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Advanced Synthesis & Catalysis

Wiley Online Library : Advanced Synthesis & Catalysis

Published: 2018-02-15T00:00:00-05:00


Aniline ortho C-H Sulfuration/Cyclization with Elemental Sulfur for Efficient Synthesis of 2-Substituted Benzothiazoles under Metal-Free Conditions


A three-component synthesis of 2-substituted benzothiazoles from aryl amines, elemental sulfur and styrenes or aryl acetylenes in 1-methylpyrrolidin-2-one (NMP) is described. Two C-S and one C-N bonds were selectively formed in one-pot under metal-free conditions.

Chemoenzymatic Approaches to the Synthesis of the Calcimimetic Agent Cinacalcet Employing Transaminases and Ketoreductases


Several chemoenzymatic routes have been explored for the preparation of cinacalcet, a calcimimetic agent. Transaminases (TAs) and ketoreductases (KREDs) turned out to be useful biocatalysts for the preparation of key optically active precursors. Thus, the asymmetric amination of 1-acetonaphthone yielded an enantiopure (R)-amine, which can be alkylated in one step to yield cinacalcet. Alternatively, the bioreduction of the same ketone resulted in an enantiopure (S)-alcohol, which was easily converted into the previous (R)-amine. In addition, the reduction was efficiently performed with the KRED and its cofactor co-immobilized on the same porous surface. This self-sufficient heterogeneous biocatalyst presented an accumulated total turnover number (TTN) for the cofactor of 675 after 5 consecutive operational cycles. Finally, in a preparative scale synthesis the TA-based approach was performed in aqueous medium and led to enantiopure cinacalcet in two steps and 50% overall yield.

A Tunable Route to Prepare ɑ,β-Unsaturated Esters and ɑ,β-Unsaturated-γ-Keto Esters through Copper-Catalyzed Coupling of Alkenyl Boronic Acids with Phosphorus Ylides


A tunable strategy to prepare ɑ,β-unsaturated esters and ɑ,β-unsaturated-γ-keto esters in good to excellent yields was developed through copper-catalyzed oxidative coupling of phosphorus ylides with alkenyl boronic acids under mild conditions. The reaction without water afforded ɑ,β-unsaturated esters, ketones, and amides while ɑ,β-unsaturated-γ-keto esters, 1,4-ɑ,β-unsaturated diketones and ɑ,β-unsaturated-γ-keto amides were obtained when using 5.0 equiv. of water. H2O18 labeling experiments showed that water played an important role in the formation of ɑ,β-unsaturated-γ-keto esters. A plausible formation mechanism for ɑ,β-unsaturated esters and ɑ,β-unsaturated-γ-keto esters was proposed based on mechanistic studies. Phosphonium salts could also be used directly as coupling partners instead of phosphorus ylides. The reaction exhibited a broad substrate scope, good functional group tolerance, good regioselectivity, and diverse coupling products.

N-Heterocyclic carbene-catalyzed double Michael addition: stereoselective synthesis of spirofluorenes and multisubstituted indanes


The strong Brønsted basic character of N-heterocyclic carbenes (NHCs) has been used to promote the cascade double Michael addition between fluorenes and dienones. Under catalyst loadings of 1-5 mol% of NHC, fluorene reacts with divinyl ketones (DVKs) to afford anti-spirofluorene compounds in high yields. However, when benzenedi(enones) were employed as Michael acceptors in the presence of 10 mol% of NHC, fluorene undergoes a different inter- and intramolecular cascade double Michael addition providing multi-substituted indanes in high yields with excellent diastereoselectivity.

Manganese(III)-Mediated and -Catalyzed Decarboxylative Hydroxysulfonylation of Arylpropiolic Acids with Sodium Sulfinates in Water


With water as both solvent and reactant, a novel manganese(III)-mediated and -catalyzed synthesis of β-ketosulfones through decarboxylative hydroxysulfonylation reactions of arylpropiolic acids with sodium sulfinates is described. This protocol has the advantages of mild reaction conditions, short reaction time, easy to handle reagents, purification simplicity, and being environmentally benign, which demonstrate the practical utility of this methodology.

Selenolate Anion as an Organocatalyst: Reactions and Mechanistic Studies


Abstract. A new organocatalyst, the selenolate anion [RSe]–, generated from bench stable and commercially available diphenyl diselenide or from phenyl benzyl selenide (10 mol%) is introduced. Benchmarking is performed in the conversion of benzylic chlorides into trans-stilbenes selectively at room temperature. Mechanistic studies support the intermediacy of the selenolate anion and of 1,2-diphenylethyl phenyl selenide.

Construction of Isoxazolidin-5-ones with a Tetrasubstituted Carbon Center: Enantioselective Conjugate Addition Mediated by Phase-Transfer Catalysis


An efficient enantioselective Michael reaction of readily available α-substituted N-Boc isoxazolidin-5-ones is described under phase transfer conditions with up to 95:5 er. The organocatalytic process is promoted by a low catalytic loading of a commercially available N-spiro quaternary ammonium salt. This sequence opens an entry to chiral heterocyclic platforms displaying a β-amino carbonyl motif with an α-all-carbon quaternary stereogenic center. The methodology was also successfully extended to the asymmetric amination reaction using an azodicarboxylate electrophile.

Nonenzymatic Dynamic Kinetic Resolution of in situ Generated Hemithioacetals: Access to 1,3-Disubstituted Phthalans


The first nonenzymatic DKR reaction of hemithioacetals is developed. Hemithioacetals were formed in situ via thiol addition and subsequently underwent an intramolecular oxa-Michael reaction. The scope of the reaction was quite broad ranging from aliphatic to aromatic substituents and 1,3-disubstituted-1,3-dihyroisobenzofuran products were obtained in good yields with high diastereo- and enantioselectivities.

Lewis acid-mediated defluorinative [3+2] cycloaddition/aromatization cascade of 2,2-difluoroethanol systems with nitriles


The properties of C-F bonds, including high thermal and chemical stability, make derivatization of organic fluorine-containing compounds by the activation of the C-F bond and subsequent functionalization quite challenging. We herein report a Lewis acid-mediated defluorinative cycloaddition/aromatization cascade of 2,2-difluoroethanols with nitriles as a novel synthetic method for the preparation of 2,4,5-trisubstituted oxazoles. This reaction, which involves cleavage of two C-F bonds and the consecutive formation of C-O and C-N bonds in a one-pot fashion, features a broad substrate scope and moderate to high reaction yields. Mechanistic studies revealed that the reaction is initiated by the Lewis acid-mediated ring closure of the 2,2-difluoroethanol to produce the fluoroepoxide intermediate.

A three-component cascade cyclization to construct 3-(2-oxopropyl)-2-arylisoindolinone derivatives via copper-catalyzed annulation


An efficient synthesis of a variety of poly-substituted isoindolinone derivatives via Cu-catalyzed three-component cascade cyclization among 2-formylbenzonitriles, alkyl aryl ketones/prop-1-en-2-ylbenzene and diaryliodonium salts is achieved. Various isoindolinone derivatives could be obtained in good to excellent yields. A concise synthesis of dihydroisoindolo[2,1-a]quinolin-11(5H)-ones have been achieved using this method.

Hydroaminomethylation in Aqueous Solvent Systems – An Efficient Pathway to Highly Functionalized Amines


The tandem-catalyzed hydroaminomethylation is a useful tool to synthesize linear amines from olefins and amines in an atom efficient manner. To enable the coupling of highly functionalized, hydrosoluble amines with non-water-soluble olefins, this reaction must be transferred to aqueous biphasic solvent systems. In this work, we systematically evaluate reaction conditions to provide a selective hydroaminomethylation of 1-octene with diethanolamine as model substrates. Although water is both the condensation side product and the solvent, yields of 79% were achieved using a catalytic system consisting of [Rh(cod)Cl]2 and sulfo-XantPhos. This approach was applied to other functionalized amines, proving this concept a suitable tool for the catalytic alkylation of highly functionalized amines.

Rhodium-Catalyzed Arylative Transformations of Propargylic Diols: Dual Roles of the Rhodium Catalyst


Controllable synthesis of a variety of allenic alcohols and 2,5-dihydrofurans by rhodium(I)-catalyzed arylative transformations of propargylic diols is reported. The hydroxorhodium catalyst was found to play dual roles: it catalyzed the arylation/dehydroxylation reaction of propargylic diols to afford allenic alcohols, and besides, it could convert to a cationic rhodium species in situ, which catalyzed the intramolecular hydroalkoxylation of allenic alcohols to form dihydrofurans. Remarkably, generation of the cationic rhodium species is dependent on the arylboron reagent used. Thus, the controllable synthesis is achieved by simply changing the arylboron reagent.

Practical Reagents and Methods for Nucleophilic and Electrophilic Phosphorothiolations


New late-stage phosphorothiolation methods are disclosed that allow the efficient transfer of SP(O)(OR)2 groups to diversely functionalized substrates using nucleophilic and electrophilic reagents. The nucleophilic reagent, tetramethylammonium O,O-dimethyl phosphorothioate, was synthesized in near-quantitative yield from Me3SiP(O)(OMe)2, elemental sulfur and Me4NF. Its Umpolung with N-bromophthalimide provided the electrophilic reagent, O,O-dimethyl-S-(N-phthalimido)¬phosphorothioate. Complementary methods based on these reagents enable the phosphorothiolation of diversely functionalized alkyl halides, arenediazonium salts, arylboronic acids and electron-rich arenes in good yields under mild conditions.

Visible-Light-Induced Difluoropropargylation Reaction with Benzothiazoline as a Reductant


The difluoropropargyl group is a useful moiety for biological applications such as in vivo click chemistry for molecular imaging techniques. Silyl-protected bromodifluoropropyne is an important difluoropropargylation reagent with previously unexplored radical reactivity. Herein, we report visible-light-induced thiyl-radical-catalyzed hydrodifluoropropargylation reactions between silyl-protected bromodifluoropropyne and alkenes in the presence of benzothiazoline as a critical reductant.

N-(acyloxy)phthalimides as Redox-Active Esters in Cross Coupling Reactions


Recent years have witnessed a resurgence of novel, efficient and practical protocols for radical-mediated cross coupling reactions involving N-(acyloxy)phthalimides (NHPI esters) as redox-active esters. After the initial discovery of redox active properties of NHPI esters, an exciting range of SET-based cross coupling reactions under thermal or photolytic conditions leading to diverse C-X (X = C, B, Si, Se, S) bonds have been published. The operational simplicity and broad applicability exhibited in redox active NHPI ester based cross couplings bode well for its widespread adoption. The review presented herein covers all the recent developments in the field of redox active ester (RAE)-based cross couplings since the initial discovery. Depending on the conditions employed the reactions have been categorized in to photoinduced- and non-photoinduced cross couplings with representative examples and insightful mechanistic discussions.

Copper-Catalyzed Oxidative Carbamoylation of N-Arylacrylamides with Hydrazinecarboxamides Leading to 2-(Oxindol-3-yl)acetamides


A tandem radical carbamoylation/cyclization reaction of N-arylacrylamides with hydrazinecarboxamides has been developed for facile access to 2-(oxindol-3-yl)acetamides, which had been utilized as precursors in the synthesis of natural bioactive pyrrolidinoindolines. In the presence of 1 mol% of copper(II) carbonate and 4 equiv of tert-butyl hydroperoxide, a wide range of N-arylacrylamides underwent highly regioselective carbamoylation with hydrazinecarboxamides followed by 5-exo-trig cyclization to afford structurally diverse 2-(oxindol-3-yl)acetamides in moderate to excellent yields.

Visible Light-Mediated Coupling of Thioureas and 1,3-Dicarbonyls: Towards a Leaving Group-Free Synthesis of Aminothiazoles


A synthesis of aminothiazoles from various 1,3-dicarbonyls and thioureas without a leaving group has been developed. The reaction is photocatalyzed by tetraiodofluorescein, an organic dye. Under irradiation with green LEDs, a sulfur radical is generated in situ from thiourea, followed by addition to the enol tautomer, forming the aminothiazole backbone. This novel strategy provides a greener alternative to the traditional leaving group protocols, with excellent atom economy.

Enantioselective Cyanosilylation of Alkynyl Ketones Catalyzed by Combined Systems Consisting of Chiral Ruthenium(II) Complex and Lithium Phenoxide


Asymmetric cyanosilylation of alkynyl ketones with the catalyst systems consisting of amino acid/2,2’-bis(diphenylphosphino)-1,1’-binaphthyl (BINAP) /ruthenium(II) complex and lithium phenoxide (Ru•Li cat.) was studied. The reaction was conducted in tert-butyl methyl ether (TBME) at –78 °C with a substrate-to-catalyst molar ratio (S/C) as high as 2000. A series of simple and functionalized ketones was converted into the alkynyl tertiary cyanohydrin derivatives in up to 99% ee. Appropriate selection of an amino-acid ligand of the catalyst according to the substrate structure was crucially important to achieve high enantioselectivity and a wide scope of substrates. Transformation of the chiral cyanohydrin product into a functionalized lactone was also examined.

Palladium-Catalyzed Triarylation of sp3 C–H Bonds in Heteroarylmethanes: Synthesis of Triaryl(heteroaryl)methanes


A straightforward method for the palladium-catalyzed triarylation of heteroarylmethanes at the methyl group has been developed. The reaction works with a variety of aryl halides, enabling the rapid synthesis of triaryl(heteroaryl)methanes in moderate to excellent yields.

Silver-Catalyzed Decarboxylative Couplings of Acids and Anhydrides: An Entry to 1,2-Diketones and Aryl-Substituted Ethanes


Silver-catalyzed oxidative decarboxylative couplings of carboxylic acids and anhydrides for producing 1,2-diketones and substituted ethanes have been developed. This reaction allows the generation of acyl or alkyl radicals by decarboxylation of the corresponding -keto acids, alkyl acids and anhydrides, which are sequentially coupled to efficiently construct a new C-C bond. This reaction represents a carboxylic acid decarboxylative alternative that employs a radical termination strategy.

Ynesulfonamide-Based Silica Gel and Alumina-Mediated Diastereoselective Cascade Cyclizations to Spiro[indoline-3,3'-pyrrolidin]-2-ones under Neat Conditions


The spiro[indoline-3,3'-pyrrolidin]-2-ones were synthesized via a silica gel and alumina-mediated sequential transformation based on tryptamine-derived ynesulfonamide substrates under neat conditions. The inherent tendency of C-C bond migration through Wagner-Meerwein rearrangement in the synthesis of spirooxindole was prevented by water trapping to the spiroindoleninium intermediate. The functional group tolerances of the methodology were investigated using a variety of substrates. The detailed mechanism of the sequential transformation was probed by the isotope-labeled experiments. This strategy was further applied in the formal syntheses of indole alkaloids coerulescine and horsfiline.

γ-Regioselective Functionalization of 3-Alkenylindoles via 1,6-Addition to Extended Alkylideneindolenine Intermediates


Alkylideneindolenines are widely employed key electrophilic intermediates for the α-functionalization of the C-3 side chain of indoles. However, the reactivity of their extended (vinylogous) counterparts has not been carefully explored so far. These intermediates can undergo 1,4- or 1,6-addition with functionalization at α- or γ-position of the side chain, resulting in regioisomeric mixtures of products. This work demonstrates that a complete γ-regioselectivity can be achieved in the reaction of 3-indol-3-yl allylic alcohols with various nucleophiles. This process is catalysed by just 1 mol% zinc(II) triflate at room temperature and entails the 1,6-selective addition of the nucleophile to an extended protonated alkylideneindolenine generated in situ. Indoles, pyrroles, anilines and thiols can be efficiently used as nucleophilic partners for this reaction, delivering the corresponding 3-vinyl substituted, γ-functionalised indole products in moderate to good yields.

Copper(II)-Schiff Base Complex-Functionalized Polyacrylonitrile Fiber as a Green Efficient Heterogeneous Catalyst for One-Pot Multicomponent Syntheses of 1,2,3-Triazoles and Propargylamines


A series of copper(II)-Schiff bases-functionalized polyacrylonitrile fiber catalysts were successfully prepared using copper acetate as copper source and characterized by elemental analysis, fourier-transfer infrared spectroscopy, ultraviolet-visible spectroscopy, X-ray photoelectron spectroscopy and inductively coupled plasma analysis. Excellent physical strength and thermal stability of the fiber catalysts were demonstrated by scanning electron microscopy, X-ray diffraction, thermogravimetric/ differential scanning calorimetry analysis and mechanical strength measurements. Furthermore, these catalysts were successfully applied to two one-pot multicomponent copper-catalyzed azide-alkyne cycloaddition (CuAAC) reaction and aldehyde, alkyne, amine (A3) coupling reaction in which the influences of different substituent groups on the catalytic activities of fiber catalysts were investigated in detail. Among them, the bis[N-ethyl-3,5-di-tert-butyl-salicylideneiminato]copper(II)-functionalized polyacrylonitrile fiber (PANS2F-Cu) as a green, efficient catalyst exhibited the best catalytic activity for its high hydrophobic micro-environment can aggregate the reactants to the catalytic sites and accelerate the reaction. In addition, the PANS2F-Cu has performed well in scaled-up experiment and shown excellent recyclability (at least ten times), and these enable it to have great potential for further applications.

Cobalt(II) Porphyrin Catalyzed Cascade Reaction of Pyrrolyl Ketones for Construction of Polysubstituted Pyrrolizidines and Pyrrolizines


We developed an efficient method for the synthesis of polysubstituted 3H-pyrrolizines and pyrrolizidines via a cobalt(II) porphyrin catalyzed intramolecular cyclopropanation/ring opening cascade reaction of hydrazones derived from pyrrolyl ketones. With CoII(F20TPP) as catalyst, a variety of pyrrolyl ketones underwent condensation, intramolecular cyclopropanation/ring opening cascade reaction and subsequent oxidation or reduction to give 3H-pyrrolizines or pyrrolizidines in good yields. This Co(II) catalyzed cascade reaction provides a rapid access to polysubstituted 3H-pyrrolizines and pyrrolizidines from readily accessible starting materials.

A Simple Procedure for the Synthesis of β-Hydroxyallenamides via Homoallenylation of Aldehydes


A simple one-pot synthesis of β-hydroxyallenamides is reported. This procedure entails chemo- and regioselective hydroboration of 3-en-1-ynyl-sulfonylamides with Cy2BH followed by homoallenylation of aldehydes to yield β-hydroxyallenamides (up to 94% yield and >20:1 dr). Controlled synthesis of up to three continuous stereochemical elements was realized. Density functional theory (DFT) calculations suggest a concerted Zimmerman-Traxler chair-like transition state. Initial results suggest that enantio- and diastereoselective synthesis of β-hydroxyallenamides with optically active hydroboration reagents is viable.

Cyclopropenylgold(I) Complexes as Aurated Carbenoids or Quasi-Carbenes


Highly strained hydrocarbons have always been a research target of high interest. Due to their untypical electronic structure they show interesting reactivity patterns and can easily be activated by -coordination to or insertion reactions with metal complexes. Herein we report the synthesis of a range of 3,3-disubstituted cyclopropenylgold(I) complexes. The synthesis of such compounds with a metal, which usually easily activate cyclopropenes is a double-edged sword. We found -bound vinylic gold to generally have a strong stabilising effect in terms of ring strain. The complexes show a strong distortion, preactivating the cyclopropenyls towards the ring-opening mode wich thermally generates 1-aurated vinylcarbenes which is reflected by a much faster conversion (Ea of 10 kcal/mol instead of 40 kcal/mol, the reaction proceeds at temperatures as low as -20°C instead of 200°C reported in the literature). In 3-phenyl-cyclopropenyl complexes these could be trapped intramolecularly to give indenylgold(I) complexes. The properties of these highly strained complexes were investigated, utilising a range of analytical and experimental procedures and Kohn-Sham density functional theoretic methods.

Pd-PEPPSI: Water-Assisted Suzuki–Miyaura Cross-Coupling of Aryl Esters at Room Temperature using a Practical Palladium-NHC (NHC = N-Heterocyclic Carbene) Precatalyst


A Pd-PEPPSI-catalyzed Suzuki-Miyaura cross-coupling of aryl esters via selective C–O cleavage at room temperature is reported. The developed catalyst system displays broad substrate scope with respect to both components under practical ambient reaction conditions using readily-available, cheap, modular, air- and moisture- stable Pd-NHC precatalyst (NHC = N-heterocyclic carbene). The use of water proved crucial for achieving high reactivity in this coupling. The catalyst system represents the mildest conditions for the Suzuki-Miyaura cross-coupling of aryl esters reported to date. The protocol also allowed for achieving TON >1,000 (TON = turnover number) in the Suzuki-Miyaura ester coupling for the first time.

Triflic acid-Mediated Expedient Synthesis of Benzo[a]fluorenes and Fluorescent Benzo[a]fluorenones


Fluorene based polyaromatic hydrocarbons are renowned compounds for materials applications. Herein, a straightforward route via in situ acetal formation has been presented to access benzo[a]fluorenes by triflic acid promoted cationic cycloisomerization of enynones in presence of trimethyl orthoformate under metal free conditions. In the absence of trimethyl orthoformate the same reaction results benzo[a]fluorenones. All the synthesized benzo[a]fluorenones are highly fluorescent in solution phase with high Stokes shift while the corresponding benzo[a]fluorenes are not fluorescent.

Synthesis of (−)-Pyrido[3,4-b]homotropane (PHT) and (±)-PHT via an Intramolecular Cross [3+2] Cycloaddition Strategy


An efficient synthesis of (−)-pyrido[3,4-b]homotropane (PHT) as well as (±)-PHT has been achieved in 7 steps from conveniently available starting materials. Key transformations involve an efficient construction of the core bridged 9-aza-[4.2.1]nonane skeleton via a Sc(OTf)3-catalyzed intramolecular cross [3+2] cycloaddition (IMCC) followed by Krapcho decarboxylation and Barton reductive decarboxylation. The present work supplies a general and efficient strategy for synthesis of other bridged analogues.

Palladium-Catalyzed Regioselective Aerobic Allylic C-H Oxygenation: Direct Synthesis of α,β-Unsaturated Aldehydes and Allylic Alcohols


A protocol for the synthesis of α,β-unsaturated aldehydes and allylic alcohols from simple allylic hydrocarbons with water via palladium-catalyzed functionalization of allylic C-H bonds was described. Molecular oxygen is utilized as the sole oxidant in this oxygenation of terminal alkenes. This protocol features good functional group compatibility, broad substrate scope, and high atom- and step-economy. Moreover, the synthetic utility of this method can be highlighted by its application to the synthesis of ibuprofen, which is a highly potent analgesic.

Alternative Palladium-Catalyzed Vinylic C−H Difluoroalkylation of Ketene Dithioacetals Using Bromodifluoroacetate Derivatives


A palladium-catalyzed cross-coupling of α-oxo ketene dithioacetals and bromodifluoroacetate derivatives has been developed for the synthesis of a class of CF2-containing tetra-substituted olefins, which has potential to extend to drug design and material application. The process is proposed to involve two single electron transfer processes accompanied by an alternative loop from palladium(0) to palladium(I), likely due to unique structural properties of ketene dithioacetals with β,β-dialkylthiol substituents on the olefin double bond.

Zinc-Catalyzed Enantioselective Dearomative [3+2] Cycloaddition Reaction of 3-Nitrobenzothiophenes and 3-Nitrothieno[2,3-b]yridine with 3-Isothiocyanato Oxindoles


A highly diastereo- and enantioselective dearomative [3+2] cycloaddition reaction of 3-nitrobenzothiophenes and 3-nitrothieno[2,3-b]with 3-isothiocyanato oxindoles is developed. The reaction is catalyzed by the chiral Zn(OTf)2/bis(oxazoline, and is the second example of a catalytic asymmetric dearomative cycloaddition reaction of 3-nitrobenzothiophene derivatives. A range of complex heterocyclic compounds containing three contiguous stereocenters, one of which is spirocyclic center, can be obtained in quantitative yields with excellent stereoselectivities.

Visible Light Activated Radical Denitrative Benzoylation of β-Nitrostyrenes: A Photocatalytic Approach to Chalcones


A metal-free, convenient photocatalytic approach to chalcones from β-nitrostyrenes and benzaldehydes via a radical denitrative benzoylation pathway is reported. The salient features of the protocol include the utilization of visible light as an inexpensive and ecosustainable energy source, N-hydroxyphthalimide (NHPI) as a reusable organophotocatalyst and acetonitrile as an acceptable green solvent to afford chalcones in excellent yields at room temperature in a one-pot procedure. Notably, this is the first application of β-nitrostyrenes as readily available substrates for chalcone synthesis and the first example of photocatalysis in this field.

Indium-mediated Palladium-catalyzed Allylic Alkylation of Isatins with Alkynes


An unprecedented indium-mediated palladium-catalyzed allylic alkylation of isatins with alkynes is disclosed. This reaction provides a new, practical, and straightforward route to access 3-allyl-3-hydroxy-2-oxindoles in good yields with broad substrate scope and scalability, exhibiting high atom and step economy. A primary mechanistic study reveals that indium played two roles in the reaction, first as a reductant and second as a Lewis acid. Compared with previous methods, our strategy eliminated the steps for the separation and purification of the reaction intermediates, as well as pre-installing leaving groups to allylic substrates. Moreover, our reaction did not employ moisture-sensitive allylic metal species and stoichiometric oxidants.

The Catalyst-Controlled Divergent Cascade Reactions of Homo-Propargylic Amines and Nitrones: Synthesis of Pyrrolo-Isoxazolidines and γ-Lactams


Two controllable one-pot cascade cyclization reactions of homopropargylic amines and nitrones were developed by using different metal Cu and Ag salts. The pyrroloisoxazolidines and γ-lactams were obtained in good to high yields, respectively. Herein, nitrones played dual roles, both as 1,3-dipoles and oxidants, and four stereocenters were simultaneously formed in the hydroamination cyclization-1,3-dipolar cycloaddition cascade reaction of homopropargylic amines and nitrones in the presence of AgOAc.

AuPd−Fe3O4 Nanoparticle Catalysts for Highly Selective, One-Pot Cascade Nitro-Reduction and Reductive Amination


Exceedingly chemoselective preparation of secondary amines from the cascade reaction of nitro reduction followed by reductive amination of the resulting amine with an aldehyde through the use of bimetallic AuPd alloy nanoparticle catalyst is described. We prepared a AuPd alloy nanocatalyst supported on Fe3O4 in gram scale without calcination. One pot synthesis of a number of secondary amines was achieved from a variety of nitroarenes and aryl or alkyl aldehydes under 1 atm of H2 at room temperature. No N-debenzylation was observed in the case of the reactions involving aryl aldehydes, which is often observed in the reductive amination catalysed by a transition metal catalyst such as palladium. We also accomplished efficient one-pot synthesis of a number of N-aryl substituted isoindolinone derivatives from 1-formylbenzoic acid and several nitroarenes using the same reaction conditions. Furthermore, thanks to the magnetic property of the Fe3O4 support, the AuPd−Fe3O4 NPs could be easily separated and reused up to 20 times without the loss of its catalytic activity.

Copper-catalyzed Intramolecular Carbotrifluoromethylation of Ene-Imines for the Construction of 3-(2,2,2-Trifluoro)ethylated 4-Amino-Chromans


A mild and efficient copper-catalyzed intramolecular carbotrifluoromethylation of ene-imines with Togni reagent as a trifluoromethylating reagent was realized. The reaction tolerates a range of substrates to give the corresponding 3-trifluoroethylated 4-amino-chromans in moderate to good yields. A possible mechanism was proposed based on the experimental results.

Alkene-Zipper Catalyzed Selective and Remote Retro-ene Reaction of Alkenyl Cyclopropylcarbinol


Reminiscent of biological systems, the increasingly popular concept of remote activation allows a greater strategic synthetic flexibility for the development of novel synthetic organic methodologies. In this Communication, we report that commercially available ruthenium (II)-based “alkene zipper catalyst” enables the selective transformation of a large variety of ω-alkenyl cyclopropylcarbinols into stereodefined unconjugated (E)-acyclic aldehydes bearing a quaternary stereocenter through an isomerization followed by a retro-ene reaction. To unravel this peculiar catalytic property of the “alkene zipper” and shed some light on the mechanism, a series of control experiments were performed.

Cascade Synthesis of Dihydrobenzofurans and Aurones via Palladium-Catalyzed Isocyanides Insertion into 2-Halophenoxy Acrylates


A palladium-catalyzed isocyanides insertion into 2-halophenoxy acrylates leading to an unparalleled synthesis of dihydrobenzofurans (DHBs) having two exocyclic double bonds have been achieved. While the iodo substrates gave products having an exocyclic imine bond, its bromo analogue yielded reduced secondary amines as the product. An acid hydrolysis of the exocyclic imine bond in DHBs produces various aurone esters.

Copper-Catalyzed Cross-Coupling of Secondary α-Haloamides with Terminal Alkynes: Access to Diverse 2,3-Allenamides


A copper-catalyzed C(sp)−C(sp3) cross-coupling of terminal alkynes with readily available secondary α-haloamides for the efficient synthesis of 2,3-allenamides is realized. The methodology is characterized by its wide substrate scope, which makes it an important complement to traditional methods for synthesizing allenes. A mechanism involving an alkynylcopper species is proposed.

Silver-catalyzed Double Decarboxylative Radical Alkynylation/Annulation of Arylpropiolic Acids with α-keto Acids: Access to Ynones and Flavones under Mild Conditions


Ynones are privileged building blocks in various organic syntheses of heterocyclic derivatives due to their multifunctional nature, and flavones are an important class of natural products with a wide range of biological activities. We describe the catalytic double decarboxylative alkynylation of arylpropiolic acids with α-keto acids. With Ag(I)/persulfate as the catalysis system, the valuable ynones bearing various substituents could be easily obtained. The introduction of hydroxyl substituent on ortho-site of α-keto acids make this strategy further applicable to the construction of flavone derivatives via heteroannulation in moderate to good yields with a similar silver-catalyzed system. The reactions proceed under relatively mild reaction conditions and tolerate a wide variety of functional groups. Control experiments indicated that both the reactions undergo radical processes.

Reactions Involving Tryptamines and δ-Allenyl Aldehydes: Competition between Pictet-Spengler Reaction and Cyclization to 1-Aminotetralins


The isolation of 1-aminotetralin was unexpectedly observed in the course of Pictet-Spengler reactions between tryptamines and δ-allenyl aldehydes. This discovery led to the study of a novel reactivity using aldehydes and secondary amines. DFT calculations show that the cyclization occurs in a stepwise manner that is sufficiently fast to allow high diastereoselectivity. When using allyl-tryptamines, it is possible to control the reaction, depending on the substituents, in order to have either the 1-aminotetralin or the tetrahydro-β-carboline. These competitive reactivities were studied by DFT computations.

An Efficient and Practical Method for the Enantioselective Synthesis of Tertiary Trifluoromethyl Carbinols


An efficient sulfinamide/olefin based chiral ligand, MetSulfolefin, has been developed for the enantioselective rhodium-catalysed addition of aryl-boronic acids to trifluoromethyl ketones. This shelf-stable ligand is insensitive to air, oxygen and moisture, and it is obtained in only two high yielding steps from cheap commercially available (R)-tert-butanesulfinamide. The new ligand tolerates the use of hindered boronic acids and leads to the formation of a series of chiral trifluoromethyl-substituted tertiary carbinols in high yields and excellent enantioselectivities (up to >99% ee).

Cobalt(III)−Catalyzed C−H Activation: A Secondary Amide Directed Decarboxylative Functionalization of Alkynyl Carboxylic Acids Wherein Amide NH-group Remains Unreactive


A Co(III)-catalyzed C−H activation reaction for ortho-alkenylation of benzamides (aryl/heteroaryl) and C2-alkenylation of indole derivatives have been developed using alkynyl carboxylic acid as an alkene source. A high regioselectivity has been achieved in the formation of disubstituted alkenes, and the possible cyclic products were not observed. This efficient alkenylation shows a broad range of substrate scope with a good functional group tolerance. The application of the methodology has been showcased by transforming an alkenylated amide to a 3-hydroxy isoindolinone derivative.

Organocatalytic Enantioselective Friedel-Crafts Alkylation/Lactonization Reaction of Hydroxyindoles with Methylene Oxindoles


The front cover picture, provided by Junling Zhao and co-workers, illustrates an organocatalytic enantioselective protocol for the Friedel–Crafts alkylation/lactonization reaction of hydroxyindoles with methylene oxindoles. This reaction was efficiently catalyzed by a Cinchona alkaloid-derived squaramide catalyst, affording the corresponding pyrrolodihydrocoumarin derivatives in moderate to high yields with high enantioselectivities. More importantly, this paper shows an efficient strategy for the regioselective functionalization of the indole benzene positions. Details can be found in the full paper on pages xxx–xxx. (M.-J. Xiao, D.-F. Xu, W.-H. Liang, W.-Y. Wu, A. S. C. Chan, J.-L. Zhao, Adv. Synth. Catal. 2018, 360, xxx–xxx; DOI: 10.1002/adsc.201701089)

Evaluating Gold and Selenium Chemistry for Selective Transformations of Lignin Model Compounds


Applications of gold and selenium chemistry are reported as novel approaches to promote lignin depolymerization into more valuable chemicals via selective oxidation reactions (alcohol oxidations and Baeyer-Villiger reactions). In this study, we proposed two different oxidative methodologies using Au/SiO2 and phenylseleninic acid resin (PAR) as stable and reusable catalysts to promote selective transformations of the β-O-4 linkage of lignin model compounds. After evaluating the catalytic systems under batch conditions, they were both applied in a packed-bed reactor for continuous flow operations. By using Au/SiO2 as a catalyst under flow conditions, ketones were efficiently obtained (up to 86% conversion) from the oxidation of alcohols with a residence time (tR) of 30 min. In the case of Baeyer-Villiger oxidations catalyzed by phenylseleninic acid resin, the corresponding esters were obtained in up to 91% conversion (tR=30 min). Both systems efficiently catalyzed the conversion of the lignin model compounds.

I2-Triggered Reductive Generation of N-Centered Iminyl Radicals: An Isatin-to-Quinoline Strategy for the Introduction of Primary Amides


An efficient and alternative isatin-to-quinoline strategy illustrates the metal-like behavior of molecular iodine in the N−O reduction of ketoxime acetates. This process involves N−O/C−N bond cleavages and C−C/C−N bond formation to furnish pharmacologically significant quinoline-4-carboxamide derivatives. In this process, metal catalysts and extra oxidants are unnecessary. Mechanistic studies confirm the crucial role of molecular iodine in the iminyl radical generation process, in that molecular iodine can catalyze single-electron reduction coupling reactions in a manner similar to transition metals.

Conversion of Primary Amines to Symmetrical Secondary and Tertiary Amines using a Co-Rh Heterobimetallic Nanocatalyst


Symmetrical tertiary amines have been efficiently realized from amine and secondary amines via deaminated homocoupling with heterogeneous bimetallic Co2Rh2/C as catalyst (molar ratio Co:Rh=2:2). Unsymmetric secondary anilines were produced from the reaction of anilines with symmetric tertiary amines. The Co2Rh2/C catalyst exhibited very high catalytic activity towards a wide range of amines and could be conveniently recycled ten times without considerable leaching.

Chemoselective Flow Hydrogenation Approaches to Diversify the Cytotoxic Tetrahydroepoxyisoindole Carboxamide Scaffold


An Intramolecular Diels-Alder cycloaddition reaction between a furan diene and an alkynic dienophile was performed within a flow hydrogenator fitted with an inert titanium column at 150 °C, no H2, under 100 bar pressure. A single column pass (tR=1.6 min) afforded ≈55% conversion to the tetrahydroepoxyisoindole carboxamide scaffold with a product turnover of ≈0.035 g/h, a 95% improvement over batch procedures. The cycloaddition protocol is performed in water and ethanol, and does not require catalysts or other additives. Quantitative hydrogenation of the resulting dual π-bonds within the oxabicyclo system was effected with either a 10% Pd/Al2O3 or 10% Pd/CaCO3 catalyst at 20 °C, 20 bar, with full H2 whereas utilisation of a Raney Ni catalyst under these conditions resulted in a quantitative mono-olefin reduction of the C4-C5 double-bond. With regard to di-olefin reduction, a degree of stereoselectivity was observed with the aforementioned palladium-based catalysts yielding exclusive formation of (R) configuration at C7 while utilisation of a 5% Pt/C (sulfided) catalyst at temperatures below 60 °C promoted the formation of the (S)-isomer at C7. Hence this work further highlights that flow-hydrogenation provides unprecedented convenience for establishing robust protocols to effect chemoselective transformations.

Visible-Light-Promoted Decarboxylative Giese Reactions of α-Aryl Ethenylphosphonates and the Application in the Synthesis of Fosmidomycin Analogue


An approach for the synthesis of α-aryl alkylphosphonates based on visible-light photocatalytic Giese reaction of α-aryl vinylphosphonates with aliphatic carboxylic acids has been successfully developed. This protocol tolerates a wide range of functional groups and shows broad substrate scope with regard to both the carboxylic acid and vinylphosphonate components. With sequential Giese/hydrolysis reactions as the strategy, the oxo-phosphonates could be easily accessible. The synthetic application of the hydroformylation reaction was demonstrated by the synthesis of the intermediate of α-phenyl substituted fosmidomycin analogue. Furthermore, the competitive decarboxylative alkylation of vinylphosphonate and acrylate was also investigated.

Carboxyl-Directed Conjugate Addition of C−H Bonds to α,β-Unsaturated Ketones in Air and Water


A simple ruthenium-catalyzed conjugate addition of C−H bonds to α,β-unsaturated ketones directed by a removable carboxyl group was developed as an effective protocol to synthesize ortho-alkylated benzoic acids in a greener manner. Without any additives, satisfactory to excellent yields of the targeted products were achieved in neat water, and the process characterizes in mild reaction conditions (in air and water), simple operations, and broad substrate scope. Noteworthy features of this method include mild reaction conditions (in air and water), operational simplicity and broad substrate scope. The versatility and utility of the addition products were demonstrated through further transformation into commonly inaccessible but highly useful motifs of meta-substituted alkylbenzenes and 3-substituted isochromanones.

Photoinduced N-Methylation and N-Sulfonylation of Azobenzenes with DMSO Under Mild Reaction Conditions


A photoinduced N-methylation and N-sulfonylation of azobenzenes with dimethyl sulfoxide (DMSO) was developed in the absence of an external photosensitizer under mild conditions. The reactions underwent smoothly to generate the corresponding products in high yields through a radical addition using the starting material azobenzene as a photosensitizer. This strategy features simple operation, easily available starting materials and DMSO acting as both methylating and sulfonylating agent.

Recovery and Recycling of Chiral Iridium(N,P Ligand) Catalysts from Hydrogenation Reactions


Despite the high efficiency and broad scope of chiral iridium(N,P ligand) complexes as catalysts for asymmetric hydrogenation, the problem of catalyst recovery and recycling has so far attracted little attention. We have found that at the end of a hydrogenation reaction, iridium(N,P ligand) catalysts form dimeric Ir(III) dihydride complexes, which can be converted back to the original precatalysts by addition of COD. Based on these findings, a practically simple protocol for catalyst recovery was devised. The recovered complexes showed essentially the same reactivity and enantioselectivity as the original catalysts. Especially large-scale applications and hydrogenations of less reactive substrates that require high catalyst loadings will benefit from this protocol that allows recovery and reuse of expensive iridium complexes.

Direct Synthesis of Primary Anilines via Nickel-mediated C(sp2)-H Aminations


An efficient and mild protocol for the direct conversion of arene C−H bonds to C−NH2 without the need for extra deprotection step has been established, and to the best of our knowledge, this is the first time that the synthesis of primary anilines via nickel-mediated C(sp2)-H activations has been reported. This approach utilizes 8-aminoquinoline as the directing group and sodium azide, a cheap and commercially available material, as the nitrogen source. In addition, the reaction is highly selective, affording the mono-ortho-aminated benzamides only. The reaction tolerates a broad range of substrates with diverse functional groups and the corresponding ortho-aminated benzamides were efficiently synthesized in 41–82% yields.

One-pot Synthesis of Alkynylated Coumarins via Rhodium-Catalyzed Annulation of Aryl Thiocarbamates with 1,3-Diynes or Terminal Alkynes


A convenient and selective synthesis of alkynylated coumarins from various aryl thiocarbamates and 1,3-diynes or terminal alkynes via rhodium-catalyzed C−H bond activation has been developed. In this transformation, both symmetrical and asymmetrical 1,3-diynes could be applicable, obtaining various 3-alkynylated coumarins in moderate to excellent yields. When the substituent is aryl group, the resulting compounds were found to exhibit intense fluorescence in the range of 412–443 nm with quantum yield of up to 0.57 in CH2Cl2. Moreover, the internal alkynes were readily converted to 1,2-dione, olefins, alkanes, and bisheterocycles under certain conditions.

Oxidative Catalytic Spiroketalization Leading to Diastereoselective Synthesis of Spiro[benzofuran-2,1′-isochromene]s


A new one-pot, two-step silver-catalyzed spiroketalization of the in-situ generated quinone imine ketals (QIKs) with β-alkynyl ketones has been established, enabling multiple C−O and C−C bond-forming reactions to access densely functionalized spiro[benzofuran-2,1′-isochromene] derivatives with generally good yields. The use of β-alkynyl ketones bearing alkyl and aryl groups located at the α-position of the carbonyl group could lead to highly diastereoselective spiro[chromane-2,1′-isochromene] derivatives. The reaction features broad substrate scope, mild oxidative catalytic conditions and excellent diastereoselectivity.

Chelation-promoted Efficient C−H/N−H Cross Dehydrogenative Coupling between Picolinamides and Simple Ethers under Copper Catalysis


A highly efficient copper-catalyzed C−H/N−H cross dehydrogenative coupling between picolinamides and simple ethers was developed. The reaction was promoted by the chelation assistance of removable picolinyl group and exhibited excellent TON and TOF number. This method was applicable to both N-aryl and alkyl picolinamides as well as various cyclic and acyclic ethers with good functional group compatibility. It also possessed the merit of air and moisture tolerance and easy operation.

Iridium-catalyzed Asymmetric Hydrogenation of Polycyclic Pyrrolo/Indolo[1,2-a]quinoxalines and Phenanthridines


Owing to the dehydrogenative rearomatization of hydrogenation product and poisoning effect of nitrogen atom, asymmetric hydrogenation of polycyclic nitrogen-containing heteroaromatics is still a great challenge. Herein, through in situ protection of hydrogenation products with acetic anhydride to inhibit rearomatization and poisoning effect, a novel iridium-catalyzed enantioselective hydrogenation of polycyclic nitrogen-containing heteroaromatics – pyrrolo/indolo[1,2-a]quinoxalines and phenanthridines – has been successfully developed, providing a facile access to chiral dihydropyrrolo/indolo[1,2-a]quinoxalines and dihydrophenanthridines with up to 98% ee. The strategy features broad substrate scope, easy operation and potential medicinal application.

Pd-tBuONO Cocatalyzed Aerobic Indole Synthesis


A Pd-tBuONO co-catalyzed scalable and practical synthesis of indoles with molecular oxygen as terminal oxidant is developed. Either terminal or internal 2-vinylanilines could be smoothly converted to desired indoles under one general condition. This method has been evaluated in the large scale synthesis of indomethacin and a potential anti-breast cancer drug candidate 1.

Synthesis and Reactivity of 1,1-Diborylalkanes towards C–C Bond Formation and Related Mechanisms


gem-Diborylalkanes have emerged as efficient reagents for synthesizing organoboron compounds through selective C−C bond-forming reactions. Activation of the 1,1-diborylalkanes generates carbanions with enhanced stability that are able to react with a series of electrophiles, carbonyl compounds, imines and epoxides to promote formation of a new C−C bond. These new sets of reactions have become general for a wide range of substrates and they can be understood by alternative mechanisms that justify the potential use of these reagents. The formation of C–C(B) bonds can be achieved with chemo-, diastereo- and enantioselectivity, because the nucleophilc α-boryl or α-diboryl carbanions attack in a stereoselective manner, by means of the catalyst involved. The synthesis of gem-diborylalkanes has also been promoted by innovative methods and facilitates access to multiborylated reagents with different substituents and properties.

A Heteroarylamine Library: Indium-Catalyzed Nucleophilic Aromatic Substitution of Alkoxyheteroarenes with Amines


Under indium Lewis acid catalysis, electron-rich five-membered heteroaryl electrophiles fused with/without a benzene ring were found to couple with amines to produce heteroarylamines with broad structural diversity. The heteroarylamine formation proceeds through the cleavage of a heteroaryl−OMe bond by the nucleophilic attack of the amine based on the nucleophilic aromatic substitution (SNAr) reaction. In contrast to the corresponding traditional SNAr amination, the present SNAr-based heteroaryl amination can be performed without relying on both heteroaryl electrophiles with electron-withdrawing groups and nucleophilicity-enhanced metal amides. High compatibility towards the functional groups such as NO2, Br, I, CF3, CN, CO2Et, pyridyl, thiazolyl, C=C, and OH groups was observed, thus showing the practicality and reliability of this method. Mechanistic studies indicated that a carbon−indium bond is likely to be formed on the heteroaryl ring during the process.

Inexpensive Ruthenium NNS-Complexes as Efficient Ester Hydrogenation Catalysts with High C=O vs. C=C Selectivities


Ru(NNS)(PPh3)Cl2 (NNS=2-(methylthio)-N-(pyridin-2-yl-methyl)ethan-1-amine) was employed in the hydrogenation of α,β-unsaturated esters, reaching selectivities for the allylic alcohol up to 95% in the hydrogenation of iso-butylcinnamate. In addition, several ester substrates were hydrogenated with catalyst loadings as low as 0.05 mol%. Surprisingly, selectivity of the hydrogenation of the C=O vs the C=C bonds strongly depends on the solvent.

Palladium-Catalyzed Regioselective Three-Component Cascade Bisthiolation of Terminal Alkynes


An efficient and novel NHC(N-heterocyclic carbene)-palladium-catalyzed three-component cascade bisthiolation of terminal alkynes, K2S (potassium sulfide) and diaryliodonium salts for the assembly of functionalized (Z)-1,2-bis(arylthio)alkene derivatives has been accomplished for the first time. This unique observation features a broad substrate scope, excellent functional-group tolerance, and high regioselectivity. Especially, an arylthiolate anion from diaryliodonium salts and potassium sulfide was proposed as the key intermediate in the catalytic cycle.

Pyrroline Synthesis via Visible-Light-Promoted Hydroimination of Unactivated Alkenes with N,N′-Dimethylpropylene Urea as H-Donor


Synthesis of 3,4-pyrroline derivatives via visible-light-induced hydro/oxyimination of unactivated olefins is reported. In the presence of the photoredox catalyst fac-Ir(ppy)3, the key iminyl radical intermediate can be readily generated from O-acyl oximes, and undergoes intramolecular cyclization and H-abstraction from solvent or is trapped by TEMPO to give the corresponding hydro/oxyimination product, respectively. Mechanistic investigations indicate that N,N′-dimethylpropylene urea (DMPU) works as both reducing agent for catalyst regeneration and H-donor for product formation in this process.

Direct Synthesis of Sulfinamides by the Copper-Catalyzed Electrophilic Amidation of Sulfenate Anions


A method for the construction of sulfinamides via the copper-catalyzed electrophilic amination of sulfenate anions using N-benzoyloxyamines as the amination reagents. This procedure featured with the capture of in-situ generated sulfenate anions from β-sulfinyl esters under mild conditions, which provides an efficient strategy for the synthesis of diverse sulfinamides in moderate to good yields.

Palladium-catalyzed Selective Amination of Aryl(haloaryl)amines with 9H-Carbazole Derivatives


Palladium-catalyzed amination of aryl(haloaryl)amines with 9H-carbazole derivatives was investigated. In the amination of (4-bromophenyl)phenylamine with 9H-carbazole by the use of Pd2(dba)3/PtBu3/NaOtBu catalyst, the main product was desired 9-[4-(phenylamino)phenyl]-9H-carbazole in 60% yield with conversion of (4-bromophenyl)phenylamine >99%, and the concomitant formation of 9-[4-[phenyl[4-(phenylamino)phenyl]amino]phenyl]-9H-carbazole (15% yield), which is the consecutive by-product, was observed. When XPhos was used instead of PtBu3, the desired product was provided in 81% yield and the consecutive by-product was suppressed to 7.7%. The yield of the desired product reached 98% by the use of tBu-XPhos. Such excellent yields of the desired product were also obtained with other 2-di-tert-butyl- or 2-di(1-adamantyl)phosphino-1,1’-biaryls. Various 9-(arylamino)aryl-9H-carbazoles could be synthesized from aryl(haloaryl)amines and 9H-carbazole derivatives in high yields by the use of tBu-XPhos. The amination of 4-bromotoluene with a mixture of diphenylamine and 9H-carbazole gave only 9-o-tolyl-9H-carbazole with tBu-XPhos, while the use of PtBu3 or XPhos afforded the mixture of 9-o-tolyl-9H-carbazole and diphenyl(o-tolyl)amine, indicating that Pd2(dba)3/tBu-XPhos/NaOtBu catalyst high selectively favors 9H-carbazole over diphenylamine as an amination substrate.

Naphthalenediimide – A Unique Motif in Macrocyclic and Interlocked Supramolecular Structures


This review presents a survey through macrocyclic and interlocked structures containing 1,4,5,8-naphthalendiimide residues from the synthetic point of view and also illustrates the structural particularities that dictate their main applications in supramolecular, biological and materials chemistry. The paper is organised as a comprehensive description of macrocycles, cyclophanes, catenanes, rotaxanes and metallamacrocycles along with other types of supramolecular interlocked architectures. For each category, we present the synthetic approach, the structural investigation of their properties and the developed applications as semiconductors, energy storage devices, photovoltaics, artificial photosystems, sensors, catalysts or molecular machines.

Recent Developments in the [5+2] Cycloaddition


The [5+2] cycloaddition allows the synthesis of a diversity of complex highly functionalized seven-membered products in a single step. These cycloadducts can readily be further manipulated synthetically for use in the synthesis of a number of complex natural products and important biologically active products containing seven-membered rings. In addition to the common and highly efficient [5+2] cycloadditions of (oxido)pyrylium and (oxido)pyridinium ions with various π-systems, providing an easy access to a wide range of novel heterocyclic seven-membered rings exhibiting an oxygen or nitrogen bridge, the metal-catalyzed [5+2] cycloadditions still attract a great attention and have become one of the most popular ways of constructing seven-membered compounds. Among the most important reactions are metal-catalyzed (hetero) [5+2] cycloadditions of vinyl-substituted three-membered rings, rhodium-catalyzed [5+2] cycloadditions of 3-acyloxy-1,4-enynes, and metal-catalyzed [5+2] cycloadditions of ortho-vinylphenols and ortho-vinyl/arylanilines. Abbreviations: Ar: aryl; Bipy: bipyridine; Bn: benzyl; Boc: tert-butoxycarbonyl; cod: cyclooctadiene; coe: cyclooctene; Cp: cyclopentadienyl; Cp*: pentamethylcyclopentadienyl; DABCO: 1,4-diazabicyclo[2.2.2]octane; dbcot: dibenzocyclooctatetraene; DBU: 1,8-diazabicyclo[5.4.0]undec-7-ene; DCE: 1,2-dichloroethane; de: diastereomeric excess; DIPEA: diisopropylethylamine; DMAP: 4-(N,N-dimethylamino)pyridine; DMF: N,N-dimethylformamide; dppb: 1,4-bis(diphenylphosphino)butane; dppe: 1,2-bis(diphenylphosphino)ethane; ee: enantiomeric excess; Hept: heptyl; Hex: hexyl; HFIP: hexafluoroisopropyl alcohol; L: ligand; M: metal; MCPBA: 3-chloroperoxybenzoic acid; MOM: methoxymethyl; Mes: mesyl; MS: molecular sieves; Naph: naphthyl; NBD: norbornadiene; Ns: nosyl (4-nitrobenzenesulfonyl); Pent: pentyl; Phth: phthaloyl; Piv: pivaloyl; PMB: p-methoxybenzyl; rr: regioselectivity ratio; r.t.: room temperature; TBS: tert-butyldimethylsilyl; TES: triethylsilyl; Tf: trifluoromethanesulfonyl; TFA: trifluoroacetic acid; TFE: 2,2,2-trifluoroethanol; THF: tetrahydrofuran; TIPS: triisopropylsilyl; TMP: 2,2,6,6-tetramethylpiperidine; TMS: trimethylsilyl; Tol: tolyl; T[...]

Water-Mediated One-pot Three-Component Synthesis of Hydrazinyl-Thiazoles Catalyzed by Copper Oxide Nanoparticles Dispersed on Titanium Dioxide Support: A Green Catalytic Process


The present work describes the catalytic activity of copper oxide nanoparticles dispersed on titanium dioxide in water for one-pot synthesis of a library of hydrazinyl-thiazoles via a three-component reaction of various aldehydes/ketones with thiosemicarbazide and different phenacyl bromides. The structure of the synthesized compound, (E)-4-(4-bromophenyl)-2-(2-(4-methoxybenzylidene) hydrazinyl)thiazole is confirmed by single crystal X-ray diffraction studies. The catalyst prepared by a molten-salt method is characterized by X-ray diffraction, field emission scanning electron microscopy, transmission electron microscopy, energy dispersive X-ray spectroscopy, X-ray photoelectron spectroscopy, Auger electron spectroscopy and electron spin resonance spectroscopy. The noteworthy advantages of this method include its broad substrate scope, clean reaction profile, short reaction times and high yields at low catalyst loading. Further, the product does not require any chromatographic purification and the method has the potential for large-scale applications in pharmaceutical industries. In addition, the developed catalyst can be recovered and reused for 5 times without significant loss of activity. Mechanistic studies suggest that the reaction begins with the activation of the carbonyl group of both aldehyde/ketone and phenacyl bromide by copper oxide nanoparticles supported on titanium dioxide in water. These studies reveal that the reaction proceeds via the formation of thiosemicarbazone intermediate.

Copper-Catalyzed Stereoselective Defluorinative Borylation and Silylation of gem-Difluoroalkenes


The copper-catalyzed stereoselective defluorinative borylation and silylation of gem-difluoroalkenes was developed. The protocol led to the exclusive formation of Z type monofluoroalkenyl borons and silanes in generally good efficiency with broad substrate scope. The products formed could be readily transformed to other F-containing molecules by taking advantage of the versatile reactivities of C−B and C−Si bonds. Experimental and theoretical mechanistic studies were conducted which support an olefin insertion/syn-planar β-F elimination pathway.

Rhodium(III)-Catalyzed Selective Direct Olefination of Imidazoles


Rhodium(III)-catalyzed chelation-assisted highly regio- and stereoselective direct olefination of imidazoles with olefins has been developed. A broad range of C2-substituted N-(2-pyrimidyl)imidazoles underwent smooth C5-olefination with both activated and unactivated olefins to furnish the corresponding products in good to excellent yields with high tolerance of functional groups on both coupling partners in the presence of a cationic rhodium(III) catalyst. The combination of a catalytic amount of Cu(OAc)2 (copper(II) acetate) and O2 (oxygen) serves as the terminal oxidant. This protocol strongly relies on the use of 2-substituted imidazoles as the substrates, and the presence of readily installable and removable pyrimidyl directing group was found to be critical for catalysis. Mechanistic studies suggest the involvement of a five-membered rhodacycle as the key intermediate in the catalytic cycle. The method can also be extended to the coupling reaction of benzimidazoles with olefins.

Rhodium-Catalyzed Regioselective Ortho C−H Olefination of 2-Arylindoles via NH-Indole-Directed C−H Bond Cleavage


In the past decades, C−H oxidative olefination of indole at C-2, C-3, C-4 and C-7 positions was well addressed. We report here a rhodium-catalyzed NH-indole-directed ortho C−H bond olefination of 2-arylindoles. This cross-dehydrogenative-coupling proved to be broad in substrate scope, tolerating a variety of functional groups. The synthesis of 6H-isoindolo[2,1-α]indoles via rhodium-catalyzed ortho C−H olefination and subsequent intramolecular aza-Michael reaction of 2-arylindoles was also demonstrated.

Metal-Free Azidation of α-Hydroxy Esters and α-Hydroxy Ketones Using Azidotrimethylsilane


We herein report a commercially available perchloric acid catalyst capable of catalyzing the azidation of α-hydroxy esters, α-hydroxy ketones and taddols using azidotrimethylsilane in dichloromethane at room temperature. Various substituted tertiary alcohols are well tolerated in this reaction. Cα-tetrasubstituted α-amino acid derivatives were prepared by one-pot sequential azidation and hydrogenation procedure. The advantage of this newly developed method includes operational simplicity, ready availability of catalyst, scale-up ability, and also good functional group compatibility.

Rh-Catalyzed Annulation of ortho-C−H Bonds of 2-Arylimidazoles with 1,4,2-Dioxazol-5-ones toward 5-Arylimidazo[1,2-c]quinazolines


A Rh-catalyzed unique and direct approach for constructing a series of 5-arylimidazo[1,2-c]quinazolines in moderate to excellent yields from simple and readily available 2-arylimidazoles and 3-phenyl-1,4,2-dioxazol-5-ones was described. This procedure proceeds with sequential ortho-C−H bond amidation and cyclization, which represents a facile and straightforward pathway to access such frameworks.

Visible Light-Induced Synthetic Approach for Selenylative Spirocyclization of N-Aryl Alkynamides with Molecular Oxygen as Oxidant


A visible light-induced (blue LED) radical cascade has been devised to effect selenylative spirocyclization of N-aryl alkynamides at room temperature under oxygen atmosphere and without the aid of external photocatalyst. The protocol is operationally simple, scalable, and offers clean synthesis of 3-selenospiro[4,5]trienones in high yields (up to 92%). A novel spiro-ring-opening strategy has also been accomplished to access fully substituted acryl amides.

N-Arylated Sulfoximines as Cross-Coupling Building Blocks


The application of borylated N-aryl sulfoximines as newly designed synthetic building blocks in Suzuki-type cross coupling reactions offers rapid access to a wide range of N-biaryl derivatives with potential relevance for medicinal chemistry and crop protection in good to excellent yields (up to 98%).

Synthesis of 7-Azaindole Amidated Derivatives: An Efficient Usage of Acyl Azides as the Nitrogen Source


The dual behaviour of acyl azides in transition-metal-catalyzed direct C−H amidation is investigated. Variously substituted acyl azides reacted smoothly with 7-azaindoles providing a diversity of C−C or C−N 7-azaindole amidated derivatives. This amidation reaction shows an excellent controllability, which is believed to be dependent on catalyst system.

Mild Ring Contractions of Cyclobutanols to Cyclopropyl Ketones via Hypervalent Iodine Oxidation


An iodine-mediated oxidative ring contraction of cyclobutanols has been developed. The reaction allows the synthesis of a wide range of aryl cyclopropyl ketones under mild and eco-friendly conditions. A variety of functional groups including aromatic or alkyl halides, ethers, esters, ketones, alkenes, and even aldehydes are nicely tolerated in the reaction. This is in contrast with traditional synthetic approaches for which poor functional group tolerance is often a problem. The practicality of the method is also highlighted by the tunability of iodine oxidation system. Specifically, combining the iodine(III) reagent with an appropriate base allows the reaction to accommodate a range of challenging electron-rich arene substrates. The facile scalability of this reaction is also exhibited herein.

Enantioselective Conjugate Addition of 2-Acylimidazoles with Nitroalkenes Promoted by Chiral-at-Metal Rhodium(III) Complexes


An enantioselective conjugate addition of 2-acylimidazoles with nitroalkenes catalyzed by chiral-at-metal rhodium(III) complex under mild reaction conditions was developed, affording versatile γ-nitro ketone skeletons in good yields with excellent enantioselectivities (up to >99% ee).

Regioselective C-7 Nitration of 8-Aminoquinoline Amides Using tert-Butyl Nitrite


Regioselective C-7 nitration of 8-aminoquinoline amide has been achieved using tert-butyl nitrite under metal-free conditions at ambient temperature. The protocol is applicable to various aryl, heteroaryl as well as aliphatic carboxamides, and exhibits high functional group compatibility. The present method provides selective mononitrated quinoline derivatives. Experimental results suggest that the reaction likely proceeds through a radical pathway.

Hydration and Intramolecular Cyclization of Homopropargyl Sulfonamide Derivatives Catalyzed by Silver Hexafluoroantimonate(V): Synthesis of Structurally Diverse 2,3-Dihydro-1H-Pyrroles


We have developed an efficient, simple protocol for synthesis of structurally diverse functionalized 2,3-dihydro-1H-pyrroles by hydration and intramolecular cyclization of homopropargyl sulfonamide derivatives. Mechanistic experiments revealed that the sulfonamide nitrogen participated in the hydration reaction by chelating the Ag atom of the catalyst to assist in the formation of the hydration intermediate. The protocol accommodated a wide range of substrates and was used for a formal synthesis of (S)-nicotine.

Construction of Vicinal Tetrasubstituted Stereogenic Centers via a Mannich-Type Organocatalyzed Addition of Δ2-Pyrrolin-4-ones to Isatin Imines


Racemic Δ2-pyrrolin-4-ones (i. e. 4-pyrrolones), easily available in two steps from N-protected α-amino acids, undergo organocatalysed asymmetric Mannich-type addition to isatin-derived ketimines to furnish the non-racemic oxindole-Δ2-pyrrolin-4-one adducts, stereoselectively (up to 96% ee, dr≥15:1). The oxindole–pyrrolone products feature vicinal tetrasubstituted carbon stereocenters. The developed protocol has a broad substrate scope and tolerates diverse substituents at position C-5 in 4-pyrrolones and at positions N-1 and C-5/7 in isatin imines.

Direct Reductive Amination of Carbonyl Compounds Catalyzed by a Moisture Tolerant Tin(IV) Lewis Acid


Despite the ever-broadening applications of main-group ‘frustrated Lewis pair’ (FLP) chemistry to both new and established reactions, their typical intolerance of water, especially at elevated temperatures (>100 °C), represents a key barrier to their mainstream adoption. Herein we report that FLPs based on the Lewis acid iPr3SnOTf are moisture tolerant in the presence of moderately strong nitrogenous bases, even under high temperature regimes, allowing them to operate as simple and effective catalysts for the reductive amination of organic carbonyls, including for challenging bulky amine and carbonyl substrate partners.

Diastereoselective Electrophilic Trifluoromethylthiolation of Chiral Oxazolidinones: Access to Enantiopure α-SCF3 Alcohols


Lithium imide enolates featuring Evans’ chiral oxazolidinone auxiliary were involved in diastereoselective α-trifluoromethylthiolation with electrophilic SCF3 donors. Diastereopure products were isolated and converted to enantiopure α-SCF3 alcohols without racemisation.

Synthesis of 2-(Trifluoromethyl)-dibenzopyranones with Rhodium(III)-catalyzed Formal anti-Michael Addition as Key Step


A novel rhodium(III)-catalyzed synthesis of 2-(trifluoromethyl)-dibenzopyranones from easily available 4-(trifluoromethyl)-p-quinols and N-methoxyarylamides is described. Rhodium(III)-catalyzed formal anti-Michael addition was proposed to be a crucial step in this [3+3] annulation with N-methoxyarylamides as effective 1,3-dipoles, providing a concise and efficient approach for the construction of trifluoromethyl-containing dibenzopyranones under mild reaction conditions.

Synthesis of Chiral Sulfonyl Lactones via Copper-Catalyzed Asymmetric Radical Reaction of DABCO⋅(SO2)


In the present work, an asymmetric copper-catalyzed radical multi-component cascade reaction of an unsaturated carboxylic acid, aryldiazonium tetrafluoroborate, and DABCO⋅(SO2)2 (DABSO) has been developed for the enantioselective synthesis of sulfonyl lactones. In this reaction, this SO2 surrogate, DABSO was applied for the first time in the construction of chiral compounds. This multiple-step asymmetric radical reaction was carried out under mild conditions and tolerated a wide range of substrates, resulting in the corresponding sulfonyl lactones with up to 95% chemical yields and 88% ee. The current reaction enriches the research contents of DABSO, and provides a new and efficient strategy to chiral functionalized lactones bearing quarternary stereogenic center.

Regioselective Synthesis of Angular Isocoumarinselenazoles: A Benzoselenazole-directed, Site-specific, Ruthenium-catalyzed C(sp2)-H Activation


The synthesis of new, angular isocoumarinselenazoles is described, which involves the construction of 2-amino benzoselenazoles and their regioselective C2N-alkylation and alkyne insertion. An expeditious and metal-free synthesis of 2-aminobenzoselenazoles by the reaction of methyl 3-amino-4-fluorobenzoate and isoselenocyanates was achieved. Further N-alkylation of the 2-aminobenzoselenazoles resulted the formation of two regioisomers with different reactivities towards the alkyne insertion. The regioselective construction of the α-pyrone ring on the benzo[1,3-d]selenazole skeleton was achieved via a ruthenium (II)-catalyzed oxidative annulation. It is clear that the selenazole nitrogen plays an important role in the observed selectivity.

Organocatalytic Synthesis of Oxazolines and Dihydrooxazines from Allyl-Amides: Bypassing the Inherent Regioselectivity of the Cyclization


A selective and efficient methodology for the construction of either oxazolines or dihydrooxazines from the corresponding allyl-amides is reported. Bypassing the inherent selectivity of the cyclization and depending on the substitution pattern of the substrate, a selective epoxidation-cyclization was developed leading to either the five-membered or the six-membered ring, upon simple and complementary reaction conditions. The cyclization products were obtained in good to excellent yields and high selectivities.

Efficient Synthesis of Amines by Iron-Catalyzed C=N Transfer Hydrogenation and C=O Reductive Amination


Here we report the catalytic transfer hydrogenation (CTH) of non-activated imines promoted by a Fe-catalyst in the absence of Lewis acid co-catalysts. Use of the (cyclopentadienone)iron complex 1, which is much more active than the classical ‘Knölker complex’ 2, allowed to reduce a number of N-aryl and N-alkyl imines in very good yields using iPrOH as hydrogen source. The reaction proceeds with relatively low catalyst loading (0.5–2 mol%) and, remarkably, its scope includes also ketimines, whose reduction with a Fe-complex as the only catalyst has little precedents. Based on this methodology, we developed a one-pot CTH protocol for the reductive amination of aldehydes/ketones, which provides access to secondary amines in high yield without the need to isolate imine intermediates.

Front Cover Picture: Photocatalytic Oxidative Bromination of Electron-Rich Arenes and Heteroarenes by Anthraquinone (Adv. Synth. Catal. 4/2018)


The front cover picture, provided by Daniel Petzold and Burkhard König, illustrates how visible light and protons increase the oxidation potential of an anthraquinone-based photocatalyst synergistically. The increased oxidative power enables the efficient and selective bromination of various electron-rich arenes and heteroarenes under very mild reaction conditions and with excellent functional group tolerance. Details can be found in the communication on pages 626–630 (D. Petzold, B. König, Adv. Synth. Catal. 2018, 360, 626–630; DOI 10.1002/adsc.201701276).

Recent Advances in Palladium-Catalyzed Cross-Coupling Reactions at ppm to ppb Molar Catalyst Loadings


We review here new developments in decreasing the catalyst loadings in palladium-catalyzed C–C bond-formation reactions to mol ppm or mol ppb levels. This decreases the cost of the catalyst and the toxicity of the reaction system, making the reaction more attractive to industry. The Heck reaction, Sonogashira reaction, Suzuki–Miyaura cross-coupling reaction, other cross-coupling reactions, and allylic arylation reactions are separately discussed to show clearly the progress made in each type of reaction. Apart from the catalyst loading, the other parameters of the reaction (temperature, solvent, etc.) are briefly discussed to illustrate the shift toward greener conditions. For most reactions, this shift is underway or well advanced, and catalyst loadings have been decreased to below 1 mol ppm. An abundance of catalytic systems are now available, and it is sometimes difficult to identify the best one, because the substrates examined can vary widely from publication to publication. In the future, emphasis should be placed on the studying the full scope of the reaction at mol ppm catalyst loadings, rather than examining a few examples at these levels during the reaction-optimization process.

Photocatalytic Oxidative Bromination of Electron-Rich Arenes and Heteroarenes by Anthraquinone


The estimated excited oxidation potential of sodium anthraquinone-2-sulfonate (SAS) increases from 1.8 V to about 2.3 V vs SCE by protonation with Brønsted acids. This increased photooxidation power of protonated anthraquinone was used for the regio-selective oxidative bromination of electron rich (hetero)arenes and drugs in good yield. The mild reaction conditions are compatible with many functional groups, such as double and triple bonds, ketones, amides and amines, hydroxyl groups, carboxylic acids and carbamates. Mechanistic investigations indicate the photooxidation of the arene followed by nucleophilic bromide addition as the likely pathway.

Palladium-Catalyzed Three-Component Tandem Reaction for One-pot Highly Stereoselective Synthesis of (Z)-α-Hydroxymethyl Allylic Sulfones


A novel method is reported for the stereoselective synthesis of highly functionalized allyl aryl sulfones. This protocol is based on a Pd-catalyzed three-component tandem reaction of sulfonyl hydrazides and aryl iodides with allenes and exhibits high (Z)-selectivity, good yields, minimal waste, ample product scope, and operational simplicity.

Organocatalytic Nitroaldol Reaction Associated with Deuterium-Labeling


A deuterium-labeling reaction of nitroalkanes in deuterium oxide and the subsequent nitroaldol reaction have been accomplished under basic and organocatalytic conditions to provide the deuterium-labeled β-nitroalcohols in high yields and high deuterium contents. β-Deuterated β-nitroalcohols could be smoothly obtained from the reaction of nitroalkanes and various electrophiles using the easily-removal basic resin WA30. Furthermore, the asymmetric nitroaldol reaction using nitromethane and α-keto esters as electrophiles in the presence of a quinine-derived organocatalyst in deuterium oxide could provide the desired β-deuterated nitroalcohol derivatives with high enantioselectivities.

Rhodium(I)-Catalyzed Arylation/Dehydroxylation of tert-Propargylic Alcohols Leading to Tetrasubstituted Allenes


Diverse tetrasubstituted allenes are obtained selectively by the reaction of tert-propargylic alcohols and arylboroxines under rhodium catalysis. The reaction is assumed to proceed through an arylation/dehydroxylation process, which involves β-hydroxide elimination of a β-hydroxy alkenyl-rhodium intermediate that is generated by regioselective arylrhodation of the tert-propargylic alcohol. In addition, when enantioenriched propargylic alcohol was used to prepare optically active allene, high efficiency of central-to-axial chirality transfer was observed. The application of current method to structural modification of pharmaceutical drugs was also showcased by a highly diastereoselective transformation of mifepristone.

Cyclopropanation of Benzene Rings by Oxidatively Generated α-Oxo Gold Carbene: One-Pot Access to Tetrahydropyranone-Fused Cycloheptatrienes from Propargyl Benzyl Ethers


Cyclopropanations of benzene rings by oxidatively generated α-oxo gold carbenes are for the first time demonstrated in a Buchner reaction, in which readily available propargyl benzyl ethers are converted in one-pot to tetrahydropyranone-fused cycloheptatrienes via sequential oxidative gold catalysis and base-promoted isomerization. Additional examples of arene cyclopropanations without fragmentation of the cyclopropane ring are also realized.

Formal [5+3] Cycloaddition of Zwitterionic Allylpalladium Intermediates with Azomethine Imines for Construction of N,O-Containing Eight-Membered Heterocycles


A formal [5+3] cycloaddition of zwitterionic allylpalladium intermediates with 1,3-dipoles is developed, providing N,O-containing eight-membered heterocyclic compounds in high yields. Catalytically generated zwitterionic allylpalladium intermediates in situ from vinylethylene carbonates or vinyloxiranes acted as dipolarophile.

Copper-Mediated Tandem C(sp2)-H Amination and Annulation of Arenes with 2-Aminopyridines: Synthesis of Pyrido-fused Quinazolinone Derivatives


An efficient and convenient copper-mediated tandem C(sp2)-H amination and annulation of arenes with 2-aminopyridines to provide 11H-pyrido[2,1-b]quinazolin-11-ones has been developed. A variety of benzamides and 2-aminopyridines bearing different substituents are compatible with this transformation