Tetrasubstituted Pyrroles Research Articles

Au]-Catalyzed Cyclization of Propargyl-Tethered Ene-Amides: Substrate-Dependent Access to Tetrasubstituted Pyrroles, Aminophenols, and Dihydropyridines.

[Au]-catalyzed and substrate-dependent intramolecular cyclization of sulfonyl ene-amides with a pendant propargyl group afford tetrasubstituted pyrroles, o-aminophenols, or 1,6-dihydropyridine carbaldehydes. While the pyrroles and aminophenols are formed when the propargylic alkyne is terminal, dihydropyridines are formed when internal alkyne is present. Internal alkyne substrates with 2-thienyl and 3-thienyl groups give different types of dihydropyridines. The dihydropyridines so obtained can be readily converted to nicotinaldehydes with concomitant sulfonyl migration upon heating in xylene.

Mn(II) Promoted Divergent-Convergent Domino Reaction Giving Dinuclear Tetrasubstituted Pyrrole Complex.

Domino reaction of benzo[d]thiazole-2-methylamine (S1) has been developed in the presence of MnCl2 ⋅ 4H2O, leading to tetrasubstituted pyrrole coordinated dinuclear Mn(II) complex 1 ([MnClP]2, P-=2,3,4,5-tetrakis(benzo[d]thiazol-2-yl)pyrrol-1-ide). The reaction process has been studied by assigning a series of intermediates based on time-dependent mass spectrometry, control experiments, crystallography, and density functional theory (DFT) theoretical calculation. A plausible mechanism involving an unprecedented divergent-convergent domino sequence has been proposed. Compound S1 could be activated by MnCl2 ⋅ 4H2O via coordination, which divergently produces two intermediates imine II (1-(benzo[d]thiazol-2-yl)-N-(benzo[d]thiazol-2-ylmethyl)methanimine) and alkene C (1,2-bis(benzo[d]thiazol-2-yl)ethene) through oxidative self-condensation and free radical coupling followed by elimination, respectively. They could then react with each other convergently via formal [3+2] cycloaddition to give deprotonated tetrasubstituted pyrrole coordinated intermediate [MnClP] after aromatization. Dimerization of [MnClP] produces the final product 1. Three C-C bonds and one C-N bond are formed through this six-step domino sequence. The corresponding organic skeleton (HP: 2,2',2'',2'''-(1H-pyrrole-2,3,4,5-tetrayl)tetrakis(benzo[d]thiazole)) has been obtained from 1 and shows a higher fluorescent quantum yield (52 %) than the reported 3,4-diphenyl substituted analogue 2,2'-(3,4-diphenyl-1H-pyrrole-2,5-diyl)bis(benzo[d]thiazole) (DPB) (42 %).

Construction of Pyridine Backbone Via Electrochemical Skeletal Editing of Pyrrole-Derivatives

Pyridine skeleton is one of the most important nitrogen-containing heterocycles that finds extensive applications in pharmaceuticals. For instance, apalutaminde and lvosidenib are used for cancer treatment and aminopyralid used is in herbicides. In fact, pyridine is the second most commonly used nitrogen-containing heterocyclic ring among drugs approved by the U.S. Food and Drug Administration, and the most commonly used among aromatic compounds.[1] Therefore, the development of efficient synthetic methods for pyridine derivatives is highly desirable.A common synthetic approach of pyridine-containing molecules relies on the modification of C-H bond of pyridine-derivatives, while this strategy limits the chemical space of available structures due to the inherent difficulties in the selective C-H functionalization in pyridine rings. In this context, skeletal editing has emerged as an innovative approach to address heavily functionalized pyridines via single atom-insertion into five-membered rings. It can not only be used in the field of late-stage functionalization but also open up a new route of retrosynthesis of drug candidates. Moreover, this reaction can more easily diversify the molecule because a library of existing skeletons can be used. For example, if a ring-expanding reaction from the pyrrole skeleton to the pyridine skeleton becomes possible, which can create molecules with the pyridine skeleton using a vast molecular library containing pyrrole skeletons. These will enable the synthesis of highly diverse molecules that were previously impossible to create.Some approaches to convert a pyrrole skeleton into a pyridine skeleton have been developed using single-atom insertion reactions, such as Ciamician-Dennsted reaction. [2] This reaction can create 3-halopyridines through haloform-derived carbenes, but it is not widely used because of the harsh conditions and low yield. Bonge-Hansen and colleagues have recently reported the reaction which transforms the indole skeleton into the quinoline skeleton.[3] In this ring expansion reaction, a carbon atom derived from ethyl diazoacetate (EDA) is inserted into the indole skeleton. While this reaction is so useful, it requires not only expensive rhodium catalysts to increase the electrophilicity of the EDA, but also requires pre-reaction of the EDA to create α-halo EDA. On the other hand, Levin has recently reported a powerful reaction that use α-chlorodiazirines as a carbon source.[4] This reaction is advantageous since it does not require any transition metal catalysts, while installable functional group is limited to the available α-chlorodiazirine-derivatives.With these backgrounds in mind, in this work, we demonstrate an electrochemical ring-expansion reaction that converts a pyrrole skeleton into a pyridine skeleton. The pyrrole derivatives are easily oxidized by anodic oxidation to generate electrophilic radical cation species. Owing to its high reactivity, it can easily react with other nucleophiles including EDA under ambient conditions. This reaction is economical and eco-friendly because it does not need a metal catalyst. Reactions were performed using tetra-substituted pyrrole with various N-substituted groups (1) as a model compound. Under the optimized condition with using 1 (PG = H) as a substrate and EDA as a nucleophile, the carbon insertion product (2) was successfully obtained as an isomeric mixture. Remarkably, when using 1 with an electron-withdrawing N-protecting group, carboxylated product at 4-position of pyridine ring, 3, was obtained. These results imply that the insertion position varies depending on the electronic nature of protecting groups. Furthermore, it was also revealed that carbon insertion and decarboxylated product in a single step, 4, was selectively obtained by installing a specific N-protecting group. In conclusion, we have demonstrated that the first electrochemical skeletal editing reaction using pyrrole-derivatives and EDA. In the presentation, detail of the optimizations, as well as the implementation of flow electrochemistry will also be discussed[1] E. Vitaku, D. T. Smith, J. T. Njardarson, J. Med. Chem. 2014, 57, 10257−10274.[2] G. L. Ciamician, M. Dennstedt, Ber. Dtsch. Chem. Ges. 1881, 14 (1), 1153−1163.[3] M. Mortén, M. Hennum, T. Bonge-Hansen, Beilstein J. Org. Chem. 2015, 11, 1944–1949.[4] B. D. Dherange, P. Q. Kelly, J. P. Liles, J. P. Sigman, M. D. Levin, J. Am. Chem. Soc. 2021, 143, 11337−11344 Figure 1

Molecular Editing of Pyrroles via a Skeletal Recasting Strategy.

Heterocyclic scaffolds are commonly found in numerous biologically active molecules, therapeutic agents, and agrochemicals. To probe chemical space around heterocycles, many powerful molecular editing strategies have been devised. Versatile C-H functionalization strategies allow for peripheral modifications of heterocyclic motifs, often being specific and taking place at multiple sites. The past few years have seen the quick emergence of exciting "single-atom skeletal editing" strategies, through one-atom deletion or addition, enabling ring contraction/expansion and structural diversification, as well as scaffold hopping. The construction of heterocycles via deconstruction of simple heterocycles is unknown. Herein, we disclose a new molecular editing method which we name the skeletal recasting strategy. Specifically, by tapping on the 1,3-dipolar property of azoalkenes, we recast simple pyrroles to fully substituted pyrroles, through a simple phosphoric acid-promoted one-pot reaction consisting of dearomative deconstruction and rearomative reconstruction steps. The reaction allows for easy access to synthetically challenging tetra-substituted pyrroles which are otherwise difficult to synthesize. Furthermore, we construct N-N axial chirality on our pyrrole products, as well as accomplish a facile synthesis of the anticancer drug, Sutent. The potential application of this method to other heterocycles has also been demonstrated.

An Efficient One-Pot, Three-Component Synthesis of Tetrasubstituted Pyrroles under Catalyst- and Solvent-Free Conditions

AbstractAn environmentally benign, catalyst- and solvent-free, three-component synthesis of tetrasubstituted pyrroles was established. The reaction proceeds via a nucleophilic attack of primary amine on dialkyl acetylenedicarboxylate followed by Michael addition with β-nitrostyrene and successive intramolecular cyclization and aromatization to yield 1,2,3,4-tetrasubstituted pyrroles in good to excellent yields. A wide range of primary amines including aromatic amines and benzylamines were coupled with differently substituted β-nitrostyrenes and dialkyl acetylenedicarboxylate. Furthermore, compared to previous reported methods, the present study is highly atom economical and environmentally benign and can be scaled up.

Tetrasubstituted Pyrrole Derivative Mimetics of Protein-Protein Interaction Hot-Spot Residues: A Promising Class of Anticancer Agents Targeting Melanoma Cells.

A new series of tetrasubstituted pyrrole derivatives (TSPs) was synthesized based on a previously developed hypothesis on their ability to mimic hydrophobic protein motifs. The resulting new TSPs were endowed with a significant toxicity against human epithelial melanoma A375 cells, showing IC50 values ranging from 10 to 27 μM, consistent with the IC50 value of the reference compound nutlin-3a (IC50 = 15 μM). In particular, compound 10a (IC50 = 10 μM) resulted as both the most soluble and active among the previous and present TSPs. The biological investigation evidenced that the anticancer activity is related to the activation of apoptotic cell-death pathways, supporting our rational design based on the ability of TSPs to interfere with PPI involved in the cell cycle regulation of cancer cells and, in particular, the p53 pathway. A reinvestigation of the TSP pharmacophore by using DFT calculations showed that the three aromatic substituents on the pyrrole core are able to mimic the hydrophobic side chains of the hot-spot residues of parallel and antiparallel coiled coil structures suggesting a possible molecular mechanism of action. A structure-activity relationship (SAR) analysis which includes solubility studies allows us to rationalize the role of the different substituents on the pyrrole core.

Modular Synthesis of Tetrasubstituted Pyrroles via an Annulative Migration Reaction of Allenyl Ketones and p-Toluenesulfonylmethyl Isocyanide.

The metal-free cyclization of allenyl ketones and p-toluenesulfonylmethyl isocyanide (TosMIC), promoted by Cs2CO3, provides a convenient access to tetrasubstituted pyrroles in which an acyl group undergoes 1,2-migration. This tandem Michael addition/annulative migration synthetic strategy is general and high-yielding for various substituted allenyl ketones. Moreover, a phosphoryl or ester moiety is also a suitable functionality to enable such migration.

Modular Synthesis of Tetrasubstituted Pyrroles through a Four-Component Cyclization Strategy Using Ammonium Salt as the Nitrogen Source.

A four-component synthesis of tetrasubstituted pyrroles was developed under metal-free conditions. The pyrrole ring was formed in one pot through [2 + 1 + 1 + 1] condensation using ammonium salt as the nitrogen source. In this strategy, 1,4-naphthoquinones and maleimides were used as the versatile C2 fragments to provide substituted benzo[f]isoindole-4,9-diones and pyrrolo[3,4-c]pyrrole-1,3-diones, respectively. This work is highlighted by using ammonium salt as the nitrogen source, readily available starting materials and multibond formation (two C-C and two C-N bonds) in a single operation.

A Catalyst‐ and Solvent‐ Free Synthesis of Tetra‐Substituted Pyrroles by Multicomponent Reaction

AbstractA facile, catalyst‐ and solvent‐ free, three‐component reaction was developed for the synthesis of tetrasubstituted pyrroles at room temperature and under white light. The reaction proceeds via enamine formation between primary amines with 1,3‐dicarbonyl compounds followed by Michael addition with β‐nitro styrene and subsequent intramolecular cyclization and aromatization to yield 1,2,3,4‐tetrasubstituted pyrroles in good to excellent yields. Further, the present strategy is highly atom‐economical and environmentally benign. The preliminary in vitro cytotoxic studies on a set of compounds were performed against Hepatocellular carcinoma cells (HepG2) and one of the compounds 4 ac showed significant activity with an IC50 value of 17.82 μM.

Organo-photocatalytic Synthesis of Functionalized Pyrroles from 2H-Azirines and α-Substituted Nitroalkenes

AbstractAn efficient organo-photocatalytic method for the synthesis of tetrasubstituted pyrroles bearing a ketone, ester, alcohol, or nitro group at the 3-position has been developed. The reaction involves visible-light-mediated formal [3+2] dipolar cycloaddition between 2H-azirines and α-substituted nitroalkenes followed by a denitration or debromination sequence. The notable features of the protocol are excellent regioselectivity, wide substrate scope, and high yields of the products.

Au-catalyzed neighboring hydroxymethyl group directed cycloaddition of alkyne with diazadienes: Synthesis of polysubstituted pyrroles

Polysubstituted pyrroles are very important scaffolds in many bioactive natural products and synthetic pharmaceuticals. Here, a new gold-catalyzed cycloaddition of alkynes with azadienes to access tetrasubstituted pyrroles is demonstrated. The neighboring hydroxylmethyl group serves a very important directing group through an addition/cycloaddition/elimination cascade. Diverse polysubstituted pyrroles were synthesized in good yields under mild conditions in one step, and tricyclic pyrrole containing heterocycles were easily obtained through derivatization.

Synthesis of unsymmetrically tetrasubstituted pyrroles and studies of AIEE in pyrrolo[1,2-a]pyrimidine derivatives.

Pyrroles are among the most important heterocycles in pharmaceuticals and agrochemicals. Construction of pyrrole scaffolds with different substituents and a free NH group, however, is challenging. Herein, a metal-free method for the synthesis of unsymmetrically tetrasubstituted NH-pyrroles using a consecutive chemoselective double cyanation is reported. The desired pyrroles were obtained with yields up to 99% and good functional group tolerance. Mechanistic studies identified a reaction mechanism that features a subtle sequence of first cyano-addition and migration, followed by cyano-addition and aromatization to afford the pyrrole skeleton. Pyrrolo[1,2-a]pyrimidines are synthesized as the synthetic applications of NH-pyrroles, and these pyrrolo[1,2-a]pyrimidines exhibit unpredicted time-dependent aggregation-induced emission enhancement (AIEE) properties.

Iron-Catalyzed One-Pot Synthesis of Indole-Tethered Tetrasubstituted Pyrroles and Their Transformations to Indolizino[8,7-b]indole Derivatives

AbstractWe have developed an efficient iron-catalyzed one-pot reaction of tryptamines, ynones and nitroolefins, affording indole-tethered tetrasubstituted pyrroles in acceptable to good yields. Other aromatic and aliphatic amines can also be utilized in this process, delivering the corresponding highly functionalized tetrasubstituted pyrroles. Indolizino[8,7-b]indole derivatives could be obtained through TFA-, TfOH- or Fe(OTf)3-mediated cyclizations via dearomatization of indole. Unexpected dibrominated products, 7,9-dibromo-6,11-dihydro-5H-indolizino[8,7-b]indoles, were formed when trimethylphenylammonium tribromide (PTAP) was employed as electrophilic cyclization promoter.

Redox-Neutral 1,3-Dipolar Cycloaddition of 2H-Azirines with 2,4,6-Triarylpyrylium Salts under Visible Light Irradiation.

A novel visible light mediated redox-neutral 1,3-dipolar cycloaddition of 2H-azirines with 2,4,6-triarylpyrylium tetrafluoroborate salts providing tetrasubstituted pyrroles has been developed. The 2,4,6-triarylpyrylium salt acts as dipolarophile as well as photosensitizer in the reaction, under blue light irradiation. The control experiments indicated single electron oxidation of 2H-azirines by photoexcited pyrylium salts, followed by coupling between an azaallenyl radical cation and triarylpyranyl radical as the key mechanistic feature. The mild conditions, wide substrate scope, and complete regioselectivity are the noticeable attributes of the reaction.

Nickel-catalyzed formal [3 + 2]-cycloaddition of 2H-azirines with 1,3-dicarbonyl compounds for the synthesis of pyrroles

An efficient nickel-catalyzed formal [3 + 2]-cycloaddition of 2H-azirines with 1,3-dicarbonyl compounds for the synthesis of tetrasubstituted pyrroles has been developed. This transformation involves cleavage of the CN double bond and the construction of new CC and CN bonds. The reaction employs readily available starting materials, tolerates a wide range of functional groups, and affords tetrasubstituted pyrroles in good to high yields under mild reaction conditions. A gram-scale reaction was performed to demonstrate the scale-up applicability of this synthetic method.

FeCl3 mediated dimerization of dihydropyrrolo[2,1-a]isoquinolines and chlorination of tetrasubstituted pyrroles

We have developed a mild and direct dimerization of dihydropyrrolo[2,1-a]isoquinolines through FeCl3-mediated oxidative homocoupling. A series of dimeric dihydropyrroloisoquinoline derivatives were obtained in acceptable to excellent yields (up to >99%). Attempts to expand this dimerization system to the synthesis of dimeric pyrroles failed and chlorination products were obtained in most cases instead of dimeric pyrroles.

Tetra-substituted pyrrole derivatives act as potent activators of p53 in melanoma cells.

Cutaneous melanoma, the most aggressive form of skin cancer, is characterized by activating BRAF mutations. Despite the initial success of selective BRAF inhibitors, only few patients exhibited complete responses, whereas many showed disease progression. Melanoma is one of the few types of cancer in which p53 is not frequently mutated, but p53 inactivation can be indirectly achieved by a stable activation of MDM2 induced by a deletion in CDKN2A (Cyclin Dependent Kinase Inhibitor 2A) locus, encoding for p16INK4A and p14ARF, two tumor suppressor genes. In this study, we tested the efficacy of the previously synthesized tetra-substituted pyrrole derivatives, 8g, 8h and 8i, in melanoma cell lines, and we compared the effects of the most active of these, the 8i compound, with that exerted by Nutlin 3, a well-known inhibitor of p53-MDM2 interaction. The obtained results showed that 8i potentiates the inhibitory effect of Nutlin 3 and the combined use of 8i and Nutlin 3 triggers apoptosis and significantly impairs melanoma viability. Finally, the 8i compound reduces p53-MDM2 interaction and induces p53-HSP90 complex formation, suggesting that the observed raise in p53 transcriptional activity could be mediated by HSP90. Because the main feature of melanoma is the resistance to most chemotherapeutics, our studies suggest that the 8i tetra-substituted pyrrole derivative, restoring p53 functions and its transcriptional activities, may have potential application, at least as adjuvant, in the treatment of human melanoma.

A solvent and transition metal-free, highly efficient Brønsted acidic ionic liquid promoted one-potthree-component reactions for the synthesis of tetrasubstituted pyrroles

The present protocol describes a highly efficient, transition metal and solvent-free one-pot annulation of amines, dialkyl acetylenedicarboxylates and β-nitrostyrene using imidazolium Brønsted acidic ionic liquid for the synthesis of tetrasubstituted pyrroles. A diverse functionalized tetrasubstituted pyrroles derivatives were obtained with excellent yields under transition metal and solvent-free conditions. The Brønsted acidic ionic liquid can be easily recovered and reused for the next reaction without any effects on the yields of the products. This green protocol provides structurally complex, medicinally important tetrasubstituted pyrroles with various substitution patterns in a one-pot operation.

Visible-Light-Induced C (sp3)–H Functionalization of Tosylhydrazones: Synthesis of Polysubstituted Pyrroles under Metal-Free Conditions

Iodine catalyzed C (sp3)-H functionalization of tosylhydrazones with β-enamino esters under visible light irradiation for the synthesis of trisubstituted pyrroles has been described. The present method is also applicable to α- substituted tosylhydrazones to yield the tetra-substituted pyrroles.

Four components synthesis of 1,2,3,4-tetrasubstituted pyrroles using iron (iii) phosphate as a green activator.

A simple synthesis of 1,2,3,4-tetrasubstituted pyrrole derivatives is reported from the reaction of aromatic aldehydes, β–dicarbonyl compounds, amines and nitromethane in the presence of iron (III) phosphate under reflux conditions. The use of iron (III) phosphate as a green activator, mild reaction conditions and synthesis of some unprecedented tetrasubstituted pyrroles are the features of this protocol.