Substrate-Controlled Divergent Synthesis of Benzimidazole-Fused Quinolines and Spirocyclic Benzimidazole-Fused Isoindoles.

A Rh(III)-catalyzed annulation of 2-arylbenzimidazoles with α-diazo carbonyl compounds via C-H activation/carbene insertion/intramolecular cyclization is explored. The switchable product selectivity is achieved by the use of distinct α-diazo carbonyl compounds. Benzimidazole-fused quinolines are obtained through [4 + 2] annulation exclusively when 2-diazocyclohexane-1,3-diones are used, where they act as a C2 synthon. Alternatively, diazonaphthalen-1(2H)-ones merely function as a one-carbon unit synthon to generate a quaternary center through [4 + 1] cyclization to afford spirocyclic benzimidazole-fused isoindole naphthalen-2-ones. A thorough mechanistic study reveals the course of the reaction.

Parallel Synthesis of Pyrazolone-Fused Cinnolines by the Palladium-Catalyzed [4 + 2] Annulation of Pyrazol-3-ones with Substituted Allenoates.

The synthesis of pyrazolone-fused cinnolines from pyrazol-3-ones and α,γ-substituted allenoates via a palladium-catalyzed C-H activation/annulation cascade was developed. Mechanistic studies revealed the course of the reaction. Initially, N-acyl-valine ligand-assisted ortho-C-H activation gives ortho-alkenylated intermediate. Subsequent cyclopalladation and migratory insertion of allenoate give a seven-membered palladacycle. Reductive elimination finally furnishes pyrazolone-fused cinnolines.

Pd(II)-Catalyzed [5 + 2] Cyclization of N-Triflyl Aryl Indoles and α,γ-Substituted Allenoates: A Route to Indole-Fused Benzodiazepines.

A Pd(II)-catalyzed [5 + 2] annulation between N-triflyl aryl indoles and α,γ-substituted allenoates for the synthesis of indole-fused benzodiazepines is reported. This protocol is highly efficient when N-acetylated valine amino acid and DMSO have been used as ligand and cosolvent, respectively. The substrate scope can be further extended to disubstituted allenoates. A reaction mechanism has been proposed based on the mechanistic studies. Mechanistically, the N-acetylated valine amino acid ligand accelerates C-H activation of the C(sp2)-H bond. Consequent cyclopalladation leads to the formation of a six-membered palladacycle. Subsequent coordination and migratory insertion of an allenoate forms the possible eight-membered intermediate. Reductive elimination followed by a [1,3]-H shift results in the indole-fused benzodiazepines.

Rapid Synthesis of Benzimidazole-Fused Isoindoles by Rh(III)/Ru(II)-Catalyzed [4 + 1] Cascade C-H/N-H Annulation of 2-Arylbenzimidazoles with Alkynoates and Alkynamide.

A Rh(III)-catalyzed [4 + 1] cyclization of 2-arylbenzimidazoles with alkynoates through C-H activation/ortho-alkenylation/intramolecular annulation cascade to obtain benzimidazole-fused isoindoles is reported. The reaction of the Rh catalyst and internal alkyne ester provides benzo[4,5]imidazo[2,1-a]isoindole acetate exclusively. Conversely, internal alkyne amide participates in the annulation process in the presence of a Ru catalyst to provide benzo[4,5]imidazo[2,1-a]isoindole acetamide. The alkyne acts as a C1 synthon and undergoes [4 + 1] cyclization rather than traditional [4 + 2] annulation.

Rh(III)-Catalyzed Switchable [4 + 1] and [4 + 2] Annulation of N-Aryl Pyrazolones with Maleimides: An Access to Spiro Pyrazolo[1,2-a]indazole-pyrrolidine and Fused Pyrazolopyrrolo Cinnolines.

A rhodium(III)-catalyzed controllable [4 + 1] and [4 + 2] annulation of N-aryl pyrazolones with maleimides as C1 and C2 synthon has been explored for the synthesis of spiro[pyrazolo[1,2-a]indazole-pyrrolidines] and fused pyrazolopyrrolo cinnolines. The product selectivity was achieved through time-dependent annulation. The [4 + 1] annulation reaction involves sequential Rh(III)-catalyzed C-H alkenylation of N-aryl pyrazolone, followed by an intramolecular spirocyclization via aza-Michael-type addition to afford spiro[pyrazolo[1,2-a]indazole-pyrrolidine]. However, prolonged reaction time converts in situ formed spiro[pyrazolo[1,2-a]indazole-pyrrolidine] into fused pyrazolopyrrolocinnoline. This unique product formation switch proceeds via strain-driven ring expansion through a 1,2-shift of the C-C bond.

Rh(III)-Catalyzed (4 + 1) Annulation of Pyrazol-3-ones with Alkynoates via Ortho-Alkenylation/Cyclization Cascade: Synthesis of Indazole-Fused Pyrazoles.

A facile synthesis of novel indazole-fused pyrazoles from pyrazol-3-ones and alkynoate esters/amides via Rh(III)-catalyzed sequential C-H activation/ortho-alkenylation/intramolecular cyclization cascade is reported. The important characteristic of this method is that the resulting scaffold bearing quaternary carbon has been obtained through unusual [4 + 1] rather than expected [4 + 2] addition where alkynoate acts as a one-carbon unit.

Substrate-controlled Rh(III)-catalyzed regiodivergent annulation towards fused and spiro benzimidazoles.

A Rh(III)-catalyzed cascade C-H activation and cyclization of 2-aryl benzimidazoles with maleimides for the synthesis of benzimidazole-fused isoquinolines and benzimidazole-spiro isoindoles is reported. Switchable selectivity towards the formation of these two distinct products can be achieved using unsubstituted and substituted benzimidazoles at the ortho-position of the phenyl ring. Mechanistically, C-H activation followed by migratory insertion of maleimide forms a Heck-type intermediate. Unsubstituted benzimidazole undergoes aza-Michael addition to form a (4 + 2) fused product, whereas ortho-substituted phenyl benzimidazole causes steric clash to deliver a (4 + 1) spiro-adduct favorably via acid-catalyzed intramolecular annulation.

Catalyst-Controlled Regioselective Synthesis of Benzotriazlolodiazepin-7-ones and Benzotriazolodiazocin-8-ones.

A catalyst-controlled highly chemoselective and regioselective intramolecular cycloamidation of triazol-1-ylbenzamides toward the synthesis of scarcely known heterocycles is reported. In the presence of a palladium catalyst, this cycloisomerization reaction afforded substituted benzotriazlolodiazepin-7-ones via intramolecular insertion of a palladium into C-C triple bond in a 7-exo-dig way. Alternatively, the use of a silver catalyst in the reaction produced substituted benzotriazolodiazocin-8-ones in a highly regioselective manner through 8-endo-dig intramolecular ring closure.

One-Pot Synthesis of Unsymmetrical Bis-Heterocycles: Benzimidazole-, Benzoxazole-, and Benzothiazole-Linked Thiazolidines.

A one-pot, three-component synthesis of benzimidazole-linked thiazolidines from 2-cyanomethyl benzimidazole, iso-, isothio-, or isoselenocyanates and 1,2-dichloroethane is reported. Isolation of the key intermediate formed during the course of the reaction validates its mechanistic pathway. Under the same reaction conditions, benzimidazole-linked/fused thiazinanes were obtained when 1,3-dichloropropane or diiodomethane was used.

Enantioselective Synthesis of Hydantoin and Diketopiperazine-Fused Tetrahydroisoquinolines via Pictet-Spengler Reaction.

An enantioselective synthesis of iso-, isothio-, and isoselenohydantoin and diketopiperazine-fused tetrahydroisoquinolines from l-Dopa was reported. The route consists of an Pictet-Spengler reaction of ( S)-2-amino-3-(3,4-dimethoxyphenyl)propanoates with various aldehydes to afford diastereomeric tetrahydroisoquinolines. Next step, the tetrahydroisoquinolines were further reacted with iso-, isothio-, or isoselenocyanates to construct hydantoin. Similarly, the diketopiperazine moiety was constructed by subjecting tetrahydroisoquinolines to a condensation reaction with chloroacetyl chloride followed by nucleophilic addition with various primary amines.

One-pot synthesis of 4-arylidene imidazolin-5-ones by reaction of amino acid esters with isocyanates and α-bromoketones.

A simple and new multicomponent reaction for the one-pot synthesis of substituted 4-arylidene imidazolin-5-ones from l-amino acid methyl esters, iso-, isothio- or isoselenocyanates, and α-bromoketones is demonstrated. Isolation of thiohydantoin and 5-benzylidene 2-thioxoimidazolidin-4-one intermediates revealed a possible reaction mechanism. The strategy was further extended to the synthesis of 2-iminothiazolines and 2-thioxoimidazolin-4-ones.

Base Controlled Three-Component Regioselective Synthesis of 2-Imino Thiazolines and 2-Thioxoimidazolin-4-ones.

Base-controlled regioselective synthesis of 2-imino thiazolines and 2-thioxoimidazolin-4-ones was achieved to use a one-pot reaction between chiral amino esters, isothiocyanates, and α-bromoketones/alkyl halides. This three-component coupling reaction in acetonitrile provides 2-imino thiazolines, whereas the formation of 2-thioxoimidazolin-4-ones was observed under basic conditions at ambient temperature. The corresponding products were obtained in good to excellent yield with broad substrate scope. Isolation of thiourea and thiohydantoin intermediates disclosed the course of the reaction mechanism.

Synthesis of Aminofuran-Linked Benzimidazoles and Cyanopyrrole-Fused Benzimidazoles by Condition-Based Skeletal Divergence.

A condition-based skeletal divergent synthesis was explored to achieve skeletal diversity in two component condensation reaction. Cyanomethyl benzimidazole was reacted with α-bromoketone under thermal conditions to furnish 2-aminofuranyl-benzimidazoles, while the same reaction afforded 3-cyano-benzopyrrolo-imidazoles under microwave irradiation. Two nonequivalent nucleophilic centers on benzimidazole moiety were manipulated elegantly by different reaction conditions to achieve the skeletal diversity.

Silver(I)-Catalyzed Regioselective Synthesis of Triazole Fused-1,5-Benzoxazocinones.

An efficient and regioselective synthesis of novel 1,2,3-triazole-fused-1,5-benzoxazocinones through intramolecular cyclization of substituted ethynyl triazoyl benzoic acids was explored. A crucial precursor 5-iodo-1,2,3-triazole benzoate was obtained from substituted 2-azido benzoic acid esters in a single step through a Copper-Catalyzed Azide-Alkyne Cycloaddition (CuAAC) reaction using a CuI/NBS catalytic system. A carbon-carbon triple bond was installed through a Sonogashira coupling reaction by various terminal alkynes. Finally, the 1,4,5-substituted ethynyl triazoyl benzoic acids were cyclized by a AgOTf-mediated intramolecular cyclization to afford 8-endo-dig 1,2,3-triazole-fused-1,5-benzoxazocinones exclusively.

One-Pot Three-Component Synthesis of 2-Imino-1,3-Thiazolines on Soluble Ionic Liquid Support.

An efficient one-pot, three-component synthesis of 2-imino-1,3-thiazolidines and 2-imino-1,3-thiazolines using ionic liquid-tethered 2-aminobenzimidazoles was reported. The protocol includes reaction of ionic liquid attached 2-aminobenzimidazoles with isothiocyanates to afford isothioureas, followed by its base induced inter and intramolecular nucleophilic displacement reactions with 1,2-dichloroethane (EDC) which results in thiazolidine ring formation. In the next to the last step, the ionic liquid support was removed by methanolysis to deliver 2-imino-1,3-thiazolidines, which were sequentially oxidized with manganese(III) triacetate to yield 2-imino-1,3-thiazolines. The salient feature of this method is the use of 1,2-dichloroethane as a synthetic equivalent for α-haloketone to avoid the use of toxic halogenating reagents.

Regioselective piperidine-catalyzed tandem imination-isocyanate annulation to fused tricyclic triazines.

A novel tandem imination-isocyanate-mediated annulation was explored. Ionic liquid-immobilized 2-aminobenzimidazoles react sequentially with aldehydes and isocyanates to give highly functionalized benzimidazole-embedded triazines. The second-stage transformation revealed that the formation of triazinone functionality is entirely regioselective to allow rapid assembly of biologically interesting tricyclic skeletons. In conjunction with the application of microwave irradiation and IL support, this method provides an efficient route to access substituted benzoimidazotriazines.

Design and synthesis of new biprivileged molecular scaffolds: indolo-fused benzodiazepinyl/quinoxalinyl benzimidazoles.

The present article describes the design and synthesis of new biprivileged molecular scaffolds with diverse structural features. Commercially available, simple heterocyclic building blocks such as 4-fluoro-3-nitrobenzoic acid, 2-chloro-3-nitrobenzoic acid, and indoline were utilized for the synthesis of the novel heterocycles. Pictet-Spengler-type condensation was used as a key step to construct tetracyclic indolo-benzodiazepines and indolo-quinoxalines linked with substituted benzimidazoles. Analysis of single crystals of representative compounds showed that these molecular skeletons have the potential to present various substituents with distinct three-dimensional orientations.