Sequential Intramolecular Cyclization Research Articles

Carbonylative Synthesis of Fused Quinoxalinones via Palladium-Catalyzed Cascade Cyclization of 2-Heteroaryl Iodobenzene and NaN3

A facile and straightforward approach for the synthesis of fused quinoxalinones via palladium-catalyzed cascade carbonylative cyclization of 2-heteroaryl iodobenzene and NaN3 has been achieved. The transformation might undergo cascade carbonylation, formation of acyl azide, a Curtius rearrangement, and an intramolecular cyclization sequence. The obtained heterocycle products can be easily transformed into other structurally diverse valuable compounds, which demonstrates the synthetic utility of the developed protocol.

One-pot organocatalyzed synthesis of tricyclic indolizines.

Indolizines and their saturated derivatives are important structural motifs present in several biologically active compounds of both natural and synthetic origin. We describe herein a one-pot approach for the synthesis of tricyclic indolizines catalyzed by a bicyclic imidazole-alcohol. The protocol is based on an aqueous Morita-Baylis-Hillman reaction between pyridine-2-carboxaldehydes and six- or seven-membered cyclic enones, followed by sequential intramolecular cyclization and dehydration. So, in a single operational step two new bonds (C-C and C-N) are formed in an organocatalyzed process that takes place in simple conditions (stirring in water at 60 °C for 12 h) and with great atom economy (water as the sole byproduct), affording the purified compounds in yields ranging from 19 to 70%. The facility of the cyclization strongly depends on the size of the cycloalkenone ring: while MBH adducts derived from six-, seven- or eight-membered cycloenones are readily transformed into the corresponding indolizines, cyclopentenone-derived MBH adducts do not cyclize. A competition experiment revealed that cycloheptenone-derived MBH adducts cyclize faster than cyclohexenone-derived adducts. Model DFT calculations have been performed to rationalize these reactivity trends.

Synthesis of Tetrahydro-5H-indolo[2,3-b]quinolines through Copper-Catalyzed Cascade Reactions of Aza-o-quinone Methides with Indoles.

A variety of tetrahydro-5H-indolo[2,3-b]quinolines were prepared in 40-97% yields through a copper(II)-catalyzed cascade reaction of aza-o-quinone methides generated in situ from 2-(chloromethyl)anilines and indoles. Experimental results showed that the reaction underwent double 1,4-additions and sequential intramolecular cyclization. The present method features broad substrate scope, good functional group tolerance, and easy gram scalable preparation of indolo[2,3-b]quinolines.

Visible‐Light‐Induced Acylation/Arylation of Alkenes via Aryl Migration/Desulfonylation

AbstractA new photoinduced acylation/arylation of N‐(arylsulfonyl)acrylamide with acyl oxime esters through a nitrogen‐centered radical protocol has been disclosed for efficient preparation of functionalized indolin‐2‐ones, which proceeds through a cascade acyl radical addition of carbon‐carbon double bond, aryl migration, desulfonylation, and intramolecular cyclization sequence. This redox‐neutral strategy features excellent selectivity, good substituent tolerance, and wide substrate scope.

Decarboxylative Intramolecular Cyclization and Sequential Halogenation of Cyclic Enol Carbonates —Synthesis of Stereochemically-defined Seven-membered Carbocycles—

The intramolecular cyclization for the construction of 7-membered carbocycles triggered by the decarboxylation of a cyclic enol carbonate was studied. In this study, it was found that the treatment of the alkene-tethered cyclic enol carbonate with a metal halide resulted in the decarboxylation and sequential intramolecular cyclization, followed by halogenation to give a functionalized 7-membered ketone with high stereoselectivity. Among the Lewis acidic metal halides, titanium tetrachloride was the most effective for this transformation. This method was applicable for a variety of substrates.

Silver‐Catalyzed Three‐Component Coupling Reaction of Amines, 2‐Isocyanobenzaldehydes, and 2,2,2‐Trifluorodiazoethane and Synthesis of Trifluoromethyl‐Substituted Indolo[1,2‐c]quinazolines

AbstractA silver‐catalyzed three‐component coupling reaction of amines, 2‐isocyanobenzaldehydes, and 2,2,2‐trifluorodiazoethane has been developed. This reaction provides an efficient method for the construction of CF3‐containing dihydroquinazolines. On the basis of this reaction, using trifluorodiazoethyl‐substituted dihydroquinazolines as synthons, trifluoromethyl‐substituted indolo[1,2‐c]quinazolines were prepared in high yields via a TBHP/KI‐mediated sequential intramolecular cyclization and aromatization process.magnified image

Rh/Ag-Mediated Peri-Selective Heteroarylation/Single Electron Transfer Annulation Cascade of 1-(Methylthio)naphthalenes and Analogues: Road Less Traveled to Benzo[de]thioacenes

Reported herein is a one-shot synthesis of benzo[de]thioacenes via a Rh-catalyzed peri-selective heteroarylation/Ag-mediated SET intramolecular cyclization sequence of 1-(methylthio)naphthalenes and heteroatom-embedded analogues in HFIP. Moreover, the different alcohols enable an exquisite switch in the reaction process. t-BuOH instead of HFIP delivers biaryl sulfides rather than cyclized products. By separation of rhodacycle species, control experiments, EPR experiments, and especially capture and isolation of thiophene radical adduct with BHT, the mechanistic pathway has been illustrated clearly. The formation of a sulfur-bridged six-membered ring via SET cyclization of the cation-radical to the methylthio group presented herein is intrinsically different from the conventional acid-mediated cyclization of sulfoxides. The annulative π-extension developed herein exemplifies the high compatibility of oxidative C–H activation and radical chemistry.

MOF‐promoted Three‐component Synthesis of Functionalized Pyrano[3,2‐c]chromen under Mild Conditions

A convenient and efficient route for synthesis of various derivatives of 3‐benzoyl‐4‐phenyl‐2‐(trifluoromethyl)pyrano[3,2‐c]chromen‐5(4H)‐one has been used via tandem Knoevenagel condensation–Michael addition and intramolecular cyclization sequence. These products have been synthesized in the presence of catalytic amount of metal–organic framework (MOF) and potassium carbonate as one‐pot, three‐component reaction. MOF catalyst has been separated easily with external magnet, and high purity of products has been obtained after washing with ethanol. This protocol has advantages of simplicity, mild condition, and high yield. More importantly, MOF has been easily recycled for three times.

Cyclization and oxidation of o-bromophenylacetamides for the synthesis of oxindoles and isoindigoes

N-substituted oxindoles were obtained through a facile KOH/DMSO promoted intramolecular cyclization of o-bromophenylacetamides in good yields. Furthermore, isoindigo derivatives were readily synthesized through sequential intramolecular cyclization, oxidation and condensation of o-bromophenylacetamide in the presence of copper (II) acetate monohydrate, iodobenzene diacetate and KOH/DMSO. This method provides a convenient synthesis of a range of oxindoles and symmetrical biologically important (E)-bisindole-2-ones using o-bromophenylacetamide as sole starting material. The reaction mechanism is elucidated in light of the control experiment results.

Palladium-catalyzed intermolecular coupling of 2-haloallylic acetates with simple phenols, and sequential formation of benzofuran derivatives through the intramolecular cyclization

We accomplished the synthesis of 2-substituted benzofuran derivatives by the palladium-catalyzed reaction of 2-haloallylic acetates with simple phenols in the presence of a base. The reaction proceeded through the intermolecular attack of the nucleophile on the central carbon atom of the π-allyl group, carbon-halogen bond cleavage, and sequential intramolecular cyclization.

Iron-Catalyzed Intermolecular Hydrothiolation of Internal Alkynes with Thiosalicylic Acids, and Sequential Intramolecular Cyclization Reaction

We demonstrate the iron-catalyzed intermolecular coupling of internal alkynes and thiosalicylic acid derivatives. The reaction was effectively catalyzed by the Fe(acac)2/1,10-phenanthroline catalyst in toluene/HFIP (hexafluoroisopropyl alcohol) as the reaction solvent and afforded several types of 1,3-oxathiine derivatives in moderate to high yields through the intermolecular hydrothiolation and sequential intramolecular cyclization.

Palladium-catalyzed intermolecular coupling of 3-substituted propargylic carbonates with phenols: Synthesis of 2-substituted benzofuran derivatives

Abstract We accomplished the synthesis of 2-substituted benzofuran derivatives by the palladium-catalyzed reaction of 3-substituted propargylic carbonates with phenols. The 2-substituted benzofuran derivatives were obtained through the intermolecular coupling of the 3-substituted propargylic carbonates with phenols, and sequential intramolecular cyclization reaction.

Efficient Access to Original 6-Substituted 5-Nitro-2,3-dihydro­imidazo[2,1-b]oxazoles

A one-pot sequential intramolecular cyclization and Suzuki–Miyaura or Sonogashira reaction under microwave irradiation are reported in the 5-nitro-2,3-dihydroimidazo[2,1-b]oxazole series. The intramolecular cyclization of 1-(2,4-dibromo-5-nitro-1H-imidazol-1-yl)propan-2-ol between the hydroxyethyl group and the bromine atom at the 2-position is carried out first, followed by optimization and generalization of the Suzuki–Miyaura and Sonogashira cross-coupling reactions of the bromine atom at the 4-position. The various boronic acids and alkynyl derivatives used to perform these palladium-catalyzed cross-coupling reactions allowed to substitute the 6-position of 5-nitro-2,3-dihydroimidazo[2,1-b]oxazole compounds.

ChemInform Abstract: Visible‐Light‐Induced Cyclization of Electron‐Enriched Phenyl Benzyl Sulfides: Synthesis of Tetrahydrofurans and Tetrahydropyrans.

A new approach to the preparation of tetrahydrofurans and tetrahydropyrans through a photoredox catalytic process is described. The introduction of a phenylsulfanyl auxiliary group permits the substrates to be readily oxidized to form cationic intermediates for sequential intramolecular cyclization. The method features mild reaction conditions and operational simplicity.

ChemInform Abstract: Copper‐Nitrene Triggered Annulation of α‐Acyl Cinnamides: Access to Isoxazol‐3(2H)‐ones.

AbstractIsoxazol‐3(2H)‐ones are prepared starting from α‐acyl cinnamides and tosyliminophenyliodinane catalyzed by Cu(OAc)2 under very mild conditions via a tandem aza‐Michael addition and intramolecular cyclization sequence.

Chemodivergent, One-Pot, Multi-Component Synthesis of Pyrroles and Tetrahydropyridines under Solvent- and Catalyst-Free Conditions Using the Grinding Method.

A highly efficient, chemoselective synthesis of a library of polysubstituted pyrroles and tetrahydropyridines has been achieved through the one-pot, multicomponent reactions of ethyl (E)-3-(aryl/alkyl amino) acrylates, 2,2-dihydroxy-1-arylethan-1-ones, and malononitrile under solvent- and catalyst-free grinding conditions. The selective formation of pyrrole or tetrahydropyridines relied on substitution of the N-aryl of ethyl (E)-3-(4-arylamino) acrylates. These reactions presumably occurred via a domino Knoevenagel condensation and Michael addition followed by an intramolecular cyclization sequence of reactions in a single transformation.

Solid-Phase Synthesis of Amine/Carboxyl Substituted Prolines and Proline Homologues: Scope and Limitations.

A solid-phase procedure is used to synthesize racemic peptidomimetics based on the fundamental peptide unit. The peptidomimetics are constructed around proline or proline homologues variably substituted at the amine and carbonyl sites. The procedure expands the diversity of substituted peptidomimetic molecules available to the Distributed Drug Discovery (D3) project. Using a BAL-based solid-phase synthetic sequence the proline or proline homologue subunit is both constructed and incorporated into the peptidomimetic by an α-alkylation, hydrolysis and intramolecular cyclization sequence. Further transformations on solid-phase provide access to a variety of piperazine derivatives representing a class of molecules known to exhibit central nervous system activity. The procedure works well with proline cores, but with larger six- and seven-membered ring homologues the nature of the carboxylic acid acylating the cyclic amine can lead to side reactions and result in poor overall yields.

Visible-Light-Induced Cyclization of Electron-Enriched Phenyl Benzyl Sulfides: Synthesis of Tetrahydrofurans and Tetrahydropyrans

A new approach to the preparation of tetrahydrofurans and tetrahydropyrans through a photoredox catalytic process is described. The introduction of a phenylsulfanyl auxiliary group permits the substrates to be readily oxidized to form cationic intermediates for sequential intramolecular cyclization. The method features mild reaction conditions and operational simplicity.

Synthesis of Multisubstituted Triphenylenes and Phenanthrenes by Cascade Reaction of o-Iodobiphenyls or (Z)-β-Halostyrenes with o-Bromobenzyl Alcohols through Two Sequential C–C Bond Formations Catalyzed by a Palladium Complex

o-Bromobenzyl alcohol has been developed as a novel annulating reagent, bearing both nucleophilic and electrophilic substituents, for the facile synthesis of polycyclic aromatic hydrocarbons. A palladium/electron-deficient phosphine catalyst efficiently coupled o-iodobiphenyls or (Z)-β-halostyrenes with o-bromobenzyl alcohols to afford triphenylenes and phenanthrenes, respectively. The present cascade reaction proceeded through deacetonative cross-coupling and sequential intramolecular cyclization. An array of experimental data suggest that the reaction mechanism involves the equilibrium of 1,4-palladium migration.

Asymmetric Annulation of Donor-Acceptor Cyclopropanes with Dienes.

An efficient [4 + 3] cycloaddition reaction of D-A cyclopropanes with dienes has been successfully developed. The reaction proceeds well with various dienolsilyl ethers in the presence of Lewis acid, delivering a variety of cycloheptenes and [n,5,0]carbobicycles with excellent stereoselectivity. The asymmetric version of this reaction is also realized using a newly designed chiral Cy-TOX ligand, providing a new approach to access optically active cycloheptenes and [n,5,0]carbobicycles. Mechanisic study reveals that the reaction involves a stepwise pathway, which undergoes an unusual ring opening of five-membered [3 + 2] intermediate and sequential intramolecular cyclization to afford the thermodynamically stable [4 + 3] annulation product.