Preparation of 2-aryl and 2-aryloxymethyl imidazo[1,2-a]pyridines and related compounds

A series of substituted 2-aryl imidazo[1,2-a]pyridines has been prepared in which a variety of substituents are introduced on the 4′-position of the phenyl ring and on the 3, 5 , 6 or 7 position of the heterocyclic ring. Most examples have acetamido, bromo, cyano, or formyl substituents at the 4′-position. Analogous imidazo-[2,1-b]fhiazoles and imidazo[1,2-a]pyrimidines have also been prepared. Another series of compounds consisting of 4′-formylphenoxymethyl derivatives of imidazole, the three positional isomers of pyridine, thiazole, benzimidazole and ring-substituted imidazo[1,2-a]pyridines has been prepared. 2-(4′-Formylphenylethenyl) derivatives of imidazole and imidazo[1,2-a]pyridine were also prepared.     

Core-Modified Coelenterazine Luciferin Analogues: Synthesis and Chemiluminescence Properties

In this work on the design and studies of luciferins related to the blue-hued coelenterazine, the synthesis of heterocyclic analogues susceptible to produce a photon, possibly at a different wavelength, is undertaken. Here, the synthesis of O-acetylated derivatives of imidazo[1,2-b]pyridazin-3(5 H)-one, imidazo[2,1-f][1,2,4]triazin-7(1 H)-one, imidazo[1,2-a]pyridin-3-ol, imidazo[1,2-a]quinoxalin-1(5 H)-one, benzo[f]imidazo[1,2-a]quinoxalin-3(11 H)-one, imidazo[1′,2′:1,6]pyrazino[2,3-c]quinolin-3(11 H)-one, and 5,11-dihydro-3 H-chromeno[4,3-e]imidazo[1,2-a]pyrazin-3-one is described thanks to extensive use of the Buchwald–Hartwig N-arylation reaction. The acidic hydrolysis of these derivatives then gave solutions of the corresponding luciferin analogues, which were studied. Not too unexpectedly, even if these were “dressed” with substituents found in actual substrates of the nanoKAZ/NanoLuc luciferase, no bioluminescence was observed with these compounds. However, in a phosphate buffer, all produced a light signal, by chemiluminescence, with extensive variations in their respective intensity and this could be increased by adding a quaternary ammonium salt in the buffer. This aspect was actually instrumental to determine the emission spectra of many of these luciferin analogues.     

Convenient synthesis of fused heterocycles from α-ketohydroximoyl chlorides and heterocyclic amines

Nitroso derivatives of imidazo[1,2-a]pyridine ( 11, 13, 14 ), imidazo[1,2-a]pyrimidine ( 15 ), imidazo[1,2-a]pyrazine ( 16 ), imidazo[1,2-b]pyrazole ( 17 ), and imidazo[1,2-b]-1,2,4-triazole ( 19 ) were obtained in good yields from α-ketohydroximoyl chlorides 3 and 2-aminopyridines ( 4–6 ), 2-aminopyrimidine ( 7 ), 2-aminopyrazine ( 8 ), 5-amino-3-phenylpyrazole ( 9 ), and 3-amino-2H-1,2,4-triazole ( 10 ), respectively. Under different conditions, the reaction of 3 with 3-amino-2H-1,2,4-triazole ( 10 ) and 2-aminopyrazine ( 8 ) afforded the noncyclized substitution products 18 and 22 , respectively. The structures of the products were assigned and confirmed on the basis of their elemental analyses, spectral data, and alternate synthesis wherever possible.     

Synthesis and properties of cyanomethyl derivatives of imidazo[1,2-<Emphasis Type="Italic">a</Emphasis>]pyridine,imidazo[1,2-<Emphasis Type="Italic">a</Emphasis>]pyrimidine,and imidazo[2,1-<Emphasis Type="Italic">b</Emphasis>]thiazole

2-Cyanomethyl derivatives were obtained of imidazo[1,2-a]pyridine, imidazo[1,2-a]pyrimidine, and imidazo[2,1-b]thiazole, and their reactivity was investigated by an example of imidazo[1,2-a]pyridine: It was subjected to nitration, bromination, azo coupling and nitrosation. Acylation of the methylene group effected by amino acids esters with a subsequent addition of the amino group to the cyano group resulted in the formation of 5-amino-4-imidazo[1,2-a]-pyridin-2-yl-1-phenyl-1,2-dihydro-3H-pyrrol-3-one and 2-amino-1-ethyl-3-imidazol[1,2-a]pyridin-2-yl-4(1H)-quinolinone.     

Cyclocondensation of <Emphasis Type="Italic">N</Emphasis>-aryl-3-oxobutanethioamides with 2-aminoimidazole and 2-aminobenzimidazole

Cyclization of N-aryl-3-oxobutanethioamides with 2-aminoimidazole and 2-aminobenzimidazole gave 7-methyl-5,8-dihydroimidazo[1,2-a]pyrimidine-5-thione or 2-methylpyrimido[1,2-a]benzimidazole-4(1H)-thione and 4-(arylamino)-2-methylpyrimido[1,2-a]benzimidazoles whose ratio depends on the nature of aryl substituents in the initial butanethioamides and on the presence of a protic solvent.     

Reactions of α-ketohydrazidoyl halides with some heterocyclic amines. Facile synthesis of arylazo derivatives of fused heterocycles with a bridgehead nitrogen atom

Arylazo derivatives of imidazo[2,1-b]thiazoles, imidazo[1,2-b]pyrazoles, imidazo[1,2-b]-s-triazoles, imidazo[1,2-a]pyrimidines, and imidazo[1,2-a]pyridines were obtained in good yields from α-keto hydrazidoyl halides and 2-aminothiazole, 5-aminopyrazole, 5-aminotriazole, 2-aminopyrimidine, and 2-aminopyridine, respectively (cf. Tables I and II). The structures of the products were assigned and confirmed on the basis of their elemental analyses, spectra, and alternate synthesis wherever possible.     

Synthesis of pyrimido[1,2-a]benzimidazoles from ethyl 2-ethoxymethylidene-3-oxo-3-(polyfluoroalkyl)propionates

Cyclization of ethyl 2-ethoxymethylidene-3-oxo-3-polyfluoroalkylpropionates with benzimidazol-2-amine in boiling 1,4-dioxane followed two concurrent pathways with participation of fluoroacyl and ethoxycarbonyl fragments and formation of, respectively, ethyl 4-hydroxy-4-polyfluoroalkyl-1,4-dihydropyrimido-[1,2-a]benzimidazole-3-carboxylates and 3-polyfluoroacylpyrimido[1,2-a]benzimidazol-4-ols. Dihydropyrimido[1,2-a]benzimidazole derivatives undergo dehydration to give ethyl 4-(polyfluoroalkyl)pyrimido[1,2-a]benzimidazole-3-carboxylates, whereas the hydroxy group in 3-polyfluoroacylpyrimido[1,2-a]benzimidazol-4-ols is capable of being replaced by the amino group of the second benzimidazole molecule with formation of 4-(1H-benzimidazol-2-ylamino)-3-polyfluoroacylpyrimido[1,2-a]benzimidazoles.     

Some novel heterocyclic systems derived from 7-amino-2,3-dihydro-8-nitro-1H-pyrrolo[1,2-α]benzimidazole and the corresponding diamine

The preparation of 7-amino-2,3-dihydro-8-nitro-1H-pyrrolo[1,2-a]benzimidazole from 1,4-diacetamido-2,3-dinitrobenzene is described. Reaction of this compound with 2,5-dimethoxytetrahydrofuran produces 2,3-dihydro-8-nitro-7-N-pyrrolo-1H-pyrrolo[1,2-a]benzimidazole, which can be cyclised to produce two new heterocyclic ring systems, 9,10-dihydro-8H-pyrrolo[1,2-a]pyrrolo(1′,2′:1,2]imidazo[5,4-f]quinoxaline and 9,10-dihydro-8H-pyrrolo[2,1-c]pyrrolo[1′,2′:1,2]imidazo[4,5-h][1,2,4]benzotriazine. The corresponding diamine, 7,8-diamino-2,3-dihydro-1H-pyrrolo[1,2-a]benzimidazole undergoes a variety of condensation reactions to produce several new heterocyclic systems, for example, with formic acid, 1,7,8,9-tetrahydroimidazo-[4,5-e]pyrrolo[2,1-6]benzimidazole is formed and with diacetyl, 9,10-dihydro-2,3-dimethyl-8H-pyrrolo-[1′,2′:1,2]imidazo[5,4-y]quinoxaline is obtained.     

Research on heterocyclic compounds. XXIII. Phenyl derivatives of fused imidazole systems

The reaction of various heteroarylamines with ethyl 2-benzoyl-2-bromoacetate was used to obtain some imidazo[1,2-a]pyridines, imidazo[1,2-a]pyrimidines, imidazo[2,1-b]thiazoles and imidazo[2,1-b]benzothiazoles characterized by the presence of a phenyl moiety on the imidazole ring. In the case of thiazole and benzothiazole derivatives, unexpected by-products were isolated and their structures elucidated.     

Photoelectron spectroscopy of heterocycles. Azaindenes and azaindolizines

The HeI photoelectron (PE) spectra of indole ( 1 ), benzimidazole ( 2 ), indazole ( 3 ), 3-chloro-indazole ( 4 ), imidazo[1,2-b]pyridazine ( 5 ), 6-chloroimidazo[1,2-b]pyridazine ( 6 ), 2-phenyl-imidazo[1,2-b]pyridazine ( 7 ), 2-phenyl-6-chloroimidazo[1,2-b]pyridazine ( 8 ), tetrazolo[1,2-a]-pyridine ( 9 ) and 8-cyanotetrazolo[1,5-a]pyridine ( 10 ) have been recorded. The spectra of 2–10 are of special interest for studying lone pair interactions. The assignment of the PE spectra submitted here, conjointly with the electronic structure of the studied compounds is discussed on the basis of molecular orbital calculations.     

Reactions of 4-aminocycloheptimidazoles with alkyl iodides,acyl chlorides,and α-haloketones

The reactions of 4-amino-2-phenylcycloheptimidazole with alkyl iodides and α-bromoketones gave respectively 1-alkyl- and 1-acetonyl- (or 1-phenacyl)-substituted cycloheptimidazol-4(1H)-ones, while the reactions with acyl chlorides gave 4-arylamino-2-phenylcycloheptimidazoles. On the other hand, 2,4-diaminocycloheptimidazole were benzoylated with benzoyl chloride on the amino group at the 2- and/or 4-position and reacted with α-haloketones to give tricyclic 2-substituted 9-aminocyclohept[d]imidazo[1,2-a]imidazoles.     

(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.     

Heterocyclization of 3-(R-amino)-3-methylthio-1-phenylpropenones and 5-benzoyl-6-methylthio-1,2-dihydropyridin-2-ones with 1,2- and 1,3-dinucleophilic reagents

The interaction of 3-(R-amino)-3-methylthio-1-phenylpropenones and 1-alkyl-5-benzoyl-3-ethoxy-carbonyl-6-methylthio-1,2-dihydropyridin-2-ones with N,N- and N,C-1,2- and 1,3-dinucleophiles proceeded regioselectively by [3 + 2] and [3 + 3] cyclocondensation with the formation of derivatives of pyrazole, benzimidazo[1,2-a]-pyridine, benzimidazo[1,2-a]pyrimidine, imidazo[1,2-a]pyrimidine, [1,2,4]triazolo[4,3-b]pyridazine, and 6,7-dihydro-2H-pyrazolo[3,4-b]pyridine. The regioselectivity of the reactions carried out was analyzed.     

Formylation of Furyl-substituted Imidazo[1,2-a]pyridine, Imidazo[1,2-a]pyrimidine and Imidazo[2,1-b]thiazole

Vilsmeier formylation of 2-(2-furyl)-substituted imidazo[1,2-a]pyridine and imidazo[1,2-a]pyrimidine, and also 6-(2-furyl)imidazo[2,1-b]thiazole with 1 mole of reagent occurs at the free position of the imidazole ring, while with an excess of the reagent it also occurs at the position 5 of the furyl group.     

3-Substituted imidazo[1,5-a]pyridines

Cyclization of amides of 2-aminomethylpyridine gave imidazo[1,5-a]pyridines. In several examples the literature preparation (phosphorus oxychloride) gave extensive tar formation. The use of phosphorus trichloride-triethylamine (?20°) gave the desired imidazo[1,5-a]pyridines.     

Fused polycyclic nitrogen-containing heterocycles 20. Thiazolo[3,4-<Emphasis Type="Italic">a</Emphasis>]quinoxalines from 4-hydroxy-2-phenyliminothiazolidines and C-substituted 1,2-phenylenediamines

The condensation of 4-hydroxy-3,5-diphenyl-2-phenyliminothiazolidine with 4,5-dimethyl-1,2-phenylenediamine affords 7,8-dimethyl-3-phenyl-1-phenyliminothiazolo[3,4-a]quinox-alin-4(5 H)- one; the condensation with 1,2-phenylenediamines containing different substituents at positions 4 and 5 gives both theoretically possible isomeric thiazolo[3,4-a]quinoxalines, which differ in the distribution of these substituents between positions 7 and 8 in the benzene ring of the quinoxaline system. 3a-Hydroxy-7,8-dimethyl-3-phenyl-l-phenylimino-3,3a-di-hydrothiazolo[3,4-a]quinoxalin4(5 H)- one was isolated and characterized as the intermediate of the reaction giving rise to thiazolo[3,4-a]quinoxaline from 4,5-dimethyl-1,2-phenylene-diamine. This intermediate is a covalent hydrate of the final product.     

The synthesis of azahomotryptophane derivatives. The transformation of N-trifluoroacetyl-5-bromo-4-oxonorvaline methyl ester into 4-(imidazo[1,2-a]azinyl-3)-4-oxohomoalanine derivatives

Azatryptophane homologues, 4-(imidazo[1,2-a]pyridinyl-3)- 9a-9f and 4-(imidazo[1,2-a]pyrimidinyl-3)-4-oxohomoalanine derivatives 9g-91 , were prepared from N,N-dimethyl-N′-(pyridinyl-2)- 6a-6f and N,N-dimethyl-N-(pyriniidinyl-2)formamidines 6g-6i , and (S)-N-trifluoroacetyl-5-bromo-4-oxonorvaline methyl ester ( 2 ) and its (R,S)-isomer.     

Acetylenchemie. 9. Mitt. Anellierte imidazole aus N-propinylamid-vorstufen

The Compound 2-(N-Formyl-N-prop-2′-inyl)aminopyridine was cyclised in boiling formic acid to 3-methylimidazo[1,2-a]pyridine, with 3-methylene-2H-imidazo[1,2-a]pyridine as the intermediate. Under similar conditions the 1,3-diprop-2-inylpyrimido[4,5-b]quinoline-2,4-dione resulted from 1-methylimidazo[1,2-a]quinoline-4-carbonic acid-N-2-prop-2′-inylamide and from the 1-prop-2′-inylbenzo[b][1,8]naphthyridin-2-one the 1-methylbenzo[b]imidazo[1,2,3-ij]naphthyridine-4,7-dione as a new ring system, was obtained.     

Preparation of imidazo[2,1-b]quinazolin-5(3H)-ones and related tricyclic systems using a novel,double displacement reaction

New methodology is described for the construction of tricyclic heterocycles. Thus, a double displacement reaction of l-(2-fluorobenzoyl)-2-methylthio-2-imidazoline ( 8a ) with 1,1-dialkylhydrazines gave 10-substituted 2,10-dihydroimidazo[2,1-b]quinazolin-5(3H)-ones in good yield. The corresponding 1-(2-nitrobenzoyl)-2-meth-ylthio-2-imidazolines also underwent double displacement reactions with hydrazines. Other tricyclics made using double displacement reactions were pyrimido[2,1-b]quinazolines, imidazo[1,2-a]pyrido[2,3-d]pyrimidines, and imidazo[1,2-a]pyrazolo[3,4-d]pyrimidines. Treatment of 8a with hydrazine hydrate or methylhydrazine gave products resulting from displacement, but did not afford fused benzotriazepinones.     

The synthesis of certain 8-cyano-2,4-disubstituted-imidazo[1,5-a] pyrimidines

A number of imidazo[1,5-a]pyrimidine-8-carboxamides were synthesized by reacting various β-dicarbonyl compounds with 5(4)-aminoimidazole-4(5)carboxamide (AICA, 1 ), the non-ribosylated form of AICAR, a key intermediate in the metabolic pathway of purine biosynthesis. Cyclization of 1 with ethylacetoacetate yielded 2-methylimidazo[1,5-a]pyrimidin-1H-4-one-8-carboxamide ( 2 ). The treatment of 2 with phosphorus oxychloride gave 4-chloro-8-cyano-2-methylimidazo[1,5-a]pyrimidine ( 3 ). Various nucleophiles displaced the 4-chloro substituent of 3 under mild conditions. However, the 4-methylthio group of 8-cyano-2-methyl-4-methylthioimidazo[1,5-a)pyrimidine ( 8a ) was also displaced under very mild conditions. Even more strangely, the 4-diethylamino group of 8-cyano-4-diethylamino-2-methylimidazo[1,5-a]pyrimidine ( 5a ) was displaced by ammonia to give 4-amino-8-cyano-2-methylimidazo[1,5-a]pyrimidine ( 7 ).