Photoinduced Ring-Opening and Phototoxicity of an Indolin-3-one Derivative.

The study of a fluorescent indolin-3-one derivative is reported that, as opposed to its previously described congeners, selectively undergoes photoactivated ring-opening in apolar solvents. The excited state involved in this photoisomerization was partially deactivated by the formation of singlet oxygen. Cell studies revealed lipid droplet accumulation and efficient light-induced cytotoxicity.

Catalytic Asymmetric ß-Oxygen Elimination.

A catalytic enantioselective ß-O-elimination reaction is reported in the form of a zirconium-catalyzed asymmetric opening of meso-ketene acetals. Furthermore, a regiodivergent ß-O-elimination is demonstrated. The reaction proceeds under mild conditions, at low catalyst loadings, and produces chiral monoprotected cis-1,2-diols in good yield and enantiomeric excess. The combination with a Mitsunobu reaction or a one-pot hydroboration/Suzuki reaction sequence then gives access to additional diol and aminoalcohol building blocks. A stereochemical analysis supported by DFT calculations reveals that a high selectivity in the hydrozirconation step is also important for achieving high enantioselectivity, although it does not constitute the asymmetric step. This insight is crucial for the future development of related asymmetric ß-elimination reactions.

A Titanium-Catalyzed Reductive α-Desulfonylation.

A titanium(III)-catalyzed desulfonylation gives access to functionalized alkyl nitrile building blocks from α-sulfonyl nitriles, circumventing traditional base-mediated α-alkylation conditions and strong single electron donors. The reaction tolerates numerous functional groups including free alcohols, esters, amides, and it can be applied also to the α-desulfonylation of ketones. In addition, a one-pot desulfonylative alkylation is demonstrated. Preliminary mechanistic studies indicate a catalyst-dependent mechanism involving a homolytic C-S cleavage.

Kilian Muñiz (1970-2020).

Kilian Muñiz passed away unexpectedly on March 16th, 2020, at the age of only 49. Kilian was a leading figure in the field of catalytic (di-)amination reactions. He will be remembered as one of the finest, most passionate chemists, a dear colleague, and, most of all, as a close friend.

Titanium(III)-Catalyzed Reductive Decyanation of Geminal Dinitriles by a Non-Free-Radical Mechanism.

A titanium-catalyzed mono-decyanation of geminal dinitriles is reported. The reaction proceeds under mild conditions, tolerates numerous functional groups, and can be applied to quaternary malononitriles. A corresponding desulfonylation is demonstrated as well. Mechanistic experiments support a catalyst-controlled cleavage without the formation of free radicals, which is in sharp contrast to traditional stoichiometric radical decyanations. The involvement of two TiIII species in the C-C cleavage is proposed, and the beneficial role of added ZnCl2 and 2,4,6-collidine hydrochloride is investigated.

Reductive C-O, C-N, and C-S Cleavage by a Zirconium Catalyzed Hydrometalation/ß-Elimination Approach.

A zirconium catalyzed reductive cleavage of Csp3 and Csp2 carbon-heteroatom bonds is reported that makes use of a tethered alkene functionality as a traceless directing group. The reaction is successfully demonstrated on C-O, C-N, and C-S bonds and proposed to proceed via a hydrozirconation/ß-heteroatom elimination sequence of an in situ formed zirconium hydride catalyst. The positional isomerization of the catalyst further enables the cleavage of homoallylic ethers and the removal of terminal allyl and propargyl groups.

Strategies for the Synthesis of Chiral Carbon-Bridged Group†IV ansa-Metallocenes.

This minireview provides a survey of the various synthetic approaches to chiral ansa-metallocenes of Ti, Zr, and Hf containing a carbon-based bridge. The individual strategies to install substitution patterns at either the cyclopentadienyl framework or the bridging unit are highlighted with focus on the progress made towards a direct preparation of single complex stereoisomers. The review further includes the discussion of potential problems such as the formation of undesired diastereomers, the threat of racemization of enantiopure material, and synthetic challenges originating from the synthesis, purification, and isolation of the target complexes. The review has been written with the goal in mind to facilitate the design and synthesis of new chiral ansa-metallocene derivatives for emerging research areas in asymmetric catalysis and organometallic chemistry.

Development, Scope, and Applications of Titanium(III)-Catalyzed Cyclizations to Aminated N-Heterocycles.

The exceptionally mild conditions of a titanium(III)-catalyzed cyclization reaction paired with a convenient acid/base extraction have enabled the straightforward synthesis, isolation, and direct N-functionalization of amino heterocycles such as 3-aminoindoles and -pyrroles. The unprotected heterocycles are ideal building blocks for the installation of aminated indoles and pyrroles into target molecules, but their sensitivity has previously impeded their synthesis by modern catalytic methods. This full paper presents the development and extended scope of the new cyclization methodology. The transformation of the products into fused bis-indoles is also demonstrated along with the discovery of an unusual palladium-catalyzed reductive biphenyl coupling reaction. The titanium(III)-catalyzed cyclization has also been applied to the synthesis of substituted 3-iminoindolines, which are of potential interest for applications in natural product synthesis and exhibit tunable blue-to-green fluorescence properties.

A Unified Approach to Customized Chiral Carbon-Bridged ansa-Metallocenes.

Chiral ansa-metallocenes are privileged catalysts for a range of stereoselective transformations. Their synthesis, however, has remained a tremendous challenge, which has prevented a broad and systematic exploration for applications in synthesis and catalysis. A modular approach to such ansa-metallocenes that enables a facile modification of the ring substitution and the ligand bridge, as well as the introduction of various core metals, is described. The complexes were formed with good rac-selectivity and could be isolated with high purity. The strength of the approach was demonstrated by the synthesis of several new and previously known complexes, including a unique helical chiral ansa-metallocene. Using a chiral ligand, a moderate central-to-planar chirality transfer was observed.

Understanding titanium-catalysed radical-radical reactions: a DFT study unravels the complex kinetics of ketone-nitrile couplings.

The computational investigation of a titanium-catalysed reductive radical-radical coupling is reported. The results match the conclusions from an earlier experimental study and enable a further interpretation of the previously observed complex reaction kinetics. Furthermore, the interplay between neutral and cationic reaction pathways in titanium(iii)-catalysed reactions is investigated for the first time. The results show that hydrochloride additives and reaction byproducts play an important role in the respective equilibria. A full reaction profile is assembled and the computed activation barrier is found to be in reasonable agreement with the experiment. The conclusions are of fundamental importance to the field of low-valent titanium catalysis and the understanding of related catalytic radical-radical coupling reactions.

Catalytic Reductive Synthesis and Direct Derivatization of Unprotected Aminoindoles, Aminopyrroles, and Iminoindolines.

A titanium(III)-catalyzed radical cyclization to unprotected 3-aminoindoles, 3-aminopyrroles, or 3-iminoindolines is reported. The reaction is non-hazardous, scalable, and allows facile isolation of the free products by extraction. The method is demonstrated on a large substrate scope and it further allows the direct installation of various nitrogen protecting groups or the synthesis of building blocks for peptide chemistry in a single sequence. Fused bisindoles can be directly accessed from the cyclization products.

Direct conjugate alkylation of α,ß-unsaturated carbonyls by Ti(III)-catalysed reductive umpolung of simple activated alkenes.

The titanium(iii)-catalysed cross-selective reductive umpolung of Michael-acceptors represents a unique direct conjugate ß-alkylation reaction. It allows the cross-selective preparation of 1,6- and 1,4-difunctionalised building blocks without the requirement of stoichiometric organometallic reagents. In this full paper, the development and scope of the titanium(iii)-catalysed cross-selective reductive umpolung of Michael-acceptors is described. Based on the observed selectivities and additional mechanistic experiments a refined mechanistic proposal is presented.

Mechanism of the Ti(III)-Catalyzed Acyloin-Type Umpolung: A Catalyst-Controlled Radical Reaction.

The titanium(III)-catalyzed cross-coupling between ketones and nitriles provides an efficient stereoselective synthesis of α-hydroxyketones. A detailed mechanistic investigation of this reaction is presented, which involves a combination of several methods such as EPR, ESI-MS, X-ray, in situ IR kinetics, and DFT calculations. Our findings reveal that C-C bond formation is turnover-limiting and occurs by a catalyst-controlled radical combination involving two titanium(III) species. The resting state is identified as a cationic titanocene-nitrile complex and the beneficial effect of added Et3N·HCl on yield and enantioselectivity is elucidated: chloride coordination initiates the radical coupling. The results are fundamental for the understanding of titanium(III)-catalysis and of relevance for other metal-catalyzed radical reactions. Our conclusions might apply to a number of reductive coupling reactions for which conventional mechanisms were proposed before.

Metal-Catalyzed ß-Functionalization of Michael Acceptors through Reductive Radical Addition Reactions.

Transition-metal-catalyzed radical reactions are becoming increasingly important in modern organic chemistry. They offer fascinating and unconventional ways for connecting molecular fragments that are often complementary to traditional methods. In particular, reductive radical additions to α,ß-unsaturated compounds have recently gained substantial attention as a result of their broad applicability in organic synthesis. This Minireview critically discusses the recent landmark achievements in this field in context with earlier reports that laid the foundation for today's developments.

A Titanium(III)-Catalyzed Reductive Umpolung Reaction for the Synthesis of 1,1-Disubstituted Tetrahydroisoquinolines.

A catalytic reductive C1-acylation of 3,4-dihydroisoquinolines is presented that gives direct access to 1,1-disubstituted tetrahydroisoquinolines. The reaction is a titanium(III)-catalyzed reductive umpolung process in which nitriles act as effective acylation agents. The method is highly chemo- and regioselective and is demonstrated in 20 examples. It is well-suited for the large-scale synthesis of functionalized tetrahydroisoquinoline products, which is exemplified in the form of a six-step synthesis of (±)-3-demethoxyerythratidinone.

Titanium-catalyzed reductive umpolung reactions with a metal-free terminal reducing agent.

A new method for titanium-catalyzed reductive umpolung reactions is reported that overcomes the traditional requirement for a stoichiometric metallic reductant. With N,N'-disilylated tetramethyldihydropyrazine as a potent organic reducing agent, reductive carbonyl-nitrile, enone-acrylonitrile and pinacol coupling reactions can be achieved in good yields and stereoselectivities. [Cp2TiI2] is a superior catalyst to [Cp2TiCl2], which is rationalized by a faster generation of the active catalyst [Cp2TiI]. A mechanism is proposed that is in agreement with the experimental results.

Synthesis of bridged benzazocines and benzoxocines by a titanium-catalyzed double-reductive umpolung strategy.

A sequence of two titanium(III)-catalyzed reductive umpolung reactions is reported that allows the rapid construction of benzazo- and benzoxozine building blocks. The first step is a reductive cross-coupling of quinolones or chromones with Michael acceptors. This reaction proceeds with complete syn-selectivity for the quinolone functionalization while the anti-diastereomers are obtained as the major products from chromones. With different reaction conditions, the stereochemical outcome can be altered to afford the syn-chromanone products as well. A subsequent reductive ketyl radical cyclization forges the tricyclic title compounds in good yields. A stereochemical model explaining the observed stereoselectivities is provided and the product configurations were unambiguously verified by X-ray analyses and 2D NMR spectroscopic experiments.

Reductive umpolung reactions with low-valent titanium catalysts.

The coupling of similarly polarized carbon fragments can be achieved by a reductive umpolung strategy. This gives access to compounds with functional groups in even bond distances, which are difficult to synthesize by other means. Low-valent titanium catalysts enable such couplings under mild conditions. This account covers the recent progress on this topic with a focus on the development of cross-selective coupling reactions and stereoselective examples.

The cross-selective titanium(III)-catalysed acyloin reaction.

A titanium(III)-catalysed intermolecular reductive coupling of ketones or imines with nitriles is described, which gives direct access to α-hydroxylated and α-aminated ketones. This coupling reaction is cross-selective and a catalytic version of the classical acyloin condensation. A reaction mechanism that is supported by first DFT calculations is discussed.