An air- and moisture-stable ruthenium precatalyst for diverse reactivity.

Versatile, efficient and robust (pre)catalysts are pivotal in accelerating the discovery and optimization of chemical reactions, shaping diverse synthetic fields such as cross-coupling, C-H functionalization and polymer chemistry. Yet, their scarcity in certain domains has hindered the advancement and adoption of new applications. Here we present a highly reactive air- and moisture-stable ruthenium precatalyst [(tBuCN)5Ru(H2O)](BF4)2, featuring a key exchangeable water ligand. This versatile precatalyst drives an array of transformations, including late-stage C(sp2)-H arylation, primary/secondary alkylation, methylation, hydrogen/deuterium exchange, C(sp3)-H oxidation, alkene isomerization and oxidative cleavage, consistently outperforming conventionally used ruthenium (pre)catalysts. The generality and applicability of this precatalyst is exemplified through the potential for rapid screening and optimization of photocatalytic reactions with a suite of in situ generated ruthenium photocatalysts containing hitherto unknown complexes, and through the rapid discovery of reactivities previously unreported for ruthenium. The diverse applicability observed is suggestive of a generic platform for reaction simplification and accelerated synthetic discovery that will enable broader applicability and accessibility to state-of-the-art ruthenium catalysis.

Olefin Dihydroxylation Using Nitroarenes as Photoresponsive Oxidants.

Vicinal diols are abundant among natural and synthetic molecules, and also represent valuable intermediates throughout organic synthesis. Olefin dihydroxylation is an effective strategy to access these derivatives owing to the broad range and availability of alkene feedstocks. OsO4 is among the most used reagents to achieve this transformation, yet its high toxicity and cost remain concerning. Herein, we present a mechanistically distinct strategy for olefin dihydroxylation using nitroarenes as photoresponsive oxidants. Upon purple LEDs irradiation, these species undergo a [3+2]-photocycloaddition with a wide range of olefins to give stable 1,3,2-dioxazolidine intermediates. These species can be accumulated in solution and then reduced in situ to the desired diols, utilising readily accessible and easy to handle solid reagents as H2 surrogates.

Photoexcited nitroarenes for the oxidative cleavage of alkenes.

The oxidative cleavage of alkenes is an integral process that converts feedstock materials into high-value synthetic intermediates1-3. The most viable method to achieve this in one chemical step is with ozone4-7; however, this poses technical and safety challenges owing to the explosive nature of ozonolysis products8,9. Here we report an alternative approach to achieve oxidative cleavage of alkenes using nitroarenes and purple-light irradiation. We demonstrate that photoexcited nitroarenes are effective ozone surrogates that undergo facile radical [3+2] cycloaddition with alkenes. The resulting 'N-doped' ozonides are safe to handle and lead to the corresponding carbonyl products under mild hydrolytic conditions. These features enable the controlled cleavage of all types of alkenes in the presence of a broad array of commonly used organic functionalities. Furthermore, by harnessing electronic, steric and mediated polar effects, the structural and functional diversity of nitroarenes has provided a modular platform to obtain site selectivity in substrates containing more than one alkene.

A radical approach for the selective C-H borylation of azines.

Boron functional groups are often introduced in place of aromatic carbon-hydrogen bonds to expedite small-molecule diversification through coupling of molecular fragments1-3. Current approaches based on transition-metal-catalysed activation of carbon-hydrogen bonds are effective for the borylation of many (hetero)aromatic derivatives4,5 but show narrow applicability to azines (nitrogen-containing aromatic heterocycles), which are key components of many pharmaceutical and agrochemical products6. Here we report an azine borylation strategy using stable and inexpensive amine-borane7 reagents. Photocatalysis converts these low-molecular-weight materials into highly reactive boryl radicals8 that undergo efficient addition to azine building blocks. This reactivity provides a mechanistically alternative tactic for sp2 carbon-boron bond assembly, where the elementary steps of transition-metal-mediated carbon-hydrogen bond activation and reductive elimination from azine-organometallic intermediates are replaced by a direct, Minisci9-style, radical addition. The strongly nucleophilic character of the amine-boryl radicals enables predictable and site-selective carbon-boron bond formation by targeting the azine's most activated position, including the challenging sites adjacent to the basic nitrogen atom. This approach enables access to aromatic sites that elude current strategies based on carbon-hydrogen bond activation, and has led to borylated materials that would otherwise be difficult to prepare. We have applied this process to the introduction of amine-borane functionalities to complex and industrially relevant products. The diversification of the borylated azine products by mainstream cross-coupling technologies establishes aromatic amino-boranes as a powerful class of building blocks for chemical synthesis.

Reaction of Nitrogen-Radicals with Organometallics Under Ni-Catalysis: N-Arylations and Amino-Functionalization Cascades.

Herein, we report a strategy for the generation of nitrogen-radicals by ground-state single electron transfer with organyl-NiI species. Depending on the philicity of the N-radical, two types of processes have been developed. In the case of nucleophilic aminyl radicals direct N-arylation with aryl organozinc, organoboron, and organosilicon reagents was achieved. In the case of electrophilic amidyl radicals, cascade processes involving intramolecular cyclization, followed by reaction with both aryl and alkyl organometallics have been developed. The N-cyclization-alkylation cascade introduces a novel retrosynthetic disconnection for the assembly of substituted lactams and pyrrolidines with its potential demonstrated in the short total synthesis of four venom alkaloids.

A novel synthesis of N-hydroxy-3-aroylindoles and 3-aroylindoles.

A straightforward indole synthesis via annulation of C-nitrosoaromatics with conjugated terminal alkynones was realised achieving a simple, highly regioselective, atom- and step economical access to 3-aroylindoles in moderate to good yields. Further functionalizations of indole scaffolds were investigated and an easy way to JWH-018, a synthetic cannabinoid, was achieved.

Benzoate Cyclometalation Enables Oxidative Addition of Haloarenes at a Ru(II) Center.

The first Ru(II)-catalyzed arylation of substrates without a directing group was recently developed. Remarkably, this process only worked in the presence of a benzoate additive, found to be crucial for the oxidative addition step at Ru(II). However, the exact mode of action of the benzoate was unknown. Herein, we disclose a mechanistic study that elucidates the key role of the benzoate salt in the C-H arylation of fluoroarenes with aryl halides. Through a combination of rationally designed stoichiometric experiments and DFT studies, we demonstrate that the aryl-Ru(II) species arising from initial C-H activation of the fluoroarene undergoes cyclometalation with the benzoate to generate an anionic Ru(II) intermediate. The enhanced lability of this intermediate, coupled with the electron-rich anionic Ru(II) metal center renders the oxidative addition of the aryl halide accessible. The role of an additional (NMe4)OC(CF3)3 additive in facilitating the overall arylation process is also shown to be linked to a shift in the C-H pre-equilibrium associated with benzoate cyclometalation.

Cyclometallated ruthenium catalyst enables late-stage directed arylation of pharmaceuticals.

Biaryls are ubiquitous core structures in drugs, agrochemicals and organic materials that have profoundly improved many aspects of our society. Although traditional cross-couplings have made practical the synthesis of many biaryls, C-H arylation represents a more attractive and cost-effective strategy for building these structural motifs. Furthermore, the ability to install biaryl units in complex molecules via late-stage C-H arylation would allow access to valuable structural diversity, novel chemical space and intellectual property in only one step. However, known C-H arylation protocols are not suitable for substrates decorated with polar and delicate functionalities, which are commonly found in molecules that possess biological activity. Here we introduce a class of ruthenium catalysts that display a unique efficacy towards late-stage arylation of heavily functionalized substrates. The design and development of this class of catalysts was enabled by a mechanistic breakthrough on the Ru(II)-catalysed C-H arylation of N-chelating substrates with aryl (pseudo)halides, which has remained poorly understood for nearly two decades.

Ruthenium-Catalyzed C-H Arylation of Benzoic Acids and Indole Carboxylic Acids with Aryl Halides.

Herein we report the first Ru-catalyzed C-H arylation of benzoic acids with readily available aryl (pseudo)halides. The reaction, which does not require the use of silver salt additives, allows the arylation of previously challenging hindered benzoic acids and the use of generally unreactive ortho-substituted halorarenes. Furthermore, our new protocol can efficiently be applied to indole carboxylic acids, thus allowing access to C7-, C6-, C5- and C4-arylated indole compounds, a departure from the classical enhanced reactivity of the C2 and C3 positions of indole.

Ru-Catalyzed C-H Arylation of Fluoroarenes with Aryl Halides.

Although the ruthenium-catalyzed C-H arylation of arenes bearing directing groups with haloarenes is well-known, this process has never been achieved in the absence of directing groups. We report the first example of such a process and show that unexpectedly the reaction only takes place in the presence of catalytic amounts of a benzoic acid. Furthermore, contrary to other transition metals, the arylation site selectivity is governed by both electronic and steric factors. Stoichiometric and NMR mechanistic studies support a catalytic cycle that involves a well-defined η(6)-arene-ligand-free Ru(II) catalyst. Indeed, upon initial pivalate-assisted C-H activation, the aryl-Ru(II) intermediate generated is able to react with an aryl bromide coupling partner only in the presence of a benzoate additive. In contrast, directing-group-containing substrates (such as 2-phenylpyridine) do not require a benzoate additive. Deuterium labeling and kinetic isotope effect experiments indicate that C-H activation is both reversible and kinetically significant. Computational studies support a concerted metalation-deprotonation (CMD)-type ruthenation mode and shed light on the unusual arylation regioselectivity.

Metalation dictates remote regioselectivity: ruthenium-catalyzed functionalization of meta C(Ar)-H Bonds.

Remote control: The title reaction is effective for the sulfonation and alkylation of arenes bearing directing groups. Initial ortho metalation of the substrate forms an intermediate which does not evolve towards functionalization at the CM bond. Instead, the ruthenium catalyst acts as a strong electron-donating group, thus directing a remote electrophilic attack.

Clinical performance of fiber post restorations in endodontically treated teeth: 2-year results.

PURPOSE: This study evaluated the 2-year outcome of post-and-core restorative procedures in endodontically treated teeth. The effect of baseline factors (tooth type, number of residual coronal walls, and type of definitive restoration) on restoration failure was assessed. MATERIALS AND METHODS: The consecutive sample design included 150 patients. A total of 162 teeth (57 anterior and 105 posterior) were restored. Sixty-nine teeth had 3 or 4 residual coronal walls, while 93 teeth had 2 or fewer walls. Crowns and direct resin composite restorations were placed in 121 and 41 teeth, respectively. After 23 to 25 months, all patients were evaluated. Logistic regression was used to identify the joint effect of variables recorded at baseline (P < .05). RESULTS: The only failure modes observed were post debonding (4.3%, 2 in anterior teeth and 5 in posterior teeth) and endodontic failure (3.0%, 2 in anterior teeth and 3 in posterior teeth). All post debondings occurred in teeth with 2 or fewer coronal walls that were crown covered. All endodontic failures occurred in crown-covered teeth (1 failure in a tooth with 3 walls and the remaining 4 failures in teeth with 2 or fewer walls). Logistic regression found no statistical significance for any of the variables recorded at baseline. CONCLUSION: Restorations placed with the use of a fiber post and core resulted in 4.3% post debondings and 3.0% endodontic failures after 2 years of clinical service.

The influence of operator variability on adhesive cementation of fiber posts.

PURPOSE: The aim of this study was to evaluate the influence of the operator's experience on the outcome of fiber post cementation using an etch-and-rinse acetone-based adhesive. MATERIALS AND METHODS: Fifteen human anterior teeth were used in the study. One trained operator performed the endodontic procedures and prepared the roots for the insertion and cementation of the posts. At this point, teeth were divided into 3 groups and distributed to 3 operators to lute the posts: an expert operator (EO), a moderately experienced operator (ME), and an operator with a low level of experience (LE). Quartz fiber posts (DT Light Post #1 or #2, RTD) were used. Posts were cemented using Prime&Bond NT Dual Cure adhesive system (Dentsply Caulk) in combination with the dual-curing resin cement Calibra (Dentsply Caulk). The post retention was assessed with the "thin-slice" push-out test. One-way ANOVA was performed to examine the effect of the operator on push-out strength, followed by post-hoc multiple comparisons using Tukey's test, with the significance level set at alpha = 95%. RESULTS: The results of push-out strength testing were as follows: EO (12.44+/-3.63 MPa), ME (11.68+/-2.64 MPa), LE (11.18+/-3.12 MPa). No statistically significant differences were determined among the three groups. CONCLUSION: There was no statistically significant difference in the retention measured for fiber posts luted by operators with different levels of clinical experience. Given the parameters of this investigation, the level of operator experience in luting fiber posts does not affect post retention under laboratory conditions.

Use of anatomic post and core for reconstructing an endodontically treated tooth: a case report.

A clinical case is presented in which a new type of fiber post was used in combination with the proprietary dual-curing resin cement to bond in a wide, nonrounded root canal. The anatomic post was inserted and the relining resin photopolymerized. The anatomic post was then removed and a luting procedure was performed, as for any other translucent post. The clinical procedure was simple, and a superior fit to the root canal walls was achieved, thus reducing the amount of cement needed. The luting procedure described can be proposed as a clinical technique for routine use when the prepared root canal is too wide or not perfectly round.

Influence of a microbrush on bonding fiber post into root canals under clinical conditions.

OBJECTIVE: The objective of this clinical report was to evaluate the effectiveness of a microbrush as a carrier of priming-adhesive solution in formation of resin tags, adhesive lateral branches, and resin-dentin interdiffusion zone (RDIZ) when the brush was used to bond fiber posts under clinical conditions. STUDY DESIGN: Twenty endodontically treated teeth, already scheduled for extraction for endodontic or periodontal reasons, were selected for this study. The patients were informed, and their written consent was obtained. The samples were randomly divided into 2 groups of 10 samples each. In group 1, One-Step (Bisco, Schaumburg, Ill) was applied with a brush with Duo-Link resin cement (Bisco). In group 2, One-Step was applied with a microbrush with Duo-Link resin cement (Bisco). Use of the adhesive systems and resin cements was strictly according to manufacturers' instructions. The priming-adhesive solution was light-cured before the dual resin cement and the post were placed. Twenty Aestheti-Plus posts (white quartz fiber posts; RTD, St. Egreve, France) were used. A week after application, the root samples were extracted and processed for SEM observations. RESULTS: Both adhesive systems showed RDIZ and resin tag and adhesive lateral branch formation. In Group 2 samples, RDIZ morphology was easily detectable and uniform along root canals. Also, resin tag formation was well represented in all thirds. In group 1 samples, resin tag formation at the apical third and RDIZ formation was less evident. Statistically significant differences were found among the two groups at the apical third. CONCLUSION: The microbrush permitted a more uniform RDIZ and resin tag formation along the entire length of the canal than did the standard brush. The microbrush can be routinely used for bonding fiber posts into root canal preparations.