Pyrrole Products Research Articles

Pd/IHept-Catalyzed Regioselective Annulation of 2-Fluoroallyl Carbonates with Enaminones: Synthesis of Fully Substituted Pyrroles

AbstractThe Pd/IHept-catalyzed regioselective annulation of 2-fluoroallyl carbonates with enaminones has been developed. This method allows the efficient synthesis of a variety of fully substituted pyrroles with high regioselectivity. Experimental data demonstrate that the fluorinated alkene intermediate is initially formed, which then undergoes C–F cleavage/annulation to give the pyrrole products. Furthermore, it is evident that both the substitution and annulation steps necessitate the participation of the Pd/IHept catalyst.

Cascade [3 + 2] Annulation of 1,3-Dicarbonyl Compounds and Ethyl Secondary Amines for Pyrrole Synthesis via Poly C(sp3)-H Bond Functionalization.

The synthesis of polyfunctionalized pyrroles via the cascade reactions of 1,3-dicarbonyl compounds and two molecules of ethyl secondary amines has been realized via simple iodine catalysis in the presence of Dess-Martin periodinane (DMP). The formation of the target pyrrole products involves the formation of one new C-C and two new C-N bonds via the major functionalization of six C(sp3)-H bonds, presenting a highly novel and efficient synthetic protocol toward pyrrole scaffolds.

Ag-Catalyzed Switchable Synthesis of Site-Specifically Functionalized Pyrroles via Azafulvenium Intermediates.

Here, we present a versatile, silver-catalyzed multi-auto-tandem reaction involving enamines, alkynals, and nucleophiles, utilizing the highly reactive intermediate azafulvenium. This method allows for flexible and switchable regiodivergent reactions through either intermolecular or intramolecular nucleophilic attacks, which can be controlled by adjusting the catalytic conditions. A range of site-specific functionalized or polycyclic fused pyrrole products were efficiently produced with a high level of chemocontrol.

Enal-azomethine ylides: application in the synthesis of functionalized pyrroles.

Rhodium-catalyzed [3 + 2] annulation of diazoenals and N-alkyl imines resulted in N-alkyl-pyrrole-3-carbaldehyde derivatives. The reaction involves thermal 6π-electrocyclization and aromatization of a new class of enal-azomethine ylides (EAYs). The EAYs derived from dihydroisoquinoline and 2H-azirine gave fused-pyrrole and pyridine derivatives, respectively. The synthetic importance of pyrrole products has been demonstrated by one-step synthesis of the biologically relevant pyrrolo[3,2-c]quinoline scaffold as well as pyrrolo[2,1-a]isoquinoline which is a core structure of lamellarin alkaloids.

Synthesis of 5‐Trifluoromethylpyrroles from Heating‐Induced Annulation of Pyridinium 1,4‐Zwitterionic Thiolates with CF3‐Imidoyl Sulfoxonium Ylides

AbstractA heating‐induced desulfuration annulation of pyridinium 1,4‐zwitterionic thiolates and CF3‐substituted imidoyl sulfoxonium ylides has been achieved, allowing a route to biologically important 5‐trifluoromethylpyrroles. The transformation proceeds through an unusual ((3+3)‐1) pathway under metal‐free conditions with the extrusion of 4‐methoxypyridine, sulfur and DMSO. The scale‐up reaction and further transformation of the obtained pyrrole products have been performed to demonstrate the synthetic utility of the developed method.

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.

Technology for the production of disubstituted pyrroles

In this work, we studied the catalytic synthesis of pyrrole and their derivatives from ketoximes and acetylene in the liquid phase under normal conditions in the presence of homogeneous catalysts. Mathematical modeling of the experiment was carried out using the Box-Wilson method and the optimal conditions for the synthesis of a number of pyrroles were found. The catalytic synthesis of pyrrole under vapor phase conditions in the presence of heterogeneous catalysts has been studied. Low-temperature polyfunctional catalysts have been developed that provide the highest yield of pyrroles.

Computational insights into the mechanisms and origins of switchable selectivity in gold(i)-catalyzed annulation of ynamides with isoxazoles via 6π-electrocyclizations of azaheptatrienyl cations.

Electrocyclizations of acyclic conjugated π-motifs have emerged as a versatile and effective strategy for accessing various ring systems with excellent functional group tolerability and controllable selectivity. Typically, the realization of 6π-electrocyclization of heptatrienyl cations to afford seven-membered motif has proven difficult due to the high-energy state of the cyclizing seven-membered intermediate. Instead, it undergoes the Nazarov cyclization, affording a five-membered pyrrole product. However, the incorporation of a Au(i)-catalyst, a nitrogen atom and tosylamide group in the heptatrienyl cations unexpectedly circumvented the aforementioned high energy state to afford a seven-membered azepine product via 6π-electrocyclization in the annulation of 3-en-1-ynamides with isoxazoles. Therefore, extensive computational studies were carried out to investigate the mechanism of Au(i)-catalyzed [4+3] annulation of 3-en-1-ynamides with dimethylisoxazoles to produce a seven-membered 4H-azepine via the 6π-electrocyclization of azaheptatrienyl cations. Computational results showed that after the formation of the key α-imino gold carbene intermediate, the annulation of 3-en-1-ynamides with dimethylisoxazole occurs via the unusual 6π-electrocyclization to afford a seven-membered 4H-azepine exclusively. However, the annulation of 3-cyclohexen-1-ynamides with dimethylisoxazole occurs via the commonly proposed aza-Nazarov cyclization pathway to majorly generate five-membered pyrrole derivatives. The results from the DFT predictive analysis revealed that the key factors responsible for the different chemo-, and regio-selectivities observed are the cooperating effect of the tosylamide group on C1, the uninterrupted π-conjugation pattern of the α-imino gold(i) carbene and the substitution pattern at the cyclization termini. The Au(i)-catalyst is believed to assist in the stabilization of the azaheptatrienyl cation.

Construction of pyrroles, furans and thiophenes via intramolecular cascade desulfonylative/dehydrogenative cyclization of vinylidenecyclopropanes induced by NXS (X = I or Br).

Pyrroles, furans, and thiophenes are important structural motifs in biologically active substances, pharmaceuticals and functional materials. In this paper, we disclose an efficient synthetic strategy for the rapid construction of multisubstituted pyrroles, furans, and thiophenes via NXS mediated desulfonylative/dehydrogenative cyclization of vinylidenecyclopropanes (VDCPs). The advantages of this method include wide substrate range, high efficiency and synthetic usefulness of the heterocyclic products under metal-free and mild conditions. The derivatization of pyrrole products and the preparation of functional molecules successfully demonstrated the synthetic potential of the products as platform molecules. The reaction mechanism has been investigated on the basis of control experiments and DFT calculations.

3-Alkyl-2-pyridyl Directing Group-Enabled C2 Selective C-H Silylation of Indoles and Pyrroles via an Iridium Catalyst.

An iridium-catalyzed, directing group-enabled site selective intra- and intermolecular silylation of indoles and pyrroles with hydrosilanes has been developed under ligand-free conditions. Fine-tuning of the removable 3-alkyl-2-pyridyl directing group was found to be crucial for achieving high yields for C2-silylated indole and pyrrole products. Moreover, the scalability was demonstrated, and further transformations of the silylation products were achieved.

Palladium(II)-Catalyzed [2+2+1] Annulation of Alkynes and Hydroxylamines: A Rodox-Neutral Approach to Fully Substituted Pyrroles.

A palladium-catalyzed [2+2+1] annulation of alkynes and hydroxylamines has been developed for the rapid construction of fully substituted pyrroles. This transformation involves sequential nucleophilic-addition of hydroxylamine to alkyne, alkyne migratory insertion, and synergistic demetallization cyclization, which provides a redox-neutral annulation approach to pyrrole derivatives. Moreover, the strategy enabled alteration of the photophysical properties of pyrrole products by varying the aryl substituents, thus leading to the development of N-functionalized tetraarylpyrroles as new fluorophores.

DFT Rationalization of Gold(I)-Catalyzed Couplings between Alkynyl Thioether and Nitrenoid Derivatives: Mechanism, Selectivity Patterns, and Effects of Substituents.

The present work focuses on a theoretical investigation of mechanistic features, chemoselectivity, regioselectivity, and effect of substituents in the gold-catalyzed reactions of alkynyl thioethers and isoxazoles. The DFT calculations reveal that the nucleophilic attack of isoxazole to a β-position of catalyst-bound ynamide forms a vinyl intermediate. This undergoes cleavage of the N-O isoxazole bond and isomerizes to form an α-imino α'-sulfenyl gold carbene complex with stabilization of the Au-S interaction. For 3,5-dimethylisoxazole, the reaction follows a formal [3 + 2] cycloaddition pathway and a 1,3-H migration to give the pyrrole products. Replacement of 3,5-dimethylisoxazole by 3,5-dimethyl-4-phenylisoxazole leads to the formation of deacylative annulation products and desulfenylated 3-acylated pyrroles. Reactions with 4-methyl-3,5-diphenylisoxazoles induce the formation of N-acylated pyrroles and desulfenylated 3-acylated pyrroles. For the minor pathway, the α-addition and 1,2-S migration result in sulfur-substituted β-keto enamide derivatives. In addition, the unique features of regio- and chemoselectivity were rationalized by the distortion and interaction analysis. Apart from fully rationalizing the experimental results, the theoretical DFT data give an important support for comprehending related types of reaction mechanisms.

Three‐Component Reaction to 1,4,2‐Diazaborole‐Type Heteroarene Systems

AbstractThe borane FmesBH2 reacts in a three‐component reaction with an isonitrile and a small series of organonitriles to give rare examples of the class of dihydro‐1,4,2‐diazaborole derivatives. In a related way, annulated BN‐indolizine derivatives became conveniently available, as were dihydro‐1,4,2‐oxaza‐ or thiazaborole derivatives. The nucleophilic framework of a dihydro‐1,4,2‐diazaborole example allowed for an uncatalyzed acylation reaction. It also served as a 1,3‐dipolar reagent and underwent a [3+2] cycloaddition/[4+2] cycloreversion sequence when treated with methyl propiolate to give the respective pyrrole product. The [3+2] cycloaddition product of a dihydro‐1,4,2‐diazaborole derivative with N‐phenylmaleimide was isolated and its heterobicyclo[2.2.1]heptane derived structure characterized by X‐ray diffraction.

Three-Component Reaction to 1,4,2-Diazaborole-Type Heteroarene Systems.

The borane FmesBH2 reacts in a three-component reaction with an isonitrile and a small series of organonitriles to give rare examples of the class of dihydro-1,4,2-diazaborole derivatives. In a related way, annulated BN-indolizine derivatives became conveniently available, as were dihydro-1,4,2-oxaza- or thiazaborole derivatives. The nucleophilic framework of a dihydro-1,4,2-diazaborole example allowed for an uncatalyzed acylation reaction. It also served as a 1,3-dipolar reagent and underwent a [3+2] cycloaddition/[4+2] cycloreversion sequence when treated with methyl propiolate to give the respective pyrrole product. The [3+2] cycloaddition product of a dihydro-1,4,2-diazaborole derivative with N-phenylmaleimide was isolated and its heterobicyclo[2.2.1]heptane derived structure characterized by X-ray diffraction.

Highly Enantioselective Iridium(I)‐Catalyzed Hydrocarbonation of Alkenes: A Versatile Approach to Heterocyclic Systems Bearing Quaternary Stereocenters

AbstractWe report a versatile, highly enantioselective intramolecular hydrocarbonation reaction that provides a direct access to heteropolycyclic systems bearing chiral quaternary carbon stereocenters. The method, which relies on an iridium(I)/bisphosphine chiral catalyst, is particularly efficient for the synthesis of five‐, six‐ and seven‐membered fused indole and pyrrole products, bearing one and two stereocenters, with enantiomeric excesses of up to >99 %. DFT computational studies allowed to obtain a detailed mechanistic profile and identify a cluster of weak non‐covalent interactions as key factors to control the enantioselectivity.

Stereoselective Organocatalytic Construction of Spiro Oxindole Pyrrolidines Using Unsaturated α‐Ketoesters and α‐Ketoamides

AbstractWe have investigated the stereoselective formation of spiro oxindole pyrrolidines via formal [3+2] cycloaddition of oxindole imines with ketoesters and ketoamides. Bifunctional squaramide organocatalyst was able to induce enantioselectivity of up to 60 % ee, increased to 72 % ee after re‐crystallization, in the formation of spiro pyrrolidines with ketoesters. Interestingly, ketoamides provided alternative spiro oxindole pyrrole products in addition to the main product, which was formed via a different reaction pathway. Structures of spiro oxindole pyrrolidine as well as pyrrole products were confirmed by X‐ray crystallographic analysis. Two new squaramide based catalysts were synthesized and tested. DFT calculation helped elucidate the reaction course.

Metal-Free Synthesis and Photophysical Properties of 1,2,4-Triarylpyrroles.

A three-component reaction has been developed for the construction of multiaryl-substituted pyrrole derivatives from arylketones, amines, and nitrovinylarenes under metal-free conditions. Hence, homologous 1,2,4-triaryl-substituted pyrrole products were obtained in good to high yields. Furthermore, 2,3,5-triaryl-substituted pyrroles were selectively formed in the absence of nitrovinylarenes. The photophysical properties of some pyrrole products have been investigated to show good aggregation-induced emission (AIE) activity.

Coordination of Uranyl to the Redox-Active Calix[4]pyrrole Ligand.

Reaction of [Li(THF)]4[L] (L = Me8-calix[4]pyrrole]) with 0.5 equiv of [UVIO2Cl2(THF)2]2 results in formation of the oxidized calix[4]pyrrole product, [Li(THF)]2[LΔ] (1), concomitant with formation of reduced uranium oxide byproducts. Complex 1 can also be generated by reaction of [Li(THF)]4[L] with 1 equiv of I2. We hypothesize that formation of 1 proceeds via formation of a highly oxidizing cis-uranyl intermediate, [Li]2[cis-UVIO2(calix[4]pyrrole)]. To test this hypothesis, we explored the reaction of 1 with either 0.5 equiv of [UVIO2Cl2(THF)2]2 or 1 equiv of [UVIO2(OTf)2(THF)3], which affords the isostructural uranyl complexes, [Li(THF)][UVIO2(LΔ)Cl(THF)] (2) and [Li(THF)][UVIO2(LΔ)(OTf)(THF)] (3), respectively. In the solid state, 2 and 3 feature unprecedented uranyl-η5-pyrrole interactions, making them rare examples of uranyl organometallic complexes. In addition, 2 and 3 exhibit some of the smallest O-U-O angles reported to date (2: 162.0(7) and 162.7(7)°; 3: 164.5(5)°). Importantly, the O-U-O bending observed in these complexes suggests that the oxidation of [Li(THF)]4[L] does indeed occur via an unobserved cis-uranyl intermediate.

Ninhydrin reaction with phenylethylamine: unavoidable by-products

Ninhydrin and phenylethylamine reacted to form a complex mixture from which four products were isolated: a benzo-fused spiroheterocyclic and a pyrrole product resulting from tricomponent condensation between ninhydrin, phenylethylamine and phenylacetaldehyde produced in situ, a 2-amino-1,3-indandione dimerisation-dehydrogenation product and a Schiff base. This article analyses these compounds’ structure and proposes reaction mechanisms contributing to knowledge regarding ninhydrin and phenylethylamine chemical reactivity. Ninhydrin and phenylethylamine reacted to form a benzo-fused spiroheterocyclic, a pyrrole, a 2-amino-1,3-indandione dimerisation-dehydrogenation product and a Schiff base.

Enantio- and Diastereoselective Synthesis of Chromeno[4,3-b]pyrrole Derivatives Bearing Tetrasubstituted Chirality Centers through Carbene Catalyzed Cascade Reactions.

An NHC-catalyzed cascade cycloaddition reaction is developed for quick access to structurally sophisticated tetrahydrochromeno[4,3-b]pyrrole derivatives. A sterically congested tetrasubstituted chirality carbon center is formed during the cyclization process. All the α-, β-, and carbonyl carbons of the enal substrates are functionalized in chemo- and stereoselective fashion. The multicyclic chromeno[4,3-b]pyrrole products are generally afforded in good yields with excellent enantio- and diastereoselectivities. Heavily substituted pyrroline derivatives can be afforded from the chiral products through simple protocols.