Jan Streuff

Direct synthesis of bicyclic guanidines through unprecedented palladium(ii) catalysed diamination with copper chloride as oxidant.

Palladium catalysed intramolecular guanidine transfer to alkenes can be accomplished with copper chloride as the oxidant to give bicyclic guanidines with complete selectivity and in high yields.

A palladium-catalysed enolate alkylation cascade for the formation of adjacent quaternary and tertiary stereocentres

The catalytic enantioselective synthesis of densely functionalized organic molecules that contain all-carbon quaternary stereocentres is a challenge to modern chemical methodology. The catalytically controlled, asymmetric α-alkylation of ketones represents another difficult task and is of major interest to our and other research groups. We report here a palladium-catalysed enantioselective process that addresses both problems simultaneously and allows the installation of vicinal all-carbon quaternary and tertiary stereocentres at the α-carbon of a ketone in a single step. This multiple bond-forming process is carried out on readily available β-ketoester starting materials and proceeds by conjugate addition of a palladium enolate, generated in situ, to activated Michael acceptors. As a result, the CO2 moiety of the substrate is displaced by a C–C fragment in an asymmetric cut-and-paste reaction with high yield, diastereomeric ratio and enantiomeric excess. The selective construction of multiple adjacent stereocentres is an important challenge for synthetic organic methodology, and only a handful of catalytic methods exist that can forge adjacent quaternary and tertiary stereocentres. Here, a palladium-catalysed multiple-bond-forming cascade leads to the construction of such systems in high yield, diastereomeric ratio and enantiomeric excess.

Intramolecular Diamination of Alkenes with Palladium(II)/Copper(II) Bromide and IPy2BF4: The Role of Halogenated Intermediates

The oxidative intramolecular diamination of alkenes with tethered ureas and related groups as the nitrogen source has been investigated both with the iodonium reagent IPy(2)BF(4) (Py=pyridine) and under palladium catalysis in the presence of copper(II) bromide as a reoxidant. For terminal alkenes, the two procedures enable selective and high-yielding transformations. Studies with deuterated material led to the conclusion that the reactions proceed through different stereochemical pathways. An advanced protocol for palladium-catalyzed diamination through six-membered-ring annulation was also developed, and the first examples of the intramolecular diamination of internal alkenes are described. In this case, the same stereochemical outcome was observed for the iodonium-promoted and palladium-catalyzed transformations. On this basis, it was possible to determine the importance of aminohalogenated intermediates in both diamination reactions. Overall, the disclosed procedures broaden significantly the synthetic applicability of the oxidative intramolecular diamination of alkenes.

Synthesis of Diamino Carboxylic Esters by Palladium‐Catalyzed Oxidative Intramolecular Diamination of Acrylates

Unligated palladium(II) salts catalyze the oxidative diamination of acrylic esters to yield 2,3-diamino carboxylic esters. The reaction employs copper(II) bromide as oxidant and proceeds with good to excellent stereoselectivities and complete chemoselectivity. Preliminary mechanistic studies provide evidence for the involvement of a direct amination of the C--Pd bond in the alpha position relative to the ester group. This protocol significantly broadens the overall scope of the palladium-catalyzed diamination of alkenes and represents the first direct diamination of functionalized nonterminal substrates. The reaction yields readily protected 2,3-diamino acid derivatives, which can be considered as highly functionalized building blocks for subsequent synthesis. The use of one of these new diamination products as a suitable starting material in a short synthesis of the alkaloid absouline is demonstrated as an example.

Enantioselective Titanium(III)-Catalyzed Reductive Cyclization of Ketonitriles†

Reduction, please! The title reaction affords α-hydroxyketones, a common structural motif in biologically active natural products, in good yields and high enantioselectivities at room temperature. The commercially available ansa-titanocene 1 was found to be an efficient catalyst for this process, which presumably proceeds by addition of a ketyl radical to a nitrile.

Metal-free diamination of alkenes employing bromide catalysis

A unique metal-free intramolecular diamination of alkenes based on bromide catalysis is reported that uses only potassium bromide and sodium chlorite avoiding any use of transition metal. This unprecedented halide catalysis is of general applicability, uses economic reagents, can be conveniently up-scaled and proceeds under mild and selective conditions that surpass all conventional transition metals in scope.

First palladium- and nickel-catalyzed oxidative diamination of alkenes: Cyclic urea, sulfamide, and guanidine building blocks*

We recently reported the first catalytic diamination of alkenes. This protocol calls for the use of Pd(II) as catalyst in combination with PhI(OAc)2 as terminal oxidant and furnishes the final diamines as cyclic ureas. It consists of an unprecedented two-step reaction of aminopalladation and Csp3-N-bond formation involving a Pd(IV) species. Introduction of Ni(II) catalysts for homogeneous oxidation allows for an efficient diamination with sulfamides, which lead to convenient liberation of the free diamines. In related protocols, the substrate scope of the diamination has been broadened to the formation of cyclic guanidines.

Metal-Catalyzed β-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,β-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 todays developments.

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.

Mechanism of the TiIII-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.