transition-metal-catalyzed decarboxylative coupling november 13, 2007 dino alberico

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  • Transition-Metal-Catalyzed Decarboxylative Coupling

    November 13, 2007

    Dino Alberico

  • Decarboxylative CouplingDecarboxylative Biaryl CouplingDecarboxylative Heck-Type Coupling

  • Biaryl CompoundsNatural ProductsPharmaceuticalsAgrochemicalsLigandsPAHLiquid Crystals

  • Biaryl Formation Using Transition MetalsX, Y: I, Br, Cl, OTf, ONs, B, Sn, Si, Zn, Mg, HTransition Metal (either stoichiometric or catalytic): Cu, Ni, Pd, Pt, Ru, Rh, IrHassan, J.; Svignon, M.; Gozzi, C.; Schulz, E.; Lemaire, M. Chem. Rev. 2002, 102, 1359.

  • Ullmann CouplingKelly, T. R.; Xie, R. L. J. Org. Chem. 1998, 63, 8045. Ullmann, F.; Bielecki, J. Chem. Ber. 1901, 34, 2174.Example:Drawbacks: - stoichiometric amount of copper - high reaction temperatures - limited to symmetrical biaryls - unsymmetrical biaryl can be formed by using aryl halides of different reactivity but require a large excess of the activated aryl halide

  • Transition-Metal-Catalyzed Cross-CouplingLin, S.; Danishefsky, S. J. Org. Lett. 2000, 2, 2575.Suzuki CouplingStille CouplingSauer, J.; Heldmann, D. K.; Pabst, R. Eur. J. Org. Chem. 1999, 1, 313.

  • Transition-Metal-Catalyzed Cross-CouplingAmatore, C.; Jutand, A.; Negri, S.; Fauvarque, J.-F. J. Organomet. Chem. 1990, 390, 389. Bumagin, N. A.; Sokolova, A. F.; Beletskaya, I. P. Russ. Chem. Bull. 1993, 42, 1926.Hatanaka, Y.; Hiyama, T. Synlett 1991, 845.Negishi CouplingHiyama CouplingKumada Coupling

  • Direct ArylationCross-CouplingDirect ArylationChallenge: - how to arylate a typically unreactive aryl C-H bond - how to selectively arylate an aryl C-H bond 1. Alberico, D.; Scott, M. E.; Lautens, M. Chem. Rev. 2007, 107, 174. (Shameless Promotion)2. Seregin, I. V.; Gevorgyan, V. Chem. Soc. Rev. 2007, 36, 1173.

  • Direct ArylationBringmann, G.; Ochse, M.; Gtz, R. J. Org. Chem. 2000, 65, 2069. Intramolecular Direct ArylationExamples:Julie Ct, Shawn K. Collins

  • Direct ArylationOi, S.; Aizawa, E.; Ogino, Y.; Inoue, Y. J. Org. Chem. 2005, 70, 3113. Intermolecular Direct Arylation Using a Directing GroupExamples:Alexandre Larive, James Mousseau, Andr Charette

  • Direct ArylationPivsa-Art, S.; Satoh, T.; Kawamura, Y.; Miura, M.; Nomura, M. Bull. Chem. Soc. Jpn. 1998, 71, 467. Intermolecular Direct Arylation Electronic Bias of HeterocyclesExamples:Ohta, A.; Akita, Y.; Ohkuwa, T.; Chiba, M.; Fukunaga, R.; Miyafuji, A.; Nakata, T.; Tani, N.; Aoyagi, Y. Heterocycles, 1990, 31, 1951.

  • Cross-Coupling of Aromatic C-H SubstratesLi, X.; Hewgley, B.; Mulrooney, C.A.; Yang, J.; Kozlowski, M.C. J. Org. Chem. 2003, 68, 5500. Stuart, D. S.; Fagnou, K. Science 2007, 316, 1172.Stuart, D. S.; Villemure, E.; Fagnou, K. J. Am. Chem. Soc. 2007, 129, 12072.Dwight, T. A.; Rue, N. R.; Charyk, D.; Josselyn, R.; DeBoef, B.Org. Lett. 2007, 9, 3137. Hull, K. L.; Sanford, M. S. J. Am. Chem. Soc. 2007, 129, 11904.

  • Limitations to Aforementioned Transition-Metal Catalyzed Methodspreparation of organometallic partner can require several synthetic steps more solvents, more purifications, more time, higher costs, more harmful to the enviroment a stoichiometric amount of undesired, and sometimes toxic, organometallic by-product is produced- challenging to control regioselectivity for intermolecular direct arylation reactions of arenes, a directing group is needed; which may take several steps to introduce and then remove if not desired in the final product- challenging to control regioselectivity- large excess of one arene is needed- an excess of oxidant is needed (sometimes an organometallic reagent is used)

  • Aryl-Aryl Bond Formation via Decarboxylative CouplingAdvantages (for best case scenario): - aryl carboxylic acids are ubiquitous in nature - many are commercially available and inexpensive - easier to control regioselectivity - no extra steps are needed to introduce the acid moiety- fewer purifications- use of less solvent- less time - less energy wasted www.carbonfootprint.com- lower costs- more environmentally friendly - more environmentally friendly CO2 by-product (compared to toxic organometallic reagents) Albert Arnold (Al) Gore Jr.Nobel Peace Prize 2007Academy Award Winner 2007CO2 Sucks!Baudoin, O. Angew. Chem. Int. Ed. 2007, 46, 1373.Disadvantages:

  • Its Done in NatureEnzymatic decarboxylation of orotidine monophosphate (OMP), followed by protonation of the carbanionBegley, T. P.; Ealick, S. E. Curr. Opin. Chem. Biol. 2004, 8, 508.

  • Earlier Work Stoichiometric Transition MetalPeschko, C.; Winklhofer, C.; Steglich, W. Chem. Eur. J. 2000, 6, 1147.Nilsson, M. Acta Chem. Scand. 1966, 20, 423.

  • Catalytic Decarboxylative Coupling of Heteroaryl CarboxylatesEffect of the Additive:Forgione, P.; Brochu, M.-C.; St-Onge, M.; Thesen, K. H.; Bailey, M. D.; Bilodeau, F. J. Am. Chem. Soc. 2006, 128, 11350.

  • St-Onge Decarboxylative Coupling ReactionStarting Materials:Products:

  • Scope of the Aryl Bromide

  • Proposed Mechanism

  • Comparison of Regioselectivity with Direct Arylation

  • Decarboxylative Coupling of Aromatic CarboxylatesThese substrates were selected for optimization for two reasons:

    1. Reactants, products, and by-products can be detected by GC

    2. The product is a precursor to Boscalid (BASF)Goossen, L. J.; Deng, G.; Levy, L. M. Science 2006, 13, 662.Goossen, L. J.; Rodriguez, N.; Melzer, B.; Linder, C.; Deng, G.; Levy, L. M. J. Am. Chem. Soc. 2007, 129, 4824.

  • OptimizationOther Notable Reagents: Pd Source: PdCl2 Ligands: BINAP, P(Cy)3 Additives: KBr, NaF Base: Ag2CO3 Solvents: DMSO, DMPU, diglyme

  • Proposed Mechanism

  • Scope of Aryl Halide

  • Scope of Aryl CarboxylateStoichiometric Cu Conditions: Works well for a wide range of aryl carboxylic acids.

    Catalytic Cu Conditions: Only works with 2-nitro substituted aryl carboxylic acid.

  • Examining the DecarboxylationIn order to design an effective catalyst for a range of carboxylic acids, they examined the relative reactivity toward decarboxylation compared to 2-nitrobenzoic acid. Aryl-Aryl Coupling - Stoichiometric Cu: excellent yieldAryl-Aryl Coupling - Catalytic Cu: excellent yieldProtodecarboxylation - Catalytic Cu: excellent yieldDiscrepancies:Aryl-Aryl Coupling - Stoichiometric Cu: modest yieldAryl-Aryl Coupling - Catalytic Cu: no reactionProtodecarboxylation - Catalytic Cu: modest yield

  • Examining the Decarboxylation

  • More General Catalytic Copper Conditions

  • Application Synthesis of ValsartanBuhlmayer, P.; Furet, P.; Criscione, L.; de Gasparo, M.; Whitebread, S.; Schmidlin, T.; Lattmann, R.; Wood, J. Bioorg. Med. Chem. Lett. 1994, 4, 29.

  • Application Synthesis of Valsartan

    Goossen, L. J.; Melzer, B. J. Org. Chem. 2007, 72, 7473.

  • Application Synthesis of Valsartan

  • Decarboxylative Coupling of Electron-Rich Aryl CarboxylatesOther Reagents Examined: Catalyst Source: PdCl2(MeCN)2, Pd(O2CCF3)2, Pd(CN)2, Pd(OAc)2, Pd(dppf)2Cl2(CH2Cl2)2, Pd(PPh3)4, Pd2(dba)3, NiCl2(PPh3)2, Ni(acac)2 Ligands: BINAP, P(Cy)3, DavePhos, xanthphos Additives: LiBH4, LiCl, MgCl, CaCl2, CsCl, BiCl3, CuI Base: Li2CO3, Na2CO3, K2CO3, Cs2CO3, AgOAc, TMSOK Solvents: DMA, DMF, DMSO/DMF mixtures, sulfolaneBecht, J.-M.; Catala, C.; Le Drain, C.; Wagner, A. Org. Lett. 2007, 9, 1781. Optimization:

  • Scope of Aryl Carboxylate

  • Scope of Aryl Iodide

  • Decarboxylative Heck-Type Coupling

  • Heck-Mizoroki ReactionMizoroki, T.; Mori, K.; Ozaki, A. Bull. Chem. Soc. Jpn. 1971, 44, 581. Heck, R. F.; Nolley, J. P., Jr. J. Org. Chem. 1972, 37, 2320. Review: Beletskaya, I. P.; Cheprakov, A. V. Chem. Rev. 2000, 100, 3009. Example:Larson, R. D. et. al. J. Org. Chem. 1996, 61, 3398.

  • Mechanism of the Heck Reaction of Aryl Halides

  • Decarboxylative Heck-Type CouplingOptimized Conditions:Notes: - 5:95 DMSO/DMF is important - DMF alone or DMSO alone gave lower yields - at least one ortho substitutent is neededMyers, A. G.; Tanaka, D.; Mannion, M. R. J. Am. Chem. Soc. 2002, 124, 11250.

  • ScopeScope of Aryl Carboxylic Acid:Scope Of Alkene:

  • Side ReactionsImportance of 5% DMSO-DMFImportance of ortho substituentThese side reactions probably occur by a C-H insertion or ortho-palladation reaction

  • Arylation of 2-Cycloalken-1-onesTanaka, D.; Myers, A. G. Org. Lett. 2004, 6, 433.

  • Reaction of 2-Methyl-cyclopenten-1-one

  • Heck Reactions of Aryl Carboxylates vs Aryl Halidesineffective in decarboxylative Heck-type coupling

  • Mechanistic Studies Insight into the Decarboxylation StepHeck Reaction with Aryl Halides Oxidative Addition OccursHeck Reaction with Aryl Carboxylic Acids What Happens?Tanaka, D.; Romeril, S. P.; Myers, A. G. J. Am. Chem. Soc. 2005, 127, 10323.

  • Mechanistic Studies Insight into the Decarboxylation Step1H NMR StudiesAt 80 oC, A and B start disappearing and C forms.After 15 min at 80 oC, only C is observed.

  • Mechanistic Studies Insight into the Decarboxylation Step13C NMR StudiesAfter 8 min at 60 oC, C and 13CO2 observed

  • X-Ray of Palladium Intermediate

  • Proposed Mechanism for the Decarboxylation StepTrifluoroacetate Plays a Key Role in the Decarboxylative Palladation- an excess of NaO2CCF3 only slightly slowed the rate of decarboxylative palladation addition of 1.1 equiv of LiBr or nBu4NBr resu

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