An expedient, regioselective synthesis of novel 2-alkylamino- and 2-alkylthiothiazolo[5,4-e]- and -[4,5-g]indazoles and their anticancer potential

Several novel 2-alkylamino- and 2-alkylthiothiazolo[5,4-e]- and -[4,5-g]indazoles and their 6-alkyl and 8-alkyl derivatives have been synthesised in high overall yields starting from 5-nitro and 6-nitroindazoles in a three-step route involving the regioselective cyclisation of thioureidoindazoles and indazolyl dithiocarbamates as the key steps. Some assorted thiazoloindazoles have been screened for anticancer properties, which demonstrated the anticancer potential of at least one product, justifying its further follow-up.     

An expedient, regioselective synthesis of 2-alkylamino- and 2-alkylthiothiazolo[5,4-e]indoles

1-Benzenesulfonyl-5-aminoindole 5, prepared from 5-nitroindole 3, was condensed with alkyl isothiocyanates and separately with carbon disulfide and alkyl bromides/iodides to furnish efficiently the corresponding N-alkyl-thioureidoindoles 6a-c and the alkyl N-(indol-5′-yl)dithiocarbamates 9a-e, respectively. Their cyclisation using N-bromosuccinimide (NBS) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), in the cold, followed by indolic N-deprotection, furnished regioselectively the 2-alkylamino- and the 2-alkylthiothiazolo[5,4-e]indoles 8a-c and 11a-e, respectively, in good overall yields.     

Novel 6-substituted benzothiazol-2-yl indolo[1,2-c]quinazolines and benzimidazo[1,2-c]quinazolines

The synthetic route to and a preliminary biological evaluation of novel indolo[1,2-c]quinazolines (8) and benzimidazo[1,2-c]quinazolines (9) are described. The products were obtained by condensation of the appropriate diamines (e.g. 2-(2-aminophenyl)indole or 2-(2-aminophenyl)benzimidazole) with 2-cyanobenzothiazoles. This work further demonstrates the general applicability of microwaves for a facile and rapid access to original heterocycles with potential pharmaceutical value.     

Studies on uracils: a facile one-pot synthesis of oxazino[4,5-d]-, pyrano[2,3-d]-, pyrido[2,3-d]- and pyrimido[4,5-d]pyrimidines using microwave irradiation in the solid state

N,N-Dimethyl-5-formylbarbituric acid 1 reacts with maleimide 2 and phenyl isocyanate/phenyl isothiocyanate 4 under microwave-assisted conditions in the solid phase to afford pyrano[2,3-d]pyrimidines 3 and oxazino[4,5-d]pyrimidines 5 in excellent yields. Under identical conditions, N,N-dimethyl-6-amino-5-formyluracil 6 reacts with 2 and 4 to give pyrido[2,3-d]pyrimidine derivative 7 and pyrimido[4,5-d]pyrimidines 8 in high yields.     

Synthesis of tricyclic isoindoles and thiazolo[3,2-c][1,3]benzoxazines

The thermolysis of (3R,9bS)-5-oxo-2,3,5,9b-tetrahydrothiazolo[2,3-a]isoindole-3-carboxylic acids in Ac₂O led to novel 3-methylene-2,5-dioxo-3H,9bH-oxazolo[2,3-a]isoindoles and chiral (9bS)-5-oxo-2,3,5,9b-tetrahydrothiazolo[2,3-a]isoindoles were obtained on FVP. Starting from l-cysteine methyl ester (3R,10bR)-5-oxo-2,3-dihydro-10bH-[1.3]thiazolo[3,2-c][1,3]benzoxazines were obtained as single stereoisomers. The thermolysis of (3R,10bR)-5-oxo-2,3-dihydro-10bH-[1.3]thiazolo[3,2-c][1,3]benzoxazine-3-carboxylic acid in Ac₂O gave 5-acetyl-2-phenyl-2,3-dihydrothiazole. The structures of methyl (3R,9bS)-5-oxo-2,3,5,9b-tetrahydrothiazolo[2,3-a]isoindole-3-carboxylate 1a and methyl (2R,4R)-N-chlorocarbonyl-2-(2-hydroxyphenyl)thiazolidine-4-carboxylate 9 were determined by X-ray crystallography.     

A facile synthesis and herbicidal activities of novel fluorine-containing thiazolo[4,5-d]pyrimidin-7(6H)-ones

Eighteen novel 5-alkylamino-6-aryl-3-phenyl-2-thioxo-2,3-dihydrothiazolo[4,5-d]pyrimidin-7(6H)-ones 5a-r were designed and easily synthesized via a tandem aza-Wittig reaction. Treatment of iminophosphorane 2 with aromatic isocyanate gave carbodiimide 3, which reacted with fluoro-substituted alkylamines to provide the title compounds in 65-87% isolated yields using sodium ethoxide as catalyst. All compounds 5 were confirmed by IR, ¹H NMR, MS and elemental analysis, and compound 5p was further analyzed by single-crystal X-ray diffraction. The preliminary bioassay indicated that some compounds showed significant inhibition activities against the root growth of rape and barnyard grass at a dosage of 100 mg/L.     

Synthesis of 1-benzyl-8,9-dihydroimidazo[4,5-c]pyrrolo[3,2-g]quinolin-4(5H)-one via palladium-catalyzed intramolecular arylation

The synthesis of a novel tetracyclic structure, 8,9-dihydroimidazo[4,5-c]pyrrolo[3,2-g]quinolin-4(5H)-one, has been achieved by a convergent pathway. Coupling of the weakly nucleophilic hindered aromatic amine with 1-benzylimidazole-4-carboxylic acid, 7, afforded the corresponding amide 9 using a DCP/DMF complex; subsequent Heck-type arylation leading to desired tetracyclic molecule imidazo[4,5-c]-pyrrolo[3,2-g]quinolin-4(5H)-one.     

A facile synthesis of indolo[3,2,1-jk]carbazoles via palladium-catalyzed intramolecular cyclization

A new efficient synthesis of indolo[3,2,1-jk]carbazoles by the palladium-catalyzed cyclization of N-(2-bromoaryl)carbazoles is described. The reaction involves intramolecular C-C bond formation, coupled with the cleavage of a C-X bond and a C-H bond on carbazole ring. Substitutions on N-aryl core with either electron-donating or electron-withdrawing groups are introduced, and different reaction factors for cyclization are evaluated.     

Substituted chromones in [3+2] cycloadditions with nonstabilized azomethine ylides: synthesis of 1-benzopyrano[2,3-c]pyrrolidines and 1-benzopyrano[2,3-c:3,4-c′]dipyrrolidines

Chromones bearing electron-withdrawing substituents at the 2- or 3-position react with nonstabilized azomethine ylides to produce 1-benzopyrano[2,3-c]pyrrolidines in good yields. Reactions of 3-cyanochromones proceed diastereoselectively to give 1-benzopyrano[2,3-c]pyrrolidines and tetrahydro-1H-spiro[chromeno[2,3-c]pyrrol-9,5′-oxazolidine]-9a-carbonitriles, depending on the reactant ratio, as a result of a 1,3-dipolar cycloaddition of the azomethine ylide at the double bond and carbonyl group of the chromone system. The latter undergoes demethylenation and recyclization into a novel hexahydrochromeno[2,3-c:3,4-c′]dipyrrole tetracyclic system on heating with hydrochloric acid.     

2-Oxobenzo[h]chromene: a novel entry for the concise and efficient synthesis of indeno[1,2-c]phenanthrenes

An efficient and concise synthesis of 7-sec-amino-5,13-dihydro-6H-indeno[1,2-c]phenanthrene-8-carbonitriles is described through base catalyzed ring transformation of 4-sec-amino-2-oxo-5,6-dihydro-2H-benzo[h]chromene-3-carbonitriles with 1-indanone in moderate to good yields.     

Novel synthesis of benzo[b]carbazoles

A new method was adopted for the synthesis of benzo[b]carbazoles by Claisen condensation followed by Fischer indole cyclization. Newly synthesized benzo[b]carbazoles were treated with ethanol amine in the presence of polyphosphoric acid which leads to the formation of pyrazino carbazoles. All the synthesized compounds were characterized by all spectral means.     

Cycloalkano[1″,2″:4,5;4″,3″:4′,5′]bis(pyrrolo[2,3-c]pyrimido[5,4-e]pyridazines): synthesis, structure and mechanism of their formation

Reactions of 3-alkylamino-6,8-dimethylpyrimido[4,5-c]pyridazine-5,7(6H,8H)-diones with cyclohexyl- and cycloheptylamines in the presence of AgPy₂MnO₄ produce novel cycloalkano[1″,2″:4,5;4″,3″:4′,5′]bis(pyrrolo[2,3-c]pyrimido[5,4-e]pyridazines). Detailed information concerning the scope and mechanism of these transformations is discussed.     

An efficient synthesis of 4H,5H-pyrano[3,4-c]pyran-4,5-diones from a suitably functionalized 2H-pyran-2-one

An efficient synthesis of ethyl 7-aryl-2-methyl-4H,5H-pyrano[3,4-c]pyran-4,5-dione-1-carboxylate 5, and ethyl 6-aryl-3-cyano-2H-pyran-2-one-4-acetate 6 has been delineated by reaction of suitably functionalized 2H-pyran-2-ones 1 with ethyl acetoacetate 2.     

Convenient DABCO-catalyzed one-pot synthesis of multi-substituted pyrano[2,3-c]pyrazole dicarboxylates

We developed an efficient and simple one-pot synthesis of functionalized multi-substituted 2,4-dihydro-pyrano[2,3-c]pyrazole dicarboxylates from β-ketoesters, hydrazine, dimethyl acetylenedicarboxylate and malononitrile in EtOH. This four-component one-pot reaction carried out in the presence of DABCO catalyst showed advantages over a one-pot three-component method in its simple procedure, high yield and low toxicity.     

Synthesis of pyrrolo[3,4-b]pyrroles and perhydrothiazolo[3′,4′-2,3]pyrrolo[4,5-c]pyrroles

The 1,3-dipolar cycloaddition reactions of various N-tethered alkenyl aldehydes with some cyclic and acyclic amino acids have been studied. Some key sulfonamides having strategically positioned aldehyde and olefinic tether have been synthesized and effectively subjected to intramolecular azomethine ylide cycloaddition reaction resulting in a series of pyrrolo[3,4-b]pyrrole and its N-1-C-2 derivatives, and a series of novel heterotricyclic compounds, perhydrothiazolo[3′,4′-2,3]pyrrolo[4,5-c]pyrroles, in good yields. The intramolecular cycloaddition reaction was found to be highly stereoselective to form only cis-fused cycloadducts in all cases.     

Short and efficient access to imidazo[1,2-a]pyrrolo[3,2-c]pyridine derivatives

Access to N-protected or N-free imidazo[1,2-a]pyrrolo[3,2-c]pyridine derivatives as potential antiviral compounds was achieved in good yields from N-protected 7-amino-8-halo-2-methylimidazo[1,2-a]pyridines by catalytic coupling of terminal acetylenes under mild conditions using [PdCl₂(PPh₃)₂] or [Cu(Phen)(PPh₃)₂]NO₃.     

CuCl-catalyzed one-pot synthesis of 5,6-dihydropyrazolo[1,5-c]quinazolines

A simple and efficient procedure for the preparation of 5,6-dihydropyrazolo[1,5-c]quinazolines via CuCl-catalyzed tandem reaction of 5-(2-bromoaryl)-1H-pyrazoles with aldehydes and aqueous ammonia under nitrogen atmosphere has been developed. The usefulness of this novel methodology was showcased by its successful application in the preparation of a potential Eg5 inhibitor.     

Synthesis of dipyrrolo[3,4-a:3,4-c]carbazoles: new kinase inhibitors

Two dipyrrolo[3,4-a:3,4-c]carbazole stereoisomers were unexpectedly obtained by Diels–Alder dimerization of 3-indolylmaleimide. Three dimensional structures of both stereoisomers were confirmed by X-ray analysis. Moreover compound 4 inhibits protein kinases in vitro, especially Pim-3, in the sub-micromolar range.     

Polyethylene glycol (PEG-400): an efficient green reaction medium for the synthesis of benzo[4,5]imidazo[1,2-a]-pyrimido[4,5-d]pyrimidin-4(1H)-ones under catalyst-free conditions

A simple and an efficient eco-friendly methodology has been developed for the synthesis of benzo[4,5]imidazo[1,2-a]-pyrimido[4,5-d]pyrimidin-4(1H)-ones in excellent yields under catalyst-free-conditions using inexpensive and non-toxic polyethylene glycol (PEG-400) medium. This new protocol offers an environmental acceptability, shorter reaction time, room temperature, low cost, high yields, and recyclability of the PEG-400 medium are the important features. This method provides a green and much improved protocol over the existing methods.     

Preparation of 2,4,5-trisubstituted pyrazolo[4,3-c]quinolin-3-ones

The preparation of pyrazolo[4,3-c]quinolinones is reported starting from 2-substituted-5-(2-fluorophenyl)-3-oxo-2,4-dihydro-3H-pyrazol-3-ones. A one-pot protocol, in which condensation with an orthoamide followed by substitution with a primary amine and subsequent S_NAr-cyclization to provide rapid access to 4- and 5-substituted pyrazolo[4,3-c]quinolinones was developed.