Strategies for Synthesis of Imidazo[1,2‐a]pyridine Derivatives: Carbene Transformations or C−H Functionalizations

The imidazo[1,2‐a]pyridines are an important target in organic synthetic chemistry and have attracted critical attention of chemists mainly due to the discovery of the interesting properties exhibited by a great number of imidazo[1,2‐a]pyridine derivatives. Although lots of synthetic methods of imidazo[1,2‐a]pyridines have been developed in the past years, the chemistry community faces continuing challenges to use green reagents, maximize atom economy and enrich the functional group diversity of product. Undoubtedly, with its low cost and lack of environmentally hazardous byproducts, cascade reactions and C?H functionalizations are ideal strategies for this field. In this record we highlight some of our progress toward the goal to synthesis of imidazo[1,2‐a]pyridine derivatives through carbene transformations or C?H functionalizations.     

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.     

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.     

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 of 2‐imino‐7‐methyl‐2,3‐dihydroimidazo[1,2‐a]‐pyrimidin‐5(1H)‐ones and their reactions with nucleophiles

[2‐Alkylthio‐6‐methyl‐4‐oxopyrimidin‐3(4H)‐yl]acetonitriles ( 3‐5 ) treated with sodium methoxide in methanol followed by ammonium chloride were cyclized to 2‐imino‐7‐methyl‐2,3‐dihydroimidazo[1,2‐a]‐pyrimidin‐5(1H)‐ones ( 6‐8 ). Under acid or base‐catalyzed hydrolysis they were converted to 7‐methyl‐imidazo[1,2‐a]pyrimidine‐2,5‐[1H,3H]‐diones ( 9‐11 ), whereas in the reaction with butyl‐ or benzylamine the corresponding 7‐methyl‐2‐(substitutedamino)imidazo[1,2‐a]pyrimidin‐5(3H)‐ones ( 13‐18 ) were produced. The latter were found to exist in two tautomeric forms in CDCl₃ solution.     

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.     

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.     

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).     

Fused Heterocycles: Synthesis and Antitubercular Activity of Novel 6‐Substituted‐2‐(4‐methyl‐2‐substituted phenylthiazol‐5‐yl)H‐imidazo[1,2‐a]pyridine

A series of 6‐substituted‐2‐(4‐methyl‐2‐substituted phenylthiazol‐5‐yl)H‐imidazo[1,2‐a]pyridine derivatives 4a , 4b , 4c , 4d , 4e , 4f , 4g , 4h , 4i , 4j , 4k , 4l is described. The antitubercular activity of the synthesized compounds was determined against Mycobacterium smegmatis MC² 155 strain. From the activity result, it was found that the phenyl or 4‐fluorophenyl group at 2 position of thiazole nucleus and bromo substituent at 6 position of imidazo[1,2‐a]pyridine showed good antitubercular activity.     

Metalation and halogen‐metal exchange in the imidazo[1,2‐a]quinoxaline series

The n‐butyllithium and lithium 2,2,6,6‐tetramethylpiperidide metalation and the halogen‐metal exchange of imidazo[1,2‐a]quinoxaline derivatives followed by quenching with various electrophiles were studied. The reaction conditions have been optimized and various C₁ substituted imidazo[1,2‐a]quinoxalines were obtained in high yields.     

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.     

One‐pot Sequential Reactions Featuring a Copper‐catalyzed Amination Leading to Pyrido[2′,1′:2,3]imidazo[4,5‐c]quinolines and Dihydropyrido[2′,1′:2,3]imidazo[4,5‐c]quinolines

Tetracyclic skeletons combining an imidazo[1,2‐a]pyridine moiety with a quinoline framework such as pyrido[2′,1′:2,3]imidazo[4,5‐b]quinoline are stimulating increasing interests since they are close isosteres of a series of powerful antiproliferative compounds. In this paper, we report a novel methodology for the synthesis of pyrido[2′,1′:2,3]imidazo[4,5‐c]quinolines through one‐pot sequential reactions of commercially available or readily obtainable 2‐aminopyridines, 2‐bromophenacyl bromides, aqueous ammonia, and aldehydes. Moreover, dihydropyrido[2′,1′:2,3]imidazo[4,5‐c]quinolines could also be obtained in a similar manner by using various ketones as the substrates in place of aldehydes. Notably, the whole procedure combines condensation/amination/cyclization reactions in one pot to give complex compounds in a simple and practical manner. Compared with literature methods, the synthetic strategy reported herein has the advantages of readily available starting materials, structural diversity of products, good functional group tolerance, and obviation of step‐by‐step operations.     

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.     

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.     

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.     

One‐pot Combinatorial Synthesis of Benzo[4,5]imidazo‐[1,2‐a]thiopyrano[3,4‐d]pyrimidin‐4(3H)‐one Derivatives

A series of novel fused tetracyclic benzo[4,5]imidazo[1,2‐a]thiopyrano[3,4‐d]pyrimidin‐4(3H)‐one derivatives were synthesized via the reaction of aryl aldehyde, 2H‐thiopyran‐3,5(4H,6H)‐dione, and 1H‐benzo[d]imidazol‐2‐amine in glacial acetic acid. This protocol features mild reaction conditions, high yields and short reaction time.     

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 pyrazolo[1,5‐a]‐, 1,2,4‐triazolo[1,5‐a]‐ and imidazo[1,2‐a]pyrimidines related to zaleplon,a new drug for the treatment of insomnia

This paper describes the preparation of some pyrazolo[1,5‐a]‐, 1,2,4‐triazolo[1,5‐a]‐ and imidazo[1,2‐a]‐pyrimidines substituted on the pyrimidine moiety by a 4‐[(N‐acetyl‐N‐ethyl)amino]phenyl group. A new synthesis of related benzo[h]pyrazolo[1,5‐a]‐, benzo[h]pyrazolo[5,1‐b]‐ and benzo[h]1,2,4‐triazolo[1,5‐a]‐quinazolines is also reported.     

An approach to novel fused triazole or tetrazole derivatives starting from benzimidazo[1,2‐a]quinazoline‐5(7H)‐one and 5,7‐dihydro‐5‐oxopyrido[3′,2′:5,6]pyrimido[1,2‐a]benzimidazole

The synthetic potential of the title compounds benzimidazo[1,2‐a]quinazoline‐5(7H)‐one 2a and 5,7‐dihydro‐5‐oxopyrido[3′,2′:5,6]pyrimido[1,2‐a]benzimidazole 2b for the construction of novel polyhetero‐cyclic frameworks is reported. Compounds 2a,b , by conversion into their thio analogues 3a,b , were used for the synthesis of tetrazole ( 5a,b ) and triazole ( 7a,b ) derivatives, as well as for an unexpected synthesis of tri‐azoles 8a,b , isomers of 7a,b , resulting from the occurrence of a Dimroth rearrangement.     

Recent Advances in Imidazo[5,1‐f][1,2,4]triazin‐4(3H)‐ones Chemistry: An Overview of the Synthetic Routes to Vardenafil and Its Analogues

The biological and medicinal properties of imidazo[5,1‐f][1,2,4]triazin‐4(3H)‐ones and its analogues have prompted enormous research aimed at developing synthetic routes to these heterocycles. This review focuses on the chemical properties associated with these systems.