Novel Carbazole‐Based N‐Heterocyclic Carbene Ligands to Access Synthetically Relevant Stilbenes in Pd‐Catalyzed Coupling Processes

A series of new carbazole‐based N‐heterocyclic carbene (NHC) ligands have been synthesized in a simple and facile synthetic route and subsequently used in a Pd/carbazole‐based NHC catalytic system, which was found to be effective in catalyzing Heck reactions to provide substituted stilbene derivatives in good yields. Several bioactive stilbenes, including pterostilbene, pinosylvin, trimethoxy resveratrol, and resveratrol, were synthesized in good yields, and a 10 mmol scale‐up was also performed for trimethoxy resveratrol. The synthetic application was also extended by performing a double‐tandem chemoselective Heck reaction followed by Miyaura borylation in a one‐pot procedure to give single‐step access to synthetically useful stilbenyl boronate esters. Similarly, a unique triple‐tandem protocol of a chemoselective Heck reaction/Miyaura borylation/Suzuki–Miyaura coupling reaction sequence was performed for the one‐pot modification of biologically relevant molecules.     

Pd‐Mediated Multicomponent Synthesis of Highly Functionalized Pyridines and Consequential C—C Coupling Using Suzuki Reaction in One Pot: Their In Vitro Evaluation as Potential Antibacterial Agents

Pd‐mediated construction of pyridine scaffold and subsequent Suzuki‐based C—C coupling reaction in one pot has been accomplished for the synthesis of 4‐biaryl substituted 2‐amino‐3‐cyanopyridines via multicomponent reaction. The present multicomponent reaction is useful in structural elaboration of pyridine framework and also helpful in design and synthesis of novel and diverse analogs of complex heterocyclic compounds other than present reported molecules. Antibacterial activities of the synthesized compounds were systematically evaluated. The correlation between functional group variation and biological activities of the compounds has been evaluated against human pathogenic gram‐positive and gram‐negative bacterial strains.     

Hypervalent Iodine‐Mediated Selective Oxidative Functionalization of (Thio)chromones with Alkanes

C?C bond formation is the most fundamental way for the chain propagation in organic molecules. This achievement through tandem oxidation of two different C?H bonds represents the state of the art in organic synthesis. Selective functionalization of the ubiquitous aliphatic C?H bonds offers an attractive option for this oxidative cross‐coupling methodology. To develop such a methodology under mild and “metal‐free” conditions remains challenging. Herein, we report hypervalent iodine‐mediated selective oxidative functionalization of aliphatic C?H bonds of alkanes with chromones and (thio)chromones. A wide range of alkanes, both cyclic and acyclic, has been found to react selectively and predictably in good yields. The developed methodology is also the first report of a direct oxidative functionalization of the C‐2 position of (thio)chromones with alkanes to access bioactive compounds.     

Palladium‐Catalyzed Ligand‐Free C‐N Coupling Reactions: Selective Diheteroarylation of Amines with 2‐Halobenzimidazoles

2‐Aminobenzimidazoles are widely present in a number of bioactive molecules. Generally, the preparation of these molecules could be realized by the mono‐substitution of 2‐halobenzimidazoles with amines. However, rare examples were reported for the di‐substituted products and the selectivity of mono‐ vs. di‐substitution was relatively low. Considering the potential values of the di‐substituted products, we accomplished the first selective diheteroarylation of amines with 2‐halobenzimidazoles. Notably, this Pd‐catalyzed transformation was realized under ligand‐free conditions. Accordingly, numerous target products were efficiently produced from various aromatic or aliphatic amines and 2‐halobenzimidazoles. It was worth noting that two representative products were further confirmed by X‐ray crystallography. More significantly, this catalytic process could be applied to the synthesis and discovery of new bioactive compounds, which demonstrated the synthetic usefulness of this newly developed approach.     

Synthesis of 2‐Dihydrooxadiazolinyl Chromones

Reactions of the substituted 2‐formyl chromones with aroylhydrazines gave corresponding 2‐(aroylhydrazonomethylidyne) chromones. Then 2‐(3′‐acetyl‐5′‐aryl‐2′,3′‐dihydro‐1′,3′,4′‐oxadiazol‐2′‐yl) chromones were prepared by these 2‐(aroylhydrazonomethylidyne) chromones under refluxing with Ac₂O. All target compounds were characterized through elemental analysis and IR, ¹H NMR, MS.     

The palladium‐catalyzed C‐N cross‐coupling reaction of diheteroaryl disulfides with heterocyclic amines

The Pd‐catalyzed cross‐coupling reaction of 1, 2‐di(pyrimidin‐2‐yl) disulfides with heterocyclic amines including 2‐amino pyrimidines and 1,3,4‐thiadiazol‐2‐amines to deliver symmetrical C‐N coupling products in moderate to good yields is reported. This method provides an opportunity for synthesis of bioactive molecules and pharmaceutically interesting compounds containing heterocycle motifs. The reported protocol shows good functional group compatibility, and provides a new strategy for preparation of C2‐amination pyrimidine derivatives from heterocyclic disulfides.     

Efficient Synthesis of New 2H‐Chromene Retinoids Hybrid Derivatives by Suzuki Cross‐coupling Reactions

In an attempt to improve anticancer activity, a series of retinoids–chromene hybrids was described. The novel heterocyclic chromene–retinoids hybrid including oxygen as a heteroatom in a six‐membered cyclic ring (2H‐chromene or 2H‐1‐benzopyran) was designed and synthesized by introducing different groups such as an aromatic or styrylphenyl ring in 6‐position of 2H‐chromene. These novel compounds were synthesized by using the efficient cascades one‐pot process involving Wittig–Horner–Emmons reaction and Suzuki–Miyaura cross‐coupling pallado‐catalyzed reactions with 60% to 90% overall yields. These new compounds were tested against glioblastoma multiforme brain cancer, medulloblastoma, neuroblastoma cell lines, and breast cancer MCF‐7 cell lines. Two of them exhibited an appreciable anti‐tumor activity in the low micromolar range, which opens new perspectives for therapeutic application on humans.     

A Novel and Facile Synthesis of 2‐(Benzofuran‐2‐yl)benzo[h]quinoline‐3‐carboxylic Acid Derivatives

A simple and concise approach for the synthesis of a series of new heterocyclic systems of 2‐(benzofuran‐2‐yl)benzo[h]quinoline‐3‐carboxylic acid derivatives ( 3a–3g ) is described. The synthetic strategy features the one‐pot reaction of ethyl 2‐(chloromethyl)benzo[h]quinoline‐3‐carboxylate ( 2 ) with various substituted salicylaldehydes as well as 2‐hydroxy‐1‐naphthaldehyde as a key step. The substrate 2 was prepared in good yield by a mild, efficient and direct reaction of 1‐naphthylamine ( 1 ) with Vilsmeier‐Haack reagent. The structures of all the new compounds were identified by spectral data and elemental analysis.     

Palladacyclopentadienyl complexes bearing purine‐based N‐heterocyclic carbenes: A new class of promising antiproliferative agents against human ovarian cancer

A complete protocol for the synthesis of new palladacyclopentadienyl complexes with purine‐based carbenes as supporting ligands is described. The new organometallic compounds were exhaustively characterized using NMR and infrared spectroscopies and elemental analysis. The single‐crystal X‐ray structure of complex 2b coordinating also a triphenylphosphine was resolved. Some of these complexes showed an antiproliferative activity comparable to or better than that of cisplatin on two human ovarian cancer lines: A2780 (cisplatin‐sensitive) and A2780cis (cisplatin‐resistant). Moreover, for complexes 2 and 3 (coordinating one purine‐based N‐heterocyclic carbene ligand and one phosphine) the cytotoxicity is associated with an evident induction of apoptosis. Finally, complexes 3 , bearing one purine‐based N‐heterocyclic carbene ligand and one 1,3,5‐triaza‐7‐phosphaadamantane, proved practically inactive on non‐tumour fibroblast cells (MRC‐5).     

Nonsteroidal anti-inflammatory drugs based new 1,2,3-triazole derivatives: Their design,one-pot synthesis and in vitro evaluation

A series of novel and small molecules containing structural features of some well-known nonsteroidal anti-inflammatory drugs (NSAIDs) such as mefenamic acid or ibuprofen or naproxen and a heterocyclic moiety, for example, benzoxepine or quinoline were designed where a substituted 1,2,3-triazole was used as a linker. These molecules were initially designed as potential antibacterial agents. Synthesis of these compounds was carried out using a Cu-catalyzed azide-alkyne cycloaddition (CuAAC) as the key step to construct the central 1,2,3-triazole ring. The methodology involved regioselective and in situ azide formation from a dichloro derivative of heterocycle followed by click reaction with the appropriate alkyne containing the NSAID framework in the same pot. This one-pot sequential reaction afforded 24 target compounds in good yields. To assess their antibacterial properties, all the synthesized compounds were tested against both Gram-positive and Gram-negative species bacterial strains. One compound was found to be effective against the Gram-negative species P. aeruginosa. This compound also showed selective cytotoxicity against two cancer cell lines (COLO-205 and HOP-62) but no significant effect against noncancerous cell line (HEK293).     

The reaction of heteroaroyl‐substituted heterocyclic ketene aminals with 2,3,4,6‐tetra‐O‐acetyl‐β‐D‐glucopyranosyl azide

The reaction of heteroaroyl‐substituted heterocyclic ketene aminals with 2,3,4,6‐tetra‐O‐acetyl‐β‐D ‐glucopyranosyl azide was investigated and a series of potential bioactive compounds, 1‐glucopyranosyl‐4‐heterocyclic‐5‐heteroaryl‐1,2,3‐triazoles, were obtained in good yields. Both the reaction rate and the yield were strongly affected by the heteroaryl and heterocyclic groups. In order to improve their water solubility, the deprotection of 1‐glucopyranosyl‐4‐heterocyclic‐5‐heteroaryl‐1,2,3‐triazole was carried out. © 2002 Wiley Periodicals, Inc. Heteroatom Chem 13:242–247, 2002; Published online in Wiley Interscience (www.interscience.wiley.com). DOI 10.1002/hc.10023     

Synthesis and Characterization of 2‐Pyridylsulfur Pentafluorides

Current approaches to prepare SF₅‐substituted heterocycles during the synthesis of targeted heterocyclic compounds require the use of SF₅‐functionalized aryl or alkyne reagents or SF₅Cl as a source of the SF₅ functional group. Herein we report that excess oxidative fluorination of 2,2′‐dipyridyl disulfide with a KF/Cl₂/MeCN system leads to the formation of thirteen new 2‐pyridylsulfur chlorotetrafluorides (2‐SF₄Cl‐pyridines). These molecules are found to undergo further chlorine–fluorine exchange reactions by treatment with silver(I) fluoride enabling ready access to a series of ten new substituted 2‐pyridylsulfur pentafluorides (2‐SF₅‐pyridines). This is the first preparatively simple and readily scalable example of the transformation of an existing heterocyclic sulfur functionality to prepare SF₅‐substituted heterocycles.     

Synthesis of 2-(4-Quinolyl) and 2-(3-Quinolyl) Chromone Derivatives

In continuing search of the structure-activity relationship of heterocyclic chromones, 4-quinolyl and 3-quinolyl moieties were each introduced to the C-2 position of chromones. A total of 12 quinolyl chromones were synthesized. 4-Quinolinecarboxaldehyde was condensed with 2-hydroxyacetophenones to provide the chalcones. These intermediates were then subjected to selenium dioxide dehydrogenation to yield the 6 new 4-quinolyl chromones. 3-Quinolinecarboxaldehyde was condensed with 2-hydroxyacetophenones in the presence of dilute alkali to give aldol compounds of chalcones (dehydration products of aldols). Ring cyclization of the chalcones yielded the other 6 new 3-quinolyl chromones.     

Investigation of the Reaction between 3‐Benzisothiazolones,an Isoindole Isoster and Activated Acetylenes: Synthesis of Heterocyclic Backbones for Building Bioactive Molecules

Investigation of the reaction between benzo[d]isothiazol‐3‐one, 2‐aminobenzo[d]isothiazol‐3‐one, its isoster 2‐aminoisoindolin‐1‐one, and activated acetylenes, in the presence of triphenylphosphine, led us to synthesize novel heterocyclic compounds that could be attractive for the building of biologically active molecules. A one‐pot PPh₃‐promoted tandem reaction, with acetylene dicarboxylates and dibenzoylacetylene, afforded new tricyclic pyrazolo‐fused benzisothiazoles. The PPh₃‐promoted reaction between benzisothiazolones and methyl propiolate afforded 1,4‐benzothiazepine‐5‐one derivatives, via an isothiazole ring expansion. These studies are providing additional insights in benzisothiazolone chemistry and describe simple and original synthetic accesses to novel derivatives.     

Cu‐Catalyzed Aerobic Oxidative Cyclizations of 3‐N‐Hydroxyamino‐1,2‐propadienes with Alcohols,Thiols, and Amines To Form α‐O‐, S‐, and N‐Substituted 4‐Methylquinoline Derivatives

A one‐pot, two‐step synthesis of α‐O‐, S‐, and N‐substituted 4‐methylquinoline derivatives through Cu‐catalyzed aerobic oxidations of N‐hydroxyaminoallenes with alcohols, thiols, and amines is described. This reaction sequence involves an initial oxidation of N‐hydroxyaminoallenes with NuH (Nu=OH, OR, NHR, and SR) to form 3‐substituted 2‐en‐1‐ones, followed by Brønsted acid catalyzed intramolecular cyclizations of the resulting products. Our mechanistic analysis suggests that the reactions proceed through a radical‐type mechanism rather than a typical nitrone‐intermediate route. The utility of this new Cu‐catalyzed reaction is shown by its applicability to the synthesis of several 2‐amino‐4‐methylquinoline derivatives, which are known to be key precursors to several bioactive molecules.     

An Efficient Amide‐Aldehyde‐Alkene Condensation: Synthesis for the N‐Allyl Amides

The allylamine skeleton represents a significant class of biologically active nitrogen compounds that are found in various natural products and drugs with well‐recognized pharmacological properties. In this personal account, we will briefly discuss the synthesis of allylamine skeletons. We will focus on showing a general protocol for Lewis acid‐catalyzed N‐allylation of electron‐poor N‐heterocyclic amides and sulfonamide via an amide‐aldehyde‐alkene condensation reaction. The substrate scope with respect to N‐heterocyclic amides, aldehydes, and alkenes will be discussed. This method is also capable of preparing the Naftifine motif from N‐methyl‐1‐naphthamide or methyl (naphthalene‐1‐ylmethyl)carbamate, with paraformaldehyde and styrene in a one‐pot manner.     

A Novel Ionic Liquid Based on Imidazolium Cation as an Efficient and Reusable Catalyst for the One‐pot Synthesis of Benzoxazoles,Benzthiazoles, Benzimidazoles and 2‐Arylsubstituted Benzimidazoles

A novel dicationic ionic liquid based on imidazolium cation is designed, synthesized and successfully used as catalyst for the one‐pot synthesis of benzoxazoles, benzthiazoles, benzimidazoles and 2‐arylsubstituted benzimidazoles. The remarkable feature of this new catalyst is its ethyleneoxy bridge which participates in dissolving organic compound in ionic liquid. The application of this ionic liquid is studied in a new one‐pot method for synthesis of heterocyclic compounds under solvent‐free conditions. Simple and convenient procedure, high conversion, reusability of catalyst, easy purification and shorter reaction time are the advantageous features of this method.     

Coumarin‐tethered (benz)imidazolium salts and their silver(I) N‐heterocyclic carbene complexes: Synthesis,characterization, crystal structure and antibacterial studies

A series of new sterically modulated chlorocoumarin‐substituted (benz)imidazolium salts and their bis‐N‐heterocyclic carbene silver(I) complexes were prepared and characterized. The complexes were prepared in good yields following the in situ deprotonation method by treating azolium salts with silver(I) oxide in the dark. All the compounds were characterized using various spectroscopic and analytical methods. Additionally, one of the benzimidazolium salts was characterized using single‐crystal X‐ray diffraction technique. In this salt, intermolecular π–π stacking interactions operate between benzimidazole as well as coumarin heterocyclic systems with adjacent molecules. In the preliminary antibacterial studies, the silver complexes were found more active than the corresponding salts against a panel of bacterial strains. Interestingly, the complexes displayed improved antibacterial efficacy against Escherichia coli strain, comparable with that of the standard drug ampicillin.     

Aerobic Double Dehydrogenative Cross Coupling between Cyclic Saturated Ketones and Simple Arenes

The synthesis of 3‐aryl‐2‐cyclohexenones is a topic of current interest as they are not only privileged structures in bioactive molecules, but they are also relevant feedstocks for the synthesis of substituted phenols or anilines, which are ubiquitous structural elements both in drug design and medicinal chemistry. A simple and sustainable one‐pot aerobic double dehydrogenative reaction under mild conditions for the introduction of arenes in the β‐position of cyclic ketones has been developed. Starting from the corresponding saturated ketone, this reaction sequence proceeds under relatively low Pd catalyst loading and involves catalytic amounts of electron‐transfer mediators (ETMs) under ambient oxygen pressure.