Design, synthesis and in vitro antitumor evaluation of novel pyrazole-benzimidazole derivatives.

A series of novel pyrazole-benzimidazole derivatives (6-42) have been designed, synthesized and evaluated for their in vitro antiproliferative activity against the HCT116, MCF-7 and Huh-7 cell lines. Among them, compounds 17, 26 and 35 showed significant antiproliferative activity against HCT116 cell lines with the IC50 values of 4.33, 5.15 and 4.84 µM, respectively. Moreover, fluorescent staining studies showed compound 17 could induce cancer cells apoptosis. The flow cytometry assay revealed that compound 17 could induce cell cycle arrest at G0/G1 phase. All in all, these consequences suggest that pyrazole-benzimidazole derivatives could serve as promising compounds for further research to develop novel and highly potent cancer therapy agents.

Syntheses of Z-Iodovinylfurans and 2-Acyl Furans via Controllable Cyclization of Ynenones.

A divergent synthesis of Z-iodovinylfurans and 2-acyl furans promoted by NIS via controllable cyclization of ynenones is reported. The reaction proceeded by sequential 5-exo-dig electrophilic cyclization to intermediate 2-(iodomethylene)-2H-furanium cation D, providing a range of synthetically valuable and useful trisubstituted furan derivatives 2 and 3 in moderate to excellent yields. This approach is metal-free, mild, and atom-economic, with good selectivity and high stereoselectivity.

Cyclopropanation of Benzene Rings by Oxidatively Generated α-Oxo Gold Carbene: One-Pot Access to Tetrahydropyranone-Fused Cycloheptatrienes from Propargyl Benzyl Ethers.

Cyclopropanations of benzene rings by oxidatively generated α-oxo gold carbenes are for the first time demonstrated in a Buchner reaction, in which readily available propargyl benzyl ethers are converted in one-pot to tetrahydropyranone-fused cycloheptatrienes via sequential oxidative gold catalysis and base-promoted isomerization. Additional examples of arene cyclopropanations without fragmentation of the cyclopropane ring are also realized.

Gold-Catalyzed Oxidation Terminal Alkyne: An Approach to Synthesize Substituted Dihydronaphthalen-2(1H)-ones and Phenanthrenols.

A facile gold-catalyzed oxidation terminal alkynes to synthesize substituted dihydronaphthalen-2(1H)-ones 3 and phenanthrenols 5 was realized. Various useful structures and drug precursors were generated in up to 99% yield under mild condition and low catalyst loading.

Gold-Catalyzed Oxidation/C-H Functionalization of Ynones: Efficient and Rapid Access to Functionalized Polycyclic Salicyl Ketones.

An efficient strategy to construct salicyl ketones through gold-catalyzed oxidation/C-H functionalization of ynones is reported. A variety of functionalized salicyl ketones are readily accessed by utilizing this non-diazo approach, thus providing a viable alternative to synthetically useful salicyl ketones with a yield up to 98 %. The α-oxo gold carbenes generated in situ through gold-catalyzed oxidation of ynones can be trapped effectively by internal aryl and heteroaromatic groups. Electronic and steric effects were also investigated in this reaction. The anticancer activity of one salicyl ketone analogue was investigated and its cytotoxicity assays against the PC-3 prostate cancer cell line and SKOV-3 human ovarian carcinoma cell line yield IC50 were 0.81±0.05 and 0.87±0.15 µm, respectively, demonstrating that salicyl ketone analogues showed good anticancer activity.

Enantioselective oxidative gold catalysis enabled by a designed chiral P,N-bidentate ligand.

A newly developed P,N-bidentate ligand enables enantioselective intramolecular cyclopropanation by a reactive α-oxo gold carbene intermediate generated in situ. The ligand design is based on our previously proposed structure (with a well-organized triscoordinated gold center) of the carbene intermediate in the presence of a P,N-bidentate ligand. A C2-symmetric piperidine ring was incorporated in the ligand as the nitrogen-containing moiety. A range of racemic transformations of α-oxo gold carbene intermediates have been developed recently, and this new class of chiral ligands could enable their modification for asymmetric synthesis, as demonstrated in this study.

Gold-Catalyzed Oxidation of Propargylic Ethers with Internal C-C Triple Bonds: Impressive Regioselectivity Enabled by Inductive Effect.

Inductive perturbations of C-C triple bonds are shown to dictate the regiochemistry of gold-catalyzed oxidation of internal C-C triple bonds in the cases of propargylic ethers, resulting in highly regioselective formation of ß-alkoxy-α,ß-unsaturated ketones (up to >50/1 selectivity) via α-oxo gold carbene intermediates. Ethers derived from primary propargylic alcohols can be reliably transformed in good yields, and various functional groups are tolerated. With substrates derived from secondary propargylic alcohols, the development of a new P,N-bidentate ligand enables the minimization of competing alkyl group migration to the gold carbene center over the desired hydride migration; the preferred migration of a phenyl group, however, results in efficient formation of a α-phenyl-ß-alkoxy-α,ß-unsaturated ketone. These results further advance the surrogacy of a propargyl moiety to synthetically versatile enone function with reliable and readily predictable regioselectivity.

Gold-catalyzed regioselective oxidation of propargylic carboxylates: a reliable access to α-carboxy-α,ß-unsaturated ketones/aldehydes.

Gold-catalyzed intermolecular oxidation of carboxylates of primary or secondary propargylic alcohols are realized with excellent regioselectivity, which is ascribed to inductive polarization of the C-C triple bond by the electron-withdrawing carboxy group. The gold carbene intermediates thus generated undergo selective 1,2-acyloxy migration over a 1,2-C-H insertion, and the selectivities could be dramatically improved by the use of a P,S-bidentate ligand, which is proposed to enable the formation of tris-coordinated and hence less electrophilic gold carbene species. α-Carboxy α,ß-unsaturated ketones/aldehydes can be obtained with fair to excellent yields.

Chemoselective Transformations of Amides: An Approach to Quinolones from ß-Amido Ynones.

An efficient and chemoselective transformation of ß-amido ynones to 3-acyl-substituted quinolones 2 and 3-H-quinolones 4 has been developed. In this reaction, ß-cyclic amido ynones can be selectively transformed into quinolones 2 in anhydrous EG via a selective C═O bond cleavage, 1,5-O migration, and C═C bond recombination process. The practical approach of this reaction renders it a viable alternative for the construction of various quinolones.

Rh(II)-Catalyzed Chemoselective Oxy-alkynylation of Acceptor-Acceptor Carbenes: Synthesis of C2-Quaternary Alkyne-Substituted 3(2H)-Furanones.

A Rh(II)-catalyzed oxy-alkynylation of acceptor-acceptor carbenes using EBX reagents was successfully developed. The key alkyne-transfer step is likely to occur through a tandem process involving a ß-addition, an α-elimination, and a 1,2-shift, which was supported by the formation of alkylidene carbene. Various diverse C2-quaternary alkyne-substituted benzofuran-3-ones and 2,2,4,5-tetrasubstituted 3(2H)-furanones can be synthesized smoothly, depending on the choice of diazo compounds and the base additives. Furthermore, this reaction is characterized by mild conditions, high functional group compatibility, and a broad substrate scope.

Tempering the reactivities of postulated α-oxo gold carbenes using bidentate ligands: implication of tricoordinated gold intermediates and the development of an expedient bimolecular assembly of 2,4-disubstituted oxazoles.

2,4-Oxazole is an important structural motif in various natural products. An efficient modular synthesis of this structure has been achieved via a [3 + 2] annulation between a terminal alkyne and a carboxamide using a gold-catalyzed oxidation strategy. The postulated reactive intermediate, a terminal α-oxo gold carbene, previously known to be highly electrophilic and hence unlikely to be trapped by stoichiometric external nucleophiles, is coerced to react smoothly with the carboxamide en route to the oxazole ring by a P,N- or P,S-bidentate ligand such as Mor-DalPhos; in stark contrast, often-used ligands such as monodentate phosphines and N-heterocyclic carbenes are totally ineffective. The role of these bidentate phosphines in this reaction is attributed to the formation of a tricoordinated gold carbene intermediate, which is less electrophilic and hence more chemoselective when reacting with nucleophiles. The success in using bidentate phosphine ligands to temper the reactivities of in situ-generated gold carbenes is likely to open many new opportunities to apply oxidative gold catalysis to the development of novel methods, and the implication of tricoordinated gold intermediates in homogeneous gold catalysis should stimulate further advances in gold catalysis.

Divergent synthesis of benzene derivatives: Brønsted acid catalyzed and iodine-promoted tandem cyclization of 5,2-enyn-1-ones.

Highly substituted benzene derivatives, including alkoxy-, iodoalkoxy-, and diiodo-substituted benzenes, can be selectively synthesized via Brønsted acid catalyzed and iodine-promoted tandem carbocyclization respectively. This reaction involved a direct process for C-C bond formation from 5,2-enyn-1-ones, and different reaction systems (Brønsted acids/electrophiles with solvents) afforded different substituted benzenes. Furthermore, the halogenated moiety and alkoxy group can be readily introduced into the benzene in a position which has not been easily obtained previously.

Palladium-catalyzed divergent reactions of 1,6-enyne carbonates: synthesis of vinylidenepyridines and vinylidenepyrrolidines.

A method for preparing five- or six-membered heterocyclic compounds from enyne carbonates via palladium catalysis was developed. Enyne carbonates were transformed into 3-vinylidene-1-tosylpyridines 2 in the presence of PdI(2) as the catalyst. Using Pd(dba)(2) as the catalyst, 3-vinylidene-1-tosylpyrrolidines 3 were obtained. Further functionalizations of compounds 3 were carried out in a one-pot manner.

Palladium-Catalyzed Carbene Migratory Insertion/Carbonylation Cascade Reaction: Synthesis of 2-Indolones with a C3 All-Carbon Quaternary Center.

An attractive palladium-catalyzed three-component reaction of ortho-amino aryl diazo esters, allyl carboxylates, and carbon monoxide (CO) has been developed. This catalytic system rendered domino carbene migratory insertion and carbonylation. Remarkably, 2-indolones 3 with a C3 all-carbon quaternary center can be selectively obtained in good to excellent yields via one-pot synthesis, in which two different C-C bonds and one C-N bond were formed in a straightforward manner.

Brønsted acid catalyzed cyclization of hydroxylated enynes: a concise synthesis of five-membered heterocycles.

A mild and direct pathway for the formation of five-membered heterocyclic compounds from hydroxylated enynes has been developed. In this reaction, hydroxylated enynes were selectively transformed into five-membered heterocyclic compounds 2, with an allene moiety at the 3-position, in the presence of F(3) CSO(3) H (0.1 mol %). When R(1) , R(2) =Ph, diphenylvinyl-2,3-dihydro-1H-pyrrole (2 y) was obtained. With HSbF(6) (5 mol %) as the catalyst, polycyclic skeletons 3 and 4 with adjacent stereocenters were obtained. When R(1) =H and R(2) =styrene, 1,3-dienyl-2,5-dihydro-1H-pyrrole (6 as) was formed. This Brønsted acid catalyzed domino process involves the formation of an allene carbocation intermediate, which can be readily trapped by olefins to give various novel five-membered heterocyclic skeletons.

Sc(OTf)3-catalyzed synthesis of indoles and SnCl4-mediated regioselective hydrochlorination of 5-(arylamino)pent-3-yn-2-ones.

Highly substituted indole derivatives bearing alkyl and aryl moieties can be prepared by Sc(OTf)(3)-catalyzed Friedel-Crafts alkenylation of 5-(arylamino)pent-3-yn-2-ones. In addition, a method for regioselective hydrochlorination of 5-(arylamino)pent-3-yn-2-ones mediated by SnCl(4) in moderate to good yields (up to 84%) has been developed. The resulting exclusive Z-selectivity of the C-Cl bond can be further exploited using cross C-N coupling reactions.

Iodine-induced regioselective C-C and C-N bonds formation of N-protected indoles.

A mild, metal-free, and environmently benign iodine-promoted regioselective C-C and C-N bonds formation of N-protected indole derivatives giving 2,3'-biindoles 2 and 4-(1H-indol-2-yl)morpholines 4 is successfully demonstrated. Various bioactive 2,3'-biindoles and 4-(1H-indol-2-yl)morpholines, bearing electron-rich to moderately electron-poor substituents, can be prepared in moderate to good yields.

Pd(0)-catalyzed [1,5]-sigmatropic hydrogen shift of propargylic esters toward substituent naphthylamines.

A novel and convenient carboannulation method for the synthesis of highly substituted naphthylamine derivatives has been developed though a Pd(0)-catalyzed [1,5]-sigmatropic hydrogen shift and cyclization reaction of propargyl esters.

Platinum/scandium-cocatalyzed cascade cyclization and ring-opening reaction of tertiary amines with substituted salicylaldehydes to synthesize 3-(aminoalkyl)coumarins.

The synthesis of 3-(aminoalkyl)coumarins starting with a platinum/scandium-cocatalyzed oxidative dehydrogenation of α,ß-C(sp(3))-H bonds of tertiary amines in the presence of ambient oxygen followed by reactions with substituted salicylaldehydes is revealed. The in situ formed enamines reacted with various salicylaldehydes, which resulted in the development of a one-pot synthetic protocol involving aldol reaction, cyclization, and then ring-opening.

Gold(I)-Catalyzed Oxidative Amination of ß-Amino-ynones to Quaternary Ammonium-olate Salts: The Benefit of a P,N-Bidentate Ligand.

A novel P,N-bidentate ligand-assisted gold-catalyzed oxidative amination of ß-amino-ynones has been developed, allowing the simple and efficient construction of various quaternary ammonium-olate salts in good to excellent yields. These unprecedented quaternary ammonium-olate salts can be isolated and purified via simple suction filtration. The broad substrate scope, easy purification, easy further transformation, and mild conditions make it a viable alternative for the synthesis of various quaternary ammonium-olate salts.