Fischer Indole Research Articles

Ready access to 7,8-dihydroindolo[2,3-d][1]benzazepine-6(5H)-one scaffold and analogues via early-stage Fischer ring-closure reaction.

Paullone isomers are known as inhibitors of tubulin polymerase and cyclin dependent kinases (Cdks), which are potential targets for cancer chemotherapy. Herein we report an efficient and clean pathway to the fourth isomer, which remained elusive so far, namely 7,8-dihydroindolo[2,3-d][1]benzazepin-6(5H)-one. Moreover, we demonstrate the generality of our pathway by synthesizing two closely related analogues, one containing a bromo substituent and the other one incorporating an 8-membered instead of a 7-membered ring. The key transformation in this four-step synthesis, with an overall yield of 29%, is the Fischer indole reaction of 2-nitrophenylacetyl acetoacetate with 1-benzyl-1-phenylhydrazine in acetic acid that delivers methyl 2-(1-benzyl-3-(2-nitrophenyl)-1H-indol-2-yl)acetate in 55% yield.

Mechanochemical Fischer indolisation: an eco-friendly design for a timeless reaction

We developed an environmentally friendly mechanochemical protocol to induce an effective Fischer indolisation to synthesize indoles and indolines taking advantage of oxalic acid and dimethylurea.

New approaches to ondansetron and alosetron inspire a versatile, flow photochemical method for indole synthesis.

An oxidative photocyclisation of N-arylenaminones to indoles is described, that mirrors the Fischer indole synthesis but uses anilines in place of arylhydrazines. Its value is exemplified with new approaches to the WHO-listed APIs ondansetron and alosetron.

An Approach to the Construction of Benzofuran-thieno[3,2-b]indole-Cored N,O,S-Heteroacenes Using Fischer Indolization.

A series of 6H-benzofuro[2′,3′:4,5]thieno[3,2-b]indoles were readily synthesized from methyl 3-aminothieno[3,2-b]benzofuran-2-carboxylates using a one-pot procedure with Fischer indolization as the key step. At the same time, 3-aminothieno[3,2-b]benzofuran-2-carboxylates were prepared from 3-chlorobenzofuran-2-carbaldehydes in three steps, including replacement of the Cl atom at the C-3 position of these starting substrates onto the -SCH2CO2Me moiety, conversion of the CHO group at the C-2 position into the CN group, followed by base-promoted cyclization of the formed carbonitrile. The present route was elaborated by us because we failed to obtain directly the desired 3-aminothiophene-2-carboxylate by reaction of 3-chlorobenzofuran-2-carbonitrile with methyl thioglycolate in the presence of various bases. In turn, 3-chlorobenzofuran-2-carbaldehydes were prepared from benzofuran-3(2H)-ones following the Vilsmeier–Haack–Arnold reaction.

Total Synthesis via Biomimetic Late-Stage Heterocyclization: Assignment of the Relative Configuration and Biological Evaluation of the Nitraria Alkaloid (±)-Nitrabirine.

The racemic total synthesis of nitrabirine (5) together with its previously undescribed epimer 2-epi nitrabirine (5') is accomplished via a six-step route based on a biomimetic late-stage heterocyclization. This allowed the assignment of the relative configuration of nitrabirine by the lanthanide-induced shifts (LIS) experiment, which was later on confirmed by X-ray diffraction of obtained single crystals. Furthermore, oxidation studies demonstrated that the direct N-oxidation of nitrabirine does not yield nitrabirine N-oxide as reported earlier. In contrast, the reaction of hydrogen peroxide with nitrabirine (5) yields the salt 24', whereas 2-epi nitrabirine (5') surprisingly leads to a previously uncharacterized product 22 under the same conditions. Finally, a Fischer indole reaction gave access to novel tetracyclic nitrabirine derivatives 26a-d. A comprehensive biological evaluation of nitrabirine (5), 2-epi nitrabirine (5'), and all derivatives synthesized in this study revealed general biofilm dispersal effects against Candida albicans. Moreover, specific compounds showed moderate antibacterial activities as well as potent cytotoxic activities.

Synthesis of 6H,7H-chromeno[3′,4′:4,5]thieno[3,2-b]indol-6-ones using the Fischer indolization reaction

A series of 6H,7H-chromeno[3′,4′:4,5]thieno[3,2-b]indol-6-ones, bearing thieno[3,2-b]indole and coumarin parts in their fused molecules, were readily prepared using one-pot procedure based on reaction of 3-aminothieno[3,2-c]coumarins, in situ formed from 3-aminothieno[3,2-c]coumarin-2-carboxylates, with arylhyrazines according to the Fischer indole synthesis. In turn, the synthesis of methyl 3-aminothieno[3,2-c]coumarin-2-carboxylates were carried out in two steps from available 4-hydroxycoumarins. To this end, 4-hydroxycoumarins were successively treated with POCl3-DMF complex and hydroxylamine hydrochloride to obtain 4-chloro-3-cyanocoumarins. The latter substrates further reacted with methyl thioglycolate in the presence of NaOMe to give the required 3-aminothiophene-2-carboxylate precursors.

Catalytic Asymmetric Fischer Indolization by Desymmetrization of Cyclopentane-1,3-diones

Catalytic Asymmetric Fischer Indolization by Desymmetrization of Cyclopentane-1,3-diones

Tetrahydrocarbazoles by mechanochemical Fischer indolisation

The Fischer indolisation (FI) typically proceeds in the presence of a Brønsted or Lewis acid in an organic solvent at elevated temperatures. Herein, we report that tetrahydrocarbazoles (THCs) are accessible by mechanochemical FI at ambient temperature. Using phenylhydrazine hydrochlorides in the presence of silica is critical for this solid-state variant of the FI.

Concise total synthesis of nauclefine: A regioselective Rhodium(III)-catalyzed oxidative C-H activation approach

Abstract A concise total synthesis of the plant indole alkaloid natural product nauclefine (1) was accomplished from the commercially available nicotinic acid and the known compound in 6 steps. The synthesis features a regioselective rhodium(III)-catalyzed oxidative C-H activation for the construction of the key naphthyridinone ring. The intramolecular Mitsunobu-type annulation, allylic oxidation and Fischer indolization were used successively to complete the total synthesis of nauclefine (1).

Chiral Spirocyclic Phosphoric Acids and Their Growing Applications

AbstractChiral spirocyclic phosphoric acids (SPAs) are introduced in 2010 and have been versatile catalysts capable of promoting a wide range of asymmetric organocatalytic reactions, such as multi‐component reactions, Friedel–Crafts reactions, Pictet–Spengler reactions, Fischer indolizations, cycloaddition reactions, desymmetrization reactions, dearomatization reactions, conjugate addition reactions and rearrangement reactions, etc. Moreover, a diverse range of applications in metal‐organic cooperative catalysis, organic photoredox catalysis, total synthesis, materials science and molecular recognition are beautifully illustrated. This account summarizes the past decade's advances in this field and highlights the selected but not comprehensive significant achievements. What is the most favorite and original chemistry developed in your research group?Developing SPINOL‐phosphoric acids (SPAs), TM‐SPINOL‐phosphoric acids (SPAs 2.0) and PCP‐derived planar chiral phosphoric acids (PPAs) for asymmetric catalysis.What is the most important personality for scientific research?Curiosity, optimism, self‐confidence and persistence.What's your hobbies? What's your favorite book(s)?I enjoy cooking. My favorite book is Journey to the West.Who influences you mostly in your life?My mother.What is your favorite journal(s)?The journals publishing the original and systematic work of synthetic chemistry.Could you please give us some advices on improving Chinese Journal of Chemistry?Fast review, fast publication, fast promotion via new media.

Why is an experimental regioselectivity of Fischer indole syntheses observed: A mechanistic model DFT study

The Fischer indole synthesis of the ketone 1 with phenylhydrazine is studied using DFT methods. A detailed reaction mechanism is proposed and evaluated, including different plausible diaza-Cope rearrangement pathways. Cis -/ trans -stereochemistry of the substrate 1 leads to different pathways and products. In addition, the influence of hydrazine protonation on the mechanism is investigated. Only implicit solvation at the PCM-M06–2X/6–311++G(d,p) level of theory predicts correctly the product stability. Furthermore, the importance of nitrogen protonation resulting in lower (and feasible) activation energies for the key step is shown. In agreement with experimental data, the pathways leading to observed products possess the lowest activation barriers. With the proposed mechanism, the correct thermodynamic and kinetic control for this rather complicated reaction is calculated, and the procedure should be able further predict regioselectivity of related systems. • The complete mechanism of a Fischer Indol Cyclization is investigated. • Regioselectivity can be explained with DFT calculations. • Proton catalysis and implicit solvation mandatory for correct results.

An Effective Route to Dithieno[3,2-b:2′,3′-d]thiophene-Based Hexaheteroacenes

AbstractA series of 12H-[1]benzo[4′′,5′′]thieno[2′′,3′′:4′,5′]thieno[2′,3′:4,5]thieno[3,2-b]indoles were efficiently prepared in three steps starting from available benzo[b]thieno[2,3-d]thiophen-3(2H)-ones. These fused ketones were treated with the Vilsmeier reagent and hydroxylamine hydrochloride to give the corresponding 3-chlorobenzo[b]thieno[2,3-d]thiophene-2-carbonitriles, which then reacted with methyl sulfanylacetate to form methyl 3-aminobenzo[4′,5′]thieno[2′,3′:4,5]thieno[3,2-b]thiophene-2-carboxylates, in accordance with the Fiesselmann thiophene synthesis protocol. Finally, the desired N,S-heterohexacenes were obtained by conversion of these fused 3-aminothiophene-2-carboxylates into the corresponding 3-aminothiophene intermediates, which acted as synthetic equivalents of thiophen-3(2H)-ones, followed by their acid-promoted reaction with arylhydrazines, in accordance with the Fischer indolization procedure.

Effect of Terminal Alkylation of Aryl and Heteroaryl Hydrazines in the Fischer Indole Synthesis

The effect of alkylation on the terminal position of aryl and heteroaryl hydrazines in the Fischer indole synthesis was examined. Compared to their unalkylated counterparts, reactions using alkylated hydrazines provided indole products with higher yields and faster rates. The reactions can be conducted at lower temperatures and are compatible with acid-sensitive functionality. The terminally alkylated hydrazines were readily prepared by a new two-step sequence and held as stable hydrazinium salts. The mild formation of the salts along with the favorable Fischer indole reaction conditions highlights the potential of this approach in later-stage synthetic use.

Catalytic Enantioselective Desymmetrizing Fischer Indolization through Dynamic Kinetic Resolution

AbstractThe first catalytic enantioselective Fischer indolization of prochiral diketones containing enantiotopic carbonyl groups is developed and shown to proceed through dynamic kinetic resolution (DKR). Catalyzed by the combination of a spirocyclic chiral phosphoric acid and ZnCl2 (Lewis acid assisted Brønsted acid), this direct approach combines 2,2‐disubstituted cyclopentane‐1,3‐diones with N‐protected phenylhydrazines to furnish cyclopenta[b]indole derivatives containing an all‐carbon quaternary stereocenter with good to excellent enantioselectivities.

Catalytic Enantioselective Desymmetrizing Fischer Indolization through Dynamic Kinetic Resolution.

The first catalytic enantioselective Fischer indolization of prochiral diketones containing enantiotopic carbonyl groups is developed and shown to proceed through dynamic kinetic resolution (DKR). Catalyzed by the combination of a spirocyclic chiral phosphoric acid and ZnCl2 (Lewis acid assisted Brønsted acid), this direct approach combines 2,2-disubstituted cyclopentane-1,3-diones with N-protected phenylhydrazines to furnish cyclopenta[b]indole derivatives containing an all-carbon quaternary stereocenter with good to excellent enantioselectivities.

Synthetic Approaches to Tricyclic Aminoketones in the Total Synthesis of Aspidosperma and Kopsia Alkaloids.

Aspidosperma and kopsia alkaloids are significant functional molecules because of their potent biological activities. Their intricate structures present an intrinsic synthetic challenge and thus attract significant attention from synthetic organic academic community. Over the past decades, a series of elegant strategies has been developed, in particular, the Stork's original Fischer indolization of tricyclic aminoketones 1. Herein, we report a comprehensive review on various synthetic approaches access to tricyclic aminoketones 1 and provide a practical guidance to readers whose are interested in employing tricyclic aminoketones 1 as versatile building blocks in the realm of total synthesis of aspidosperma, kopsia and structurally related alkaloids.

Synthesis and Characterization of 5-MeO-DMT Succinate for Clinical Use.

To support clinical use, a multigram-scale process has been developed to provide 5-MeO-DMT, a psychedelic natural product found in the parotid gland secretions of the toad, Incilius alvarius. Several synthetic routes were initially explored, and the selected process featured an optimized Fischer indole reaction to 5-MeO-DMT freebase in high-yield, from which the 1:1 succinate salt was produced to provide 136 g of crystalline active pharmaceutical ingredient (API) with 99.86% peak area by high-performance liquid chromatography (HPLC) and a net yield of 49%. The report provides in-process monitoring, validated analytical methods, impurity formation and removal, and solid-state characterization of the API essential for subsequent clinical development.

Green Fischer Indole Synthesis Using a Steroidal Ketone in a Conductively Heated Sealed-Vessel Reactor for the Advanced Undergraduate Laboratory

Highly efficient microwave-assisted organic synthesis is now commonplace in both industry and academia. Recently, a conductively heated sealed-vessel reactor was introduced that acts very similarly to a microwave reactor and is more affordable. Application of such reactors in teaching laboratories is advantageous because of the restricted window of time available to perform experiments and because it avoids long reaction times that are unpopular with students. These reactors thus allow reactions that were previously considered impractical for the teaching laboratory, such as the Fischer indole synthesis, to now be very feasible. We designed a clean and efficient Fischer indole synthesis to introduce advanced undergraduate students to this important method in heterocycle synthesis, which has been highly under-represented in the curriculum. It also introduces it in the context of a more complex ketone of biological relevance (a steroid). This laboratory exercise can be used to teach about Green Chemistry Principles, product analysis (TLC, NMR, MS, UV–vis), and a complex multistep mechanism. It can also act as a starting point to teach terpenoid biosynthesis, some key concepts in medicinal chemistry such as pharmacophores and pro-drugs, and even to open discussions on the societal impacts of steroids.

Design and Synthesis of Cage Molecules as High Energy Density Materials for Aerospace Applications

AbstractThis account deals with our work on cage systems that was reported during the past two decades. Here, we summarized various new synthetic routes to diverse cage polycycles by employing Claisen rearrangement, Diels−Alder (DA) reaction, [2+2] photocycloaddition, Grignard addition, Fischer indolization, ring‐closing metathesis (RCM), Van Leusen oxazole synthesis, and rearrangement reaction as key steps. Several heterocyclic cage frameworks (oxacycles and oxazoles), polycyclic bisindoles, cage spirocycles, cage energetic systems,D3‐trishomocubanes, cage propellanes and unusual polycycles were designed starting with inexpensive and easily accessible starting materials. In some occasions, we also prepared biologically important triquinane frameworks starting with readily available cage diones via photo‐thermal olefin metathesis strategy under microwave irradiation conditions. This new protocol avoids specialized equipment such as flash vacuum pyrolysis. Additionally, we have also shown interesting rearrangements in cage frameworks to generate unusual new and cage systems with the aid of the Lewis acids such as BF3.OEt2. Moreover, these functionalized cage systems can be considered as a useful candidates in material science, medicinal chemistry, and also in drug in design.

In with the Old, Out with the New: Homologation of Fischer Indolization to Synthesize Quinolines

Key words quinoline synthesis - homologation - diaza-Cope rearrangement