Cu

Cu-Bindungen Cu-H Cu-C Cu-O Cu-F CuI Enthalpie (kJ/mol) 228 „250“ 269 413 217 Elektronegativität 1.90 Pauling Ion coordination type Radius / pm Cu(I) 4-coordinate, tetrahedral 74 Cu(II) 71 4-coordinate, square-planar 6-coordinate, octahedral 91 87 Cu(III) 68

Sandmeyer Reaktion 1884 Cu(I) katalysiert durch Single Electron Transfer die Bildung der Arylradikales. Durch Reaktion mit dem Nukleophil (CuX2) wird Cu(I) regeneriert

2x SET oder Cu(I)->Cu(III)

Cu – Organyle: Cuprate unlöslich in Et2O Zugabe von Li-Organyl zu Cu-X Inverse Zugabe Generelles Problem der Cuprate: Löslichkeit Cuprate höherer Ordnung

Cuprate Me4Cu2Li2 180° Monomer

Cuprate in Aktion Cuprate sauerstoffempfindlich temperaturlabil =>Tieftemperatur

Cuprate in Aktion ? ?

Cuprate in Aktion Säurelabiles Ketal Tosylat: E2 versus SN2

Cuprate in Aktion In THF geringere Selektivität Et2O: Li als Lewissäure

Cuprate in Aktion Vinylkation, benzylisch sp-Hybrid: linear

Cuprate in Aktion Lineares sp-Vinylkation nicht zugänglich

Cuprate in Aktion HMPA

Cuprate in Aktion R2CuLi immer ein R für den Müll? => Dummy Liganden

Cuprate in Aktion 17 Stufen 1 Jahr Arbeit Cu-Acetylid wird favorisiert durch: Rückbindung Azidität Löslichkeit

Cuprate in Aktion Kein HMPA!

Cyano-Cuprate in Aktion SN‘

Cyano-Cuprate

Cuprate höherer Ordnung Normale Cuprate: R2CuLi Cuprate höherer Ordnung R3CuLi2 R3Cu2Li .....

Höhere Cyano-Cuprate in Aktion Mesityloxid sterische Hinderung

Eglington pKa = 29 Stabil, schwerlöslich sp Hybrid => linear Reduktive Eliminierung

Glaser

Eglington/Glaser Produkte Pd(II) führt schneller zum gleichen Produkt (bei RT!) => häufig unerwünschte Reaktion durch Pd- oder Cu-Kontaminierung

Schutz vor Eglington/Glaser Destillation => Cu/Pd-frei Die Kontaminierung mit Cu oder Pd ist durch LC an Kieselgel nicht leicht zu entfernen Gleichgewicht: Aceton flüchtig

Sonogashira sp-sp2 Kupplung Reduktive Eliminierung Oxidative Addition Sonogashira, K.Tet. Lett. 1975, 4467 Transmetallierung

Sonogashira Kupplung Wässriges NH3! A. Mori Chem. Lett. 2002, 756

Journal of the Chemical Society, Perkin Transactions 1: Organic and Bio-Organic Chemistry 1998, (3), 561-568

Cu-freie Sonogashira CuI 1 mmol 0.0025 € PtBu3 1mmol 2,46 € W.A. Hermann EuJOC 2000, 3679

Wacker Prozess 1956 Synthese von Acetaldehyd aus Ethylen

Wacker Prozess Quadratisch planarer Pd-Alken-p-Komplex trans-Chlorid ist stabiler. Aber nur der syn-Komplex kann oxopalladieren Pd(II) entspricht ungefähr H+ => Markovnikov Orientierung b-Hydrideliminierung erfolgt auschliesslich synplanar

Palladium- und Kupfer- katalysierte Aminierung Kupplung von Alkylaminen und Aryl-Iodiden

Voltaren® = Diclofenac Umsatz 2001 > 1 Mill €

Alkyl-/Arylaminierung Reduktive Aminierung => R = Alkyl Synthese durch SNAr? Inkompatibel mit vielen funktionellen Gruppen

Ullmann C-N Kupplung Drastische Reaktionsbedingungen

Traditionelle C-N Verknüpfung Addition von Aminen an Aren Intermediate Regioisomere Direkte SNAr von Arylhalogeniden grosser Reagenzüberschuss hochpolare Lösungsmittel hohe Reaktionstemperatur hochaktivierte Aromaten

Hartwig-Buchwald Aminierung 1995 Palladium-katalysierte Aminierung von Arylhalogeniden und -triflaten X = I, Br, Cl, OTf Base = KOBut, Cs2CO3 L = PPh3, BINAP, PBut3

Buchwald-Aminierung BINAP: 2,2'-Bis-diphenylphosphanyl-[1,1']binaphthalenyl Hinderung der Biphenylrotation für zu stabilen Rotameren => Enantiomere Rotamere = Atropisomerie Oxidative Addition Reduktive Eliminierung Ligandenaustausch

Buchwald-Aminierung Oxidative Addition Reduktive Eliminierung Ligandenaustausch

C-N Kreuzkupplung ist nützlich, aber... Substrate mit funktionellen Gruppen: NH oder OH am Arylhalogenid, machen Probleme (Redox, Chelate) Pd-katalysierte Reaktionen sind empfindlich: O2 und H2O Pd ist teuer

Kupfer-katalysierte Aminierung 2001 Milde Methode: O2-stabiles CuI as catalyst, Ethylenglycol als Ligand und technisches Isopropanol als Solvens

Einfluss des Diol-Liganden

Optimale Reaktionsbedingungen Katalysatoren: CuI oder CuOAc K3PO4 oder Cs2CO3 als Base 2-Propanol oder n-Butanol

Aryliodidide mit Benzylaminen

Einfacher Zugang zu 6-Aminoimidazol[1,2-a]pyridinen

Sharpless Asymmetrische Dihydroxylierung (AD) Gehört die überhaupt zur Metallorganik? http://www.scripps.edu/chem/sharpless/research/ad.html

AD development 1912 Hofmann catalytic, “diastereoselective”, NaClO3 1936 Criegee 3+2 mechanism of dihydroxylation 1942 Criegee LAC - Ligand Acceleration Effect of pyridine 1976 VanRheenen Upjohn process: NMO as oxidant 1980 Sharpless/Hentges ee%, stoichiometric 1988 Sharpless/Jacobsen ee%, catalytic 1990 Tsuji K3Fe(CN)6 Tit took some time to develop the AD as we know it today, starting from Hofmann’s catalytic dihydroxylation in 1912. Here are some hallmarks of the reaction. The Sharpless gap from 1980 to 1988 was caused by the tremendous success story of the asymmetric epoxidation, which gave a number of other groups a chance to come up with non-catalytic auxiliaries.

Ligands However, during a sabbatical at CaltechBarry Sharpless had some free time free to think over the lingering problem and asked Jacobsen to readdress the issue. He took Hentges ligand, Upjohn’s NMO and thus it took off.

AD-Mechanismus? [3+2] L [2+2] DDG points to two different enantioselective pathways, which is at first glance inconsistant with a concerted mechanism Isotope effects 3+2 Michaelis Menten kinetics => intermediate in LAC DDG => 2 pathways in LAC DV# = -12 ml/mol (3+2: -25 ml/mol) ligand free

AD - katalytischer Zyklus OX - L H2O Biphasic System is absolutely crucial MeSO2NH solves the problem for 1,2 disubstituted, and trisubstituted, but not for 1,1 ´-di- or mono substituted olefins Slow addition

The optimum structure of stilbene with OsO4-DHQD2PHAL

Mnemonic Devices b a SE NE NW SW Dihydroquinidine N O R b a SE NE NW DHDQ2-PHAL DHQ2-PHAL SW Mnemonic Devices Phthalazine Anthraquinone For those of us who care less about the mechanism but rather care about what they can use the reaction for. Here all important Mnemonic Device N Dihydroquinine

LIGAND SAR Little contribution 10% Ligand 2 % K2OsO5 Large No effect Erythro only 10% Ligand 2 % K2OsO5 Large contribution on rate no effect on binding SPOS Enhances binding and rate aromates enhance binding and rate

OXIDANTS K3Fe(CN)6 K3Fe(CN)6 catalytic via anodic oxidation tBuOOH lower ee% H2O2 even lower ee% K2SO5 Here I am happy to bring some of my own, yet unpublished work to your attention. Generally Jacobsen’s epoxidation and AD complement rather well

AD - Commercial Ligands $/g AD-mixa/b 50g 75 SFr 2 SFr/mmol PHAL PYR DHQ Aldrich 33,649-1 17$ Aldrich 33,648-3 Fluka 53959 58$ Aldrich 39,273-1 Aldrich 41,897-8 71 $ Fluka 53951 DHQD

Daumenregeln PYR PHAL PHAL IND PHAL PHAL PYR PHAL Ligand ee% 30-97 70-97 Jacobsen 20-80 90-99.8 90-99 20-97

Die Grenzen der AD-Reaktion 98 PYR 88 PYR 83 PHAL 74 PHAL 52 PHAL 98 PHAL 66 PHAL 61 PHAL

Limitations Cis-olefins are among the only class of substrates for which no examples exceeding 90% ee have been produced. Terminal olefins with small substituents give low ee's. 8-15 membered rings !mnemonic! Cyclic Enol-ethers DHChiNic 74% yield 92% ee Lit. 70-80% ee Here I am happy to bring some of my own, yet unpublished work to your attention. Generally Jacobsen’s epoxidation and AD complement rather well

AA - Asymmetric Aminohydroxylation regioselectivity The Asymmetric Aminohydroxylation involves the conversion of a properly substituted alkene to an amino alcohol. Osmium tetroxide is used as a catalyst and one of the various cinchona ligands is used to enantioselectively deliver the the heteroatoms to the olefin. The cinchona ligands are responsible for not only enantioselectivity, they also improve regio- and chemoselectivity. Water is used as an oxygen source, and there are several possible nitrogen sources. http://www.scripps.edu/chem/sharpless/research/aa.html

AA - Asymmetric Aminohydroxylation PHAL AQN The Asymmetric Aminohydroxylation involves the conversion of a properly substituted alkene to an amino alcohol. Osmium tetroxide is used as a catalyst and one of the various cinchona ligands is used to enantioselectively deliver the the heteroatoms to the olefin. The cinchona ligands are responsible for not only enantioselectivity, they also improve regio- and chemoselectivity. Water is used as an oxygen source, and there are several possible nitrogen sources. http://www.scripps.edu/chem/sharpless/research/aa.html

AA - Selectivity The ratio of of the two constitutional isomers is dependant largely on the substrate, but the regioselectivity can be controlled to a degree by using the appropriate solvent and ligand. (vide infra) Facial selectivity can be determined using the simple mnemonic adopted from the AD reaction.

AA - Mechanism regioselectivity ligand free Various chloramine salts can be used as the nitrogen source. Sulfonamides, amides, carbamates, and various amino-heterocycles can all be used. A good general rule is that the smaller the nitrogen source, the more selective the reaction. Enantiomeric excesses are generally between 60% and 99% for the sulfonamide variant, and between 80% and 99% for the carbamamte and amide variant. It was found that water increases catalytic turnover, thus not only increasing the rate of reaction, but also the enantiomeric excess, as the second, racemic catalytic cycle is largely avoided.

AA - Nitrogen Sources 3 equivalents 1.1 equivalents amino-heterocycles Various chloramine salts can be used as the nitrogen source. Sulfonamides, amides, carbamates, and various amino-heterocycles can all be used. A good general rule is that the smaller the nitrogen source, the more selective the reaction. Enantiomeric excesses are generally between 60% and 99% for the sulfonamide variant, and between 80% and 99% for the carbamamte and amide variant. It was found that water increases catalytic turnover, thus not only increasing the rate of reaction, but also the enantiomeric excess, as the second, racemic catalytic cycle is largely avoided. While the sulfonamide variant is easier to run, the ee's are generally lower than the carbamate and amide variants. The smaller the nitrogen source, the higher the enantioselectivity (Chloramine-M > Chloramine-T)