Tricyclic Heterocycles Research Articles

ChemInform Abstract: Copper‐Catalyzed C—H Alkynylation/Intramolecular Cyclization Cascade for the First Synthesis of Trifluoromethylated Pyrrolo[1,2‐a]quinolines.

A highly efficient and simple route for the first synthesis of CF3-substututed pyrrolo[1,2-a]quinolines from quinolines, terminal alkynes, and methyl 4,4,4-trifluorobut-2-ynoate is reported. The noteworthy feature of this report is that the method involves a two-step protocol to synthesize tricyclic heterocycles in a one-pot fashion through CuI-catalyzed C–H alkynylation for the formation of alkynyl-substituted 1,2-dihydroquinolines, followed by a CuII-assisted intramolecular cyclization under air. This strategy tolerates a wide range of substrates with a variety of functional groups under mild conditions, and gives the products in good to excellent yields.

One-pot synthesis of bi- and tricyclic heterocyclic compounds using benzotriazole chemistry

Microwave-mediated one-step synthesis of several bi- and tricyclic heterocycles via the intermolecular cyclization of N-acylbisbenzotriazoles with ortho-phenylenediamine in good yield is reported.

Microwave-Assisted Intramolecular Ullmann Diaryl Etherification as the Post-Ugi Annulation for Generation of Dibenz[b,f][1,4]oxazepine Scaffold.

A sequence of the Ugi four-component reaction (U-4CR) and microwave-assisted intramolecular Ullmann etherification has been established for efficient generation of a dibenz[b,f][1,4]oxazepine scaffold. The U-4CR, using 2-aminophenols and 2-bromobenzoic acids or 2-bromobenzaldehydes as the inputs, was carried out in MeOH at 50-60 °C for 2-3 days to form a collection of 22 linear products in 46-90% yields. A microwave-assisted intramolecular Ullmann etherification was then used to transform these acyclic U-4CR products into the cleft-shaped 6/7/6-fused tricyclic heterocycles. The intramolecular Ullmann diaryl ether formation was catalyzed by 10 mol % of CuI and 30 mol % of N,N-dimethylglycine hydrochloride (DMG·HCl) in the presence of Cs2CO3 with microwave irradiation (150 °C, 30 min) to furnish dibenz[b,f][1,4]oxazepin-11(10H)-ones and dibenz[b,f][1,4]oxazepin-11(10H)-carboxamides in 64-100% yields.

ChemInform Abstract: Synthesis of Carbazoles and Carbazole‐Containing Heterocycles via Rhodium‐Catalyzed Tandem Carbonylative Benzannulations.

Polycyclic aromatic compounds are important constituents of pharmaceuticals and other materials. We have developed a series of Rh-catalyzed tandem carbonylative benzannulations for the synthesis of tri-, tetra-, and pentacyclic heterocycles from different types of aryl propargylic alcohols. These tandem reactions provide efficient access to highly substituted carbazoles, furocarbazoles, pyrrolocarbazoles, thiophenocarbazoles, and indolocarbazoles. While tricyclic heterocycles could be derived from vinyl aryl propargylic alcohols, tetra- and pentacyclic heterocycles were synthesized from diaryl propargylic alcohols. The tandem carbonylative benzannulation is initiated by a π-acidic rhodium(I) catalyst-mediated nucleophilic addition to alkyne to generate a key metal-carbene intermediate, which is then trapped by carbon monoxide to form a ketene species for 6π electrocyclization. Overall, three bonds and two rings are formed in all of these tandem carbonylative benzannulation reactions.

Convergent Synthesis of Diverse Nitrogen Heterocycles via Rh(III)-Catalyzed C-H Conjugate Addition/Cyclization Reactions.

The development of Rh(III)-catalyzed C-H conjugate addition/cyclization reactions that provide access to synthetically useful fused bi- and tricyclic nitrogen heterocycles is reported. A broad scope of C-H functionalization substrates and electrophilic olefin coupling partners is effective, and depending on the nature of the directing group, cyclic imide, amide, or heteroaromatic products are obtained. An efficient synthesis of a pyrrolophenanthridine alkaloid natural product, oxoassoanine, highlights the utility of this method.

Copper‐Catalyzed C–H Alkynylation/Intramolecular Cyclization Cascade for the First Synthesis of Trifluoromethylated Pyrrolo[1,2‐a]quinolines

A highly efficient and simple route for the first synthesis of CF3‐substututed pyrrolo[1,2‐a]quinolines from quinolines, terminal alkynes, and methyl 4,4,4‐trifluorobut‐2‐ynoate is reported. The noteworthy feature of this report is that the method involves a two‐step protocol to synthesize tricyclic heterocycles in a one‐pot fashion through CuI‐catalyzed C–H alkynylation for the formation of alkynyl‐substituted 1,2‐dihydroquinolines, followed by a CuII‐assisted intramolecular cyclization under air. This strategy tolerates a wide range of substrates with a variety of functional groups under mild conditions, and gives the products in good to excellent yields.

A direct synthetic route to fused tricyclic quinolones from 2,3-diaminoquinolin-4(1H)one

Abstract Fused tricyclic heterocycles are useful compounds in many areas of chemistry. In this study, 2,3-diaminoquinolin-4(1H)one (5), a key intermediate for the preparation of tricyclic compounds, was prepared from isatoic anhydride in four steps with high yields under mild conditions and an easy workup, with most of the reactions carried out in aqueous medium. Compound 5 was transformed into a series of tricyclic fused products 8 and 9.

Synthesis of Carbazoles and Carbazole-Containing Heterocycles via Rhodium-Catalyzed Tandem Carbonylative Benzannulations.

Polycyclic aromatic compounds are important constituents of pharmaceuticals and other materials. We have developed a series of Rh-catalyzed tandem carbonylative benzannulations for the synthesis of tri-, tetra-, and pentacyclic heterocycles from different types of aryl propargylic alcohols. These tandem reactions provide efficient access to highly substituted carbazoles, furocarbazoles, pyrrolocarbazoles, thiophenocarbazoles, and indolocarbazoles. While tricyclic heterocycles could be derived from vinyl aryl propargylic alcohols, tetra- and pentacyclic heterocycles were synthesized from diaryl propargylic alcohols. The tandem carbonylative benzannulation is initiated by a π-acidic rhodium(I) catalyst-mediated nucleophilic addition to alkyne to generate a key metal-carbene intermediate, which is then trapped by carbon monoxide to form a ketene species for 6π electrocyclization. Overall, three bonds and two rings are formed in all of these tandem carbonylative benzannulation reactions.

Discovery of Novel Tricyclic Heterocycles as Potent and Selective DPP-4 Inhibitors for the Treatment of Type 2 Diabetes.

In our efforts to develop second generation DPP-4 inhibitors, we endeavored to identify distinct structures with long-acting (once weekly) potential. Taking advantage of X-ray cocrystal structures of sitagliptin and other DPP-4 inhibitors, such as alogliptin and linagliptin bound to DPP-4, and aided by molecular modeling, we designed several series of heterocyclic compounds as initial targets. During their synthesis, an unexpected chemical transformation provided a novel tricyclic scaffold that was beyond our original design. Capitalizing on this serendipitous discovery, we have elaborated this scaffold into a very potent and selective DPP-4 inhibitor lead series, as highlighted by compound 17c.

Synthesis of 5-carboxy-6-methyl-3,4-dihydro-2(1H)-pyridone derivatives and their electrochemical oxidation to 2-pyridones

A series of variously substituted 5-carboxy-6-methyl-3,4-dihydro-2(1H)-pyridone derivatives were synthesized and their oxidation potentials determined by cyclic voltammetry. The resulting 2-pyridone structure and a tricyclic heterocycle which was formed during an attempted synthesis of 4-(2-hydroxyphenyl) substituted 3,4-dihydro-2(1H)-pyridone were confirmed by single crystal X-ray crystallography.

ChemInform Abstract: Prins‐Driven Friedel—Crafts Reaction for the Stereoselective Synthesis of Hexahydroindeno[2,1‐c]pyran Derivatives.

AbstractTreatment of (E)‐diphenylalkenes bearing a primary ethanol side chain with aliphatic or aromatic aldehydes under conditions A) produces the desired tricyclic heterocycle as scaffold of various natural substances and pharmaceutical agents.

ChemInform Abstract: Regioselective One‐Pot Three‐Component Synthesis of Quinoline Based 1,2,4‐Triazolo[1,5‐a]quinoline Derivatives.

A one-pot three-component approach for the synthesis of 2-(piperidin-1-yl) quinoline based 1,2,4-triazolo[1,5-a]quinoline derivatives (4a–l) has been described by the reaction of aldehyde (1a–f), methyl 2-cyanoacetate (2) and enaminones (3a–b). Different regioselectivities of the reaction are attained with different catalysts and the highest regioselectivity is achieved by L-proline. This new procedure provides an efficient method to construct fused tricyclic heterocycles containing 1,2,4-triazole analogues. In this regard, we have used the least amount of amphoteric catalyst, like L-proline, ammonium acetate and a mixture of pyrolidine with acetic acid, to obtain the 1,4-dihydroquinoline derivative 5a as a by-product. The salient features of this protocol are the mild reaction conditions, high yield (75–85%) and higher regioselectivity toward the desired products 4a–l. The structures of the title compounds were confirmed by FT-IR, 1H NMR, 13C NMR and mass spectrometry.

Heterocycles [h]-fused to 4-oxoquinoline-3-carboxylic acid. Part XI: Synthesis and antibacterial activity of 4-fluoro-6-oxoimidazo[4,5-h]quinoline-7-carboxylic acids

AbstractA series of 2-hetaryl-4-fluoro-9-cyclopropyl-6-oxo-1H-imidazo[4,5-h]quinoline-7-carboxylic esters (3a–f) and their corresponding acids4a–fhave been preparedviamicrowave-assisted cyclocondensation reaction with some hetarene carboxaldehydes. The structures for these new esters and acids are based on spectral (IR, MS, and NMR) data. Thein vitroantimicrobial assay of4a–fhetaryl derivatives, their aryl analogues1d–g, and the imidazo-unsubstituted acid1ashowed that all of these tricyclic heterocycles possess a good level of antibacterial activity. Among them, compound1aexhibited the highest effect against both, Gram-positive (minimum inhibitory concentrations [MICs] 0.15–3.0 μg mL–1) and Gram-negative bacteria (MICs 0.7–3.0 μg mL–1). An excellent activity was recorded also for the halo-phenyl derivatives1f,gand for the furan derivatives4e,f, especially toward Gram-positive strains andBacillus subtilisandHaemophilus influenzae, respectively.

Investigation of a Late‐Stage Derivatiza­tion Approach to Isatogens: Discovery of New Reaction Pathways

AbstractWe have developed a new strategy for preparing 2‐substituted indolone N‐oxides (isatogens) by substitution reactions with aryl‐ and alkyl‐organometallic reagents. This approach allows a range of substituents to be incorporated at a late stage and complements existing methods that necessitate their early stage incorporation during substrate preparation. Further chemistry has been found to take place at the nitrone moiety; intramolecular dipolar cycloaddition provides access to angularly fused tricyclic heterocycles. More unusually however, these compounds are prone to further addition by organozinc reagents leading to 2,2‐disubstituted 3‐oxindole products.

Sequential Multicomponent Reactions and a Cu-Mediated Rearrangement: Diastereoselective Synthesis of Tricyclic Ketones.

A novel Cu-mediated rearrangement reaction based on bisamides containing a thiazolidine substructure opens the possibility for diastereoselective synthesis toward a tricyclic annulated and bridged heterocyclic system. The required precursors are easily synthesizable by a two-step synthetic pathway using the concept of sequential multicomponent reactions, i.e. the Asinger and Ugi reactions. Due to this synthesis strategy, a number of unique tricyclic heterocycles, characterized by high diversity, are synthesized in an effective manner.

Burmese thanaka powder and benedict’s reagent to struggle the liaison dangereuse: inverse psoriasis plus intertrigo

Psoralens are a class of tricyclic aromatic heterocycles that have been used as chemical probes to study DNA and RNA structures. On exposure to UV light, psoralens form chemical cross-links to the DNA bases in three steps [8-10]. The first step is intercalation of psoralen between two adjacent base pairs. The second step is formation of a monoadduct, i.e., one psoralen photoreacts to one strand of DNA. The third step is the cross-linking of the same psoralen to the other strand of DNA. Many researchers have confirmed that the formation of monoadduct psoralen-DNA-thymine (to yield the cellular apoptosis) can be the sole responsible of the clinical attempt to cure psoriasis, where the theory is accepted, that psoriasis may have the capacity to develop when the immune system mistakes a normal skin cell for a pathogen, and sending out faulty signals that may cause overproduction of new skin cells, so that the disease could be considered as a neoplastic manifestation at all.

ChemInform Abstract: Stereoselective Lewis Base Catalyzed Formal 1,3‐Dipolar Cycloaddition of Azomethine Imines with Mixed Anhydrides.

AbstractAzomethine imines generated in situ from (II) react with esters generated in situ from 2‐phenylacetic acid derivatives (I) and benzoyl chloride in a dipolar cycloaddition reaction to afford tricyclic heterocycles of type (III) or (VI) with high diastereoselectivity and enantioselectivity.

One-pot synthesis and UV-Visible absorption studies of novel tricyclic heterocycle tethered Xanthene-1,8-diones

A series of new tricyclic heterocyclic xanthene-1,8-diones tethered with chromophoric dibenzo [b, d]furan, dibenzo[b, d]thiophene and 9-methyl-9H-carbazoles were synthesized through one-pot condensation of dibenzo[b, d]furan-2-carbaldehyde, dibenzo[b, d] thiophene-2-carbaldehyde and 9-methyl-9H-carbazole-3-carbaldehyde with cyclic 1,3-dicarbonyls in the presence of recyclable PPA-SiO2 catalyst under solvent-free conditions. Further, UV-Visible absorption properties of all the synthesized compounds were investigated in CHCl3, THF and acetonitrile. A series of new tricyclic heterocyclic xanthene-1,8-diones tethered with chromophoric dibenzo[b,d]furan, dibenzo[b,d]thiophene and 9-methyl-9H-carbazoles were synthesized through one-pot condensation of corresponding aldehydes with cyclic 1,3-dicarbonyls in the presence of recyclable PPA-SiO2 catalyst under solvent free conditions. Further UV-Visible absorption properties of all the synthesized compounds were investigated in various solvents.

ChemInform Abstract: Syntheses of 3‐[(Alkylamino)methylene]‐6‐methylpyridine‐2,4(1H,3H)‐diones, 3‐Substituted 7‐Methyl‐2H‐pyrano[3,2‐c]pyridine‐2,5(6H)‐dione Fluorescence Probes, and Tetrahydro‐1H,9H‐2,10‐dioxa‐9‐azaanthracen‐1‐ones.

AbstractVarious bicyclic and tricyclic heterocycles are synthesized by condensation and ring‐closing reactions, e.g. Knoevenagel and lactonization reaction.

ChemInform Abstract: Tuneable Radical Cyclizations: A Tin‐Free Approach Towards Tricyclic and Spirocyclic Heterocycles via a Common Precursor.

ChemInform Abstract: Tuneable Radical Cyclizations: A Tin‐Free Approach Towards Tricyclic and Spirocyclic Heterocycles via a Common Precursor.