Photoredox Ring Opening 1,2-Alkylarylation of Alkenes with Sulfonium Salts Toward Thioether-Substituted Oxindoles.

A novel strategy for the difunctionalization of electron-deficient alkenes with aryl sulfonium salts to access remote sulfur-containing oxindole derivatives by using in situ-formed copper(I)-based complexes as a photoredox catalyst is presented. This method enables the generation of the C(sp3)-centered radicals through site selective cleavage of the C-S bond of aryl sulfonium salts under mild conditions. Moreover, the oxidation reactions of desired products provide a new strategy for the preparation of sulfoxide or sulfone-containing compounds. Importantly, this approach can be easily applied to late-stage modification of pharmaceuticals molecules.

Photocatalytic radical cyclization of N-(o-cyanobiaryl)acrylamides with oxime esters.

A visible-light-mediated radical cascade cyclization of N-(o-cyanobiaryl)acrylamides with oxime esters for the assembly of acyl-containing pyrido[4,3,2-gh]phenanthridines has been developed. The present protocol tolerates a wide range of oxime esters through a single reaction via fragmentation, radical addition, nitrile insertion, and cyclization under mild conditions.

Electro-oxidative three-component cascade coupling of isocyanides with elemental sulfur and amines for the synthesis of 2-aminobenzothiazoles.

2-Aminobenzothiazoles are commonly encountered in various functional compounds. Herein, we disclose an electro-oxidative three-component reaction for the effective synthesis of 2-aminobenzothiazoles under mild conditions, utilizing non-toxic and abundant elemental sulfur as the sulfur source. Both aliphatic amines and aryl amines demonstrate good compatibility at room temperature, highlighting the broad functional group tolerance of this approach. Additionally, elemental selenium demonstrated reactivities comparable to those of elemental sulfur.

Recent advances in ring-opening of cyclobutanone oximes for capturing SO2, CO or O2via a radical process.

Cyclobutanone oximes and their derivatives are pivotal core structural motifs in organic chemistry. Iminyl-radical-triggered C-C bond cleavage of cyclobutanone oximes delivers an efficient strategy to produce stable distal cyano-substituted alkyl radicals, which can capture SO2, CO or O2 to form cyanoalkylsulfonyl radicals, cyanoalkylcarbonyl radicals or cyanoalkoxyl radicals under mild conditions. In the past several years, cyanoalkylsulfonylation/cyanoalkylcarbonyaltion/cyanoalkoxylation has attracted a lot of interest. In this updated report, the strategies for trapping SO2, CO or O2via iminyl-radical-triggered ring-opening of cyclobutanone oximes are summarized.

Iron-Promoted Oxidative Alkylation/Cyclization of Ynones with 4-Alkyl-1,4-dihydropyridines: Access to 2-Alkylated Indenones.

An iron-promoted oxidative tandem alkylation/cyclization of ynones with 4-alkyl-substituted 1,4-dihydropyridines for the efficient synthesis of 2-alkylated indenones is described. The process occurs via oxidative homolysis of a C-C σ-bond in 1,4-dihydropyridines to generate an alkyl radical followed by the addition of C-C triple bonds in ynones and intramolecular cyclization. A wide range of alkyl radicals could be efficiently transferred to generate a series of synthetically useful 2-alkylated indenones with excellent selectivity under mild conditions.

Alkylation/Ipso-cyclization of Active Alkynes Leading to 3-Alkylated Aza- and Oxa-spiro[4,5]-trienones.

A method for the preparation of 3-alkylated spiro[4.5]trienones via alkylation/ipso-cyclization of activated alkynes with 4-alkyl-DHPs under transition-metal-free conditions is proposed. This alkylation successively undergoes the generation of alkyl radicals, addition of alkyl radicals to the alkynes, and intramolecular ipso-cyclization. The mechanism studies suggest that the alkylation/ipso-cyclization involves a radical process. This ipso-cyclization procedure shows a series of advantages, such as accessibility, mild conditions, high efficiency, greater safety, and an environmentally friendly method.

Cu-catalyzed oxidative denitrogenation of 3-aminoindazoles for the synthesis of isoquinolinones.

A Cu-catalyzed oxidative dual arylation of active alkenes via the cleavage of two C-N bonds of 3-aminoindazoles is presented for constructing isoquinolinones. Importantly, 3-aminoindazoles are used as efficient arylating agents through a radical process. This method has a good substrate scope and functional group compatibility.

Transition-metal-free alkylation strategy: facile access to alkylated oxindoles via alkyl transfer.

The transition-metal-free alkylation/cyclization of activated alkenes using Hantzsch ester derivatives as effective alkyl reagents is described. A wide variety of valuable oxindoles was constructed in a single step with excellent selectivity. The reaction occurs through the formation of alkyl radical species followed by the tandem addition/annulation of olefins under oxidative conditions. This protocol is expected to offer inspiration for developing novel and efficient applications of Hantzsch esters in organic synthesis.

Recent advances in total syntheses of natural products containing the benzocycloheptane motif.

Covering: 2010 to 2020Benzocycloheptane is a fundamental and unique structural motif found in pharmaceuticals and natural products. The total syntheses of natural products bearing the benzocycloheptane subunit are challenging and there are only a few efficient approaches to access benzocycloheptane. Thus, new methods and innovative strategies for preparing such natural products need to be developed. In this review, recent progress in the total syntheses of natural products bearing the benzocycloheptane motif is presented, and key transformations for the construction of benzocycloheptane are highlighted. This review provides a useful guide for those engaged in the syntheses of natural products containing the benzocycloheptane motif.

Synthetic applications of type II intramolecular cycloadditions.

Type II intramolecular cycloadditions ([4+2], [4+3], [4+4] and [5+2]) have emerged recently as an efficient and powerful strategy for the construction of bridged ring systems. In general, type II cycloadditions provide access to a wide range of bridged bicyclo[m.n.1] ring systems with high regio- and diastereoselectivity in an easy and straightforward manner. In each section of this review, an overview of the corresponding type II cycloadditions is presented, which is followed by highlights of method development and synthetic applications in natural product synthesis. The goal of this review is to provide a survey of recent advances in the field covering literature up to 2020. The review will serve as a useful reference for organic chemists engaged in the total synthesis of natural products containing bridged bicyclo[m.n.1] ring systems and provide strong stimulus for invention and further advances in this exciting research field.

Asymmetric Total Synthesis of Cyclocitrinol.

The first and asymmetric total synthesis of cyclocitrinol, an unusual C25 steroid, has been accomplished in a linear sequence of 18 steps from commercially available compound 11. The synthetically challenging bicyclo[4.4.1] A/B ring system with a strained bridgehead (anti-Bredt) double bond of cyclocitrinol was constructed efficiently and diastereoselectively via a type II intramolecular [5 + 2] cycloaddition.

Metal-Free Radical [2+2+1] Carbocyclization of Benzene-Linked 1,n-Enynes: Dual C(sp(3))-H Functionalization Adjacent to a Heteroatom.

A new metal-free oxidative radical [2+2+1] carbocyclization of benzene-linked 1,n-enynes with two C(sp(3))-H bonds adjacent to the same heteroatom is described. This method achieves two C(sp(3))-H oxidative functionalizations and an annulation, thus providing efficient and general access to a variety of fused five-membered carbocyclic hydrocarbons.

Palladium-catalyzed oxidative difunctionalization of alkenes with α-carbonyl alkyl bromides initiated through a Heck-type insertion: a route to indolin-2-ones.

The oxidative interception of various σ-alkyl palladium(II) intermediates with additional reagents for the difunctionalization of alkenes is an important research area. A new palladium-catalyzed oxidative difunctionalization reaction of alkenes with α-carbonyl alkyl bromides is described, in which the σ-alkyl palladium(II) intermediate is generated through a Heck insertion and trapped using an aryl C(sp(2))-H bond. This method can be applied to various α-carbonyl alkyl bromides, including primary, secondary, and tertiary α-bromoalkyl esters, ketones, and amides.

Radical relay strategy for the construction of alkylsulfonated indolo[2,1-a]isoquinoline-6(5H)-ones via SO2 insertion/Smiles rearrangement.

A new radical relay approach for the efficient construction of alkylsulfonated indolo[2,1-a]isoquinoline-6(5H)-ones in moderate to good yields under mild conditions via SO2 insertion/Smiles rearrangement/intramolecular cyclization is developed. This approach utilizes 4-alkyl substituted Hantzsch esters as alkyl radical sources and further undergoes in situ SO2 insertion to obtain alkylsulfonyl radical species, which avoids the use of unstable alkyl sulfonyl chlorides and highly toxic sulfonyl hydrazides. Additionally, this method for the direct assembly of alkylsulfonated polycyclic molecule skeletons displays high chemical selectivity, broad substrate scope, and step-economy.

Radical Cascade Cyclization of N-(o-Cyanobiaryl)acrylamides with Sulfonium Salts via Synergetic Photoredox and Copper Catalysis.

As the magic methyl effect is well acknowledged in pharmaceutical molecules, the development of simple and efficient methods for the installment of methyl groups on complex molecules is highly coveted. Hence, we provide a general strategy for radical cascade cyclization of N-(o-cyanobiaryl)acrylamides by utilizing sulfonium salts as the sources of methyl radical and merging photoredox and copper catalysis. This novel protocol can access a wide variety of methylation or remote thioether-substituted benzo-fused N-heterocycle derivatives, which can be easily transformed into diverse highly valuable sulfone and sulfoximine compounds via late-stage diversification. Moreover, to further demonstrate the synthetic utility of this conversion, the methyl(phenyl)sulfide, which serves as both raw material and byproduct, can be recovered and reused in this transformation. The scale-up experiment for the one-pot two-step process directly offers the target product in good yield under the standard conditions.

Oxidative Difunctionalization of N-Aryl Bicyclobutyl Amides with Aldehydes: Divergent Synthesis of Acylated and Alkylated 3-Spirocyclobutyl Oxindoles.

An efficient and operationally simple oxidative radical difunctionalization of N-aryl bicyclobutyl (BCB) amides with aldehydes is described. It was found that acylated 3-spirocyclobutyl oxindoles were generated from the coupling of BCB-amides and aromatic aldehydes, while reactions gave exclusively decarbonylative alkylarylation products using alkyl aldehydes as radical precursors.

Photoredox-Catalyzed Alkylarylation of N-Aryl Bicyclobutyl Amides with α-Carbonyl Alkyl Bromides: Access to 3-Spirocyclobutyl Oxindoles.

A visible-light-induced radical alkylarylation of N-aryl bicyclobutyl amides with α-carbonyl alkyl bromides for the synthesis of functionalized 3-spirocyclobutyl oxindoles is described in which ß-selective radical addition of the alkyl radical to N-aryl bicyclobutyl amides forms a key radical intermediate followed by interception with intrinsic arene functional group. This approach can be applicable to a wide range of α-carbonyl alkyl bromides, including primary, secondary, and tertiary α-bromoalkyl esters, ketones, nitriles, and nitro compounds.

Synthetic Study toward the Total Synthesis of Taxezopidines A and B.

A concise synthetic approach to construct the [6,8,6]-tricyclic core of taxezopidines A and B, which contains a synthetically challenging bridged bicyclo[5.3.1]undecane ring system bearing most of the desired functionalized groups and stereocenters, has been established. This approach features a diastereoselective type II intramolecular Diels-Alder furan reaction. The stereochemistry of the acetoxy group at the allylic position of the dienophile alkene group, such as in 6a, was found to be critical for achieving the desired highly diastereoselective outcome.

Long-term results of paclitaxel plus cisplatin with concurrent radiotherapy for loco-regional esophageal squamous cell carcinoma.

AIM: To evaluate the long-term effectiveness and late toxicities of paclitaxel (PTX) plus cisplatin (DDP) with concurrent radiotherapy for locally advanced esophageal squamous cancer. METHODS: Between 2008 and 2011, 76 patients were enrolled in a phase II study on the treatment of loco-regionally advanced esophageal cancer with radiotherapy (68.4 Gy/44 fractions or 61.2 Gy/34 fractions) combined with 4-cycle chemotherapy consisting of DDP (25 mg/m2 per day for 3 d) and PTX (175 mg/m2 for 3 h). The primary endpoints were overall survival and progression-free survival, and the secondary endpoints were toxicity and the treatment failure pattern. RESULTS: A total of 76 patients were enrolled in this study, of whom 63.2% finished the whole regimen. The 5-year survival rates for the per-protocol population and intent-to-treat population were 25.4% and 26.4%, respectively, and the median survival rates were 23.7 mo and 28.5 mo, respectively. Grade 3 or 4 late toxicity was observed in only one patient (heart failure). In log-rank analysis, the pretreatment stage (stage II + III: 36.1 mo vs stage IV: 14.9 mo) and the completed cycle (1-3 cycles: 16.1 mo vs 4 cycles: 35.5 mo) were significant prognostic factors (P = 0.037 < 0.05 and P = 0.013 < 0.05). CONCLUSION: Radiotherapy combined with chemotherapy consisting of PTX and DDP is a safe and effective definitive treatment for loco-regionally advanced esophageal squamous cancer.