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.

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.

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.

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.

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.

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 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.

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.

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.

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.

Time and Temperature Dependent Palladium-Catalyzed Stereo- and Regioselective Alkoxy-arylation of Triple Bonds: Synthesis of (E)/(Z)-1,1-Disubstituted-3-(1-Phenylalkylidene)-1,3-dihydroisobenzofurans.

The development of synthetic strategies enabling the stereo- and regio-selective synthesis of organic molecules is indispensable in the pharmaceutical industry. This work describes a stereo- and regioselective synthesis of (E)/(Z)-1,1-disubstituted-3-(1-arylalkylidene)-1,3-dihydroisobenzofurans catalyzed by palladium. The DHIBFs are achieved from readily available aryl bromides and ortho-alkyne tertiary alcohols via intermolecular aryl Heck coupling and intramolecular oxo-cyclization of the suitably situated hydroxyl group. Significantly, it was demonstrated that a Z-isomer was formed as a substantial isomer at 80 °C for 6 h, whereas the stable E-isomer was the predominant one at slightly vigorous conditions (100 °C for 12 h). In addition, careful observation has also led to the realization that this double isomerization from Z- to E-isomer was triggered in the NMR tube itself in CDCl3 at room temperature. Significantly, this protocol, for the first time, enabled the synthesis of heavily substituted dihydroisobenzofurans, especially, bearing a tetra-substituted double bond.

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.

Palladium-Catalyzed Aerobic Oxidative Coupling of ortho-(Alkynyl)styrenes with Allylic Alcohols via 6-endo-dig Cyclization: Regioselective Construction of Polysubstituted Naphthalenes.

An efficient protocol is described for the regioselective construction of polysubstituted functionalized naphthalenes from easily accessible ortho-(alkynyl)styrenes under mild reaction conditions. The reaction proceeds via cycloaromatization and intermolecular coupling of ortho-(alkynyl)styrenes with allylic alcohols catalyzed by PdCl2. Notably, the reaction is successful under open air as the green oxidant source. A range of functional groups (F, Cl, Br, NO2, and ester) including protecting free OH groups were found to be compatible.

A Domino Palladium-Catalyzed Cyclization: One-Pot Synthesis of 4b-Alkyl-10-phenyl-4b,5-dihydroindeno[2,1-a]indenes via Carbopalladation Followed by C-H Activation.

An effective domino one-pot [Pd]-catalysis for the construction of novel tetracyclic compounds was described. This process involved in the construction of three C-C bonds from simple and readily available 1-bromo-2-isopropenylbenzenes and internal alkynes. A variety of fused tetracyclic dihydroindeno-indenes were accomplished.

Palladium-Catalyzed Acylations: One-Pot Synthesis of Indenones.

An efficient, one-pot synthesis of substituted indenones was accomplished starting from simple o-iodoketones and aldehydes. [Pd]-catalyzed direct acylation of o-iodoketones with aldehydes was employed as the key step. Subsequent intramolecular aldol condensation afforded the indenones. Notably, a variety of indenones were achieved. Significantly, the natural product neolignan was accomplished in one pot.

Palladium-Catalyzed Environmentally Benign Acylation.

Recent trends in research have gained an orientation toward developing efficient strategies using innocuous reagents. The earlier reported transition-metal-catalyzed carbonylations involved either toxic carbon monoxide (CO) gas as carbonylating agent or functional-group-assisted ortho sp(2) C-H activation (i.e., ortho acylation) or carbonylation by activation of the carbonyl group (i.e., via the formation of enamines). Contradicting these methods, here we describe an environmentally benign process, [Pd]-catalyzed direct carbonylation starting from simple and commercially available iodo arenes and aldehydes, for the synthesis of a wide variety of ketones. Moreover, this method comprises direct coupling of iodoarenes with aldehydes without activation of the carbonyl and also without directing group assistance. Significantly, the strategy was successfully applied to the synthesis n-butylphthalide and pitofenone.

Domino [Pd]-Catalysis: One-Pot Synthesis of Isobenzofuran-1(3H)-ones.

An efficient domino [Pd]-catalysis for the synthesis of isobenzofuran-1(3H)-ones is presented. The strategy shows broad substrate scope and is amenable to o-bromobenzyl tertiary/secondary/primary alcohols. Significantly, the method was applied to the synthesis of antiplatelet drug n-butyl phthalide and cytotoxic agonist 3a-[4'-methoxylbenzyl]-5,7-dimethoxyphthalide.

Metal-Free Domino One-Pot Decarboxylative Cyclization of Cinnamic Acid Esters: Synthesis of Functionalized Indanes.

Trifluoroacetic acid promoted unprecedented domino reaction for the synthesis of diverse indanes starting from simple cinnamic acid esters is described. Their formation can be explained via acid triggered decarboxylation of cinnamic acid esters and subsequent inter/intramolecular cyclization. Overall process involves in the intramolecular cleavage of two σ-bonds (C-O and C-C) and inter/intramolecular construction of two/one C-C σ-bond(s). Significantly, this protocol was successful without the aid of any metal salts.

Domino One-Pot Process for the Synthesis of Isobenzofuran-1(3H)-ones via [Cu]-Catalysis Using Water as the Green Solvent.

An efficient domino one-pot strategy via [Cu]-catalyzed intermolecular "cyanation" of o-bromobenzyl alcohols → in situ intramolecular "nucleophilic attack" → "hydrolysis" is presented, for the synthesis of isobenzofuran-1(3H)-ones. Significantly, the reaction is successfully carried out under environmentally benign conditions, using water as sole green solvent.