Advances in the synthesis of functionalized tetrahydropyridazines from hydrazones.

The tetrahydropyridazine motif is widely present in plenty of natural products and biologically active molecules. Easily prepared from the condensation of carbonyls with hydrazines, hydrazones are versatile synthetic building blocks that are frequently used in organic synthesis. Hydrazones are also utilized in the synthesis of nitrogen-containing molecules, especially nitrogen-containing heterocycles. The presence of the CN-N unit in the product makes hydrazones ideal substrates for the synthesis of tetrahydropyridazine derivatives. Here, in this review, we summarize the recent progress in the construction of variously substituted tetrahydropyridazines from different hydrazone derivatives together with mechanism discussions.

Organophotocatalytic pyridination of N-arylglycines with 4-cyanopyridines by decarboxylative and decyanative radical-radical coupling.

A photocatalytic decarboxylative aminoalkylation of 4-cyanopyridines with N-arylglycines is achieved, providing 4-(aminomethyl)pyridine derivatives in moderate to good yields. This organic photocatalytic reaction undergoes a radical-radical cross-coupling process under redox-neutral conditions, featuring simple operation, readily available N-arylglycines and a broad substrate scope. Mechanistic investigations indicated that a proton-coupled electron-transfer process was involved to enable the single electron transfer between the reduced photocatalyst and 4-cyanopyridine in the presence of N-arylglycines.

Metal-free polychloromethylation/cyclization of unactivated alkenes towards ring-fused tricyclic indolones and benzoimidazoles.

Polychloromethylative cyclization of N-alkenyl indoles was developed under metal-free conditions to afford tricyclic pyridoindolones and pyrroloindolones in moderate to good yields. In the reaction, commercially available CHCl3 and CH2Cl2 were employed as tri- and dichloromethyl radical sources. Moreover, tri- and dichloromethylated polycyclic benzoimidazoles can also be obtained under standard conditions.

Recent advances in C-H functionalization of 2H-indazoles.

2H-Indazoles are one class of the most important nitrogen-containing heterocyclic compounds. The 2H-indazole motif is widely present in bioactive natural products and drug molecules that exhibit distinctive bioactivities. Therefore, much attention has been paid to access diverse 2H-indazole derivatives. Among them, the late-stage functionalization of 2H-indazoles via C-H activation is recognized as an efficient approach for increasing the complexity and diversity of 2H-indazole derivatives. In this review, we summarized recent achievements in the late-stage functionalization of 2H-indazoles, including the C3-functionalization of 2H-indazoles through transition metal-catalyzed C-H activation or a radical pathway, transition metal-catalyzed ortho C2'-H functionalization of 2H-indazoles and remote C-H functionalization at the benzene ring in 2H-indazoles.

Metal-free polychloromethyl radical-initiated cyclization of unactivated N-allylindoles towards pyrrolo[1,2-a]indoles.

A metal-free polychloromethyl radical-initiated cyclization of unactivated alkenes was developed using CH2Cl2 and CHCl3 as the di- and trichloromethyl radical sources. Variously substituted N-allyl-indoles were successfully transformed into the corresponding C2-(di- and trichloromethyl) pyrrolo[1,2-a]indoles in moderate to good yields. This reaction has a broad substrate scope and good functional group tolerance. Dibromomethylated products can also be obtained using CH2Br2 under standard conditions.

Three-component synthesis of arylsulfonyl-substituted indolo[2,1-a]isoquinolinones and benzimidazo-[2,1-a]isoquinolin-6(5H)-ones by SO2 insertion and radical cascade cyclization.

An efficient arylsulfonylation/cyclization of 2-aryl-N-methacryloyl indoles with potassium metabisulfite and aryldiazonium tetrafluoroborates was developed. A series of variously substituted arylsulfonyl indolo[2,1-a]isoquinolin-6(5H)-ones were formed in moderate to good yields via utilization of the nature abundant inorganic salt potassium metabisulfite as a SO2 surrogate. Additionally, this three-component protocol can also be employed for the synthesis of arylsulfonyl-substituted benzimidazo-[2,1-a]isoquinolin-6(5H)-ones.

RhIII -Catalyzed C6-Selective Oxidative C-H/C-H Crosscoupling of 2-Pyridones with Thiophenes.

A rhodium(III)-catalyzed C6-selective dehydrogenative cross-coupling of 2-pyridones with thiophenes was developed for the synthesis of 6-thiophenyl pyridin-2(1H)-one derivatives. In this reaction, the excellent site selectivity was controlled by the 2-pyridyl directing group on the nitrogen of the pyridone ring. Control experiments indicated that the N-pyridyl was essential for the transformation. To the best of our knowledge, this procedure is the first successful example of the direct C6 heteroarylation of 2-pyridones with electron-rich thiophene derivatives. 4-Pyridone was also used as substrate to generate the corresponding C2 heteroarylated product. Moreover, this pyridyl directing group was readily removable to generate the biheteroaryl structures with a free N-H group.

Recent advances in rhodium-catalyzed C(sp2)-H (hetero)arylation.

Arylation is a common behaviour in organic synthesis for the construction of complex structures, especially the biaryls. Among those reported arylation procedures, transition-metal-catalyzed direct C(sp2)-H arylation has been rapidly developed in recent decades and has become a reliable alternative to traditional cross-coupling procedures using organometallic reagents. Great achievements in rhodium-catalyzed C(sp2)-H arylation have been witnessed during the last decade. Aryl halides, simple arenes, aryl boronic acids, arylsilanes, aryl aldehyde, aryl carboxylic acid, diazides, etc. were successfully utilized as arylating reagents under rhodium-catalyzed conditions. In this review, recent achievements in rhodium-catalyzed arylations through C(sp2)-H bond activation were summarized together with the mechanism discussions.

Peroxide-mediated synthesis of benzimidazo[2,1-a]isoquinoline-6(5H)-ones via cascade methylation/ethylation and intramolecular cyclization.

A metal-free oxidative radical methylation/arylation of 2-arylbenzoimidazoles with DTBP as the oxidant and methyl radical source was developed. The reaction proceeds through a sequential methyl radical addition/cyclization pathway and affords a series of methyl functionalized benzimidazo[2,1-a]isoquinoline-6(5H)-ones in moderate to good yields. Besides, the ethylation/arylation of 2-arylbenzoimidazoles was also achieved with DTAP.

DTBP-promoted site-selective α-alkoxyl C-H functionalization of alkyl esters: synthesis of 2-alkyl ester substituted chromanones.

The direct C-H functionalization of ethyl acetates was developed, delivering a variety of 1-(4-oxochroman-2-yl)ethyl acetate derivatives by reacting with chromones. This reaction has a wide substrate scope with excellent site-selective C-H activation at the inactive α-hydrogen of the alkoxyl group instead of the α-hydrogen of the carbonyl group under radical conditions. Compared with other protocols for the α-alkoxyl C-H functionalization of alkyl esters, a distinguishing feature of this reaction is that no metal catalyst was required, with DTBP as the sole oxidant.

Rhodium-catalyzed C-H activation/cyclization of aryl sulfoximines with iodonium ylides towards polycyclic 1,2-benzothiazines.

The synthesis of 1,2-benzothiazine derivatives through rhodium-catalyzed C-H activation/cyclization of S-aryl sulfoximines with iodonium ylides was developed for the first time. In this report, C-H and N-H bond functionalization was realized towards a series of tricyclic and tetracyclic sulfoximine derivatives with moderate to excellent yields under simple reaction conditions.

Alkylarylation of N-allylbenzamides and N-allylanilines with simple ethers for the direct construction of ether substituted dihydroisoquinolinones and indolines.

A radical-initiated cascade addition and cyclization of N-allylbenzamides with simple ethers to construct ether-substituted dihydroisoquinolinones was performed in the presence of CuI. The cleavage of the sp3 C-H bond in ether and the sp2 C-H bond in phenyl was involved in this reaction. Moreover, the arylalkylation of N-allylanilines was also realized under similar reaction conditions, providing ether-functionalized indolines in good to moderate yields.

Rh(iii)-Catalyzed regioselective C4 alkylation of indoles with allylic alcohols: direct access to ß-indolyl ketones.

A Rh(iii)-catalyzed and weak coordination carbonyl guided direct C4 alkylation of indoles with allylic alcohols was developed with excellent regioselectivity. This reaction was conducted under mild conditions, leading to a variety of ß-indolyl ketones with good functional group tolerance in moderate to good yields.

The Silver-Promoted Phosphonation/Alkynylation of Alkene Proceeding with Radical 1,2-Alkynyl Migration.

The silver-promoted phosphonation/alkynylation of vinyl in α-aryl α-alkynyl allylic alcohols with phosphine oxide was developed, affording a series of α-alkynyl γ-ketophosphine oxides in moderate to good yields. This procedure involved the radical 3-exo-dig cyclization, proceeding with the radical 1,2-alkynyl migration rather than the aryl migration.

Copper-Catalyzed Cascade Denitrogenative Transannulation/Hydrolyzation of 3-Aminoindazoles toward 2,2-Disubstituted Indanones.

A copper-catalyzed cascade denitrogenative transannulation/hydrolyzation of 3-aminoindazoles with N-(2-methylallyl)anilines was developed, affording a variety of 2-(aminomethyl)-2-methyl-indanones in moderate to good yields. 2-Cyanophenyl radical, which generated from oxidative denitrogenation of 3-aminoindazole, was proved as the reaction intermediate. This reaction features, along with the ready availability of starting materials, a cascade cleavage of two C-N bonds and construction of two C-C bonds in one pot.

Rhodium-catalyzed C-H activation/annulation of amidines with 4-diazoisochroman-3-imines toward isochromeno[3,4-c]isoquinolines.

A rhodium-catalyzed C-H activation/annulation of amidines with 4-diazoisochroman-3-imines has been established to afford a series of 8-amino-5H-isochromeno[3,4-c]isoquinolines in moderate to good yields with good functional group tolerance. This reaction proceeded in a sequential C-H activation/carbene migration insertion/intramolecular annulation procedure and featured the construction of a C-C and C-N bond in one pot. UV-vis and fluorescence spectral analyses of these highly fused heteroarenes were performed.

Copper-catalyzed acylation of pyrazolones with aldehydes to afford 4-acylpyrazolones.

Copper-catalyzed direct acylation of the alkenyl C-H bond in 1,2-dihydro-3H-pyrazol-3-ones has been developed, affording a series of 4-acylpyrazolones in moderate to good yields. Notably, this protocol involves readily accessible substrates and reagents, which have good functional group tolerance leading to pyrazolone derivatives under mild reaction conditions.

Rhodium-Catalyzed Site-Selective ortho-C-H Activation: Enone Carbonyl Directed Hydroarylation of Maleimides.

Enone carbonyl directed 1,4-addition of ortho-C-H bond in chalcones to maleimides was developed under the catalysis of Rh(III). This reaction furnished a variety of chalcone-based pharmacologically useful 3-arylated succinimide derivatives in good yields with excellent selectivity.

Site-specific hydroxyalkylation of chromones via alcohol mediated Minisci-type radical conjugate addition.

A metal-free site-specific C2-hydroxyalkylation of chromones through the Minisci-type reaction using simple alcohols was developed. This transformation proceeds via radical sp3 C-H activation and subsequent conjugate addition, generating a series of C2-hydroxyalkylated chromanones in moderate to good yields. Besides, ethers were also compatible in this Minisci reaction, leading to corresponding C2 ether-substituted chromanones.

Metal-free oxidative decarbonylative alkylation of chromones using aliphatic aldehydes.

A decarbonylative alkylation of chromones via radical conjugate addition under metal-free conditions was developed using aliphatic aldehydes as alkylating reagents. A series of 2-tertiary, secondary, and even primary alkylated chromanones were obtained in moderate to excellent yields.