XAT-Catalysis for Intramolecular Biaryl Synthesis.

Radical ipso-substitution offers an alternative to organometallic approaches for biaryl synthesis, but usually requires stoichiometric reagents such as tributyltin hydride. Here, we demonstrate that visible light photoredox catalysis can be used for ipso-biaryl synthesis, via a halogen-atom transfer (XAT) regime. Using amide substrates that promote ipso- over unwanted ortho-addition, we demonstrate smooth biaryl formation with no constraint on the electronic character of the migrating arene ring. The photoreaction can be combined in one operation to achieve a formal arylation of the inert aniline C-N bond.

Aminoarylation of alkynes using diarylanilines.

Intermolecular aminoarylation of alkynes is described, via addition of diarylanilines to alkynes and Smiles-Truce rearrangement. The transformation manipulates the C-N bond of anilines directly, with no requirement for organometallic reagents or transition metal catalysis. The enaminoate products are versatile building blocks for different classes of heterocycles.

Cascade Aryne Aminoarylation for Biaryl Phenol Synthesis.

We describe a transition metal-free approach to hindered 3-amino-2-aryl phenols through a cascade nucleophilic addition / Smiles-Truce rearrangement of a functionalized Kobayashi aryne precursor. Under anionic conditions, secondary alkyl amines add to the aryne intermediate to set up an aryl transfer from a neighboring sulfonate group. The use of a sulfonate, rather than the more typical sulfonamide, enables access to phenolic biaryl products that are important motifs in natural products and pharmaceuticals.

Regiodivergent Arylation of Pyridines via Zincke Intermediates.

An arylation protocol for pyridines is described, via the ring-opened Zincke intermediate. Treatment of pyridines with triflic anhydride and a secondary amine produces an azahexatriene species, which undergoes regioselective Pd-catalyzed arylation at the putative C4 position. Recyclization then provides the pyridine products. Alternatively, metal-free arylation with a diaryliodonium salt is selective for the pyridine meta-position, affording a regiodivergent approach to pyridine biaryls from a common intermediate.

Aryne-Enabled C-N Arylation of Anilines.

Anilines are potentially high-value arylating agents, but are limited by the low reactivity of the strong C-N bond. We show that the reactive intermediate benzyne can be used to both activate anilines, and set-up an aryl transfer reaction in a single step. The reaction does not require any transition metal catalysts or stoichiometric organometallics, and establishes a metal-free route to valuable biaryl products by functionalizing the aniline C-N bond.

Synthesis of Functionalized Pyrrolidinone Scaffolds via Smiles-Truce Cascade.

Arylsulfonamides have been found to react with cyclopropane diesters under simple base treatment to give α-arylated pyrrolidinones. This one-pot process comprises three steps: nucleophilic ring-opening of the cyclopropane, reaction of the resulting enolate in a Smiles-Truce aryl transfer, and lactam formation. The reaction represents a new, operationally simple approach to biologically active pyrrolidinones and expands Smiles-Truce arylation methods to encompass sp3 electrophilic centers in cascade processes.

An NHC-Catalyzed Desulfonylative Smiles Rearrangement of Pyrrole and Indole Carboxaldehydes.

The use of catalysis methods to enable Smiles rearrangement opens up new substrate classes for arylation under mild conditions. Here, we describe an N-heterocyclic carbene (NHC) catalysis system that accesses indole and pyrrole aldehyde substrates in a desulfonylative Smiles process. The reaction proceeds under mild, transition-metal-free conditions and captures acyl anion reactivity for the synthesis of a diverse array of 2-aroyl indoles and pyrroles from readily available sulfonamide starting materials.

NHC Catalysis for Umpolung Pyridinium Alkylation via Deoxy-Breslow Intermediates.

Umpolung N-heterocyclic carbene (NHC) catalysis of non-aldehyde substrates offers new pathways for C-C bond formation, but has proven challenging to develop in terms of viable substrate classes. Here, we demonstrate that pyridinium ions can undergo NHC addition and subsequent intramolecular C-C bond formation through a deoxy-Breslow intermediate. The alkylation demonstrates, for the first time, that deoxy-Breslow intermediates are viable for catalytic umpolung of areniums.

Diarylamine Synthesis via Desulfinylative Smiles Rearrangement.

Diarylamines are obtained directly from sulfinamides through a novel rearrangement sequence. The transformation is transition metal-free and proceeds under mild conditions, providing facile access to highly sterically hindered diarylamines that are otherwise inaccessible by traditional SNAr chemistry. The reaction highlights the distinct reactivity of the sulfinamide group in Smiles rearrangements versus that of the more common sulfonamides.

NHC Catalysis for Umpolung Pyridinium Alkylation via Deoxy-Breslow Intermediates.

Umpolung N-heterocyclic carbene (NHC) catalysis of non-aldehyde substrates offers new pathways for C-C bond formation, but has proven challenging to develop in terms of viable substrate classes. Here, we demonstrate that pyridinium ions can undergo NHC addition and subsequent intramolecular C-C bond formation through a deoxy-Breslow intermediate. The alkylation demonstrates, for the first time, that deoxy-Breslow intermediates are viable for catalytic umpolung of areniums.

Truce-Smiles Rearrangements by Strain Release: Harnessing Primary Alkyl Radicals for Metal-Free Arylation.

The ring-opening of 3-aminocyclobutanone oximes enables easy generation of primary alkyl radicals, capable of undergoing an unprecedented strain-release, desulfonylative radical Truce-Smiles rearrangement, providing divergent access to valuable 1,3 diamines and unnatural ß-amino acids. Characterized by mild conditions and wide scope of migrating species, this protocol allows the modular assembly of sp3 -aryls under transition metal-free, room-temperature conditions.

A visible light-mediated, decarboxylative, desulfonylative Smiles rearrangement for general arylethylamine syntheses.

A decarboxylative, desulfonylative Smiles rearrangement is presented that employs activated-ester/energy transfer catalysis to decarboxylate ß-amino acid derived starting materials at room-temperature under visible light irradiation. The radical Smiles rearrangement gives a range of biologically active arylethylamine products highly relevant to the pharmaceutical industry, chemical biology and materials science. The reaction is then applied to the synthesis of a chiral unnatural amino acid, 2-thienylalanine, used in the treatment of phenylketonuria. We also show how the reaction can proceed under metal-free and catalyst-free conditions.

Arylation and alkenylation of activated alkyl halides using sulfonamides.

A variety of quaternary aryl amino acid derivatives can be synthesised using tandem SN2/Smiles rearrangement chemistry involving aryl sulfonamides and α-chloro carbonyl compounds. The reaction harnesses a sulfur dioxide extrusion pathway to construct a C-N and C-Caryl bond under simple conditions with no requirement for organometallics or transition metal catalysts. The reaction is also successful for alkenyl sulfonamides, producing sterically congested quaternary alkene amino acid derivatives.

Ortho C-H arylation of arenes at room temperature using visible light ruthenium C-H activation.

A ruthenium-catalyzed ortho C-H arylation process is described using visible light. Using the readily available catalyst [RuCl2(p-cymene)]2, visible light irradiation was found to enable arylation of 2-aryl-pyridines at room temperature for a range of aryl bromides and iodides.

Arylation Using Sulfonamides: Phenylacetamide Synthesis through Tandem Acylation-Smiles Rearrangement.

A range of electron-poor and heterocyclic sulfonamides react with phenylacetyl chlorides to produce benzhydryl derivatives in a single step. The reaction proceeds via tandem amide bond formation/Dohmori-Smiles rearrangement under the simple conditions of an aqueous base. In the case of o-nosylamides, a further reaction takes place at the nitro group to yield indazoles.

meta-Selective C-H Activation of Arenes at Room Temperature Using Visible Light: Dual-Function Ruthenium Catalysis.

Ruthenium-catalyzed meta-C-H activation of arenes at room temperature is reported to proceed under blue-light irradiation. A variety of heteroarenes are compatible with this photochemical process, which leads to the corresponding meta C-C coupling products in good to very good yields. Initial mechanistic studies suggest a single-electron transfer process occurs between a photoexcited RuII -cyclometalated complex and alkyl halides, enabling meta-C-H functionalization reaction via carbon-centered radicals.

Alkene Carboarylation through Catalyst-Free, Visible Light-Mediated Smiles Rearrangement.

A light-mediated Truce-Smiles arylative rearrangement is described that proceeds in the absence of any photocatalyst. The protocol creates two C-C bonds from simple starting materials, with the installation of an aryl ring and a difluoroacetate moiety across unactivated alkenes. The reaction proceeds via a radical mechanism, utilizing a light-mediated reduction of ethyl bromodifluoroacetate by N,N,N',N'-tetramethylethylenediamine (TMEDA) to set up intermolecular addition to an unactivated alkene, followed by Truce-Smiles rearrangement.

Ruthenium-Catalyzed meta-Carboxylation.

The meta-carboxylation of arenes containing pyridine and other azine-directing groups is reported. Using carbon tetrabromide as the C1 source, ruthenium(III) trichloride catalysis enables functionalization of the arene meta-C-H position, affording carboxy methyl ester products after in situ reaction with methanol.

Synthesis of Triarylamines via Sequential C-N Bond Formation.

A one-pot domino N-arylation protocol is described using diaryliodonium reagents under copper catalysis. The reaction uses both aryl groups of the diaryliodonium reagent to generate triarylamines starting from simple anilines, representing an atom-economical preparation of an important class of organic material building blocks.