Chiral Cyclopentadienyls: Enabling Ligands for Asymmetric Rh(III)-Catalyzed C-H Functionalizations

Transition-metal catalyzed C-H functionalizations became a complementary and efficient bond-forming strategy over the past decade. In this respect, Cp*Rh(III) complexes have emerged as powerful catalysts for a broad spectrum of reactions giving access to synthetically versatile building blocks. Despite their high potential, the corresponding catalytic enantioselective transformations largely lag behind. The targeted transformations require all the remaining three coordination sites of the central rhodium atom of the catalyst. In consequence, the chiral information on a competent catalyst can only by stored in the cyclopentadienyl unit. The lack of suitable enabling chiral cyclopentadienyl (Cp-x) ligands is the key hurdle preventing the development of such asymmetric versions. In this respect, an efficient set of chiral Cp-x ligands useable with a broad variety of different transition-metals can unlock substantial application potential. This Account provides a description of our developments of two complementary classes of C-2-symmetric Cp-x derivatives. We have introduced a side- and back-wall concept to enforce chirality transfer onto the central metal atom. The first generation consists of a fused cyclohexane unit having pseudo axial methyl groups as chiral selectors and a rigidifying acetal moiety. The second ligand generation derives from an atrop-chiral biaryl-backbone and which possesses adjustable substituents at its 3,3'-positions. Both ligand families can be modulated in their respective steric bulk to adjust for the specific needs of the targeted application. The cyclopentadienes can be metalated under standard conditions. The corresponding chiral rhodium(I) ethylene complexes are relatively air and moisture and represent storable stable precatalysts for the targeted asymmetric Rh(III)-catalyzed C-H functionalizations. These complexes are then conveniently oxidized in situ by dibenzoyl peroxide to give the reactive (CpRh)-Rh-x(III)(OBz)(2) species. For instance, this catalyst is used for directed C-H activations of aryl hydroxamates and the subsequent enantioselective trapping with olefins, providing dihydroisoquinolones in very high enantioselectivities. In addition, we have established highly selective intramolecular trapping reactions with tethered higher substituted alkenes giving dihydrobenzofurans with quaternary stereogenic centers. Concerning intermolecular reactions, allene coupling partners allow for an enantioselective hydroarylation yielding substituted allylated compounds. A trapping process of the cyclometalated intermediate with diazo reactants enables the enantioselective construction of isoindolinones. Moreover, the catalysts can be used for the construction of atropchiral biaryl motives using a dehydrogenative Heck-type reaction. The development of flexibly adjustable chiral Cp-x ligands is described in this Account showcasing their applicability for a variety of Rh(III) catalyzed CH functionalization reactions. These Cp-x derivatives hold promise as powerful steering ligands for further transition-metals used in asymmetric catalysis.

New polynuclear catalysts for atom-transfer radical addition reactions

Laurent Quebatte

Homo- and heterobimetallic complexes of the late transitions metals have been synthesized by metathesis reactions of the corresponding chloro-bridged dimers. These reactions have the advantage of being fast and giving rise to structurally defined products in quantitative yield. Complexes with three chloro-bridges of the general formula [LM(μ-Cl)3RuLm] (LM = (arene)Ru, CpIr, or CpRh; RuLm = RuCl(PPh3)2 or RuCp*) were investigated in detail and several of these were structurally characterized. Evidence is provided that triply bridged complexes of this kind can undergo fast exchange reactions. The complexes with the fragment {RuCl(PPh3)2} were found to catalyze atom-transfer radical addition (ATRA) reactions. Structurally related complexes with chelating 1,4-bis(diphenylphosphino)butane (dppb) or 1,4-bis(dicyclohexylphosphino)butane (dcypb) ligands instead of the two PPh3 ligands could likewise be generated. A total of 69 different combinations were prepared and tested in a combinatorial fashion for their ability to catalyze the ATRA of CCl4 to styrene. Two combinations were found to be remarkably active and the corresponding complexes [CpRh(μ-Cl)3RuCl(PPh3)2] and [{(tpc)Rh(μ-Cl)3Ru(dcypb)}2(μ-N2)] were identified and structurally characterized. They proved to be among the most active catalysts described so far. Other ATRA catalysts were investigated. The cationic complex [CpRu(PPh3)2-(CH3CN)]OTf was found to display a higher stability than the related neutral catalyst [Cp*RuCl(PPh3)2]. Total TONs of up to 890 for the addition of CHCl3 to styrene were obtained at a temperature of only 40°C. For the first time, ATRA reactions are reported using a mixture of [(arene)RuCl2]2 and PCy3 as the catalyst precursors. As a product of the reaction between [(C6H3iPr3)-RuCl2]2 and PCy3, the tetranuclear complex [{(C6H3iPr3)Ru(μ-Cl)3RuCl(PCy3)}2(μ-N2)] was isolated, which itself proved to be highly active. When the arene and the N2 ligands of the latter were exchanged for a cymene ligand and an ethylene ligand, respectively, the resulting binuclear complex [(cymene)Ru(μ-Cl)3RuCl(PCy3)(η2-C2H4)] was obtained. It proved to be even more efficient than the dinitrogen complex and allowed the Kharasch addition of CCl4 to 1-olefins to be carried out at a temperature as low as 0°C. The observed TOFs (1100 h-1 at 24°C and 1550 h-1 at 40°C) are comparable to those reported for the most active catalysts.

EPFL2006

Developing Reactions of Strained Rings

Daniele Perrotta

Carbo- and heterocyclic structures containing nitrogen-substituted stereocenters are recurrent structural motifs in natural and bioactive compounds, therefore constituting a privileged class of synthetic targets. In this regard, substituted three- and four-membered carbocycles are powerful building blocks. Activation by a catalyst allows for an efficient exploitation of their ring strain, enabling a large variety of transformations. In particular, activation via oxidative addition by transition metals has been widely applied in annulations of these rings. Another common mode of activation consists in the use of Lewis acids to promote heterolytic ring opening of electron-poor strained rings, among which donor-acceptor cyclopropanes and cyclobutanes stand out for their well-established and broad chemistry. In this thesis, intermolecular annulations of three-membered carbocycles via oxidative addition by transition metals were first investigated. We mainly focused on the use of aminocyclopropanes as well as more strained aminomethylidenecyclopropanes. Despite a broad screening of transition metal complexes and modifications of the cyclopropane structure, no desired product could be formed. The use of aminomethylidene cyclopropanes in Lewis acid catalyzed intermolecular annulations was also studied. Employing aldehydes as reaction partners delivered highly functionalized 2-aminotetrahydrofurans. Instead, the use of all-carbon dipolarophiles for the synthesis of carbocycles was not successful. Subsequently, we explored enantioselective transformations of donor-acceptor cyclopropanes. We first investigated a new Lewis acid catalyzed DYKAT of donor-acceptor aminocyclopropanes with 2-siloxyfurans as dipolarophiles. After a thorough optimization, the desired product could be obtained in high er. However, the yield was not satisfactory, and any attempt to improve it by modifying the structure of the aminocyclopropane or by screening additives and reaction conditions was unsuccessful. On the other hand, we succeeded in the development of the first Lewis Acid catalyzed enantioselective desymmetrization of donor-acceptor meso-diaminocyclopropanes. The methodology consists in a copper(II) catalyzed Friedel-Crafts alkylation of indoles and a pyrrole, and delivers enantioenriched urea derivatives, which are recurrent structures in natural and bioactive compounds. The reaction tolerates electronically and sterically diverse substituents on the benzene ring of the indole. The choice of appropriate protecting groups on the cyclopropane was required to guarantee its solubility and to maintain good levels of enantioselectivity. The modification of an underexplored subclass of bisoxazoline ligands, bearing bulky diarylmethanol groups in alpha to the nitrogen atoms, was essential for obtaining high enantiomeric ratios, and led to the synthesis of several novel ligands. Finally, we developed Lewis acid catalyzed [4+2] annulations of donor-acceptor aminocyclobutanes with aromatic aldehydes, which afforded useful 2-aminotetrahydropyrans. A scandium catalyst was employed for the annulation of unsubstituted aminocyclobutanes, which delivered products in yields up to 95% and diastereoselectivities up to 17:1. On the other hand, one equivalent of a cheap and non-toxic iron Lewis acid was required for substituted aminocyclobutanes, which afforded densely functionalized six-membered heterocycles bearing three stereocenters in diastereoselectivities up to 5:1.

EPFL2018

Activation of small molecules promoted by multimetallic complexes supported by redox active ligands

Davide Toniolo

The activation of small molecule is a topic of high current interest. A variety of homogeneous end heterogeneous catalysts have been studied to be able to promote chemical transformation of industrial relevance under mild condition and therefore decrease the costs. Often the most performant catalysts are composed by rare and precious metals such as Pd, Pt, Rh, Ir, making the catalyst expensive and not suitable for large scale reactions. Lots of effort is put in researching ways to substitute precious and rare metal while keeping catalytic efficiency and selectivity. F-elements have shown to be able to perform many chemical transformations that are common to d-metals, promoting also in some cases unusual chemical reactivity. Differently from transition metals, f-elements present a unique coordina-tion chemistry, governed by electrostatic interaction with the ligand environment and steric constrain. During my PhD I focused my attention on the synthesis of highly reactive, low valent metal complex-es based of f-elements for the activation of small molecules. In particular, two main pathways have been followed to promote the multi-electrons transfer necessary for the transformation of the substrate: The first approach consists in the use of redox active ligands to support the metal centre and act as electron reservoir in order to increase the number of electrons exchanged during the reaction. This method has been used for d-, f- and d- mixed f-elements complexes, resulting to be an elegant way for the preparation of multimetallic compounds capable of promoting multi-electron transfer reaction. In the second approach, divalent classic lanthanides have been stabilized thanks to the bulky tris(tert-butoxide)siloxide ligand that resulted a to be a useful tool for the formation of highly reactive bimetal-lic complexes. The reactivity of the synthetized complexes towards small molecules such as CO2, CS2 and arenes has been tested, proving the ability of those compounds to act as multielectron reducing reagents. Moreo-ver, we proved that multidentate Schiff base ligands are capable of stabilizing low valent d-metal com-plexes allowing the formation bonding interaction between different metals with the enhancement of the magnetic properties.

EPFL2020