Development and Scale-Up of a New Sulfone-Based Bismacycle as a Universal Precursor for Bi(V)-Mediated Electrophilic Arylation.

The scope and practical utility of bismuth(V)-mediated electrophilic arylation have been greatly improved by the recent development of user-friendly protocols based on modular bismacycle reagents. Here, we report the scalable synthesis of a new bench-stable bismacycle bromide and demonstrate that it can be used as a "universal precursor" in electrophilic arylation. Relative to established syntheses of related bismacycles, the new protocol benefits from improved step- and vessel-economy, reduced production time, and the complete elimination of cryogenic temperatures and undesirable solvents (EtO and CHCl).

Synthesis of Highly Functionalized Bismacycles via Post-Transmetallation Modification of Arylboronic Acids.

Bismacycles featuring a sulfone-bridged scaffold have recently been developed as versatile and convenient electrophilic arylating agents. Here, we report that the exocyclic aryl group, which is ultimately transferred to a nucleophilic coupling partner, can be functionalized through cross-coupling, heteroatom substitutions, oxidations and reductions, and protecting group manipulations. This "postsynthetic modification" approach provides concise and divergent access to complex aryl bismacycles.

Coaxial Dielectric Spectroscopy as an In-Line Process Analytical Technique for Reaction Monitoring.

The suitability of broadband dielectric spectroscopy (DS) as a tool for in-line (in situ) reaction monitoring is demonstrated. Using the esterification of 4-nitrophenol as a test-case, we show that multivariate analysis of time-resolved DS data-collected across a wide frequency range with a coaxial dip-probe-allows reaction progress to be measured with both high precision and high accuracy. In addition to the workflows for data collection and analysis, we also establish a convenient method for rapidly assessing the applicability of DS to previously untested reactions or processes.

Photochemically Mediated Ring Expansion of Indoles and Pyrroles with Chlorodiazirines: Synthetic Methodology and Thermal Hazard Assessment.

We demonstrate that arylchlorodiazirines serve as photo-activated halocarbene precursors for the selective one-carbon ring expansion of N-substituted pyrroles and indoles to the corresponding pyridinium and quinolinium salts. Preliminary investigations indicate that the same strategy also enables the conversion of N-substituted pyrazoles to pyrimidinium salts. The N-substituent of the substrate plays an essential role in: (1) increasing substrate scope by preventing product degradation, (2) enhancing yields by suppressing co-product inhibition, and (3) activating the azinium products towards subsequent synthetic manipulations.

meta-Selective C-H arylation of phenols via regiodiversion of electrophilic aromatic substitution.

Electrophilic aromatic substitution is among the most widely used mechanistic manifolds in organic chemistry. Access to certain substitution patterns is, however, precluded by intrinsic and immutable substituent effects that ultimately restrict the diversity of the benzenoid chemical space. Here we demonstrate that the established regioselectivity of electrophilic aromatic substitution can be overcome simply by diverting the key σ-complex intermediate towards otherwise inaccessible substitution products.

Modular Synthesis of α,α-Diaryl α-Amino Esters via Bi(V)-Mediated Arylation/S2-Displacement of Kukhtin-Ramirez Intermediates.

We report a concise and modular approach to α,α-diaryl α-amino esters from readily available α-keto esters. This mild, one-pot protocol proceeds via ketone umpolung, with formation of a Kukhtin-Ramirez intermediate preceding sequential electrophilic arylation by Bi(V) and S2 displacement by an amine. The methodology is compatible with a wide range of anilines and primary amines - including derivatives of drugs and proteinogenic amino acids - Bi(V) arylating agents, and α-keto ester substrates.

Umpolung Synthesis of Pyridyl Ethers by Bi -Mediated O-Arylation of Pyridones.

We report that O-selective arylation of 2- and 4-pyridones with arylboronic acids is affected by a modular, bismacycle-based system. The utility of this umpolung approach to pyridyl ethers, which is complementary to conventional methods based on S Ar or cross-coupling, is demonstrated through the concise synthesis of Ki6783 and picolinafen, and the formal synthesis of cabozantib and golvatinib. Computational investigations reveal that arylation proceeds in a concerted fashion via a 5-membered transition state.

Bismuth-Mediated α-Arylation of Acidic Diketones with ortho-Substituted Boronic Acids.

The α-arylation of cyclic and fluoroalkyl 1,3-diketones is made challenging by the highly stabilized nature of the corresponding enolates, and is especially difficult for sterically demanding aryl partners. As a general solution to this problem, we report the Bi-mediated oxidative coupling of acidic diones and ortho-substituted arylboronic acids. Starting from a bench-stable bismacycle precursor, a sequence of B-to-Bi transmetallation, oxidation and C-C bond formation furnishes the arylated diones.

Phosphine-Catalyzed Aryne Oligomerization: Direct Access to α,ω-Bisfunctionalized Oligo(-arylenes).

A phosphine-catalyzed oligomerization of arynes using selenocyanates was developed. The use of JohnPhos as a bulky phosphine is the key to accessing α,ω-bisfunctionalized oligo(-arylenes) with RSe as the substituent at one terminus and CN as the substituent at the other. The formation of RPSeR' cations, serving as sterically encumbered electrophiles, hinders the immediate reaction that affords the 1,2-bisfunctionalization product and instead opens a competitive pathway leading to oligomerization.

Polyurethanes and Polyallophanates via Sequence-Selective Copolymerization of Epoxides and Isocyanates.

Aryl isocyanates are introduced as comonomers for ring-opening copolymerization (ROCOP) with epoxides. Informed by studies of reaction kinetics, we show that divergent sequence selectivity for AB- and ABB-type copolymers can be achieved with a single dimagnesium catalyst. The resulting materials respectively constitute a new class of polyurethanes (PUs) and a new class of materials featuring an unprecedented backbone structure, the polyallophanates (PAs).

Modular bismacycles for the selective C-H arylation of phenols and naphthols.

Given the important role played by 2-hydroxybiaryls in organic, medicinal and materials chemistry, concise methods for the synthesis of this common motif are extremely valuable. In seeking to extend the lexicon of synthetic chemists in this regard, we have developed an expedient and general strategy for the ortho-arylation of phenols and naphthols using readily available boronic acids. Our methodology relies on in situ generation of a uniquely reactive Bi(V) arylating agent from a bench-stable Bi(III) precursor via telescoped B-to-Bi transmetallation and oxidation.

Synthesis of Air-stable, Odorless Thiophenol Surrogates via Ni-Catalyzed C-S Cross-Coupling.

Thiophenols are versatile synthetic intermediates whose practical appeal is marred by their air sensitivity, toxicity and extreme malodor. Herein we report an efficient catalytic method for the preparation of S-aryl isothiouronium salts, and demonstrate that these air-stable, odorless solids serve as user-friendly sources of thiophenols in synthesis. Diverse isothiouronium salts featuring synthetically useful functionality are readily accessible by nickel-catalyzed C-S cross-coupling of (hetero)aryl iodides and thiourea.

Au-Catalyzed Biaryl Coupling To Generate 5- to 9-Membered Rings: Turnover-Limiting Reductive Elimination versus π-Complexation.

The intramolecular gold-catalyzed arylation of arenes by aryl-trimethylsilanes has been investigated from both mechanistic and preparative aspects. The reaction generates 5- to 9-membered rings, and of the 44 examples studied, 10 include a heteroatom (N, O). Tethering of the arene to the arylsilane provides not only a tool to probe the impact of the conformational flexibility of Ar-Au-Ar intermediates, via systematic modulation of the length of aryl-aryl linkage, but also the ability to arylate neutral and electron-poor arenes-substrates that do not react at all in the intermolecular process.

Gold-catalyzed oxidative coupling of arylsilanes and arenes: origin of selectivity and improved precatalyst.

The mechanism of gold-catalyzed coupling of arenes with aryltrimethylsilanes has been investigated, employing an improved precatalyst (thtAuBr3) to facilitate kinetic analysis. In combination with linear free-energy relationships, kinetic isotope effects, and stoichiometric experiments, the data support a mechanism involving an Au(I)/Au(III) redox cycle in which sequential electrophilic aromatic substitution of the arylsilane and the arene by Au(III) precedes product-forming reductive elimination and subsequent cycle-closing reoxidation of the metal. Despite the fundamental mechanistic similarities between the two auration events, high selectivity is observed for heterocoupling (C-Si then C-H auration) over homocoupling of either the arylsilane or the arene (C-Si then C-Si, or C-H then C-H auration); this chemoselectivity originates from differences in the product-determining elementary steps of each electrophilic substitution.

Gold-catalyzed direct arylation.

Biaryls (two directly connected aromatic rings, Ar(1)-Ar(2)) are common motifs in pharmaceuticals, agrochemicals, and organic materials. Current methods for establishing the Ar(1)-Ar(2) bond are dominated by the cross-coupling of aryl halides (Ar(1)-X) with aryl metallics (Ar(2)-M). We report that, in the presence of 1 to 2 mole percent of a gold catalyst and a mild oxidant, a wide range of arenes (Ar(1)-H) undergo site-selective arylation by arylsilanes (Ar(2)-SiMe(3)) to generate biaryls (Ar(1)-Ar(2)), with little or no homocoupling (Ar(1)-Ar(1)/Ar(2)-Ar(2)).

Application of the lithiation-borylation reaction to the rapid and enantioselective synthesis of the bisabolane family of sesquiterpenes.

The expedient enantioselective synthesis of 5 bisabolane sesquiterpenes has been achieved using a common, one-pot lithiation-borylation reaction of secondary benzylic carbamates and either protodeboronation or oxidation to give the natural products in fewer than 5 steps, with high yield and >94 : 6 er.

Gold-catalysed oxyarylation of styrenes and mono- and gem-disubstituted olefins facilitated by an iodine(III) oxidant.

1-Hydroxy-1,2-benziodoxol-3(1H)-one (IBA) is an efficient terminal oxidant for gold-catalysed, three-component oxyarylation reactions. The use of this iodine(III) reagent expands the scope of oxyarylation to include styrenes and gem-disubstituted olefins, substrates that are incompatible with the previously reported Selectfluor-based methodology. Diverse arylsilane coupling partners can be employed, and in benzotrifluoride, homocoupling is substantially reduced.

Arylsilanes: application to gold-catalyzed oxyarylation of alkenes.

Arylsilanes are efficient reagents for the gold-catalyzed oxyarylation of alkenes (21 examples, up to 85% isolated yield). Using commercially available Ph(3)PAuCl and readily prepared, benign arylsilanes, these two- and three-component reactions proceed smoothly in air. The oxidant, Selectfluor, not only facilitates entry to the Au(I/III) manifold but also provides a fluoride anion for silane activation, thereby avoiding the need for addition of a stoichiometric base.