A convenient synthesis of novel pyrido(1′,2′:1,2)imidazo[5,4‐d]‐1,2,3‐triazinones from imidazo[1,2‐a]pyridines

The imidazo[1,2‐a]pyridine system was investigated as a synthon for the building of very attractive fused triazines, a planar, angular tri‐heterocycle with potential biological activity. Thus ethyl 3‐nitroimidazo[1,2‐a]pyridine‐2‐carboxylate was treated with ammonia or with an excess of primary amines to generate the corresponding substituted nitro carboxamidoimidazopyridines. The nitro substituent in the latter products, was reduced to yield 3‐amino‐2‐carboxamidoimidazo[1,2‐a]pyridine derivatives, which in turn were treated with nitrous acid to furnish 1‐oxo‐2‐substituted pyrido(1′,2′:1,2)imidazo[5,4‐d]‐1,2,3‐triazines.     

Comparative Study on the Reactivity of 6‐Haloimidazo[1,2‐a]pyridine Derivatives towards Negishi‐ and Stille‐Coupling Reactions

The scope of the Suzuki‐cross‐coupling reaction of 6‐haloimidazo[1,2‐a]pyridines is dependent on the availability of the (hetero)arylboronic acids. Thus, with the aim to develop expanded applications of (hetero)arylations of imidazo[1,2‐a]pyridines, we investigated the Negishi‐ and Stille‐cross‐coupling reactions at the 6‐position. Remarkably, attempts to apply the Negishi‐cross‐coupling conditions to the organozinc derivative prepared from 6‐haloimidazo[1,2‐a]pyridine via a lithium? zinc exchange led to the 5‐phenyl compound 3 in 54% yield instead of the desired 6‐phenyl isomer (Scheme 1). In contrast, various commercially available halogenated five‐ or six‐membered‐ring heterocycles were efficiently coupled to the 6‐(trialkylstannyl)imidazo[1,2‐a]pyridine under Stille conditions (Table 2).     

Convenient Synthesis of Alkenyl‐, Alkynyl‐, and Allenyl‐Substituted Imidazo[1,2‐a]pyridines via Palladium‐Catalyzed Cross‐Coupling Reactions

A systematic study on the Stille and Sonogashira cross‐coupling of iodinated imidazo[1,2‐a]pyridines was performed, permitting the preparation of various vinyl‐, ethynyl‐, and allenyl‐substituted derivatives. These methods are particularly valuable, given their experimental simplicity and high degree of flexibility with regard to functional groups that can be introduced in positions 3, 6, or 8 of the imidazo[1,2‐a]pyridine core. Effects concerning different substitution positions and the nature of the 2‐substituent under various reaction conditions are reported in detail for the above types of unsaturated groups introduced.     

Synthesis and biological study of some new chalcones and oxopyrimidines containing imidazo[1,2‐a]pyridine nucleus

Heterosubstituted chalcones and oxopyrimidines were synthesized by the reaction of 2‐(4‐Chlorophenyl)imidazo[1,2‐a]pyridine‐3‐carbaldehyde 1 and different aryl acetophenone in the presence of catalytic amount of 40% alkali to give (2E)‐3‐(2‐(4‐chlorophenyl)imidazo[1,2‐a]pyridin‐3‐yl)‐1‐arylprop‐2‐en‐1‐ones 2a – l . Compounds 2a – l on reaction with urea in the presence of basic catalyst such as KOH to give 6‐(2‐(4‐chlorophenyl)imidazo[1,2‐a]pyridin‐3‐yl)‐4‐aryl pyrimidin‐2(1H)‐ones 3a – l . Their IR, ¹H‐NMR, MASS spectral data, and elemental analysis were in accord with assigned structure. All the newly synthesized compounds were screened for their antimicrobial activity. J. Heterocyclic Chem., (2012).     

Regio‐ and Site Selectivity in the Reactions of Hydrazonoyl Chlorides with 3‐substituted Indolin‐2‐one Derivatives

The reaction of 3‐(3‐amino‐5‐oxo‐1,5‐dihydropyrazol‐4‐ylidene)‐1,3‐dihydroindol‐2‐one with N‐aryl‐2‐oxopropane hydrazonoyl chlorides in dioxane in the presence of triethylamine proceeded regio‐ and site selectively to give 3‐(2‐arylazo‐3‐methyl‐6‐oxo‐imidazo[1,2‐b ]pyrazol‐7‐ylidene‐indol‐2‐ones rather than the isomeric form 3‐(3‐arylazo‐2‐methyl‐6‐oxo‐imidazo[1,2‐b ]pyrazol‐7‐ylidene‐indol‐2‐ones. On the other hand, the reaction of N ’‐(2‐oxoindoline‐3‐ylidene)hydrazinecarbothiohydrazide with hydrazonoyl chlorides in refluxing ethanol and in the presence of triethylamine proceeded regio‐ and site selectively to give the respective 3‐(substituted‐1,3,4‐thiadiazol‐2‐ylidenehydrazono)indolin‐2‐ones. The mechanism of formation of the new products was also discussed. The structure assigned for the products was established by elemental and spectral data (¹H‐NMR, IR, and Mass) and NOE experiment. Moreover, the biological activity of the products was evaluated against some fungi and bacteria, and the results obtained revealed the high potency of some of them compared with the used standard references.     

Polycyclic N‐Heterocyclic Compounds. Part 75: Synthesis of 2,4‐Disubstituted 5,6‐dihydro[1]benzoxepino[5,4‐d]pyrimidines and 12‐Substituted 1,2,4,5‐Tetrahydro[1]benzoxepino[4,5‐e]imidazo[1,2‐c]pyrimidines as Potential Antiplatelet Aggregators

Libraries of tricyclic 2‐substituted 4‐alkylamino‐5,6‐dihydro[1]benzoxepino[5,4‐d]pyrimidines and tetracyclic 12‐substituted 1,2,4,5‐tetrahydro[1]benzoxepino[4,5‐e]imidazo[1,2‐c]pyrimidines were synthesized as part of our research to develop new effective antiplatelet drugs. Several alkyl and aryl groups were used as substituents at the 2‐position. Evaluation of the effects of the newly synthesized compounds on collagen‐induced platelet aggregation revealed several promising antiplatelet candidates with potencies superior to aspirin.     

Preparation of substituted 1,3‐dihydro‐2H‐imidazo[4,5‐c]pyridin‐2‐ones

A new synthetic route to 6‐substituted‐imidazo[4,5‐c]pyridin‐2‐ons from 4‐aminopyridine has been investigated. 4‐Aminopyridine protected as alkyl carbamates were nitrated with dinitrogen pentoxide to the corresponding methyl, i‐propyl and t‐butyl 3‐nitropyridin‐4‐yl carbamates ( 5a‐c ) in 51‐63 % yields. Attempts to substitute these in the 6‐position by the ONSH and the VNS techniques succeeded with butyl‐amine and the t‐butyl carbamate 9 . From the methyl or t‐butyl 3‐nitropyridin‐4‐yl carbamates 5a, 5c 1,3‐dihydro‐2H‐imidazo[4,5‐c]pyridin‐2‐one ( 1 ) was formed in 73 and 39 % yields, respectively. t‐Butyl 6‐N‐butylamin‐3‐aminopyridin‐4‐yl carbamate ( 6 ) gave 6‐butylamino‐1,3‐dihydro‐2H‐imidazo[4,5‐c]‐pyridin‐2‐one (7) in 53 % yield.     

One‐Pot Multicomponent Synthesis of Novel Substituted Imidazo[1,2‐a]Pyridine Incorporated Thiazolyl Coumarins and their Antimicrobial Activity

A series of novel substituted imidazo[1,2‐a]pyridine incorporated thiazolyl coumarin derivatives ( 4a , 4b , 4c , 4d , 4e , 4f , 4g , 4h , 4i , 4j , 4k , 4l , 4m , 4n , 4o , 4p , 4q , 4r , 4s , 4t ) were synthesized in good yields via one‐pot multicomponent condensation of substituted imidazo[1,2‐a]pyridine‐3‐carbaldehyde ( 3a , 3b , 3c , 3d , 3e ), thiosemicarbazide ( 2 ), and substituted 3‐(2‐bromoacetyl)‐2H‐chromen‐2‐ones ( 1a , 1b , 1c , 1d )/2‐(2‐bromoacetyl)‐3H‐benzo[f]chromen‐3‐one ( 1e ) in refluxing ethanol with catalytic amount of acetic acid. All the synthesized compounds ( 4a , 4b , 4c , 4d , 4e , 4f , 4g , 4h , 4i , 4j , 4k , 4l , 4m , 4n , 4o , 4p , 4q , 4r , 4s , 4t ) have been characterized by IR, NMR, and mass spectral studies as well as elemental analyses and evaluated for their in vitro antimicrobial activity against different bacterial and fungal strains. All the compounds displayed moderate antibacterial activity with minimum inhibitory concentration 150 µg/mL, but none of the compounds have shown any antifungal activity.     

Vertically π‐Expanded Imidazo[1,2‐a]pyridine: The Missing Link of the Puzzle

The dehydrogenative coupling of imidazo[1,2‐a]pyridine derivative has been achieved for the first time. In cases in which the most‐electron‐rich position of the electron‐excessive heterocycle was blocked by a naphthalen‐1‐yl substituent, neither oxidative aromatic coupling nor reaction under Scholl conditions enabled the fusion of the rings. The only method that converted the substrate into the corresponding imidazo[5,1,2‐de]naphtho[1,8‐ab]quinolizine was coupling in the presence of potassium in anhydrous toluene. Moreover, we discovered new, excellent conditions for this anion‐radical coupling reaction, which employed dry O₂ from the start in the reaction mixture. This method afforded vertically fused imidazo[1,2‐a]pyridine in 63 % yield. Interestingly, whereas the fluorescence quantum yield (Φ_fl) of compound 3 , despite the freedom of rotation, was close to 50 %, the Φ_fl value of flat naphthalene‐imidazo[1,2‐a]pyridine was only 5 %. Detailed analysis of this compound by using DFT calculations and a low‐temperature Shpol′skii matrix revealed phosphorescence emission, thus indicating that efficient intersystem‐crossing from the lowest‐excited S₁ level to the triplet manifold was the competing process with fluorescence.     

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.     

(Hetero)Arylation of 6‐Halogenoimidazo[1,2‐a]pyridines Differently Substituted at C(2): Influence of the 2‐Substituent on the Suzuki Cross‐Coupling Reaction

We previously reported that reactivity towards the Suzuki cross‐coupling reaction of 3‐iodoimidazo[1,2‐a]pyridines substituted at C(2) is largely influenced by the nature of this 2‐substituent. Hence, with the aim to expand the scope of this coupling process to the 6‐position of this series, it seemed important to similarly determine the influence of the nature of the 2‐substituent (H, alkyl, or aryl) on the rate of coupling. From this work, the Suzuki‐type cross‐coupling was shown to proceed efficiently on 6‐bromo‐2‐methyl‐ and 2‐(4‐fluorophenyl)imidazo[1,2‐a]pyridines, whereas the 6‐Br derivative unsubstituted at C(2) appeared to be poorly reactive. By modifying the reaction conditions in terms of catalyst and base, and the nature of the halogen, the reactivity of the unsubstituted series was largely enhanced. Finally, this work led us to establish efficient and convenient Suzuki reaction conditions for the 6‐(hetero)arylation of 6‐halogenoimidazo[1,2‐a]pyridines depending on the nature of the 2‐substituent and boronic acid.     

Synthesis of Novel 1,2,3‐Triazole/Isoxazole‐Functionalized Imidazo[4,5‐b]pyridin‐2(3H)‐one Derivatives,Their Antimicrobial and Anticancer Activity

A series of novel 1,2,3‐triazole/isoxazole‐functionalized imidazo[4,5‐b]pyridine‐2(3H)‐one derivatives 7 and 8 were prepared starting from pyridin‐2(1H)‐one 1 in a series of steps. Initially, compound 1 was converted into imidazo[4,5‐b]pyridine‐2(3H)‐one 5 via formation of 2‐alkylamino/amino‐6‐phenyl‐4‐(trifluoromethyl)nicotinonitrile 3 followed by hydrolysis 4 and Hoffman type rearrangement 5 . Compound 5 was further reacted with propargyl bromide to form exclusively N‐propargylated derivatives 6 . Compounds 6 were cyclized with arylazides/aryloximes in the presence of CuI and sodium hypochlorite, respectively, and obtained title products 7 and 8 . All the final products 7 and 8 were screened for antimicrobial and anticancer activity.     

Synthesis of 6‐Aryl‐4H‐imidazo[1,2‐b][1,2,4]triazoles and 6‐Aryl‐thiazolo[3,2‐b][1,2,4]triazoles

The cyclization of the derivatives of 3‐aminotriazole, 2‐(5‐substituted 4H‐1,2,4‐triazol‐3‐ylamino)‐1‐arylethanones and 2‐(4H‐1,2,4‐triazol‐3‐ylthio)‐1‐arylethanones to yield 6‐aryl‐4H‐imidazo[1,2‐b][1,2,4]triazoles and 6‐aryl‐thiazolo[3,2‐b][1,2,4]triazoles has been described.     

A Convenient and Facile Hantzsch Synthesis of Aryl Imidazo[1,2‐b]Isoxazolyl‐N‐aryl Thiazol Amines

The Hantzsch synthesis of novel aryl imidazo[1,2‐b]isoxazolyl‐N‐aryl thiazol amines 5 analogues were described. Reaction of 3‐aminoisoxazole 1 with substituted phenacyl bromides 2 in dry ethanol afforded the corresponding 6‐methyl‐3‐arylimidazo[1,2‐b]isoxazoles 3 in good yields. Compounds 3 on reaction with chloroacetyl chloride in 1,4‐dioxane furnished the corresponding 2‐chloro‐1‐(6‐methyl‐3‐arylimidazo[1,2‐b]isoxazol‐2‐yl)ethanones 4 . Compounds 4 on heating with N‐aryl thioureas in an oil bath underwent cyclization to afford the title compounds viz., imidazo[1,2‐b]isoxazolyl‐N‐aryl thiazol amines 5 in moderate to good yields by Hantzsch synthesis.     

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.     

Studies with Heterocyclic β‐Enaminoniriles: A Simple Route for the Synthesis of Polyfunctionally Substituted Thiophene,Imidazo[1,2:1′,6′]pyrimido[5,4‐b]thiophene and Thieno[3,2‐d]pyrimidine Derivatives

Reaction of 3,5‐diaminothiophene‐2‐carbonitrile derivatives 3a‐c with ethoxycarbonylmethyl isothiocyanate and/or N‐[bis(methylthio)methylene]glycine ethyl ester led to formation of 7‐substituted‐8‐amino‐5‐thioxo‐6H‐imidazo[1,2:1′,6′]pyrimido[5,4‐b]thiophene‐2(3H)‐one derivatives 6a‐c and 7‐substituted‐8‐amino‐5‐(methylthio)imidazo[1,2:1′,6′]pyrimido[5,4‐b]thiophene‐2(3H)‐one 7a‐c , respectively. Also, the synthetic potential of the β‐enaminonitrile moiety in 3a‐c has been explored; it proved to be a promising candiate for the synthesis of 1,6‐disubstituted‐2,4‐diamino‐7,8‐dihydro‐8‐oxopyrrolo[1,2‐a]thieno[2,3‐e]pyrimidine derivatives 10a‐f and pyrido[2′,3′:6,5]pyrimido[3,4‐a]benzimidazole derivatives 12a,b .     

Selective Synthesis of 1,2‐Diarylpyrrolo[3,4‐b]pyridine‐5,7‐diones via Cyclization Reaction of β‐Enamino Imides with Cinnamaldehydes

The novel 1,2‐diaryl substituted pyrrolo[3,4‐b]pyridine‐5,7‐diones were selectively synthesized in high yields by the base catalyzed cyclization reaction of 3‐arylamino‐1‐methyl‐1H‐pyrrole‐2,5‐diones with cinnamaldehyde and its derivatives in acetonitrile at room temperature. However, when piperidinium trifluoroacetate was employed as catalyst, the reaction afforded a mixture of 1,2‐diaryl and 1,4‐diaryl substituted pyrrolo[3,4‐b]pyridine‐5,7‐diones in comparable yields.     

Synthesis of Novel Imidazo[1,2‐a]pyridin‐2‐amines from Arylamines and Nitriles via Sequential Addition and I2/KI‐Mediated Oxidative Cyclization

A novel and practical strategy for the construction of imidazo[1,2‐a]pyridin‐2‐amine frameworks has been developed. The present sequential approach involves addition of arylamines to nitriles and I₂/KI‐mediated oxidative C?N bond formation without purification of the intermediate amidines. This operationally simple synthetic process provides a facile access to a variety of new 2‐amino substituted imidazo[1,2‐a]pyridines and related heterocyclic compounds in an efficient and scalable fashion.     

Synthesis and Evaluation of Imidazo[1,2‐a]pyridine Analogues of the ZSTK474 Class of Phosphatidylinositol 3‐Kinase Inhibitors

Using a scaffold‐hopping approach, imidazo[1,2‐a]pyridine analogues of the ZSTK474 (benzimidazole) class of phosphatidylinositol 3‐kinase (PI3K) inhibitors have been synthesized for biological evaluation. Compounds were prepared using a heteroaryl Heck reaction procedure, involving the palladium‐catalysed coupling of 2‐(difluoromethyl)imidazo[1,2‐a]pyridines with chloro, iodo or trifluoromethanesulfonyloxy (trifloxy) substituted 1,3,5‐triazines or pyrimidines, with the iodo intermediates being preferred in terms of higher yields and milder reaction conditions. The new compounds maintain the PI3K isoform selectivity of their benzimidazole analogues, but in general show less potency.     

2‐Amino‐8‐(2‐deoxy‐2‐fluoro‐β‐D‐arabinofuranosyl)imidazo[1,2‐a]‐1,3,5‐triazin‐4(8H)‐one: Synthesis and Conformation of a 5‐Aza‐7‐deazaguanine Fluoronucleoside

Nucleobase‐anion glycosylation of 2‐[(2‐methyl‐1‐oxopropyl)amino]imidazo[1,2‐a]‐1,3,5‐triazin‐4(8H)‐one ( 6 ) with 3,5‐di‐O‐benzoyl‐2‐deoxy‐2‐fluoro‐α‐D ‐arabinofuranosyl bromide ( 8 ) furnishes a mixture of the benzoyl‐protected anomeric 2‐amino‐8‐(2‐deoxy‐2‐fluoro‐D ‐arabinofuranosyl)imidazo[1,2‐a]‐1,3,5‐triazin‐4(8H)‐ones 9 / 10 in a ratio of ca. 1 : 1. After deprotection, the inseparable anomeric mixture 3 / 4 was silylated. The obtained 5‐O‐[(1,1‐dimethylethyl)diphenylsilyl] derivatives 11 and 12 were separated and desilylated affording the nucleoside 3 and its α‐D anomer 4 . Similar to 2′‐deoxy‐2′‐fluoroarabinoguanosine, the conformation of the sugar moiety is shifted from S towards N by the fluoro substituent in arabino configuration.