Concise and diversity-oriented synthesis of novel scaffolds embedded with privileged benzopyran motif

A branching DOS strategy for an unbiased natural product-like library with embedded privileged benzopyran motif was established to provide complexity and diversity of resulting heterocycles with desired drug-likeness. The importance of skeletal diversity conducted on a privileged substructure was demonstrated through the biological evaluation of a small molecule library representing 22 unique core skeletons via in vitro cytotoxicity assay.     

Cascade synthesis with (triphenylphosphoranylidene)-ethenone as a versatile reagent for fast synthesis of heterocycles and unsaturated amides under microwave dielectric heating

A general procedure for the synthesis of a large variety of compounds comprising an alpha, beta,-unsaturated carbonyl functionality was developed. The use of one-pot cascade synthesis with (triphenylphosphora-nylidene)ethenone as a versatile reagent for various formations including heterocycles of different ring sizes and unsaturated amides in combination with microwave dielectric heating is described. The method was used to synthesize a small library of unsaturated amides.     

Preparation of 6-substituted quinoxaline JSP-1 inhibitors by microwave accelerated nucleophilic substitution

A small library of 6-aminoquinoxalines has been prepared by nucleophilic substitution of 6-fluoroquinoxaline with amines and nitrogen-containing heterocycles under computer-controlled microwave irradiation. Some compounds were found to be potent inhibitors of JNK Stimulatory Phosphatase-1 (JSP-1) in an in vitro biological assay.     

Sequential Ugi/Heck cyclization strategies for the facile construction of highly functionalized N-heterocyclic scaffolds

A new strategy employing an Ugi four-component reaction and a microwave-assisted intramolecular Heck cyclization in a sequential fashion to access an array of N-containing heterocycles is reported. The two-step sequence generated compounds of significant molecular complexity from trivial starting materials in an expedient fashion with excellent yields. The route was also amenable to solid-phase chemistry demonstrating potential for library generation.     

Parallel solution-phase synthesis of acrylonitrile scaffolds carrying L-alpha-amino acidic or D-glycosyl residues

A practical and straightforward protocol for the preparation of a solution-phase library of acrylonitrile scaffolds is reported. Target compounds were obtained in high yield, stereoselectivity, and purity by two simple and practical steps from cyanoacetic acid. Moreover, our study proposes a synthetic approach starting from the constructed library to obtain three-membered heterocycles.     

One‐Step Synthetic Access to Isosteric and Potent Anticancer Nitrogen Heterocycles with the Benzo[c]phenanthridine Scaffold

A versatile one‐step two‐component cyclization to build new tetracyclic nitrogen heterocycles is described. Ortho‐methylhetarenecarbonitrile components were condensed with aldehydes to access a large library of differently substituted ring systems. The heterocyclic core can be easily modified by variation of the position of the endocyclic nitrogen atom in the o‐methylhetarenecarbonitrile substrate. The manner of the nucleophilic attack that leads to the condensation can be triggered by different electron‐density distribution in the molecule induced by the position of the nitrogen atom. Taking this into account, there is an electronic preference that leads to either pyridophenanthrolines or the corresponding pyridoazacarbazoles as the main products. We demonstrate the high antitumor potential of some of our synthesized heterocycles, which is strongly dependent on the substitution pattern introduced through the aldehyde component. The position and number of endocyclic nitrogen atoms play an important role regarding cytotoxicity of the studied compounds.     

Supported TBD-assisted solution phase diversification of formyl-aza-heterocycles through alkylation-knoevenagel one pot sequences

An efficient solution-phase parallel procedure to perform the structural diversification of some formyl-nitrogen heterocycles (A) using the reusable TBD supported base is described. The library synthesis is based in a consecutive Alkylation-Knoevenagel functionalisation that uses alkyl halides (B), Michael acceptors (C) and activated methylene compounds (D) as diversity elements.     

Ruthenium-catalyzed enantioselective carbon-carbon bond forming reaction via allenylidene-ene process: synthetic approach to chiral heterocycles such as chromane, thiochromane, and 1,2,3,4-tetrahydroquinoline derivatives

Our previously disclosed ruthenium-catalyzed carbon-carbon bond forming reactions between propargylic alcohols and alkenes via an allenylidene-ene type pathway have been successfully applied to an enantioselective intramolecular cyclization for a variety of chiral heterocycles such as chromane, thiochromane, and 1,2,3,4-tetrahydroquinoline derivatives (up to 99% ee) by use of a suitable optically active diruthenium complex as a catalyst. The methodology described in this paper becomes a novel synthetic approach to chiral heterocycles, the structures of which are widely found in many natural and biologically active compounds.     

Solid-phase synthesis of tetrasubstituted pyrazoles, novel ligands for the estrogen receptor

Most ligands for the estrogen receptor (ER) are not well suited for synthesis by combinatorial means, because their construction involves a series of carbon-carbon bond forming reactions that are not uniformly high yielding. In previous work directed to overcoming this limitation, we surveyed various phenol-substituted five-membered heterocycles, hoping to find a system that would afford both high ER binding affinity and whose synthesis could be adapted to solid-phase methods (Fink et al. Chem. Biol. 1999, 6, 206-219.) In this report, we have developed a reliable and efficient solid-phase method to prepare the best of these heterocycles, the tetrasubstituted pyrazoles, and we have used this methodology to produce small, discrete libraries of these novel ER ligands. We used a combination of FT-IR and nanoprobe (1)H NMR-MAS to characterize intermediates leading up to the final pyrazole products directly on the bead. We also developed a scavenging resin, which enabled us to obtain products free from inorganic contaminants. We prepared a 12-member test library, and then a 96-member library, and in both cases we determined product purity and ER binding affinity of all of the library members. Several interesting binding affinity patterns have emerged from these studies, and they have provided us with new directions for further exploration, which has led to pyrazoles having high affinity and potency as agonists and antagonists toward the ER alpha subtype.     

TiO2 band shift by nitrogen-containing heterocycles in dye-sensitized solar cells: a periodic density functional theory study

A density functional theory (DFT) method (periodic DMol3) with full geometry optimization was used to study the adsorption of nitrogen-containing heterocycles such as pyrazole, imidazole, 1,2,4-triazole, pyridine, pyrimidine, pyrazine, and 4-t-butylpyridine (TBP) on TiO2 anatase (101), (100), and (001) surfaces. All structures displayed a negative shift in the TiO2 Fermi level upon adsorption of N-containing heterocycles. Additionally, the heterocycles were examined as an additive in an I-/I3- redox electrolyte solution of dye-sensitized TiO2 solar cell. The DFT results indicated that the negative shift of TiO2 Fermi level was due to the adsorbate dipole moment component normal to the TiO2 surface plane, and corresponded to the enhanced open-circuit photovoltage (Voc) and the reduced short-circuit photocurrent density (Jsc) in a dye-sensitized solar cell.     

Azides in the Synthesis of Various Heterocycles

In this review, we focus on some interesting and recent examples of various applications of organic azides such as their intermolecular or intramolecular, under thermal, catalyzed, or noncatalyzed reaction conditions. The aforementioned reactions in the aim to prepare basic five-, six-, organometallic heterocyclic-membered systems and/or their fused analogs. This review article also provides a report on the developed methods describing the synthesis of various heterocycles from organic azides, especially those reported in recent papers (till 2020). At the outset, this review groups the synthetic methods of organic azides into different categories. Secondly, the review deals with the functionality of the azido group in chemical reactions. This is followed by a major section on the following: (1) the synthetic tools of various heterocycles from the corresponding organic azides by one-pot domino reaction; (2) the utility of the chosen catalysts in the chemoselectivity favoring C−H and C-N bonds; (3) one-pot procedures (i.e., Ugi four-component reaction); (4) nucleophilic addition, such as Aza-Michael addition; (5) cycloaddition reactions, such as [3+2] cycloaddition; (6) mixed addition/cyclization/oxygen; and (7) insertion reaction of C-H amination. The review also includes the synthetic procedures of fused heterocycles, such as quinazoline derivatives and organometal heterocycles (i.e., phosphorus-, boron- and aluminum-containing heterocycles). Due to many references that have dealt with the reactions of azides in heterocyclic synthesis (currently more than 32,000), we selected according to generality and timeliness. This is considered a recent review that focuses on selected interesting examples of various heterocycles from the mechanistic aspects of organic azides.     

Strained heterocycles in radical chemistry

Over the last few decades the use of radicals in synthesis has witnessed an explosive growth through introduction of efficient chain and electron-transfer reactions. Strained heterocycles, in particular, have emerged as a highly versatile and readily available class of radical precursors. The generation of carbinyl radicals of heterocycles has resulted in many elegant applications of heteroatom-centered radicals, such as beta fragmentations, cyclizations, and intramolecular hydrogen atom abstractions. Direct electron transfer to strained heterocycles has been realized through the use of arene radical anions. The method combines the virtues of radical and organometallic chemistry to yield useful functionalized organolithium compounds. Epoxides have been opened with high regioselectivity by titanocene(III) reagents in either stoichiometric or catalytic quantities to yield beta-titanoxy radicals. This development has resulted in many new applications in natural product synthesis.     

Sodium Phosphaethynolate as a Building Block for Heterocycles

Phosphorus‐containing heterocycles have evolved from laboratory curiosities to functional components, such as ligands in catalytically active metal complexes or molecular constituents in electronic devices. The straightforward synthesis of functionalized heterocycles on a larger scale remains a challenge. Herein, we report the use of the phosphaethynolate (OCP)^? anion as a building block for various sterically unprotected and functionalized hydroxy substituted phosphorus heterocycles. Because the resulting heterocycles are themselves anions, they are building blocks in their own right and allow further facile functionalization. This property may be of interest in coordination chemistry and material science.     

Synthetic Routes to Selected Heterocycles Containing Antipyrine Moiety

This review deals with the synthetic potentiality and utility of antipyrine and its derivatives in the synthesis of 4‐substituted antipyrine and other heterocycles containing antipyrine moiety such as thiazole, pyrazolopyridines, pyrazolopyrimidines, and pyrazolotriazines. The reactions that cover the methods of synthesizing the aforementioned heterocycles such as addition, condensation, and cyclization were also reviewed.     

Solid-phase parallel synthesis of natural product-like diaza-bridged heterocycles through Pictet-Spengler intramolecular cyclization

A multistep, practical solid-phase strategy for the synthesis of natural product-like diaza-bridged heterocycles was developed. A key step in the library synthesis is tandem acidolytic cleavage with subsequent in situ iminium formation followed by the Pictet-Spengler intramolecular cyclization. The Pictet-Spengler-type intramolecular cyclization step was regioselective and diastereoselective to give final products as single diastereomers in exceptional yields and purities, which was confirmed by NMR structural study and LC/MS analysis. This approach is exemplified by the preparation of a 384-member library of 3,9-diazabicyclo[3.3.1]non-6-en-2-one skeletons, fused with indole and dihydroxybenzene and diversified at two bridging nitrogen atoms, using the solid-phase parallel synthetic methodology without further purification. In this pilot library, two diastereomerically enriched diaza-bridged core skeletons were modified by amide and urea bond formation on bridging nitrogen atoms, and this scheme exhibits the potential for expansion to obtain further diversification.     

Hybrid hetarylhydrazones and enamines of Furan-2(3H)-ones as a framework for the synthesis of poly-N-heterocycles

Substituted furan-2(3H)-ones can act as platform compounds to obtain easily various functionalized derivatives as well as heterocycles with different heteroatoms patterns. In this study, we suppose a simple and effective way to reach poly-N-heterocycles using a set of hybrid hetarylhydrazones and enamines based on furan-2(3H)-ones as a starting material. The presence of a few reaction centers in these the hybrid furan-2(3H)-one derivatives allows them to undergo some intramolecular rearrengements with opening furan ring as well as with keeping it unaffected followed by the increase of complexity of the resulting heterocycles, depending on reaction conditions. It was found that the reaction conditions and the nature of the substituents in the hydrazone fragment affect the direction of the interaction and the nature of the resulting products. Different approaches form a framework which allowed us to create a library of substituted annelated poly-N-heterocycles with highly prominent biological effects. Analysis of the possible biological effects was performed in silico which allows us to reveal leading structures among all synthesized compounds.     

Aqueous N-heterocyclization of primary amines and hydrazines with dihalides: microwave-assisted syntheses of N-azacycloalkanes, isoindole, pyrazole, pyrazolidine, and phthalazine derivatives

[reactions: see text] The synthesis of nitrogen-containing heterocycles from alkyl dihalides (ditosylates) and primary amines and hydrazines via a simple and efficient cyclocondensation in an alkaline aqueous medium that occurs under microwave irradiation is described. This improved greener synthetic methodology provides a simple and straightforward one-pot approach to the synthesis of a variety of heterocycles, such as substituted azetidines, pyrrolidines, piperidines, azepanes, N-substituted 2,3-dihydro-1H-isoindoles, 4,5-dihydropyrazoles, pyrazolidines, and 1,2-dihydrophthalazines.     

Cocondensation reactions of nitrogen-containing heterocycles with lithium atoms at 77 K

Lithium atoms were cocondensed with aromatic nitrogen-containing heterocycles in the presence of THF at 77 K. The reaction products in the case of the heterocyclic five-membered rings (imidazole) resulted in a C-H bond activation and led to the corresponding aryl lithium compound. Other heterocycles such as pyridine and pyrimidine led to the formation of a non-lithiated aromatic product, in which the parent compound was dimerised with hydrogen being lost. A special case was found, when substituted pyridines carrying methyl and methoxy groups were reacted under these cocondensation conditions. Here a dimeric species is found again, but the product is dilithiated at the two nitrogen atoms and two hexadienes rings were found instead of an aromatic system. DFT calculations at the B3LYP/6-31G** level of theory were carried out in order to interpret the pathways of the cocondensation reactions and identify the possible intermediates involved. In all reactions σ-complexes between lithium molecules and the heterocycles were found as stable intermediates.     

Copper-diamine-catalyzed N-arylation of pyrroles, pyrazoles, indazoles, imidazoles, and triazoles

This paper details the copper-catalyzed N-arylation of pi-excessive nitrogen heterocycles. The coupling of either aryl iodides or aryl bromides with common nitrogen heterocycles (pyrroles, pyrazoles, indazoles, imidazoles, and triazoles) was successfully performed in good yield with catalysts derived from diamine ligands and CuI. General conditions were found that tolerate functional groups such as aldehydes, ketones, alcohols, primary amines, and nitriles on the aryl halide or heterocycle. Hindered aryl halides or heterocycles were also found to be suitable substrates using the conditions reported herein.     

Pt-catalyzed cyclization/migration of propargylic alcohols for the synthesis of 3(2H)-furanones, pyrrolones, indolizines, and indolizinones

Several heterocycles such as furanones, pyrrolones, and indolizines, which are of pharmacological importance, are easily accessed via the Pt(II)-catalyzed heterocyclization/1,2-migration of propargylic ketols or hydroxy imine derivatives. This method sidesteps the challenges of traditional heteroaromatic oxygenation strategies such as regioselectivity and functional group tolerance in the syntheses of these heterocycles.