Imidazo[2,1‐b]thiazoles,imidazo[2,1‐b]imidazoles and Pyrrolo[1,2‐c]imidazoles. synthesis,structure and evaluation of benzodiazepine receptor binding

As a continuation of our studies on bicyclic heterocycles with benzodiazepine receptor affinity, derivatives with a 5:5 bicyclic skeleton, namely imidazo[2,1‐b]thiazoles, imidazo[2,1‐b]imidazoles and pyrrolo[1,2‐c]imidazoles were prepared. The compounds possessed an aromatic substituent with different spatial arrangement and distance to the bicyclic skeleton. X‐ray structure analysis was performed for Z‐2‐(4‐chlorobenzylidene)‐5,5‐diphenyl‐2,3,5,6‐tetrahydroimidazo[2,1‐b]imidazoline‐3,6‐dione ( 6a ) and 5‐amino‐6‐cyano‐7‐phenyl‐1‐oxo‐3‐thioxo‐2,3‐dihydro‐1H‐pyrrolo[1,2‐c]imidazole ( 20a ). In contrast to the previously described arylideneimidazo[2,1‐b]thiazepinones the smaller heterocyclic ring systems investigated in this study were devoid of meaningful benzodiazepine receptor affinity as well as anti‐convulsant activity.     

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.     

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.     

Synthese von pyridylphenyl-imidazo[2,1-b]thiazolen

The synthesis of the isomeric 6(5)-phenyl-5(6)-pyridyl-2,3-dihydroimidazo[2,1-b]thiazoles are described. Only the synthesis of 5-phenyl-6-(2-pyridyl)-2,3-dihydroimidazo[2,1-b]thiazole failed.     

Cyclic isothioureido compounds. II. Reaction of trans-3a,4,5,9b-tetrahydronaphth[1,2-d]-imidazoline-2-thiones with α-bromoketones

The reaction of trans-3a,4,5,9b-tetrahydronaphth[1,2-d]imidazoline-2-thiones ( 8 ) with α-bromoketones gave, depending upon the structure of the α-bromoketones, reaction solvent and reaction temperature, the hydrobromides of tetrahydronaphth[1,2-d]imidazolin-2-ylthiomethyl ketone ( 10 ), hexahydro-8-hydroxynaphth[1′,2′:4,5]imidazo[2,1-b]thiazoles ( 5, 11, 19 and 20 ) or tetrahydronaphth[1′,2′:4,5]imidazo[2,1-b]-thiazoles ( 12 and 16 ). Structural determinations based on ir and nmr spectroscopies are discussed.     

Transformations of methyl L-(—)-thiazolidine-4-carboxylate, 2-amino-2-thiazoline and 2-aminothiazole into thiazoloazines and azolothiazoles

In the search for potential immunomodulators methyl L-(—)-thiazolidine-4-carboxylate (2), 2-amino-2-thiazoline (12), and 2-aminothiazole (19) were transformed into derivatives of various bicyclic systems. Thus, from compound 2 derivatives of perhydrothiazolo[3,4-a]pyrazine 4 and 5, perhydrothiazolo[4,3-c]-[1,4]oxazine 7, and perhydroimidazo[1,5-c]thiazole 9a,b, from compound 12 derivatives of 2,3-dihydro-thiazolo[2,3-b]pyrimidine 13a,b , and from compound 19 derivatives of imidazo[2,1-b]thiazole 21, 22, 24, and 25 were prepared. 6-(p-Sulfamoylphenyl)-7-oxoperhydroimidazo[1,5-c]thiazole-5-thione (9a) was found to exhibit immunorestoration activity.     

Intramolecular cyclizations leading to bridgehead bicyclics 2. 5,5-dialkylhydantoin derivatives

The effect of substituenls in the 5-position on the course of hydantoin intramolecular alkylation reactions was studied. Dialkyl and diaryl substituted intermediates resulted in the same type product, 2,3-dihydro-6,6-disubstituted imidazo[2,1-b]oxazole-5(6H)ones, indicating alkylation on oxygen rather than nitrogen. The mass spectral and nmr characteristics of these bicyclic compounds are discussed.     

Synthesis of Imidazo[1,2‐a]pyridines and Imidazo[2,1‐b]thiazoles Attached to a Cycloalkyl or Saturated Heterocycle Containing a Tertiary Hydroxy Substitution

A new method has been developed for the synthesis of imidazo[1,2‐a]pyridines, imidazo[2,1‐b]thiazoles, and benzo[d]imidazo[2,1‐b]thiazoles attached to a cycloalkyl or saturated heterocycle containing a tertiary hydroxy substitution. Readily available substituted 2‐aminopyridines, 2‐aminothiazoles, and 2‐aminobenzothiazoles were treated with bromohydroxycycloalkyl ethanones to afford the desired products in good yields.     

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.     

Phosphorylation of imidazo[2,1‐b]thiazoles with phosphorus(III) halides in the presence of bases

The reaction of phosphorus(III) halides with 6‐substituted imidazo[2,1‐b]thiazoles in the presence of bases proceeds regioselectively and affords 5‐phosphinoimidazo[2,1‐b]thiazoles, useful synthons for the preparation of various P(III) and P(V) derivatives. 5‐Phosphinoimidazo[2,1‐b]thiazoles are selectively alkylated at the phosphorus or heterocyclic nitrogen atom, depending on the alkylating agent. © 2005 Wiley Periodicals, Inc. Heteroatom Chem 16:648–655, 2005; Published online in Wiley InterScience ( www.interscience.wiley.com ). DOI 10.1002/hc.20166     

Heteroarylation of 6-Aryl-2,3-dihydroimidazo[2,1-b]thiazole with N-(Ethoxycarbonyl)heteroaromatic Salts

The ethyl chloroformate salts of a variety of benzo-fused six membered π-deficient heteroaromatics, including quinoline, isoquinoline, 4-chloroquinoline, 3-bromoquinoline, phthalazine, and quinazoline, reacted with 6-aryl-2,3-dihydroimidazo[2,1-b]thiazole at the 5-position. The dihydroheteroaromatic adducts were oxidized by o-chloranil, sulfur, or electrochemical methodology to form the 5-heteroaromatic-6-aryl-2,3-dihydroimidazo[2,1-b]thiazoles, 10-15 . In each example, the regiochemistry of addition to the heteroaromatic ring was established.     

Synthesis of anthra[b]thiophenes and benzo[b]naphtho[d]thiophenes

All isomers of the parent anthra[b]thiophenes and benzo[b]naphtho[d]thiophenes, namely anthra[2,3-b]thio-phene, anthra[2,1-b]thiophene, anthra[1,2-b]thiophene, benzo[b]naphtho[2,3-d]thiophene, benzo[b]naphtho[2,1-d]thiophene and benzo[b]naphtho[1,2-d]thiophene were synthesized using a new procedure.     

Die Synthese von 2,3,4,5-1H-Tetrahydroimidazo[2,1-b]chinazolin-2,5-dionen und analogen 2,3,4,5-1H-Tetrahydroimidazo[1,2-a]thieno[2,3-d] (bzw. [3,2-d])-pyrimidin-2,5-dionen

The Synthesis of 2,3,4,5-1H-Tetrahydroimidazo[2,1-b]quinazolin-2,5-diones and analogous 2,3,4,5-1H-Tetrahydroimidazo[1,2-a]thieno[2,3-d] (or [3,2-d])-pyrimidin-2,5-diones The syntheses of various imidazo [2, 1-b]quinazolinediones and their thiophene analogs are described.     

Oxone®-mediated direct arylselenylation of imidazo[2,1-b]thiazoles,imidazo[1,2-a]pyridines and 1H-pyrazoles

Oxone mediated reaction of imidazo[2,1-b]thiazole, imidazo[1,2-a]pyridine and 1H-pyrazole derivatives with diaryl diselenides is presented here. The methodology represents an efficient and simple protocol for carrying out the selective synthesis of 5-arylselanyl-imidazo[2,1-b]thiazoles, 3-arylselanyl-imidazo[1,2-a]pyridines and 4-arylselanyl-1H-pyrazoles in high yields using a stable, nontoxic and cheap oxidant. The reactions were conducted at 60?°C in air using acetonitrile as solvent. Alternatively, the use of ultrasound irradiation is presented as a tool for fast and efficient energy transfer that significantly reduced the reaction time.     

Synthèse d'hétérocycles en catalyse par transfert de phase

A general study of the chemical behavior of heterocyclic anions, dianions and dianionic reagents under phase transfer catalysis conditions allowed us to synthesize various heterocyclic compounds such as imidazo[2,1-b]thiazole and derivatives; imidazo[2,1-b]thiazine and imidazo[2,1-b]benzothiazepine. Reaction conditions e.g., catalyst, solvent, temperature, etc., are indicated.     

Thermolyzed products of naphth[1,2-d]imidazo[2,1-b]-thiazole-2,3-dione

Themolysis of naphth[1,2-d]imidazo[2,1-b]thiazole-2,3-dione ( 1 ) in dimethylformamide gave an intermediate 2-isocyanatonaphtho[1,2-d]thiazole ( 2 ), which underwent [4 + 4] cyclodimerization to yield dinaphtho-[1″,2″:4,5;1′″,2′″:4′,5′]dithiazolo[3,2-a:3′,2′-e]-1,3,5,7-tetrazocine-9,19-dione ( 3 ). The possible [4 + 2] cycloadduct, 3-(2-naphtho-[1,2-d]-thiazolyl)naphtho[1′,2′:4,5]thiazolo[3,2-a]-1,3,5-triazine-2,4-dione ( 4 ), an usual dimer type of heterocyclic isocyanates was not produced. Discrimination between the two isomers was established on the basis of spectral analyses.     

Synthesis of triphenyleno[b]thiophenes

The synthesis of all the isomers of triphenyleno[b]thiophenes namely, triphenyleno[l,2-b]thiophene, triphenyleno[2,1-b]thiophene and triphenyleno[2,3-b]thiophene is described.     

Research on heterocyclic compounds. XXI. Synthesis of imidazo[2,1-b]benzothiazole and imidazo[2,1-b]thiazole derivatives

The reaction of some 2-aminobenzothiazoles and 2-aminothiazoles with ethyl 3-bromo-4-oxopentanoate was investigated with the aim to obtain the corresponding imidazo[2,1-b]benzothiazole and imidazo[2,1-b]-thiazole derivatives, respectively. In some cases, two unexpected side products were obtained together with the required compound and their structures were elucidated: e.g., 2-aminobenzothiazole reacted with ethyl 3-bromo-4-oxopentanoate to give ethyl 2-methylimidazo[2,1-b]benzothiazole-3-acetate together with ethyl imi-dazo[2,1-b]benzothiazole-2-propionate and ethyl 3-(benzothiazol-2-yl)amino-4-oxopentanoate.     

Diverse synthesis of pyrimido[1,2-a]benzimidazoles and imidazo[2,1-b]benzothiazoles via CuI-catalyzed decarboxylic multicomponent reactions of heterocyclic azoles,aldehydes and alkynecarboxylic acids

We have developed a straightforward approach to diverse synthesis of 2,3-, 2,4-disubstituted pyrimido [1,2-a]benzimidazoles, 2,4,10-trisubstituted 2,10-dihydropyrimido [1,2-a]benzimidazoles and 2,3-disubstituted imidazo [2,1-b]benzothiazoles via multicomponent reactions (MCRs) of heterocyclic azoles, aldehydes with easily storable and handling alkynecarboxylic acids. In the presence of a catalytic amount of CuI and K₂CO₃, the pyrimido [1,2-a]benzimidazole or imidazo [2,1-b]benzothiazole scaffold could be rapidly constructed through a 6-endo-dig or 5-exo-dig cyclization, respectively. The preliminary mechanistic study suggested that the formation of 2,3- disubstituted pyrimido [1,2-a]benzimidazoles, which completes the assembly of the scaffold and its C-3 position functionalization in one pot, undergoes a novel cascade process involving a decarboxylation, A [3] coupling, 6-endo-dig cyclization, nucleophilic addition and dehydration.     

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.