Direct Annulation Research Articles

Isoselenazole Synthesis by Rh-Catalyzed Direct Annulation of Benzimidates with Sodium Selenite

Organoselenium compounds have attracted significant research interest because of their potent therapeutic activities and indispensable applications in the organic chemistry field. The selenation reactions conventionally rely on the use of sensitive Se reagents; thus, new synthetic methods with improved efficiency and operational simplicity have recently been of particular interest. In this manuscript, we report a Rh-catalyzed direct selenium annulation using tractable sodium selenite (Na2SeO3) as the limiting reagent. The selenite species was converted to highly electrophilic SeO(OBz)2 in situ upon treatment with Bz2O, thereby undergoing C–H/N–H double nucleophilic selenation. A series of benzimidates successfully underwent selenation under mild reaction conditions to afford isoselenazole derivatives.

Construction of Thienopyrroles through Rhodium-Catalyzed Direct Annulation of (Acetylamino)thiophenes with Alkynes

AbstractThe direct annulative coupling of 3-(acetylamino)thiophenes with internal alkynes proceeds smoothly under rhodium catalysis through acetylamino-directed C–H bond cleavage at the C2-position, leading to the effective construction of 4-acetylthieno[3,2-b]pyrrole derivatives. The acetyl directing group on the annulation product is readily removed to produce the 4-unprotected thieno[3,2-b]pyrrole derivative.

Elemental sulfur promoted condensation of indoles and 1,2-phenylenediamines

Synthesis of 6H-indolo[2,3-b]quinoxaline often requires the use of non-commercial starting materials, thus is limited to certain substrates. Herein we report a method for direct annulation of commercial indoles and 1,2-phenylediamines towards the synthesis of 6H-indolo[2,3-b]quinoxalines. Reactions proceeded in the presence of elemental sulfur, 4-(dimethylamino)pyridine (DMAP) base, and DMSO solvent. An array of 6H-indolo[2,3-b]quinoxalines which bearing functionalities such as unprotected phenol, pyrazole, cyano, and secondary amine were obtained in moderate yields.

Direct annulation between glycine derivatives and thiiranes through photoredox/iron cooperative catalysis.

A visible-light-induced aerobic oxidative [2+3] cycloaddition reaction between glycine derivatives and thiiranes has been disclosed, which provides an efficient and atom-economical strategy for the rapid synthesis of thiazolidine-2-carboxylic acid derivatives and the post-modification of glycine-derived dipeptides under mild conditions with good yield and high diastereoselectivities. A preliminary mechanistic study favors a pathway involving a cooperative photoredox catalysis and iron catalysis.

Metal-free direct annulation of 2-aminophenols and 2-aminothiophenols with unactivated amides through transamidation: Access to polysubstituted benzoxazole and benzothiazole derivatives

We herein report a simple yet novel oxidant, metal and solvent-free green protocol for synthesising differently 2-substituted 1,3-benzoxazoles and benzothiazoles from 2-aminophenol hydrochloride salt unactivated amide as in situ carbon source. Further, the hydrogen ion of hydrochloride played a crucial role in amide activation followed nucleophilic attack that through eliminations of amine as a side product, and de-hydrolysis step leads to final annulation. This versatile strategy is applicable to a wide variety of differently substituted o-aminophenols, unactivated aliphatic and aromatic amides, yielding the corresponding product in good to excellent yields in a single step.

Brønsted Acid Catalyzed Direct Annulation of Alkoxyallenes and Naphthols to Chroman Ketals

AbstractA straightforward Brønsted acid-catalyzed and scalable annulation of alkoxyallenes with simple naphthols was developed, affording chroman ketals in 49–84% yields. The versatile chroman ketals can be easily converted into coumarins by 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ)-mediated oxidation, and a series of 2-substituted chromans via nucleophilic substitutions.

Redox‐Neutral Vicinal Difunctionalization of Five‐Membered Heteroarenes with Dual Electrophiles

AbstractA new reaction mode of palladium/norbornene (Pd/NBE) cooperative catalysis is reported involving the selective coupling of two different carbon‐based electrophiles for vicinal double C‐H functionalization of five‐membered heteroarenes in a site‐selective and redox‐neutral manner. The key is to use alkynyl bromides as the second electrophile, which allows vicinal difunctionalization of a wide range of heteroarenes including pyrroles, thiophenes and furans at their C4 and C5 positions. One‐ or two‐step tetrafunctionalizations of simple pyrrole and thiophene have also been realized. The C2‐substituted NBEs prove most effective in these reactions, and the mechanistic exploration discloses the origin of the high selectivity of this transformation. Synthetic utility of this method has been exemplified in the concise preparations of thiophene‐containing organic materials and a protein kinase inhibitor analogue. Preliminary success has also been achieved in a direct annulation event, using a tethered ketone as the second electrophile.

Redox‐Neutral Vicinal Difunctionalization of Five‐Membered Heteroarenes with Dual Electrophiles

A new reaction mode of palladium/norbornene (Pd/NBE) cooperative catalysis is reported involving the selective coupling of two different carbon-based electrophiles for vicinal double C-H functionalization of five-membered heteroarenes in a site-selective and redox-neutral manner. The key is to use alkynyl bromides as the second electrophile, which allows vicinal difunctionalization of a wide range of heteroarenes including pyrroles, thiophenes and furans at their C4 and C5 positions. One- or two-step tetrafunctionalizations of simple pyrrole and thiophene have also been realized. The C2-substituted NBEs prove most effective in these reactions, and the mechanistic exploration discloses the origin of the high selectivity of this transformation. Synthetic utility of this method has been exemplified in the concise preparations of thiophene-containing organic materials and a protein kinase inhibitor analogue. Preliminary success has also been achieved in a direct annulation event, using a tethered ketone as the second electrophile.

Deacylation-Aided C─H Alkylative Annulation through C─C Cleavage of Unstrained Ketones.

Arene- and heteroarene-fused rings are pervasive in biologically active molecules. Direct annulation between a C─H bond on the aromatic core and a tethered alkyl moiety provides a straightforward approach to access these scaffolds; however, such a strategy is often hampered by the need of special reactive groups and/or less compatible cyclization conditions. It would be synthetically appealing if a common native functional group can be used as a handle to enable a general C─H annulation with diverse aromatic rings. Here, we show a deacylative annulation strategy for preparing a large variety of aromatic-fused rings from linear simple ketone precursors. The reaction starts with homolytic cleavage of the ketone α C─C bond via a pre-aromatic intermediate, followed by a radical-mediated dehydrogenative cyclization. Using widely available ketones as the robust radical precursors, this deconstructive approach allows streamlined assembly of complex polycyclic structures with broad functional group tolerance.

Palladium(II)-catalyzed direct annulation of 2-chloronicotinaldehyde with 2-bromothiophenol via novel C(formyl)-C(aryl) coupling strategy

Palladium(II)-catalyzed direct annulation of 2-chloronicotinaldehyde with 2-bromothiophenol via novel C(formyl)-C(aryl) coupling strategy

LUDOX HS-40 Catalyzed Pot, Atom and Step Economic (PASE) Synthesis of Pyran Annulated Heterocyclic Scaffolds

A simple pot, atom and step economic (PASE) synthesis of 2-amino-3-aroyl-4-aryl-tetrahydro-5H-chromen-5-one and hitherto unreported 2-amino-3-aroyl-4-aryl-dihydro-pyrano[3,2-c]chromen-5-one, 2-amino-3-aroyl-dihydrospiro[chromene-4,3'-indoline]-2',5(6H)-dione, 2-amino-3-aroyl-dihydro-5H-spiro[cyclopenta[b]pyran-4,3'-indoline]-2',5-dione, and 2'-amino-3'-aroyl-dihydro-2H-spiro[acenaphthylene-1,4'-chromene]-2,5'(6'H)-dione has been developed using LUDOX HS-40, a commercially available innocuous and inexpensive catalyst via direct annulations of benzoylacetonitrile, aldehyde/isatin/acenaphthoquinone and dimedone/cyclicdiketone/4-hydroxycoumarins in ethanol. This protocol offers advantages such as wide range of substrate scope, operational simplicity, higher yields, and cost-effectiveness.

Enantioselective Synthesis of Azoniahelicenes by Rh-Catalyzed C-H Annulation with Alkynes.

A rhodium(III)-catalyzed enantioselective C-H activation/annulation process is disclosed. With a catalyst derived from a chiral CpRh(III) complex and a chiral acid, the direct annulation reactions between 1-aryl isoquinoline derivatives and alkynes take place smoothly to afford a series of chiral azoniahelicenes in excellent yields and enantioselectivity (up to 99% yield and 96% ee). Mechanistic studies suggest that C-H bond cleavage may be the turnover-limiting step.

Coumarins by Direct Annulation: β-Borylacrylates as Ambiphilic C3 -Synthons.

Modular β‐borylacrylates have been validated as programmable, ambiphilic C3‐synthons in the cascade annulation of 2‐halo‐phenol derivatives to generate structurally and electronically diverse coumarins. Key to this [3+3] disconnection is the BPin unit which serves a dual purpose as both a traceless linker for C(sp2)–C(sp2) coupling, and as a chromophore extension to enable inversion of the alkene geometry via selective energy transfer catalysis. Mild isomerisation is a pre‐condition to access 3‐substituted coumarins and provides a handle for divergence. The method is showcased in the synthesis of representative natural products that contain this venerable chemotype. Facile entry into π‐expanded estrone derivatives modified at the A‐ring is disclosed to demonstrate the potential of the method in bioassay development or in drug repurposing.

Coumarins by Direct Annulation: β‐Borylacrylates as Ambiphilic C3‐Synthons

AbstractModular β‐borylacrylates have been validated as programmable, ambiphilic C3‐synthons in the cascade annulation of 2‐halo‐phenol derivatives to generate structurally and electronically diverse coumarins. Key to this [3+3] disconnection is the BPin unit which serves a dual purpose as both a traceless linker for C(sp2)–C(sp2) coupling, and as a chromophore extension to enable inversion of the alkene geometry via selective energy transfer catalysis. Mild isomerisation is a pre‐condition to access 3‐substituted coumarins and provides a handle for divergence. The method is showcased in the synthesis of representative natural products that contain this venerable chemotype. Facile entry into π‐expanded estrone derivatives modified at the A‐ring is disclosed to demonstrate the potential of the method in bioassay development or in drug repurposing.

Cp*M-Catalyzed Direct Annulation with Terminal Alkynes and Their Surrogates for the Construction of Multi-Ring Systems

Transition-metal-catalyzed C–H activation followed by oxidative cyclization with unsaturated coupling partners has been a valuable synthetic tool for the multiring molecular scaffolds. This Perspec...

A Green Nanopalladium-Supported Catalyst for the Microwave-Assisted Direct Synthesis of Xanthones

We report an efficient, selective, rapid and eco-friendly protocol for the one-step synthesis of a small xanthone library via an intermolecular catalytic coupling from readily available salicylaldehydes and 1,2-dihaloarenes under ligand-free conditions. To achieve this advantageous direct annulation, we used a novel recoverable palladium nanocatalyst supported on a green biochar under microwave irradiation. Unlike other existing palladium-based approaches, our synthetic strategy showed a greater operational simplicity, drastic reduction in reaction times, and an excellent tolerance to diverse functional groups. The reaction proceeds in very good yields and with high regioselectivity. The novel heterogeneous catalyst can be recycled and reused up to four times without significant loss of activity.

DMF as Methine Source: Copper‐Catalyzed Direct Annulation of Hydrazides to 1,3,4‐Oxadiazoles

AbstractAn unprecedented Cu‐catalyzed direct annulation of hydrazides with N,N‐dimethylformamide (DMF) was developed, providing an efficient synthesis of valuable 1,3,4‐oxadiazoles. This process features the short reaction time and can be safely conducted on gram scale. The reaction also facilitated the convenient synthesis of 1,3,4‐oxadiazole‐2(3H)‐ones. Moreover, the mechanistic studies suggest that the source of CH is from the N‐methyl group of DMF.magnified image

Concise Pyrimido[4,5‐d]pyrimidine Synthesis via Direct Annulation of N‐Uracil Amidines with Benzaldehydes Under Transition Metal Free Conditions

AbstractA novel and concise route towards the synthesis of pyrimido[4,5‐d]pyrimidines via a direct annulation reaction of N‐uracil amidines with benzaldehydes under transition metal free conditions has been described. The requisite precursors N‐uracil amidines are obtained via SNAE reaction on 6‐chlorouracil with amidines. A series of pyrimido[4,5‐d]pyrimidines has been synthesized in good to excellent yields by the direct annulation of N‐uracil amidines with benzaldehydes using Cs2CO3 as base and molecular oxygen as oxidant in tBuOH at 100 0C. This synthetic protocol has a number of advantages such as‐ operational simplicity, use of green oxidant, avoidance of transition metal catalysts or ligands, and easy accessibility of the starting materials, making it a highly practical approach to access various pyrimido[4,5‐d]pyrimidines of biological interest.

Palladium/Norbornene-Catalyzed Indenone Synthesis from Simple Aryl Iodides: Concise Syntheses of Pauciflorol F and Acredinone A.

To show the synthetic utility of palladium/norbornene (Pd/NBE) cooperative catalysis, here we report concise syntheses of indenone-based natural products, pauciflorol F and acredinone A, which are enabled by direct annulation between aryl iodides and unsaturated carboxylic acid anhydrides. Compared to the previous indenone-preparation approaches, this method allows simple aryl iodides to be used as substrates with complete control of the regioselectivity. The total synthesis of acredinone A features two different Pd/NBE-catalyzed ortho acylation reactions for constructing penta-substituted arene cores, including the development of a new ortho acylation/ipso borylation.

TiCl4-n-Bu3N-mediated cascade annulation of ketones with α-ketoesters: a facile synthesis of highly substituted fused γ-alkylidene-butenolides.

A facile protocol for the synthesis of highly substituted fused γ-alkylidene butenolides using direct annulation of ketones with α-ketoesters, which proceeds through TiCl4-n-Bu3N mediated aldol addition followed by an intramolecular enol-lactonization/cyclization cascade, is reported. Diverse 6-5, 7-5 and 8-5 fused bicyclic γ-ylidene butenolides and highly substituted monocyclic analogs related to biologically relevant natural products were prepared from readily accessible ketone and α-ketoester building blocks. The highly step-economic cascade nature, good substrate scope, easy access to complex products with good to excellent yields, gram-scalability, demonstration of synthetic utility, and unambiguous structural confirmation through X-ray crystallography analyses and analogy are the salient features of this work.