OC4 2.1 Polar Catalysis Slides - Palladium WiSe 2024 PDF

John J. Molloy Fortgeschrittene Synthesemethoden OC4 Winter Semester 2024⁄2025 1  2. Polar – Catalysis 2.1 Palladium Catalysis 2.2 C-H Activation 2.3 Olefin Metathesis 2.4 Organocatalysis 2 2.1 Pa...

John J. Molloy Fortgeschrittene Synthesemethoden OC4 Winter Semester 2024⁄2025 1  2. Polar – Catalysis 2.1 Palladium Catalysis 2.2 C-H Activation 2.3 Olefin Metathesis 2.4 Organocatalysis 2 2.1 Palladium Catalysis 2.1.1 Elementary Steps 2.1.2 General Mechanism 2.1.3 Suzuki-Miyaura Reaction 2.1.4 Stille, Hiyama, Kumada, Negishi 2.1.5 Sonogashira Reaction 2.1.6 Heck Reaction 2.1.7 Buchwald-Hartwig Reaction 2.1.8 Tsuji-Trost Reaction 3  2.1 Palladium Catalysis Importance of Catalysis The synthesis of organic molecules is highly important in a number of research areas Medicinal Chemistry Agrochemicals Materials Catalysis is essential for the continued production of many products used in society Ø Allows reactions to be performed easier Ø Enables products to be made cheaper and faster There are three major fields of catalysis in organic chemistry: Transition metal catalysis Organocatalysis Enzymatic (bio)catalysis 4  2.1 Palladium Catalysis Importance of palladium catalysis While other metals have similar reactivity and many benefits over palladium (cost, environmental impact, toxicity), palladium continues to be the number one metal catalyst of choice when constructing carbon-carbon or carbon-heteroatom bonds. This is due to a number of reasons: Operationally simple Reliable – Many methods exist High functional group tolerance Selective (Chemo, regio, stereo) In a recent review of the medicinal chemistry literature, >40% of C-C bonds were made by a Suzuki- Miyaura reaction, just one of a number of reactions. Nobel Prize in Chemistry in 2010. Suzuki Negishi Heck 5  2.1 Palladium Catalysis 2.1.1 Elementary Steps Homogeneous palladium catalysis typically involves two-electron redox cycles, where the palladium metal centre changes between 0 and +2 oxidation state at various stages of the catalytic cycle. Palladium can also access +3 and +4 oxidation states under highly oxidising conditions. These states are referred to as high-valent palladium. 6 2.1 Palladium Catalysis 7 2.1 Palladium Catalysis 8 2.1 Palladium Catalysis 9  2.1 Palladium Catalysis 2.1.2 General Mechanism 10  2.1 Palladium Catalysis 2.1.2.1 Generating Pd(0) from Pd (II) Pd(0) is the active catalyst for many cross-coupling reactions. Can be more convenient to prepare Pd(0) in situ from Pd(II). Pd(0) is required for the cross-coupling reactions – how do you prepare Pd(0) from Pd(II)? 11  2.1 Palladium Catalysis 2.1.2.1 Generating Pd(0) from Pd (II) 12  2.1 Palladium Catalysis 2.1.2.1 Generating Pd(0) from Pd (II) 13  2.1 Palladium Catalysis 2.1.2.1 Generating Pd(0) from Pd (II) Buchwald generated a series of precatalysts to allow rapid formation of Pd(0). Now commercial. Mechanism proceeds via reductive elimination to form a relatively electron rich Pd(0) species. Significantly improves cross-coupling by forming the active palladium species faster. This can aid cross-coupling reactions where the coupling partners are unstable. 14 Buchwald, Chem. Sci. 2013, 4, 916-920  2.1 Palladium Catalysis 2.1.2.2 Oxidative Addition 15  2.1 Palladium Catalysis 2.1.2.2 Oxidative Addition 16  2.1 Palladium Catalysis 2.1.2.3 Transmetallation 17  2.1 Palladium Catalysis 2.1.2.4 Reductive Elimination 18  2.1 Palladium Catalysis 2.1.3 Suzuki-Miayura Reaction Reviews: (a) Suzuki, Che 95, 2457. (b) Danishefsky, Angew. C Ed. 2001, 40, 4544. (c) Sasaki, Synlett 2004, (d) Miyaura, Top. Curr. Ch 11. Use of R-Cl: (a) Fu, Angew. Ch 1998, 37, 3387. (b) Fu, J. Am. Chem. Soc. 2000, 122 Role of base: (a) Soderquis Chem. 1998, 63, 461. (b) Kishi, J. Am. Chem. Soc. 1987 (c) Wright, J. Org. Chem. 1994 (d) Thompson, J. Org. Chem. 1984 19  2.1 Palladium Catalysis 2.1.3.1 Mechanism a) Amatore, Jutand, Chem. Eur. J. 2011, 17, 2492. (b) Hartwig, J. Am. Chem. 20 Soc. 2011, 133, 2116. (c) Schmidt, Russ. J. Gen. Chem. 2011, 81, 1573. (d)  2.1 Palladium Catalysis 2.1.3.2 Boron Reagents A variety of boron reagents can be used in the Suzuki-Miyaura reaction (Mainly esters and acids). Lloyd-Jones, Chem. Soc. Rev. 2014, 43, 412-443 21  2.1 Palladium Catalysis 2.1.3.2 Boron Reagents Molander, Acc. Chem. Res. 2007, 40, 275. 2.1.3.3 Iterative Synthesis (a) Burke, J. Am. Chem. Soc. 2007, 129, 6716.(b) Burke, J. Am. Chem. Soc. 2008, 22 130, 466.(c) Burke, J. Am. Chem. Soc. 2008, 130, 14084.  2.1 Palladium Catalysis Burke, Science 2015, 347, 1221. 2.1.3.3 Iterative Synthesis 23  2.1 Palladium Catalysis 2.1.3.4 Bulky Phosphine Ligands Initially coupling of aryl chlorides was not successful in the SM reaction. The use of bulky electron rich ligands generates a coordinatively unsaturated palladium complex which can readily undergo oxidative addition. The less saturated palladium complex can also enable oxidative addition even with sterically hindered aryl halides. Senanayake, Angew. Chem. Int. Ed. 2010, 49, 5879. 24 2.1 Palladium Catalysis 25  2.1 Palladium Catalysis 2.1.4 Stille, Hiyama, Kumada, Negishi 2.1.4.1 Stille Reaction Reviews: (a) Farina, Org. React. 1998, 50, 1. (b) Stille, Angew. Chem., Int. Ed. Engl. 1986, 25, 508. 26  2.1 Palladium Catalysis 2.1.4.1 Stille Reaction 27  2.1 Palladium Catalysis 2.1.4.2 Hiyama Reaction Review: Hiyama, Top. Curr. Chem. 2002, 28 219, 61.  2.1 Palladium Catalysis 2.1.4.2 Hiyama Reaction 29  2.1 Palladium Catalysis 2.1.4.3 Kumada Reaction Review: Tamao, Top. Curr. Chem. 2002, 219, 30 1.  2.1 Palladium Catalysis 2.1.4.3 Kumada Reaction 31  2.1 Palladium Catalysis 2.1.4.4 Negishi Reaction Reviews: (a) Negishi, Acc. Chem. Res. 1982, 15, 340. (b) Stanforth, Tetrahedron 1998, 54, 263 32 (c) Lessene, Aust. J. Chem. 2004, 57, 107.  2.1 Palladium Catalysis 2.1.4.4 Negishi Reaction Williams, J. Am. Chem. Soc. 1998, 120, 11198. 33  2.1 Palladium Catalysis 2.1.4.4 Negishi Reaction 34  2.1 Palladium Catalysis 2.1.4.5 Carbonylation Carrying out the reaction under an atmosphere of carbon monooxide allows carbonyl insertion into the Pd-C bond prior to transmetallation and reductive elimination. Synthesis of ketone products. Martin, Org. Lett. 2008, 10, 5301. 35  2.1 Palladium Catalysis 2.1.4.5 Carbonylation Past Paper Question (Klausur 2015) 36  2.1 Palladium Catalysis 2.1.4.5 Carbonylation Solution 37  2.1 Palladium Catalysis 2.1.5 Sonogashira Reaction The Sonogashira reaction employs terminal alkynes as the coupling partner in a dual catalytic system using copper to generate a copper acetylide. Reviews: Sonogashira, J. Organom Chem 2002, 653, 46 Chinchilla, Chem. Rev. 2007, 107, 87 38  2.1 Palladium Catalysis 2.1.5 Sonogashira Reaction 39  2.1 Palladium Catalysis 2.1.6 Heck First publications: (a) Mizorok Bull. Chem. Soc. Jpn. 1971, 44, 581. (b) Heck, J. Org. Chem. 1972, 37, 2320. Reviews: (a) Belestkaya, Chem. Rev. 2000, 100, 3009. 40 (b) Overman, Chem. Rev. 2000, 100, 2945. (c) Cabri, Acc. Chem. Res. 1995, 28, 2.  2.1 Palladium Catalysis 2.1.6 Heck 41  2.1 Palladium Catalysis 2.1.6 Heck A closer look at the mechanism of neutral and cationic Heck.. 42  2.1 Palladium Catalysis 2.1.6 Heck A closer look at the mechanism of neutral and cationic Heck.. 43  2.1 Palladium Catalysis 2.1.6 Heck A closer look at the mechanism of neutral and cationic Heck.. 44  2.1 Palladium Catalysis 2.1.6 Heck When it is not possible for the Pd(II) intermediate to become syn-coplanar to a β-hydride, other pathways (cascade processes) can become available. 45  2.1 Palladium Catalysis 2.1.6 Heck When it is not possible for the Pd(II) intermediate to become syn-coplanar to a β-hydride, other pathways (cascade processes) can become available. de Meijere, Tetrahedron Lett. 1996, 52, 11545. 46  2.1 Palladium Catalysis 2.1.6 Heck Β-hydride elimination is reversible. The products can undergo “alkene walking”-positional isomerization to form the most stable product. 47  2.1 Palladium Catalysis 2.1.6 Heck Pfaltz, Synthesis 1997, 1338. Keay, J. Am. Chem. Soc. 1996, 108, 10766. 48  2.1 Palladium Catalysis 2.1.6 Heck 49  2.1 Palladium Catalysis 2.1.6 Heck 50  2.1 Palladium Catalysis 2.1.7 Buchwald-Hartwig Reaction Reviews: (a) Buchwald, Angew. Chem. Int. Ed. 2008, 47, 6338. (b) Hartwig, Synlett 2006, 1283. 51 2.1 Palladium Catalysis 52  2.1 Palladium Catalysis 2.1.8 Tsuji-Trost Reaction Reviews: Chem. Rev. 2003, 103, 2921; Acc. Chem. Res. 2000, 33, 336. 53  2.1 Palladium Catalysis 2.1.8 Tsuji-Trost Reaction 2.1.8.1 Regioselectivity 54  2.1 Palladium Catalysis 2.1.8 Tsuji-Trost Reaction 2.1.8.1 Regioselectivity In some instances, a switch in ligand or nucleophile can alter regioselectivity to favour the branched product. However, typically this is more readily achieved using alternative transition metal catalysts such as molybdenum or iridium. 55  2.1 Palladium Catalysis 2.1.8.2 Stereoselectivity – From Predefined Stereochemistry 56  2.1 Palladium Catalysis 2.1.8.2 Stereoselectivity – From Predefined Stereochemistry Trost, J. Am. Chem. Soc. 1980, 102, 5979. Negishi, J. Chem. Soc., Chem. Commun. 1982, 160. 57  2.1 Palladium Catalysis 2.1.8.3 Stereoselectivity – Use of Chiral Ligands The process is compatablie with a chiral ligand on palladium – allows asymmetric reactions J. Am. Chem. Soc. 1992, 114, 9327. Acc. Chem. Res. 2000, 33, 336. Pure Appl. Chem. 1988, 60, 7. Example: Stolz, Chem. Asian J. 2007, 2, 1476 58  2.1 Palladium Catalysis 2.1.8.3 Stereoselectivity – Use of Chiral Ligands 59 Trost, J. Am. Chem. Soc. 2005, 127, 17180; Trost, Krische, J. Am. Chem. Soc. 1996, 118, 6297;