mo 2-Ru 3-Ru 4-Ru (Grubbs' 1st (Grubbs' 2nd Generation Catalyst) Generation Catalyst) • ROMP is thermodynamically favored for strained ring systems, such as 3-, 4-, 8- and larger- membered compounds. • When bridging groups are present (bicyclic olefins) the !G of polymerization is typically • The well-defined catalysts shown above have been used widely for the olefin metathesis more negative as a result of increased strain energy in the monomer. reaction. Titanium- and tungsten-based catalysts have also been developed but are less used. • Block copolymers can be made by sequential addition of different monomers (a • Schrock's alkoxy imidomolybdenum complex 1-Mo is highly reactive toward a broad range of consequence of the "living" nature of the polymerization). substrates; however, this Mo-based catalyst has moderate to poor functional group tolerance, high sensitivity to air, moisture or even to trace impurities present in solvents, and exhibits thermal instability. Ring-Closing Metathesis (RCM): • Grubbs' Ru-based catalysts exhibit high reactivity in a variety of ROMP, RCM, and CM processes and show remarkable tolerance toward many different organic functional groups. 6 RCM • The electron-rich tricyclohexyl phosphine ligands of the d Ru(II) metal center in alkylidenes 2- + H2C CH2 Ru and 3-Ru leads to increased metathesis activity. The NHC ligand in 4-Ru is a strong "-donor and a poor #-acceptor and stabilizes a 14 e– Ru intermediate in the catalytic cycle, making this catalyst more effective than 2-Ru or 3-Ru. • Ru-based catalysts show little sensitivity to air, moisture, or minor impurities in solvents. These • The reaction can be driven to the right by the loss of ethylene. catalysts can be conveniently stored in the air for several weeks without decomposition. All of the catalysts above are commercially available, but 1-Mo is significantly more expensive. • The development of well-defined metathesis catalysts that are tolerant of many functional groups yet reactive toward a diverse array of olefinic substrates has led to the rapid acceptance of the RCM reaction as a powerful method for forming carbon-carbon double bonds and for macrocyclizations. Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1, 953–956. • Where the thermodynamics of the closure reaction are unfavorable, polymerization of the Schwab, P.; France, M. B.; Ziller, J. W.; Grubbs, R. H. Angew. Chem., Int. Ed Engl. 1995, substrate can occur. This partitioning is sensitive to substrate, catalyst, and reaction conditions. 34, 2039–2041. Nguyen, S.-B. T.; Grubbs, R. H. J. Am. Chem. Soc. 1993, 115, 9858–9859. M. Movassaghi, L. Blasdel 1 Myers The Olefin Metathesis Reaction Chem 115 Mechanism: Dissociative: P = P(c-Hex)3 EtO C CO Et • The olefin metathesis reaction was reported as early as 1955 in a Ti(II)-catalyzed 2 2 polymerization of norbornene: Anderson, A. W.; Merckling, M. G. Chem. Abstr. 1955, 50, R = 3008i. • 15 years later, Chauvin first proposed that olefin metathesis proceeds via P P P P metallacyclobutanes: Herisson, P. J.-L.; Chauvin, Y. Makromol. Chem. 1970, 141, 161–176. Cl H –P Cl H Cl H Cl Cl Ru Cl Ru Cl Ru Cl Ru H H H H H • It is now generally accepted that both cyclic and acyclic olefin metathesis reactions proceed P via metallacyclobutane and metal-carbene intermediates: Grubbs, R. H.; Burk, P. L.; Carr, D. R R R D. J. Am. Chem. Soc. 1975, 97, 3265–3266. R R P Cl H Ru – C2H4 P(c-Hex)3 Cl H Cl H P Ru H Cl c-C5H6(CO2Et)2 P(c-Hex)3 EtO2C CO2Et 5 mol% P P P P Cl Cl H Cl H Cl CD Cl , 25 ºC H 2 2 EtO2C CO2Et Cl Ru Cl Ru Cl Ru Cl Ru H H H P +P EtO C CO Et EtO2C CO2Et EtO C CO Et EtO2C CO2Et 2 2 • A kinetic study of the RCM of diethyl diallylmalonate using a Ru-methylidene describes two 2 2 possible mechanisms for olefin metathesis: Associative: • The "dissociative" mechanism assumes that upon binding of the olefin a phosphine is displaced from the metal center to form a 16-electron olefin complex, which undergoes metathesis to form the cyclized product, regenerating the catalyst upon recoordination of the phosphine. P R P P P Cl H Cl H Cl H Cl Ru Cl Ru Cl Ru Cl Ru H • The "associative" mechanism assumes that an 18-electron olefin complex is formed which Cl H H H H undergoes metathesis to form the cyclized product. P P P P R R R c-C5H6(CO2Et)2 • Addition of 1 equivalent of phosphine (with respect to catalyst) decreases the rate of the – C2H4 reaction by as much as 20 times, supporting the dissociative mechanism. P P P Cl H Cl H Cl • It was concluded in this study that the "dissociative" pathway is the dominant reaction Cl Ru Cl Ru Cl Ru manifold (>95%). H H P P P Dias, E. L.; Nguyen, S.-B. T.; Grubbs, R. H. J. Am. Chem. Soc. 1997, 119, 3887–3897. EtO2C CO2Et EtO2C CO2Et EtO2C CO2Et M. Movassaghi 2 Myers The Olefin Metathesis Reaction Chem 115 Catalytic RCM of Dienes: Synthesis of Tri- and Tetrasubstituted Cyclic Olefins via RCM substrate product time (h) yield (%)a yield yield substratea product with 3-Ru (%)b with 1-Mo (%)c O O X = CF3 1 93 N X N X R R = CH E E 93 100 X = O t-Bu 1 91 E E 3 i-Pr 98 100 t-Bu NR 96 O Ph O Ph R 25 97 Ph 2 84 Br NR NR CH2OH 98 decomp O Ph O Ph E E 5 86 E E 97 100 CH3 CH O 3 O E E 8 72 E E Ph Ph 96 100 CH3 CH O O Ph 3 Ph 1 87 E E O O – No RCMd No RCMd CH3 R R = CO2H R 1 87 E E CH2OH 1 88 H3C E E CH3 CHO 1 82 NR 93 a 2-4 mol% 2-Ru, C6H6, 20 ºC H3C CH3 • Five-, six-, and seven-membered oxygen and nitrogen heterocycles and cycloalkanes are formed E E efficiently. H3C E E • Catalyst 2-Ru can be used in the air, in reagent-grade solvents (C6H6, CH2Cl2, THF, t-BuOH). NR 61 H3C In contrast to the molybdenum catalyst 1-Mo, which is known to react with acids, alcohols, and CH3 • CH aldehydes, the ruthenium catalyst 2-Ru is stable to these functionalities. 3 E • Free amines are not tolerated by the ruthenium catalyst; the corresponding hydrochloride salts E E E undergo efficient RCM with catalyst 2-Ru. 96e 100e PhCH2 H CH2Ph – 4 mol% 2-Ru N Cl a b c d N E = CO2Et. 0.01 M, CH2Cl2, 5 mol%. 0.1 M, C6H6, 5 mol%. Only recovered starting material 20 ºC, 36 h and an acyclic dimer were observed. eThe isomeric cyclopentene product is not observed. CH2Cl2; NaOH • Functional group compatibility permitting, the Mo-alkylidene catalyst is typically more effective for 79% RCM of substituted olefins. Fu, G. C.; Nguyen, S.-B. T.; Grubbs, R. H. J. Am. Chem. Soc. 1993, 115, 9856–9857. Kirkland, T. A.; Grubbs, R. H. J. Org. Chem. 1997, 62, 7310–7318. M. Movassaghi 3 Myers The Olefin Metathesis Reaction Chem 115 Geminal Substitution Recyclable Ru-Based Metathesis Catalysts MesN NMe O P(c-Hex)3 O R R <1 mol% 1-Mo Cl H Cl H R R Ru Ru 25 ºC, 0.5-1 h Cl Cl R R R R neat O O H3C H3C R = H 0%; (polymerization) CH3 CH3 CH3 95% 5a-Ru 5b-Ru recovered substratea product cat time (h) temp (ºC) yield (%)b catalyst (%)b • Standard "Thorpe-Ingold" effects favor cyclization with gem-disubstituted substrates. TBSO H TBSO H 5a-Ru 0.5 22 99 75 Forbes, M. D. E.; Patton, J. T.; Myers, T. L.; Maynard, H. D.; Smith, D. W.; Schulz, G. R., Jr.; Wagener, K. B. J. Am. Chem. Soc. 1992, 114, 10978-10980. BnO H RCM of Temporarily Connected Dienes BnO H 5a-Ru 2.0 22 95 89 Ts H3C CH3 H3C CH3 2-5 mol% OH N NTs 5a-Ru 1.0 40 99 88 Si 1-Mo or 3-Ru Si KF O O HO R n n R R C6H6, CH2Cl2 H2O2 n m m 23 ºC, 0.5-5 h m CH3 80-93% CH3 73–76% CH3 m = 1-3, n = 0-2 5b-Ruc 0.3 22 87 98 O CH3 O CH3 CH3 CH3 OH OH H C • RCM of allyl- or 3-butenylsilyloxy dienes (n≥1) proceeded efficiently with alkylidene 3-Ru, 3 5b-Ru 2 22 75 95 while the more sterically hindered vinylsilyl substrates (n=0) required the use of alkylidene CH3 1-Mo.