Regioselectivity in methylation and phenylation of the zwitterionic pyrido[2,1-f]-as-triazinium-1- and 3-olates and thiolates

Substituted derivatives of the title ring system have been synthesized and the regioselectivity in methylation and phenylation of the zwitterionic pyrido[2,1-f]-as-triazinium 1- and 3-olates 4a-g and 10 and thiolates 7a,b and 12 has been studied by nmr techniques. Depending on the soft or hard nature of the used reagent (methyl iodide, trimethyloxonium hexafluorophosphate or diphenyliodonium tetrafluoroborate), the reaction yielded NMe 5 and/or OMe 6,11a and NPh 14 or OPh 11b products in the case of olates; while thiolates gave NMe 8 and/or SMe 9,13a and SPh 13b, 15 compounds. Mechanistic suggestions are given to rationalize the observed phenomena.     

Rearrangement reactions of heterocycles. 12. Rearrangement of 6-substituted pyrido[1,2-a]pyrimidines to isomeric 1,8-naphthyridines and some of their further reactions

2-Amino-6-methylpyridine ( 4 ) reacts with active malonates 2a-d or 3a-d either in acetone solution with triethylamine as catalyst at room temperature or with active malonates 2a-d in acetone solution at reflux temperature to yield the pyrido[1,2-a]pyrimidines 5a-d . 2,6-Diaminopyridine ( 8 ) already reacts without triethylamine with 2a-d at room temperature to afford the pyrido[1,2-a]pyrimidines 9a-d . At higher temperatures pyrido[1,2-a]pyrimidines 5 and 9 are rearranged via ketene intermediates [1] to yield the 1,8-naphthyridines 6a-d , and 10a-d , respectively. The naphthyridines 6 and 10 can also be synthesized directly from 4 or 8 using either diethyl malonates 1 or — with better results — the active malonates 2 at 240–250°. Further reaction of 10a-e with 2c,d leads to the pyridonaphthyridines 12a-f . Nitration of 6c yields the nitro derivative 16 and chlorination of 6c,d gives 15c,d , while the chlorination of 10c affords the di-chloro derivative 17 .     

Asymmetric construction of pyrido[1,2-a]-1H-indole derivatives via a gold-catalyzed cycloisomerization

Pyrido[1,2-a]-1H-indoles are important scaffolds found in many biologically active compounds. Herein, we first developed an IPrAuCl/AgSbF₆-catalyzed cycloisomerization of N-1,3-disubstituted allenyl indoles affording pyrido[1,2-a]-1H-indoles. Then the axial-to-central chirality transfer starting from enantio-enriched N-1,3-disubstituted allenylindoles affording optically active pyrido[1,2-a]-1H-indoles has been realized in excellent yields and enantioselectivities. A mechanism has been proposed based on mechanistic studies. Synthetic applications have also been demonstrated.

We reported an IPrAuCl/AgSbF₆-catalyzed cycloisomerization of enantio-enriched N-1,3-disubstituted allenylindoles affording optically active pyrido[1,2-a]-1H-indoles in excellent yields and enantioselectivities.     

A new domino reaction based on [4+2]-cycloadditions of pyrido[1,2-a]pyrazines with azadienophiles

The reaction of pyrido[1,2-a]pyrazines 1 with nitroso compounds 2 provides pyridyl substituted 1,2,4-triazinones 4 via a domino reaction which involves a cycloaddition and a ring transformation reaction. The intermediate and regioselective formed oxadiazines 4′ were trapped by complexation yielding the (CO)₄Mo-complex 5. Derivatives of diazene such as N-phenyltriazolindione 6a , phthalazinedione 6b or esters of azodicarboxylic acid 6c-6f reacted with 1 to give different derivatives of 1,2,4-triazine 7a-f . The use of oxygen gave oxadiazinones 8 .     

Recent developments in the chemistry of bicyclic 6-6 systems: Chemistry of pyrido[1,2-c]pyrimidines

The present review provides a study on the structural features, reactions, and synthetic methodologies of pyrido[1,2-c]pyrimidines. The maximum deviation from the mean plane of the pyridopyrimidine skeleton of 4-(pyridin-2-yl)-1H-pyrido[1,2-c]pyrimidine-1,3(2H)-dione indicated a reasonably planar system. The aim of this review is to give an overview of the diverse methodologies that have been reported on the chemistry of pyrido[1,2-c]pyrimidines. The different synthetic routes have been grouped according to the way the pyrido[1,2-c]pyrimidine moiety has been created. Thus, pyrido[1,2-c]pyrimidine compounds were obtained by the formation of one bond α to the bridgehead nitrogen atom [6+0(β)] and formation of two bonds from ([3+3], [4+2], and [5+1]) atom fragments. The mechanistic pathways of the reactions are discussed.     

Synthesis of pyrido[3,2-e]pyrrolo[2,1-c][1,2,4]triazines from pyrido[3,2-e][1,2,4]triazine derivatives

In carrying on our interest in heteropolycyclic structures with biological activities, we projected the preparation of compounds containing the pyrido[3,2-e][1,2,4]triazine or pyrido[2,3-b][1,4]triazepine systems. The established synthetic approach for the preparation of latter system led to the triazine derivatives 5a-f while a new bicyclic triazepine structure 6 is accomplished with difficulty. In expanding the pyridotriazine structure, we obtained derivatives of a new tricyclic structure, 5-substituted-6a-ethyloxycarbonyl-5,6,6a,7-tetrahydropyrido[2,3-e]pyrrolo[2,1-c][1,2,4]triazin-9(8H)-ones 8 in which the triazine ring is fused with a pyrrole nucleus. Compounds 5a-f and 8a,b will be tested as potential CNS depressant, antiinflammatory, analgesic and antibacterial agents.     

Amino acids in the synthesis of heterocyclic systems. The synthesis of 4-oxo-4H-pyrido[1,2-a]pyridines and 4-oxo-4H-pyrido[1,2-a]pyrimidines

The pyridine and quinoline derivatives 2, 3 , and 6 with an activated methylene group atα-position in respect to the ring nitrogen atom were converted with 1, 8 , or 9 into fused pyrido[1,2-a]pyridine derivatives 4, 5, 7 , and 10 . In an analogous manner were the aminopyridines 16 and 17 transformed with thiazolone 9 into pyrido[1,2-a]pyrimidine derivatives 20, 21, 25 , and 26 .     

(8,9-Dihydro-7H-imidazo[1,2-c][1,3]diazepin-5-yl)-cyanamide und homologe imidazo-bizyklen

The reaction of the 2-(ω-aminoalkyl)imidazoles 4a-f with N-cyanodi-phenylimidocarbonate ( 7 ) leads to appropriately hydrogenated imidazo-[1,5-a]imidazoles, imidazo[1,2-c][1,3]diazepines and imidazo[1,2-c][1,3]diazocines ( 9a-f ), which are similar to (7,8-dihydroimidazo)[1,2-c]pyrimidin-5-yl)cyanamides ( 3 )[1] in respect to their chemical and spectroscopic properties.     

Synthesis of pyrido[2,3-d]pyrimidin-4-one derivatives

This paper describes one-pot synthesis of 5H-[1,3]thiazolo[3,2-a]pyrido[3,2-e]pyrimidin-5-one 4 , 5H-dipyri-do[1,2-a:3′,2′-e]pyrimidin-5-one 10 and 5H-pyrido[3,2-e]pyrimido[1,2-a]pyrimidin-5-one 15 and some of their derivatives, starting with 2-chloro-3-pyridine carboxilic acid 1. Compounds 4 and 10 reacted with phosphorus pentasulfide to give the respective 5-thione analogues, 5 from 4 and 11 from 10 . Boiling the 5-thione derivatives with hydrazine hydrate, the respective 5-hydrazono derivatives 6 from 5 and 12 from 11 were obtained. The 5-acetyl hydrazono, 7 , and the 5-isopropylidenehydrazono, 8 , derivatives were also prepared from 6 , and the 5-propionylhydrazono derivatives, 13 , from 12 . Compound 4 reacted with hydrazine to give an adduct with two molecules of hydrazine and the probable structure 16 . Treating this adduct with acetone a monohydrazone 17 was obtained. Boiling a suspension of this adduct in DMF, it gave 6,10-dihydro-6H-pyrido[3′,2′:5,6]pyrimido[2,1-c][1,2,4]triazin-5-one 20 .     

Transformations of the pyrido[1,2-a]pyrazine ring system into imidazo[1,2-a]pyridines,imidazo[1,2-a]pyrimidines and 2-oxa-6a, 10c-diazaaceanthrylenes

Transformations of methyl 3-dimethylamino-2-(1-methoxycarbonyl-4-oxo-4H-pyrido[1,2-a]pyrazin-3-yl)acrylate with some cyanomethylenecarbonyl group containing compounds or cyanamide into imidazo-[1,2-a]pyridines, irmdazo[1,2-a]pyrimidines and 2-oxa-6a, 10c-diazaaceanthrylenes are described.     

Electrochemical properties of pyrido[1′,2′:1,2]imidazo[4,5-b]pyrazine and pyrido[1′,2′:1,2]imidazo[4,5-b]quinoxaline derivatives

The peak potentials (Ep) of 3-substituted pyrido[1′,2′:1,2]imidazo[4,5-b]pyrazine and pyrido[1′,2′:1,2]-imidazo[4,5-b]quinoxaline derivatives are sufficiently correlated with Hammett substituent constant ～_m and with the PM3 calculated LUMO energy levels, and the linear relationship between electron potentials of 9-substituted pyridoimidazoquinoxalines and the LUMO energy levels is also found out.     

Synthesis of 1H-pyrazino[1,2-a]pyrido[2,3-e]pyrazine and 2H-Pyrano[2,3-b]pyrido[2,3-e]pyrazine Derivatives

With a continuing interest on heteropolycyclic structures which may show biological activities, we synthesized new tricyclic derivatives in which the pyridopyrazine skeleton is fused with pyrazine 7 and 8, B , n = 1. However, the initial design of obtaining also the cyclohomologous structure B (n = 2) produced instead a pyranopyridopyrazine derivative 11 . Thus during the attempt to prepare a pyridodiazepine intermediate, beside a very small amount of the desired product 10 , the pyridopyrazine 9 was obtained. The latter compound reacted with chloroacetyl chloride/chloroketene to give 4-carbethoxy-10-(chloroacetyl)-5,10-dihydro-5-methyl-2H-pyrano[2,3-b]pyrido[2,3-e]pyrazin-2-one ( 11 ). In studying the behavior of this derivative, compounds 12–14 were obtained. Compounds 4b,c, 5a,b, 7, 8, 9 and 14 have been submitted to preliminary pharmacological screening as CNS depressant agents.     

Fused pyrimidine systems: XIII. Synthesis and some transformations of 1,3-thiazolo(thiazino)-fused pyrido[3,4-d]pyrimidines

2-[Allyl(propargyl)sulfanyl]pyrido[3,4-d]pyrimidin-4-ones at heating in polyphosphoric acid undergo an intramolecular cyclization with the formation of pyrido[4,3-e]thiazolo-[3,2-a]pyrimidin-5-ones of angular structure. Under similar conditions the cyclization of 2-(cinnamylsulfanyl)pyrido[3,4-d]-pyrimidin-4-one results in a linear pyrido[3′,4′:4,5]pyrimido-[2,1-b][1,3]thiazin-6-one. The iodocyclization of the same substrates affords the corresponding 9-(iodomethyl)(iodomethylidene)pyrido[4,3-e][1,3]thiazolo-[3,2-a]pyrimidin-5-ones and 3-iodopyrido[3′,4′:4,5]pyrimido[2,1-b][1,3]thiazin-6-one of angular structure. 9-(Iodomethyl)-8,9-dihydro-5H-pyrido[4,3-e][1,3]thiazolo[3,2-a]pyrimidin-5-one treated with sodium azide gave 9-(azidomethyl) derivative whose cyclization with substituted alkynes in the presence of copper compounds provided pyrido [4,3-e][1,3]thiazolo[3,2-a]pyrimidinylmethyltriazoles.     

One step synthesis of pyrimido[1,2-a][1,8]naphthyridinones,pyrido[1,2-a]pyrimidinones and 1,8-naphthyridinones. Antihypertensive agents. V

The condensation of 2,6-diaminopyridine and 2-acetamido-6-aminopyridine with β-keto esters in polyphosphophoric acid was studied. In this reaction some 1,8-naphthyridinones, pyrido[1,2-a]pyrimidinones and pyrimido[1,2-a][1,8]naphthyridinones variously substituted were obtained.     

Derivatives of 2,3-Dihydrocyclopenta[d] pyrido[1,2-a] pyrimidin-10(1H)one

The annulation of 2-amino-3-hydroxy-, 2-amino-3-carboxy-, and 2-amino-3-methylpyridine with ethyl cyelopenlanone-2-earboxylate led to the 5-hydroxy-, 2 , 5-carboxy-, 3, and 5-methyl-, 4 , derivatives of the 2,3-dihydrocycloperita[d]pyrido[1,2-a]pyrimidin-10(1H) one heterocycle. Alkylation of 2 with α-bromotolue, ne gave the 5-benzyloxy derivative.     

Green synthesis of pyrido[2,1-a]isoquinolines and pyrido[1,2-a]quinolins using Fe3O4-MNPs as efficient nanocatalyst: Study of antioxidant activity

In this work, synthesis of pyrido[2,1-a]isoquinolines and pyrido[1,2-a]quinolins in excellent yield using multicomponent reaction of phthalaldehyde, methyl amine, methyl malonyl chloride, alkyl bromides, and triphenylphosphine in the presence of catalytic amount of Fe₃O₄-MNPs with aqueous sodium hydroxide at 80°C was investigated. The reduction of ferric chloride solution with Clover Leaf water extract caused to synthesis of magnetic iron oxide nanoparticles (Fe₃O₄-MNPs) as a green method. As well, antioxidant activity was studied for the some newly synthesized compounds such as 6a , 6c , 9b , and 9c using the DPPH radical trapping and reducing of ferric ion experiments and comparing results with synthetic antioxidants (TBHQ and BHT). As a result, compounds 6a , 6c , 9b , and 9c show good DPPH radical trapping and excellent reducing strength of ferric ion.     

Pyrrolo- and pyrido[1,2-a]indoles via an intramolecular wittig reaction

Several pyrrolo- and pyrido[1,2-a]indoles were prepared via an intramolecular Wittig reaction in good yields. This reaction sequence represents a facile entry into the mitosene ring system.     

Heterocyclizations in the pyrido[2,3-b]pyrazine series

In this paper, we report the results of heterocyclizations in the pyrido[2,3-b]pyrazine series to give the pyrido[2,3-e] or [3,2-e]pyrrolo[1,2-a]pyrazine. The Clauson-Kaas reaction on 2,3-diaminopyridine is investigated; regioselectivity on the 3-amino group is shown by ¹H- and ¹³C-nmr. Synthesis and reactivity of the original pyrazino[2,3-g]indolizine series is also reported.     

Benzimidazole condensed ring systems. 1. Syntheses and biological investigations of some substituted pyrido[1,2-a]benzimidazoles

The synthesis of some substituted 3-hydroxy-1-oxo-1H,5H-pyrido[1,2-a]benzimidazole-4-carbonitriles and 4-ethyl carboxylates 3 and their 0- and N-dialkyl derivatives 5,6 is described. 3-Ethoxy-5-ethyl-2-phenyl-1H,5H-pyrido[1,2-a]benzimidazol-1-one 7 was obtained during the course of ethylating the parent ester 3t with triethyl phosphate. Chlorination of 3 with phosphorus oxychloride afforded the corresponding 1,3-dichloropyrido[1,2-a]benzimidazoles 8 which were converted to a variety of azido, amino, morpholino and methoxy derivatives of the system. The synthesis of the indolopyridobenzimidazole 15 is also described. Two compounds exhibited in vitro antibacterial activity. Many compounds were screened for antileukemic, antimicrobial, herbicidal and plant antifungal potencies but were inactive.