One-Pot Synthesis of N-Fused Benzimidazo-ß-carbolines through Sequential Propargylation/aza-Cycloisomerization Approach.

The first sequential acid-catalyzed propargylation/base-mediated aza-cycloisomerization between indolyl-benzimidazoles and propargylic alcohols is described. This protocol enables the one-pot construction of N-fused benzimidazo-ß-carbolines in good yields. The synthetic utility of this approach is demonstrated by the assembly of an aza-helicene and also by a gram-scale reaction.

Flow and On-Water Synthesis and Cancer Cell Cytotoxicity of Caffeic Acid Phenethyl Amide (CAPA) Derivatives.

Caffeic acid phenethyl ester (CAPE) is a phenolic natural product with a wide range of biological activities, including anticancer activity; however, the ester group of CAPE is metabolically labile. The corresponding amide, CAPA, has improved metabolic stability but limited anticancer activity relative to CAPE. We report the synthesis using flow and on-water Wittig reaction approaches of five previously reported and five novel CAPA analogues. All of these analogues lack the reactive catechol functionality of CAPA and CAPE. Cytotoxicity studies of CAPE, CAPA, and these CAPA analogues in HeLa and BE(2)-C cells were carried out. Surprisingly, we found that CAPA is cytotoxic against the neuroblastoma BE(2)-C cell line (IC50 = 12 µM), in contrast to the weak activity of CAPA against HeLa cells (IC50 = 112 µM), and the literature reports of the absence of activity for CAPA against a variety of other cancer cell lines. One novel CAPA analogue, 3f, was identified as having cytotoxic activity similar to CAPE in HeLa cells (IC50 = 63 µM for 3f vs. 32 µM for CAPE), albeit with lower activity against BE(2)-C cells (IC50 = 91 µM) than CAPA. A different CAPA analogue, 3g, was found to have similar effects against BE(2)-C cells (IC50 = 92 µM). These results show that CAPA is uniquely active against neuroblastoma cells and that specific CAPA analogues that are predicted to be more metabolically stable than CAPE can reproduce CAPA's activity against neuroblastoma cells and CAPE's activity against HeLa cells.

Seleno/Thio-functionalized ipso-Annulation of N-Propiolyl-2-arylbenzimidazole to Construct Azaspiro[5,5]undecatrienones.

Till date, the ipso-cyclization of propiolamides is limited to provide azaspiro[4,5]decatrienones. Herein, we present the first example of ipso-carbocyclization, leading to azaspiro[5,5]-undecatrienones from N-propiolyl-2-arylbenzimidazoles, involving both the radical-based and electrophilic reactions. This report establishes an access to a wide range of chalcogenated (SCN/SCF3/SePh) benzimidazo-fused azaspiro[5,5]undecatrienones in good yields.

One-Pot Arylative Benzannulation of 2-Carbonyl-3-propargyl Indoles with Boronic Acids Leading to Arylated Carbazoles.

Arylative annulation of 2-carbonyl-3-propargyl indoles with boronic acids under sequential palladium/triflic acid catalysis is described. The present strategy to provide di- and triaryl carbazoles in one pot involves benzannulation through difunctionalization of alkynes. The strategy showed a good substrate scope with respect to boronic acids as well as 2-carbonyl-3-propargyl indoles to afford the corresponding carbazoles in decent yields.

Palladium-catalyzed ortho-vinylation of ß-naphthols with α-trifluoromethyl allyl carbonates: one-pot access to naphtho[2,1-b]furans.

Highly regio- and stereoselective palladium-catalyzed ortho-vinylation of ß-naphthols (2) has been reported using easily accessible CF3-allyl carbonates (1). The regioselective nucleophilic γ-attack of the CF3-π-allyl-Pd-intermediate is the key to furnish (Z)-CF3-vinylnaphthols (3) in good yields. Furthermore, we achieved a one-pot synthesis of CF3-naphtho[2,1-b]furans (4) through an uninterrupted ortho-vinylation/oxidative radical cyclization reaction sequence.

Dearomative ipso-Cyclization to Spiropseudoindoxyls: An Extendable Approach To Access Indolo[3,2-c]quinolinones and Isocryptolepine.

A metal-free oxidative intramolecular dearomative spirocyclization of indole-3-formyl-2-carboxamides has been developed for the first time, affording spiropseudoindoxyls in good yields. This domino process proceeds through sequential oxidation, decarboxylation and ipso-arylation. The unique feature of this approach includes the compatibility of N-protected-indole-2-carboxamides. Further, a hitherto unknown rearrangement of spiropseudoindoxyls to indoloquinolones has been achieved. The synthetic utility of this strategy has also been showcased by the construction of a natural alkaloid, isocryptolepine.

Ag-Catalyzed Domino Decarboxylative Alkylation/Dearomative Annulation: Entry to Fused-Pyrido[4,3-b]Indolones.

Here we report the development of unprecedented silver-catalyzed intramolecular annulations of N-acrolyl-2-(3-indolyl) benzimidazoles with alkyl carboxylic acids to construct complex fused-pentacyclic alkaloid scaffolds. Divergent reactivities are noticed with altered groups at C2-indole of the substrate. The reaction proceeds through decarboxylative alkylation, followed by dearomative annulation in a domino manner with excellent diastereoselectivity. Owing to the reactivity of the tert-OH group, these aza-enriched scaffolds can be further functionalized.

Access to Diverse Seleno-spirocyclohexadienones via Ag(II)-Catalyzed Selenylative ipso-Annulation with Se and Boronic Acids.

An efficient and straightforward synthesis of diversified seleno-azaspiro-2,5-cyclohexadienones from N-(4-methoxy aryl)propiolamides using elemental selenium and boronic acids has been demonstrated. The reaction proceeds through silver-catalyzed oxidative dearomatization in the presence of potassium persulfate (K2S2O8) as the oxidant. Further, this approach was extended to N-(4-methoxy aryl)propiolates and biaryl ynones to access the corresponding selenylated oxospiro-2,5-cyclohexadienones and spiro[5,5]trienones, respectively. The present three-component method offers the diverse substitutions on selenium involving two C-Se and one C-C bond formations.

Domino Reaction of 2,4-Diyn-1-ols with 1,3-Dicarbonyl Compounds: Direct Access to Aryl/Heteroaryl-Fused Benzofurans and Indoles.

A domino propargylation/furanylation (intramolecular exo-dig-cyclization)/benzannulation reaction of 2,4-diyn-1-ols with 1,3-dicarbonyl compounds has been developed for the first time. This provides a novel and effective method for the preparation of aryl/heteroaryl-fused benzofurans from easily accessible starting materials in a single step. The methodology was extended to pyrrolyl-benzannulation to obtain aryl/heteroaryl-fused indoles. Further, application of this approach in the synthesis of eustifoline D and dictyodendrin structural frameworks has been demonstrated.

Ag-Catalyzed Oxidative ipso-Cyclization via Decarboxylative Acylation/Alkylation: Access to 3-Acyl/Alkyl-spiro[4.5]trienones.

A strategy to functionalized spiro[4.5]trienones, by domino silver-catalyzed decarboxylative acylation or alkylation/ ipso-cyclization of N-arylpropiolamides with α-keto acids/alkyl carboxylic acids, is presented. This transformation offers a wide range of substituted 3-acyl/alkyl-spiro[4.5]trienones in high yields with a broad substrate scope. The approach was further extended to access fused tricyclic frameworks, 6,7-dihydro-3H-pyrrolo[2,1-j]quinoline-3,9(5H)-diones.

One-Pot Assembly of 3-Hydroxycarbazoles via Uninterrupted Propargylation/Hydroxylative Benzannulation Reactions.

A novel strategy for the synthesis of 3-hydroxycarbazoles involving the consecutive propargylation/palladium-catalyzed hydroxylative benzannulation of indole-2-carbonyls with propargylic alcohols has been exploited. This one-pot procedure leads to a wide range of substituted 3-hydroxycarbazoles in high yield with a broad substrate scope. The method was further extended to access furano-carbazole derivatives from dialkynols via tandem annulations.

One-Pot Synthesis of Triazolo-Heterolignans: Biological Evaluation and Molecular Docking Studies as Tubulin Inhibitors.

BACKGROUND: The anti-mitotic activity of podophyllotoxin derivative targeting tubulin enzyme proved them as strong polymerization inhibitors. The introduction of heteroatom along with different heteroaryl systems in naturally obtained lignans created a latitude for design of bioactive components. A novel one-pot sequential propargylation/cycloaddition reaction strategy has been followed to synthesize triazolo-heterolignans. OBJECTIVE: To screen anti-proliferative activity of novel heterolignans and to determine their mode of action. METHOD: SRB assay, Cytotoxicity evaluation, PI uptake for analysis of cell cycle, caspase-3 activity, Western blot analysis and Immunofluorescence and molecular docking studies. RESULTS: SRB assay of synthesised compounds were provided compound 3a and 5f to be highly active among the synthesized compounds. The Compound 3a showed cell cycle arrest at G2/M phase and 5f arrest the cells at G1 phase. Compound 5f displayed caspase 3 mediated apoptotic effect at lower levels. Compound 3a and 5f displayed microtubule disassembly inhibition same as paclitaxel and found to be occupying colchicine binding site of tubulin, both ligands were depicted π-cation interaction with Lys352 residue and triazole ring accommodated at the lactone binding site. CONCLUSION: A novel one-pot sequential propargylation/cycloaddition reaction has been developed for the synthesis of triazolo-heterolignans. Compound 3a and 5f were displayed good cytotoxic activities and found to inhibit microtubule disassembly. The importance of triazole ring of heterolignans has been studied by molecular docking experiments and results were compared.