A Unified Approach to the Isomeric α-, β-, γ-, and δ-Carbolines via their 6,7,8,9-Tetrahydro Counterparts

Yan, Qingqing; Gin, Emma; Banwell, Martin G.; Willis, Anthony C.; Carr, P.D.

doi:10.1021/acs.joc.7b00323

Cited by 39 publications

(27 citation statements)

References 72 publications

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“…In the given example, commercially available pyridine derivative 144 was coupled with cyclohexenone 143 , and the reductive cyclization of cross‐coupling product 145 was proceeded as expected, giving tetrahydrocarboline 146 with a mild yield (Scheme 26). Under the inert atmosphere, compound 146 was aromatized in diphenyl ether at 210 °C to afford γ‐carboline ( 3 ) with a yield of 77% [60a] …”

Section: Synthetic Methods Of γ‐Carbolinementioning

confidence: 99%

Synthesis Strategies for α‐, β‐, γ‐ and δ‐Carbolines

Zhang

Wang

et al. 2021

Asian J Org Chem

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Carbolines are widely present in various natural products and biological molecules. Numerous studies have shown the broad biological activities of these heterocyclic motifs, such as anticancer, antiviral, antibacterial, antiarrhythmic, and antidepressant activities, making carbolines very important in pharmaceutical applications. According to the different positions of nitrogen atom on the pyridine ring, carbolines are divided into four types, named α‐, β‐, γ‐ and δ‐carbolines. So far, numbers of strategies have been developed for each carboline, whereas the synthetic methods of four carbolines are different from each other. In this review, the synthetic strategy of four carbolines were summarized, providing the potential use of these scaffolds in therapeutic applications.

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Section: Synthetic Methods Of γ‐Carbolinementioning

confidence: 99%

Synthesis Strategies for α‐, β‐, γ‐ and δ‐Carbolines

Zhang

Wang

et al. 2021

Asian J Org Chem

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“…It starts with the palladium-catalyzed Ullmann cross-coupling of bromonitropyridine 39 with readily available α-iodinated cyclohexenone 40 . Engaging the ensuing product 41 (80%) in a reductive cyclization reaction gives tetrahydrocarboline 42 (83%), which is then dehydrogenated to give the fully aromatic compound 43 (83%) representing the structure of the natural product harman …”

Section: Application To the Synthesis Of Heterocyclesmentioning

confidence: 99%

The Palladium-Catalyzed Ullmann Cross-Coupling Reaction: A Modern Variant on a Time-Honored Process

et al. 2018

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Cross-coupling reactions, especially those that are catalyzed by palladium, have revolutionized the way in which carbon-carbon bonds can be formed. The most commonly deployed variants of such processes are the Suzuki-Miyaura, Mizoroki-Heck, Stille, and Negishi cross-coupling reactions, and these normally involve the linking of an organohalide or pseudohalide (such as a triflate or nonaflate) with an organo-metallic or -metalloid such as an organo-boron, -magnesium, -tin, or -zinc species. Since the latter type of coupling partner is often prepared from the corresponding halide, methods that allow for the direct cross-coupling of two distinct halogen-containing compounds would provide valuable and more atom-economical capacities for the formation of carbon-carbon bonds. While the venerable Ullmann reaction can in principle achieve this, it has a number of drawbacks, the most significant of which is that homocoupling of the reaction partners is a competitive, if not the dominant, process. Furthermore, such reactions normally occur only under forcing conditions (viz., often at temperatures in excess of 250 °C). As such, the Ullmann reaction has seen only limited application in this regard, especially as a mid- to late-stage feature of complex natural product synthesis. This Account details the development of the palladium-catalyzed Ullmann cross-coupling reaction as a useful method for the assembly of a range of heterocyclic systems relevant to medicinal and/or natural products chemistry. These couplings normally proceed under relatively mild conditions (<100 °C) over short periods of time and, usually, to the exclusion of (unwanted) homocoupling events. The keys to success are the appropriate choice of coupling partners, the form of the copper metal employed, and the choice of reaction solvent. At the present time, the cross-coupling partners capable of engaging in the title reaction are confined to halogenated and otherwise electron-deficient arenes and, as complementary reactants, α- or β-halogenated, α,β-unsaturated aldehydes, ketones, esters, lactones, lactams, and cycloimides. Nitro-substituted (and halogenated) arenes, in particular, serve as effective participants in these reactions, and the products of their coupling with the above-mentioned carbonyl-containing systems can be manipulated in a number of different ways. Depending on the positional relationship between the nitro and carbonyl groups in the cross-coupling product, the reduction of the former group, which can be achieved under a range of different conditions, provides, through intramolecular nucleophilic addition reactions, including Schiff base condensations, access to a diverse range of heterocyclic systems. These include indoles, quinolines, quinolones, isoquinolines, carbazoles, and carbolines. Tandem variants of such cyclization processes, in which Raney cobalt is used as a catalyst for the chemoselective reduction (by dihydrogen) of nitro and nitrile groups (but not olefins), allow for the assembly of a range of structurally challenging nat...

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“…[2] However, methods for the synthesis of tetrahydrocarbolines, particularly, tetrahydro-α-carbolines are rare. [8][9][10][11][12][13][14][15][16] Substrates for the synthesis of tetrahydro-α-carbolines via various intra-and intermolecular cyclizations include 3-substituted indoles, [8] 2-substituted indoles, [9] tosyliminoindolines [10][11][12][13][14] and others such as nitropyridine [15] and o-iodobenzamide. [16] While tosyliminoindoline and its derivatives have been employed for the synthesis of a wide variety of heterocycles, [17] they react in a [4 + 2] [10][11] or [3 + 3] [12][13][14] fashion in the synthesis of tetrahydro-α-carbolines (Scheme 1a).…”

Section: Introductionmentioning

confidence: 99%

“…Several methods have been developed for the efficient construction of carboline moieties [2] . However, methods for the synthesis of tetrahydrocarbolines, particularly, tetrahydro‐ α ‐carbolines are rare [8–16] . Substrates for the synthesis of tetrahydro‐ α ‐carbolines via various intra‐ and intermolecular cyclizations include 3‐substituted indoles, [8] 2‐substituted indoles, [9] tosyliminoindolines [10–14] and others such as nitropyridine [15] and o ‐iodobenzamide [16] .…”

Section: Introductionmentioning

confidence: 99%

One‐Pot Regio‐ and Diastereoselective Synthesis of Tetrahydro‐α‐carbolines via Cascade Reactions of Iminoindolines with Morita‐Baylis‐Hillman Bromides of Nitroalkenes

2022

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A mild and metal-free method for the one-pot synthesis of highly substituted tetrahydro-α-carbolines from Morita-Baylis-Hillman (MBH) bromides of nitroalkenes and iminoindolines has been demonstrated. Cascade reaction of MBH bromides with tosyliminoindolines occurs with regio-as well as diastereoselectivity in a formal [3 + 3] manner to form various tetrahydro-α-carbolines with wide substrate scope under mild conditions. All the products were obtained in high yields within a short reaction time. Also, the synthetic efficiency of the methodology was demonstrated by a gram scale experiment and by further converting them into 3-nitro-α-carbolines.

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A Unified Approach to the Isomeric α-, β-, γ-, and δ-Carbolines via their 6,7,8,9-Tetrahydro Counterparts

Cited by 39 publications

References 72 publications

Synthesis Strategies for α‐, β‐, γ‐ and δ‐Carbolines

Synthesis Strategies for α‐, β‐, γ‐ and δ‐Carbolines

The Palladium-Catalyzed Ullmann Cross-Coupling Reaction: A Modern Variant on a Time-Honored Process

One‐Pot Regio‐ and Diastereoselective Synthesis of Tetrahydro‐α‐carbolines via Cascade Reactions of Iminoindolines with Morita‐Baylis‐Hillman Bromides of Nitroalkenes

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