Substrate-Controlled Product Divergence in Iron(III)-Catalyzed Reactions of Propargylic Alcohols: Easy Access to Spiro-indenyl 1,4-Benzoxazines and 2-(2,2-Diarylvinyl)quinoxalines.

We report herein unprecedented cascade reactions of O-propargyl-N-tosyl-amino phenols with 10 mol% FeCl3 in DCE at room temperature for 0.67-3 h to form spiro-indenyl 1,4-benzoxazines with 38-89 % yield. Replacing the substrates' oxygen atom by a N-tosylimine group followed by treatment with the same catalyst and solvent at 80 °C produced 2-(2,2-diarylvinyl)quinoxalines in 12-20 h with up to 62 % yield. Mechanistic understanding provided an insight into the transformations. The use of simple substrates and an environmentally benign low-cost catalyst, broad substrate scope and tolerance of diverse functional groups makes the methodology inherently attractive.

Iron(III)-Catalyzed Carboannulations of Homopropargylic Alcohols: A One-Pot General Synthesis of 4-(2,2-Diarylvinyl)quinolines and 4-(2,2-Diarylvinyl)-2H-chromenes.

A simple and efficient approach for the general synthesis of 4-(2,2-diarylvinyl)quinolines 5 and 4-(2,2-diarylvinyl)-2H-chromenes 6 has been developed using Fe(III)-catalyzed intramolecular annulations of homopropargyl substrates 1 and 2, respectively. The high yields (up to 98%) achieved using simple substrates, an environmentally benign low-cost catalyst, and less hazardous reaction conditions make the methodology inherently attractive.

Palladium-Catalyzed Synthesis of 1-Vinyltetrahydro-ß-carbolines and Aza-spiroindolenines: Access to the Syntheses of 1-Vinyl-ß-carbolines and Eudistomins Y1 and Y2.

A general synthesis of 1-vinyltetrahydro-ß-carbolines (THBCs) has been achieved via palladium(0)-catalyzed cyclocondensation between allenyltryptamines and aryl iodides. Aza-spiroindolenines could also be accessed from the N-unsubstituted indole substrates by simply tweaking the reaction conditions. DDQ-mediated oxidation of THBCs easily afforded ß-carbolines, which could be synthetically transformed into 1-aroyl-ß-carbolines of pharmacological interest. Formal total syntheses of eudistomins Y1 and Y2 have also been achieved.

Palladium(II)-Catalyzed Cascade Reactions of Ene-Ynes Tethered to Cyano/Aldehyde: Access to Naphtho[1,2-b]furans and Benzo[g]indoles.

An efficient palladium(II)-catalyzed cascade reaction of ene-yne substrates carrying cyano/aldehyde group is described. It involves successive hetero- and benz-annulations in one pot via trans-oxo/aminopalladation onto alkyne, followed by 1,2-addition to cyano/aldehyde, providing a convenient synthesis of both naphtho[1,2-b]furans and benzo[g]indoles. The reaction constitutes a fast intramolecular assembly through several carbon-carbon and carbon-heteroatom bond formations taking place in one pot. The reactions are operationally simple, compatible with a range of functional groups and atom-economical in nature.

Palladium-catalysed stereoselective synthesis of 4-(diarylmethylidene)-3,4-dihydroisoquinolin-1(2H)-ones: expedient access to 4-substituted isoquinolin-1(2H)-ones and isoquinolines.

An efficient method has been developed for the stereoselective synthesis of 4-(diarylmethylidene)-3,4-dihydroisoquinolin-1(2H)-ones 7 through tandem Heck-Suzuki coupling at rt using easily available substrates. DBU easily converted the exocyclic double bond of these compounds to endo, furnishing 8 and 9. Reduction of the carbonyl group of 7 was smoothly carried out with borane dimethyl sulphide. Subsequent treatment with KOtBu provided an easy access to 4-substituted isoquinolines 10a if carried out in refluxing 1,4-dioxane, while reaction in DMF at rt led to the incorporation of an extra hydroxyl group at the benzylic position of the isoquinolines to give 10b. This straightforward and metal free procedure would serve as a better alternative to the prevalent procedures. Few of the products could also be transformed into heterocyclic scaffolds structurally resembling known bioactive compounds.

A potent betulinic acid analogue ascertains an antagonistic mechanism between autophagy and proteasomal degradation pathway in HT-29 cells.

BACKGROUND: Betulinic acid (BA), a member of pentacyclic triterpenes has shown important biological activities like anti-bacterial, anti-malarial, anti-inflammatory and most interestingly anticancer property. To overcome its poor aqueous solubility and low bioavailability, structural modifications of its functional groups are made to generate novel lead(s) having better efficacy and less toxicity than the parent compound. BA analogue, 2c was found most potent inhibitor of colon cancer cell line, HT-29 cells with IC50 value 14.9 µM which is significantly lower than standard drug 5-fluorouracil as well as parent compound, Betulinic acid. We have studied another mode of PCD, autophagy which is one of the important constituent of cellular catabolic system as well as we also studied proteasomal degradation pathway to investigate whole catabolic pathway after exploration of 2c on HT-29 cells. METHODS: Mechanism of autophagic cell death was studied using fluorescent dye like acridine orange (AO) and monodansylcadaverin (MDC) staining by using fluorescence microscopy. Various autophagic protein expression levels were determined by Western Blotting, qRT-PCR and Immunostaining. Confocal Laser Scanning Microscopy (CLSM) was used to study the colocalization of various autophagic proteins. These were accompanied by formation of autophagic vacuoles as revealed by FACS and transmission electron microscopy (TEM). Proteasomal degradation pathway was studied by proteasome-Glo™ assay systems using luminometer. RESULTS: The formation of autophagic vacuoles in HT-29 cells after 2c treatment was determined by fluorescence staining--confirming the occurrence of autophagy. In addition, 2c was found to alter expression levels of different autophagic proteins like Beclin-1, Atg 5, Atg 7, Atg 5-Atg 12, LC3B and autophagic adapter protein, p62. Furthermore we found the formation of autophagolysosome by colocalization of LAMP-1 with LC3B, LC3B with Lysosome, p62 with lysosome. Finally, as proteasomal degradation pathway downregulated after 2c treatment colocalization of ubiquitin with lysosome and LC3B with p62 was studied to confirm that protein degradation in autophagy induced HT-29 cells follows autolysosomal pathway. CONCLUSIONS: In summary, betulinic acid analogue, 2c was able to induce autophagy in HT-29 cells and as proteasomal degradation pathway downregulated after 2c treatment so protein degradation in autophagy induced HT-29 cells follows autolysosomal pathway.

A Palladium-Catalyzed Method for the Synthesis of 2-(α-Styryl)-2,3-dihydroquinazolin-4-ones and 3-(α-Styryl)-3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxide: Access to 2-(α-Styryl)quinazolin-4(3H)-ones and 3-(α-Styryl)-1,2,4-benzothiadiazine-1,1-dioxides.

An efficient synthesis of 2-(α-styryl)-2,3-dihydroquinazolin-4-ones and 3-(α-styryl)-3,4-dihydro-1,2,4-benzothiadiazine-1,1-dioxides has been achieved in 39-94% yield through palladium-catalyzed cyclocondensation of aryl/vinyl iodides with allenamides 13-15 and 22, respectively. Base treatment of the N-tosylated products provides an easy access to 2-(α-styryl)quinazolin-4(3H)-ones and 3-(α-styryl)-1,2,4-benzothiadiazine-1,1-dioxides, hitherto unknown heterocycles. The method has been tested with phenyl substituted allenamides, applied for bis-heteroannulation, and used in the preparation of analogues of the natural product Luotonin F.

One-Pot Access to Benzo[a]carbazoles via Palladium(II)-Catalyzed Hetero- and Carboannulations.

A Pd(II)-catalyzed direct synthesis of benzo[a]carbazoles has been achieved through aminopalladation of alkynes, followed by intramolecular nucleophilic addition of the generated carbon-palladium bond to a tethered cyano/aldehyde group. Compared to literature procedures, this synthetic approach is operationally simple, uses simple substrates, and offers a fast intramolecular assembly resulting in the direct synthesis of benzo[a]carbazoles in which a wide variation of substituents at different sites is well-tolerated, leaving enough opportunity for diversification.

Facile synthesis of 2-arylmethylindoles and 2-vinylic indoles through palladium-catalyzed heteroannulations of 2-(2-propynyl)aniline and 2-(2-propynyl)tosylanilide.

A facile method for the general synthesis of 2-arylmethylindoles has been developed through the reaction of 2-(2-propynyl)aniline or 2-(2-propynyl)tosylanilide with aryl iodides in the presence of Pd(OAc)2, PPh3, and DBU. 2-(2-Propynyl)tosylanilide is found to be reactive also towards electron deficient alkenes in the presence of Pd(OAc)2 and sodium iodide under an oxygen atmosphere, providing easy access to 2-vinylic indoles which possess exclusive E-stereochemistry in the side chain double bond. Operational simplicity, compatibility of the various functional groups, and ease of product formation are the hallmarks of these methods. A mechanism has been proposed to explain the product formation.

A solvent controlled regioselective synthesis of 2- and 4-substituted α-carbolines under palladium catalysis.

A facile method for the chemodivergent synthesis of α-carbolines 1via palladium catalyzed [3+3] annulations of tosyliminoindolines 6 with α, ß-unsaturated aldehydes 7 is described. Mechanistically, this cascade reaction proceeds through either a carba-Michael (in DMF) or aza-Michael (in NMA) pathway followed by intramolecular cyclization of the intermediate. A preliminary photo-physical study on selected products is also reported.

Palladium-catalyzed approach for the general synthesis of (E)-2-arylmethylidene-N-tosylindolines and (E)-2-arylmethylidene-N-tosyl/nosyltetrahydroquinolines: access to 2-substituted indoles and quinolines.

A facile and efficient method for the synthesis of (E)-2-arylmethylidene-N-tosylindolines and (E)-2-arylmethylidene-N-tosyl/nosyltetrahydroquinoline variants has been developed through palladium-catalyzed cyclocondensation of aryl iodides with readily available 1-(2-tosylaminophenyl)prop-2-yn-1-ols and their higher homologues, respectively. The proposed reaction mechanism invokes the operation of trans-aminopalladation during cyclization (5/6-exo-dig), which ensures exclusive (E)-stereochemistry in the products. The method is fast, operationally simple, totally regio- and stereoselective, and versatile enough to access a variety of 2-substituted indoles and quinolines. The reactions proceeded efficiently with a wide variety of substrates and afforded the corresponding products in moderate to excellent yields.

Palladium-Catalyzed Benzannulations of 1-(Indol-2-yl)but-3-yn-1-ols: Easy Access to Functionalized Carbazoles.

An atom-economical direct synthesis of carbazoles having aryl and aryl ketone groups has been achieved through Pd(II)-catalyzed cascade reactions between 1-(indol-2-yl)but-3-yn-1-ols and aldehydes. The reaction proceeds through alkyne-carbonyl metathesis, an uncommon pathway using palladium catalysts, and constitutes a fast intermolecular assembly through four carbon-carbon bond formations in one pot. Absence of the aldehyde substrate resulted in the formation of C4-aryl-substituted carbazoles. The reaction is amenable to the synthesis of biscarbazole derivatives.

Palladium(0)-Catalyzed Heteroannulations of Allenamides: General Synthesis of δ-Carbolines and Benzofuro[3,2-b]pyridines.

Palladium(0)-catalyzed reactions between allenamides 3 or 4 and aryl iodides/bromides 5/6 provide an easy access to δ-carbolines 1 or benzofuro[3,2-b]pyridines 2. The reaction constitutes a fast intermolecular assembly that takes place in one pot, and the choice of the phosphine ligand is critical for success. A plausible reaction mechanism is proposed. The reaction is amenable to the synthesis of bis-heteroannulated products.

A rapid and facile method for the general synthesis of 3-aryl substituted 4,5,6,7-tetrahydro[1,2,3]triazolo[1,5-a]pyrazines and their ring fused analogues.

We report a general and facile method that provides rapid entry into 3-aryl substituted 4,5,6,7-tetrahydro[1,2,3]triazolo[1,5-a]pyrazines and their ring fused analogues in one-pot under palladium-copper catalysis. The methodology utilises simple and easily available substrates of broad range. The applicability of this reaction for the synthesis of optically active products has been demonstrated. A plausible reaction mechanism has also been proposed.

An efficient strategy for the general synthesis of 3-aryl substituted pyrazolo[5,1-c][1,4]benzoxazines and pyrazolo[1,5-a][1,4]benzodiazepin-6(4H)-ones.

An efficient strategy for the general synthesis of 3-aryl substituted pyrazolo[5,1-c][1,4]benzoxazines and pyrazolo[1,5-a][1,4]benzodiazepin-6(4H)-ones has been developed using intramolecular 1,3-dipolar cycloaddition. The hydrazonoyl chloride, the precursor of the cycloadduct, is accessed easily through a two-step reaction carried out in one-pot. It is then used without purification for the base induced formation of the nitrilimine, which undergoes subsequent in situ intramolecular cycloaddition with an alkyne to afford the desired product. The reaction protocol has also been applied in bis-heteroannulation and in the synthesis of uracil derivatives of biological interest. The operational simplicity of the process, the use of cheap starting materials, and the relatively short reaction times required make the process convenient and practical.

Palladium(0)-catalysed regioselective cyclisations of 2-amino(tosyl) benzamides/sulphonamides: the stereoselective synthesis of 3-ylidene-[1,4]benzodiazepin-5-ones/benzo[f][1,2,5]thiadiazepine-1,1-dioxides.

The Pd(0) catalysed cyclisation reactions between tert-butyl propargyl carbonates and 2-aminotosyl benzamides or sulphonamides deliver 1,4-benzodiazepin-5-ones or sultam derivatives, key components of many biologically active compounds. But 2-amino benzamides/sulphonamides require propargyl carbonates substituted at acetylenic carbon to undergo the reaction resulting in the stereoselective formation of the said products.

Synthesis, cytotoxicity, and structure-activity relationship (SAR) studies of andrographolide analogues as anti-cancer agent.

A series of analogues of andrographolide, prepared through chemo-selective functionalization at C14 hydroxy, have been evaluated for in vitro cytotoxicities against human leukemic cell lines. Two of the analogues (6a, 9b) exhibited significant potency. Preliminary studies on structure-activity relationship (SAR) revealed that the α-alkylidene-γ-butyrolactone moiety of andrographolide played a major role in the activity profile. The structures of the analogues were established through spectroscopic and analytical data.

An expedient and facile route for the general synthesis of 3-aryl substituted 1,2,3-triazolo[1,5-a][1,4]benzodiazepin-6-ones and 1,2,3-triazolo[1,5-a][1,5]benzodiazocin-7-ones.

We describe herein a convenient approach for the general synthesis of novel tricyclic scaffolds incorporating a fusion of the 1,2,3-triazole ring with difficultly obtainable medium sized rings such as [1,4]benzodiazepin-5-ones and [1,5]benzodiazocin-6-ones through Sonogashira coupling of an aryl iodide with 2-amino-N-methyl-N-(prop-2-ynyl)benzamide or homologue followed by in situ diazotisation, azidation and cycloaddition reactions. The strategy also allows easy accessibility of the corresponding amide-reduced analogues. The operational simplicity and easy substrate availability make the process cost effective and practical.

Palladium(ii) catalysed cascade strategy for the synthesis of dibenzo[5,6:7,8]cycloocta[1,2-b]indol-10-ols/-10(15H)-ones: easy access to 1,3,5,7-cyclooctatetraenes (COTs).

An atom-economic Pd(ii)-catalysed cascade cyclisation of 2-(biphenylethynyl)anilines tethered to an aldehyde or cyano group leads to the formation of dibenzo[5,6:7,8]cycloocta[1,2-b]indol-10-ols 6 or dibenzo[5,6:7,8]cycloocta[1,2-b]indol-10(15H)-ones 8 with high yields (up to 95%). The reaction proceeds via amino-palladation of the alkyne followed by nucleophilic addition onto the aldehyde/cyano group. Treatment of 6 with p-TsOH·H2O smoothly provided cyclooctatetraene (COT) derivatives 7.

Expedient and rapid synthesis of 1,2,3-triazolo[5,1-c]morpholines through palladium-copper catalysis.

A one-pot approach using palladium-copper as catalyst has been developed for the synthesis of morpholines fused with 1,2,3-triazole. Good regioselectivity, mild reaction conditions, high yields and short reaction time are the hallmarks of this method.