A Multicomponent Reaction of Arynes,Isocyanides, and Terminal Alkynes: Highly Chemo‐ and Regioselective Synthesis of Polysubstituted Pyridines and Isoquinolines

Many components make light work : A novel synthetic strategy for the preparation of pyridines and isoquinolines in high chemo‐ and regioselectivity has been developed. By manipulating the reaction conditions, either product can be generated smoothly in a highly efficient and atom‐economic manner (see scheme).

     

Transition-Metal-Free Reverse Reactivity of (2-Alkynyl)-Arylaldimines: Assembly of Functionalized Amino-Indinones

Transition-metal-free regioselective synthesis of functionalized amino-indenones by the reaction of ortho-alkynylaldehydes with a broad range of primary amines by intramolecular cyclization has been described. The designed reaction proceeds through KOH-mediated Prins-type cyclization and DMSO-promoted oxidation of the cyclopent-2-en-1-one system. The proposed mechanism and role of solvent were well supported by control experiments. For the first time, we have disclosed the reverse reactivity of (2-alkynyl)-arylaldimines in a super basic system.     

Transition-Metal-Free Three-Component Radical 1,2-Amidoalkynylation of Unactivated Alkenes

A transition-metal-free radical 1,2-amidoalkynylation of unactivated alkenes is presented. α-Amido-oxy acids were used as amidyl radical precursors, which were oxidized by an organic photoredox catalyst (4CzlPN). The electrophilic N-radicals chemoselectively reacted with various aliphatic alkenes and the adduct radicals were then trapped by ethynylbenziodoxolone (EBX) reagents to eventually provide the amidoalkynylation products. These transformations, which were conducted under practical and mild conditions, showed high functional group tolerance and broad substrate scope. Mechanistic studies supported the radical nature of these cascades.     

Rapid Synthesis of Zwitterionic Phosphonium Benzoates by a Three‐Component Coupling Involving Phosphines,Arynes and CO2

A mild and easy to perform multicomponent coupling involving phosphines, arynes generated from 2‐(trimethylsilyl)aryl triflates, and CO₂ allowing the transition‐metal‐free synthesis of zwitterionic phosphonium benzoates has been developed. The reaction proceeds via the generation of 1 : 1 zwitterionic intermediates from phosphines and arynes followed by the interception with CO₂ to deliver the carboxylates in moderate to good yields instead of the anticipated benzooxaphosphol‐3(1H)‐ones.     

Double Heteroatom Functionalization of Arenes Using Benzyne Three‐Component Coupling

Arynes participate in three‐component coupling reactions with N, S, P, and Se functionalities to yield 1,2‐heteroatom‐difunctionalized arenes. Using 2‐iodophenyl arylsulfonates as benzyne precursors, we could effectively add magnesiated S‐, Se‐, and N‐nucleophilic components to the strained triple bond. In the same pot, addition of electrophilic N, S, or P reagents and a copper(I) catalyst trapped the intermediate aryl Grignard to produce a variety of 1,2‐difunctionalized arenes.     

Transition-Metal-Free Multicomponent Reaction of Quinoxalinones with Alkenes and Zhdankin Reagent through Photoredox Catalysis

A photo-induced three-component coupling reaction of quinoxalinones with unactivated alkenes and azidobenziodoxolone (ABX, Zhdankin reagent) was developed. The protocol provides an efficient approach for the synthesis of various bioactive organoazides with quinoxalinone scaffold in moderate to good yields under mild conditions. This reaction is environmentally friendly avoiding the use of expensive transition-metal photocatalysts and stoichiometric oxidants.     

Magnesium Methoxide-Assisted Synthesis of 2,4,6-Triaryl Pyridines

A new three-component reaction of chalcones, ketones, and ammonia assisted by magnesium methoxide is described. The corresponding 2,4,6-triaryl pyridines (Kröhnke pyridines) are formed in fair to good yields (34–76%) within 3 h. The method also provides a facile way to synthesize 2(6)-difluoromethyl pyridines via an interesting mechanism.     

Regio- and Diastereoselective Aldol Products through Three-Component Coupling Reactions of Difluoroboroxy Fischer Carbene Molybdenum Complexes

The reaction of difluoroboroxy Fischer carbene complexes , vinyl ketones, and aldehydes leads to the regioselective formation of aldol-like products (see reaction scheme). The reaction also shows a high degree of diastereofacial selectivity when chiral aldehydes are used. These results show that this is a very attractive process since the regioselective formation of aldols from nearly symmetrical ketones still remains an unsolved problem.     

Ligand Controlled Regiodivergent C1 Insertion on Arynes for Construction of Phenanthridinone and Acridone Alkaloids

A palladium‐catalyzed regiodivergent C₁ insertion multicomponent reaction involving aryne, CO, and 2‐iodoaniline is established to construct the scaffolds of phenanthridinone and acridone alkaloids. Regioselective control is achieved under the guidance of selective ligands. The phenanthridinones are solely obtained under ligand‐free condition. In comparison, application of the electron‐abundant bidentate ligand dppm afforded the acridones with high efficiency. The release rate of the aryne from the precursor assists the regioselectivity of insertion as well, which was revealed through interval NMR tracking. A plausible mechanism was suggested based on the control experiments. Representative natural products and two types of natural product analogues were synthesized divergently through this tunable method.     

Double Heck Cross‐Coupling Reactions of Dibrominated Pyridines

Double Heck cross‐coupling reactions of 2,3‐ and 3,5‐dibromopyridine with various alkenes afforded the corresponding novel di(alkenyl)pyridines. The Heck reaction of 2,5‐dibromopyridine unexpectedly afforded 5,5′‐di(alkenyl)‐2,2′‐bipyridines by palladium‐catalyzed dimerization to give 5,5′‐dibromo‐2,2′‐bipyridine and subsequent twofold Heck reaction.     

Synthesis of Isocoumarins through Three‐Component Couplings of Arynes,Terminal Alkynes,and Carbon Dioxide Catalyzed by an NHC–Copper Complex

A copper‐catalyzed multicomponent coupling reaction between in situ generated ortho‐arynes, terminal alkynes, and carbon dioxide was developed to access isocoumarins in moderate to good yields. The key to this CO₂‐incorporating reaction was the use of a versatile N‐heterocyclic carbene/copper complex that was able to catalyze multiple transformations within the three‐component reaction.     

Hantzsch Ester as a Visible-Light Photoredox Catalyst for Transition-Metal-Free Coupling of Arylhalides and Arylsulfinates

Diethyl 2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (HEH) has been utilized as a visible-light photoredox catalyst for the cross coupling of arylhalides and arylsulfinates without transition metal, sacrificial agent, and mediator. This method is compatible with various functional groups and provides diaryl sulfones in good to high yields. Mechanistic studies indicate that this reaction undergoes the stepwise light irradiation of HE⁻, single electron transfer (SET) in donor–acceptor complex (DAC) from *HE⁻ to arylhalide, trapping of aryl radical with sulfinate, and SET oxidation of sulfone radical anion by HE^. to sulfone by the DAC method.     

Predicting New Ugi–Smiles Couplings: A Combined Experimental and Theoretical Study

Following our previous mechanistic studies of multicomponent Ugi‐type reactions, theoretical calculations have been performed to predict the efficiency of new substrates in Ugi–Smiles couplings. First, as predicted, 2,4,6‐trichlorophenol experimentally gave the corresponding aryl‐imidate. Theoretical predictions of nitrosophenols as good acidic partners were then successfully confirmed by experiments. In the latter case, the reaction offers a new access to benzimidazoles.     

Chemoselective Synthesis of Polysubstituted Pyridines from Heteroaryl Fluorosulfates

A selection of heteroaryl fluorosulfates were readily synthesized using commercial SO₂F₂ gas. These substrates are highly efficient coupling partners in the Suzuki reaction. Through judicious selection of Pd catalysts the fluorosulfate functionality is differentiated from bromide and chloride; the order of reactivity being: ‐Br> ‐OSO₂F> ‐Cl. Exploiting this trend allowed the stepwise chemoselective synthesis of a number of polysubstituted pyridines, including the drug Etoricoxib.