Synthesis of 2‐amino‐s‐triazino[1,2‐a]benzimidazoles as potential antifolates from 2‐guanidino‐ and 2‐guanidino‐5‐methylbenzimidazoles

The syntheses of 2‐amino‐s‐triazino[1,2‐a]benzimidazoles from 2‐guanidinobenzimidazoles were successfully carried out by a ring annelation reaction. The regiochemistry of the ring closure of 5‐methyl‐2‐guanidinobenzimidazole with diethyl azodicarboxylate, aldehydes, acetone, diethyl ethoxymethylenemalonate and orthoesters, leading to the formation of s‐triazine ring was studied. High regioselectivity was not observed in any of these reactions. However, the synthesis of s‐triazino[1,2‐a]benzimidazole system was found to be more regioselective than its 3,4‐dihydro analogue. NOESY experiment indicated that the compound, 2‐amino‐4,4‐dimethyl‐3,4‐dihydro‐s‐triazino[1,2‐a]benzimidazole existed predominantly as the 3,4‐dihydro tautomer in dimethyl sulfoxide. It was found to inhibit bovine dihydrofolate reductase with IC₅₀ 10.9 μM.     

Some nucleophilic substitutions in 2‐cyano‐3‐nitroimidazo[1,2‐a]pyridine

In some nucleophilic substitution reactions of 2‐cyano‐3‐nitroimidazo[1,2‐a]pyridine, nitrogen (alkylamines, guanidine) and oxygen nucleophiles (alkoxides) underwent substitution of the 2‐cyano group, while sulfur nucleophiles (alkylthiols) underwent substitution of the 3‐nitro group.     

Synthesis of new spiro‐[isothiochromene‐3,5′‐isoxazolidin]‐4(1H)‐ones

A series of seven new 2′,3′,4′‐substituted spiro[isothiochromene‐3,5′‐isoxazolidin]‐4(1H)‐ones ( 7‐13 ) has been prepared in the reaction of benzylidene(phenyl)azane oxide ( 5 ) or benzylidene(methyl)azane oxide ( 6 ) with (3Z)‐3‐(4‐substituted‐benzylidene)‐1H‐isothio‐ chromen‐4(3H)‐one ( 1‐4 ). The reaction occurs by a 1,3‐dipolar cycloaddition mechanism that leads to the regiospecific formation of various spiroisoxazolidines ( 7‐13 ).     

Synthesis of 9‐[1‐benzyl‐5‐(alkylsulfonyl)‐1H‐2‐imidazolyl]perhydro‐1,8‐acridinediones

Tricyclic dihydropyridines like ZM244085 are potential K_ATP channel openers. In this study 3‐cyanophenyl ring of ZM244085 was replaced with imidazolyl ring. So, 9‐[1‐benzyl‐5‐(alkylsulfonyl)‐1H‐2‐imidazolyl]perhydro‐1,8‐acridinediones ( 5d‐f ) were synthesized from 2‐alkylsulfonyl‐1‐benzyl‐5‐formylimidazole ( 4d‐f ) and cyclohexane‐1,3‐dione according to classical Hantzch synthesis as potential potassium channel modulators.     

Furan ring opening ‐ indole ring closure: Synthesis of furo[2′,3′:3,4]‐cyclohepta[1,2‐b]indolium chlorides

A new synthetic approach to furo[2′,3′:3,4]cyclohepta[1,2‐b]indolium chlorides is elaborated starting from 2‐acetylaminoaryldifurylmethanes or 2‐aminoaryldifurylmethanes under treatment with methanolic HCl solution. The reaction proceeds in three steps: recyclization, intramolecular cyclization, and disproportionation. In this case the furan ring takes part in building up both pyrrole and seven‐membered rings. The same salts can be obtained directly from 2‐acetylaminobenzaldehydes and 2‐methylfuran under similar conditions without isolation of corresponding 2‐acetylaminoaryldifurylmethanes.     

A facile synthesis of 2‐substituted thieno[3′,2′‐5,6]‐pyrido[4,3‐d]pyrimidin‐4(3H)‐ones

The thienopyridine derivative 2 , obtained from reaction of acetoacetic ester with 1 in the presence of tin tetrachloride, was treated with triphenylphosphine in hexachloroethane and Et₃N to give iminophosphorane 3 . Iminophosphorane 3 reacted with phenyl isocyanate to give carbodiimide 4 , which was further treated with phenols or ethenol to produce 2‐substituted 5,8,9‐trimethyl‐3‐phenyl‐thieno[3′,2′‐5,6]pyrido[4,3‐d]pyrimidin‐4(3H)‐ones 5 in presence of catalytic amount of K₂CO₃ or EtONa. The structures of compounds 5 were confirmed by ¹H NMR, IR, MS, and elemental analysis.     

Ring closure reactions of pyrido[2,3‐d]pyrimidines to pyrano[2′,3′:4,5]‐ and oxazolo[5′,4′:4,5]pyrido[2,3‐d]pyrimidines

The cyclocondensation of 5‐hydroxy‐pyrido[2,3‐d]pyrimidines 1 with malonates gives pyrano[2′,3′:4,5]‐pyrido[2,3‐d]pyrimidines 2 . Nitration of 1 and reduction with zinc in the presence of carboxylic acids/anhydrides gave 2‐alkyloxazolo[5′,4′:4,5]pyrido[2,3‐d]pyrimidines 4 , which were ring‐opened to 6‐aminopyrido[2,3‐d]pyrimidines 5, 6 and 7 . Cyclization of 6‐aminopyrido[2,3‐d]pyrimidines 6 with benzoylchlorides 8 gave 2‐aryloxazolo[5′,4′:4,5]pyrido[2,3‐d]pyrimidines 9 . Reaction conditions for the cyclization have been studied by differential scanning calorimetry (DSC).     

Novel regioselective synthesis of 3′H,4H‐spiro[chromene‐3,2′‐[1,3,4]thiadiazol]‐4‐one containing compounds

A variety of 3″,5″‐diaryl‐3″H,4′H‐dispiro[cyclohexane‐1,2′‐chromene‐3′,2″‐[1,3,4]thiadiazol]‐4′‐ones 3a‐c were synthesized regioselectively through the reaction of 4′H,5H‐trispiro[cyclohexane‐1,2′‐chromene‐3′,2″‐[1,3,4]oxadithiino[5,6‐c]chromene‐5″,1″′‐cyclohexan]‐4′‐one ( 1 ) with nitrilimines (generated in situ via triethylamine dehydrohalogenation of the corresponding hydrazonoyl chlorides 2a‐c ) in refluxing dry toluene. Single crystal X‐ray diffraction studies of 3a,b add support for the established structure. Similarly, 3′,5′‐diaryl‐2,2‐dimethyl‐3′H,4H‐spiro[chromene‐3,2′‐[1,3,4]thiadiazol]‐4‐ones 5a‐c were obtained in a regioselective manner through the reaction of 2,2,5′,5′‐tetramethyl‐4H,5′H‐spiro[chromene‐3,2′‐[1,3,4]oxadithiino[5,6‐c]chromen]‐4‐one ( 4a ) with nitrilimines under similar reaction conditions. On the other hand, reaction of 2,5′‐diethyl‐2,5′‐dimethyl‐4H,5′H‐spiro[chromene‐3,2′‐[1,3,4]oxadithiino‐[5,6‐c]chromen]‐4‐one ( 4b ) with nitrilimines in refluxing dry toluene afforded the corresponding 3′,5′‐diaryl‐2‐ethyl‐2‐methyl‐3′H,4H‐spiro[chromene‐3,2′‐[1,3,4]thiadiazol]‐4‐ones 5d‐f as two unisolable diastereoisomeric forms.     

Regioselective synthesis of 4‐aryloxymethylene‐2,3,5‐trihydrothiopyrano[3,2‐b]indoles by the thio‐claisen rearrangement of 3‐(4′‐aryloxybut‐2′‐ynylthio)indoles

A number of new 4‐aryloxymethylene‐2,3,5‐trihydrothiopyrano[3,2‐b]indoles are regioselectively synthesized in 78‐84% yield by the thio‐Claisen rearrangement of 3‐(4′‐aryloxybut‐2′‐ynylthio)indoles. The endocyclic double bonded products are isolated by introducing electron withdrawing acetyl group at the indole nitrogen and also can be converted to the corresponding exocyclic isomers by deacetylation and subsequent heating.     

Cyclocondensation reactions of heterocyclic carbonyl compounds XII. The double course of cyclization of 3‐(2‐aminobenzyl)‐1,2‐dihydro‐quinoxaline‐2‐one

The cyclocondensation reaction of compound 1 in boiling hydrochloric acid had an unexpected course. Instead of supposed 5,11‐dihydro‐quinoxalino[2,3‐b]quinoline 6a , 2‐(indol‐2‐yl)‐benzimidazole 4 was isolated as the major product.     

Synthetic approaches to bridgehead nitrogen methanesulfonamide derivatives of 3‐amino‐2‐thioxo‐2,3‐dihydrothieno[2,3‐d]pyrimidin‐4(1H)‐ones,potential cox‐2 selective inhibitors

Methane sulfonamide derivatives of 3‐amino‐2‐thioxo‐2,3‐dihydrothieno[2,3‐d]pyimidin‐4(1H)‐one, potential selective COX‐2 inhibitors, were synthesized and their structural elucidation is here reported. Some derivatives, at 10 μM concentration, showed a significant percentage of inhibition in some in vitro experiments.     

Synthesis of new heteroaromatic nitrogen ligands: Pyrimido‐[4″,5″:4′,5′]‐thieno[3′,2′:4,5]thieno[3,2‐d]pyrimidines and 1,2,3‐triazine[4″,5″:4′,5′]thieno[3′,2′:4,5]thieno[3,2‐d]‐1,2,3‐triazines

An efficient one‐pot access for the synthesis of the previously unreported tetracyclic fused pyrimido‐[4″,5″:4′,5′]thieno[3′,2′:4,5]thieno[3,2‐d]pyrimidine ( 3 ) and 1,2,3‐triazine[4″,5″:4′,5′]thieno‐[3′,2′:4,5]thieno‐[3,2‐d]‐1,2,3‐triazine ( 5 ) heteroaromatic nitrogen ligands is described. The title compounds 3 and 5 were obtained from 3,4‐diaminothieno[2,3‐b]thiophene‐2,5‐dicarbonitrile and phosgeniminium chloride and sodium nitrite/HCl, respectively. Substituted condensed thieno[2,3‐b]thiophene derivatives 4 and 6 were synthesized by nucleophilic displacement of the chloroderivatives 3 and 5 .     

An Efficient synthesis of pyrimido[4,5‐b]quinoline and indeno[2′,1′:5,6]pyrido[2,3‐d]pyrimidine derivatives via multicomponent reactions in ionic liquid

A series of pyrimido[4,5‐b]quinoline and indeno[2′,1′:5,6]pyrido[2,3‐d]pyrimidine derivatives were synthesized via the three‐component reaction of an aldehyde, 6‐aminopyrimidine‐2,4‐dione and 5,5‐dimethyl‐1,3‐cyclohexanedione or 1,3‐indanedione in ionic liquid 1‐n‐butyl‐3‐methylimidazolium bromide ([bmim]Br). This protocol has the advantages of easier work‐up, milder reaction conditions, high yields and an environmentally benign procedure compared with other methods.     

Thermolysis of N,N″‐1,ω‐alkanediyl‐bis[n′‐organylthiourea] derivatives

The course of microwave assisted or conventional thermal intramolecular heterocyclization of the title compounds has been found to be dependent on the length of the alkanediyl chain. While 1,3‐propanediyl‐bisthioureas 5a‐c gave both 2‐thioxoperhydropyrimidine‐1‐carbothioamides 8a‐c and 8‐amino‐3,4,5,6‐tetrahydro‐1,3,7‐thiadiazocine‐2‐thiones 10a‐c , thermolysis of 1,4‐butanediyl‐bisthioureas 6a‐c and 1,6‐hexanediyl‐bisthioureas 7a‐c under the same conditions gave solely 9‐amino‐4,5,6,7‐tetrahydro‐1,3,8‐thiadiazonine‐2‐thiones 11a‐c and 11‐amino‐1‐thia‐3,10‐diazacycloundec‐10‐ene‐2‐thiones 12a‐c , respectively. Symmetric N,N′‐diorganylthioureas 4a‐c were formed in all cases as minor byproducts.     

New TRANS/CIS tetrahydroisoquinolines. 3. [1,3]‐oxazolo‐[3,2‐B]‐tetrahydroisoquinolinones having an angular aryl substituent

The parent compound 5‐oxo‐10a‐phenyl‐2,3,10,10a‐tetrahydro‐5H‐[1,3]‐oxazolo‐[3,2‐b]‐isoquinoline‐10‐carboxylic acid ( 5 ) was prepared in large scale and a good yield by reaction between homophthalic anhydride ( 3 ) and 4,5‐dihydro‐2‐phenyl‐1,3‐oxazole ( 4 ). Thus, the closure of the isoquinoline ring and fusion of the 1,3‐oxazol ring occur in one step. Trans configuration was assumed for the product. The parent acid 5 was converted in four steps to the target aminomethyl derivatives 9a‐1 . The latter contain four features that make them interesting from pharmaceutical point of view.     

One pot synthesis of diarylpyrido[3,2‐c]coumarins

Various diarylpyrido[3,2‐c]coumarins 3a‐l have been synthesized in one step by reacting 4‐hydroxy coumarins 1a‐d with α,β‐unsaturated ketones 2a‐c in the presence of ammonium acetate and acetic acid under Kroehnke's reaction conditions.     

Microwave induced synthesis of the thiazolidine‐2,4‐dione motif and the efficient solvent free‐solid phase parallel syntheses of 5‐benzylidene‐thiazolidine‐2,4‐dione and 5‐benzylidene‐2‐thioxo‐thiazolidine‐4‐one compounds

Novel microwave induced method for the synthesis of thiazolidine‐2,4‐dione motif under solvent phase conditions is developed. Further we report an efficient, microwave assisted method for the parallel syntheses of biologically important 5‐benzylidene‐thiazolidine‐2,4‐dione and 5‐benzylidene‐2‐thioxothiazolidine‐4‐one compounds under solid‐phase and solvent‐free conditions. A comparative study between the developed microwave methods and the conventional methods is described. We have also illustrated the possible mechanism behind to address the reason why piperidine, acetic acid and silica gel enhanced the Knoevenagel condensation reaction.     

Synthesis and characterization of some novel 2‐{2‐[1‐(3‐substituted‐phenyl)‐1H‐1,2,3‐triazol‐4‐yl‐] ethyl}‐1‐substituted‐1H‐benzo [d] imidazole derivatives

Synthesis of some novel 2‐{2‐[1‐(3‐substitutedphenyl)‐1H‐1,2, 3‐triazol‐4‐yl‐]ethyl)‐1H‐benzo[d]‐imidazole derivatives, by the condensation of o‐phenylenediamine with 3‐(1‐(3‐substituted‐phenyl)‐1H‐1,2,3‐triazol‐4‐yl) propanoic acid and then subsequent reactions with different substituted alkyl halides as electrophiles are mentioned. The synthesized compounds were characterized by ¹H NMR, EI‐MS and IR spectroscopic techniques.     

Synthesis and characterization of 4‐aryl‐5‐(1‐aryl‐2‐methyl‐2‐nitropropyl)‐1,2,3‐selenadiazoles

The synthesis of a new set of selenadiazoles, 4‐aryl‐5‐(1‐aryl‐2‐methyl‐2‐nitropropyl)‐1,2,3‐selenadiazoles ( 4 ) derived from 2‐[4‐methyl‐4‐nitro‐1,3‐diarylpentylidene]‐1‐hydrazinecarboxamide ( 3 ) has been reported. THF has been found to be the solvent of choice for this reaction. Structural features of 3 and 4 have been analyzed by NMR and X‐ray techniques.