Multisubstituted N-fused heterocycles via transition metal-catalyzed cycloisomerization protocols

Two complementary protocols for assembly of multisubstituted N-fused heterocycles have been developed. It was demonstrated that 1,3-disubstituted N-fused heterocycles, including indolizines, pyrroloquinoxalines, and pyrrolothiazoles can easily be synthesized via an exceptionally mild and efficient method involving a novel silver-catalyzed cycloizomerization of propargyl-containing heterocycles. Alternatively, 1,2-disubstituted heterocycles can be accessed through the novel cascade transformation involving an alkyne-vinylidene isomerization with concomitant 1,2-shift of hydrogen, silyl, stannyl, or germyl groups. This mild and simple method allows for selective and highly efficient synthesis of indolizines, pyrroloisoquinolines, pyrroloquinoxalines, pyrrolopyrazines, and pyrrolothiazoles.     

Pt-catalyzed cyclization/1,2-migration for the synthesis of indolizines, pyrrolones, and indolizinones

Indolizine, pyrrolone, and indolizinone heterocycles are easily accessed via the Pt(II)-catalyzed cycloisomerization or a tandem cyclization/1,2-migration of pyridine propargylic alcohols and derivatives. This method provides an efficient synthesis of highly functionalized heterocycles from readily available substrates. [reaction: see text]     

A pyrone remodeling strategy to access diverse heterocycles: application to the synthesis of fascaplysin natural products

The synthesis of diverse N-fused heterocycles, including the pyrido[1,2-a]indole scaffold, using an efficient pyrone remodeling strategy is described. The pyrido[1,2-a]indole core was demonstrated to be a versatile scaffold that can be site-selectively functionalized. The utility of this novel annulation strategy was showcased in a concise formal synthesis of three fascaplysin congeners.

The synthesis of diverse N-fused heterocycles, including the pyrido[1,2-a]indole scaffold, using an efficient pyrone remodeling strategy is described.     

Mechanistically diverse copper-, silver-, and gold-catalyzed acyloxy and phosphatyloxy migrations: efficient synthesis of heterocycles via cascade migration/cycloisomerization approach

A set of cycloisomerization methodologies of alkynyl ketones and imines with concurrent acyloxy, phosphatyloxy, or sulfonyloxy group migration, which allow for the efficient synthesis of multisubstituted furans and N-fused heterocycles, has been developed. Investigation of the reaction course by way of employing 17O-labeled substrates allowed for elucidation of the mechanisms behind these diverse transformations. It was found that, while the phosphatyloxy migration in conjugated alkynyl imines in their cycloisomerization to N-fused pyrroles proceeded via a [3,3]-sigmatropic rearrangement, the analogous cycloisomerization of skipped alkynyl ketones proceeds through two consecutive 1,2-migrations, resulting in an apparent 1,3-shift, followed by a subsequent 1,2-migration through competitive oxirenium and dioxolenylium pathways. Investigations of the 1,2-acyloxy migration of conjugated alkynyl ketones en route to furans demonstrated the involvement of a dioxolenylium intermediate. The mechanism of cycloisomerization of skipped alkynyl ketones containing an acyloxy group was found to be catalyst dependent; Lewis and Br?nsted acid catalysts caused an ionization/SN1' isomerization to the allene, followed by cycloisomerization to the furan, whereas transition metal catalysts evoked a Rautenstrauch-type mechanistic pathway. Furthermore, control experiments in the cycloisomerization of skipped alkynyl ketones under transition metal catalysis revealed that, indeed, these reactions were catalyzed by transition metal complexes as opposed to Br?nsted acids resulting from hydrolysis of these catalysts with eventual water. Further synthetic utility of the obtained phosphatyloxy-substituted heterocycles was demonstrated through their efficient employment in the Kumada cross-coupling reaction with various Grignard reagents.     

Aqueous N-heterocyclization of primary amines and hydrazines with dihalides: microwave-assisted syntheses of N-azacycloalkanes, isoindole, pyrazole, pyrazolidine, and phthalazine derivatives

[reactions: see text] The synthesis of nitrogen-containing heterocycles from alkyl dihalides (ditosylates) and primary amines and hydrazines via a simple and efficient cyclocondensation in an alkaline aqueous medium that occurs under microwave irradiation is described. This improved greener synthetic methodology provides a simple and straightforward one-pot approach to the synthesis of a variety of heterocycles, such as substituted azetidines, pyrrolidines, piperidines, azepanes, N-substituted 2,3-dihydro-1H-isoindoles, 4,5-dihydropyrazoles, pyrazolidines, and 1,2-dihydrophthalazines.     

Aza-Michael addition of 1,2-diazoles to structurally diverse enones: Efficient methods toward β-amino ketones

An efficient and mild protocol was realized using 1,2-diazoles and related heterocycles with cyclic and acyclic enones in presence of T3P (2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide) toward the regioselective formation of N-cycloalkyl heterocycles at room temperature. The developed reaction conditions showcased good selectivity over a wide range of 1,2-diazoles and enones by delivering N-cycloalkyl heterocycles in excellent yields.     

Syntheses of Some New N‐Linked Pyrimidine‐2‐amines with Pyrazinopyrimidines,Thienopyrimidines, and Benzazoles via Reactions of Various Nucleophiles with Cyanamides

New heterocycles containing 2‐aminopyrimidine moiety linked with pyrazino[1,2‐c ]pyrimidines, thieno[2,3‐d ]pyrimidines, benzimidazoles, benzothiazoles, and benzoxazoles have been prepared by an efficient method starting from N ‐(pyrimidin‐2‐yl)cyanamides.     

On the validity of Au-vinylidenes in the gold-catalyzed 1,2-migratory cycloisomerization of skipped propargylpyridines

A mechanism of the Au-catalyzed cycloisomerization of propargylpyridines has been investigated. Both DFT computational and experimental results strongly support generation of a Au-carbene via a cyclization/proton transfer sequence over the previously proposed path involving a Au-vinylidene intermediate. For the β-Si-substituted Au-carbene (G = SiR(3)), a 1,2-Si migration was shown to be kinetically favored over a 1,2-H shift. This study highlights the importance of alternative pathways that could explain reactivities commonly attributed to an alkyne-vinylidene isomerization in Au catalysis.     

Alkylaminopropenones and alkylamino-propenoates as efficient and versatile synthons in microwave-assisted combinatorial synthesis

A simple and fast one-pot method using microwave irradiation for the synthesis of a number of small libraries of diverse heterocycles is described in this paper. The two-step one-pot method includes the formation of alkylaminopropenones or alkylaminopropenoates in 5 min at 180 degrees C and a subsequent treatment with dinucleophiles for 3 to 5 min at 150 degrees C to 180 degrees C to form a variety of biologically interesting heterocycles in a cascade-type reaction. The combination of combinatorial chemistry and microwave-assisted synthesis was found to be very efficient.     

Visible-Light-Driven One-Pot Synthesis of Benzimidazoles,Benzothiazoles, and Quinazolinones Catalyzed by Scalable and Reusable Ba-Doped CoMoO4 Nanoparticles Under Air Atmosphere

Herein we report a simple and efficient oxidative coupling of various aryl methyl amines with diverse coupling partners, such as o-phenylenediamine (benzene-1,2-diamine), 2-aminobenzenethiol and 2-aminobenzamide, to synthesize the corresponding heterocycles using scalable and reusable heterogeneous catalysts under visible light irradiation. A systematic investigation led to the synthesis of benzimidazoles, benzothiazoles and quinazolinones under air atmosphere in very good to excellent yields. The strategy is atom economical and found to be tolerance towards different functional groups, and wide range of substrate scope. Furthermore, the methodology was demonstrated for its suitability on scale up and reusability. The density functional theory (DFT) calculations and the analysis of band structures of pristine and Ba doped CoMoO₄ systems showed that the doping of Ba in place of Co improved the catalytic performance of the system.     

Improved and expanded one-pot,two-component Boulton-Katritzky syntheses of N–N bond containing bicyclic heterocycles

Improved and expanded one-pot, two-component syntheses of bicyclic heterocycles containing a 3-N-acyl-3-amino-1,2-pyrazole motif from N′-hydroxy-carboxyamidines and acylbenzotriazoles have been developed. Importantly, this sequence obviates the need for hydrazine or N-aminating reagents to synthesize the key nitrogen–nitrogen (N–N) bond of these heterocycles, which is formed via Boulton-Katritzky rearrangement. A diverse array of pharmaceutically relevant N–N containing heterocycles has been prepared with this methodology using readily available reagents without the need for special equipment or conditions.     

Pt-catalyzed cyclization/migration of propargylic alcohols for the synthesis of 3(2H)-furanones, pyrrolones, indolizines, and indolizinones

Several heterocycles such as furanones, pyrrolones, and indolizines, which are of pharmacological importance, are easily accessed via the Pt(II)-catalyzed heterocyclization/1,2-migration of propargylic ketols or hydroxy imine derivatives. This method sidesteps the challenges of traditional heteroaromatic oxygenation strategies such as regioselectivity and functional group tolerance in the syntheses of these heterocycles.     

Organoaluminum-mediated selective 1,2-rearrangement of γ,γ-disubstituted γ-amino α,β-unsaturated carbonyl compounds leading to unsymmetrically substituted pyrroles

γ,γ-Dialkyl-γ-amino-α,β-unsaturated carbonyl compounds were found to undergo selective skeletal rearrangement under the influence of modified organoaluminum Lewis acid to give unsymmetrically substituted pyrroles through the rapid Paal-Knorr type cyclization upon acidic hydrolysis. This new structural reorganization of amino carbonyl compounds triggered by the 1,2-alkyl shift provides a unique entry to the synthesis of pyrroles, an important class of heterocycles with diverse biological activities.     

A new, one-pot, multi-component synthesis of imines of 3-amino-2-arylimidazo[1,2-a]pyridines, 3-amino-2-arylimidazo[1,2-a]pyrazines, and 3-amino-2-arylimidazo[1,2-a]pyrimidines

An efficient, one-pot, multi-component synthesis of 3-amino-2-arylimidazo[1,2-a]pyridines, 3-amino-2-arylimidazo[1,2-a]pyrazines, and 3-amino-2-arylimidazo[1,2-a]pyrimidines is described. Heating a mixture of a 2-aminopyridine, 2-aminopyrazine or 2-aminopyrimidine, a benzaldehyde, and imidazoline-2,4,5-trione under solvent-free conditions afforded imine derivatives of the title compounds in excellent yields. Single-crystal X-ray analysis conclusively confirms the structure of these bridgehead bicyclic 5-6 heterocycles.     

Aromatic annulation strategy for naphthalenes fused at 1,2- and 3,4-positions with two heterocycles

An efficient regioselective naphthoannulation strategy able to fuse a newly formed naphthalene ring at its 1,2- and 3,4- positions to two different heterocycles has been developed.     

Solvent‐Driven Iodine‐Mediated Oxidative Strategies for the Synthesis of Bis(imidazo[1,2‐a]pyridin‐3‐yl)sulfanes and Disulfanes

Two efficient iodine‐mediated strategies, which are economical and one‐pot, are described to access bis(imidazo[1,2‐a ]pyridin‐3‐yl)sulfanes and bis(imidazo[1,2‐a ]pyridin‐3‐yl)disulfanes in chloroform and acetic acid, respectively, by a direct oxidative homocoupling of imidazo‐heterocycles using inexpensive sodium sulfide as a sulfur source. These strategies are scalable, and an array of substrates delivered their corresponding stable sulfur‐bridged imidazo‐heterocycles in excellent yields.     

A base-catalyzed, direct synthesis of 3,5-disubstituted 1,2,4-triazoles from nitriles and hydrazides

A convenient and efficient one step, base-catalyzed synthesis of 3,5-disubstituted 1,2,4-triazoles by the condensation of a nitrile and a hydrazide is presented. A diverse range of functionality and heterocycles are tolerated under the reaction conditions developed, and the reactivity of the nitrile partner is relatively insensitive to electronic effects.     

Pd-Catalyzed Aerobic Intermolecular 1,2-Diamination of Conjugated Dienes: Regio- and Chemoselective Synthesis of Piperazines and 2-Piperazinones

Dinitrogen heterocycles are among the most important molecular structures, and the synthesis of these types of structures through intermolecular 1,2-diamination of olefins is a direct and efficient method. However, the types of nitrogen sources are mostly derived from ureas or arylamines, and nitrogen sources from aliphatic amines are still limited due to their distinct electronic and steric effects. Herein, we report a palladium-catalyzed aerobic intermolecular 1,2-diamination of conjugated dienes, using ethanediamine and α-amino amide derivatives as nitrogen sources respectively, for the synthesis of piperazines and 2-piperazinones in good yields (up to 95 %) and with high regio- and chemoselectivities.     

A novel and facile synthesis of 2-oxo-1,2-dihydropyridine-fused 1,3-diazaheterocycles via heterocyclic ketene aminals and Konevenagel adducts formed by phthalic anhydride and ethyl cyanacetate

An efficient synthetic pathway to 2-oxo-1,2-dihydropyridine-fused 1,3-diaza heterocycles from heterocyclic ketene aminals,phathalic anhydride and ethyl cyanacetate was established.This protocol involved aza-ene reaction/imine-enamine tautomerization/enamine-ester exchange/ring-opening reaction sequence.     

Catalytic Asymmetric Synthesis of Axially Chiral Diaryl Ethers through Enantioselective Desymmetrization

Axially chiral diaryl ethers are a type of unique atropisomers bearing two potential axes, which have potential applications in a variety of research fields. However, the catalytic enantioselective synthesis of these diaryl ether atropisomers is largely underexplored when compared to the catalytic asymmetric synthesis of biaryl or other types of atropisomers. Herein, we report a highly efficient catalytic asymmetric synthesis of diaryl ether atropisomers through an organocatalyzed enantioselective desymmetrization protocol. The chiral phosphoric acid-catalyzed asymmetric electrophilic aromatic aminations of the symmetrical 1,3-benzenediamine type substrates afforded a series of diaryl ether atropisomers in excellent yields and enantioselectivities. The facile construction of heterocycles by the utilizations of the 1,2-benzenediamine moiety in the products provided access to a variety of structurally diverse and novel azaarene-containing diaryl ether atropisomers.