Andreas Gansäuer

Catalytic, Highly Regio- and Chemoselective Generation of Radicals from Epoxides: Titanocene Dichloride as an Electron Transfer Catalyst in Transition Metal Catalyzed Radical Reactions

Sensitive functional groups like halides, ketones, or tosylates pose no difficulties in the new, [Cp2TiCl2]-catalyzed, radical reaction [Eq. (1)]. The conversions proceed with excellent chemoselectivity, which in many cases is complementary to that of established reactions.

Reductive C–C Bond Formation after Epoxide Opening via Electron Transfer

This review presents a description of the C–C bond-forming reactions that have emerged in the field of titanocene mediated or catalyzed epoxide opening over the last 5 years or so. The powerful tandem sequences for polycylization will be especially emphasized.

A Catalytic Enantioselective Electron Transfer Reaction: Titanocene-Catalyzed Enantioselective Formation of Radicals from meso-Epoxides.

A rationally designed titanium(III) catalyst allows the opening of epoxides with high enantioselectivity. This reaction [Eq. (1)] constitutes the first example of an enantioselective transition metal catalyzed radical reaction that proceeds by electron transfer.

Catalytic, Atom‐Economical Radical Arylation of Epoxides

The development of efficient catalytic reactions is one of the central aspects of chemistry and arguably the most important for the invention of novel sustainable processes. Radicalbased transformations are among the most attractive methods for use in catalytic cycles owing to the ease of radical generation, high functional group tolerance, and selectivity in C C bond formation. Herein we present such a process, an atom-economical titanocene-catalyzed intramolecular arylation of epoxide-derived radicals. Our approach exploits the innate capability of the titanocene(III)/(IV) redox couple to undergo reversible electron-transfer reactions. This allows the implementation of both oxidative additions and reductive eliminations in single-electron steps into catalytic cycles. The key step of our method is presumed to be a proton-coupled electron transfer (PCET). It constitutes the pivotal single-electron reductive elimination, provides the driving force for efficient rearomatization of the radical s-complex, and negates the need for sacrificial co-reductants or oxidants necessary in radical-based chain processes or catalytic reactions. This issue is critical in Minisci reactions, radical additions to electron deficient heteroarenes, which often require stoichiometric amounts of metal (Fe, Ag) salts and oxidants (H2O2 or organic peroxides). More recently, significant progress towards more sustainable radical arylation has been reported by Heinrich et al. In these reactions, aryl diazonium salts are employed as radical precursors. Nevertheless, titanium trichloride has to be employed in stoichiometric amounts for radical generation in rather acidic media (aqueous HCl). Our catalytic cycle is shown in Scheme 1. It is initiated by the single-electron oxidative addition of [Cp2TiCl] to the substrate generating radical intermediate A. Addition of the

Catalytic enantioselective radical cyclization via regiodivergent epoxide opening.

A catalytic enantio- and diastereoselective radical cyclization using a regiodivergent epoxide opening (REO) for radical generation is described. It is demonstrated for the first time that the diastereoselectivity of cyclizations of acyclic radicals can be controlled catalytically. Building blocks for important applications in stereoselective synthesis are readily accessed.

Catalysis via homolytic substitutions with C-O and Ti-O bonds: oxidative additions and reductive eliminations in single electron steps.

In a combined theoretical and experimental study, an efficient catalytic reaction featuring epoxide opening and tetrahydrofuran formation through homolytic substitution reactions at C-O and Ti-O bonds was devised. The performance of these two key steps of the catalytic cycle was studied and could be adjusted by modifying the electronic properties of the catalysts through introduction of electron-donating or -withdrawing substituents to the titanocene catalysts. By regarding both steps as single electron versions of oxidative addition and reductive elimination, a mechanism-based platform for the design of catalysts and reagents for electron transfer reactions evolved that opens broad perspectives for further investigations.

Ti‐Catalyzed Barbier‐Type Allylations and Related Reactions

Titanocene(III) complexes, easily generated in situ from commercial Ti(IV) precursors, catalyze Barbier-type allylations, intramolecular crotylations (cyclizations), and prenylations of a wide range of aldehydes and ketones. The reaction displays surprising and unprecedented mechanistic subtleties. In cyclizations a fast and irreversible addition of an allyl radical to a Ti(III)-coordinated carbonyl group seems to occur. Intermolecular additions to conjugated aldehydes proceed through a coupling of a Ti(IV)-bound ketyl radical with an allyl radical. Reactions of ketones with allylic halides take place by the classical addition of an allylic organometallic reagent. The radical coupling processes enable transformations such as the highly regioselective alpha-prenylation that are otherwise difficult to achieve. The mild reaction conditions and the possibility to employ titanocene complexes in only catalytic quantities are highly attractive features of our protocol. These unusual properties have been taken advantage of for the straightforward synthesis of the natural products rosiridol, shikalkin, and 12-hydroxysqualene.

Titanocene‐Catalysed Electron Transfer‐Mediated Opening of Epoxides

The use of epoxides as substrates for radical reactions via electron transfer is described. The discussion of the evolution of stoichiometric reagents focuses on recent developments in the field of titanocene(III) reagents. Special attention is devoted to the emergence of catalytic conditions for this useful procedure that has led to the discovery of reagent-controlled radical reactions by variations of the cyclopentadienyl ligands.

Sustainable radical reduction through catalytic hydrogen atom transfer.

A system with coupled catalytic cycles is described that allows radical reduction by hydrogen atom abstraction from rhodium hydrides. These intermediates are generated from H2 activation by Wilkinsons catalyst. Radical generation is carried out by titanocene-catalyzed electron transfer to epoxides.

Unprecedented Barbier-type reactions catalysed by titanocene(III)

Selective Barbier-type allylations, benzylations and propargylations of aldehydes and ketones can be carried out under extremely mild conditions employing titanocene(III) complexes as catalysts. In this way, chiral titanocene catalysts provided yields ranging from 50-80% of optically active products.