An Efficient Synthesis of Some Novel 3‐Cyano‐4‐imino‐2‐(methylthio)4H‐pyrido[1,2‐a]pyrimidine and Their Derivatives

Pyrazolo pyrimido pyrimidine ( 4a–k ) was prepared by the reaction of compound 3‐cyano‐4‐imino‐2‐(methylthio)4H‐pyrido[1,2‐a]pyrimidine ( 3 ) with hydrazine hydrate, phenyl hydrazine, 2‐hydrazino benzothiazole, and 6‐substituted hydrazine benzothiazole in N,N‐dimethylformamide and anhydrous potassium carbonate. These synthesized compounds were characterized by elemental analysis IR, ¹H NMR, and mass spectral data.     

Green One‐Pot Solvent‐Free Synthesis of Pyrazolo[1,5‐a]pyrimidines,Azolo[3,4‐d]pyridiazines,and Thieno[2,3‐b]pyridines Containing Triazole Moiety

Synthesis of pyrazolo[1,5‐a]pyrimidines, [1,2,4]triazolo[1,5‐a]pyrimidine, 8,10‐dimethyl‐2‐(5‐methyl‐1‐phenyl‐4,5‐dihydro‐1H‐1,2,3‐triazol‐4‐yl)pyrido[2′,3′:3,4]‐pyrazolo[1,5‐a]pyrimidine, benzo[4,5]imidazo[1,2‐a]pyrimidine via heterocyclic amines, and sodium 3‐hydroxy‐1‐(5‐methyl‐1‐phenyl‐1H‐1,2,3‐triazole‐4‐yl)prop‐2‐en‐1‐one were carried out. Also, synthesis of isoxazoles, and pyrazoles from sodium 3‐hydroxy‐1‐(5‐methyl‐1‐phenyl‐1H‐1,2,3‐triazole‐4‐yl)prop‐2‐en‐1‐one and hydroxymoyl chlorides and hydrazonoyl halides, respectively, were made. Analogously, (1,2,3‐triazol‐4‐yl)thieno[2,3‐b]pyridine derivatives were obtained from sodium 3‐hydroxy‐1‐(5‐methyl‐1‐phenyl‐1H‐1,2,3‐ triazole‐4‐yl)prop‐2‐en‐1‐one and cyanothioacetamide followed by its reacting with active methylene compounds. In addition to full characterization of all synthesized compounds, they were tested to evaluate their antimicrobial activities, and some compounds showed competitive activities to those of tetracycline, the typical antibacterial drug, and clotrimazole, the typical antifungal drug.     

An Efficient Synthesis of Spiro‐oxindole Derivatives by Three‐Component Reactions in Water

An efficient synthesis of (3S)‐1,1′,2,2′,3′,4′,6′,7′‐octahydro‐9′‐nitro‐2,6′‐dioxospiro[3H‐indole‐3,8′‐[8H]pyrido[1,2‐a]pyrimidine]‐7′‐carbonitrile is achieved via a three‐component reaction of isatin, ethyl cyanoacetate, and 1,2,3,4,5,6‐hexahydro‐2‐(nitromethylidene)pyrimidine. The present method does not involve any hazardous organic solvents or catalysts. Also the synthesis of ethyl 6′‐amino‐1,1′,2,2′,3′,4′‐hexahydro‐9′‐nitro‐2‐oxospiro[3H‐indole‐3,8′‐[8H]pyrido[1,2‐a]pyrimidine]‐7′‐carboxylates in high yields, at reflux, using a catalytic amount of piperidine, is described. The structures were confirmed spectroscopically (IR, ¹H‐ and ¹³C‐NMR, and EI‐MS data) and by elemental analyses. A plausible mechanism for this reaction is proposed (Scheme 2).     

Unequivocal total assignment of 13C and 1H NMR spectra of some pyrido[1,2‐a]pyrimidine derivatives by 2D‐NMR

We report the total assignments of the ¹³C and ¹H NMR spectra of some 4‐methyl‐2‐oxo‐(2H)‐pyrido[1,2‐a]pyrimidine and 2‐methyl‐4‐oxo‐(4H)‐pyrido[1,2‐a]pyrimidine derivatives. The products were characterized by ¹H and ¹³C NMR and reported data for similar compounds. No comparative data for the two sets of isomeric compounds with respect to ¹³C and ¹H NMR have been reported to date. We made some detailed studies of the 2D NMR spectra of these compounds and observed that assignments made for non‐protonated carbon atoms by us and those reported in the literature for similar compounds need correction. The revised assignments were made on the basis of heteronuclear single quantum correlation (HSQC) and heteronuclear multiple bond correlation (HMBC) techniques. Copyright © 2003 John Wiley & Sons, Ltd.     

Synthesis and reactions of 10,10‐dimethyl‐10H‐pyrido[1,2‐a]indol‐6‐ones

Cyclocondensation of 2,3,3‐trimefhyl‐3H‐indoles 2 with malonates 3 gives 8‐hydroxy‐10,10‐dimefhyl‐10H‐pyrido[1,2‐a]indol‐6‐ones 4 , which were halogenated in position 7, 8 and 9 with sulfuryl chloride, bromine or phosphoroxychloride to give the corresponding halo‐10,10‐dimethyl‐10H‐pyrido[1,2‐a]indoles 5, 6, 7 and 8 . Amination affords the 8‐amino‐10,10‐dimethyl‐10H‐pyrido[1,2‐a]indol‐6‐one 9 . Nitration gives either the 10,10‐dimethyl‐7‐nitro‐10H‐pyrido[1,2‐a]indoles 10 or 10,10‐dimethyl‐7‐hydroxy‐10H‐pyrido[1,2‐a]indoles 11 , depending on the conditions.     

Synthesis and reactions of 11H‐benzo[b]pyrano[3,2‐f]indolizines an pyrrolo[3,2,1‐ij]pyrano[3,2‐c]quinolines

2‐Methyl‐3H‐indoles 1 cyclize with two equivalents of ethyl malonate 2 to form 4‐hydroxy‐11H‐benzo[b]pyrano[3,2‐f]indolizin‐2,5‐diones 3, whereas 2‐mefhyl‐2,3‐dihydro‐1H‐indoles 9 give under similar conditions regioisomer 8‐hydroxy‐5‐methyl‐4,5‐dihydro‐pyrrolo[3,2,1‐ij]pyrano[3,2‐c]quinolin‐7,10‐diones 10 . The pyrone rings of 3 and 9 can be cleaved either by alkaline hydrolysis to give 7‐acetyl‐8‐hydroxy‐10H‐pyrido[1,2‐a]indol‐6‐ones 4 or 5‐acetyl‐6‐hydroxy‐2‐methyl‐1,2‐dihydro‐4H‐pyrrolo‐[3,2,1‐ij]quinolin‐4‐ones 11 , respectively. Chlorination of 3 and 9 with sulfurylchloride gives under subsequent ring opening 7‐dichloroacetyl‐8‐hydroxy‐10H‐pyrido[1,2‐a]indol‐6‐ones 5 or 5‐dichloracetyl‐6‐hydroxy‐2‐methyl‐1,2‐dihydro‐4H‐pyrrolo[3,2,1‐ij]quinolin‐4‐ones 12 . The dichloroacetyl group of 5 can be reduced with zinc to 7‐acetyl‐8‐hydroxy‐10H‐pyrido[1,2‐a]indol‐6‐ones 7. Treatment of the acetyl compounds 4, 7 and 11 with 90% sulfuric acid cleaves the acetyl group and yields 8‐hydroxy‐10H‐pyrido[1,2‐a]‐indol‐6‐ones 6 and 8 , and 6‐hydroxy‐2‐methyl‐1,2‐dihydro‐4H‐pyrrolo[3,2,1‐ij]quinolin‐4‐ones 13 . Reaction of dichloroacetyl compounds 12 with sodium azide yields 6‐hydroxy‐2‐methyl‐5‐(1H‐tetrazol‐5‐ylcarbonyl)‐1,2‐dihydro‐4H‐pyrrolo[3,2,1‐ij]quinolin‐4‐ones 14 via intermediate geminal diazides.     

Synthesis of Heteroannulated Chromeno[2,3‐b]Pyridines: DBU Catalyzed Reactions of 2‐Amino‐6‐methylchromone‐3‐Carboxaldehyde with Some Heterocyclic Enols and Enamines

New series of heteroannulated chromeno[2,3‐b]pyridines were easily and efficiently synthesized from DBU‐catalyzed condensation of 2‐amino‐6‐methylchromone‐3‐carboxaldehyde with a variety of heterocyclic enols and enamines, namely, 4‐hydroxycoumarin, 4‐hydroxy‐1‐methylquinolin‐2(1H)‐one, 2‐hydroxy‐4H‐pyrido[1,2‐a]pyrimidin‐4‐one, 4‐hydroxy‐2H‐pyrano[3,2‐c]quinoline‐2,5(6H)‐dione, 4(6)‐aminouracil and 5‐amino‐3‐methyl‐1H‐pyrazole. Structures of the new synthesized products were deduced on the basis of their analytical and spectral data.     

A Convenient Synthesis of 2H‐Pyran‐2‐ones,Fused Pyran‐2‐ones,and Pyridones Bearing a Thiazole Moiety

The versatile enaminonitrile, 2‐cyano‐3‐(dimethylamino)‐N‐(4‐phenylthiazol‐2‐yl)‐acrylamide ( 2 ), reacts with some C,O‐binucleophiles (acetylacetone and dimedone) in refluxing acetic acid to afford the pyranone 4 , the chromene 6 derivatives, and with C,N‐binucleophiles (2‐(benzothiazol‐2‐yl)acetonitrile and 2‐(1H‐benzimidazol‐2‐yl)acetonitrile) to afford the respective 1H‐pyrido[2,1‐b]benzothiazole 8 and pyrido[1,2‐a]benzimidazole 10 derivatives. Similar treatment of 2 with phenol, resorcinol, α‐naphthol and β‐naphthol in boiling acetic acid gave the coumarin derivatives 12 , 14 , 16 , and 18 , respectively. The utility of enaminonitrile 2 for the synthesis of 6H‐pyrano[3,2‐d]isoxazole 20 , pyrano[2,3‐c]pyrazole 22 , and pyrano[2,3‐d]pyrimidine 24 derivatives was also explored via its reaction with 3‐phenylisoxazol‐5(4H)‐one, 3‐methyl‐1‐phenyl‐1H‐pyrazol‐5(4H)‐one, and barbituric acid, respectively. The mechanistic aspects for the formation of the new compounds were also discussed.     

Synthesis and Reactions of Some Novel Triazolo‐, Azolo‐, Tetrazolo‐Pyridopyrimidine and Their Nucleoside Derivatives

Pyridopyrimidine reacted with aromatic aldehydes afforded the arylhydrazone 2a,b which could be cyclized into the pyrido[2,3‐d][1,2,4]triazolo[4,3‐a]pyrimidine 3a,b , with formic acid, and carbon disulphide to give pyrido[2,3‐d][1,2,4]traizolo[4,3‐a]pyrimidine 4, 5. Reaction of 1 with nitrous acid afforded tetrazolo[1,5‐a]pyrido[2,3‐d]pyrimidine 6 , which was reduced by zinc dust to give 2‐amino‐pyrido‐[2,3‐d]pyrimidine 7. Finally the reaction of 2‐hydrazino 1 with D‐xylose or D‐glucose afforded the acyclic N‐nucleoside 8, 11 which were converted into tetra/penta O‐acetate acyclic C‐nucleoside 9, 12 in acetic anhydride/pyridine. De‐acetylation of compounds 9, 12 afforded C‐nucleosides 10, 13.     

Regioselective C3 Alkenylation of 4 H‐pyrido[1,2‐a]pyrimidin‐4‐ones via Palladium‐Catalyzed CH Activation

A general and efficient palladium‐catalyzed direct C3 alkenylation of 4H‐pyrido[1,2‐a]pyrimidin‐4‐ones using AgOAc/O₂ as the oxidant has been developed. A variety of 4H‐pyrido[1,2‐a]pyrimidin‐4‐ones were successfully coupled with acrylate esters, styrenes, methylvinylketone, and acrylamide in moderate to excellent yields. The reaction exhibited complete regio‐ and stereoselectivity. This transformation provides an attractive new approach to functionalize 4H‐pyrido[1,2‐a]pyrimidin‐4‐ones.     

Synthesis and reactions of 2‐chloro‐2‐(hydroximino)‐1‐(4‐methyl‐2‐phenylthiazol‐5‐yl)ethanone

3‐Nitrosoimidazo[1,2‐a]pyridine, 3‐nitrosoimidazo[1,2‐a]pyrimidine, 3‐nitrosoquinoxaline, 2‐nitroso‐4H‐benzo[b]thiazine, 2‐nitroso‐4H‐benzo[b]oxazine, isoxazoles, isoxazolo[3,4‐d]pyridazines and pyrrolo[3,4‐d]isoxazole‐4,6‐dione were synthesized from 2‐chloro‐2‐(hydroximino)‐1‐(4‐methyl‐2‐phenylthiazol‐5‐yl)ethanone and different reagents. Structures of the newly synthesized compounds were confirmed by elemental analysis and spectral data.     

Synthesis of 1R‐1H‐Imidazo[1,2‐a]pyridin‐4‐ium‐8‐olate Derivatives

A new method based on reaction of 4‐bromobut‐2‐enoates with N‐alkylimidazoles was proposed for obtaining 1R‐1H‐imidazo[1,2‐a]pyridin‐4‐ium‐8‐olate and 1‐R‐8‐methoxy‐1H‐imidazo[1,2‐a]pyridin‐4‐ium derivatives. The structures of synthesized compounds were confirmed by ¹H, ¹³C NMR, elemental analysis, and X‐ray data.     

Preparation of 2,3‐dihydro‐1H,5H‐pyrido[3,2,1‐ij]quinoline‐1,5‐dione derivatives

The 2,3‐dihydro‐7‐methyl‐1H,5H‐pyrido[3,2,1‐ij]quinoline‐1,5‐dione derivatives 9 and 10 were prepared from 3‐(5,7‐dimethoxy‐4‐methyl‐2‐oxo‐2H‐quinolin‐1‐yl)propionitrile ( 6 ). Cyclodehydration of the amide 8 gave 1,2‐dihydro‐7,9‐dimethoxy‐6‐methylpyimido[1,2‐a]quinolin‐3‐one ( 11 ).     

Synthesis of some novel pyrazolo[1,5‐a]pyrimidine, 1,2,4‐triazolo[1,5‐a]pyrimidine,pyrido[2,3‐d]pyrimidine,pyrazolo[5,1‐c]‐1,2,4‐triazine and 1,2,4‐triazolo[5,1‐c]‐1,2,4‐triazine derivatives incorporating a thiazolo[3,2‐a]benzimidazole moiety

E‐3‐(N,N‐Dimethylamino)‐1‐(3‐methylthiazolo[3,2‐a]benzimidazol‐2‐yl)prop‐2‐en‐1‐one ( 2 ) was synthesized by the reaction of 1‐(3‐methylthiazolo[3,2‐a]benzimidazol‐2‐yl)ethanone ( 1 ) with dimethylformamide‐dimethylacetal. The reaction of 2 with 5‐amino‐3‐phenyl‐1H‐pyrazole ( 4a ) or 3‐amino‐1,2,4‐(1H)‐triazole ( 4b ) furnished pyrazolo[1,5‐a]pyrimidine and 1,2,4‐triazolo[1,5‐a]pyrimidine derivatives 6a and 6b , while the reaction of enaminone 2 with 6‐aminopyrimidine derivatives 7a,b afforded pyrido[2,3‐d]pyrimidine derivatives 9a,b , respectively. The diazonium salts 11a or 11b coupled with compound 2 to yield the pyrazolo[5,1‐c]‐1,2,4‐triazine and 1,2,4‐triazolo[5,1‐c]‐1,2,4‐triazine derivatives 13a and 13b . Some of the newly synthesized compounds exhibited a moderate effect against some bacterial and fungal species.     

First synthesis of novel pentaheterocyclic ring system of 1,2,4‐triazolo[2″,3″:6′,1′]pyrimido[4′,5′:2,3]pyrido[1,2‐a]benzimidazole

Reaction of 1‐amino‐3‐arylpyrido[1,2‐a]benzimidazole‐2,4‐dicarbonitrile (1) with dimethylformamide‐dimethylacetal (DMF‐DMA) gave 1 ‐[N,N‐(dimethylaminomethylene)amino]‐3‐arylpyrido[1,2‐a]benzimidazole‐2,4‐dicarbonitrile (2). Compounds (1) reacted with triethylorthoformate yielding 1‐[N‐(ethoxymethylene)amino]‐3‐arylpyrido[1,2‐a]benzimidazole‐2,4‐dicarbonitrile (3). 3‐Amino‐4‐imino‐5‐aryl‐6‐cyanopyrimido[5′,4′:5,6]pyrido[1,2‐α] benzimidazole (4) was synthesized via condensation of either (2) or (3) with hydrazine hydrate. Reactions of (4) with acetic anhydride, ethyl chloroformate or aryl isothiocyanate yielded the respective derivative of the new ring system namely 1,2,4‐triazolo[2″,3″:6′,1′]pyrimido[4′,5′:2,3]pyrido[1,2‐a]benzimidazole (5–7).     

Synthesis,Crystal Structure,and Ultraviolet–Visible Spectrum of 8–Substituted–10,10–Dimethyl–10H–pyrido[1,2–a]indolium Perchlorates–Containing Thienyl Moiety

Two novel compounds, 8–[2–(2–thienyl)vinyl]–10,10–dimethyl–10H–pyrido[1,2–a] indolium perchlorate ( 3a ) and 8–[2–(5–phenyl–2–thienyl)vinyl]–10,10–dimethyl–10H–pyrido[1,2–a]indolium perchlorate ( 3b ) were synthesized and characterized by IR, ¹H–NMR, elemental analyses, and X–ray diffraction. Crystal structural analysis suggested that either 3a or 3b exhibited good coplanarity and rings and vinyl in the target molecule could make up a large conjugated system. Ultraviolet–visible absorption analysis indicated both 3a and 3b possessed large maximum absorptions, and 3b underwent a significant redshift (43.0 nm) in comparison with 3a .     

Synthesis of [1,2‐a] benzimidazolo‐1,3,5‐triazin‐2‐thione, [1,2‐a] benzimidazolo‐1,3,5‐thiadiazin‐2‐thione, [1,2‐a] benzimidazolo‐1,3,5‐triazin‐2‐amine,and [1,2‐a] benzimidazol‐2‐yl amidrazone

N‐benzimidazol‐2‐yl imidate type 1 reacts with thiourea, carbon disulfide, cyanamide, and hydrazide to give, respectively, [1,2‐a] benzimidazolo‐1,3,5‐triazin‐2‐thione 2 , [1,2‐a] benzimidazolo‐1,3,5‐thiadiazin‐2‐thione 3 , [1,2‐a] benzimidazolo‐1,3,5‐triazin‐2‐amine 4 , and [1,2‐a] benzimidazol‐2‐yl amidrazone 5 with good yields. Structures elucidation of all newly synthesized heterocyclic compounds was based on the data of IR, ¹H NMR, ¹³C NMR, elemental analysis, and MS of some products. © 2010 Wiley Periodicals, Inc. Heteroatom Chem 21:279–283, 2010; Published online in Wiley InterScience ( www.interscience.wiley.com ). DOI 10.1002/hc.20618     

Ferrocenyl,Alkyl, and Aryl‐Pyrido[2,3‐d]Pyrimidines as Vasorelaxant of Smooth Muscle of Rat Aorta via cAMP Conservation Through Phosphodiesterase Inhibition

New pyrido[2,3‐d]pyrimidines 11 , 12 , 13 , and 21 have been synthesized. The vasorelaxant effect on smooth muscle isolated from rat aorta, via PDEs inhibition, of these compounds along with other pyrido[2,3‐d]pyrimidines 14 , 15 , 16 , 17 , 18 , 19 , 20 reported earlier by our group, has also been determined. These pyrido[2,3‐d]pyrimidines 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 were synthesized by the reaction of ferrocenyl‐ethynyl ketones ( 1 , 2 , 3 , 4 ) or α‐alkynyl ketones ( 5 , 6 , 7 , 8 , 9 , 10 ) with 6‐amino‐1,3‐dimethyluracil using [Ni(CN)₄]^?4 as an active catalytic species, formed in situ in a Ni(CN)₂/NaOH/H₂O/CO/KCN aqueous system. Evaluation of the vasorelaxant effect of compounds 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 demonstrated that all compounds relax the tissue in a concentration‐dependent manner. The structural changes do not alter the effectiveness; however, there are differences related to potency expressed as EC₅₀. Compounds 12 (7‐ferrocenyl‐1,3‐dimethyl‐5‐(m‐tolyl)‐pyrido[2,3‐d]pyrimidine) and 13 (7‐ferrocenyl‐1,3‐dipropyl‐5‐(4‐metoxyphenyl)‐pyrido[2,3‐d]pyrimidine) were the most potent compounds, even more than rolipram, reference drug; the EC₅₀ was 0.41 ± 0.02 μM and 0.81 ± 0.11 μM for 12 and 13 , correspondingly. The EC₅₀ of compounds 15 (7‐ferrocenyl‐1,3‐dimethyl‐5‐phenyl‐pyrido[2,3‐d]pyrimidine), 14 (7‐ferrocenyl‐5‐(3,5‐dimethoxyphenyl)‐1,3‐dimethylpyrido[2,3‐d]pyrimidine), and 19 (5‐n‐butyl‐7‐ethyl‐1,3‐dimethylpyrido[2,3‐d]pyrimidine) was similar to EC₅₀ of rolipram. Compounds 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 significantly induce concentration‐dependent vasorelaxation in endothelium‐intact aortic rings. In addition, the relaxation responses to each compound in either endothelium‐intact or endothelium denuded aortic rings were comparable, suggesting that removal of the functional endothelium has no significant influence on its intrinsic vasorelaxant activity. In vitro capability of conserving cyclic‐AMP or cyclic‐GMP (adenosine and guanosine 3′, 5′‐cyclic monophosphate) via PDE inhibition for compounds 12 , 13 , 14 , 15 and 19 was evaluated. Compounds 15 and 19 show the highest percent inhibition effect (94.83% and 83.98%, respectively) for the decomposition of c‐AMP. Docking studies showed that the compound 15 was selective for the inhibition of PDE‐4.     

Synthesis of Some New Heterocycles Derived from Ethyl 7‐Amino‐3‐(3‐methyl‐5‐oxo‐1‐phenyl‐2‐pyrazolin‐4‐yl)‐5‐aryl‐5H‐thiazolo[3,2‐a]pyrimidine‐6‐carboxylate of Biological Importance

Ethyl 7‐amino‐3‐(3‐methyl‐5‐oxo‐1‐phenyl‐2‐pyrazolin‐4‐yl)‐5‐aryl‐5H‐thiazolo[3,2‐a]pyrimidine‐6‐carboxylate was synthesized by the reaction of 4‐(2‐aminothiazol‐4‐yl)‐3‐methyl‐5‐oxo‐1‐phenyl‐2‐pyrazoline with arylidene ethyl cyanoacetate and it transformed to related fused heterocyclic systems via reaction with various reagents. The biological activities of these compounds were evaluated.     

The Use of 2‐Chloro‐4H‐4‐oxo‐pyrido[1,2‐a]pyrimidine as a Building Block in the Synthesis of Some New Heterocyclic Compounds

New approaches for the synthesis of some heterocyclic compounds, such as the pyridopyrimidodiazepine derivative 3 , pyrazolopyrido[1,2‐a]pyrimidine derivative 4 , tetrazolo[1.5‐a][1,8]naphthyridine derivative 9 , pyrazolylpyrido[1,2‐a]pyrimidine derivatives 10a , 10b , 12 , pyrrolopyrido[1,2‐a]pyrimidine derivatives 14a , 14b , 14c , 14d , and 16a , 16b , starting from 2‐chloro‐4H‐4‐oxo‐pyrido[1,2‐a]pyrimidine ( 1 ), are described.