Heterocyclic Products Research Articles

Base-promoted cascade radical difluoroalkylation/cyclization of acrylamides for the synthesis of CF2-containing oxindoles and isoquinoline-1,3-diones

A base-promoted cascade radical difluoroalkylation/cyclization of acrylamides with ICF2COOEt to synthesize CF2-containing oxindoles and isoquinoline-1,3-diones in moderate to excellent yields was developed under transition metal-free and catalyst-free conditions. This reaction tolerated a variety of functional groups and provided an alternative and mild method for the preparation of difluoroester-substituted five- and six-membered nitrogen-containing heterocyclic products.

Rhodium(III)‐Catalyzed Heteroannulations of 3‐Sulfolene Derivatives through C(sp2)−H Activation: Access to Pyridine ortho‐Quinodimethane Precursors

AbstractHydroxamates derived from 3‐sulfolene‐3‐carboxylic acid can be involved in intra‐ and intermolecular rhodium(III)‐catalyzed heteroannulations with alkynes proceeding through C(sp2)−H bond activation. These transformations allow for a straightforward access to diversely substituted pyridones, and to pyridines fused to a sulfolene ring after functional group transformations. Subsequent cheletropic elimination of sulfur dioxide can be achieved under microwave irradiation to generate pyridine ortho‐quinodimethanes. These results demonstrate that the scope of rhodium(III)‐catalyzed C(sp2)−H functionalizations can be extended to sulfolenes, a yet unexplored class of alkenes in these latter transformations, thereby affording access to valuable classes of heterocyclic products.

Assembling high nitrogen isomeric energetic molecules via a lithium-mediated concerted [2 + 3] reaction of two diazo compounds

The search for high nitrogen isomeric energetic molecules and comparison of their structure–property relationship are always attractive in the field of energetic materials. In this paper, a novel lithium-mediated concerted [2 + 3] reaction with two diazo compounds has been accomplished which leads to the simultaneous formation of two isomeric cyanotetrazoles (2a and 2b). The cyano group in cyanotetrazoles was further converted to tetrazole or tetrazole N-oxide to form tricyclic heterocyclic products (3a, 3b, 7a, and 7b). The energetic properties of the compounds were studied. A representative compound 3a (Td = 220 °C, D = 9052 m s−1, IS = 13 J, FS = 200 N) has better detonation performances, higher thermal stability and lower mechanical sensitivities than RDX, which is expected to serve as a potential energetic material.

Steglich’s Base Catalyzed Three-Component Synthesis of Isoxazol-5-Ones

4-(Dimethylamino)pyridine (DMAP) has been used as an efficient Brønsted organo-base catalyst for the one-pot, three-component cyclization of various aldehydes, β-keto esters, and hydroxylamine hydrochloride. In this organocatalyzed reaction, 3,4-disubstituted isoxazole-5(4H)-ones were efficiently formed in high yields and relatively shorter reaction times. Using 8 mol% of DMAP, a mixture of water–ethanol solvent system, and 80 °C gave the best results. The three-component heterocyclization using arylaldehydes containing electron releasing groups is well performed and heterocyclic products were obtained in good to high isolated yields. Aldehydes with electron withdrawing groups did not lead to the formation of products. This method has many advantages such as broad substituent scope, mild and eco‐friendly conditions, step and atom economy, commercially available, and inexpensive organo-basic catalyst.

Carboline derivatives based on natural pityriacitrin as potential antifungal agents

Carboline alkaloids are a class of important heterocyclic natural products, which usually present extensive bioactivities. During the course of our research for active compounds from natural products, the pityriacitrin and pityriacitrin B belonged carboline alkaloids have been isolated from a Chinese Burkholderia sp. NBF227, which indicated potential antifungal activities. So, in order to develop these carboline alkaloids as potential fungicidal agents, a series of pityriacitrin derivatives were investigated for their antifungal activities against Phytophthora capsici , Sclerotinia sclerotiorum , Botrytis cinerea and Rhizoctonia solani , and the results demonstrated that compounds 4 , 10 and 19 displayed broad-spectrum antifungal activities. In addition, in vivo bioassay also indicated that compounds 4 and 10 could protect the pepper leaves and grape fruits against infection by P . capsici and B . cinerea , respectively. The possible mechanism of antifungal action for these compounds was also explored. • Carboline derivatives displayed broad-spectrum in vitro fungicidal activities. • Compounds 4 and 10 could protect the pepper leaves against infection by P. capsici. • Compounds 4 could protect the grape fruits against infection by B. cinerea. • The possible mechanism of antifungal action for compound 4 has also been explored.

Frontispiece: Nickel‐Catalyzed Arylative Cyclizations of Alkyne‐ and Allene‐Tethered Electrophiles using Arylboron Reagents

This review summarizes recent progress in nickel-catalyzed arylative cyclizations of alkyne- and allene-tethered electrophiles using arylboron reagents, which are useful methods for the preparation of diverse carbo- and heterocyclic products. In many cases, nickel catalysis enables unique modes of reactivity not readily available to other metal catalysts. The scope of the reactions is discussed in detail, and general mechanistic concepts underpinning the processes are described. More information can be found in the review article by S. M. Gillbard and H. W. Lam et al. (DOI: 10.1002/chem.202104230)

Pyrazolon-ditiocarbonic acid and dibromoalcanes – cyclic keto-ditioacetals formation vs. open chain products: A theoretical study

Alkyl-bis(5-hydroxy-3-methyl-1-phenyl-1H-pyrazole-4-carbodithioates) are interesting targets as they are useful complexing agents for transition metal ion extraction. Anyhow, the intents of their synthesis lead to heterocyclic products and not to the desired molecules. To gain insight into the reaction, we carried out a theoretical investigation on the reaction mechanism and the involved activation energies and the relative thermodynamic stabilities of the desired and obtained.

Double Addition Reactions Involving Vinyl-Substituted N-Heterocycles and Active Methylene Compounds.

A series of conjugate addition reactions have been performed with vinyl-substituted N-heterocycles in acid-catalyzed conversions. Using active methylene compounds, double conjugate addition reactions have been accomplished to provide dipyridyl and related heterocyclic products. These conversions have utilized 1,3-dicarbonyl compounds, cyano esters, a cyano sulfone, and malonyl nitrile as nucleophiles. The Michael accepting groups include vinyl-substituted pyridines, quinoline, and pyrazine. Double conjugate addition reactions have also been accomplished with 2,6-divinylpyridine and related systems.

Complete genome sequences of the antibiotic sulfamethoxazole-mineralizing bacteria Paenarthrobacter sp. P27 and Norcardiodes sp. N27.

Sulfonamide antibiotics (SAs) have been produced and consumed on a large scale over the last few decades. SAs are a typical class of refractory contaminants that are omnipresent in various environments. Although several [phenyl]-SA-degrading bacteria and their corresponding genomes have been documented, limited genetic information is available for the degraders of heterocyclic products (e.g., 3-amino-5-methylisoxazole [3A5MI] produced via sulfamethoxazole [SMX] catabolism). In this study, the previously isolated SMX-mineralizing bacterial partners, Paenarthrobacter sp. P27 (responsible for the initial cleavage of the -C-S-N- bond of SMX and further degradation of [phenyl]-SMX) and Norcardiodes sp. N27 (responsible for 3A5MI catabolism), were further studied and their complete genomes were sequenced. Complete degradation and bacterial growth were verified by pure-culture experiments with SMX or 3A5MI as the sole carbon, nitrogen, and energy source. By cross-feeding strains P27 and N27, complete catabolism of SMX could be achieved over a wide range of initial SMX concentrations. Moreover, strain P27 was capable of transforming the additional nine SA representatives into their corresponding nitrogen-containing heterocyclic products, strongly indicating the broad substrate spectrum and marked bioremediation potential of strain P27. The genome of strain P27 contained the highly homologous monooxygenase gene cluster, sadABC, which initially attacked the sulfonamide molecules. The complete genome sequences of the two important degraders will benefit future research centering on the molecular mechanism underlying advanced SMX mineralization and will aid in further understanding the interspecific interactions and metabolite exchanges for the optimization of artificially constructed synthetic functional microbiomes.

Stereochemical Behavior of Pairs of P-stereogenic Phosphanyl Groups at the Dimethylxanthene Backbone.

The P-stereogenic bis(phosphanes) 7 and 9, featuring pairs of P(Mes)-ethynyl or vinyl substituents at the dimethyl xanthene backbone show rather low barriers of stereochemical inversion at phosphorus. π-Conjugative effects are probably causing these low inversion barriers. Compound 7 reacted with B(C6 F5 )3 to form the nine-membered heterocyclic product 10, featuring a [P]-C≡C-B(C6 F5 )3 substituent. Compound 7 was converted to the bis[P(Mes)vinyl] xanthene derivative 9, which gave the zwitterionic P(H)(Mes)-CH=CH-B(C6 F5 )3 containing product 16 upon treatment with B(C6 F5 )3 . Thermally induced epimerization barriers at phosphorus of ca. 20 to 27 kcal mol-1 were calculated by DFT for the alkenyl- and alkynyl-P derived systems 6 to 9, 15 and 16 and experimentally determined for the examples 7 and 16.

Synthesis of Natural Products by C-H Functionalization of Heterocycless.

Total synthesis is considered by many as the finest combination of art and science. During the last decades, several concepts were proposed for achieving the perfect vision of total synthesis, such as atom economy, step economy, or redox economy. In this context, C-H functionalization represents the most powerful platform that has emerged in the last years, empowering rapid synthesis of complex natural products and enabling diversification of bioactive scaffolds based on natural product architectures. In this review, we present an overview of the recent strategies towards the total synthesis of heterocyclic natural products enabled by C-H functionalization. Heterocycles represent the most common motifs in drug discovery and marketed drugs. The implementation of C-H functionalization of heterocycles enables novel tactics in the construction of core architectures, but also changes the logic design of retrosynthetic strategies and permits access to natural product scaffolds with novel and enhanced biological activities.

Significant Broadening of the Substrate Scope for the Hydrated Imidazoline Ring Expansion (HIRE) via the Use of Lithium Hexamethyldisilazide

AbstractSubstrates that are insufficiently activated towards the hydrated imidazoline ring expansion (HIRE) process have been previously found to deliver exclusively the products of aminoalkyl side-chain ring expansion. Attempted reversal of the process by thermal activation towards HIRE failed. We have found that for such problematic substrates the HIRE-type ring expansion can be effectively achieved by applying lithium hexamethyldisilazide (LHMDS) in toluene. LHMDS is thought to promote intramolecular transamidation, which leads to ring-expanded 10- and 11-membered heterocyclic products in modest to good yields. The process significantly broadens the substrate scope amenable to the HIRE strategy.

Visible‐Light‐Driven Base‐Promoted Radical Cascade Difluoroalkylation‐Cyclization‐Iodination of 1,6‐Enynes with Ethyl Difluoroiodoacetate

AbstractA visible‐light‐driven base‐promoted radical cascade difluoroalkylation/5‐exo‐dig cyclization/iodination of 1,6‐enynes with ethyl difluoroiodoacetate was developed under catalyst‐free and oxidant‐free conditions. The difluoroalkylated pyrrolidines and tetrahydrofuran derivatives were generated with good functional group tolerance and high Z/E stereoselectivity. This reaction provided an alternative and mild method for the preparation of highly functionalized and vinyl C−I bonds containing five‐membered heterocyclic products.

Nickel-Catalyzed Arylative Cyclizations of Alkyne- and Allene-Tethered Electrophiles using Arylboron Reagents.

The use of arylboron reagents in metal‐catalyzed domino addition–cyclization reactions is a well‐established strategy for the preparation of diverse, highly functionalized carbo‐ and heterocyclic products. Although rhodium‐ and palladium‐based catalysts have been commonly used for these reactions, more recent work has demonstrated nickel catalysis is also highly effective, in many cases offering unique reactivity and access to products that might otherwise not be readily available. This review gives an overview of nickel‐catalyzed arylative cyclizations of alkyne‐ and allene‐tethered electrophiles using arylboron reagents. The scope of the reactions is discussed in detail, and general mechanistic concepts underpinning the processes are described.

Recent advances in the biosynthesis strategies of nitrogen heterocyclic natural products.

Covering: 2015 to 2020Nitrogen heterocyclic natural products (NHNPs) are primary or secondary metabolites containing nitrogen heterocyclic (N-heterocyclic) skeletons. Due to the existence of the N-heterocyclic structure, NHNPs exhibit various bioactivities such as anticancer and antibacterial, which makes them widely used in medicines, pesticides, and food additives. However, the low content of these NHNPs in native organisms severely restricts their commercial application. Although a variety of NHNPs have been produced through extraction or chemical synthesis strategies, these methods suffer from several problems. The development of biotechnology provides new options for the production of NHNPs. This review introduces the recent progress of two strategies for the biosynthesis of NHNPs: enzymatic biosynthesis and microbial cell factory. In the enzymatic biosynthesis part, the recent progress in the mining of enzymes that synthesize N-heterocyclic skeletons (e.g., pyrrole, piperidine, diketopiperazine, and isoquinoline), the engineering of tailoring enzymes, and enzyme cascades constructed to synthesize NHNPs are discussed. In the microbial cell factory part, with tropane alkaloids (TAs) and tetrahydroisoquinoline (THIQ) alkaloids as the representative compounds, the strategies of unraveling unknown natural biosynthesis pathways of NHNPs in plants are summarized, and various metabolic engineering strategies to enhance their production in microbes are introduced. Ultimately, future perspectives for accelerating the biosynthesis of NHNPs are discussed.

Isolation of unique heterocycles formed from pyridine-thiocarboxamides as diiodine, iodide, or polyiodide salts

The reaction of pyridine-thiocarboxamides with I2 provided a variety of novel heterocyclic products as iodide, triiodide, and/or pentaiodide salts. Bismuth triiodide was incorporated as a crystallization aid to access other structural types.

Chiral phosphoric acid-catalyzed regio- and enantioselective reactions of functionalized propargylic alcohols

Chiral phosphoric acid has been utilized for covalent activation of propargylic alcohols to act as pre-catalyst. With this activation mode, a range of highly regio- and enantioenriched heterocyclic products could be generated efficiently from racemic propargylic alcohols.

Enantioselective [2 + 2] cycloaddition of 1,2-dihydroquinolines with 3-olefinic oxindoles via Brønsted acid catalysis

A highly diastereo- and enantioselective Brønsted acid-catalyzed [2 + 2] cycloaddition generating heterocyclic products with four contiguous stereocenters in good to excellent yields with high stereoselectivities is reported.

Knoevenagel‐Cyclization Cascade Reactions of Substituted 5,6‐Dihydro‐2H‐Pyran Derivatives

AbstractThe diastereoselective domino‐Knoevenagel‐IMHDA reactions of 5,6‐dihydro‐2H‐pyran derivatives containing an o‐formylaryl amine or ether moiety were performed with active methylene reagents. In the spiro heterocyclic products representing a novel skeleton, a tetrahydroquinoline or chroman unit is fused with two pyran rings and the bridgehead carbon atoms are chirality centers formed diastereoselectively. Depending on the substitution pattern, a domino Knoevenagel‐[1,5]‐hydride shift‐cyclization sequence was identified as a competing pathway, which resulted in the formation of tetrahydroquinoline derivatives with a 5,6‐dihydro‐2H‐pyran‐3‐yl substituent. The relative configurations of the products were determined by means of the characteristic NOE correlations and single crystal X‐ray diffraction analysis. Antiproliferative activity assays of two products against A2780 and WM35 human cancer cell lines showed low micromolar IC50 values down to 2.99 μM.

Design, Synthesis and Antibacterial Activity screening of Novel Bis cyclic Imides Linked to Trimethoprim Drug

Cyclic imides are well known important organic compounds that exhibit diverse biological activities like anti - inflammatory, antibacterial, analgesic, hypoglycemic and antifungal activities. Besides these compounds are useful building blocks in the synthesis of many drugs and pharmaceuticals. On the other hand trimethoprim is a well-known antibiotic that is used in combination with Sulfamethoxazole in treating urinary tract infections, bacterial infections and acute invasive diarrhea. Moreover Schiff bases represent the most active intermediates that exhibit wide spectrum of biological activities and play a vital role in the production of different pharmaceutical and bioactive heterocycles. Based on all these facts, it seems worthwhile to design and synthesize new molecules that contain these three active moieties (cyclic imide, trimethoprim and Schiff base) together in the same molecule since this may exhibit the new compounds high biological activity and may open possibilities for fighting bacterial infections.