DFT studies on the mechanism of Ag2CO3‐catalyzed hydroazidation of unactivated terminal alkynes with TMS‐N3: An insight into the silver(I) activation mode

Silver‐mediated hydroazidation of unactivated alkynes has been developed as a new method for the synthesis of vinyl azides. Density functional theory calculations toward this reaction reveal that terminal alkynes with TMS‐N₃ participated hydroazidation proceed through HN₃ formation, deprotonation and silver acetylides formation, nucleophilic addition, and protonation of terminal carbon by AgHCO₃. It is also found that water molecules and activation modes of Ag (I) have a significant influence on the title reaction mechanism. Initially, catalyst Ag₂CO₃ coordinates preferentially with internal N atom of TMS–N₃ to assist water as hydrogen source and proton‐shuttle in facilitating HN₃ formation. Then, the regioselective anti‐addition of HN₃ to triple bond of active silver‐acetylide or ethynyl carbinols affords product vinyl azide via Ag–C σ‐bond activation or Ag…C π‐coordination activation modes, and the former one is more favorable. The origin of the difference regioselectivity is ascribed to the electronic and orbital effects of the reactive sites. Moreover, Ag₂CO₃ is the critical catalyst, acting as activator, base, and stabilizer to promote the HN₃ and vinyl azide formation. Water molecule plays an important role as proton shuttle to promote HN₃ and key active silver acetylides formation, thus improving the yield of product. © 2017 Wiley Periodicals, Inc.     

One‐Pot,Three‐Component Synthesis of 1‐(2‐Hydroxyethyl)‐1H‐1,2,3‐triazole Derivatives by Copper‐Catalyzed 1,3‐Dipolar Cycloaddition of 2‐Azido Alcohols and Terminal Alkynes under Mild Conditions in Water

A safe, efficient, and improved procedure for the regioselective synthesis of 1‐(2‐hydroxyethyl)‐1H‐1,2,3‐triazole derivatives under ambient conditions is described. Terminal alkynes reacted with oxiranes and NaN₃ in the presence of a copper(I) catalyst, which is prepared by in situ reduction of the copper(II) complex 4 with ascorbic acid, in H₂O. The regioselective reactions exclusively gave the corresponding 1,4‐disubstituted 1H‐1,2,3‐triazoles in good to excellent yields. This procedure avoids the handling of organic azides as they are generated in situ, making this already powerful click process even more user‐friendly and safe. The remarkable features of this protocol are high yields, very short reaction times, a cleaner reaction profile in an environmentally benign solvent (H₂O), its straightforwardness, and the use of nontoxic catalysts. Furthermore, the catalyst could be recovered and recycled by simple filtration of the reaction mixture and reused for ten consecutive trials without significant loss of catalytic activity. No metal‐complex leaching was observed after the consecutive catalytic reactions.     

Silver‐Catalyzed Stereoselective Aminosulfonylation of Alkynes

A silver‐catalyzed intermolecular aminosulfonylation of terminal alkynes with sodium sulfinates and TMSN₃ is reported. This three‐component reaction proceeds through sequential hydroazidation of the terminal alkyne and addition of a sulfonyl radical to the resultant vinyl azide. The method enables the stereoselective synthesis of a wide range of β‐sulfonyl enamines without electron‐withdrawing groups on the nitrogen atom. These enamines are found to be suitable for a variety of further transformations.     

Strain‐Promoted Reaction of 1,2,4‐Triazines with Bicyclononynes

Strain‐promoted inverse electron‐demand Diels–Alder cycloaddition (SPIEDAC) reactions between 1,2,4,5‐tetrazines and strained dienophiles, such as bicyclononynes, are among the fastest bioorthogonal reactions. However, the synthesis of 1,2,4,5‐tetrazines is complex and can involve volatile reagents. 1,2,4‐Triazines also undergo cycloaddition reactions with acyclic and unstrained dienophiles at elevated temperatures, but their reaction with strained alkynes has not been described. We postulated that 1,2,4‐triazines would react with strained alkynes at low temperatures and therefore provide an alternative to the tetrazine cycloaddition reaction for use in in vitro or in vivo labelling experiments. We describe the synthesis of a 1,2,4‐triazin‐3‐ylalanine derivative fully compatible with the fluorenylmethyloxycarbonyl (Fmoc) strategy for peptide synthesis and demonstrate its reaction with strained bicyclononynes at 37 °C with rates comparable to the reaction of azides with the same substrates. The synthetic route to triazinylalanine is readily adaptable to late‐stage functionalization of other probe molecules, and the 1,2,4‐triazine‐SPIEDAC therefore has potential as an alternative to tetrazine cycloaddition for applications in cellular and biochemical studies.     

Strain‐Promoted 1,3‐Dithiolium‐4‐olates–Alkyne Cycloaddition

Reported here is the reactivity of mesoionic 1,3‐dithiolium‐4‐olates towards strained alkynes, leading to thiophene cycloaddition products. In the process, the potential of these dipoles towards orthogonal reaction with azides, allowing efficient double ligation reactions, was discovered. A versatile process to access benzo[c]thiophenes, in an unprecedented divergent fashion, was developed and provides a new entry to unconventional polyaromatic thiophenes.     

Chemo‐ and Regioselective Rhodium(I)‐Catalyzed [2+2+2] Cycloaddition of Allenynes with Alkynes

A highly chemo‐ and regioselective partially intramolecular rhodium(I)‐catalyzed [2+2+2] cycloaddition of allenynes with alkynes is described. A range of diverse polysubstituted benzene derivatives could be synthesized in good to excellent yields, in which the allenynes served as synthetic equivalent to the diynes. A high regioselectivity could be observed when allenynes were treated with unsymmetrical alkynes.     

Copper‐catalyzed Synthesis of N‐alkylated 2‐(4‐substituted‐1H‐1,2,3‐triazol‐1‐yl)‐1H‐indole‐3‐carbaldehyde by Step‐wise and One‐pot Three‐component Huisgen's 1,3‐dipolar Cycloaddition Reaction

An efficient method for the synthesis of N‐alkylated 2‐(4‐substituted‐1H‐1,2,3‐triazol‐1‐yl)‐1H‐indole‐3‐carbaldehyde has been developed starting from oxindole and indole using Huisgen's 1,3‐dipolar cycloaddition reaction of organic azides to alkynes. The effect of catalysts and solvent on these reactions has been investigated. Among all these conditions, while using CuSO₄·5H₂O, DMF was found to be the best system for this reaction. It could also be prepared in a one‐pot three‐component manner by treating equimolar quantities of halides, azides, and alkynes. The Huisgen's 1,3‐dipolar cycloaddition reaction was performed using CuSO₄·5H₂O in DMF with easy work‐up procedure.     

Synthesis of New Hybrid Heterocyclic Compounds Having 1,2,3‐Triazole and Isoxazole via Click Chemistry

A simple and highly efficient method for the regioselective synthesis of isoxazolyl‐1,4‐disubstituted‐1,2,3‐triazoles 6a , 6b , 6c , 6d , 6e , 6f , 6g , 6h , 6i , 6j , 6k , 6l in good to excellent yields from terminal alkynes having isoxazole scaffold 4a , 4b , 4c and various azides through Cu(I)‐catalyzed 1,3‐dipolar cycloaddition is described. The reaction proceeds smoothly in 1:1 mixture of t‐BuOH and water at RT. The structures of all newly synthesized hybrid heterocycles are established on the basis of spectral data ir, ¹H nmr, mass, and elemental analysis.     

Rhodium/Silver‐Cocatalyzed Transannulation of N‐Sulfonyl‐1,2,3‐triazoles with Vinyl Azides: Divergent Synthesis of Pyrroles and 2 H‐Pyrazines

The first cyclization reaction between vinyl azides and N‐sulfonyl‐1,2,3‐triazoles is reported. A Rh/Ag binary metal catalyst system proved to be necessary for the successful cyclization. By varying the structure of vinyl azides, such reaction allows the divergent synthesis of pyrroles and 2H‐pyrazines. The cyclization reactions feature a broad substrate scope, good functional group tolerance, high reaction efficiency, and good to high product yields.     

An Elegant Synthesis of a New Class of 1‐(Substituted)‐1H‐1,2,3‐triazol‐4‐yl)methyl)diphenylphosphineoxides by Microwave Irradiation

A simple and efficient one‐pot microwave‐assisted click formation of 1‐(substituted)‐1H‐1,2,3‐triazol‐4‐yl)methyl)diphenylphosphineoxide derivatives via Huisgen regioselective [3+2]‐cycloaddition of an in situ generated organic azides and diphenyl(prop‐2‐yn‐1‐yl)phosphine oxide in highly polar DMSO‐H₂O medium. This synthetic protocol is mild, requires shorter reaction time, and afforded products in excellent yields with high regioselectivity.     

Synthesis of α‐Trifluoromethylated Ketones from Vinyl Triflates in the Absence of External Trifluoromethyl Sources

A novel method for the conversion of vinyl triflates into α‐trifluoromethylated ketones in the absence of external trifluoromethyl sources is described. This process accomplishes an efficient migration of the trifluoromethyl group of the triflate to the α‐position in the ketone through a radical process. The reaction proceeds by the addition of a trifluoromethyl radical to the vinyl triflate and subsequent fragmentation of the trifluoromethane sulfonyl radical. Based on this reaction, a one‐pot two‐step procedure for the trifluoromethylation of ketones was developed. The method presented herein also allows the transfer of perfluoroalkyl groups from vinyl perfluoroalkanesulfonates, which are readily accessible from alkynes and perfluoroalkanesulfonic acids.     

Mechanism of Gold(I)‐Catalyzed Conia‐ene Reaction of β‐Ketoesters with Alkynes: A DFT Study

Density functional calculations have been performed to comparatively investigate two possible pathways of Au(I)‐catalyzed Conia‐ene reaction of β‐ketoesters with alkynes. Our studies find that, under the assistance of trifluoromethanesulfonate (TfO), the β‐ketoester is the most likely to undergo Model II to isomerize into its enol form, in which TfO plays a proton transfer role through a 6‐membered ring transition state. The coordination of the Au(I) catalyst to the alkynes triple bond can enhance the eletrophilic capability and reaction activity of the alkynes moiety, which triggers the nucleophilic addition of the enol moiety on the alkynes moiety to give a vinyl‐Au intermediate. This cycloisomerizaion step is exothermal by 21.3 kJ/mol with an energy barrier of 56.0 kJ/mol. In the whole catalytic process, the protonation of vinyl‐Au is almost spontaneous, and the formation of enol is a rate‐limiting step. The generation of enol and the activation of Au(I) catalyst on the alkynes are the key reasons why the Conia‐ene reaction can occur in mild condition. These calculations support that Au(I)‐catalyzed Conia‐ene reactions of β‐ketoesters with alkynes go through the pathway 2 proposed by Toste.     

Stereodivergent Alkyne Hydrofluorination Using Protic Tetrafluoroborates as Tunable Reagents

The discovery of safe, general, and practical procedures to prepare vinyl fluorides from readily available precursors remains a synthetic challenge. The metal‐free hydrofluorination of alkynes constitutes an attractive though elusive strategy for their preparation. Introduced here is an inexpensive and easily handled reagent that enables the development of simple and scalable protocols for the regioselective hydrofluorination of alkynes to access both the E and Z isomers of vinyl fluorides. These reaction conditions were suitable for a diverse collection of alkynes, including several highly functionalized pharmaceutical derivatives. Computational and experimental mechanistic studies support C?F bond formation through vinyl cation intermediates, with the E‐ and Z‐hydrofluorination products forming under kinetic and thermodynamic control, respectively.     

An Efficient and Convenient Synthesis of Ethyl 1‐(4‐Methoxyphenyl)‐5‐phenyl‐1H‐1,2,3‐triazole‐4‐carboxylate

The “click chemistry” of using organic azides and terminal alkynes is arguably the most efficient and straightforward route to the synthesis of 1,2,3‐triazoles. In this paper, an alternative and direct access to ethyl 1‐(4‐methoxyphenyl)‐5‐phenyl‐1H‐1,2,3‐triazole‐4‐carboxylate is described. Treatment of ethyl diazoacetate with 4‐methoxyaniline derived aryl imines in the presence of 1,8‐diazabicyclo[5.4.0]undec‐7‐ene provided fully substituted 1,2,3‐triazoles in good to high chemical yields. The base‐mediated reaction tolerates various substituted phenyl imines as well as ethyl diazoacetate or the more bulky diazoacetamide. A reasonable mechanism is proposed that involves the addition of an imine nitrogen atom to the terminal nitrogen atom of the diazo compound, followed by aromatization to give the 1,2,3‐triazole. The presence of the 4‐carboxy group is advantageous as it can be easily transformed into other functional groups.     

Highly Efficient Ultrasonic‐Assisted CuCl‐Catalyzed 1,3‐Dipolar Cycloaddition Reactions in Water: Synthesis of Coumarin Derivatives Linked with 1,2,3‐Triazole Moiety

By introducing ultrasound irradiation into “on water” CuCl‐catalyzed 1,3‐dipolar Huisgen cycloaddition, the reaction efficiencies were notably promoted toward a wide variety of applicable azides and alkynes at room temperature, and a series of coumarin derivatives linked with 1,2,3‐triazole moiety were synthesized using the optimized conditions.     

Catalytic CN Bond Alkynylation of N‐Benzylic Sulfonamides with Terminal Alkynes

A new cross‐coupling reaction of N‐benzylic sulfonamides with terminal alkynes for the synthesis of internal alkynes is reported. In the presence of 5 mol% of (Tf)₂NH/Bi(OTf)₃ (1:1), a broad range of N‐benzylic sulfonamides react smoothly with arylacetylenes to afford structurally diverse internal alkynes in moderate to excellent yields. We reasoned that vinyl cations could be formed by the regioselective attack of terminal alkynes with benzyl cations generated in situ from N‐benzylic sulfonamides under acidic conditions, which then eliminated to form a carbon‐carbon triple bond.     

Enantioselective and Regioselective Pyrone Diels–Alder Reactions of Vinyl Sulfones: Total Synthesis of (+)‐Cavicularin

The total synthesis of (+)‐cavicularin is described. The synthesis features an enantio‐ and regioselective pyrone Diels–Alder reaction of a vinyl sulfone to construct the cyclophane architecture of the natural product. The Diels–Alder substrate was prepared by a regioselective one‐pot three‐component Suzuki reaction of a non‐symmetric dibromoarene.     

Copper-catalyzed hydrative amide synthesis with terminal alkyne, sulfonyl azide, and water

It is shown for the first time that N-sulfonyl amides can be efficiently prepared by an unconventional approach of the hydrative reaction between terminal alkynes, sulfonyl azides, and water in the presence of copper catalyst and amine base under very mild conditions. The present route is quite general, and a wide range of alkynes and sulfonyl azides are readily coupled catalytically with water to furnish amides in high yields. A variety of labile functional groups are tolerated under the conditions, and the reaction is regioselective in that only terminal alkynes react while double or internal triple bonds are intact. The reaction can be readily scaled up and is also adaptable to a solid-phase procedure with high efficiency.     

Direct synthesis of 1,5-disubstituted-4-magnesio-1,2,3-triazoles, revisited

After revisiting earlier works reporting the regioselective synthesis of 1,5-disubstituted-1,2,3-triazoles via the addition of bromomagnesium acetylides to azides, much improved yields of the products were obtained for a wide array of azides and alkynes. The intermediates of that reaction can be trapped with different electrophiles to regioselectively form 1,4,5-trisubstituted 1,2,3-triazoles. [reaction: see text]     

Pyrene‐Excimers‐Based Antenna Systems

A series of dendrimeric compounds bearing pyrene units were synthesized to afford light‐harvesting antennae based on the formation of intramolecular excimers. The synthetic plan profited from the efficiency of the Huisgen reaction, the 1,3‐dipolar cycloaddition of azides and terminal alkynes, which allowed ready assembly of the different building blocks. The three molecular antennae obtained, of increasing generation, revealed efficient energy transfer both in solution and in the solid state.