An Axially Chiral Styrene-Phosphine Ligand for Pd-Catalyzed Asymmetric N-Alkylation of Indoles.

An efficient palladium-catalyzed enantioselective direct N-alkylation of indoles using a novel type of axially chiral styrene-phosphine ligand SJTU-PHOS-1 was developed. This reaction demonstrated good functional group compatibility and a wide range scope of substrates in mild conditions. Moreover, the DFT calculations expounded the coordination mode of the metal catalyst and the axially chiral styrene-phosphine ligand in the enantioselectivity control.

Axially chiral styrene-based organocatalysts and their application in asymmetric cascade Michael/cyclization reaction.

An axially chiral styrene-based organocatalyst, featuring a combination of axially chiral styrene-based structure and a pyrrole ring, has been designed and synthesized. This catalyst demonstrates remarkable capabilities in producing a wide range of densely substituted spirooxindoles that feature an alkyne-substituted quaternary stereogenic center. These spirooxindoles are generated through mild cascade Michael/cyclization reactions, resulting in high conversion rates and exceptional enantioselectivity. Our catalytic model, based on experiments, X-ray structure analysis and DFT calculations suggests that chiral matched π-π interactions and multiple H-bonds between the organocatalyst and substrates play significant roles in controlling the stereoselectivity of the reaction.

Asymmetric Intramolecular Hydroalkylation of Internal Olefin with Cycloalkanone to Directly Access Polycyclic Systems.

An asymmetric intramolecular hydroalkylation of unactivated internal olefins with tethered cyclic ketones was realized by the cooperative catalysis of a newly designed chiral amine (SPD-NH2 ) and PdII complex, providing straightforward access to either bridged or fused bicyclic systems containing three stereogenic centers with excellent enantioselectivity (up to 99 % ee) and diastereoselectivity (up to >20 : 1 dr). Notably, the bicyclic products could be conveniently transformed into a diverse range of key structures frequently found in bioactive terpenes, such as Δ6 -protoilludene, cracroson D, and vulgarisins. The steric hindrance between the Ar group of the SPD-NH2 catalyst and the branched chain of the substrate, hydrogen-bonding interactions between the N-H of the enamine motif and the C=O of the directing group MQ, and the counterion of the PdII complex were identified as key factors for excellent stereoinduction in this dual catalytic process by density functional theory calculations.

Electrochemical collective synthesis of labeled pyrroloindoline alkaloids with Freon-type methanes as functional C1 synthons.

Utilization of Freon-type methanes as functional one-carbon synthons in the synthesis of various deuterated indoline alkaloids was demonstrated here. A series of halomethyl radicals were generated from electro-reductive C-X cleavage of Freon-type methanes and captured efficiently by acrylamides to provide various halogenated oxindoles via radical cyclization. This reaction features good functional group tolerance, and deuterium and fluorine atoms could be introduced facilely from Freon-type methanes. Further transformation of halogenated oxindoles enabled the synthesis of many (labeled) bioactive drug molecules and skeletons, such as deuterated (±)-physostigmine, deuterated (±)-esermethole and deuterated (±)-lansai B.

Facile Benzylic Alkylation of Arenes with Alcohols by Catalysis with Spirocyclic NHC IrIII Pincer Complex.

A facile benzylic alkylation of indenes and other arenes was developed from readily available primary and secondary alcohols using our newly investigated CCC pincer IrIII catalyst (SNIr-H). Excellent regioselectivity and yield (89 %) of the C3-alkylated indenes were obtained. Additionally, the challenging sp2 C-alkylation was readily accomplished. This method could be utilized for the synthesis of the analogs of a histamine H1 receptor antagonist and the functional material template molecule, indeno[2,1-a]indene. A hemilabile IrIII -dihydride intermediate was proposed based on control experiments and previous density functional theory (DFT) calculations for the borrowing hydrogen mechanism and is key to the success of this IrIII catalyst in the reduction of unactivated multi-substituted olefin intermediates.

Bioinspired Palladium-Catalyzed Intramolecular C(sp3 )-H Activation for the Collective Synthesis of Proline Natural Products.

Bioinspired palladium-catalyzed intramolecular cyclization of amino acid derivatives containing a vinyl iodide moiety by C-H activation enabled rapid access to a wide range of functionalized proline derivatives with an exocyclic olefin. To demonstrate the practicality of this methodology, the functionalized prolines were used as intermediates for the synthesis of several natural products: lucentamycin A, oxotomaymycin, oxoprothracarcin, and barmumycin.

Phosphoric Acid Catalyzed Electrophilic Thiocyanation of Indoles: Access to SCN-Containing Aryl-Indole Compounds.

A phosphoric acid catalyzed electrophilic thiocyanation of 3-aryl indoles, which provides an efficient and modular approach to SCN-containing 3-aryl indole compounds, was developed for the first time. A variety of 2-SCN-3-aryl indoles were obtained with moderate to excellent yields. Furthermore, catalytic asymmetric manner of this reaction was also studied. Using chiral phosphoric acid as the catalyst, axially chiral SCN-containing 3-aryl indoles were obtained in moderate to good yields with moderate enantioselectivity.

Chiral Selenide/Achiral Sulfonic Acid Cocatalyzed Atroposelective Sulfenylation of Biaryl Phenols via a Desymmetrization/Kinetic Resolution Sequence.

Enantioselective synthesis of axially chiral sulfur-containing biaryl derivatives through the electrophilic sulfenylation of biaryl phenols has been achieved for the first time. This catalytic asymmetric system, which involves sequential desymmetrization and kinetic resolution, is enabled by a combination of a novel 3,3'-disubstituted BINOL-derived selenide catalyst and an achiral sulfonic acid. Control experiments and computational studies suggest that multiple noncovalent interactions between the cocatalysts and substrate, especially a network of hydrogen bond interactions, play a crucial role in determining the enantioselectivity and reactivity.

Brønsted acid-catalyzed solvent-controlled regioselective hydrothiolation and diastereoselective cascade cyclization of dienes.

A highly regio- and diastereo-selective Brønsted acid-catalyzed tandem hydrothiolation/Friedel-Crafts reaction of linear 1,3-dienes has been developed for the first time, which provides a metal-free and atom-economic way of constructing thiochromane derivatives. Meanwhile, by changing the solvent, 4,3-addition hydrothiolation of 1,3-dienes was also discovered. The origin of the observed selectivity was explained by density functional theory calculations.

Enantioselective Synthesis of 3,3'-Disubstituted 2-Amino-2'-hydroxy-1,1'-binaphthyls by Copper-Catalyzed Aerobic Oxidative Cross-Coupling.

A challenging direct asymmetric catalytic aerobic oxidative cross-coupling of 2-naphthylamine and 2-naphthol, using a novel CuI /SPDO system, has been successfully developed for the first time. Enantioenriched 3,3'-disubstituted NOBINs were achieved and could be readily derived to divergent chiral ligands and catalysts. This reaction features high enantioselectivities (up to 96 % ee) and good yields (up to 80 %). The DFT calculations suggest that the F-H interactions between CF3 of L17 and H-1,8 of 2-naphthol, and the π-π stacking between the two coupling partners could play vital roles in the enantiocontrol of this cross-coupling reaction.

Divergent Synthesis of Trifluoromethyl Sulfoxides and ß-SCF3 Carbonyl Compounds by Tandem Trifluoromethylthiolation/Rearrangement of Allylic and Propargylic Alcohols.

A selenium-catalyzed trifluoromethylthiolation/[2,3]-sigmatropic rearrangement of tertiary allylic and propargylic alcohols which could provide straightforward and facile access to trifluoromethyl sulfoxides was developed. Various allylic and allenic trifluoromethyl sulfoxides were obtained with moderate to excellent yields. Meanwhile, a Lewis acid mediated trifluoromethylthiolation/1,2-rearrangement to synthesize ß-SCF3 carbonyl compounds was also accomplished. These two tandem reactions feature with mild reaction conditions and metal-free. During these two reactions, the chemoselectivity of electrophilic trifluoromethylthiolation was revealed.

Lewis-Acid-Mediated Intramolecular Trifluoromethylthiolation of Alkenes with Phenols: Access to SCF3-Containing Chromane and Dihydrobenzofuran Compounds.

A Lewis-acid-mediated intramolecular trifluoromethylthiolation of alkenes with phenols that can offer direct access to SCF3-containing chromane and dihydrobenzofuran compounds was disclosed for the first time. Numerous SCF3-containing chromanes were obtained in moderate to good yields using γ-substituted 2-allyphenols as substrates. Meanwhile, various SCF3-containing dihydrobenzofurans with oxa-quaternary centers were also delivered in moderate to good yields using ß-substituted 2-allyphenols as substrates.

Fe-Catalyzed Sequential C(sp3)-H/N-H Annulation of 2-Methylindoles with Ethyl Trifluoropyruvate at Room Temperature: Construction of Pyrrolo[1,2-α]indoles.

An efficient and benign iron-catalyzed room-temperature method was developed for direct sequential C(sp3)-H/N-H annulation to construct pyrroloindole scaffolds. This strategy features cheap and readily available raw materials and mild room-temperature reaction conditions and provides a green and practical method for the one-pot rapid synthesis of a wide range of diversely functionalized pyrrolo[1,2-α]indoles.

Total Synthesis of Fawcettimine-Type Alkaloid, Lycojaponicumin A.

The efficient total synthesis of lycojaponicumin A (1) has been accomplished for the first time. The remarkable features of this novel strategy include the following: (1) rapid construction of tricyclic intermediate 4 through a regio- and stereoselective semipinacol ring expansion, which simplified the construction of rings A and B of 1; (2) the subsequent regio- and stereoselective formation of the highly strained rings C-E of 1 through a tandem oxa-hetero [3 + 2] cycloaddition/N-cycloalkylation.

Highly Chemo-, Site-, and Enantioseletive para C-H Aminoalkylation of N-Monosubstituted Aniline Derivatives Affording 3-Amino-2-oxindoles.

In general, enantioselective C-H functionalization of N-monosubstituted anilines is a highly challenging task owing to the competitive chemoselective N-H bond insertion reactions. In this paper, we reported a direct highly chemo-, site-, and enantioselective para C-H aminoalkylation of N-monosubstituted aniline derivatives with isatin-derived ketimines in the presence of chiral phosphoric acids (CPAs) and offered a practical strategy for para asymmetric C-H functionalization of anilines containing N-H bonds.

Cobalt-Catalyzed Ortho-C(sp2)-H Amidation of Benzaldehydes with Dioxazolones Using Transient Directing Groups.

An efficient and convenient cobalt-catalyzed ortho-C(sp2)-H amidation of benzaldehydes employing dioxazolones as the aminating reagent has been developed. The key feature of this protocol is the use of green and economic earth-abundant metals cobalt as the catalyst with the p-chloroaniline as the transient directing group. Further application of our approach was demonstrated by the synthesis of C1r serine protease inhibitor 45 and elastase inhibitor 49.

Rhodium(iii)-catalysed cascade [3 + 2] annulation of N-aryloxyacetamides with 3-(hetero)arylpropiolic acids: synthesis of benzofuran-2(3H)-ones.

Herein, a cascade [3 + 2] annulation of N-aryloxyacetamides with 3-(hetero)arylpropiolic acids affording benzofuran-2(3H)-ones via rhodium(iii)-catalyzed redox-neutral C-H functionalization/isomerization/lactonization using an internal oxidative directing group O-NHAc was achieved. This catalytic system provides a regio- and stereoselective approach to synthesize (Z)-3-(amino(aryl)methylene)benzofuran-2(3H)-ones with exclusive Z configuration selectivity, acceptable yields and good functional group tolerance. Preliminary investigations on ultraviolet-visible and fluorescence behaviors reveal that the annulation products may be applied as a promising fluorescent probe for sensing metal cations, especially for cerium (Ce3+).

Highly atroposelective synthesis of nonbiaryl naphthalene-1,2-diamine N-C atropisomers through direct enantioselective C-H amination.

Nonbiaryl N-C atropisomer is an important structural scaffold, which is present in natural products, medicines and chiral ligands. However the direct enantioselective C-H amination to access optically pure N-C atropisomer is still difficult and rare. Here we report a π-π interaction and dual H-bond concerted control strategy to develop the chiral phosphoric acids (CPAs) catalyzed direct intermolecular enantioselective C-H amination of N-aryl-2-naphthylamines with azodicarboxylates as amino sources for the construction of atroposelective naphthalene-1,2-diamines. This type of N-C atropisomers is stabilized by intramolecular hydrogen bond and the method features a broad range of substrates, high yields and ee values, providing a strategy to chirality transfer via the modification of N-C atropisomers.

Asymmetric N-Hydroxyalkylation of Indoles with Ethyl Glyoxalates Catalyzed by a Chiral Phosphoric Acid: Highly Enantioselective Synthesis of Chiral N,O-Aminal Indole Derivatives.

A method of SPINOL-derived chiral phosphoric acid catalyzed asymmetric intermolecular N-hydroxyalkylation of multisubstituted indoles with ethyl glyoxalates is described in this report. This protocol provides an alternative, convenient, and direct strategy for efficient access to structurally unique α-chiral indole N,O-acyclic aminals with a broad substrate scope and good to excellent enantioselectivities. The synthetic utility of this methodology is illustrated by a gram-scale experiment and the subsequent efficient synthesis of more complex chiral N,O-aminal indole derivatives.