Ring Walking Mediated by Ni-Ni Species as a Vehicle for Enabling Distal C(sp)-H Functionalization of Aryl Pivalates.

Herein, we report the utilization of Ni-Ni species as a manifold for enabling a "ring-walking" event by dynamic translocation of the metal center over the arene backbone. Experimental and computational studies support a translocation occurring via a 1,2-hydride shift. The synthetic applicability of the method is illustrated in a series of C-C bond formations that occur at distal C(sp)-H sites of simple aryl pivalates.

Synthesis of 1,2-diaminotruxinic δ-cyclobutanes by BF-controlled [2 + 2]-photocycloaddition of 5(4)-oxazolones and stereoselective expansion of δ-cyclobutanes to give highly substituted pyrrolidine-2,5-dicarboxylates.

The irradiation of ()-4-arylidene-5(4)-oxazolones 1a-1u with blue light (465 nm) in the presence of the photosensitizer [Ru(bpy)](BF) (2.5 mol%) and the Lewis acid BF·OEt (2 equiv.) in deoxygenated methanol at room temperature affords the corresponding 1,2-diaminotruxinic cyclobutane bis-amino esters 2a-2u stereoselectively as the δ-isomer.

Mechanistic studies of the palladium-catalyzed S,O-ligand promoted C-H olefination of aromatic compounds.

Pd-catalyzed C-H functionalization reactions of non-directed substrates have recently emerged as an attractive alternative to the use of directing groups. Key to the success of these transformations has been the discovery of new ligands capable of increasing both the reactivity of the inert C-H bond and the selectivity of the process. Among them, a new type of S,O-ligand has been shown to be highly efficient in promoting a variety of Pd-catalyzed C-H olefination reactions of non-directed arenes.

Four-Step Synthesis of (-)-4-epi-Presilphiperfolan-8α-ol by Intramolecular Iron Hydride Atom Transfer-Mediated Ketone-Alkene Coupling and Studies to Access trans-Hydrindanols with a Botryane Scaffold.

From an (R)-(+)-pulegone-derived building block that incorporates the stereo-defined tertiary carbon bearing a methyl group, as found in the targeted sesquiterpenoid, a four-step synthesis of (-)-4-epi-presilphiperfolan-8-α-ol was achieved. The key processes involved are a ring-closing metathesis leading to a bridged alkene-tethered ketone and its subsequent Fe -mediated metal-hydride atom transfer (MHAT) transannular cyclization. This synthetic method, implying an irreversible addition of a carbon-centered radical upon a ketone by means of a hydrogen atom transfer upon the alkoxy radical intermediate, was also applied in the synthesis of trans-fused hydrindanols structurally related to botrydial compounds.

Organocatalytic Enantioselective α-Nitrogenation of α,α-Disubstituted Aldehydes in the Absence of a Solvent.

A highly efficient enantioselective α-nitrogenation method of α,α-disubstituted aldehydes with azodicarboxylates promoted by a chiral carbamate-monoprotected cyclohexa-1,2-diamine as organocatalyst has been developed. The process was carried out without any solvent, and the corresponding α,α-disubstituted α-nitrogenated aldehydes were obtained with excellent yields and enantioselectivities up to 99% . The sustainability of the procedure was established through the calculation of green metrics, such as EcoScale and E-factor.

Synthesis of the ABC Ring of Calyciphylline A-Type Alkaloids by a Stereocontrolled Aldol Cyclization: Formal Synthesis of (±)-Himalensine A.

A synthetic approach to a functionalized ABC-tricyclic framework of calyciphilline A-type alkaloids, a building block toward this class of alkaloids, is reported. The key synthetic steps involve a radical cyclization to form the hydroindole system and piperidine ring closure through a stereocontrolled aldol cyclization. The resulting alcohol allows the methyl group to be installed in the bowl-shaped azatricyclic structure; this crucial reaction takes place with configuration retention.

Conformational Flexibility as a Tool for Enabling Site-Selective Functionalization of Unactivated C-O Bonds in Cyclic Acetals.

A dual catalytic manifold that enables site-selective functionalization of unactivated C-O bonds in cyclic acetals with aryl and alkyl halides is reported. The reaction is triggered by an appropriate σ*-p orbital overlap prior to C-O cleavage, thus highlighting the importance of conformational flexibility in both reactivity and site selectivity. The protocol is characterized by its excellent chemoselectivity profile, thus offering new vistas for activating strong C-O linkages.

An Expedient Method for the Umpolung Coupling of Enols with Heteronucleophiles.

In this paper, we present an unprecedented and general umpolung protocol that allows the functionalization of silyl enol ethers and of 1,3-dicarbonyl compounds with a large range of heteroatom nucleophiles, including carboxylic acids, alcohols, primary and secondary amines, azide, thiols, and also anionic carbamates derived from CO . The scope of the reaction also extends to carbon-based nucleophiles. The reaction relies on the use of 1-bromo-3,3-dimethyl-1,3-dihydro-1λ [d][1,2]iodaoxole, which provides a key α-brominated carbonyl intermediate.

Gold(I)-Catalyzed Cycloisomerization/Hetero-Diels-Alder Reaction/Ring Opening Cascade to Functionalized Cyclopentadienes.

Six- and seven-membered ring-fused, functionalized cyclopentadienes can be obtained in moderate to excellent yields by a cascade process entailing the Au(I)-catalyzed propargyl Claisen rearrangement/Nazarov cyclization of propargyl vinyl ethers, the hetero-Diels-Alder reaction with dialkylazodicarboxylates, and the spontaneous conversion of cycloaddition products into cyclopentadienes by a highly regioselective cleavage of a C-N bond. Depending on the treatment of the crude reaction mixtures, two types of products can be obtained: cyclopentadienes with pendant hydrazine and aldehyde moieties that intramolecularly react to form hemiaminals are obtained in 43-52% overall yields when the crude reaction mixtures are left over KCO in a DCM solution. Instead, by reducing the aldehyde group just after addition of the heterodienophile, the regioselective C-N bond cleavage generates the corresponding cyclopentadienes bearing a hydrazine and an alcohol appendage in excellent yields (66-82%) over four steps, all in one pot.

Synthesis of Cyclometalated Gold(III) Complexes via Catalytic Rhodium to Gold(III) Transmetalation.

A catalytic method to synthesize a broad array of cyclometalated (C^N)gold(III) complexes is reported here. An unprecedented Rh-to-Au transmetalation allows the facile transfer of (C^N) ligands between these two metals in a redox-neutral process. The reaction employs commercially available precursors and proceeds under mild and environmentally benign conditions.

Stereoselective, Ruthenium-Photocatalyzed Synthesis of 1,2-Diaminotruxinic Bis-amino Acids from 4-Arylidene-5(4)-oxazolones.

The irradiation of ()-2-phenyl-4-aryliden-5(4)-oxazolones in deoxygenated CHCl at 25 °C with blue light (465 nm) in the presence of [Ru(bpy)](BF) (5% mole ratio) as a triplet photocatalyst promotes the [2+2] photocycloaddition of the C═C bonds of the 4-arylidene moiety, thus allowing the completely regio- and stereoselective formation of cyclobutane-bis(oxazolone)s as single stereoisomers. Cyclobutanes have been unambiguously characterized as the μ-isomers and contain two -oxazolones coupled in an -head-to-head form. The use of continuous-flow techniques in microreactors allows the synthesis of cyclobutanes in only 60 min, compared with the 24-48 h required in batch mode.

Stereoselective Alkylation of Chiral Titanium(IV) Enolates with -Butyl Peresters.

Here, we present a new stereoselective alkylation of titanium(IV) enolates of chiral -acyl oxazolidinones with -butyl peresters from Cα-branched aliphatic carboxylic acids, which proceeds through the decarboxylation of the peresters and the subsequent formation of alkyl radicals to produce the alkylated adducts with an excellent diastereoselectivity. Theoretical calculations account for the observed reactivity and the outstanding stereocontrol. Importantly, the resultant compounds can be easily converted into ligands for asymmetric and catalytic transformations.

Zinc Iodide Catalyzed Synthesis of Trisubstituted Allenes from Terminal Alkynes and Ketones.

A straightforward, user-friendly, efficient protocol for the one pot, ZnI-catalyzed allenylation of terminal alkynes with pyrrolidine and ketones, toward trisubstituted allenes, is described. Trisubstituted allenes can be obtained under either conventional heating or microwave irradiation conditions, which significantly reduces the reaction time. A sustainable, widely available, and low-cost metal salt catalyst is employed, and the reactions are carried out under solvent-free conditions.

Unexpected metal-free synthesis of trifluoromethyl arenes tandem coupling of dicyanoalkenes and conjugated fluorinated sulfinyl imines.

A novel strategy for the synthesis of policyclic trifluoromethyl arenes has been devised. It involves a DBU-promoted tandem cycloaromatization reaction of dicyanoalkenes and fluorinated conjugated sulfinyl imines. This unprecedented transformation is a metal-free and air-tolerant process that takes place from readily available starting materials under mild reaction conditions.

Indium(III)-Catalyzed Stereoselective Synthesis of Tricyclic Frameworks by Cascade Cycloisomerization Reactions of Aryl 1,5-Enynes.

The indium(III)-catalyzed cascade cycloisomerization reaction of 1,5-enynes with pendant aryl nucleophiles is reported. The reaction proceeds in cascade under mild reaction conditions, using InI (5 mol %) as a catalyst with a range of 1,5-enynes furnished with aryl groups (phenyl and phenol) at alkene ( and Z isomers) and with terminal and internal alkynes. Using 1-bromo-1,5-enynes, a one-pot sequential indium-catalyzed cycloisomerization and palladium-catalyzed cross-coupling with triorganoindium reagents were developed.

Pentannulation of N-heterocycles by a tandem gold-catalyzed [3,3]-rearrangement/Nazarov reaction of propargyl ester derivatives: a computational study on the crucial role of the nitrogen atom.

The tandem gold(I)-catalyzed rearrangement/Nazarov reaction of enynyl acetates in which the double bond is embedded in a piperidine ring was computationally and experimentally studied. The theoretical calculations predict that the position of the propargylic acetate substituent has a great impact on the reactivity. In contrast to our previous successful cyclization of the 2-substituted substrates, where the nitrogen favors the formation of the cyclized final product, the substitution at position 3 was computed to have a deleterious effect on the electronic properties of the molecules, increasing the activation barriers of the Nazarov reaction.

Au-Catalyzed Hydroalkynylation of Haloalkynes.

The Au-catalyzed reaction between terminal alkynes and aromatic haloalkynes proceeds through divergent pathways depending on the nature of the catalyst counteranion. Thus, cationic complexes containing strongly basic NHC ligands and noncoordinating anions such as BAr catalyze the cis haloalkynylation of the terminal alkyne, whereas introduction of a weakly basic triflate counteranion results in the stereoselective hydroalkynylation of the haloalkyne, yielding haloenyne products in good yields and complete trans selectivity. Experimental and computational studies suggest that the hydroalkynylation reaction takes place via nucleophilic attack of the terminal alkyne to the C2 carbon of the activated haloalkyne, assisted by a concerted proton abstraction by the triflate, and that the protodeauration is the turnover-limiting step, in agreement with an observed primary kinetic isotope effect.

Intramolecular Palladium(II)-Catalyzed 6- C-H Alkenylation Directed by the Remote -Protecting Group: Mechanistic Insight and Application to the Synthesis of Dihydroquinolines.

A protocol for the Pd(II)-catalyzed C-H alkenylation reaction of substituted -allylanilines via an unusual 6- process has been developed. A density functional theory (DFT) study of the mechanistic pathway has shown that the coordination of the remote protecting group to the palladium center is determinant for the control of the regioselectivity in favor of the 6- process. The reaction would proceed via prior activation of the alkene.

Stereoselective Decarboxylative Alkylation of Titanium(IV) Enolates with Diacyl Peroxides.

Simple treatment of chiral titanium(IV) enolates with diacyl peroxides produces highly diastereoselective decarboxylative alkylations to efficiently deliver the corresponding adducts, most of which are not accessible through any of the current alkylating procedures. Such an unprecedented alkylation proceeds through an SET process that triggers the decomposition of the peroxide into a carbon-centered radical that finally combines with the resulting Cα radical. The procedure has been applied to the enantioselective synthesis of arundic acid.

Oxidant speciation and anionic ligand effects in the gold-catalyzed oxidative coupling of arenes and alkynes.

The mechanism of the gold-catalyzed oxidative cross-coupling of arenes and alkynes has been studied in detail combining stoichiometric experiments with putative reaction intermediates and DFT calculations. Our data suggest that ligand exchange between the alkyne, the Au(i)-catalyst and the hypervalent iodine reagent is responsible for the formation of both an Au(i)-acetylide complex and a more reactive "non-symmetric" I(iii) oxidant responsible for the crucial Au(i)/Au(iii) turnover. Further, the reactivity of the generated Au(iii)-acetylide complex is governed by the nature of the anionic ligands transferred by the I(iii) oxidant: while halogen ligands remain unreactive, acetato ligands are efficiently displaced by the arene to yield the observed Csp-Csp cross-coupling products through an irreversible reductive elimination step.

An umpolung strategy to react catalytic enols with nucleophiles.

The selective synthesis of α-functionalized ketones with two similar enolizable positions can be accomplished using allylic alcohols and iridium(III) catalysts. A formal 1,3-hydrogen shift on allylic alcohols generates catalytic iridium-enolates in a stereospecific manner, which are able to react with electrophiles to yield α-functionalized ketones as single constitutional isomers. However, the employment of nucleophiles to react with the nucleophilic catalytic enolates in this chemistry is still unknown.

Brønsted Base Catalyzed One-Pot Synthesis of Stereodefined Six-Member Carbocycles Featuring Transient Trienolates and a Key Intramolecular 1,6-Addition.

A catalyst-driven one-pot reaction sequence is developed for the enantio- and diastereoselective synthesis of tetrasubstituted cyclohexenes from simple unsaturated ketones or thioesters. The method involves a tertiary amine/squaramide-catalyzed α-selective addition of transiently generated trienolates to nitroolefins, subsequent base-catalyzed double bond isomerization, and an intramolecular (vinylogous) 1,6-addition reaction, a rare key carbocyclization step that proceeded with essentially perfect stereocontrol.

α-Branched Ketone Dienolates: Base-Catalysed Generation and Regio- and Enantioselective Addition Reactions.

In this study, the unique capacity of bifunctional Brønsted bases to generate α-branched ketone dienolates and control both site- and stereoselectivity of their addition reactions to representative classes of carbon electrophiles (i.e., vinyl sulfones, nitroolefins, formaldehyde) is documented.