Synthesis of 3,5-Disubstituted-1,2,4-thiadiazoles via NaH-DMF-Promoted Dehydrogenative Intramolecular N-S Bond Formation.

A facile transition-metal-free synthesis of 3,5-bis(het)aryl/arylaminothiadiazoles has been reported. The overall protocol involves base-mediated tandem thioacylation of amidines with dithioesters or aryl isothiocyanates in DMF solvent and subsequent in situ intramolecular dehydrogenative N-S bond formation of thioacylamidine intermediates under an inert atmosphere. A probable mechanism involving a carbamoyl anion, generated by deprotonation of DMF, acting as a radical initiator has been suggested.

Domino Synthesis of Thiazolo-Fused Six- and Seven-Membered Nitrogen Heterocycles via Intramolecular Heteroannulation of In-Situ-Generated 2-(Het)aryl-4-amino-5-functionalized Thiazoles.

Synthesis of novel 2-(het)aryl-substituted thiazolo-fused six- and seven-membered heterocycles, such as thiazolo[4,5-b]pyridin-5(4H)-ones, thiazolo[4,5-c]isoquinolin-5(4H)-ones, thiazolo[4,5-b]quinolin-9(4H)-ones, 4H-benzo[e]thiazolo[4,5-b]azepine-5,10-diones, have been developed in a single-pot operation via intramolecular heteroannulation of in-situ-generated 2-(het)aryl-4-amino-5-functionalized thiazoles. These 4-amino-5-functionalized thiazoles were readily obtained in a one-pot process by treatment of a range of (het)aryldithioesters with cyanamide in the presence of NaH, followed by in situ S-alkylation-intramolecular condensations of the resulting thioimidate salts with appropriate activated methylene halides. On the other hand, the corresponding 4H-benzo[b]thiazolo[4,5-e][1,4]diazepin-10(9H)-ones were synthesized in a two-step process, requiring prior isolation of 5-carboethoxy-4-(2-nitrophenyl)aminothiazoles and their subsequent reductive cyclization. The activated methylene halides employed in these reactions for the synthesis of various thiazolo-fused heterocycles were methyl bromocrotonate, ethyl 2-(bromomethyl)benzoate, 2-fluorophenacyl bromides, ethyl 2-(2-bromoacetyl)benzoate, and ethyl bromoacetate. Several of these thiazolo-fused heterocycles display yellow green to green fluorescence, and their absorption and emission spectra have also been examined.

Thiophene-Based Dual Modulators of Aß and Tau Aggregation.

Alzheimer's disease is characterized by the accumulation of amyloid beta (Aß) and Tau aggregates in the brain, which induces various pathological events resulting in neurodegeneration. There have been continuous efforts to develop modulators of the Aß and Tau aggregation process to halt or modify disease progression. A few small-molecule-based inhibitors that target both Aß and Tau pathology have been reported. Here, we report the screening of a targeted library of small molecules to modulate Aß and Tau aggregation together with their in vitro, in silico and cellular studies. In vitro ThT fluorescence assay, dot blot assay, gel electrophoresis and transmission electron microscopy (TEM) results have shown that thiophene-based lead molecules effectively modulate Aß aggregation and inhibit Tau aggregation. In silico studies performed by employing molecular docking, molecular dynamics and binding-free energy calculations have helped in understanding the mechanism of interaction of the lead thiophene compounds with Aß and Tau fibril targets. In cellulo studies revealed that the lead candidate is biocompatible and effectively ameliorates neuronal cells from Aß and Tau-mediated amyloid toxicity.

Single-Pot Preparation of 4-Amino-2-(het)aryl-5-Substituted Thiazoles Employing Functionalized Dithioesters as Thiocarbonyl Precursors.

An effective, diversity oriented, one-pot reaction of 4-amino-2-(het)aryl/alkyl-5-functionalized thiazoles has been disclosed, utilizing aryl/heteroaryl/alkyl dithioesters as thiocarbonyl coupling partners in a modified Thorpe-Ziegler type cyclization. The reaction proceeds at room temperature, under mild conditions, in excellent yields, displaying broad functional group compatibility at 2 and 5 positions of thiazoles. This synthetic strategy has been further expanded for the one-pot construction of two highly potent tubulin polymerization inhibitors, i.e., 2-(het)aryl-4-amino-5-(3,4,5-trimethoxyaroyl) thiazoles, in high yields.

Synthesis of Substituted Benzo[b]thiophenes via Base-Promoted Domino Condensation-Intramolecular C-S Bond Formation.

A novel synthesis of 2,3-substituted benzothiophenes is reported, involving a tandem base-mediated condensation of o-iodoarylacetonitriles/acetates/ketones with (hetero)aryldithioesters and an intramolecular C-S bond formation. The reaction affords diversely substituted benzothiophenes and heterofused thiophenes in excellent yields.

Reaction of 1,3-Bis(het)arylmonothio-1,3-diketones with Sodium Azide: Regioselective Synthesis of 3,5-Bis(het)arylisoxazoles via Intramolecular N-O Bond Formation.

An efficient new synthesis of 3,5-bis(het)arylisoxazoles, involving the reaction of 1,3-bis(het)arylmonothio-1,3-diketones with sodium azide in the presence of IBX catalyst, has been reported. The reaction proceeds at room temperature in high yields and is applicable to a broad range of substrates including the synthesis of 5-methyl-3-arylisoxazoles, a key subunit present in several ß-lactamase-resistant antibiotics. A probable mechanism for the formation of isoxazoles has been suggested. A few of the 5-styryl/arylbutadienyl-3-(het)arylisoxazoles have also been synthesized by reacting the corresponding 1-(het)aryl-1-(methylthio)-4-(het)arylidene-but-1-en-3-ones with sodium azide at higher temperatures. The reaction of ß-ketodithioesters with sodium azide is shown to furnish ß-ketonitriles in good yields.

Aza-Annulation of 1,2,3,4-Tetrahydro-ß-carboline Derived Enaminones and Nitroenamines: Synthesis of Functionalized Indolizino[8,7-b]indoles, Pyrido[1,2-a:3,4-b']diindoles, Indolo[2,3-a]quinolizidine-4-ones and Other Tetrahydro-ß-carboline Fused Heterocycles.

Aza-annulation of novel 1,2,3,4-tetrahydro-ß-carboline derived enaminones and nitroenamines with various 1,2- and 1,3-bis electrophiles, such as oxalyl chloride, maleic anhydride, 1,4-benzoquinone, 3-bromopropionyl chloride, itaconic anhydride, and imines (from formaldehyde and primary amines), has been investigated. These methodologies provide simple one-step pathways for efficient construction of highly functionalized tetrahydro-ß-carboline 1,2-fused, five- and six-membered heterocyclic frameworks, such as indolizino[8,7-b]indoles, pyrido[1,2-a:3,4-b']diindoles, indolo[2,3-a]quinolizidines, and pyrimido[1',6':1,2]pyrido[3,4-b]indoles, which are core structures of many naturally occurring indole alkaloids with diverse bioactivity.

Domino Synthesis of 2-Substituted Benzothiazoles by Base-Promoted Intramolecular C-S Bond Formation.

A new, transition-metal-free, domino synthesis of 2-substituted benzothiazoles has been developed, involving base-promoted one-pot addition of active methylene compounds to o-iodoarylisothioacyanates and subsequent intramolecular C-S bond formation of the resulting thioamidate anion. The reaction proceeds at room temperature within 1-3 h, affording diversely substituted benzothiazoles in high yields. A possible radical intermediate pathway, via an SRN1 mechanism, has been proposed for intramolecular C-S bond formation.

Synthesis of 2,4,5-Trisubstituted Oxazoles with Complementary Regioselectivity from α-Oxoketene Dithioacetals and ß-(Methylthio)-ß-(het)aryl-2-propenones.

An efficient protocol for the synthesis of 2,5-substituted 4-acyloxazoles and the related 2,4-substituted 5-acyloxazoles with complementary regioselectivity from the corresponding α-oxoketene dithioacetals or ß-(het)aryl/(methylthio)enone precursors has been reported. In the first protocol, the α-oxoketene dithioacetals or ß-(methylthio)enones were converted to the corresponding α-bromo-ß-(methylthio)enones followed by copper catalyzed inter/intramolecular annulation of these intermediates with various primary amides affording 2-(het)aryl/alkyl-4-(het)aroyl-5-(methylthio)/(het)aryloxazoles via concomitant formation of the C4-N and C5-O bond via enamide intermediates. In the second approach, the starting α-oxoketene dithioacetals or ß-(methylthio)-ß-(het)arylenones were subjected to base induced conjugate addition-elimination with various primary amides to furnish ß-aroylenamides, which, on subsequent iodine catalyzed intramolecular oxidative C-H functionalization/C-O bond formation, afforded the corresponding regioisomeric 2-(het)aryl/alkyl-4-(methylthio)/(het)aryl-5-(het)aroyloxazoles in excellent yields. The methodology has also been extended for the synthesis of regioisomeric 4- or 5-aminooxazoles and 4- or 5-( n-butyl)oxazoles from the corresponding 4- or 5-(methylthio)oxazoles.

One-Pot Synthesis of 2-(Het)aryl/alkyl-3-cyanobenzofurans from 2-(2-Bromoaryl)-3-(het)aryl-3-(methylthio)acrylonitriles and Benzyl Carbamate.

A one-pot synthesis of 2-(het)aryl/alkyl-3-cyanobenzofurans has been reported. The overall sequence involves base-induced reaction of 2-(2-bromoaryl)-3-(het)aryl-3-(methylthio)acrylonitriles with benzyl carbamate, generating α-(het)aroyl-α-(2-bromoaryl)acetonitriles, which are in situ subjected to copper-catalyzed intramolecular O-arylation, furnishing the 2-(het)aryl/alkyl-3-cyanobenzofurans in high yields. A probable mechanism for the base-induced cleavage of 2-(2-bromoaryl)-3-(het)aryl-3-(methylthio)acrylonitriles to α-(het)aroyl-α-(2-bromoaryl)acetonitriles in the presence of benzyl carbamate has been proposed.

Synthesis of Thieno-Fused Five- and Six-Membered Nitrogen and Oxygen Heterocycles via Intramolecular Heteroannulation of 4,5-Substituted 3-Amino or 3-Hydroxy 2-Functionalized Thiophenes.

Diverse general high-yield routes for novel thieno-fused five- and six-membered nitrogen and oxygen heterocycles such as thieno[3,2-b]pyrroles, thieno[3,2-b]furans, thieno[3,2-b]indoles, thieno[3,2-b]benzofurans, thieno[3,2-b]pyridine-5-ones, thieno[3,2-b]pyran-5-ones, thieno[3,2-b]isoquinolin-5-ones, thieno[3,2-b]chromen-5-ones, thieno[3,2-b]quinolin-9-ones, and thieno[3,2-b]chromen-9-ones have been developed via in situ or stepwise intramolecular heteroannulation of newly synthesized 4,5-substituted 3-amino- or 3-hydroxy 2-functionalized thiophenes. These substituted 3-amino/hydroxythiophenes were readily obtained in high yields from easily accessible precursors, in a sequential one-pot process, by treatment of a range of (het)aryl/unsubstituted acetonitriles or acetates with (het)aryl dithioesters in the presence of LDA, followed by in situ alkylation-intramolecular condensation of the resulting enethiolate salts with functionalized activated methylene halides. The functionalized activated methylene halides employed in these reactions for the synthesis of various thieno-fused heterocycles were cinnamyl bromide, 2-bromobenzyl chloride, bromocrotonate, 2-(bromomethyl)benzoate, and 2-chlorophenacyl bromide. A few of the 4,5-substituted 3-amino/hydroxy-2-stryrylthiophenes (or 2-acrylates) displayed strong fluorescence, and their absorption/emission spectra have also been examined.

Synthesis of Substituted Benzo[b]thiophenes via Sequential One-Pot, Copper-Catalyzed Intermolecular C-S Bond Formation and Palladium-Catalyzed Intramolecular Arene-Alkene Coupling of Bis(het)aryl/alkyl-1,3-monothiodiketones and o-Bromoiodoarenes.

A new, convergent, one-pot synthesis of 2,3-substituted benzo[b]thiophenes from readily available 1,3-bis(het)aryl-1,3-monothiodiketones and o-bromoiodoarenes involving a sequential copper-catalyzed intermolecular C-S coupling followed by palladium-catalyzed intramolecular arene-alkene coupling of in situ generated ß-(o-bromoaryl)thiovinylketones has been described. Synthesis of a few thieno- and furano-fused 2-(het)aroylethylidenethiochromenes via intramolcular direct C-H (het)arylation of ß-(o-bromoaryl)thioenones carrying 2-thienyl/furyl groups under different palladium-catalyzed conditions has also been reported.

Amine Directed Pd(II)-Catalyzed C-H Activation-Intramolecular Amination of N-Het(aryl)/Acyl Enaminonitriles and Enaminones: An Approach towards Multisubstituted Indoles and Heterofused Pyrroles.

An efficient route to multisubstituted indoles has been developed through intramolecular oxidative C-H activation-amination of readily available 2-(het)aryl-3-(het)aryl/alkyl-3-(het)aryl/acylaminoacrylonitrile/enaminone precursors in the presence of either palladium acetate/cupric acetate catalytic system under oxygen atmosphere or palladium acetate/silver carbonate in the presence of pivalic acid as additive. The method is compatible with a diverse range of substituents on the aryl ring as well as at the 2- and 3-positions of the indole ring. The versatility of this method was further demonstrated by elaborating it for the synthesis of heterofused pyrroles such as thieno[2,3-b]pyrroles, thieno[3,2-b]pyrroles, pyrrolo[2,3-b]indoles, and pyrrolo[2,3-b]pyridines in good yields. Probable mechanisms for the formation of these indoles have been suggested.

Diversity-Oriented Synthesis of Substituted Benzo[b]thiophenes and Their Hetero-Fused Analogues through Palladium-Catalyzed Oxidative C-H Functionalization/Intramolecular Arylthiolation.

An efficient, high yielding route to multisubstituted benzo[b]thiophenes has been developed through palladium-catalyzed intramolecular oxidative C-H functionalization-arylthiolation of enethiolate salts of α-aryl-ß-(het)aryl/alkyl-ß-mercaptoacrylonitriles/acrylates or acrylophenones. The overall strategy involves a one-pot, two-step process in which enethiolate salts [generated in situ through base-mediated condensation of substituted arylacetonitriles, deoxybenzoins, or arylacetates with (het)aryl (or alkyl) dithioates] are subjected to intramolecular C-H functionalization-arylthiolation under the influence of a palladium acetate (or palladium chloride)/cupric acetate catalytic system and tetrabutylammonium bromide as additive in N,N-dimethylformamide (DMF) as solvent. In a few cases, the yields of benzo[b]thiophenes were better in a two-step process by employing the corresponding enethiols as substrates. In a few examples, Pd(OAc)2 (or PdCl2) catalyst in the presence of oxygen was found to be more efficient than cupric acetate as reoxidant, furnishing benzothiophenes in improved yields by avoiding formation of side products. The method is compatible with a diverse range of substituents on the aryl ring as well as on the 2- and 3-positions of the benzothiophene scaffold. The protocol could also be extended to the synthesis of a raloxifene precursor and a tubulin polymerization inhibitor in good yields. The versatility of this newly developed method was further demonstrated by elaborating it for the synthesis of substituted thieno-fused heterocycles such as thieno[2,3-b]thiophenes, thieno[2,3-b]indoles, thieno[3,2-c]pyrazole, and thieno[2,3-b]pyridines in high yields. A probable mechanism involving intramolecular electrophilic arylthiolation via either a Pd-S adduct or palladacycle intermediate has been proposed on the basis of experimental studies.

Reaction of cyclic α-oxoketene dithioacetals with methylene isocyanides: a novel pyrrole annulation-ring-expansion domino process.

The title reaction provides a direct entry to a range of biologically relevant annulated pyrroles via a domino process involving a regioselective one-carbon homologation of cyclic ketones as the key step.

Molecular diversity through novel organosulfur synthons: versatile templates for heterocycle synthesis.

This review highlights some of our recent work on design and development of new synthetic methods for diverse classes of heterocycles employing novel organosulfur synthons i.e. polarized ketene dithioacetals, N, S-acetals, ß-oxodithioesters and 2,3-(hetero)aryl-3-(methylthio)acrylonitriles, easily accessible from a wide range of active methylene compounds.

Synthesis of 2,5-bis(hetero)aryl 4'-substituted 4,5'-bisoxazoles via copper(I)-catalyzed domino reactions of activated methylene isocyanides with 2-phenyl- and 2-(2-thienyl)-4-[(aryl/heteroaryl)(methylthio)methylene]oxazol-5(4H)-ones.

An efficient straightforward synthesis of 2,5,4'-trisubstituted 4,5'-bisoxazoles via copper(I)-catalyzed domino reactions of 2-phenyl- and 2-(2-thienyl)-4-[(aryl/heteroaryl)methylene]-5-oxazolones with activated methylene isocyanides has been reported. The overall domino process comprised of formation of one C-C and two C-O bonds involves initial nucleophilic ring opening of oxazolones by cupriomethylene isocyanides followed by sequential construction of two oxazole rings in the presence of copper catalyst. The broad substrate scope and excellent functional group compatibility of the reaction has been demonstrated by employing a variety of heteroaryl- and aryl-substituted oxazolones and activated methylene isocyanides, yielding bisoxazoles with three potential points of diversity. A probable mechanism for this novel copper-catalyzed domino process has been proposed.

Regio- and chemoselective metalation of arenes and heteroarenes using hindered metal amide bases.

The preparation of highly functionalized organometallic compounds can be achieved by direct C-H activation of a broad range of unsaturated substrates using lithium chloride solubilized 2,2,6,6-tetramethylpiperidide bases (TMP(n)MX(m)⋅p LiCl). These are excellent reagents for converting a wide range of aromatic and heterocyclic substrates into valuable organometallic reagents with broad applications in organic synthesis.

2-phenyl-4-bis(methylthio)methyleneoxazol-5-one: versatile template for diversity oriented synthesis of heterocycles.

4-Bis(methylthio)methylene-2-phenyloxazol-5-one (1) has been shown to be a versatile template for the synthesis of novel heterocyclic scaffolds. The key protocol involves nucleophilic ring opening of 1 with various primary aliphatic, aromatic amines and diamines to give open-chain amide adducts which are transformed into 4-bis(methylthio)methylene-2-phenyl-1-alkyl/arylimidazol-5-(4H)-ones (5) in good yields in the presence of anhydrous NaOAc/AcOH. Similarly, the amide adducts 4h-i from 3,4-dimethoxyphenylethylamine and tryptamine undergo interesting rearrangement in the presence of POCl(3) to furnish 1-(2-phenyl-5-methylthio-4-thiazolyl)dihydroisoquinoline and ß-carboline derivatives 8-9 in good yields. The amide adduct 14 from o-phenylenediamine on exposure to refluxing acetic acid or in the presence of Ag(2)CO(3) affords substituted 3H-1,5-benzodiazepinone, 2-(5-methylthio-2-phenyl-4-oxazolyl)-1H-benzimidazole and trisubstituted oxazole (15-17), whereas the bis-adduct from ethylenediamine yields ethylene bridge tethered bis-imidazole 23 and bis-oxazole 24 under similar reaction conditions. Probable mechanisms for the formation of various products have been suggested.

Efficient routes to pyrazolo[3,4-b]indoles and pyrazolo[1,5-a]benzimidazoles via palladium- and copper-catalyzed intramolecular C-C and C-N bond formation.

Efficient synthetic routes to pyrazolo[3,4-b]indoles and pyrazolo[1,5-a]benzimidazoles via intramolecular palladium- and copper-catalyzed cyclization of 1-aryl/1-unsubstituted 5-(2-bromoanilino)pyrazole precursors via intramolecular C-C and C-N bond formation have been reported.