Ring Junction Nitrogen Research Articles

Rh(III)-Catalyzed C-H Activation/Annulation for the Construction of Quinolizinones and Indolizines.

A catalytic-condition-controlled synthesis strategy was reported to build quinolizinone and indolizine derivatives from the easily available enamide and triazole substrates with high regioselectivity and good functional group tolerance. More especially, this transformation has successfully fulfilled a C-H bond activation of terminal olefin from enamides followed by a [3 + 3] and a [2 + 3] cyclization cascade under different catalytic conditions, respectively, to provide two kinds of potentially biologically active heterocyclic scaffolds with a ring-junction nitrogen atom. Mechanistically, the methoxyamine formyl group serves as either a traceless directing group (DG) or an oxidizing DG via the C-N and C-C cleavage in this protocol.

Recent Advances in the Light-assisted Synthesis of Ring Junction Nitrogen Heterocycles

Abstract: Nitrogen ring junction heterocycles play a crucial role in synthetic organic chemistry due to their remarkable activity. The fused nitrogen ring junction compounds are abundant in nature; they have excellent biological activity and are used against various health issues. To make selective nitrogen ring junction products from the nitrogen ring junction heterocycles, expensive chemicals and catalysts, like expensive transition metal complexes and metal composites, are required. To neglect the drawbacks of conventional synthesis methods like long reaction times, by-product formation, lower selectivity, and low yields, an alternative of nonconventional light-mediated techniques can be opted for. The light source uses a radical mechanism that reduces by-product formation, provides a regio-selective product, increases yield, decreases reaction time, is cost-effective, and does not require special catalysts or chemicals. There are a variety of light sources, viz., UV, visible, IR, laser, and X-ray. The UV, visible light, white, green, and blue LED light sources are widely used in the photochemical method. This review emphasizes the light-mediated synthesis of nitrogen-ring junction heterocyclic compounds.

Synthesis of mono-fluorinated heterocycles with a ring-junction nitrogen atom via Rh(iii)-catalyzed CF3-carbenoid C–H functionalization and defluorinative annulation

A Rh-catalyzed two-fold C–F bond cleavage enabled [4 + 2] annulation reaction via CF3-carbenoid C–H functionalization of arenes with indoles or various classes of azoles as the directing groups was developed.

Regio- and Enantioselective Synthesis of Dihydropyrido[1,2-a]indoles via Catalytic Asymmetric Annulative Allylic Alkylation.

A palladium-catalyzed asymmetric annulative allylic alkylation reaction of 2-[(1H-indol-2-yl)methyl]malonates with (E)-but-2-ene-1,4-diyl dicarbonates is described, leading to the regio- and enantioselective synthesis of dihydropyrido[1,2-a]indoles with a chiral cyclic allyl stereocenter adjacent to the ring-junction nitrogen atom in moderate to good yields. The salient features of this protocol include mild conditions, a broad substrate scope, and good compatibility with substituents as well as high regio- and stereoselectivities, providing a catalytic asymmetric entry for fabricating chiral pyridoindole scaffolds.

Enantioselective Construction of the Cycl[3.2.2]azine Core via Organocatalytic [12 + 2] Cycloadditions.

The first enantioselective [12 + 2] cycloaddition has been developed for the construction of a chiral cycl[3.2.2]azine core, a tricyclic moiety with a central ring-junction nitrogen atom, by an operationally simple one-step organocatalytic process. The reaction concept builds upon aminocatalytically generated 12π-components derived from 5H-benzo[a]pyrrolizine-3-carbaldehydes reacting with different electron-deficient 2π-components and affording the complex scaffold of benzo[a]cycl[3.2.2]azine (indolizino[3,4,5-ab]isoindole) with excellent enantio- and diastereoselectivity in good yields. The developed reaction is robust toward diverse substituent patterns and has been extended to different classes of electron-deficient 2π-components by minor variations in reaction setup. The obtained [12 + 2] cycloadducts are electron-deficient in nature, and their reaction with nucleophiles have been demonstrated. The enantioselective [12 + 2] cycloaddition with α,β-unsaturated aldehydes as the electron-deficient 2π-components relies upon an unconventional, simple aminocatalyst. In order to understand the high stereoselectivity of the [12 + 2] cycloaddition for this simple catalyst, combined experimental and computational investigations were performed. The investigations point to activation of both the 5H-benzo[a]pyrrolizine-3-carbaldehyde and the α,β-unsaturated aldehyde by the aminocatalyst and that the reaction proceeds by a stepwise cycloaddition, where especially the ring-closure is crucial for the stereochemical outcome. For other electron-deficient 2π-components, such as α,β-unsaturated ketoesters and nitroolefins, a more sterically demanding aminocatalyst has been applied and the corresponding [12 + 2] cycloadducts are obtained with excellent stereoselectivity. The [12 + 2] cycloaddition with vinyl sulfones afforded fully unsaturated systems, which display photoluminescence properties and for which quantum yields have been evaluated.

Synthesis of [5,6]-Bicyclic Heterocycles with a Ring-Junction Nitrogen Atom: Rhodium(III)-Catalyzed C-H Functionalization of Alkenyl Azoles.

The first syntheses of privileged [5,6]-bicyclic heterocycles, with ring-junction nitrogen atoms, by transition metal catalyzed C-H functionalization of C-alkenyl azoles is disclosed. Several reactions are applied to alkenyl imidazoles, pyrazoles, and triazoles to provide products with nitrogen incorporated at different sites. Alkyne and diazoketone coupling partners give azolopyridines with various substitution patterns. In addition, 1,4,2-dioxazolone coupling partners yield azolopyrimidines. Furthermore, the mechanisms for the reactions are discussed and the utility of the developed approach is demonstrated by iterative application of C-H functionalization for the rapid synthesis of a patented drug candidate.

Chemistry of bicyclic [1,3,4]thiadiazole 5-5 systems containing ring-junction nitrogen

This review provides a survey of the advances in the methods of formation and chemical reactivity of bicyclic [1,3,4]thiadiazole 5-5 systems containing ring-junction nitrogen over the period from 1989 to the beginning of 2017.

ChemInform Abstract: Asymmetric Hydrogenation of Heteroarenes with Multiple Heteroatoms

AbstractReview: [39 refs.

An Easy Access to Construct Some New Fused 1,2,4‐Triazines with Ring Junction Nitrogen Systems and Their Biological Evaluation

The chemical reactivity of 4‐amino‐6‐benzyl‐3‐mercapto‐1,2,4‐triazine‐5(4H)‐one (1) towards various aliphatic or/and mono and bis aromatic carboxylic acid derivatives to give the corresponding fused heterocyclic systems, 1,3,4‐thiadiazoles 4, 5, 6, which incorporating 1,2,4‐triazine moiety was achieved. Moreover, compound 1 was subjected to reaction either with halo acetic acids or bromo ester to afford the respective fused nitrogen ring junction systems, thiadiazole 2 and 3 or thiadiazine 7. However, while the tetracyclic ring system 9 was furnished through condensation reaction of isatine with triazine 1. In addition, some of the new synthesized compounds were evaluated as an antioxidant and antitumor agents.

Asymmetric Hydrogenation of Heteroarenes with Multiple Heteroatoms

Enantiopure heterocyclic architectures containing two or more heteroatoms in the ring system have attracted considerable attraction due to this motif playing a role of great importance in asymmetric synthesis and the pharmaceutical chemistry. This review focused on recent advances in the homogeneous asymmetric hydrogenation of heteroarenes with multiple heteroatoms, which provide an efficient and practical method to structural diverse chiral heterocyclic compounds. 1 Introduction 2 Asymmetric Hydrogenation of Five-Membered-Ring Hetero­arenes 2.1 Imidazoles and Oxazoles 2.2 Pyrazole Derivatives 2.3 Benzisoxazoles 3 Asymmetric Hydrogenation of Six-Membered-Ring Heteroarenes 3.1 Quinoxalines 3.2 Quinazolines 3.3 Pyrimidines 3.4 Pyrazines 4 Asymmetric Hydrogenation of Fused Nitrogen Heteroarenes 4.1 Heteroarenes Containing a Ring-Junction Nitrogen 4.2 Heteroarenes Containing a Fused Pyridine Ring 5 Conclusions and Outlook

An Easy Access to Construct Some Fused 1,2,4‐Triazines with Ring Junction Nitrogen Systems and Their Biological Evaluation

The chemical reactivity of 4‐amino‐6‐benzyl‐3‐mercapto‐1,2,4‐triazine‐5(4H)‐one (1) towards various aliphatic or/and mono and bis aromatic carboxylic acid derivatives to give the corresponding fused heterocyclic systems, 1,3,4‐thiadiazoles 4, 5, 6, which incorporating 1,2,4‐triazine nucleus was achieved. Moreover, compound 1 was subjected to react either with halo acetic acids or bromo ester to afford the respective fused nitrogen ring junction systems, thiadiazole 2 and 3, or thiadiazine 7. However, the tetracyclic ring system 9 was furnished through condensation reaction of isatine with triazine 1. In addition, some of the new synthesized compounds were evaluated as an antioxidant and antitumor agents.

Concise synthesis of rare pyrido[1,2-a]pyrimidin-2-ones and related nitrogen-rich bicyclic scaffolds with a ring-junction nitrogen.

Pyrido[1,2-a]pyrimidin-2-ones represent a pharmaceutically interesting class of heterocycles. The structurally related pyrido[1,2-a]pyrimidin-4-ones are associated with a broad range of useful biological properties. Furthermore, quinolizinone-type scaffolds of these sorts with a bridgehead nitrogen are expected to display interesting physico-chemical properties. However, pyrido[1,2-a]pyrimidin-2-ones are largely under-represented in current small molecule screening libraries and the physical and biological properties of the pyrido[1,2-a]pyrimidin-2-one scaffold have been poorly explored (indeed, the same can be said for unsaturated bicyclic compounds with a bridgehead nitrogen in general). Herein, we report the development of a new strategy for the concise synthesis of substituted pyrido[1,2-a]pyrimidin-2-ones from readily available starting materials. The synthetic route involved the acylation of the lithium amide bases of 2-aminopyridines with alkynoate esters to form alkynamides, which were then cyclised under thermal conditions. The use of lithium amide anions ensured excellent regioselectivity for the 2-oxo-isomer over the undesired 4-oxo-isomer, which offers a distinct advantage over some existing methods for the synthesis of pyrido[1,2-a]pyrimidin-2-ones. Notably, different aminoazines could also be employed in this approach, which enabled access to several very unusual bicyclic systems with higher nitrogen contents. This methodology thus represents an important contribution towards the synthesis of pyrido[1,2-a]pyrimidin-2-ones and other rare azabicycles with a ring-junction nitrogen. These heterocycles represent attractive structural templates for drug discovery.

Recent synthetic scenario on imidazo[1,2-a]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.

Progress in the Research of Copper Promoted C—H Functionalizations for the Synthesis of Fused Heterocycles Bearing Bridgehead Nitrogen

The copper-catalyzed C—H activation, selective functionalization and the development of cyclization strategy for the synthesis of novel fused-heterocyclic (heterocycles with ring-junction nitrogen or bridgehead nitrogen) compounds are discussed. This class of novel bridgehead nitrogen heterocycles includes indolizine, pyrazolopyridine, benzimidazole and other polyheterocyclic compounds. The series including modern amination, oxidative coupling and Csp2—H, Csp—H, Csp3—H and N—H activation catalyzed by Cu(I) or Cu(II) salts makes this green synthesis a superior and practical method providing entry into complex heterocycles. Some reaction mechanisms have also been summarized. Keywords copper-catalyzed; bridgehead nitrogen fused-heterocycles; oxidative coupling; C—H activation; N—H activation, cyclization; annulation

A One-Pot, Three-Component Synthesis of 3-(1H-Pyrazol-1-yl)-4H,7H-[1,2,4,5]tetraazino[6,1-b][1,3]benzoxazin-7-ones under Solvent-Free Conditions

A one-pot, three-component synthesis of 3-(1 H -pyrazol-1-yl)-4 H ,7 H -[1,2,4,5]tetraazino[6,1- b ][1,3]benzoxazin-7-ones is described which involves heating a mixture of 1,2-dihydro-3,6-bis(3,5-dimethyl-1 H -pyrazol-1-yl)-1,2,4,5-tetrazine, aldehydes, and dimedone in the presence of a catalytic amount of p -toluenesulfonic acid under solvent-free conditions. The bridgehead-fused 6:6:6 systems with one ring-junction nitrogen atom were obtained in excellent yields.

Three-component solvent-free synthesis of highly substituted bicyclic pyridines containing a ring-junction nitrogen

An efficient one-pot, three-component synthesis of highly substituted bicyclic pyridines containing a ring-junction nitrogen, starting from simple and readily available materials, is described. Cyclocondensation of heterocyclic ketene aminals (HKAs), triethoxymethane, and active methylene compounds by refluxing under solvent-free and catalyst-free conditions, provided bicyclic pyridines in excellent yields.

Bicyclic melatonin receptor agonists containing a ring-junction nitrogen: Synthesis, biological evaluation, and molecular modeling of the putative bioactive conformation

Employing 1,3-dipolar cycloaddition for the synthesis of the 7a-azaindole nucleus, analogues of melatonin have been synthesized and tested against human and amphibian melatonin receptors. Introducing a phenyl substituent in position 2 of the heterocyclic moiety significantly increased binding affinity to both the MT 1 and MT 2 receptors. Shifting the methoxy group from position 5 to 2 of the 7a-azaindole ring led to a substantial reduction of MT 1 binding when MT 2 recognition was maintained. We theoretically investigated the hypothesis whether the 2-methoxy function of the azamelatonin analogue 27 is able to mimic the 5-methoxy group of the neurohormone by directing its 2-methoxy function toward the methoxy binding site. DFT calculations and experimental binding differences of analogue compounds indicate that the energy gained by forming the methoxy-specific hydrogen-bond interaction should exceed the energy required for adopting an alternative conformation.

Structures of pyrido[1,2a]pyrazinium and pyrido[1,2c][1,4]oxazinium bromides studied by 1H, 13C and 15N NMR, FTIR, X-ray and DFT methods

2-R-Pyridines (R CN, CH NOH and COMe) with phenacyl bromide gave the corresponding quaternary bicyclic ring system containing one ring junction nitrogen and one extra nitrogen or oxygen atom ( 1– 3). Their structures were confirmed by 1H, 13C and 15NMR spectra in DMSO-d 6 solution using 2D NMR techniques (COSY, NEOSY, HETCOR and HMBC). The structure of 1-oxo-3-phenyl-pyrido[1,2a]pyrazinium bromide monohydrate, 1, was unambiguously confirmed by X-ray crystallography. The crystals of 1 are monoclinic, space group P2 1/ n, with a=7.730(2) Å, b=14.094(3) Å, c=12.553(3) Å, β=106.18(3)°, V=1311.3(5) Å 3 and Z=4 (at 110 K). The isolated entities of 1– 3 were analyzed by the B3LYP/6-31G(d,p) level of theory in order to get information on the electrostatic interaction between the oppositely charged groups.

Recent Development in the Chemistry of Pyrido‐oxazines, Pyrido‐thiazines, Pyrido‐diazines and Their Benzologs. Part 1.

AbstractFor Abstract see ChemInform Abstract in Full Text.

The application of 8-Methylene-des-AB-cholestan-9-one in heterosteroid synthesis

A synthesis of 10-aza-3,6-dithia-4,19-dinor-5ξ-cholestane 15 by the ACD route is described. The title CD ring compound 1 was coupled with heterocyclic A ring synthons: 2-methylpyridine, 2-mercaptopyridine, 2-mercapto-2-imidazoline and 2-mercapto-2-thiazoline. In the case of use the latest synthon cyclization of ring B afforded the cholestane analogue 15 with a ring junction nitrogen atom.