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.     

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.     

Iodobenzene‐Catalyzed Synthesis of Imidazo[1,2‐a]pyridines from Aryl Ketones with mCPBA in Ionic Liquid

Iodobenzene‐catalyzed synthesis of imidazo[1,2‐a]pyridines from aryl ketones with mCPBA as a cooxidant in ionic liquid is described. The method is simple, rapid and practical, generating Imidazo[1,2‐a]pyridines from the aryl ketone without isolation of α‐tosyloxyketones in good to excellent 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.     

Copper‐Promoted Annulation of Terminal Alkynes with 2‐Aminopyridines to Assemble 2‐Halogenated Imidazo[1,2‐a]pyridines

Copper‐promoted annulation reactions of terminal alkynes with 2‐aminopyridines have been developed for the synthesis of 2‐halogenated imidazo[1,2‐a]pyridines using copper halide as the halogen source. A variety of substrates survived under the reaction conditions and gave the desired products in good yields. This reaction features advantages such as easily available starting materials, broad substrate scope, and mild reaction conditions.     

A Facile One‐pot Synthesis of Highly Functionalized Isoxazolyl Imidazo[1,2‐a] Pyridines Through CuI‐Promoted Cyclization

A copper iodide‐promoted cyclization for the synthesis of isoxazolyl imidazo[1,2‐a] pyridines 3a , 3b , 3c , 3d , 3e , 3f , 3g , 3h , 3i , 3j in a one‐pot procedure has been investigated by interaction of 2‐aminopyridines 1a , 1b , 1c , 1d , 1e with nitrostyrylisoxazoles 2a , 2b , 2c , 2d , 2e , 2f under aerial oxidation condition. Similarly, the one‐pot reaction of 2‐amino pyridines 1a , 1b , 1c , 1d , 1e with 4‐bromonitrostyrylisoxazole 2d in the presence of copper iodide under aerial oxidation condition, followed by reaction with phenyl acetylenes in situ afforded highly functionalized imidazo[1,2‐a]pyridines 10a , 10b , 10c , 10d , 10e , 10f , 10g , 10h , 10i , 10j by the Sonogashira coupling.     

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.     

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).     

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.     

Bright,Fluorescent Dyes Based on Imidazo[1,2‐a]pyridines that are Capable of Two‐Photon Absorption

A library of imidazo[1,2‐a]pyridines was synthesized by using the Gevorgyan method and their linear and non‐linear optical properties were studied. Derivatives that contained both electron‐donating and electron‐withdrawing groups at the 2 position were comprehensively investigated. Their emission quantum yield ranged between 0.2–0.7 and it was shown to depend on the substitution pattern, most notably that on the phenyl ring. Electron‐donating substituents improved the luminescence performance of these compounds, whereas electron‐withdrawing substituents led to a more erratic behavior. Substitution on the six‐membered ring had less effect on the fluorescence properties. Extension of the delocalization increased the luminescence quantum yield. A new quadrupolar system was designed that contained two imidazo[1,2‐a]pyridine units on its periphery and a 1,4‐dicyanobenzene unit at its center. This system exhibited a large Stokes‐shifted luminescence that was affected by the polarity and rigidity of the solvent, which was ascribed to emission from an excited state with strong charge‐transfer character. This quadrupolar feature also led to an acceptable two‐photon absorption response in the NIR region.     

An Efficient One‐Pot Four‐Component Synthesis of Functionalized Imidazo[1,2‐a]pyridines

An efficient one‐pot four‐component protocol for the synthesis of imidazo[1,2‐a]pyridines was developed by condensing ethane‐1,2‐diamine ( 2 ), 1,1‐bis(methylthio)‐2‐nitroethene ( 1 ), aldehydes 3 , and activated methylene compounds in EtOH under reflux conditions (Tables 1–3). The features of this procedure are operational simplicity, good yields of products, in situ preparation of heterocyclic ketene aminals (HKA), and catalyst‐free conditions.     

Synthesis of Imidazo[1,2‐a]pyridines: C‐H Functionalization in the Direction of C‐S Bond Formation

Imidazo[1,2‐a]pyridines play an important role in medicinal chemistry. In spite of very drastic developments on syntheses and functionalization in this area, the use of inexpensive catalysts and mild reaction conditions constitutes an important role in pharmaceutical applications. This account describes our recent efforts on the development of new methods for the synthesis of imidazo[1,2‐a]pyridines using readily available starting substrates and catalysts under very mild reaction conditions. In the direction of enhancement of biological activity, we also described the synthesis of functionalized imidazo [1,2‐a]pyridine derivatives.     

Heterocyclization reaction of 2‐(2‐methylaziridin‐1‐yl)‐3‐ureidopyridines under appel's conditions

The reaction of 2‐(2‐methylaziridin‐1‐yl)‐3‐ureidopyridines 12 with triphenylphosphine, carbon tetra‐chloride, and triethylamine (Appel's conditions) led to the corresponding carbodiimides 13 , which underwent intramolecular cycloaddition reaction with aziridine under the reaction conditions to give the pyridine‐fused heterocycles, 2,3‐dihydro‐1H‐imidazo[2′,3′:2,3]imidazo[4,5‐b]pyridines 16 and 12,13‐dihydro‐5H‐1,3 ‐benzodiazepino [2′,3′:2,3] imidazo[4,5‐b]pyridines 17 .     

(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.     

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.     

Recent synthetic scenario on imidazo[1,2-<Emphasis Type="Italic">a</Emphasis>]pyridines chemical intermediate

Of the biologically important benzene fused heterocycles, the most important are those containing a ring-junction nitrogen. The majority of ring junction systems do not occur naturally, but they have been important from a theoretical viewpoint, for preparation of potentially active analogues. The imidazo[1,2-a] pyridines are an important class of nitrogen ring junction heterocyclic compounds. They have huge applications in medicinal chemistry and drug molecule production. Thus, the initial discussion focuses on synthetic strategies of imidazo[1,2-a] pyridines, and later we disclose the reactivity of the imidazo[1,2-a]pyridines. This review is intended to summarize and discuss the most recent developments of synthesis and reactivity of imidazo[1,2-a]pyridines, mainly the contributions after 2007.     

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.     

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.     

One-pot,three-component synthesis of 1-amidomethyl-imidazo[1,2-a]pyridines catalyzed by ytterbium triflate

A straightforward method has been developed for the synthesis of 1-amidomethyl-imidazo[1,2-a]pyridines by Yb(OTf)₃ catalyzed three-component reaction of aldehydes, acetamide, and imidazo[1,2-a]pyridines. A series of substituted 3-substituted imidazo[1,2-a]pyridines were synthesized in moderate to good yield (21–74%) under mild reaction condition and the catalyst was recycled for four cycles.     

Diversity-Oriented Synthesis of [2.2]Paracyclophane-derived Fused Imidazo[1,2-a]heterocycles by Groebke-Blackburn-Bienaymé Reaction: Accessing Cyclophanyl Imidazole Ligands Library

This report describes the synthesis of a [2.2]paracyclophane-derived annulated 3-amino-imidazole ligand library through a Groebke-Blackburn-Bienaymé three-component reaction (GBB-3CR) approach employing formyl-cyclophanes in combination with diverse aliphatic and aromatic isocyanides and heteroaromatic amidines. The GBB-3CR process gives access to skeletally-diverse cyclophanyl imidazole ligands, namely 3-amino-imidazo[1,2-a]pyridines and imidazo[1,2-a]pyrazines. Additionally, a one-pot protocol for the GBB-3CR by an in situ generation of cyclophanyl isocyanide is demonstrated. The products were analyzed by detailed spectroscopic techniques, and the cyclophanyl imidazo[1,2-a]pyridine was confirmed unambiguously by single-crystal X-Ray crystallography. The cyclophanyl imidazole ligands can be readily transformed to showcase their useful utility in preparing N,C-palladacycles through regioselective ortho-palladation.