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Synthesis of 2-arylindole derivatives and evaluation as nitric oxide synthase and NFkappaB inhibitors

Development of small molecule drug-like inhibitors blocking both nitric oxide synthase and NFkappaB could offer a synergistic therapeutic approach in the prevention and treatment of inflammation and cancer. During the course of evaluating the biological potential of a commercial compound library, 2-phenylindole (1) displayed inhibitory activity against nitrite production and NFkappaB with IC50 values of 38.1 ¡À 1.8 and 25.4 ¡À 2.1 muM, respectively. Based on this lead, synthesis and systematic optimization have been undertaken in an effort to find novel and more potent nitric oxide synthase and NFkappaB inhibitors with antiinflammatory and cancer preventive potential. First, chemical derivatizations of 1 and 2-phenylindole-3-carboxaldehyde (4) were performed to generate a panel of N-alkylated indoles and 3-oxime derivatives 2-7. Second, a series of diversified 2-arylindole derivatives (10) were synthesized from an array of substituted 2-iodoanilines (8) and terminal alkynes (9) by applying a one-pot palladium catalyzed Sonogashira-type alkynylation and base-assisted cycloaddition. Subsequent biological evaluations revealed 3-carboxaldehyde oxime and cyano substituted 2-phenylindoles 5 and 7 exhibited the strongest nitrite inhibitory activities (IC50 = 4.4 ¡À 0.5 and 4.8 ¡À 0.4 muM, respectively); as well as NFkappaB inhibition (IC50 = 6.9 ¡À 0.8 and 8.5 ¡À 2.0 muM, respectively). In addition, the 6?-MeO-naphthalen-2?-yl indole derivative 10at displayed excellent inhibitory activity against NFkappaB with an IC50 value of 0.6 ¡À 0.2 muM.

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Ruthenium(II)-Catalyzed Indolo[2,1-a]isoquinolines Synthesis by Tandem C-H Allylation and Oxidative Cyclization of 2-Phenylindoles with Allyl Carbonates

A novel RuII-catalyzed tandem C-H bond activation tool has been successfully developed involving allylation and oxidative cyclization of 2-phenyl indoles with allyl carbonates. This one-pot reaction is a new way to synthesize indolo[2,1-a]isoquinoline units via a simple and efficient process.

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Synthesis of Substituted 1,2,3,8-Tetrahydroindolo<5,4-b><1,3>benzodiazepin-2-ones and 5,6,7,8-Tetrahydroindolo<4,5-b><1,3>benzodiazepin-6-ones

Nitrosation (NaNO2/AcOH) of 2-phenylindoles (1a-d) and subsequent reduction of the resultant 3-nitroso-2-phenylindoles (2a-d) with sodium dithionite in alkali furnish the corresponding 3-aminoindoles (3a-d), which on condensation with ethyl chloroformate in pyridine give ethyl 2-phenylindole-3-carbamates (4a-d).The compounds 4a-d undergo smooth condensation with hydrazine hydrate (80percent) in ethanol to give 2-phenylindole-3-semicarbazides (5a-d).These semicarbazides when treated with sodium nitrite and acetic acid, the azides formed undergo spontaneous decomposition to give nitrenes which on cyclisation yield 1,2,3,8-tetrahydroindololo<5,4-b><1,3>benzodiazepin-2-ones (6a-d).Ethyl 3-phenylindole-2-carboxylates (8a-f) on treatment with hydrazine hydrate (80percent) in ethanol give the corresponding carbohydrazines (9a-f), which on reaction with sodium nitrite in acetic acid followed by refluxing the resultant acyl azides (10a-f) with anhyd. ethanol furnish ethyl 3-phenylindole-2-carbamate (11a-f). 3-Phenylindole-2-semicarbazides (12a-f), obtained in good yield from the respective carbamates by refluxing with hydrazine hydrate in ethanol, on reaction with NaNO2/AcOH afford 5,6,7,8-tetrahydroindolo<4,5-b><1,3>benzodiazepin-6-ones (13a-f).

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Merging Visible Light Photocatalysis and l-/d-Proline Catalysis: Direct Asymmetric Oxidative Dearomatization of 2-Arylindoles to Access C2-Quaternary Indolin-3-ones

A mild and effective method for asymmetric synthesis of C2-quaternary indolin-3-ones directly from 2-arylindoles by combining visible light photocatalysis and organocatalysis is described. In this reaction, 2-substituted indoles undergo photocatalyzed oxidative dearomatization, followed by an organocatalyzed asymmetric Mannich reaction with ketones or aldehydes. Products with opposite configurations are easily obtained in satisfactory yields with excellent enantio- A nd diastereoselectivity by employing readily available l- A nd d-proline as chiral organocatalysts.

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Microwave-assisted synthesis of indole- and azaindole-derivatives in water via cycloisomerization of 2-alkynylanilines and alkynylpyridinamines promoted by amines or catalytic amounts of neutral or basic salts

An efficient methodology is described and exploited for the preparation of differently substituted indoles and azaindoles via microwave-assisted cycloisomerization in water of 2-alkynylanilines and alkynylpyridinamines, which is promoted by catalytic amounts of neutral or basic salts or by stoichiometric weak organic bases. Good to high yields in the cyclization can be achieved for a variety of 2-amino(hetero)aryl alkynes. Reactions are run without any added metal catalyst. A comparison with the cycloisomerization conducted under conventional heating is also described. An efficient methodology is described for the preparation of differently substituted 1H-indoles and 1H-azaindoles via microwave-assisted cycloisomerization in water of 2-alkynylanilines and alkynylpyridinamines, promoted by catalytic amounts of neutral or basic salts or by weak organic bases.

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Alkyne Hydroamination Catalyzed by Silica-Supported Isolated Zn(II) Sites

Hydroamination is an atom-economical reaction to form C-N bonds, which are ubiquitous in organic compounds. Hydroamination has seen prolific advancements and has mostly focused on the development of homogeneous catalysts based on lanthanides or transition metals. Here, we have developed silica-supported, site-isolated Zn(II) sites through a combined surface organometallic chemistry (SOMC) and thermolytic molecular precursor (TMP) approach and show that they catalyze the intramolecular hydroamination of alkynes. This material is applicable to a broad range of substrates. On the basis of kinetics and in situ IR spectroscopic studies, we propose that the mechanism involves coordination of the aminoalkyne onto Zn(II) followed by the heterolytic activation of the N-H bond and subsequent cyclization and proton transfer.

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The sequential reactions of tetrazoles with bromoalkynes for the synthesis of (Z)-N-(2-bromo-1-vinyl)-N-arylcyanamides and 2-arylindoles

2-Arylindoles were prepared by a sequential reaction of Ag-catalyzed alpha-addition-Pd-catalyzed C-H bond functionalization of tetrazoles with bromoalkynes. A stereocontrolled Ag-catalyzed alpha-addition reaction of tetrazoles with bromoalkynes underwent smoothly to generate (Z)-N-(2-bromo-1- vinyl)-N-arylcyanamides, which were subsequently converted into 2-arylindoles through an intramolecular cyclization by Pd-catalyzed direct C-H bond functionalizations.

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Copper-mediated oxidative tandem reactions with molecular oxygen: Synthesis of 2-arylbenzoxazinone derivatives from indoles

We developed an efficient method for the transformation of indoles by utilizing a copper catalyst and molecular oxygen as the oxidant. The transformation involves a tandem oxidative process of 2-arylindoles. Our reaction afforded a variety of N-benzoyl anthranilic acids and benzoxazinones. Our investigation revealed that the choice of solvent and additives is critical in these reactions.

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Pd(II)/Bu4NBr/DMSO catalytic system for practical synthesis of indoles and pyrroles from imines through aerobic dehydrogenative cyclization

N-Aryl- and N-allylimines derived typically from substituted acetophenones undergo palladium(II)-catalyzed dehydrogenative cyclization reactions in the presence of tetrabutylammonium bromide and molecular oxygen in DMSO to afford indole and pyrrole derivatives, respectively, in moderate to good yields. The reactions are operationally simple and can be readily performed on multigram scales (up to 55 mmol).

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Microwave-accelerated Pd-catalyzed desulfitative direct C2-arylation of free (NH)-indoles with arylsulfinic acids

The rapid and efficient direct C2-arylation of free (NH)-indoles with arylsulfinic acids proceeded through a microwave-accelerated palladium-catalyzed desulfitation reaction. By using PdCl2 as a catalyst, silver acetate as an oxidant, and H2SO4 as an additive, arylsulfinic acids with both electron-donating and electron-withdrawing groups underwent desulfitative coupling with an array of free (NH)-indoles, thereby selectively providing C2-arylindoles in good yields. From C2 shining sea: The direct C2-arylation of free (NH)-indoles with arylsulfinic acids proceeded through a Pd-catalyzed desulfitation reaction. In the presence of an oxidant and an additive, 2-arylindoles were selectively afforded in good yields. Copyright

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