Acid-Mediated Domino Cyclization of ortho-Formyl Cinnamate Esters: Synthesis of Substituted Indene/Indane Esters and Indeno[a]indenones.

A BroÌ·nsted acid-driven protocol to access substituted monoarylindene esters, biarylindane esters, and indeno[a]indenones from simple ortho-formylcinnamate esters and external arenes has been revealed. Remarkably, this single-pot process enabled the construction of two, three, and four new C-C bonds in building monoarylindene esters, biarylindane esters, and indeno[a]indenones, respectively, under metal-free and mild reaction parameters via triggering the inactive cinnamate ester moiety. In addition, the present strategy is investigated with widespread substrate scope.

Electrochemical selenofunctionalization of unactivated alkenes: access to ß-hydroxy-selenides.

This work demonstrates the electrochemical construction of 2-methyl-1-aryloxy-3-(arylselanyl)propan-2-ol/2-hydroxy-2-methyl-3-(arylselanyl)propyl 2-(2-hydroxy-2-methyl-3-(arylselanyl)propoxy)benzoate starting from aryl allyl ethers/allyl benzoates and diaryl diselenides under additive-free electrochemical conditions. This environmentally friendly method was achieved through constant current electrolysis in an undivided cell setup under acid, oxidant, or catalyst-free conditions. Additionally, this technique enabled the synthesis of a variety of ß-hydroxy selenides including late-stage functionalization of drug derivatives in good to exceptional yields across various substrates under mild reaction conditions.

Acid-Promoted Domino Access to Substituted Benzo[b]carbazoles.

Herein, a straightforward BroÌ·nsted acids-promoted domino pathway to build substituted benzo[b]carbazoles has been described from easily accessible ortho-formyl (or ortho-acyl) cinnamate esters and indoles. Noticeably, the protocol was amenable to protecting group-free indoles. Notably, this methodology is based on a single-pot regioselective construction of two new C-C bonds and aromatization sequences under mild and metal-free reaction conditions. The mechanistic studies suggested the initial formation of bis-indole substituted intermediate via a dual aromatic substitution with two indole molecules at the carbonyl carbon of ortho-formyl (or ortho-acyl) cinnamate ester followed by intramolecular cyclization and aromatization with exclusion of a second indole molecule. Besides, the efficacy of this approach was also illustrated by scale-up and derivatization reactions, including the photophysical properties study.

Distal-C-H Functionalization of Biphenyl Scaffolds Assisted by Easily Removable/Recyclable Aliphatic Nitrile Templates.

We present here the distal-C-H activation/functionalization of biphenyl scaffolds using aliphatic nitrile templates. The approach has demonstrated good to exclusive meta selectivities over a wide range of olefination and acetoxylation substrates. In addition, bis-olefination has been accomplished in a one-pot, sequential manner. Notably, this technique highlights the diversification of pharmaceuticals and natural products. Consequently, the temporary directing aliphatic template has been recovered quantitively from the coupled product.

Palladium-Catalyzed [3 + 2] Annulation of ortho-Substituted Iodoarenes with Maleimides via a Consecutive Double Heck-type Strategy.

Herein, we report an efficient [3 + 2] annulation of ortho-substituted iodoarenes with maleimides via a palladium-catalyzed consecutive double Heck-type strategy, leading to fused tricyclic frameworks of pharmaceutical relevance. The protocol ensued through consecutive inter- and intramolecular Heck couplings effectively. This approach was compatible with a large variety of substrates and functional groups, and it was remarkably tolerated with unprotected maleimide.

Transition metal-free and temperature dependent one-pot access to phenanthrene-fused heterocycles via a 1,3-dipolar cycloaddition pathway.

A versatile, operationally simple, temperature-dependent, and transition metal-free one-pot protocol has been devised for the preparation of novel phenanthrene-fused pyrazoles. Notably, the overall process involved an intermolecular condensation, an intramolecular 1,3-dipolar cycloaddition, and an aromatization sequence starting from biaryl-2,2'-aldehydes bearing enoate esters with various hydrazine hydrochlorides. Notably, the sequential one-pot three-component operation has also been achieved. Importantly, it was also shown that this protocol was amenable to hydroxylamine hydrochloride as the nitrogen source and furnished phenanthrene-fused isoxazoles. Notably, the temperature dependent nature of this protocol was also demonstrated, which led to the formation of dealkoxylcarbonylated phenanthrene-fused pyrazoles at slightly higher temperatures and longer reaction times. Remarkably, this metal-free protocol effectively constructed two C-N bonds and one C-C bond and exhibited a broad substrate scope.

Acid-Mediated Cascade Cyclization Pathway to Indeno[2,1-c]chromen-6(7H)-ones.

Developing mild and effective synthetic strategies for producing significant molecules starting from readily available starting materials is indispensable in organic synthesis. Herein, we present a triflic acid-driven dual cyclization pathway to produce functionalized indeno[2,1-c]chromen-6(7H)-ones from simple 2-formyl (or 2-acyl) cinnamate esters and phenols. Notably, this protocol enabled the construction of two C-C bonds and one C-O bond under metal-free reaction conditions via the activation of the unreactive ester moiety in a single pot. The isolation of intermediate indenol-ester might suggest self-intramolecular cycloaddition by the proximate double bond of the enoate ester with the o-carbonyl moiety, followed by an electrophilic attack with phenol and a subsequent cyclocondensation pathway. In addition, the photophysical properties have also been examined.

A two-step access to fused-/spiro-polycyclic frameworks via double Heck cascade and acid-driven processes.

This report illustrates the rapid construction of two divergent classes of polycyclic frameworks, benzo[a]fluorenones and spiro-chromenone indenes, via a double Heck cascade and an acid-driven cyclization from easily accessible precursors, alkyl 2-bromocinnamate esters and diphenylacetylenes. The present strategy has surveyed a broad substrate scope and delivered an array of products with interesting structural features. Besides, fluorescence studies were performed for the synthesized benzo[a]fluorenones.

A TBADT photocatalyst-enabled radical-induced cyclization pathway to access functionalized dihydrobenzofurans.

Herein, this work describes a photoinduced visible light-mediated radical cyclization for constructing dihydrobenzofuran (DHB) scaffolds. Notably, this cascade photochemical process is tolerable with various aromatic aldehydes and diverse alkynyl aryl ethers and proceeds via an intramolecular 1,5-hydrogen atom transfer (HAT) pathway. Significantly, acyl C-H activation under mild conditions has been achieved without the use of additives or reagents. The photocatalyst, tetrabutylammonium decatungstate (TBADT), plays an important role in the present strategy by facilitating the well-known hydrogen atom transfer during the course of the reaction.

Access to distal meta-C-H functionalization of arylmethanesulfonic acid derivatives.

Herein, we report the meta-C-H olefination of arylmethanesulfonates aided by a potentially versatile aliphatic nitrile-directing group under microwave irradiation conditions with fair to very good yields and good to outstanding regioselectivities. Significantly, the protocol showed broad substrate scope including olefin-derived drugs and cyclic olefins. Remarkably, a dual meta-C-H bond was amenable to generating the bis-olefination products.

An electrochemical cascade process: synthesis of 3-selenylindoles from 2-alkynylanilines with diselenides.

Substituted organoselenium compounds are crucial structural motifs in pharmaceutical molecules. Herein, we report a metal, oxidant, and base-free electrochemical approach to access 3-selenylindoles through an oxidative cyclization of 2-alkynylanilines with diselenides. This environmentally friendly approach demonstrates a wide range of substrate scope under mild reaction conditions in an electrochemical undivided cell setup.

Functionalization of arylacetic acids via directing-group-assisted remote meta-C-H activation.

Herein, we report the first microwave-assisted remote-C-H functionalization aided by a simple nitrile directing template. Notably, the present protocol showed a broad substrate scope VIA enabling meta-C-H arylation, acetoxylation, and cyanation. Significantly, the microwave-accelerated meta-C-H functionalization was effective with short reaction times without compromising yields and site selectivity. In addition, ibuprofen drug diversification was accomplished by carrying out arylation, acetoxylation, and cyanation. Importantly, meta-dual-hetero functionalization has been presented.

Electrochemical Oxidative Annulation of Inactivated Alkynes for the Synthesis of Sulfonated 2H-Chromene Derivatives.

A unique, facile, and straightforward electrochemical oxidative annulation of inactivated propargyl aryl ethers with sulfonyl hydrazides leading to 3-sulfonated 2H-chromenes has been achieved. Significantly, this protocol involves a green approach that works under mild reaction conditions using a constant current in an undivided cell and is devoid of oxidants and catalysts. Notably, the process exhibited a broad scope and functional group tolerance to deliver 2H-chromenes and would represent an alternative and sustainable strategy versus conventional chromene synthesis.

Electrochemical synthesis of 2-alkyl-4-phenylalkan-2-ols via cathodic reductive coupling of alkynes with unactivated aliphatic ketones.

Herein, we present an efficient electrochemical method for synthesizing 2-alkyl-4-phenylalkan-2-ols through an electrochemically driven cathodic reductive coupling of the terminal and internal acetylenes with unactivated aliphatic ketones under mild conditions. The process proceeds through a ketyl radical, which then activates the aryl acetylene and causes complete reduction of the triple bond of the acetylene moiety. This strategy is environmentally benign and exhibits a broad substrate scope with ubiquitously available starting materials.

Intermolecular Sonogashira Coupling and Intramolecular 5-Exo-dig Cycloisomerization Cascade: A One-Pot Pathway for Accessing (3-Benzylbenzofuran-2-yl)(phenyl)methanones.

Herein, we present an efficient and straightforward strategy enabling access to 2,3-disubstituted benzo[b]furans. The whole synthetic process proceeds via a domino intermolecular Sonogashira coupling of 2-(2-bromophenoxy)-1-phenylethan-1-ones/alkyl 2-(2-bromophenoxy)acetates/2-(2-bromophenoxy)acetonitrile/1-(2-bromophenoxy)propan-2-one with terminal acetylenes followed by an intramolecular carbanion-yne cyclization in a 5-exo-dig manner and subsequent double-bond isomerization. Notably, two C-C bonds have been constructed in a one-pot manner and a wide variety of (3-benzylbenzofuran-2-yl)(phenyl)methanones were accomplished with good functional group tolerance.

Recyclable Aliphatic Nitrile-Template Enabled Remote meta-C-H Functionalization at Room Temperature.

This article describes the development of a new aliphatic nitrile-template-directed remote meta-selective C-H olefin functionalization reaction of arenes. Remarkably, unlike the previous reports, this process is feasible at room temperature and enabled the formation of products with excellent regioselectivity. The present protocol encompasses a broad spectrum of substituted dihydrocinnamic acids and olefins, producing meta-C-H olefinated products (up to 96% yield). In addition, the efficacy of the present method has been showcased by the synthesis of various drug analogues (e.g., cholesterol, estrone, ibuprofen, and naproxen). Significantly, the robustness of meta-olefination was also demonstrated by gram-scale synthesis. The new nitrile-based meta-directing template, in particular, could be easily synthesized in two steps and recycled under mild conditions.

A Metal-Free Path to 2-Iodo-3-alkyl-1-arylbut-2-en-1-ones and Their Application to the Domino Synthesis of Functionalized 2H-Pyran-2-ones.

We report a metal-free selective synthesis of 2-iodo-3-alkyl-1-arylbut-2-en-1-ones from propargylic alcohols that is enabled by N-iodosuccinimide. A variety of substituted propargylic alcohols are amenable to delivering the selective 2-iodoenone products in very good yields. The utility of the α-iodoenone derivatives is further extended by developing an efficient, novel, and new synthetic methodology for the synthesis of 3,5,6-trisubstituted 2H-pyran-2-ones. To the best of our knowledge, this protocol is the first of its kind to accomplish 3,5,6-trisubstituted 2H-pyran-2-ones through an unprecedented domino (formation of two C-C bonds and one C-O bond) one-pot process via intermolecular Heck coupling, base-driven Michael addition, and base-mediated double bond isomerization followed by cyclo-condensation. This protocol showed good compatibility with a wide range of iodoenones (18 examples) and 2H-pyran-2-ones (42 examples). Mechanistic studies indicate that palladium is only involved in the Heck coupling; the base solely drives the rest of the steps.

An Access to Benzo[a]fluorenes, Benzo[b]fluorenes, and Indenes Triggered by Simple Lewis Acid.

This report illustrates BF3·OEt2 promoted intramolecular cascade cycloaromatization of 1,7-ynones toward synthesizing structurally diverse benzofluorene scaffolds. Remarkably, the present protocol promotes the formation of two consecutive C-C bonds intramolecularly and undergoes aromatization under mild reaction conditions to afford the tetracyclic benzo[a]fluorene frameworks. Besides, the formation of indenes was observed when 1-bromo-2-iodoarenes are relatively more electron-rich when compared with the one originating from the terminal arylacetylenes, under controlled conditions, wherein triple bond polarity has been just reversed due to the change of electronic effects exerted by the strong +M group of 1-bromo-2-iodoarenes, which is in conjugation to the connected triple bond. The same concept to generate indenes has also been extended by using aliphatic alkyne tethered ynones. Further, it was noticed that 1,7-ynones bearing the more electron-rich 1-bromo-2-iodoarenes than the arene ring arriving from the terminal arylacetylenes lead to benzo[b]fluorenes, under thermodynamic conditions, instead of delivering the benzo[a]fluorenes. In addition, this method features metal-free conditions, easily accessible starting materials, operational simplicity, gram-scale synthesis, and a wide range of substrate scopes.

Palladium-Catalyzed Distal m-C-H Functionalization of Arylacetic Acid Derivatives.

Herein, we present m-C-H olefination on derivatives of phenylacetic acids by tethering with a simple nitrile-based template through palladium catalysis. Notably, the versatility of the method is evaluated with a wide range of phenylacetic acid derivatives for obtaining the meta-olefination products in fair to excellent yields with outstanding selectivities under mild conditions. Significantly, the present strategy is successfully exemplified for the synthesis of drugs/natural product analogues (naproxen, ibuprofen, paracetamol, and cholesterol).

Lewis Acid Mediated Domino Intramolecular Cyclization: Synthesis of Dihydrobenzo[a]fluorenes.

An efficient and facile method for the regioselective synthesis of novel dihydrobenzo[a]fluorenes from readily accessible alkynols is presented. The current strategy triggers the formation of a dual C-C bond intramolecularly via Lewis acid catalysis under mild reaction conditions. Notably, secondary as well as tertiary alcohols bearing an alkyne moiety have been smoothly transformed into the corresponding products. As a result, novel tetracyclic dihydrobenzo[a]fluorenes have been accomplished using this approach.