Nickel‐Catalyzed Cross‐Electrophile Coupling of Aryl Bromides with Pyrimidin‐2‐yl Tosylates

A new protocol for the NiCl₂ ‐catalyzed cross‐electrophile coupling of aryl bromides with pyrimidin‐2‐yl tosylates to give the corresponding C2 ‐arylation pyrimidine derivatives has been developed. This study provides an improvement over previous methods by using pyrimidin‐2‐yl tosylates instead of halides as coupling partners that are stable and easily available.     

A Facile One‐Pot Three‐Component Synthesis of 5‐(Trifluoromethyl)‐4,7‐dihydro‐[1,2,4]‐triazolo[1,5‐a]pyrimidine Derivatives in Ionic Liquid

An efficient one‐pot synthesis of 5‐(trifluoromethyl)‐4,7‐dihydro‐7‐aryl‐[1,2,4]triazolo[1,5‐a]pyrimidine derivatives was performed via the reaction of aryl aldehyde, 3‐amino‐1,2,4‐triazole and ethyl 4,4,4‐trifluoro‐3‐oxobutanoate or 4,4,4‐trifluoro‐1‐phenylbutane‐1,3‐dione in ionic liquid. This method has the advantages of short synthetic route, operational simplicities, mild reaction conditions, high yields and eco‐friendliness.     

One‐Pot Synthesis of 2‐Substituted 4‐Aryl‐4,5‐dihydro‐3,1‐benzoxazepines from 2‐(2‐Aminophenyl)‐1‐arylethanols via Dehydration of the Corresponding Amides

An efficient method for the preparation of 2‐substituted 4‐aryl‐4,5‐dihydro‐3,1‐benzoxazepine derivatives under mild conditions has been developed. The reaction of 2‐(2‐aminophenyl)ethanols 1 with acid chlorides in the presence of excess Et₃N in THF at room temperature gave the corresponding N‐acylated intermediates 2 , which were dehydrated by treatment with POCl₃ to give 2‐substituted 4‐aryl‐4,5‐dihydro‐3,1‐benzoxazepines 3 in a one‐pot reaction.     

Practical Iron‐ and Cobalt‐Catalyzed Cross‐Coupling Reactions between N‐Heterocyclic Halides and Aryl or Heteroaryl Magnesium Reagents

The reaction scope of iron‐ and cobalt‐catalyzed cross‐coupling reactions in the presence of isoquinoline (quinoline) in the solvent mixture tBuOMe/THF has been further investigated. Various 2‐halogenated pyridine, pyrimidine, and triazine derivatives were arylated under these mild conditions in excellent yields. The presence of isoquinoline allows us to perform Fe‐catalyzed cross‐coupling reactions between 6‐chloroquinoline and aryl magnesium reagents. Furthermore, it was found that the use of 10 % N,N‐dimethylquinoline‐8‐amine increases the yields of some Co‐catalyzed cross‐coupling reactions with chloropyridines bearing electron‐withdrawing substituents.     

Synthesis and Antibacterial Activities of 2‐(1‐Aryl‐5‐Methyl‐1,2,3‐triazol‐4‐yl)‐1,3,4‐Oxadiazole Derivatives

Eighteen novel 2‐(1‐aryl‐5‐methyl‐1,2,3‐triazol‐4‐yl)‐1,3,4‐oxadiazole derivatives and two acylhydrazone intermediate compounds were synthesized by various pathways starting from 1‐aryl‐5‐methyl‐1,2,3‐triazol‐4‐formhydrazide ( 1 ). All products were identified by spectroscopic analysis, and 2‐(1‐aryl‐5‐methyl‐1,2,3‐triazol‐4‐yl)‐5‐benzalthio‐1,3,4‐oxadiazole was further validated by X‐ray crystallography. Results from primary antibacterial activity tests indicated that most of the compounds were effective against E. coli, P. aeruginosa, B. subtilis and S. aureus.     

One‐Pot Synthesis of 1,4‐Dihydro‐2‐thioxo‐2H‐3,1‐benzoxazine‐4‐acetic Acid Derivatives by the Reaction of 2‐Isothiocyanatophenyl Ketones with Lithium Enolates of Acetates and Tertiary Acetamides

The one‐pot synthesis of 4‐aryl‐1,4‐dihydro‐2‐thioxo‐2H‐3,1‐benzoxazine‐4‐acetic acid derivatives 2 was achieved in good yields by the reaction of aryl(2‐isothiocyanatophenyl)methanones 1 with lithium enolates of acetates and tertiary acetamides. (2E)‐1‐(2‐Isothiocyanatophenyl)‐3‐phenylprop‐2‐en‐1‐one ( 3 ) gave 1,4‐dihydro‐4‐[(1E)‐2‐phenylethenyl]‐2‐thioxo‐2H‐3,1‐benzoxazine‐4‐acetic acid derivatives 4 in good yields as well.     

Synthesis of 4‐Arylisocoumarins (=4‐Aryl‐1H‐2‐benzopyran‐1‐ones) through Acidic Hydrolysis of (Z)‐2‐(1‐Aryl‐2‐methoxyethenyl)benzaldehydes,Followed by Oxidation

4‐Arylisocoumarins (=4‐aryl‐1H‐2‐benzopyran‐1‐ones) 6 were prepared from 2‐(1‐aryl‐2‐methoxyethenyl)‐1‐bromobenzenes 1 . Successive treatment of these bromo styrenes with BuLi and 1‐formylpiperidine gave a mixture of (E)‐ and (Z)‐2‐(1‐aryl‐2‐methoxyethenyl)benzaldehydes 2 . Hydrolysis of (Z)‐isomers with conc. HBr, followed by pyridinium chlorochromate (PCC) oxidation of the resulting 1H‐2‐benzopyran‐1‐ol derivatives 4 (and 5 ), afforded the desired products.     

A Facile Synthesis of New Pyrazolo[3,4‐d]pyrimidine Derivatives via a One‐Pot Four‐Component Reaction with Sodium Acetate Supported on Basic Alumina as Promoter

An efficient one‐pot procedure for the synthesis of 3‐amino‐6‐aryl‐2‐phenylpyrazolo[3,4‐d]pyrimidine derivatives, through the reaction of aldehydes, malononitrile, benzamidine hydrochloride, and hydrazine hydrate in the presence of basic alumina‐supported sodium acetate (AcONa/Al₂O₃) under reflux conditions, is reported. This protocol has some advantages, including the use of a simple and one‐pot synthetic approach to attain pyrazolo[3,4‐d]pyrimidine directly from four readily available starting materials, simple workup, high overall yields of the products, and the simultaneous conversion of a NO₂ to an amino group, offering an opportunity to synthesize more complex structures.     

Three‐Step Synthesis of 3‐Aryl‐2‐sulfanylthieno[2,3‐b]‐, ‐[2,3‐c]‐, or ‐[3,2‐c]pyridines from the Corresponding Aryl(halopyridinyl)methanones

A convenient three‐step procedure for the synthesis of three types of 3‐aryl‐2‐sulfanylthienopyridines 4, 8 , and 12 has been developed. The first step of the synthesis of thieno[2,3‐b]pyridine derivatives 4 is the replacement of the halo with a (sulfanylmethyl)sulfanyl group in aryl(2‐halopyridin‐3‐yl)methanones 1 by successive treatment with Na₂S?9 H₂O and chloromethyl sulfides to give aryl{2‐[(sulfanylmethyl)sulfanyl]pyridin‐3‐yl}methanones 2 . In the second step, these were treated with LDA (LiNⁱPr₂) to give 3‐aryl‐2,3‐dihydro‐2‐sulfanylthieno[2,3‐b]pyridin‐3‐ols 3 , which were dehydrated in the last step with SOCl₂ in the presence of pyridine to give the desired products. Similarly, thieno[2,3‐c]pyridine and thieno[3,2‐c]pyridine derivatives, 8 and 12 , respectively, can be prepared from aryl(3‐chloropyridin‐4‐yl)methanones 5 and aryl(4‐chloropyridin‐3‐yl)methanones 9 , respectively.     

One‐Pot Syntheses of 2‐(2‐Sulfanyl‐4H‐3,1‐benzothiazin‐4‐yl)acetic Acid Derivatives via Reactions of 3‐(2‐Isothiocyanatophenyl)prop‐2‐enoic Acid Derivatives with Thiols or Sodium Sulfide

Two efficient methods for the preparation of 2‐(2‐sulfanyl‐4H‐3,1‐benzothiazin‐4‐yl)acetic acid derivatives 3 under mild conditions have been developed. The first method is based on the reaction of 3‐(2‐isothiocyanatophenyl)prop‐2‐enoates 1a – 1c with thiols in the presence of Et₃N in THF at room temperature, leading to the corresponding dithiocarbamate intermediates 2 , which underwent spontaneous cyclization at the same temperature by an attack of the S‐atom at the prop‐2‐enoyl moiety in a 1,4‐addition manner (Michael addition) to give 2‐(2‐sulfanyl‐4H‐3,1‐benzothiazin‐4‐yl)acetates in one pot. The second method involves treatment of 3‐(2‐isothiocyanatophenyl)prop‐2‐enoic acid derivatives 1b – 1d with Na₂S leading to the formation of 2‐(2‐sodiosulfanyl‐4H‐3,1‐benzothiazin‐4‐yl)acetic acid intermediates 5 by a similar addition/cyclization sequence, which are then allowed to react with alkyl or aryl halides to afford derivatives 3 . 2‐(2‐Thioxo‐4H‐3,1‐benzothiazin‐4‐yl)acetic acid derivatives 6 can be obtained by omitting the addition of halides.     

One‐Pot Synthesis of 1,4‐Oxathiino[2,3‐b]quinoxalines or ‐pyrazines from 2,3‐Dichloroquinoxaline or ‐pyrazine and 1‐Aryl‐2‐bromoalkan‐1‐ones

An efficient one‐pot synthesis of novel heterocyclic derivatives, 2‐aryl‐1,4‐oxathiino[2,3‐b]quinoxalines or ‐pyrazines 5 , via the reaction of 2,3‐dichloroquinoxaline or ‐pyrazine with Na₂S?9 H₂O, and subsequent treatment of the resulting 2‐chloro‐3‐sodiosulfanylquinoxaline or ‐pyrazine 2 with 1‐aryl‐2‐bromo‐1‐alkanones and then NaH under mild conditions is described.     

One‐Pot Synthesis of (1,2,3‐Triazolyl)methyl 3,4‐Dihydro‐2‐oxo‐1H‐pyrimidine‐5‐carboxylates as Potentially Active Antimicrobial Agents

A simple and efficient one‐pot four‐component procedure has been developed for the synthesis of a wide range of compounds containing the (triazolyl)methyl oxo‐pyrimidine‐carboxylate system from propargyl β‐keto esters, various azides, aldehydes, and urea in the presence of catalytic amounts of (AcO)₂Cu/sodium ascorbate in AcOH. The method worked well with different aryl and heteroaryl aldehydes, and for a variety of substituents in the triazolyl part of the molecule. The antimicrobial activities of the products were evaluated against two Gram‐positive and Gram‐negative bacteria, and one fungus. Compound 5j was active against Staphylococcus aureus and Candida albicans.     

Synthesis of Acyclic Nucleosides with N‐[(Benzyloxy)(aryl)methyl] Substituents as Potential HEPT,EBPU, and TNK‐651 Analogues

The syntheses of the novel acyclic nucleosides 5a – 5m , carrying different N‐[(benzyloxy)(aryl)methyl] substituents, are described (Scheme). These compounds could be prepared in medium‐to‐good yields by either direct or silyl‐assisted coupling of the electrophiles 6 with either purine or pyrimidine nucleobases, or with different imidazole derivatives. The reactivity of the positively charged electrophilic intermediates derived from 6 upon Cl^? abstraction was rationalized by ab initio HF/6‐311G quantum‐mechanic calculations. The positive charge was found to be dispersed differently, depending on the electronic properties of the aryl substituents.     

Iron‐catalyzed cross‐coupling of heteroaromatic tosylates with alkyl and aryl Grignard reagents

An Fe(III)‐catalyzed cross‐coupling of N‐heteroaromatic tosylates with aryl and alkyl Grignard reagents is presented. The reaction proceeds at ?20°C to room temperature with short reaction time (15–30 min.), and the corresponding products are obtained with moderate to high yields. In particular, low‐cost and abundantly available FeCl₃ or Fe(acetylacetonate)₃ catalyze the reaction without other special ligands. All tested N‐heteroaromatic tosylates that are available including pyridine and pyrimidine derivatives were subject to the reaction, resulting in the expected products. Copyright © 2015 John Wiley & Sons, Ltd.     

Synthesis and Hill Inhibitory Activity of New Substituted 3‐Aryl‐5‐cyano‐6‐methylthio Pyrimidine‐2, 4‐diones

Novel substituted derivatives of 3‐aryl‐5‐cyano‐6‐methylthiopyrimidine‐2, 4‐diones were synthesized by the reaction of ethyl 2‐cyano‐3,3′‐dimethylthioacrylate with arylureas in good yields. The structures of all title compounds were evaluated by elemental analyses and ¹H NMR spectra and compound 2c was also confirmed by X‐ray diffraction. Hill reaction inhibitory activity of title compounds was assayed.     

A Novel and Efficient One‐Pot Synthesis of 2‐Aminopyrimidinones and Their Self‐Assembly

A three‐component reaction of benzaldehyde derivatives, methyl cyanoacetate, and guanidinium carbonate affords 2‐amino‐4‐aryl‐1,6‐dihydro‐6‐oxopyrimidine‐5‐carbonitriles and the four‐component reaction of benzaldehyde derivatives, methyl cyanoacetate, and guanidinium hydrochloride in the presence of piperidine leads to piperidinium salts of pyrimidinones. X‐ray crystallography data confirm self‐assembly and H‐bonding in these compounds.     

Synthesis and Fluorescent Properties of 2‐Arylamino‐5‐(3‐Aryl‐1‐Phenyl‐Pyrazol‐4‐Yl)‐1,3,4‐Thiadiazoles

A series of novel pyrazolyl‐substituted 1,3,4‐thiadiazole derivatives ( 6a‐6d, 7a‐7d, 8a‐8d ) were prepared by cyclization of the intermediate 3‐aryl‐l‐phenyl‐pyrazol‐4‐ylformaldehyde 4′‐phenylthiosemicarbazones with 0.5 M ferric chloride solution. The structures of the new compounds were confirmed by IR, ¹H NMR and elemental analysis. Simultaneously, the compounds were detected by fluorescence spectrophotometer and had preferable fluorescence activity.     

Synthesis of Some New 6,8‐Disubstituted 7,8‐Dihydropyrimido[2,3:4,3]pyrazolo[1,5‐a]pyrimidines and 6,7,8‐Trisubstituted Pyrimido[2,3:4,3]Pyrazolo[1,5‐a]Pyrimidine Derivatives

Cyclization of 5‐cyano‐1,6‐dihydro‐4‐methyl‐2‐phenyl‐6‐thioxopyrimidine 4 with excess of 85% hydrazine hydrate afforded the 3‐amino‐4‐methyl‐6‐phenylpyrazolo[3,4‐d]pyrimidine 5 , which can react with appropriate Mannich base derivatives 13a‐c and chalcones 27a,b to yield the corresponding 6,8‐disubstituted 7,8‐dihydropyrimido[2,3:4,3]pyrazolo[1,5‐a]pyrimidines 15a‐c and 30a,b , respectively. On the other hand, the 6,7,8‐trisubstituted pyrimido[2,3:4,3]pyrazolo[1,5‐a]pyrimidine derivatives 8a‐g, 20a‐e, 36 and 38 were obtained by treatment of compound 5 with appropriate 1,3‐diketones 6a‐g , 3‐dimethylamino‐1‐(substituted)prop‐2‐enones 18a‐e , 3‐aminocrotononitrile 3 , and ethoxymethylenemalononitrile 37 under acidic condition, respectively.     

Synthesis of Novel 3‐Acetyl‐2‐Aryl‐5‐(3‐Aryl‐1‐Phenyl‐Pyrazol‐4‐yl)‐2,3‐Dihydro‐1,3,4‐Oxadiazoles

A series of novel pyrazolyl‐substituted 1,3,4‐oxadiazole derivatives ( 4a‐4o ) were prepared by cyclization of the intermediate N′‐((3‐aryl‐l‐phenyl‐pyrazol‐4‐yl)methylene)arylhydrazide with acetic anhydride. The structures of the new compounds were confirmed by IR, ¹H NMR, MS and elemental analysis. Furthermore, preliminary bioassay of some of the title compounds indicated that they exhibited moderate inhibition against HIV‐1 PR.     

An Eco‐friendly Three Component Manifold for the Synthesis of α‐Aminophosphonates under Catalyst and Solvent‐free Conditions,X‐ray Characterization and Their Evaluation as Anticancer Agents

A series of α‐aminophosphonates were synthesized through one‐pot condensation of aryl aldehydes, aryl amines and diethyl phosphite in the absence of any catalyst and organic solvents. All the synthesized α‐aminophosphonates were characterized by spectral and elemental analysis and in the case of compound 4j by X‐ray crystallography. Some of these new α‐aminophosphonate derivatives were found to have cytotoxic activity on the cancer cell line DU145 in vitro by the MTT method.