Cadogan Cyclization Research Articles

Synthesis of 10H-di(1-benzothiopheno)[2,3-b:3′,2′-d]pyrrole: re-investigation of the Cadogan cyclization route

Abstract The reaction of 2-nitro-3,3′-bi(1-benzothiophene) bearing ester groups at 7- and 7′-positions under the Cadogan cyclization conditions (PPh3, o-C6H4Cl2, refl.) afforded the targeted 10H-di(1-benzothiopheno)[2,3-b:3′,2′-d]pyrrole-1,8-dicarboxylate derivative in a low yield accompanied with a byproduct. On the other hand, the Cadogan reaction of 2-nitro-3,3′-bi(1-benzothiophene) without ester groups did not provide the corresponding pyrrole but gave a mixture of thiophene-ring-opening products, from which dibenzothiophenothiopyrans were isolated. The structures of these ring-opening products were fully characterized by spectroscopic and X-ray analyses and the generation mechanism giving the byproducts was deduced. Pristine 10H-di(1-benzothiopheno)[2,3-b:3′,2′-d]pyrrole could be prepared via another route, namely nitrosation followed by cyclization and reduction.

Iminophosphorane in perylenediimide chemistry: Staudinger reaction and a visible-light-driven competitive reaction of the Cadogan cyclization

A novel bay functionalization of the perylenediimide backbone introduced an iminophosphorane group via a Staudinger reaction in the dark, while a light-driven rearrangement of the Cadogan cyclization added a hydroxy group at the 12-position.

A Minireview on the Scope of Cadogan Cyclization Reactions Leading to Diverse Azaheterocycles

AbstractFrom the last two decades, Cadogan cyclization reaction is considered as one of the best routes for the preparation of various azaheterocycles comprising carbazoles, indoles, coumarins, carbolines, pyrazoloquinoxalines, S,N‐heterotetracenes from the nitro‐based substrates by using a variety of tetravalent phosphorus‐based reagents. To date the majority of Cadogan reactions are found to be intramolecular reactions, however, interestingly, a case of intermolecular Cadogan reaction is also reported, resulting in the widening of the reaction scope for futuristic perspectives. We report the Cadogan cyclization reactions for the synthesis of azaheterocycles from 2018 to present according to multiple classes of chemical frameworks including its scope (FDA approved drugs), along with the possibilities and mechanistic developments for unexpected products.

Cyclic bridged analogs of isoCA-4: Design, synthesis and biological evaluation.

In this work, a series of cyclic bridged analogs of isocombretastatin A-4 (isoCA-4) with phenyl or pyridine linkers were designed and synthesized. The synthesis of the desired analogs was performed by the formation of nitro-vinyl intermediates, followed by a Cadogan cyclization. Structure activity relationship (SAR) study demonstrates the critical role of the combination of quinaldine as ring A, pyridine as the linker, and indole as ring B in the same molecule, for the cytotoxic activity. Among all tested compounds, compound 42 showed the highest antiproliferative activity against a panel of cancer cell lines with average IC50 values of 5.6nM. Also, compound 42 showed high antiproliferative activity against the MDR1-overexpressing K562R cell line; thus, it was 1.5- and 12-fold more active than the reference compounds, isoCA-4 and CA-4, respectively. Moreover, 42 displayed a strong antiproliferative activity against the colon-carcinoma cells (HT-29), which are resistant to combretastatin A-4 and isoCA-4, and it was found to be 8000-fold more active than natural CA-4. Compound 42 also effectively inhibited tubulin polymerization both invitro and in cells, and induced cell cycle arrest in G2/M phase. Next, we demonstrated that compound 42 dose-dependently caused caspase-induced apoptosis of K562cells through mitochondrial dysfunction. Finally, we evaluated the effect of compound 42 in human no cancer cells compared to the reference compound. We demonstrated that 42 was 73 times less cytotoxic than isoCA-4 in quiescent peripheral blood lymphocytes (PBLs). In summary, these results suggest that compound 42 represents a promising tubulin inhibitor worthy of further investigation.

Triazole‐fused indolo[2,3‐a]carbazoles: synthesis, structures, and properties

AbstractThe synthesis, structure, and photophysical and electrochemical properties of triazole fused indolo[2,3‐a]carbazole derivatives 2‐5 are reported. The key step involved in the synthesis of triazole fused indolo[2,3‐a]carbazole derivatives is the Cadogan ring closing reaction. 2‐Hexyl‐5,6‐dinitro‐2H‐benzo[d][1,2,3]triazoles having 4,7‐diaryl capping were subjected to the Cadogan cyclization reaction to obtain compounds 2‐5. In contrast to thiadiazole‐fused indolo[2,3‐a]carbazole 1, bromination of triazole‐fused indolo[2,3‐a]carbazole 4 afforded only meta‐dibrominated product with respect to the nitrogen of fused pyrrole rings on treatment with both N‐bromosuccinimide (NBS) and elemental bromine. These compounds showed positive solvatochromism in their emission spectra. Incorporation of electron‐donating substituent in the indole moiety resulted in the elevation of the highest occupied molecular orbital (HOMO) level. Density functional theory (DFT) calculations were performed to support the experimental findings.

Original Suzuki–Miyaura Coupling Using Nitro Derivatives for the Synthesis of Perylenediimide‐Based Multimers

A series of perylenediimide (PDI)‐based multimers were synthesized using an original Suzuki–Miyaura Coupling (SMC) reaction. The new approach considers the reaction between 1‐nitroPDI as the electrophilic reagent with a wide variety of boronic esters to reach PDI dimers, trimers and tetramers which are of particular interest as Non‐Fullerene Acceptors (NFAs) in organic photovoltaics. In this work, we compared the reactivity of 1‐bromoPDI and 1‐nitroPDI towards this pallado‐catalyzed cross‐coupling reaction. Considering that 1‐nitroPDI is more accessible in terms of selectivity, time reaction, purification efficiency, atom economy, etc, we have shown that the use of nitroarenes is largely favored in the preparation of these PDI‐based multimers. The latter were characterized with determination of their spectroscopic and electrochemical properties. With the aim of extending this SMC reaction to N‐annulated PDI analogues, an original and efficient transformation of nitro‐PDI into pyrrole‐fused PDI was found as an alternative to the well‐known reductive Cadogan cyclization. The SMC reaction was applied to bromo and nitro N‐annulated PDI derivatives, and DFT calculations were accomplished in order to clarify the oxidative addition step of the cross‐coupling and understand the difference of reactivity between the bromo‐ and nitro‐PDI based electrophiles.

C3‐Alkenylation between Pyrroles and Aldehydes Mediated by a Brønsted Acid and a Brønsted Base

A transition‐metal‐free, redox‐neutral, organocatalytic C3‐alkenylation of pyrroles is reported. Readily available aldehydes were employed as alkenylating agent and the reaction tolerates several key functional groups. The E‐alkenylated products were isolated in moderate to exclusive selectivity. A one‐pot two‐fold alkenylation strategy is also developed for further downstream modifications. To show the applicability, synthetically challenging indolylpyrrole derivatives were synthesized using Cadogan cyclization.

Synthesis of δ-Carbolines and the Alkaloid Quindoline through a Molybdenum-Catalyzed Cadogan Cyclization and their Photoluminescent Properties

Cadogan reductive cyclization of substituted 2-aryl-3-nitropyridines to give δ-carbolines was performed under MoO2Cl2(DMF)2 catalysis with triphenylphosphine as a ligand. A new approach for the synthesis of the alkaloid quindoline based on a Mo(VI)-catalyzed Cadogan reductive cyclization of 2-phenyl-3-nitro-5,6,7,8-tetrahydroquinoline followed by aromatization of the resulting 2,3,4,10-tetrahydro-1H-indolo[3,2-b]quinoline is proposed. Various о-nitroarylpyridines, obtained by reacting acylpyruvates and cyclic hydroxymethylene ketones with nitroacetophenone enamines, were used as starting compounds for the preparation of δ-carbolines. The synthesized δ-carbolines were found to act as phosphors; their photophysical properties were studied and a structure–property relationship was revealed.

Accessing Multiple Classes of 2 H-Indazoles: Mechanistic Implications for the Cadogan and Davis-Beirut Reactions.

The Cadogan cyclization is a robust but harsh method for the synthesis of 2 H-indazoles, a valuable class of nitrogen heterocycles. Although nitrene generation by exhaustive deoxygenation is widely accepted as the operating mechanism in the reductive cyclization of nitroaromatics, non-nitrene pathways have only been theorized previously. Here, 2 H-indazole N-oxides were synthesized through an interrupted Cadogan/Davis-Beirut reaction and are presented as direct evidence of competent oxygenated intermediates; mechanistic implications for both reactions are discussed. Isolation and characterization of these N-oxides enabled a formal Cadogan cyclization at room temperature for 2 H-indazole synthesis.

Efficient Synthesis and Characterization of Solvatochromic Fluorophore

A highly efficient designing and synthesis of an aryl‐substituted carbazole‐based fluorescent material (MeOCbzBP) has been carried out via tandem carbon–carbon (C–C)/carbon–nitrogen (C–N) bond formation by multiple Suzuki couplings and Cadogan cyclization followed by C–N cross‐couplings. Various organic solvents have been used to investigate photophysical, solvatofluorochromism, and photoluminescence characteristics of MeOCbzBP. The MeOCbzBP showed a reasonable redshifted absorption in UV region and photoluminescence enhancements in tetrahydrofuran/water mixtures. Furthermore, we also employed various theoretical functions to optimize the molecule both in the ground and excited states. A well‐known density functional theory was employed in a solvent phase with B3LYP/6‐31G(d) level of theories. We believe that the MeOCbzBP will provide a better platform to investigate the novel applications in the field of medicinal chemistry and chemical biology.

Synthesis of 3‐Aryl‐2‐(trifluoromethyl)indoles via Copper‐Catalyzed Hydroarylation and Subsequent Cadogan Cyclization

AbstractThe copper‐catalyzed hydroarylation of (trifluoromethyl)alkynes with (o‐nitrophenyl)boronic acids selectively afforded trisubstituted (trifluoromethyl)alkenes bearing an o‐nitrophenyl group. The obtained hydroarylation products were converted into 3‐aryl‐2‐(trifluoromethyl)indoles in high yields via molybdenum‐catalyzed Cadogan cyclization. Similarly, the hydroarylation product prepared from (o‐nitrophenyl)(trifluoromethyl)alkyne and (p‐anisyl)boronic acid also underwent Cadogan cyclization, albeit with a longer reaction time, affording the desired indole product in a high yield.magnified image

Efficient synthesis of aryl-substituted carbazoles via tandem double or triple suzuki coupling and cadogan cyclization

An efficient one-step method to prepare aryl-substituted carbazoles via tandem double or triple CC bond formations by multiple Suzuki couplings and CN bond formation by Cadogan cyclization has been developed. The developed method employs commercially available or easily preparable polybromonitrobenzenes and arylboronic acids as starting materials, tolerates various functional groups, and provides good yields.

One-pot synthesis of new isatin-porphyrin conjugates by the palladium Buchwald-Hartwig methodology involving β-aminoporphyrinatonickel(II) and 3-ketal isatin derivatives

A simple methodology giving rise to a new series of isatin-porphyrin conjugates and corresponding intracyclized derivatives is described. Palladium-catalyzed amination reactions of iodinated isatin derivatives containing the 3-carbonyl group protected with ketal functionalities and 2-amino-5,10,15,20-tetraphenylporphyrinatonickel(II) was the used procedure. The combination of palladium catalysts and the phosphine ligand dicyclohexylphospino-2′,4′,6’-triisopropylbiphenyl (XPhos) led to isatin-porphyrin conjugates in good yields. Nevertheless, the use of palladium acetate even resulted on the formation of additional six membered fused ring compounds. This brings a new perspective to access quinolino[2,3,4-at]porphyrins, a set of compounds which are typically obtained by harsh Cadogan or thermal cyclization approaches.

Synthesis of carbazole analogs via Grob fragmentation of norbornyl α-diketones

A regioselective synthesis of carbazole analogs belonging to both the categories of natural origin, viz., microorganisms and higher plant source is reported. The synthesis of carbazole derivatives possessing a methylester group at C-1 position has been achieved by Cadogan cyclization of nitro bi-phenyl derivatives, whereas, the carbazole analog possessing a methylester group at C-3 position was synthesized by Buchwald–Hartwig Pd-catalyzed cyclization of amino bi-phenyl derivatives. Suitably substituted bi-phenyl precursors were accessed from norbornyl α-diketones via Grob fragmentation, O-methylation and DBU aromatization reaction sequence. The reported carbazole derivatives possess structural features that are common with many carbazole natural products: mukonine, clausine-L, murrayafoline-A, and their sibling natural products.

ChemInform Abstract: One‐Pot Synthesis of Carbazoles via Tandem C—C Cross‐Coupling and Reductive Amination.

AbstractA synthetic route towards carbazoles, based on sequential C—C/C—N bond formation via Suzuki cross‐coupling and Cadogan cyclization is developed.

One-pot synthesis of carbazoles via tandem C–C cross-coupling and reductive amination

We have developed a highly efficient synthetic route to carbazoles that employs sequential C-C/C-N bond formation via Suzuki cross-coupling and Cadogan cyclization using commercially available or easily preparable starting materials. The developed method is compatible with electron neutral, rich or deficient substrates. The synthetic utility of this method was demonstrated by the concise syntheses of four natural products (glycozoline, glycozolicine, glycozolidine and clausenalene).

A straightforward synthesis of indazolo[3,2-a]isoquinolin-6-amines

Abstract 4-Substituted 1-bromoisoquinolin-3-amines were subjected to Suzuki coupling with o -nitrophenylboronic acid to yield 1-(2-nitrophenyl) isoquinolinamines, which participated in Cadogan cyclization with triethyl phosphite under microwave irradiation in a sealed vial to yield fluorescent indazolo[3,2- a ]isoquinolin-6-amines. The new compounds were also functionalized by transformation of the amino group.

5,11-Dimethyl-6,12-dimethoxyindolo[3,2-b]carbazole

The title compound, C22H20N2O2, was prepared in a twofold Cadogan cyclization followed by double N-methyl­ation. The crystal structure is characterized by a zigzag arrangement of centrosymmetric mol­ecules. The indolocarbazole framework is essentially planar [maximum deviation = 0.028 (2) Å] and the meth­oxy groups are orthogonal to this plane [C—C—O—C torsion angle = −88.2 (2)°]. The lengths of the C—N bonds are nearly identical and all C—C bonds of the pyrrole subunit are significantly longer than the C—C bonds in the benzene rings.

Synthesis of nitrodienes, nitrostyrenes, and nitrobiaryls through palladium-catalyzed couplings of β-nitrovinyl and o-nitroaryl thioethers

A highly efficient, base-free, mild protocol for the palladium-catalyzed, copper-activated desulfitative couplings of vinyl and aryl β-nitrothioethers generates a wide variety of conjugated nitroorganics. Orthogonality to traditional Suzuki–Miyaura coupling is demonstrated, as well as synthetic utility, through reductive Cadogan cyclization, for the formation of indoles, carbazoles, and pyrroles.

6,12-Bis(hexyloxy)-5H,11H-indolo[3,2-b]carbazole

The title compound, C30H36N2O2, was prepared in a twofold Cadogan cyclization. The mol­ecule is located about a center of inversion. The indolocarbazole skeleton is essentially planar [maximum deviation = 0.028 (2) Å], the C—N bond lengths are nearly identical and the C—C bond lengths of the pyrrole unit are significantly longer than those of the benzene subunits.