Sequential C-F Bond Transformation of the Difluoromethylene Unit in Perfluoroalkyl Groups: A Combination of Fine-Tuned Phenothiazine Photoredox Catalyst and Lewis Acid.

A sequential process via photoredox catalysis and Lewis acid mediation for C-F bond transformation of the CF2 unit in perfluoroalkyl groups has been achieved to transform perfluoroalkylarenes into complex fluoroalkylated compounds. A phenothiazine-based photocatalyst promotes the defluoroaminoxylation of perfluoroalkylarenes with (2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO) under visible light irradiation, affording the corresponding aminoxylated products. These products undergo a further defluorinative transformation with various organosilicon reagents mediated by AlCl3 to provide highly functionalized perfluoroalkyl alcohols. Our novel phenothiazine catalyst works efficiently in the defluoroaminoxylation. Transient absorption spectroscopy revealed that the catalyst regeneration step is crucial for the photocatalytic aminoxylation.

Carboboration-Driven Generation of a Silylium Ion for Vinylic C-F Bond Functionalization by B(C6 F5 )3 Catalysis.

Strong main-group Lewis acids such as silylium ions are known to effectively promote heterolytic C(sp3 )-F bond cleavage. However, carrying out the C(sp2 )-F bond transformation of vinylic C-F bonds has remained an unmet challenge. Herein, we describe our development of a new and simple strategy for vinylic C-F bond transformation of α-fluorostyrenes with silyl ketene acetals catalyzed by B(C6 F5 )3 under mild conditions. Our theoretical calculations revealed that a stabilized silylium ion, which is generated from silyl ketene acetals by carboboration, cleaves the C-F bond of α-fluorostyrenes. A comparative study of α-chloro or bromostyrenes demonstrated that our reaction can be applied only to α-fluorostyrenes because the strong silicon-fluorine affinity facilitates an intramolecular interaction of silylium ions with fluorine atom to cleave the C-F bond. A broad range of α-fluorostyrenes as well as a range of silyl ketene acetals underwent this C-F bond transformation.

anti-Selective Borylstannylation of Alkynes with (o-Phenylenediaminato)borylstannanes by a Radical Mechanism.

We have achieved the first anti-borylstannylation of alkynes by using (o-phenylenediaminato)borylstannanes. This reaction afforded 1-boryl-2-stannylalkenes with excellent regio- and stereoselectivity by a radical mechanism. This anti-addition manner is in sharp contrast to the syn-selectivity obtained during transition metal-catalyzed borylstannylation. The mild radical conditions enabled a broad substrate scope, and various types of aromatic and aliphatic alkynes were applicable. The origin of regio- and stereoselectivity was elucidated by DFT calculation of the reaction mechanism. The application of the borylstannylation products to cross- or homocoupling reactions provided ready access to either triarylethenes or bisborylbutadienes.

Lewis Acid-Catalyzed Diastereoselective C-C Bond Insertion of Diazo Esters into Secondary Benzylic Halides for the Synthesis of α,ß-Diaryl-ß-haloesters.

We report a formal carbon-carbon (C-C) bond insertion via the reaction of secondary benzylic halides (fluorides, chlorides, and bromides) with α-diazo esters catalyzed by Lewis acid catalysts. Secondary benzylic halides underwent elongation to afford α,ß-diaryl-ß-haloesters diastereoselectively. Density functional theory calculation revealed that the present formal C-C bond insertion was the result of Lewis acid-promoted cleavage and the re-formation of a carbon-halogen bond and that the aryl-migration step determined the diastereoselectivity. Various diarylmethyl halides and α-diazo esters were applicable to this reaction system. In addition, ring expansion in cyclic benzylic chlorides was accomplished.

Insertion of Diazo Esters into C-F Bonds toward Diastereoselective One-Carbon Elongation of Benzylic Fluorides: Unprecedented BF3 Catalysis with C-F Bond Cleavage and Re-formation.

Selective transformation of C-F bonds remains a significant goal in organic chemistry, but C-F insertion of a one-carbon-atom unit has never been established. Herein we report the BF3-catalyzed formal insertion of diazo esters as one-carbon-atom sources into C-F bonds to accomplish one-carbon elongation of benzylic fluorides. A DFT calculation study revealed that the BF3 catalyst could contribute to both C-F bond cleavage and re-formation. This elongation provided α-fluoro-α,ß-diaryl esters with a high level of diastereoselectivity. Various benzylic fluorides and diazo esters were applicable. The synthetic utility of this method was demonstrated by the synthesis of a fluoro analogue of a compound that is used as a transient receptor and potential canonical channel inhibitor.

Photoredox-Catalyzed C-F Bond Allylation of Perfluoroalkylarenes at the Benzylic Position.

Site-selective and direct C-F bond transformation of perfluoroalkylarenes was achieved with allylic stannanes via an iridium photoredox catalyst system. The present defluoroallylation proceeds exclusively at the benzylic position through perfluoroalkyl radicals generated by a single-electron transfer from an excited photoredox catalyst to perfluoroalkylarenes. A variety of perfluoroalkyl groups are applicable: linear perfluoroalkyl-substituted arenes such as Ar-nC4F9 and Ar-nC6F13 and heptafluoroisopropylarenes (Ar-CF(CF3)2) underwent site-selective defluoroallylation. DFT calculation studies revealed that the in situ generated Bu3SnF traps F- to prevent a retroreaction from the unstable perfluoroalkyl radical intermediate, and the radical intermediate favorably reacts with allylic stannanes. The synthesis of a bis(trifluoromethyl)methylene unit containing compound, which is an analog that is useful as a pharmaceutical agent for the prophylaxis or treatment of diabetes and inflammatory diseases, demonstrated the utility of this reaction.

(o-Phenylenediamino)borylstannanes: Efficient Reagents for Borylation of Various Alkyl Radical Precursors.

(o-Phenylenediamino)borylstannanes were newly synthesized to achieve radical boryl substitutions of a variety of alkyl radical precursors. Dehalogenative, deaminative, decharcogenative, and decarboxylative borylations proceeded in the presence of a radical initiator to give the corresponding organic boron compounds. Radical clock experiments and computational studies have provided insights into the mechanism of the homolytic substitution (SH 2) of the borylstannanes with alkyl radical intermediates. DFT calculation disclosed that the phenylenediamino structure lowered the LUMO level including the vacant p-orbital on the boron atom to enhance the reactivity to alkyl radicals in SH 2. Moreover, C(sp3 )-H borylation of THF was accomplished using the triplet state of xanthone.

Indium-Catalyzed C-F Bond Transformation through Oxymetalation/ß-Fluorine Elimination to Access Fluorinated Isocoumarins.

Fluorinated heterocycles have attracted much attention in the pharmaceutical and agrochemical industries. Many strategies have already been developed to achieve the synthesis of fluorinated heterocycles. Formidable challenges remain, however, in the synthesis of fluorinated isocoumarin derivatives that are among the most alluring structural motifs. Herein, the indium-catalyzed C-F bond transformation of 2-(2,2-difluorovinyl) benzoates is reported, which are readily accessible compounds, to give a diverse array of fluorinated isocoumarins. The present reaction proceeds smoothly using inexpensive reagents: a catalytic amount of indium salt in the presence of zinc salt. A theoretical calculation of potential energy profiles showed that the reaction consists of oxymetalation with the elimination of alkyl halide and the ß-fluorine elimination.

Indium-Catalyzed C-F Bond Transformation through Oxymetalation/ß-Fluorine Elimination to Access Fluorinated Isocoumarins.

Invited for the cover of this issue are Yoshihiro Nishimoto, Makoto Yasuda and co-workers at Osaka University and MOLSIS Inc.. The image depicts the crafting of a gladiator's shield to represent the reaction reported in this work. Read the full text of the article at 10.1002/chem.202100672.

(o-Phenylenediamino)borylstannanes: Efficient Reagents for Borylation of Various Alkyl Radical Precursors.

Invited for the cover of this issue are Kensuke Suzuki, Yoshihiro Nishimoto and Makoto Yasuda from Osaka University. The image depicts a circus trapeze act, with different elements of the picture representing components of the borylation reaction reported in this work. Read the full text of the article at 10.1002/chem.202004692.

Synthesis of (Z)-ß-(Carbonylamino)alkenylindium through Regioselective anti-Carboindation of Ynamides and Its Transformation to Multisubstituted Enamides.

The regioselective anti-carboindation of ynamides by using InBr3 and silylated nucleophiles was developed to synthesize (Z)-ß-(carbonylamino)alkenylindiums. The X-ray crystallographic analysis of an alkenylindium suggested that the reaction proceeded in an anti-addition fashion. In contrast to reported syn-carbometalations of ynamides by using organometallics, a cooperation of InBr3 and silylated nucleophiles to ynamides achieved an anti-addition, which was supported by DFT calculations. The scope of substrates included various ynamides and silylated nucleophiles, such as silyl ketene acetals and silyl ketene imines. The transformation of synthesized alkenylindiums by iodination, radical coupling, and Pd-catalyzed cross-coupling successfully afforded trisubstituted enamines with high regio- and stereoselectivities.

Synthesis and Characterization of Pheox- and Phebox-Aluminum Complexes: Application as Tunable Lewis Acid Catalysts in Organic Reactions.

Pheox- and Phebox-aluminum complexes were synthesized and subsequently characterized by spectroscopic analysis. These complexes acted as Lewis acid catalysts, and their catalytic activities were controlled by using the Pheox, Phebox, and heteroatom ligands. The Pheox-aluminum complex exhibited an opposite substrate selectivity to AlCl3 in a competitive hetero-Diels-Alder reaction between electron-rich and electron-deficient aldehydes.

Regio- and Stereoselective Carboindation of Internal Alkynyl Ethers with Organosilicon or -stannane Nucleophiles.

We achieved regio- and stereoselective carboindation of terminal and internal alkynyl ethers using InI3 and organosilicon or -stannane nucleophiles to synthesize (Z)-ß-alkoxyalkenylindiums. The carbometalation regio- and stereoselectively proceeded in anti-addition fashion, which was confirmed by X-ray diffraction analysis of (Z)-ß-alkoxyalkenylindium products. Theoretical calculation on the carboindation of alkynyl ethers to elucidate the effect of an alkoxy group was conducted in parallel with calculations on a carbon analogue of the alkynyl ether. Reaction profiles and computational data of carboindation suggest that the alkoxy group enhances the interaction between InI3 and an alkyne moiety and reduces the activation energy. Many types of carbon nucleophiles such as silyl ketene acetals, silyl ketene imines, a silyl cyanide, an alkynyl stannane, and an allylic stannane were applicable to the present reaction system to give highly functionalized metalated enol ethers (ß-alkoxyalkenylindiums). The prepared ß-alkoxyalkenylindiums were transformed to various functionalized tetrasubstituted enol ethers by iodination followed by Suzuki coupling. The synthesis of a seven-membered ring compound containing a phenol ether moiety was accomplished using a sequential process that included the present stereoselective carboindation.

Regioselective Synthesis of 5-Metalated 2-Pyrones by Intramolecular Oxymetalation of Carbonyl-ene-yne Compounds Using Indium Trihalide.

The oxyindation of carbonyl-ene-yne compounds with indium trihalides proceeded efficiently to give di-, tri-, and tetrasubstituted 2-pyrones bearing a carbon-indium bond. The metalated 2-pyrone and a zwitterion intermediate were identified by X-ray crystallographic analysis. The application of organoindium compounds to oxidation or cross-coupling provided easy access to various multifunctionalized 2-pyrones. Some 2-pyrone derivatives show intense fluorescence only in the solid state (aggregation-induced emission).

Generation of α-Iminyl Radicals from α-Bromo Cyclic N-Sulfonylimines and Application to Coupling with Various Radical Acceptors Using a Photoredox Catalyst.

Visible-light-induced generation of α-iminyl radicals was accomplished using α-bromo cyclic N-sulfonylimines and photoredox catalysts such as erythrosine B or Ru(bpy)3 (PF6 )2 . The generated α-iminyl radical was utilized for various radical reactions with allylation reagents, silyl enol ethers and allenyl stannane to give the corresponding coupling products. Furthermore, atom transfer radical addition (ATRA) to olefin proceeded to provide the ATRA product. This process provided a mild and efficient method for the synthesis of cyclic N-sulfonylimine-containing molecules that act as bioactive compounds and become the precursors in sultam synthesis.

Indium Catalyzed Hydrofunctionalization of Styrene Derivatives Bearing a Hydroxy Group with Organosilicon Nucleophiles.

Hydrofunctionalization is one of the most important transformation reactions of alkenes. Herein, we describe the development of an indium-triiodide-catalyzed hydrofunctionalization of alkenes bearing a hydroxy group using various types of organosilicon nucleophiles. Indium triiodide was the most effective catalyst, whereas typical Lewis acids such as TiCl4, AlCl3, and BF3·OEt2 were ineffective. Many functional groups were successfully introduced, and these resulted in yields of 31-86%. Various styrene derivatives were also applicable to this reaction. Mechanistic investigation revealed that the present hydrofunctionalization proceeded through Brønsted acid-catalyzed intramolecular hydroalkoxylation of alkenes followed by InI3-catalyzed substitution reaction of cyclic ether intermediates.

Regio- and Stereoselective Allylindation of Alkynes Using InBr3 and Allylic Silanes: Synthesis, Characterization, and Application of 1,4-Dienylindiums toward Skipped Dienes.

Regioselective anti-allylindation of alkynes was achieved using InBr3 and allylic silanes. Various types of alkynes and allylic silanes were applicable to the present allylindation. This sequential process used the generated 1,4-dienylindiums to establish novel synthetic methods for skipped dienes. The 1,4-dienylindiums were characterized by spectral analysis and treated with I2 to stereoselectively give 1-iodo-1,4-dienes. The Pd-catalyzed cross coupling of 1,4-dienylindium with iodobenzene successfully proceeded in a one-pot manner to afford the corresponding 1-aryl-1,4-diene.

Coupling Reaction of Enol Derivatives with Silyl Ketene Acetals Catalyzed by Gallium Trihalides.

A cross-coupling reaction between enol derivatives and silyl ketene acetals catalyzed by GaBr3 took place to give the corresponding α-alkenyl esters. GaBr3 showed the most effective catalytic ability, whereas other metal salts such as BF3 ⋅OEt2 , AlCl3 , PdCl2 , and lanthanide triflates were not effective. Various types of enol ethers and vinyl carboxylates as enol derivatives are amenable to this coupling. The scope of the reaction with silyl ketene acetals was also broad. We successfully observed an alkylgallium intermediate by using NMR spectroscopy, suggesting a mechanism involving anti-carbogallation among GaBr3 , an enol derivative, and a silyl ketene acetal, followed by syn-ß-alkoxy elimination from the alkylgallium. Based on kinetic studies, the turnover-limiting step of the reaction using a vinyl ether and a vinyl carboxylate involved syn-ß-alkoxy elimination and anti-carbogallation, respectively. Therefore, the leaving group had a significant effect on the progress of the reaction. Theoretical calculations analysis suggest that the moderate Lewis acidity of gallium would contribute to a flexible conformational change of the alkylgallium intermediate and to the cleavage of the carbon-oxygen bond in the ß-alkoxy elimination process, which is the turnover-limiting step in the reaction between a vinyl ether and a silyl ketene acetal.

Synthesis of Thioethers by InI3-Catalyzed Substitution of Siloxy Group Using Thiosilanes.

The substitution of a siloxy group using thiosilanes smoothly occurred in the presence of InI3 catalyst to yield the corresponding thioethers. InI3 was a specifically effective catalyst in this reaction system, while other typical Lewis acids such as BF3⋅OEt2, AlCl3, and TiCl4 were ineffective. Various silyl ethers such as primary alkyl, secondary alkyl, tertiary alkyl, allylic, benzylic, and propargylic types were applicable. In addition, bulky OSitBuMe2 and OSiiPr3 groups, other than the OSiMe3 group, were successfully substituted. The substitution reaction of enantiopure secondary benzylic silyl ether yielded the corresponding racemic thioether product, which suggested that the reaction of tertiary alkyl, secondary alkyl, benzylic, and propargylic silyl ethers would proceed via a SN1 mechanism.

Indium Tribromide Catalyzed Coupling Reaction of Enol Ethers with Silyl Ketene Imines toward the Synthesis of ß,γ-Unsaturated Nitriles.

Herein, a coupling reaction of enol ethers with silyl ketene imines in the presence of catalytic amounts of InBr3 and Me3 SiBr is described. Kinetic studies have revealed that an indium catalyst and Me3 SiBr accelerated the coupling process and the regeneration of the catalyst, respectively. Various types of enol ethers and silyl ketene imines are applicable. In addition, a formal synthesis of verapamil was achieved by using this novel coupling reaction.