Heterocyclic Frameworks Research Articles

Pd/Norbornene Collaborative Catalysis on the Divergent Preparation of Heterocyclic Sulfoximine Frameworks.

Pd/Norbornene cocatalyzed tandem C-H activation/annulation reactions of free NH-sulfoximines with aryl iodides to produce diverse polyheterocyclic sulfoximines in highly chemoselective models are reported. The reaction tolerated a broad range of functional groups under external oxidant-free conditions. The preliminary mechanistic studies using density functional theory (DFT) calculations highlighted the key role of a PdIV intermediate.

Organocatalytic Diversity-Oriented Asymmetric Synthesis of Structurally and Stereochemically Complex Heterocycles.

An asymmetric organocatalytic direct arylation approach to construct arylated quaternary stereogenic centers with a catalyst loading of 1 mol % is reported. The formation of the hemiketal moiety in stabilizing the hydroquinone intermediate proves to be important in leading to hydroquinone products instead of oxidation quinone products obtained in previously reported methods. A series of structurally and stereochemically complex heterocyclic frameworks are obtained, including spiro-, dispiro-, fused, and bridged heterocycles.

Construction of Unique Heterocyclic Frameworks by Photochemical Reaction of 5- and 6-Membered Heteroaromatics

Construction of Unique Heterocyclic Frameworks by Photochemical Reaction of 5- and 6-Membered Heteroaromatics

Natural Products with Heteroatom-Rich Ring Systems.

This review focuses on all known natural products that contain a "heteroatom-rich" ring system, specifically a five-, six- or seven-membered ring that contains three or more heteroatoms. The isolation and biological activity of these natural products is discussed, along with the biosynthetic processes that Nature employs to assemble these rare heterocyclic frameworks.

A Gold(I)‐Catalyzed Oxidative Rearrangement of Heterocycle‐Derived 1,3‐Enynes Provides an Efficient and Selective Route to Divinyl Ketones

The gold‐catalyzed oxidation of N‐tosyl‐protected 6‐alkynyl‐3,4‐dihydro‐2H‐pyridines was studied in detail to obtain divinyl ketones in which one of the double bonds is embedded in a heterocyclic framework. The best reaction conditions were then extended to different types of substrates to assess the scope of the reaction. DFT calculations were exploited to gain insight into the regio‐ and chemoselectivity of the process too. The obtained divinyl ketones were then easily cyclized by a Nazarov process and the bi‐ or polycyclic compounds used as scaffolds in the synthesis of analogues of the plant hormones strigolactones.

Diverting Reactive Intermediates Toward Unusual Chemistry: Unexpected Anthranil Products from Davis-Beirut Reaction.

The discovery of a new variation on the Davis-Beirut reaction is described in which an atypical heterocyclic framework (the anthranil or benzo[c]isoxazole framework) is formed as the result of diversion of a key reactive intermediate away from its expected reactivity-a potentially general approach to reaction design and development. Experimental and computational support for the proposed mechanism and origins of altered reactivity are described.

Cobalt Catalyzed, Regioselective C(sp2)-H Activation of Amides with 1,3-Diynes.

The development of a first row transition metal (cobalt)-based catalyst for the as yet unexplored C-H activation-driven reaction of 1,3-diynes, themselves a functional class of interest in a range of application areas, to form isoquinolinones-an important structural motif in a number of biologically active substances-is presented. This versatile and inexpensive catalyst employs a covalently attached bidendate-directing group, 8-aminoquinoline. The template directs the C-H activation and facilitates the synthesis of a wide range of alkynylated heterocycles under mild conditions and with excellent regioselectivity. This strategy provides a novel and efficient route to diverse heterocyclic frameworks as demonstrated by its late stage application in bisheterocycle syntheses.

Observations arising from a Beckmann rearrangement-Mannich cyclization approach to the azepinobisindole alkaloid iheyamine A

An overview of an iterative Beckmann rearrangement-Mannich cyclization approach to the azepinobisindole alkaloid iheyamine A is described. In a preliminary model study, the (E)-oxime 10 underwent Beckmann rearrangement to give the bisindolylacetamide 4 followed by an intramolecular Mannich cyclization affording 2-(indolin-2-yl)indole 5 containing the heterocyclic framework of the iheyamine alkaloids. However, the 2-(indolin-2-yl)indole 5 could not be converted into the azepinobisindole core of iheyamine A. When the same Beckmann-Mannich approach was applied toward the natural product itself, a result was obtained that contrasted the model study. The (E)-oxime 3 did not undergo Beckmann rearrangement, but instead an intramolecular Mannich cyclization whereby the electron rich C4 site attacked the intermediate iminum ion, generating the 4-(indolin-2-yl)indole 25 bearing the heterocyclic framework of the slime mould pigment arcyriacyanin A. Although this route did not result in the synthesis of iheyamine A being accomplished, some interesting observations related to the venerable Beckmann rearrangement and Mannich cyclization reactions are described.

Cycloadditions of Donor–Acceptor Cyclopropanes and Nitriles

Lewis acid promoted cycloaddition reactions of donor–acceptor (DA) cyclopropanes are one of the well‐studied approaches for the construction of heterocyclic and carbocyclic frameworks. During our efforts to exploit this strategy for the synthesis and functionalization of carbohydrate‐derived systems, we discovered the cycloaddition of nitriles with DA cyclopropanes. This personal account details our contributions to the development of this cycloaddition. The reaction discovery, methods development, and application in total synthesis along with related examples from others are discussed herein.

Synthesis and Antiproliferative Effect of Ethyl 4-[4-(4-Substituted Piperidin-1-yl)]benzylpyrrolo[1,2-a]quinoxalinecarboxylate Derivatives on Human Leukemia Cells.

Acute leukemia is a hematological malignancy with high incidence and recurrence rates and is characterized by an accumulation of blasts in bone marrow due to proliferation of immature lymphoid or myeloid cells associated with a blockade of differentiation. The heterogeneity of leukemia led us to look for new specific molecules for leukemia subtypes or for therapy-resistant cases. Among heterocyclic derivatives that attracted attention due to their wide range of biological activities, we focused our interest on the pyrrolo[1,2-a]quinoxaline heterocyclic framework that has been previously identified as an interesting scaffold for antiproliferative activities against various human cancer cell lines. In this work, new ethyl 4-[4-(4-substituted piperidin-1-yl)]benzylpyrrolo[1,2-a]quinoxalinecarboxylate derivatives (1 a-o) were designed, synthesized, and evaluated against five different leukemia cell lines, including Jurkat and U266 (lymphoid cell lines) and K562, U937, and HL60 (myeloid cell lines), as well as on normal human peripheral blood mononuclear cells (PBMCs). This new pyrrolo[1,2-a]quinoxaline series showed interesting cytotoxic potential against all tested leukemia cell lines. In particular, pyrroloquinoxalines 1 a and 1 m,n seem to be interesting due to their high activity against leukemia and their low activity against normal hematopoietic cells, leading to a high index of selectivity.

Thiazine-2-thiones as Masked 1-Azadienes in Cascade Dimerization Reactions).

We report the unexpected formation of a 1-azadiene dimer from 4,6-diphenyl-3,6-dihydro-2H-1,3-thiazine-2-thiones under prolonged microwave irradiation. In this manner, thiazine-2-thiones act as “masked” 1-azadiene equivalents, which makes them useful synthetic tools to access complex heterocyclic frameworks. We compare this dimerization with earlier approaches and elaborate on the observed diastereoselectivity.

A modular CuI-L-proline catalyzed one-pot route for the rapid access of constrained and privileged hetero-atom-linked medium-sized ring systems

An efficient CuI-L-proline catalyzed one-pot synthesis was developed to generate a collection of skeletally diverse heterocyclic ring systems with sizes ranging from 6 to 9. A salient feature of this design strategy is its modular synthetic utility using an SN2 reaction followed by a microwave assisted CuI-L-proline hetero-arylation, which has granted access to a series of heterocyclic frameworks including: benzo[e]pyrrolo[1,2-a][1,4]diazepin, benzo[e]pyrrolo[1,2-a][1,4]diazocin, benzo[e]pyrido[1,2-a][1,4]diazocinones, dibenzo[b,f][1,5]diazoninones, dihydrodibenzo[b,e][1,4]thiazepine, dibenzo[b,e][1,4]thiazocine and benzo[6,7][1,4]diazepino[1,2-a]indole. Moreover, the synthetic procedures described herein, allows rapid entries to synthetically challenging medium-sized heterocyclic systems with good overall yields.

Recent advances in rhodium-catalyzed asymmetric synthesis of heterocycles.

Heterocycles are crucial structural motifs that are ubiquitously present in biologically active natural products and pharmaceutically important compounds. Over the past few decades, great attention has been paid to develop efficient methodologies for the construction of diverse enantioenriched heterocyclic frameworks. This review focuses on the recent impressive progress and advances in the asymmetric synthesis of heterocycles under rhodium catalysis.

NHC as the Guiding Factor in a Copper-Catalyzed Intramolecular C Arylation of Pyrrolylimidazolium Salts: Synthesis of Luminescent Heterotetracyclic Frameworks.

3-(2/4-(2-Bromophenyl)-1H-pyrrol-3-yl)-1H-imidazol-3-ium bromides undergo a copper-catalyzed intramolecular direct C arylation under mild conditions to give new heterocyclic frameworks. The cyclizations involve the formation of betaines (imidazoliumylpyrrolides) under basic conditions and the tautomerizaton of the betaines to the corresponding NHCs, which are the reactive species responsible for the selectivity of the arylation via the formation of NHC-Cu complexes. The primary salt arylation products were dehydrohalogenated to obtain the first representatives of 7H-imidazo[2,1-a]pyrrolo[3,2-c]isoquinoline and 1H-imidazo[2,1-a]pyrrolo[3,4-c]isoquinoline heterocyclic skeletons, which were further transformed into thermodynamically more stable 1H- and 6H-tautomers, respectively, by removing of the benzyl-PG. The new heterotetracyclic systems are fluorescent in solutions with high quantum yields.

ChemInform Abstract: Intramolecular Baylis‐Hillman Reaction: Synthesis of Heterocyclic Molecules

AbstractReview: 69 refs.

ChemInform Abstract: Silver‐Catalyzed Three‐Component Approach to Quinolines Starting from Anilines, Aldehydes, and Alcohols.

A silver-catalyzed sequential formation of two C–C bonds for the construction of a series of polysubstituted quinolines from anilines, aldehydes, and alcohols under mild conditions has been developed. The transformation is effective for a broad range of substrates, including aliphatic alcohols, arylalkanols, cycloalkanols, and ethylene glycol, thereby permitting the expansion of the constituent architectures of the heterocyclic framework.

Direct synthesis of 2-/3-(trifluoromethyl)thiochroman-4-ones: Superacid-induced tandem alkylation-cyclic acylation of benzenethiols using 2-/3-(trifluoromethyl)acrylic acid

Incorporation of fluorinated heterocyclic framework into organic molecules results in profound changes in their physical, chemical and biological properties. Realizing that the fluorinated thiochroman-4-ones are important scaffolds in medicinal chemistry and are rare in the chemical literature, one-pot synthesis of 2-/3-(trifluoromethyl)thiochroman-4-ones was attempted. Direct access to 2-/3-(trifluoromethyl)thiochroman-4-ones was achieved by a tandem alkylation-cyclic acylation process promoted by superelectrophilic activation of 2-/3-(trifluoromethyl)acrylic acid in superacidic trifluoromethanesulfonic acid under microwave-assisted Friedel-Crafts alkylation of benzenethiols followed by cyclization (via intramolecular acylation). Synthesis of a series of 2-/3-(trifluoromethyl)thiochroman-4-ones from protosolvated 2-/3-(trifluoromethyl)acrylic acid intermediates and benzenethiols is described.

Design of Multifunctional IridiumIII Compounds as a Potential Therapeutic Agents from Basic Molecular Scaffolds

AbstractComplexes of the type [(η5‐C5Me5)Ir(XY)Cl]Cl [XY= bipyrazoles (4a‐b), pyrimidin‐2‐amine (5a‐b) and triazolopyrimidine (6a‐b)] have been synthesized and characterized by IR, 1H‐NMR, 13C‐NMR, ESI‐MS (Electrospray ionisation) and elemental analysis. Interaction of the complexes with Calf Thymus DNA (CT‐DNA) have been explored by electronic absorption titration, binding constants (Kb) for the interaction of complexes with DNA have been observed in the range of 0.151 ± 0.015 × 105 M−1 ‐ 1.446 ± 0.059 × 105 M−1. Molecular docking attests π‐π stacking interactions have been observed between receptor and ligands. The nucleolytic cleavage activity of compounds has been carried out on pUC19 DNA by gel electrophoresis experiments, potency has been ascribed to a multitarget mechanism of action of the compounds. Interestingly, the chelation of ligands with IrIII led to a remarkable enhancement of antibacterial activity against arbitrarily selected two Gram +ve and three Gram –ve bacterial stains. The complexes of triazolo[1,5‐a]pyrimidines have been proved the most cytotoxic compounds and show enhanced percentage viability on S. pombe compared to pyrazole incorporated heterocyclic frameworks. All complexes showed potent cytotoxicity as compared to ligands, with IC50 values ranging from 64 to 199 μM toward A549 human lung cancer cells.

Microwave Induced Synthesis of Pyrazoline Compounds Containing Substituted Benzyloxy Phenyl Ring System

<div><p><em>Green chemistry uses highly efficient and environmental benign synthetic procedures to synthesize various bioactive heterocyclic frameworks which are the useful synthons for the synthesis of medicines, plastics, petrochemicals, agrochemicals, cosmetics and many more hence the green chemistry is the need of the day. In this methodology pyrazolines have been synthesized under microwave irradiation<sup>1</sup> using ethanol /alumina. The structures of these compounds were established by elemental analysis and spectral data. The method has several advantages in comparison with conventional synthesis including clean reaction procedure, easy workup, and short reaction time giving excellent yields of product.</em></p></div>

Charting the Chemical Reactivity Space of 2,3-Substituted Furo[2,3-b]pyridines Synthesized via the Heterocyclization of Pyridine-N-oxide Derivatives.

A concise strategy for the synthesis of 2,3-substituted furo[2,3-b]pyridines is described. Mild, metal-free conditions were successfully applied to produce a range of 2-(alkyl or aryl)-3-ethylcarboxylate-furo[2,3-b]pyridines in yields of 50-91%. Then, the chemical reactivity of this heterocyclic framework was explored to develop straightforward methods for its functionalization. The pyridine moiety reactivity was successfully explored by C-H amination and borylation reactions, although C-H fluorination and radical C-H arylation processes were not as efficient. In addition, while the furopyridine core proved stable under basic conditions, the ring-opening reaction of the furan moiety with hydrazine generated a valuable new pyridine-dihydropyrazolone scaffold.