Photocatalytic Cyclization Cascades by Radical Relay toward Pyrrolo[1,2-a]indoles: Synthesis, Mechanism, and Application.

A photocatalytic annulation cascade of unactivated N-alkene-linked indoles with Langlois' reagent by a radical relay is developed at room temperature under blue LED irradiation. The reaction afforded a series of tri/difluoromethylated pyrrolo[1,2-a]indoles in moderate to good yields. The DFT study suggests that the reaction is ascribed to a rhodamine 6G-induced cyclization cascade involving vinyl addition-radical relay and hydrogen-atom-abstraction (HAA) processes, and interestingly, pyrrolo[1,2-a]indoles are applied as fluorescent dyes into the fluorescence spectrum and live-cell imaging. This paper represents an initial example on photocatalytic cyclization cascades by radical relay and the HAA process.

Iron-catalyzed ß-hydroxymethylative carbonylation of styrene under photo-irradiation.

This study describes an iron-catalyzed divergent oxidation of styrene into ß-hydroxylmethylketone and ketone under photo-irradiation. This divergence is ascribed to the use of styrene with various substituents. More importantly, methanol is oxidized into formaldehyde in the reaction and serves as a C1 synthon. Mechanism investigations show that the reaction is initiated by oxidative SET to transfer styrene into the cation radical. The reaction pathway undergoes HAT and ß-hydride elimination as well as a concerted cyclization. Particularly, several drug-like molecules, such as melperone analogue, lenperone analogue, and haloperidol analogue, are synthesized. In addition, this method is also applicable to the synthesis of natural product (R)-atomoxetine.

Solvent-promoted photochemical carbonylation of benzylic C-H bonds under iron catalysis.

This paper describes the iron-catalyzed photochemical carbonylation of benzylic C-H bonds resulting in the synthesis of various aryl ketones. Using 5 W blue LED irradiation, the reactions proceed smoothly in the presence of 2 mol% of FeBr3 in MeOH at 35 °C. The catalytic system could be extended for the oxidation of silane, thioether, and phosphine into silenol, sulphoxide, and phosphoxide, respectively. A mechanistic study suggests that a hydrogen bond-stabilized iron-hydroperoxo species is the reactive intermediate. It is shown that the reaction proceeds via a four-electron-transfer pathway, and a benzylic cation seems to be the crucial reactive species. The method is applied for the synthesis of pomalyst, haloperidol, melperone, and lenperone.

Iron/photoredox dual catalysis for acyl nitrene-based C-O bond formation towards phthalides.

This paper describes iron/photoredox dual-catalyzed acyl nitrene formation and the use of acyl nitrene in constructing various C-O bonds towards phthalides. The developed reaction starts from N-methoxyl-2-alkylbenzamides. Mechanism surveys suggest the reaction involves iron nitrene-based hydrogen atom abstraction (HAA), radical-polar crossover and O-nucleophilic SN1. Distinctively, the often-reported radical rebound in previous publications is not observed. The reaction represents the first example on acyl nitrene-based synthesis of phthalides. Moreover, it also serves as a supplement for the synthesis of marketed medicines such as 3-butylphthalides (NBP), thalidomide, Pomalyst and Otezia.

Photoredox/Iron Dual-Catalyzed Insertion of Acyl Nitrenes into C-H Bonds.

In this work, the use of N-acyloxybenzamides as efficient acyl nitrene precursors under photoredox/iron dual catalysis is reported. The resulting acyl nitrenes could be captured by various types of C-H bonds and S- or P-containing molecules. Mechanism investigations suggested that the formation of the acyl nitrene from the N-acyloxybenzamide occurs by a photoredox process, and it is believed that in this redox process oxidative N-H bond cleavage of the N-acyloxybenzamide occurs prior to reductive N-O bond cleavage of the N-acyloxybenzamide.

Palladium-Catalyzed Preparation of N-Substituted Benz[c,d]indol-2-imines and N-Substituted Amino-1-naphthylamides.

Here, we report a novel and facile protocol for the synthesis of benz[c,d]indol-2-imines via palladium-catalyzed C-C and C-N coupling of 8-halo-1-naphthylamines with isocyanides in a single step. The reaction features broad substrate scopes and mild conditions, providing an efficient alternative for the construction of antiproliferative agents and BET bromodomain inhibitors. If 0.1 mL of H2O was added to this reaction, the N-substituted amino-1-naphthylamides could be obtained easily.

Iron-catalyzed stereoselective haloamidation of amide-tethered alkynes.

In this work, by using N-methoxybenzamides as efficient acyl nitrene precursors, an iron-catalyzed formal cis-haloamidation of alkyne is reported. Without assistance of additives, the reaction worked well in the presence of 50 mol% FeCl3 or FeBr3, leading to a series of chloro/bromo-containing isoindolin-5-ones with high efficiency and wide reaction scope. In the reaction, the iron-facilitated haloamidation proceeds through a halo anion-participating concerted [3+2] cyclization to release the final products. The key intermediate ferric acyl nitrene A is generated in situ from a formal removal of MeOH.

The copper-catalyzed synthesis of (Z)-2H-naphtho[1,8-bc]thiophenes with solid emission.

In recent years, one of the main research interests of our group has been the construction of 6/5 π-systems through the regioselective conversion of parallel alkynes in naphthalene with the aim of exploiting potential fluorescent materials. Herein, the copper-catalyzed synthesis of polysubstituted (Z)-2H-naphtho[1,8-bc]thiophenes from 8-halo-1-ethynylnaphthalenes using potassium ethylxanthate as the sulfur source is reported. In this protocol, a series of thiophene-fused 6/5 π-system compounds was synthesized via copper-catalyzed Ullmann-type C(aryl)-S bond formation and the α-addition of an alkyne bond with high selectivity and in high yields. The synthesized polysubstituted (Z)-2H-naphtho[1,8-bc]thiophenes exhibited solid emission, which made them potential candidates for use in optoelectronic conjugated materials. By using DMSO/D2O (3 : 1) as the reaction solvent, the deuterated products could be obtained in good yields under standard conditions.

Radical bromination-induced ipso cyclization-ortho cyclization sequence of N-hydroxylethyl-N-arylpropiolamides.

A facile procedure is reported for the synthesis of various 2-bromo-1-phenyl-5,6-dihydro-3H,7aH-benzo[b]pyrrolo[2,1-c][1,4]oxazin-3-ones via a radical bromination-induced ipso cyclization-ortho cyclization sequence of N-arylpropiolamides in the presence of TBAB and oxone. The radical cyclization sequence involves a radical bromo α-addition into the alkyne, ipso-cyclization, and ortho-trapping of the spirocyclic intermediate.

Iron-catalyzed intramolecular acyl nitrene/alkyne metalation for the synthesis of pyrrolo[2,1-a]isoindol-5-ones.

In this work, by using N-methoxybenzamides as efficient acyl nitrene precursors, an iron-catalyzed acyl nitrene/alkyne metalation is reported for the synthesis of pyrrolo[2,1-a]isoindol-5-ones. In the reaction, a 5-exo-dig acyl nitrene/alkyne metalation is specifically observed; a counter anion-aided acyl nitrene/alkyne metalation accounts for the formation of pyrrolo[2,1-a]isoindol-5-ones. Moreover, pyrrolo[2,1-a]isoindol-5-ones possess good fluorescence properties exhibiting a long Stokes shift (>100 nm), and have been employed as small molecular probes for the detection of Hg2+, hydrazine, and cysteine.

In Vitro Hepatic Metabolism of Curcumin Diethyl Disuccinate by Liver S9 from Different Animal Species.

Liver S9 (LS9) is a nearly complete collection of all hepatic drug-metabolizing enzymes. It is a low-cost model for predicting drug metabolic activity. This study aimed to identify the suitability of using LS9 of different animal sources in drug metabolism profiling with respect to the possible translation of the in vitro outcomes to clinical studies. The in vitro hepatic metabolism of curcumin diethyl disuccinate (CDD) in LS9 of rats, dogs, monkeys, and humans was evaluated. The identity of CDD metabolites and the metabolism kinetic parameters, including degradation rate constant, in vitro/in vivo intrinsic clearance, and half-life, were determined. CDD was rapidly metabolized into monoethylsuccinyl curcumin and curcumin in LS9 of all tested species mainly by carboxylesterases (CESs), including CES1 and CES2, and butyrylcholinesterase. The in vitro intrinsic clearance of CDD was in the order of human > dog > monkey > rat, whereas that of monoethylsuccinyl curcumin in the order of dog > monkey > human > rat; this parameter was not correlated with their respective in vivo clearance, which followed the order of dog > monkey > rat > human. Therefore, in vitro drug metabolism data inferred from LS9 of nonhuman origin, especially from monkeys and dogs, cannot be used as preclinical data for human trials, as humans have a smaller liver-to-body weight ratio than monkeys, dogs, and rats. The in vivo drug metabolism is dictated by the anatomical factors of the test subject.

Copper-Catalyzed Tandem Radical Cyclization of 8-Ethynyl-1-naphthyl-amines for the Synthesis of 2H-Benzo[e][1,2]thiazine 1,1-Dioxides and its Fluorescence Properties.

A copper-catalyzed radical cascade dehydrogenative cyclization of N-tosyl-8-ethynyl-1-naphthylamines under air is described herein for the synthesis of thioazafluoranthenes. The reaction proceeds smoothly with high efficiency and a broad reaction scope. The product is indeed a new fluorophore and its photophysical properties are also investigated. Based on the results, we are pleased to find that the Stokes shift of amino-linked thioazafluoranthenes in dilute tetrahydrofuran is determined to be 143 nm (4830 cm-1).

Copper-Catalyzed Preparation of Benzo[3,4]indolo[1,2-b]isoquinoline-8-ones and Photoluminescence Exploration.

A facile synthesis of benzo[3,4]indolo[1,2-b]isoquinolin-8-ones is described. Under copper catalysis, the reaction proceeds with a high efficiency and a broad reaction scope. A deuteration experiment shows that the KIE value is 2.85. From the results on mechanism studies, copper-catalyzed C-H activation, intramolecular cis-addition of alkynes, and reductive elimination are involved. Moreover, this skeleton is indeed a new fluorophore, and its photophysical properties are also investigated.

Palladium-Catalyzed Imidoylation-Triggered [2 + 2 + 1] Cyclization of Internal Alkyne with Isocyanides.

In this work, a palladium-catalyzed [2 + 2 + 1] cyclization of internal alkynes with double isocyanides is described. This facile procedure is efficient for synthesizing various pyrrolo[3,2-c]quinolin-2-amines. The reaction worked well with a broad reaction scope. In the process, it is believed that sequential double isocyanide insertion, 6-exo-dig cyclization of alkyne, and addition of an imino group are involved.

Palladium-Catalyzed Cycloaddition of Alkynylimines, Double Isocyanides, and H2O/KOAc.

In this work, a palladium-catalyzed cyclization of alkynylimines and double isocyanides is described. This facile procedure is efficient for synthesizing various 4-amidyl-2-aminopyrroles. Mechanism investigation indicates that a four-membered ring-fused pyrrole species is a key intermediate and the reaction involves [4 + 1] cycloaddition, protonation, nucleophilic addition, 1,4-addition of isocyanide, and rearomatization. Interestingly, the linear dipyrrole derivative is found to be an appropriate fluoride ion probe with a remarkable emission change, which could serve as a potential candidate for optoelectronic conjugated materials.

Synthesis of 3-Hydroxyisoindolin-1-ones through 1,4-Dioxane-Mediated Hydroxylhydrative aza-Cyclization of 2-Alkynylbenzamide in Water.

In this work, 1,4-dioxane-mediated hydroxylhydrative aza-cyclization of 2-alkynylbenzamide is developed for the synthesis of 3-hydroxylisoindolin-1-ones. The transformation proceeds smoothly in water with good yields and a broad reaction scope. Mechanistic studies show that regioselective brimonative 5-exo-dig aza-cyclization, bromohydration of the resulting alkene groups, and hydrolysis of dibromo compounds are involved. Compared to the traditional methodologies, the synthetic procedure reported herein represents a cleaner route toward 3-hydroxylisoindolin-1-ones.

Ortho-Hydroxylative ipso-Cyclization of N-arylpropiolamide.

A facile protocol for the tunable synthesis of 10-hydroxy-1-azaspiro[4.5]deca-3,6,8-trien-2-ones and benzo[b]pyrrolo[2,1-c][1,4]oxazin-3-ones is described. A tunable synthesis has been realized by the use of ZnBr2/oxone and tetra-n-butylammonium bromide (TBAB)/oxone. The reaction proceeds smoothly with high efficiency and a broad substrate scope. Mechanistic studies indicate that an N-protecting group-assisted ortho-trapping reaction is involved. In the transformation, the reaction undergoes α-addition, ipso-cyclization, and ortho-trapping of the resulting spirocyclic species.

Tunable Synthesis of 3-Hydroxylisoquinolin-1,4-dione and Isoquinolin-1-one Enabled by Copper-Catalyzed Radical 6-endo Aza-cyclization of 2-Alkynylbenzamide.

In this work, switchable synthesis of isoquinolin-1-one and 3-hydroxylisoquinolin-1,4-dione from 2-alkynylbenzamide is reported. The transformation works well with good yields and a broad reaction scope. The synthetic switch for providing isoquinolin-1-one and 3-hydroxylisoquinolin-1,4-dione is enabled by the use of a N2 or O2 atmosphere. Mechanism studies show that the reaction proceeds in a regioselective manner via a N-center radical 6-endo-dig aza-cyclization pathway.

External Reductant-Free Palladium-Catalyzed Reductive Insertion of Isocyanide: Synthesis of Polysubstituted Pyrroles and Its Applications as a Cysteine Probe.

In this work, an unprecedented route is described for the synthesis of 2-amino-4-cyanopyrrole derivatives via palladium-catalyzed reductive isocyanide insertion of alkynyl imines. In the reactions, no external reductant is added and isocyanide plays a dual role as both a C1 synthon for imidoylation and a cyano source for cyanation. Mechanism studies suggest a [4 + 1] cycloaddition, an isocyanide insertion, ß-carbon elimination, and palladium hydride-based reduction are involved. Moreover, the application of 2-amine-4-cyanopyrroles as a cysteine probe is realized to detect cysteine.

Oxidative oxy-cyclization of 2-alkynylbenzamide enabled by TBAB/Oxone: switchable synthesis of isocoumarin-1-imines and isobenzofuran-1-imine.

A TBAB-catalyzed oxidative 6-endo-dig oxy-cyclization of 2-alkynylbenzamide is described herein for the synthesis of isocoumarin-1-imines. The transformation proceeds regioselectively and provides the final products with high efficiency and a broad reaction scope. Interestingly, an array of isobenzofuran-1-imines is also achieved under standard conditions when N-phenyl 2-trimethylsilylethynylbenzamides are used as substrates. Mechanism studies show that 3-bromomethenisobenzofuran-1-imine is a pivotal intermediate, which goes through C-O bond migration and debromination to offer the final isocoumarin-1-imines.