Synthesis of 5,7‐Disubstituted 7H‐Pyrrolo[2,3‐d]Pyrimidin‐4(3H)‐ones and Their N‐Alkylation's under Phase Transfer Conditions

5,7‐disubstituted 7H‐pyrrolo[2,3‐d]pyrimidin‐4(3H)‐ones 2 were synthesized by the cyclocondensation of 1,4‐disubstituted 2‐amino‐3‐cyanopyrrole 1 with formic acid. When comparative study of N versus O alkylation of ambident 5,7‐disubstituted 7H‐pyrrolo[2,3‐d]pyrimidin‐4(3H)‐ones 2 was carried out under liquid–liquid PTC, solid–liquid PTC, and solid–liquid solvent free conditions using various alkylating agents 3 , the N‐alkylated product 4 were obtained selectively and exclusively.     

The Influence of Condensed Cycle on Regiochemistry of Electrophilic Heterocyclization of 3‐Alkenyl‐2‐Thioxopyrimidin‐4‐One by p‐Alkoxyphenyltellurium Trichloride

Electrophilic heterocyclization of 5‐alkenyl‐1‐methyl‐6‐thioxopyrazolo[3,4‐d]pyrimidin‐4‐ones and 3‐alkenyl‐2‐thioxoquinazoline‐4‐ones under the action of p‐alkoxyphenyltellurium trichloride leads to annulation of thiazoline cycle with formation of 7‐[(p‐alkoxyphenyl)telluromethyl]‐1‐methyl‐6,7‐dihydropyrazolo[3,4‐d][1,3]thiazolo[3,2‐a]pyrimidin‐4(1H)‐ones hydrochlorides and 2‐(p‐alkoxyphenyl)dichlorotelluromethyl‐2,3‐dihydro ‐ 5H‐[1,3]thiazolo[2,3‐b]quinazolin‐5‐ones hydrochlorides. Reduction of salts by the action of excess of sodium sulfite leads to formation of arylhetaryl telluride.     

Efficient synthesis of 2‐substituted thieno[2,3‐d]pyrimidin‐4(3H)‐ones via an iminophosphorane

The carbodiimides 4 , obtained from reactions of iminophosphorane 3 with aromatic isocyanates, were reacted with secondary amines to give 2‐dialkylamino‐5‐ethyl‐6‐methyl‐thieno[2,3‐d]pyrimidin‐4(3H)‐ones 6 in the presence of catalytic amount of EtONa. Reactions of 4 with phenols or ROH in the presence of the catalytic amount of K2CO₃ or RONa gave 2‐aryloxy‐ or 2‐alkoxy‐5‐ethyl‐6‐methyl‐thieno[2,3‐d]pyrimidin‐4(3H)‐ones 6 in satisfactory yields. The effects of the nucleophiles on cyclization have been investigated. © 2008 Wiley Periodicals, Inc. Heteroatom Chem 19:266–270, 2008; Published online in Wiley InterScience ( www.interscience.wiley.com ). DOI 10.1002/hc.20424     

Facile Methods for the Synthesis of 5‐Aryl and 5‐Iodo Pyrrolo[2,3‐d]pyrimidines

An efficient and environmentally benign one‐pot method has been developed for the synthesis of 4‐amino‐5‐arylpyrrolo[2,3‐d]pyrimidines. Phthalimido acetophenones were reacted with cyanoacetamide to give 2‐amino‐4‐phenyl‐1H‐pyrrole‐3‐carboxamides, which were further converted to 5‐aryl‐3H‐pyrrolo[2,3‐d]pyrimidin‐4‐ones. A novel method is also developed for the synthesis of 4‐amino‐5‐iodopyrrolo[2,3‐d]pyrimidines.     

Investigation into the reaction of 2‐amino‐4,5‐dimethylthiophene‐3‐carboxamide with iso(and isothio)cyanates under microwave irradiation

The reaction of 2‐amino‐4,5‐dimethyl‐ thiophene‐3‐carboxamide with iso(and isothio) cyanates for the synthesis of thieno[2,3‐d]pyrimidines has been investigated. The reactions under microwave irradiation in the presence of N,N‐dimethyl acetamide as solvent gave 5,6‐dimethylthieno[2,3‐d]pyrimidine‐2,4(1H,3H)‐dione, 5,6‐dimethyl‐2‐thioxo‐2,3‐dihy‐ drothieno[2,3‐d]pyrimidin‐4(1H)‐one, and 2‐aryla‐ mino‐5,6‐dimethylthieno[2,3‐d]pyrimidin‐4(3H)‐one derivatives. These reactions probably proceed through intermediates 4,5‐dimethyl‐2‐substitutedcarbamoth‐ ioylaminothiophene‐3‐carboxamides. Two of these intermediates were isolated. © 2009 Wiley Periodicals, Inc. Heteroatom Chem 20:346–349, 2009; Published online in Wiley InterScience ( www.interscience.wiley.com ). DOI 10.1002/hc.20557     

Utility of Pyridine‐2(1H)‐thiones in the Synthesis of Novel Bis‐Thieno[2,3‐b]pyridines and Their Fused Azines

The starting materials pyridine‐2(1H)‐thiones are prepared and reacted with halogen‐containing reagents in ethanolic sodium acetate solution to give the corresponding 2‐S‐alkylpyridines, which cyclized upon their boiling in methanolic sodium methoxide solution at reflux to give the corresponding thieno[2,3‐b]pyridines in excellent yields. Bis (thieno[2,3‐b]pyridine‐2‐carboxamides), incorporating 2,6‐dibromophenoxy moiety, are prepared by the bis‐O‐alkylation of thieno[2,3‐b]pyridine‐2‐carboxamide derivatives. Two synthetic routes are designed to prepare the target molecules pyrido[3′,2′:4,5]thieno[3,2‐d]pyrimidin‐4(3H)‐ones, pyrido[3′,2′:4,5]thieno[3,2‐d][1,2,3]triazin‐4(3H)‐ones, and their bis‐analogues using thieno[2,3‐b]pyridine‐2‐carboxamides and their bis‐analogues. The structure of the target molecules is elucidated using elemental analyses as well as spectral data.     

Synthesis of Novel Substituted 2‐Lactosylthiothieno[2,3‐d]pyrimidin‐4(3H)‐one Derivatives

The title compounds substituted 2‐lactosylthiothieno[2,3‐d]pyrimidin‐4‐ones 6 were synthesized by the glycosyl reaction and alcoholysis reaction of substituted 2‐thioxo‐thieno[2,3‐d]pyrimidin‐4‐ones 4 ,which is formed by the base catalytic and acetic acidify reaction of amino esters 2 with alkyl or arylisothiocyanates and hepta‐O‐acetyl‐lactosyl bromide in good yields. All of the compounds were confirmed by NMR, ESI‐MS, and elemental analysis.     

Bis(enaminones) as Versatile Precursors for Novel Bis([1,2,4]triazolo[1,5‐a]pyrimidines) and Bis(2‐thioxo‐2,3‐dihydropyrido[2,3‐d]pyrimidin‐4(1H)‐ones)

Novel bis([1,2,4]triazolo[1,5‐a]pyrimidines) and bis(2‐thioxo‐2,3‐dihydropyrido[2,3‐d]pyrimidin‐4(1H)‐ones) were prepared utilizing bis(enaminones) as precursors. The structures of the prepared compounds were elucidated by several spectral tools as well as elemental analyses.     

Synthesis of Novel Spiro Pyrano[2,3‐d]thiazolo[3,2‐a]pyrimidine via 1,3‐Dipolar Cycloaddition of Azomethine Ylide

The reaction involving 4‐phenyl‐octahydro‐pyrano[2,3‐d]pyrimidine‐2‐thione, ethyl chloroacetate and the appropriate aromatic aldehyde yielded 2‐arylmethylidene‐5‐phenyl‐5a,7,8,9a‐tetrahydro‐5H,6H‐pyrano[2,3‐d][1,3]thiazolo[3,2‐a]pyrimidin‐3(2H)‐ones. The 1,3‐dipolar cycloaddition of 2‐arylmethylidene‐5‐phenyl‐5a,7,8,9a‐tetrahydro‐5H,6H‐pyrano[2,3‐d][1,3]thiazolo[3,2‐a]pyrimidin‐3(2H)‐ones with azomethine ylide generated by a decarboxylative route from sarcosine and acenaphthenequinone afforded 4′‐aryl‐1′‐methyl‐5″‐phenyl‐5a″,7″,8″,9a″‐tetrahydro‐2H,5″H,6″H‐dispiro[acenaphthylene‐1,2′‐pyrrolidine‐3′,2″‐pyrano[2,3‐d][1,3]thiazolo[3,2‐a]pyrimidine]‐2,3″‐diones in moderate yields. The structures of the products were determined and characterized thoroughly by NMR, MS, IR, elemental analysis, and X‐ray crystallographic analysis.     

Efficient Preparation of 2, 2′‐Disubstituted‐3, 3′‐(1, 4‐phenylene)bis‐thienopyrimidin‐4‐ones Based on an aza‐Wittig Reaction

Tandem aza‐Wittig reaction of iminophosphorane with 1, 4‐phenylene diisocyanate followed by intramolecular heteroconjugate addition annulation after addition of a nucleophilic reagent (amine, phenol, and alcohol), in the presence of catalytic K₂CO₃ or NaOR, gives selectively the functionalized substituted 2, 2′‐di(alkylamino, aryloxy)‐3, 3′‐(1, 4‐phenylene)bis(thieno[3, 2‐d]pyrimidin‐4(3H)‐ones) and 2, 2′‐di(alkylamino or alkoxy)‐3, 3′‐(1, 4‐phenylene)bis(3, 5, 6, 7‐tetrahydro‐4H‐cyclopenta[4, 5]thieno[2, 3‐d]pyrimidin‐4‐ones).     

A Convenient Synthetic Route of Diethyl (4‐Oxo‐chromeno[2,3‐d]pyrimidin‐2(5)‐yl)phosphonates

Novel diethyl (4‐oxo‐3,4‐dihydro‐2H‐chromeno[2,3‐d]pyrimidin‐2‐yl)phosphonate as two enantiomers and diethyl (4‐oxo‐1,5‐dihydro‐4H‐chromeno[2,3‐d]pyrimidin‐5‐yl) phosphonate were obtained in easy procedure via reaction of 2‐imino‐2H‐chromene‐3‐carboxamide, dimethylformamide dimethyl‐acetal, and diethyl phosphite in a simple one pot. Possible reaction mechanisms were proposed. The structures of the obtained products were confirmed by elemental analyses and spectral tools.     

Folded conformations due to arene interactions in dissymmetric and symmetric butylidene‐linker models based on pyrazolo[3,4‐d]pyrimidine,purine and 7‐deazapurine

The butylidene‐linker models 1‐[2‐(2,6‐dimethylsulfanyl‐9H‐purin‐9‐yl)‐2‐methylidenepropyl]‐4,6‐bis(methylsulfanyl)‐1H‐pyrazolo[3,4‐d]pyrimidine, C₁₈H₂₀N₈S₄, (XI), 7,7′‐(2‐methylidenepropane‐1,3‐diyl)bis[3‐methyl‐2‐methylsulfanyl‐3H‐pyrrolo[2,3‐d]pyrimidin‐4(7H)‐one], C₂₀H₂₂N₆O₂S₂, (XIV), and 7‐[2‐(4,6‐dimethylsulfanyl‐1H‐pyrazolo[3,4‐d]pyrimidin‐1‐yl)‐2‐methylidenepropyl]‐3‐methyl‐2‐methylsulfanyl‐3H‐pyrrolo[2,3‐d]pyrimidin‐4(7H)‐one, C₁₉H₂₁N₇OS₃, (XV), show folded conformations in solution, as shown by ¹H NMR analysis. This folding carries over to the crystalline state. Intramolecular π–π interactions are observed in all three compounds, but only (XIV) shows additional intramolecular C—H...π interactions in the solid state. As far as can be established, this is the first report incorporating the pyrrolo[2,3‐d]pyrimidine nucleus for such a study. In addition to the π–π interactions, the crystal structures are also stabilized by other weak intermolecular C—H...S/N/O and/or S...N/S interactions.     

New synthetic approaches to bridgehead nitrogen heterocycles. Derived from 3‐amino‐2,3‐dihydro‐5,6‐dimethyl‐2‐thioxothieno[2,3‐d]pyrimidin‐4(1H)‐one and its salts

Bridgehead nitrogen heterocycles 3a , b and 6a , b containing the thieno‐pyrimidine system have been prepared from the versatile intermediates 3‐amino‐2,3‐dihydro‐5,6‐dimethyl‐2‐thioxo‐thieno[2,3‐d]pyrimidin‐4‐(1H)‐one 1 and its hydrazinium or potassium salts 4 ; their structural elucidation is also reported.     

Synthesis and Antimicrobial Evaluation of Some Novel Pyrido[2,3‐d] Pyrimidine Derivatives and Their Ribofuranosides

2‐Amino‐3‐cyano‐4,6‐disubstituted pyridines 2a–c on treatment with arylisocyanate and arylisothiocyanate afforded 4‐imino‐3,5,7‐trisubstituted pyrido[2,3‐d] pyrimidin‐2(1H)‐ones 3a–c and 4‐imino‐3,5,7‐trisubstituted pyrido[2,3‐d]pyrimidin‐2(1H)‐thiones 4a–c , respectively. The ribofuranosides, namely, 4‐imino‐3,5,7‐trisubstituted‐1‐(2′,3′,5′‐tri‐O‐benzoyl‐β‐d ‐ribofuranosyl) pyrido[2,3‐d]pyrimidin‐2(1H)‐ones 7a–c and 4‐imino‐3,5,7‐trisubstituted‐1‐(2^′,3^′,5^′‐tri‐O‐benzoyl‐β‐D‐ribofuranosyl) pyrido[2,3‐d]pyri‐midin‐2(1H)‐thiones 8a–c , were synthesized by the condensation of trimethylsilyl derivatives of 3a–c and 4a–c with β‐d ‐ribofuranosyl‐1‐acetate‐2,3,5‐tribenzoate. The structure of newly synthesized ribofuranosides and their precursors were established by elemental analyses, IR, ¹H NMR and ¹³C NMR spectroscopy. All the synthesized compounds were screened for their antibacterial and antifungal activities against Escherichia coli, Staphylococcus aureus, Aspergillus niger, and Aspergillus flavus.     

An easy route to 2‐substituted‐2,3‐dihydro‐5(7)H‐oxazolo[3,2‐a]pyrimidin‐5‐ones and 7‐ones starting from the corresponding 2‐amino‐2‐oxazolines

The isomeric 2‐substituted‐7(5)‐methyl‐2,3‐dihydro‐5(7)H‐oxazolo[3,2‐a]pyrimidin‐5‐ones 3a‐b and 7‐ones 2a‐b,7a were synthesized by cyclocondensation from the 5‐substituted‐2‐amino‐2‐oxazolines 1a‐b with biselectrophiles. In boiling ethanol, the reaction of 1a‐b with acetylenic esters led to a mixture of 2a‐b,7a with a small amount of (E)‐2‐N‐(2‐ethoxycarbonylethylene)‐5‐substituted‐2‐iminooxazolines 5a‐b . The ring annulation between 1a‐b and diketene gave the 2‐substituted‐7‐hydroxy‐7‐methyl‐2,3,6,7‐tetrahydro‐5H‐oxazolo[3,2‐ a ]pyrimidin‐5‐ones 4a‐b which can be easily dehydrated to provide the 2‐substituted‐7‐methyl‐2,3‐dihydro‐5H‐oxazolo[3,2‐a]pyrimidin‐5‐ones 3a‐b .     

Synthesis of Fused Tetrazolo[1,5‐c] pyrrolo[3,2‐e]pyrimidines and Their Reductive Conversion to New 4‐Aminopyrrolo[2,3‐d]pyrimidines

Some new 7,9‐substituted 7H‐1,2,3,4‐tetrazolo[1,5‐c]pyrrolo[3,2‐e]pyrimidines 5 have been synthesized either by diazotization of 4‐hydrazino‐5,7‐disubstituted‐7H‐pyrrolo[2,3‐d]pyrimidines 4 obtained by hydrazinolysis of 4‐chloro‐5,7‐disubstituted 7H‐pyrrolo[2,3‐d]pyrimidines 3 or via a substitution reaction between 3 and sodium azide. 5,7‐Disubstituted‐7H‐pyrrolo[2,3‐d]pyrimidin‐4(3H)‐ones 2 were obtained by cyclocondensation of 1,4‐disubstituted 2‐amino‐3‐cyanopyrroles 1 with formic acid, which, on chlorination using phosphorus oxychloride, afforded 3. 2‐Amino‐3‐cyanopyrroles 1 were synthesized from the reaction between (2-bromo-1-(4-fluorophenyl) ethylidene) propanedinitrile and substituted aromatic amines under Gewald reaction conditions. A novel route for the synthesis of 4‐amino‐5,7‐disubstituted‐7H‐pyrrolo[2,3‐d]pyrimidines 6 by the reductive ring cleavage of 5 has been reported.     

Synthesis and Crystal Structures of Two 9‐(2‐Bromoethyl)‐Substituted 7‐Deazapurines

The 7‐(2‐bromoethyl) derivatives, 2a and 2b , of 4‐chloro‐7H‐pyrrolo[2,3‐d]pyrimidine ( 1a ) and 4‐chloro‐7H‐pyrrolo[2,3‐d]pyrimidin‐2‐amine ( 1b ) were synthesized by nucleobase anion alkylation (NaH, DMF) and crystallized. X‐Ray analyses of both compounds were performed, and they revealed significantly different positioning of the side chain relative to the heterocyclic ring, depending on the substituent (H or NH₂) at C(2).     

Synthesis and Structure of 2‐Substituted Thieno[3′,2′:5,6]pyrido[4,3‐d]pyrimidin‐4(3H)‐one Derivatives

A series of new 2‐substituted 3‐(4‐chlorophenyl)‐5,8,9‐trimethylthieno[3′,2′: 5,6]pyrido[4,3‐d]pyrimidin‐4(3H)‐ones 8 were synthesized via an aza‐Wittig reaction. Phosphoranylideneamino derivatives 6a or 6b reacted with 4‐chlorophenyl isocyanate to give carbodiimide derivatives 7a or 7b , respectively, which were further treated with amines or phenols to give compounds 8 in the presence of a catalytic amount of EtONa or K₂CO₃. The structure of 2‐(4‐chlorophenoxy)‐3‐(4‐chlorophenyl)‐5,8,9‐trimethylthieno[3′,2′: 5,6]pyrido[4,3‐d]pyrimidin‐4(3H)‐one ( 8j ) was comfirmed by X‐ray analysis.     

Synthesis of Indeno[1,2‐d]pyrimidin‐5‐Ones and Their Fluorescence in Solid State

New fluorescent compounds, 2‐substituted indeno[1,2‐d]pyrimidin‐5‐ones ( 3a , 3b , 3c , 3d ) were synthesized in good yield by the reaction of 2‐[bis(methylsulfanyl)methylene]indan‐1,3‐dione ( 1 ) with the respective amidine derivatives [guanidine carbonate ( 2a ), acetamidine hydrochloride ( 2b ), S‐methylisothiourea sulfate ( 2c ), and S‐benzylisothiourea sulfate ( 2d )]. 4‐Substituted amino‐2‐aminoindeno[1,2‐d]pyrimidin‐5‐ones ( 7b , 7c , 7d ) were synthesized by a one‐pot reaction of 1 , 2a and the respective amine compounds ( 4b , 4c , 4d ) in pyridine. These fused pyrimidine derivatives showed fluorescence in the solid state.     

Reactions of 2‐amino‐3‐cyano‐4,5,6,7‐tetrahydrobenzo[b]thiophene and 2‐amino‐3‐cyano‐4,7‐diphenyl‐5‐methyl‐4H‐pyrano[2,3‐c] pyrazole with phenylisocyanate,carbon disulfide,and thiourea

2‐Amino‐3‐cyano‐4,5,6,7‐tetrahydrobenzo[b]thiophene 1a or 2‐amino‐3‐cyano‐4,7‐di‐ phenyl‐5‐methyl‐4H‐pyrano[2,3‐c]pyrazole 2a reacted with phenylisocyanate in dry pyridine to give 2‐(3‐phenylureido)‐3‐cyanobenzo[b]thiophene 1b or 2‐disubstituted amino‐3‐cyanopyranopyrazole 2b derivative. However, when 1a and 2a were refluxed with carbon disulfide in 10% ethanolic sodium hydroxide solution, they afforded the thieno[2,3‐d]pyrimidin‐2,4‐dithione derivative 5 in the former case, 2,4‐dicyano‐1,3‐bis(dithio carboxamino)cyclobuta‐1,3‐ diene 6 and pyrazolopyranopyrido[2,3‐d]pyrimidin‐ 2,4‐dithione derivative 7 in the latter one. Treatment of 2a with thiourea in refluxing ethanol in the presence of potassium carbonate gave 2,2′‐dithiobispyrimidine derivative 9 (major) in addition to pyranopyrazole derivative 10 and 2,2′‐dithiobis ethoxypyrimidine derivative 11 in minor amounts. The structures of all products were evidenced by microanalytical and spectral data. © 2005 Wiley Periodicals, Inc. Heteroatom Chem 16:6–11, 2005; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/hc.20070