Metal Catalyzed Outer Sphere Alkylations of Unactivated Olefins and Alkynes Stephen Goble Organic Super-Group Meeting Literature Presentation October 6, 2004 1 Outline I. Background • Introduction to Carbometallation • “Inner Sphere” vs. “Outer Sphere” • Review of Seminal Work II. Catalytic Palladium Systems III. Catalytic Platinum Systems IV. Catalytic Gold Systems 2 I. Background: Carbometallation is the formal addition of a metal and a carbon atom across a double bond. • Cis addition would involve olefin insertion in to an σ-alkyl-metal species. This is an “Inner Coordination Sphere” process. cis addition [M] [M] R olefin insertion R • The alkyl-metal species could arise from: 1. Oxidative addition of the metal to an electrophile. 2. Transmetallation of a nucleophile to the metal. 3. Direct nucleophilic attack on the palladium. • Trans addition would involve an “Outer Coordination Sphere” nucleophilic attack on the metal-olefin coordination complex. trans addition [M] [M] R- R 3 First Example: Carbopalladation of an Olefin Tsuji, J. and Takahashi, H. J. Am. Chem. Soc. 1965. 87(14), 3275-3276. [Pd] O O RO2C CO R PdCl2 RO OR 2 Na2CO3 [Pd] Cl • Amino and Oxo-palladations (i.e. Wacker Process) were previously known and have since been much more widely studied. • No distinction between cis and trans nucleophilic addition made. 4 Carbopalladation on Styrene: Different Modes of Attack Proposed different modes of attack based on different observed products with MeLi vs. Na-Malonate: Murahashi, S. et. al. J. Org. Chem. 1977. 42 (17), 2870-2874. Nucleophilic Attack on Pd Olefin Insertion B-Hydride Elimination CH3Li [Pd] [Pd] CH3 PdX2 CH3 [Pd]-H Inner Sphere Mechanism Palladium Coordination Nucleophilic Attack B-hydride elimination CO R CO2R 2 NaCH(CO2R) CO R [Pd] CO2R 2 PdX2 [Pd] [Pd]-H • Outer Sphere attack usually occurs at the more substituted carbon - more stabilization of + + charge (In intermolecular processes). [Pd]- • Stoichiometric in Pd 5 First Direct Evidence of Trans Addition Kurosawa, H. et. al. Tetrahedron Lett. 1979. 3, 255-256. [Pd] O O D D THF D H + J=4.2 Hz -19 C [Pd] D H Na CHAc2 5 + - [Pd] = [Pd(n -C5H5)(PPh3)] ClO4 [Pd] O O D THF D H + J=12.3 Hz -19 C [Pd] D H D Na CHAc2 5 + - [Pd] = [Pd(n -C5H5)(PPh3)] ClO4 6 Palladium-Assisted Alkylation of Unactivated Olefins Hegedus, L. S. et. al. J. Am. Chem. Soc. 1980. 102, 4973-4979. • Wanted general procedure for Outer Sphere carbopalladations on unactivated olefins – but reduction of Pd (II) was a problem. • Overcame problem of nucleophilic reduction of Pd (II) by using NEt3, in a step- wise, one pot procedure. R' Pd(0) H R H2 flush 1. PdCl2(MeCN)2, THF, RT -60 C 2. NEt3 (2 Eq), THF, -78 C R 3. CH(Na)CO2R', THF, -60 C -60 to RT R = alkyl R' R Cl-Pd-H CH(Na)CO R' PdCl2(MeCN)2 2 THF RT THF, -60 C Pd (0) NEt3 (2 Eq) -78 C Cl Cl NEt Pd Pd 3 Cl Et3N 7 R R Palladium-Assisted Alkylation of Unactivated Olefins (Continued) Hegedus, L. S. et. al. J. Am. Chem. Soc. 1980. 102, 4973-4979. • Worked well on a variety of terminal olefins. • Internal alkenes gave only traces of reaction. • Worked with a variety of malonates. • Without triethylamine, reductive dimerization predominates. • Using HMPA as an additive the reaction works on a variety of un-stabilized nucleophiles: Enolates of ketones and esters. • Un-stabilized nucleophiles are usually ineffective because they attack the palladium first – Inner Sphere. • First Intramolecular case: CO Me PdCl2(MeCN) CO Me 2 2 42% Yield CO2Me CO2Me NEt3, THF (H2 flush) • In all cases the reaction is stoichiometric in Palladium. 8 Problems with Catalysis • Since the process is a formal reduction of the metal (Pd (II) to Pd (0) – re-oxidation of the metal is necessary. • Problem: Carbanions are very easily oxidized. – Reductive dimerization is a problem in carbopalladations: MeO2C CO2Me Pd (0) + Pd (II) + 2 MeO2C CO2Me MeO2C CO2Me – Therefore, any oxidant strong enough to oxidize the metal will probably oxidize the carbanion – preventing any desired reaction. 9 Palladium-Promoted Alkylation of Olefins by Silyl Enol Ethers • Silyl enol ethers transmetallate to Pd (II), β-H Elimination gives α,β-unsaturation: Ito, Y., Aoyama, H., Hirao, T. Mochizuki, A., and Saegusa, T. J. Org. Chem. 1978. 43(5), 1011-1013. OTMS Pd(OAc)2 O [Pd] O MeCN observed intermediate [Pd]-H oxo-π-allylpalladium • When an olefin is present, a formal insertion product is recovered : Ito, Y., Aoyama, H., Hirao, T. Mochizuki, A., and Saegusa, T. J. Am. Chem. Soc. 1979. 101(2), 494-496. O O R OTMS 2 Pd(OAc)2 + R 1 n MeCN R1 R1 R2 R2 • Works on a variety of substrates. • Since silyl enol ethers don’t get oxidized by Pd (II), they could get some weak catalysis (0.5 Molar Equiv) using a benzoquinone re-oxidant – but yields suffered. 10 Palladium-Promoted Alkylation of Olefins by Silyl Enol Ethers Ito, Y., Aoyama, H., Hirao, T. Mochizuki, A., and Saegusa, T. J. Am. Chem. Soc. 1979. 101(2), 494-496. By analogy they proposed this “Inner Sphere” mechanism: O R2 OTMS Pd(OAc) 2 R2 O [Pd] olefin R 1 MeCN R1 n n insertion n [Pd] R1 R2 [Pd] R2 Beta-H Elim R1 O n O O Isomerism OTMS n n But in a footnote they R1 R1 R2 R2 noted another possibility: R1 R 2[Pd] 11 Palladium-Promoted Alkylation of Olefins by Silyl Enol Ethers During the synthesis of (+/-)-Quadrone, the mechanism of this cyclization was explored: Kende, A. S. et al. J. Am. Chem. Soc. 1982. 104, 1784-1785. CO2Et Pd(OAc)2 OTMS MeCN O O O CO2Et O Product distributions in a model system are consistent an Outer Sphere process: O O Pd(OAc)2 MeO TMSO Pd(OAc)2 MeCN No Reaction A D O O 58% MeO Pd(OAc) 14% 2 MeCN C MeCN O O TBSO Pd(OAc) 40% LiO O 2 20% Pd(OAc)2 B MeCN E MeCN 45% 22% • If desilylation is first step: A and B and E should give same distribution, and C should not react (because it doesn’t form an enone in D). • Cyclization and enone formation does not proceed through same intermediate. 12 • Evidence supports an Outer Sphere mechanism. Pt (II) Additions to Ethylene Fanizzi, F. P et. al. J. Chem. Soc. Dalton Trans. 1992. 309-312. N Cl Cl CH2(CO2Et) Pt CO Et N Pt N 2 N Na2CO3 CO2Et DCM, RT • Addition is irreversible. - - - • Also works with inorganic nucleophiles (NO2 , N3 , NCO ). • Heating to 50 ºC gives β-hydride elimination. • Treatment of product with acids results in the facile cleavage of the Pt-C bond, regenerating Pt (II). N 0.5 M HCl Cl CO2Et Pt CO2Et N H2O CO2Et CO2Et or HCl/CHCl 3 13 Summary – Up to ~2001 • “Outer Sphere” carbopalladations are stoichiometric in palladium. • Pd/amine and Pt/amine complexes are the only known promoters. • The products of carbopalladations (alkyl-palladium complexes) undergo β- hydride elimination above -20 ºC. • The carbopalladation products can be quenched with H2 by simply flushing the system below -20 ºC. • Stabilized and non-stabilized carbon nucleophiles work well. • Using silyl enol ethers as the nucleophile allows weak catalysis (50 mol%), but technical problems with the system limit its utility. • One isolated example of a Pt (II) cationic complex adding to ethylene. No other late TM system is known. • Hegedus: “[The process] is unlikely to find extensive use in synthesis” Hegedus, L. S. Transition Metals in the Synthesis of Complex Organic Molecules. 1999. University Science Books, Sausalito, California. 14 II. First Example of TM (Pd) Catalysis - Hydroalkylation Pei, T. and Widenhoefer, R. A. J. Am. Chem. Soc. 2001. 123, 11290-11291. Looking at carbopalladations to get cyclopentanones: O O O O O O PdCl2(MeCN)2 (1 Eq) 70 % THF, 25 C expected • Surprising results: No net oxidation and endo ring closure. If no net oxidation, then Pd (II) would not be reduced and catalysis is possible: O O O O PdCl (MeCN) (5%) 2 2 81% Dioxane, 25 C • Mono terminal substitution on olefin is well tolerated. • α-substitution is tolerated. • β-keto esters give lower yields. But using TMSCl as an additive gives comparable yields (Pei. T and Widenhoefer, R. A. Chem. Comm. 2002. 650-651.) 15 Mechanistic Investigation Qian, H. and Widenhoefer, R. A. J. Am. Chem. Soc. 2003. 125, 2056-2057. 2 possible mechanisms: “Outer” vs. “Inner” Sphere O O Inner Sphere O H + Ac Path H Ac Ac H D D [Pd] D O O D D [Pd] H H D trans D OH O O D Ac Ac Ac H+ H H Outer Sphere D D Path [Pd] D D [Pd] D H D cis Br PhO S O O O O 2 Br O D H PdCl2(MeCN)2 (5%) NaOMe Dioxane, 25 C H D D D MeO C PhO S D D 2 2 16 Results are consistent with an outer coordination sphere mechanism. Mechanistic Investigation (Continued) Qian, H. and Widenhoefer, R. A. J. Am. Chem. Soc. 2003. 125, 2056-2057. Other labeling experiments: O O O O O O O O D D D D D D D O O O O O O O O D D D CD3 CD3 D D D D D • Palladium migration around the ring must occur. 17 Mechanistic Investigation (Continued) Qian, H. and Widenhoefer, R. A. J. Am. Chem. Soc. 2003. 125, 2056-2057. Plausible mechanism with palladium migration: O O O O Ac Ac [Pd] + [Pd]-H O O HCl O O Ac Ac [Pd] [Pd] [Pd] L L Pd Cl O O O Cl [Pd] Ac Ac Ac O O [Pd] [Pd] HCl 18 Extension to Non-Stabilized Enolates Wang, X., Pei, t., Han, X.