Continuous Flow Ni- or Ru-Zeolite-Catalyzed Intramolecular Dehydration of Diols and Seco-Acids for Macrocyclic Ethers and Lactones.

Herein, we report the efficient intramolecular dehydrative coupling of symmetrical and unsymmetrical diols for the synthesis of macrocyclic crown ethers in the presence of Ni-zeolite as a catalyst under continuous flow module. This method is also efficient for the intramolecular dehydrative macrolactonization of seco-acids using Ni-zeolite or Ru-zeolite. This flow catalysis is demonstrated by a wide substrate scope with one-time packed Ni-zeolite to produce 20 macrocyclic polyethers and 11 examples of broad macrolactones with water as a byproduct.

Visible Light Mediated Organophotoredox Catalyzed Synthesis of Tetraketones Using Tertiary Amines as Alkyl Synthons.

Eosin Y catalyzed syntheses of bioactive tetraketones using cyclic-1,3-diketones and tertiary amines as alkyl synthons under 18 W blue LED have been accomplished. The condition is very mild that uses air as a green oxidant and avoids previously used harsh conditions like high temperature. Diverse arrays of tertiary amines first undergo reductive quenching of excited photocatalysts to form iminium ions that upon subsequent attack by cyclic-1,3-diketones give rise to tetraketones.

Amberlyst-A26-Mediated Corey-Chaykovsky Cyclopropanation of 9-Alkylidene-9-fluorene under Continuous Process.

Herein, we have developed a continuous-process for the direct cyclopropanation of various alkenes nonconjugated with carbonyl using trimethylsulfoxonium iodide as a methylene source via the Corey-Chaykovsky cyclopropanation reaction in the presence of Amberlyst-A26 as a heterogeneous base. Several 9-alkylidene-9-fluorene derivatives successfully undergo Corey-Chaykovsky cyclopropanation to afford spiro[cyclopropane-1,9'-fluorene] in excellent yields under the continuous-process module. Furthermore, continuous process for the cyclopropanation of 3-benzylideneindolin-2-one derivatives using Amberlyst-A26 as a heterogeneous base has been described, which afford spiro[cyclopropane-1,3'-indolin]-2'-one derivatives.

Synthesis of Macrolactams from Macrolactones Using Ru-/Ir-Catalytic System under Neutral Conditions.

Herein, we report the Ru-/Ir-catalyzed synthesis of valuable macrolactams from macrolactones and esters. The ring-opening of the macrolactones was efficaciously facilitated by the Ru catalyst to generate 32 amides in the first step. In the second step, intramolecular -alkylative ring closure of amides with alcohols was succeeded by Ir catalyst to provide a series of 22 macrolactams and gave water as a byproduct.

Catalyst-Assisted Selective Vinylation and Methylallylation of a Quaternary Carbon Center Using -Butyl Acetate.

The In(OTf)-catalyzed α-vinylation of various hydroxy-functionalized quaternary carbon centers using in situ generated isobutylene from -butyl acetate is presented as a novel synthetic methodology. Moreover, -butyl acetate is a nonflammable feed stock and is a readily available source for the in situ production of vinyl substituents, as demonstrated by the vinylation reaction with quaternary hydroxy/methoxy compounds. Moreover, an excellent selectivity for methylallylation over vinylation was obtained with Ni(OTf) as a catalyst.

Continuous Flow Inter- and Intramolecular Macrolactonization under High Dilution Conditions.

An efficient continuous flow process for the macrolactonization of seco acids and diacids using diols in the presence of Mukaiyama reagent (-methyl-2-chloropyridinium iodide) has been developed for medium to large sized macrocyclic lactones. In comparison with other methods, the continuous flow process provided good to high yield in a short reaction time. By using this methodology, a wide range of macrocyclic lactones (11 compounds), dilactones (15 compounds), and tetralactone derivatives (2 compounds) with various ring sizes (12-26 atoms in the core) were synthesized in just 35 min of residence time.

Lewis Acid-Catalyzed Chemodivergent and Regiospecific Reaction of Phenols with Quaternary Peroxyoxindoles.

The indium-catalyzed regiospecific coupling of substituted phenol derivatives and quaternary peroxyoxindoles for the synthesis of C2 or C4 benzoxazin-3-one-substituted phenols via skeletal rearrangement is described. This reaction is demonstrated with 17 examples with good yields and diverse aryl substituents. In contrast to the indium-catalyzed reaction, the Cu(OTf)-catalyzed reaction of the phenol with quaternary peroxyoxindoles afforded C2 or C4 2-oxindole-substituted phenol derivatives.

Continuous-Flow Direct Azidation of Alcohols and Peroxides for the Synthesis of Quinoxalinone, Benzooxazinone, and Triazole Derivatives.

Continuous-flow reactors provide an ideal tool for the synthesis of potentially explosive but synthetically useful organic substances like organic azides due to their intrinsically small volume leading to very effective collision and highly controlled reaction conditions. Herein, we report the continuous-flow direct azidation of various alcohols by using TMSN as an azide transfer reagent in the presence of Amberlyst-15 as a recyclable catalyst. Numerous 3-hydroxy-2-oxindoles effectively undergo azide transfer to afford azide-functionalized quaternary stereocenters in a continuous-flow module.

Dehydrogenative Intramolecular Macrolactonization of Dihydroxy Compounds Using Ru-MACHO Catalyst.

Herein, we have developed a new approach for the synthesis of 11 to 21-membered macrolactones via intramolecular dehydrogenative coupling of primary alcohols by using Ru-MACHO as a catalyst and CsCO as a base. This protocol generated 11-21-ring-sized macrocycles (26 derivatives), free from an external oxidant or an additive, eliminating stoichiometric reagents and producing only hydrogen as a byproduct.

Transition-Metal-Free Alkylative Aromatization of Tetralone Using Alcohol/Amino Alcohol towards the Synthesis of Bioactive Naphthol and Benzo[/]indole Derivatives.

Herein, we report alkylative aromatization of tetralone for the synthesis of bioactive naphthols and benzo[/]indole derivatives using alcohols in the presence of NaOH via an aerobic oxidative cross-coupling protocol. This is a general and transition-metal-free method, which uses an inexpensive base, avoids inert conditions, and furnishes water and hydrogen peroxide as the byproducts. Moreover, this method demonstrated with wide substrate scope and obtained exclusive regioselectivity.

Ru-MACHO-Catalyzed Direct Inter/Intramolecular Macrocyclization of Alcohols and Ketones.

Herein we describe a new approach for end-to-end cyclization to construct macrocycles through the inter/intramolecular dehydrogenative coupling of alcohols and ketones in the presence of a Ru-MACHO catalyst. This method is highly atom economical and sustainable and can be used for many substrates. Additionally, this method results in the generation of only water as the byproduct.

Sequential Oxidative Fragmentation and Skeletal Rearrangement of Peroxides for the Synthesis of Quinazolinone Derivatives.

For the first time, the sequential reaction of peroxyoxindole that involves base-promoted oxidative fragmentation to isocyanate formation and primary amine or amino alcohol accelerated skeletal rearrangement to synthesize exo-olefinic-substituted quinazolinone or oxazoloquinazolinone is reported. The advantages of this new reaction include a broad substrate scope and transition-metal-free and room-temperature conditions. The formation of the isocyanate as a key intermediate that accelerates oxidative skeletal rearrangement has been confirmed by trapping experiments and spectroscopic evidence.

Catalytic Acceptorless Dehydrogenation of Amino Alcohols and 2-Hydroxybenzyl Alcohols for Annulation Reaction under Neutral Conditions.

A base-free and acceptorless Ru-catalyzed dehydrogenative approach has been developed for the synthesis of -heterocycles by using 1,3-dicarbonyls and amino alcohols through a domino sequential enamine formation and intramolecular oxidative cyclization strategy. This unified approach is also applicable for the synthesis of O-heterocycles involving 2-hydroxybenzyl alcohol as a coupling reactant via consecutive C-alkylation and intramolecular cyclization steps. The present protocol is general for the synthesis of varieties of biologically important scaffolds, such as tetrahydro-4-indol-4-one, 3,4-dihydroacridin-1(2)-one, and tetrahydro-1-xanthen-1-ones derivatives using a single catalytic system, viz.

Synthesis of Quaternary Spirooxindole 2H-Azirines under Batch and Continuous Flow Condition and Metal Assisted Umpolung Reactivity for the Ring-Opening Reaction.

An efficient and new approach for the synthesis of spirooxindole 2H-azirines via intramolecular oxidative cyclization of 3-(amino(phenyl)methylene)-indolin-2-one derivatives in the presence of I and Cs CO under batch/continuous flow is described. This method is mild and facile to synthesize a variety of spirooxindole 2H-azirines derivatives in gram-scale. Furthermore, we have synthesized spiroaziridine derivatives from spirooxindole 2H-azirines derivatives via addition of Grignard reagent.

Manganese-Catalyzed Synthesis of Quaternary Peroxides: Application in Catalytic Deperoxidation and Rearrangement Reactions.

Highly efficient, selective, and direct C-H peroxidation of 9-substituted fluorenes has been achieved using a Mn-2,2'-bipyridine catalyst via radical-radical cross-coupling. Moreover, this method effectively promotes the vicinal bisperoxidation of sterically hindered various substituted arylidene-9-fluorene/arylideneindolin-2-one derivatives to afford highly substituted bisperoxides with high selectivity over the oxidative cleavage of C═C bond that usually forms the ketone of an aldehyde. Furthermore, a new approach for the synthesis of ()-6-benzylidene-6-benzo[]chromene has been achieved via an acid-catalyzed skeletal rearrangement of these peroxides.

Continuous-Flow Accelerated Sulfation of Heparan Sulfate Intermediates.

We report for the first time a continuous-flow strategy to execute -sulfation modification of heparan sulfate (HS) oligosaccharides. A systematic investigation of the influence of the flow parameters on the installation of the sulfate group on glucosamine monosaccharide can aid the development of a comprehensive, quick, and reliable strategy for -sulfation of HS oligosaccharide precursors. Deprotection of the sulfated heparin intermediates led to the development of a comprehensive biologically inspired oligosaccharide library to understand the crucial structure-function relationship of HS.

Sn-Catalyzed Criegee-Type Rearrangement of Peroxyoxindoles Enabled by Catalytic Dual Activation of Esters and Peroxides.

We report here the Sn-catalyzed mild protocol for ring expansion of peroxyoxindoles to afford the series of substituted-2-benzo[][1,4]oxazin-3(4)-one derivatives. In this protocol, we showed the in situ conversion of -butyl peroxy compounds into peresters with the aid of external esters, which then underwent the ring-expansion process, and the incipient carbocation was trapped with the alcohol residue generated from the esters. The reaction is also demonstrated in a continuous flow process to afford the rearranged product in 22 min of residence time.

Ligand-Free Ru-Catalyzed Direct sp C-H Alkylation of Fluorene Using Alcohols.

The sp C-H alkylation of 9-fluorene using alcohol and a Ru catalyst via the borrowing hydrogen concept has been described. This reaction was catalyzed by the [Ru(-cymene)Cl] complex (3 mol %) and exhibited a broad reaction scope with different alcohols, allowing primary and secondary alcohols to be employed as nonhazardous and greener alkylating agents with the formation of environmentally benign water as a byproduct. A variety of 9-fluorene underwent selective and exclusive mono-C9-alkylation with primary alcohols in good to excellent isolated yield (26 examples, 50-92% yield), whereas this reaction with secondary alcohols in the absence of any external oxidants furnished the tetrasubstituted alkene as the major product.

Transition-Metal-Free Addition Reaction for the Synthesis of 3-(Aminobenzylidene/aminoalkylidene)indolin-2-ones and Its Synthetic Applications.

A novel and efficient transition-metal-free approach for the exclusive synthesis of -3-(aminobenzylidene/aminoalkylidene)indolin-2-ones in high yield from 2-oxindole and aryl/alkyl nitrile in the presence of LiOBu and 2,2'-bipyridine system is described. In addition, we disclosed a new approach towards the metal-free fluorination using selectfluor and the C═C bond cleavage using CuI and environmentally benign O.

MnO @Fe O Magnetic Nanoparticles as Efficient and Recyclable Heterogeneous Catalyst for Benzylic sp C-H Oxidation.

Herein, we report a highly chemoselective and efficient heterogeneous MnO @Fe O MNP catalyst for the oxidation of benzylic sp C-H group of ethers using TBHP as a green oxidant to afford ester derivatives in high yield under batch/continuous flow module. This catalyst was also effective for the benzylic sp C-H group of methylene derivatives to furnish the ketone in high yield which can be easily integrated into continuous flow condition for scale up. The catalyst is fully characterized by spectroscopic techniques and it was found that 0.

Reversible chemoselective transetherification of vinylogous esters using Fe-catalyst under additive free conditions.

An additive/Brønsted acid/base free, highly efficient and chemoselective transetherification of electron deficient vinylogous esters and water mediated de-alkylation using an earth-abundant Fe-catalyst under very mild reaction conditions is described. This reaction is highly selective to primary alcohols over secondary alcohols, has good functional group tolerance, is scalable to gram scale and a purification free sequential transetherification in a continuous flow mode is demonstrated.

The Rearrangement of Peroxides for the Construction of Fluorophoric 1,4-Benzoxazin-3-one Derivatives.

An unprecedented skeletal rearrangement of 3-( tert-butylperoxy)indolin-2-one using a tin catalyst has been developed. This rearrangement is highly selective to afford a series of fluorophoric ( Z)-2-arylidene and alkylidene-2 H-benzo[ b][1,4]oxazin-3(4 H)-one derivatives in good to excellent yield. In contrast with Sn(OTf), the reaction of 3-( tert-butylperoxy)indolin-2-one derivatives with FeCl afforded the Hock fragmentation product via C-C bond cleavage.

Recent Advances in the Metal-Catalyzed Activation of Amide Bonds.

The amide functional group is commonly found in peptides, proteins, pharmaceutical compounds, natural products, and polymers. The synthesis of amides is typically performed by using classical approaches that involve the reaction between a carboxylic acid and an amine in the presence of an activator. Amides are thought to be an inert functional group, because they are unsusceptible to nucleophile attack, owing to their low electrophilicity.

Ru-Catalyzed dehydrogenative synthesis of antimalarial arylidene oxindoles.

Ru(ii)-NHC catalyzes α-olefination of 2-oxindoles using diaryl methanols in the absence of an acceptor. A wide array of symmetrical and unsymmetrical diaryl methanols undergoes dehydrogenative coupling with 2-oxindole selectively to generate various substituted 3-(diphenylmethylene)indolin-2-one derivatives in good yields and produces environmentally benign by-products, H2 and H2O. This methodology was successfully applied for the synthesis of a bioactive drug i.