Highly trans‐Selective Arylation of Achmatowicz Rearrangement Products by Reductive γ‐Deoxygenation and Heck–Matsuda Reaction: Asymmetric Total Synthesis of (−)‐Musellarins A–C and Their Analogues

Fully functionalized pyranuloses derived from Achmatowicz rearrangement (AR) are versatile building blocks in organic synthesis. However, access to trans‐2,6‐dihydropyrans from pyranuloses remains underexplored. Herein, we report a new two‐step trans arylation of AR products to access 2,6‐trans‐dihydropyranones. This new trans‐arylation method built on numerous plausible, but unsuccessful, direct arylation reactions, including Ferrier‐type and Tsuji–Trost‐type reactions, was finally enabled by an unprecedented, highly regioselective γ‐deoxygenation of AR products by using Zn/HOAc and a diastereoselective Heck–Matsuda coupling. The synthetic utility of the reaction was demonstrated in the first asymmetric total synthesis of (?)‐musellarins A–C and 12 analogues in 11–12 steps. The brevity and efficiency of our synthetic route permitted preparation of enantiomerically pure musellarins and analogues (>20 mg) for preliminary cytotoxicity evaluation, which led us to identify two analogues with three‐to‐six times greater potency than the musellarins as promising new leads.     

Iron(III)‐Catalyzed Arylation of Spiro‐Epoxyoxindoles with Phenols/Naphthols towards the Synthesis of Spirocyclic Oxindoles

An efficient and highly regioselective iron(III)‐catalyzed Friedel–Crafts‐type arylation of spiro‐epoxyoxindoles with phenols was developed for rapid access to 3‐(3‐indolyl)‐oxindole‐3‐methanols, which could be further elaborated into benzofuranyl‐spirooxindoles under Mitsunobu conditions. When spiro‐epoxyoxindoles were reacted with naphthols in the presence of a catalytic amount of FeCl₃?6 H₂O in dichloromethane, they underwent a tandem Friedel–Crafts‐type arylation and O‐cyclization to yield novel naphthofuranyl‐spirooxindoles in excellent yields. This method is applied to enable the efficient and highly regioselective synthesis of a small‐molecule inhibitor of the sodium channel Na_v1.7 (±)‐XEN402, which is currently in a phase IIb clinical trial for the treatment of pain.     

Regioselective Functionalization of 7‐Azaindole by Controlled Annular Isomerism: The Directed Metalation‐Group Dance

The regioselective functionalization of 7‐azaindole by controlled annular isomerism employing a directed metalation‐group migration is reported. The N7 carbamoyl azaindoles undergo regioselective metalation and quenching with an electrophile to furnish C6‐substituted derivatives which, in the presence of a catalytic amount of ClCONR₂ promotes a carbamoyl group shift or dance from N7 to N1. A second directed metalation/electrophile quench sequence leads to 2,6‐substituted azaindoles. Optimization of the metalation conditions for C2 and C6, separately and iteratively, is presented. Using the directed metalation group dance strategy, a late‐stage deuteration of an antipsychotic drug is described. Overall, the controlled migration of the carbamoyl directing group allows multiple functionalization events of the bioactive azaindole scaffold.     

meta‐Selective C−H Arylation of Fluoroarenes and Simple Arenes

Fluorine is known to promote ortho‐C?H metalation. Based upon this reactivity, we employed an activated norbornene that traps the ortho‐palladation intermediate and is then relayed to the meta position, leading to meta‐selective C?H arylation of fluoroarenes. Deuterium experiment suggests that this meta‐arylation is initiated by ortho C?H activation and the catalytic cycle is terminated by C‐2 protonation. A dual‐ligand system is crucial for the observed high reactivity and site selectivity. Applying this approach to simple benzene or other arenes also affords arylation products with good yield and site selectivity.     

Tandem Three‐Component Synthesis of syn‐1,2‐ and syn‐1,3‐Diol Derivatives

The development of efficient methods for stereocontrolled synthesis of polyol derivatives has been of continuing interest for the synthetic community. We describe herein tandem olefin cross‐metathesis/hemiacetalization/intramolecular oxa‐Michael addition of allylic/homoallylic alcohols, α,β‐unsaturated ketones, and aldehydes, which enabled the synthesis of syn‐1,2‐ and syn‐1,3‐diol derivatives in a step‐economical manner. A series of differentially protected polyol derivatives could be obtained in subsequent transformations via chemoselective/regioselective cleavage of the acetal moiety of the tandem reaction products.     

Heteroatom‐Guided,Palladium‐Catalyzed,Site‐Selective CH Arylation of 4H‐Chromenes: Diastereoselective Assembly of the Core Structure of Myristinin B through Dual CH Functionalization

A highly site‐selective, heteroatom‐guided, palladium‐catalyzed direct arylation of 4H‐chromenes is reported. The C?H functionalization is driven not only by the substituents and structure of the substrate but also by the coupling partner being used. The diastereoselective assembly of the core structure of Myristinin B has been achieved by using a dual C?H functionalization strategy for regioselective direct arylation.     

Mixed Directing‐Group Strategy: Oxidative C−H/C−H Bond Arylation of Unactivated Arenes by Cobalt Catalysis

A mixed directing‐group strategy for inexpensive [Co(acac)₃]‐catalyzed oxidative C?H/C?H bond arylation of unactivated arenes has been disclosed. This strategy enables the arylation of a wide range of benzamide and arylpyridines effectively to afford novel bifunctionalized biaryls, which are difficult to achieve by common synthetic routes. Two different pathways, namely, a single‐electron‐transmetalation process (8‐aminoquinoline‐directed) and a concerted metalation–deprotonation process (pyridine‐directed), were involved to activate two different inert aromatic C?H bonds. Moreover, the aryl radicals have been trapped by 2,6‐di‐tert‐butyl‐4‐methylphenol to form benzylated products. This unique strategy should be useful in the design of other arene C?H/C?H cross‐couplings as well.     

Regioselective Ruthenium‐Catalyzed Carbonylative Direct Arylation of Five‐Membered and Condensed Heterocycles

A ruthenium‐catalyzed carbonylative C?H bond arylation process for the three‐component synthesis of complex aryl–(hetero)aryl ketones in an aqueous solution has been developed. By exploiting the ortho‐activating effect of nitrogen‐containing directing groups, a regioselective, successive twofold C(sp²)?C(sp²) bond formation has been achieved. This straightforward catalytic process provides access to versatile products prevalent in multiple bioactive compounds and supplies a valuable functional group for subsequent transformations.     

Efficient Synthesis of (−)‐Corynoline by Enantioselective Palladium‐Catalyzed α‐Arylation with Sterically Hindered Substrates

Sterically hindered substrates can be employed in an enantioselective palladium‐catalyzed α‐arylation with the chiral monophosphorus ligand BI‐DIME. This process enabled an efficient synthesis of the antidepressant (S)‐nafenodone, a four‐step enantioselective synthesis of the Sceletium alkaloid (+)‐sceletium A‐4, a concise five‐step enantioselective synthesis of (?)‐corynoline, as well as a three‐step preparation of (?)‐DeN‐corynoline.     

Palladium‐Catalyzed Carbonylative Annulation of 1‐Hydroxy‐o‐Carborane and Internal Alkynes via Regioselective B‐H Activation

A Pd‐catalyzed three‐component carbonylative‐annulation of 1‐hydroxy‐o‐carborane, internal alkyne and carbon monoxide has been achieved via direct and regioselective cage B?H activation. A class of C,B‐substituted carborano‐coumarin derivatives with potential applications in pharmaceuticals were facilely prepared in moderate to high yields with excellent chemoselectivity and regioselectivity. A plausible reaction mechanism including CO insertion, electrophilic B?H metalation, alkyne insertion and reductive elimination was proposed.     

Regioselective Metal‐ and Reagent‐Free Arylation of Benzothiophenes by Dehydrogenative Electrosynthesis

A novel strategy for the synthesis of biaryls consisting of a benzothiophene and a phenol moiety is reported. These heterobiaryls are of utmost interest for pharmaceutical, biological, and high‐performance optoelectronic applications. The metal‐ and reagent‐free, electrosynthetic, and highly efficient method enables the generation of 2‐ and 3‐(hydroxyphenyl)benzo[b]thiophenes in a regioselective fashion. The described one‐step synthesis is easy to conduct, scalable, and inherently safe. The products are afforded in high yields of up to 88 % and with exquisite selectivity. The reaction also features a broad scope and tolerates a large variety of functional groups.     

Microwave‐Assisted Palladium‐Catalyzed Direct Arylation of 1,4‐Disubstituted 1,2,3‐Triazoles with Aryl Chlorides

Treatment of 1,4‐disubstituted 1,2,3‐triazoles with aryl chlorides in the presence of potassium carbonate under palladium catalysis and microwave irradiation at 250 °C for 15 min leads to arylation of the triazole at the 5‐position. A variety of functional groups, including ester and hydroxy groups, are compatible. The procedure is suitable for the regioselective preparation of trisubstituted triazoles. Microwave irradiation accelerates the reaction, thus allowing the rapid synthesis of trisubstituted triazoles, which are difficult to synthesize selectively.     

Tandem Pd/Au‐Catalyzed Route to α‐Sulfenylated Carbonyl Compounds from Terminal Propargylic Alcohols and Thiols

An efficient and highly atom‐economical tandem Pd/Au‐catalyzed route to α‐sulfenylated carbonyl compounds from terminal propargylic alcohols and thiols has been developed. This one‐step procedure has a wide substrate scope with respect to substituents at the α‐position of the alcohol. Both aromatic and aliphatic thiols generated the α‐sulfenylated carbonyl products in good to excellent yields. A mechanism is proposed in which the reaction proceeds through a Pd‐catalyzed regioselective hydrothiolation at the terminal triple bond of the propargyl alcohol followed by an Au‐catalyzed 1,2‐hydride migration.     

Highly Efficient CuI‐Catalyzed N‐Arylation of Azaheterocycles with Aryl Iodides Using 1,1,1‐Tris(Hydroxymethyl)ethane as a Tridentate O‐Donor Ligand: A Shorter Route to Toloxatone and Formal Synthesis of Linezolid

An efficient copper‐catalyzed N‐arylation of azaheterocycles with aryl iodides using 1,1,1‐tris(hydroxymethyl)ethane as a tridentates O‐donor ligand has been accomplished in good to excellent yields. Moreover, this highly efficient catalyst system has been successfully demonstrated to one‐step synthesis of toloxatone and a shorter route to formal synthesis of linezolid in good yields.     

Regioselective 5‐endo‐dig Electrophilic Iodocyclization of Enediynes: A Convenient Route to Iodo‐substituted Indenes and Cyclopenta‐Fused Arenes

An efficient iodine‐mediated regioselective tandem approach for the synthesis of symmetric and asymmetric iodo‐substituted indenes and stereoselective cyclopenta [b]pyridine/thiophenes from easily accessible enediynes that proceeds by in situ formation of an iodonium intermediate followed by a regioselective 5‐endo‐dig cyclization has been described. The intramolecular electrophilic iodocyclization was selectively triggered by a distribution of electronic density along the alkyne bond. Subsequently, the iodo‐substituted indenes were diversified by employing palladium‐catalyzed cross‐coupling reactions and the coupled products were further confirmed by X‐ray crystallographic studies.     

Continuous Visible‐Light Photoflow Approach for a Manganese‐Catalyzed (Het)Arene C−H Arylation

Manganese photocatalysts enabled versatile room‐temperature C−H arylation reactions by means of continuous visible‐light photoflow, thus allowing for efficient C−H arylations in 30 minutes with ample scope. The robustness of the manganese‐catalyzed photoflow strategy was shown by visible light‐induced gram‐scale synthesis, clearly outperforming the batch performance.     

Photosensitizer‐Free Visible‐Light‐Mediated Gold‐Catalyzed 1,2‐Difunctionalization of Alkynes

Under visible‐light irradiation, the gold‐catalyzed intermolecular difunctionalization of alkynes with aryl diazonium salts in methanol affords a variety of α‐aryl ketones in moderate to good yields. In contrast to previous reports on gold‐catalyzed reactions that involve redox cycles, no external oxidants or photosensitizers are required. The reaction proceeds smoothly under mild reaction conditions and shows broad functional‐group tolerance. Further applications of this method demonstrate the general applicability of the arylation of a vinyl gold intermediate instead of the commonly used protodemetalation step. This step provides facile access to functionalized products in one‐pot processes. With a P,N‐bidentate ligand, a stable aryl gold(III) species was obtained, which constitutes the first direct experimental evidence for the commonly postulated direct oxidative addition of an aryl diazonium salt to a pyridine phosphine gold(I) complex.     

One‐Pot C−H Functionalization of Arenes by Diaryliodonium Salts

A transition‐metal‐free, mild, and highly regioselective synthesis of nitroarenes from arenes has been developed. The products are obtained in a sequential one‐pot reaction by nitration of iodine(III) reagents with two carbon ligands, which are formed in situ from iodine(I). This novel concept has been extended to formation of aryl azides, and constitutes an important step towards catalytic reactions with these hypervalent iodine reagents. An efficient nitration of isolated diaryliodonium salts has also been developed, and the mechanism is proposed to proceed by a [2,2] ligand coupling pathway.     

SBA‐15‐functionalized melamine–pyridine group‐supported palladium(0) as an efficient heterogeneous and recyclable nanocatalyst for N‐arylation of indoles through Ullmann‐type coupling reactions

SBA‐15‐functionalized melamine–pyridine group‐supported palladium(0) was found to serve as a heterogeneous and recyclable nanocatalyst for N‐arylation of indoles with aryl iodides under a low catalyst loading (0.3 mol% of Pd) through Ullmann‐type C? N coupling reactions. A variety of aryl iodides could be aminated to provide the N‐arylated products in good to excellent yields without the need of an inert atmosphere. Also, this catalyst was found to be an efficient system for the N‐arylation of other nitrogen‐containing heterocycles with aryl iodides. The heterogeneous palladium catalyst could be recovered by simple filtration of the reaction solution and reused for six cycles without significant loss in its activity. Copyright © 2015 John Wiley & Sons, Ltd.     

Synthesis of Triarylpyridines in Thiopeptide Antibiotics by Using a C−H Arylation/Ring‐Transformation Strategy

We have described a C?H arylation/ring‐transformation strategy for the synthesis of triarylpyridines, which form the core structure of thiopeptide antibiotics. This synthetic method readily gave 2,3,6‐triarylpyridines in a regioselective manner by a two‐phase approach: C?H arylation (a nickel‐catalyzed decarbonylative Suzuki–Miyaura cross‐coupling and decarbonylative C?H coupling for the synthesis of 2,4‐diaryloxazoles) and ring transformation ([4+2] cycloaddition of 2,4‐diaryloxazoles with (hetero)arylacrylic acids). To showcase these methods, we have accomplished the formal synthesis of thiopeptide antibiotics GE2270 s and amythiamicins.