Enhancement of Neighbouring‐Group Participation in Cu0‐Promoted Cross‐Coupling gem‐Difluoromethylenation of Aryl/Alkenyl Halides with 1,3‐Azolic Difluoromethyl Bromides

A copper(0)‐promoted direct reductive gem‐difluoromethylenation of unactivated aryl or alkenyl halides with benzo‐1,3‐azolic (oxa‐, thia‐ or aza‐) difluoromethyl bromides or 2‐bromodifluoromethyl‐1,3‐oxazoline has been developed for the construction of pharmaceutically important gem‐difluoromethylene‐linked twin molecules. The unique π‐conjugated aryl‐fused 1,3‐azolic moiety in difluoromethyl bromide substrates could stabilise the reaction intermediates, which promotes the reactivities, providing facile access to the cross‐coupling products in good to excellent yields, and allowing significant functional group tolerance. The reaction exhibits an enhanced neighbouring‐group‐participation effect. This method could provide a new strategy for the construction of gem‐difluoromethylene‐linked identical or nonidentical twin drugs through further functionalisation of 1,3‐azolic skeletons.     

Hypervalent Activation as a Key Step for Dehydrogenative ortho CC Coupling of Iodoarenes

Building on earlier results, a direct metal‐free α‐ arylation of substituted cyclic 1,3‐diones using ArI(O₂CCF₃)₂ reagents has been developed; unlike other arylative approaches, the arylated products retain the iodine substituent ortho to the newly formed C?C bond. The mechanism is explored by using DFT calculations, which show a vanishingly small activation barrier for the C?C bond‐forming step. In fact, taking advantage of an efficient in situ hypervalent activation, the iodoarenes are shown to undergo a cross‐ dehydrogenative C?C coupling at the C?H ortho to the iodine. When Oxone is used as terminal oxidant, the process is found to benefit from a rapid initial formation of the hypervalent ArI(OR)₂ species and the sulfate‐accelerated final coupling with a ketone. This method complements the ipso selectivity obtained in the metal‐catalyzed α‐arylation of carbonyl compounds.     

Synthesis of Boronate‐Based Benzo[fg]tetracene and Benzo[hi]hexacene via Demethylative Direct Borylation

A demethylative direct borylation is reported, which was applied to the synthesis of benzo[fg]tetracenes containing boronate ester, amide, and thioester substructures. Depending on the heteroatom adjacent to boron, the molecules showed characteristic photophysical properties, molecular arrangements, and chemical stabilities. The key to the successful synthesis is the appropriate choice of the boron source and Brønsted base. The versatility of the direct borylation was demonstrated by the synthesis of a boronate‐based benzo[hi]hexacene.     

Catalytic Decarboxylative Cross‐Coupling of Aryl Chlorides and Benzoates without Activating ortho Substituents

The restriction of decarboxylative cross‐coupling reactions to ortho‐substituted or heterocyclic carboxylate substrates was overcome by holistic optimization of a bimetallic Cu/Pd catalyst system. The combination of a CuI/Me₄phen decarboxylation catalyst and a [(MeCN)₄Pd](OTf)₂/XPhos cross‐coupling catalyst enables the synthesis of biaryls from inexpensive aryl chlorides and potassium benzoates regardless of their substitution pattern.     

Catalyst-free N-arylation using unactivated fluorobenzenes

Caught in a 'S(N) Ar'e: A one-step, high-yielding, catalyst-free method is described for N-arylation of azoles and indoles from unactivated monofluorobenzenes. This S(N) Ar reaction tolerates a wide range of substituents and can also generate halogenated N-aryl products. The reaction can also be performed simultaneously with or subsequent to a copper- or palladium-catalyzed cross-coupling reaction in the same pot.     

Electrochemical Amination in the System Ti(IV)–NH2OH–C6H6: The Efficiency of the Process in a Sulfuric Acid Solution Containing an Organic Solvent

Electrolysis of the system Ti(IV)–NH₂OH–C₆H₆ in an 11 M H₂SO₄ solution shows that using an organic solvent (acetic acid, acetonitrile) during cathodically initiated amination of aromatic substrates permits the production of aromatic amines with the overall yield by hydroxylamine reaching 91%. Due to a chain mechanism of radical substitution, the benzene amination in electrolytes containing 5 M CH₃COOH and 5.5 M CH₃CN terminates largely upon consuming 70–75 and 50–55% of the charge required theoretically for a one-electron process. The maximum efficiency of electrochemical amination is observed at low hydroxylamine conversions and the overall current efficiency for mono- and disubstituted products of the benzene amination may exceed in these conditions 750%.     

A Novel Multistep Mechanism for the Stereocontrolled Ring Opening of Hindered Sulfamidates: Mild,Green, and Efficient Reactivity with Alcohols

Cyclic hindered sulfamidates exhibited an outstanding performance in their ring‐opening reactions with alcohols and in the absence of any external activator. The mechanism of this unprecedented transformation was thoroughly studied both experimentally and theoretically. As a result, a nontrivial stepwise pathway involving solvent‐induced conversion of the sulfamidates to activated aziridinium and then to oxazolinium cations, which are finally opened at their 5‐position with inversion of configuration, is proposed. The presence of the SO₃ moiety in the sulfamidate was revealed as a “built‐in activator”. In fact, the spontaneous SO₃ cleavage takes place under the reaction conditions and avoids the subsequent step of hydrolysis after the ring opening of the sulfamidates. This is another important improvement of this methodology with respect to the standard basic conditions, allowing a greater compatibility with other functional groups. Furthermore, the carbamate group plays a key role in this mechanism. Briefly, a highly chemoselective and stereoespecific formal solvolysis of hindered sulfamidates with alcohols without further activation is described. This reaction takes place exclusively at the quaternary center with inversion of configuration, providing a new straightforward synthetic route to O‐substituted α‐methylisoserines.     

Electrochemical Amination: Efficiency of a Radical Substitution

Electrochemical amination of benzene in sulfuric acid electrolytes is studied and experimental conditions for highly efficient synthesis of primary aromatic amino compounds are determined. In the electrolysis of Ti(IV)–NH₂OH–C₆H₆ in 11 M H₂SO₄ solutions containing acetic acid or acetonitrile as organic solvents, aniline and isomeric phenylenediamines are obtained with the total yields by hydroxylamine of 95.6 and 99.6%, respectively. A monoamino compound is the main product of radical substitution in acidic organo-aqueous media. It is found that the use of acetonitrile in electrochemical process is limited to certain sulfuric acid concentrations and temperatures.     

Total Synthesis of (−)‐Haouamine B Pentaacetate and Structural Revision of Haouamine B

The enantiocontrolled total synthesis of (?)‐haouamine B pentaacetate was accomplished via an optically active indane‐fused β‐lactam, which was prepared by a newly developed Friedel–Crafts reaction. Subsequent cleavage of the β‐lactam and an intramolecular McMurry coupling reaction provided the core indane‐fused tetrahydropyridine, which led to the elucidation of the structure, as proposed by Trauner and Zubía.     

Reaction of Phenylglyoxal with Cyclopentenylmorpholine and its Arylidene Derivatives

The reaction of phenylglyoxal with cyclopentenylmorpholine and its arylidene derivatives leads to hydroxyalkylation products.     

Electrophilic Formylation of Arenes by Silylium Ion Mediated Activation of Carbon Monoxide

Arene‐stabilized silylium ions react with carbon monoxide rather than carbon monoxide adducts of silylium ions reacting with arenes. This mechanism is supported by quantum‐chemical calculations. Even sterically hindered mesitylene and electronically deactivated chlorobenzene engage in this electrophilic aromatic substitution. The silylium ion mediated formylation corresponds to Gattermann–Koch reactions promoted by strong Brønsted acids. The resulting silylcarboxonium ion of the arenecarbaldehyde was crystallographically characterized, for the first time revealing the molecular structure of this synthetically important intermediate.     

The Direct Synthesis of Arylxenon Trifluoromethanesulfonates via electrophilic substitution

The reaction of xenonbis(trifluoroacetate) and trifluoromethanesulfonic acid (triflic acid) gave the new, highly reactive unsymmetrical xenon-oxo species CF₃COOXeOSO₂CF₃. Benzene derivates, containing electron withdrawing substituents such as -F, -CF₃, -Cl or -NO₂ were electrophilic attacked by this intermediate to yield arylxenon trifluoromethanesulfonates. Via this one-pot synthesis trifluoromethanesulfonates with the cations [Xe(2,4,6-F₃C₆H₂)]⁺, [Xe(2-F-5-NO₂C₆H₃)]⁺, [Xe(2-F-5-CF₃C₆H₃)]⁺ and [Xe(3,5-(CF₃)₂C₆H₃)]⁺ were prepared. All compounds were characterized by their NMR, mass, and vibrational spectra. Additionally, several new arylxenon trifluoromethanesulfonates were detected by ¹²⁹Xe-NMR spectroscopy as products of the reaction of 1,3-F₂C₆H₄ and further deactivated benzenes with xenontrifluoroacetate trifluoromethane sulfonate. Fluoro substituents in ortho position to xenon significantly increase the thermal stability of the arylxenon trifluoromethanesulfonates obtained. The molecular structure of [Xe(2,6-F₂C₆H₃)][OSO₂CF₃] was determined by single crystal diffraction methods. The arylxenon unit is weakly coordinated by one oxygen atom of the CF₃SO₃ anion. The salt crystallizes in the triclinic space group P1 , a = 880.9(3) pm, b = 1093.9(5) pm, c = 1209.8(5) pm, α = 89.04(4)°, β = 74.23(3)°, γ = 86.03(3)°, Z = 4.     

α‐Arylation/Heteroarylation of Chiral α‐Aminomethyltrifluoroborates by Synergistic Iridium Photoredox/Nickel Cross‐Coupling Catalysis

Direct access to complex, enantiopure benzylamine architectures using a synergistic iridium photoredox/nickel cross‐coupling dual catalysis strategy has been developed. New C(sp³)? C(sp²) bonds are forged starting from abundant and inexpensive natural amino acids.