Formal [4+2]‐Annulation of Vinyl Azides with N‐Unsaturated Aldimines

Highly functionalized quinolines and pyridines could be synthesized by BF₃?OEt₂‐mediated reactions of vinyl azides with N‐aryl and N‐alkenyl aldimines, respectively. The reaction mechanism could be characterized as formal [4+2]‐annulation, including unprecedented enamine‐type nucleophilic attack of vinyl azides to aldimines and subsequent nucleophilic cyclization onto the resulting iminodiazonium ion moieties.     

Cu‐free Sonogashira Type Cross‐Coupling of 6‐Halo‐2‐cyclopropyl‐3‐(pyridyl‐3‐ylmethyl) Quinazolin‐4(3H)‐ones as Potential Antimicrobial Agents

C(sp)–C(sp2) bond formation via Sonogashira cross‐coupling reactions on 6‐halo‐2‐cyclopropyl‐3‐(pyridyl‐3‐ylmethyl)quinazolin‐4(3H )‐ones with appropriate alkynes was explored. Optimization of reaction conditions with various catalysts, ligands, bases, and solvents was conducted. The combination of PdCl₂(MeCN)₂ with X‐Phos proved to be the best metal–ligand system for this conversion in the presence of triethylamine (Et₃N) in tetrahydrofuran at room temperature for iodosubstrates, at 80°C for the bromosubstrates in 8 h, and also for the chlorosubstrates in 16 h. We also demonstrated synthesis of a successful diversity‐oriented synthesis library of highly functionalized quinazolinones via Cu‐free Sonogashira coupling of diverse aryl halides and azido‐alkyne (“click”) ligation reactions with substituted azides. The library exhibited significant antimicrobial activity when screened against several microorganisms.     

Exploring the Border between Concerted and Two‐Step Pathways of 1,3‐Dipolar Cycloadditions of Organic Azides to Cyclic Ketene N,X‐Acetals. – Synthesis and 15N‐NMR Spectra of Zwitterions and Spirocyclic Cycloadducts

Cyclic ketene N,X‐acetals 1 are electron‐rich dipolarophiles that undergo 1,3‐dipolar cycloaddition reactions with organic azides 2 ranging from alkyl to strongly electron‐deficient azides, e.g., picryl azide ( 2L ; R¹=2,4,6‐(NO₂)₃C₆H₂) and sulfonyl azides 2M – O (R¹=XSO₂; cf. Scheme 1). Reactions of the latter with the most‐nucleophilic ketene N,N‐acetals 1A provided the first examples for two‐step HOMO(dipolarophile)–LUMO(1,3‐dipole)‐controlled 1,3‐dipolar cycloadditions via intermediate zwitterions 3 . To set the stage for an exploration of the frontier between concerted and two‐step 1,3‐dipolar cycloadditions of this type, we first describe the scope and limitations of concerted cycloadditions of 2 to 1 and delineate a number of zwitterions 3 . Alkyl azides 2A – C add exclusively to ketene N,N‐acetals that are derived from 1H‐tetrazole (see 1A ) and 1H‐imidazole (see 1B , C ), while almost all aryl azides yield cycloadducts 4 with the ketene N,X‐acetals (X=NR, O, S) employed, except for the case of extreme steric hindrance of the 1,3‐dipole (see 2E ; R¹=2,4,6‐(^tBu)₃C₆H₂). The most electron‐deficient paradigm, 2L , affords zwitterions 16D , E in the reactions with 1A , while ketene N,O‐ and N,S‐acetals furnish products of unstable intermediate cycloadducts. By tuning the electronic and steric demands of aryl azides to those of ketene N,N‐acetals 1A , we discovered new borderlines between concerted and two‐step 1,3‐dipolar cycloadditions that involve similar pairs of dipoles and dipolarophiles: 4‐Nitrophenyl azide ( 2G ) and the 2,2‐dimethylpropylidene dipolarophile 1A (R, R=H, ^tBu) gave a cycloadduct 13 H , while 2‐nitrophenyl azide ( 2 H ) and the same dipolarophile afforded a zwitterion 16A . Isopropylidene dipolarophile 1A (R=Me) reacted with both 2G and 2 H to afford cycloadducts 13G , J ) but furnished a zwitterion 16B with 2,4‐dinitrophenyl azide ( 2I) . Likewise, 1A (R=Me) reacted with the isomeric encumbered nitrophenyl azides 2J and 2K to yield a cycloadduct 13L and a zwitterion 16C , respectively. These examples suggest that, in principle, a host of such borderlines exist which can be crossed by means of small structural variations of the reactants. Eventually, we use ¹⁵N‐NMR spectroscopy for the first time to characterize spirocyclic cycloadducts 10 – 14 and 17 (Table 6), and zwitterions 16 (Table 7).     

Bioorthogonal Ligation and Cleavage by Reactions of Chloroquinoxalines with ortho‐Dithiophenols

A bioorthogonal ligation and cleavage method via reactions of chloroquinoxalines (CQ) and ortho‐dithiophenols (DT) is presented. Double nucleophilic substitutions of ortho‐dithiophenols to chloroquinoxalines provide conjugates containing tetracyclic benzo[5,6][1,4]dithiino[2,3‐b]quinoxaline with strong built‐in fluorescence together with release of the other functional molecules. Three cleavable linkers were designed and successfully used in release of the molecules containing biotin from the protein conjugates. The CQ‐DT bioorthogonal reactions can be applied for the bioorthogonal ligations, bioorthogonal cleavages, and trans‐tagging of proteins, and show advantages of readily accessible unnatural orthogonal groups, appealing reaction kinetics (k₂≈1.3 m ^?1 s^?1), excellent biocompatibility of orthogonal groups, and high stability of conjugates. This complements previous bioorthogonal reactions and is a new route for protein‐fishing applications and in‐gel fluorescence analysis.     

Visible‐Light Sensitization of Vinyl Azides by Transition‐Metal Photocatalysis

Irradiation of vinyl and aryl azides with visible light in the presence of Ru photocatalysts results in the formation of reactive nitrenes, which can undergo a variety of C? N bond‐forming reactions. The ability to use low‐energy visible light instead of UV in the photochemical activation of azides avoids competitive photodecomposition processes that have long been a significant limitation on the synthetic use of these reactions.     

Transition‐Metal‐Free Formal Sonogashira Coupling and α‐Carbonyl Arylation Reactions

Transition‐metal‐free formal Sonogashira coupling and α‐carbonyl arylation reactions have been developed. These transformations are based on the nucleophilic aromatic substitution (S_NAr) of β‐carbonyl sulfones to electron‐deficient aryl fluorides, producing a key intermediate that, depending on the reaction conditions, gives the aromatic alkynes or α‐aryl carbonyl compounds. The development of these reactions is presented and, based on investigations under basic and acidic conditions, mechanisms have been proposed. To develop the formal Sonogashira coupling further, a milder, two‐step protocol is also disclosed that expands the reaction concept. The scope of these reactions is demonstrated for the synthesis of Sonogashira and α‐carbonyl arylated products from a range of electron‐deficient aryl fluorides with a variety of functional groups and aryl‐, heteroaryl‐, alkyl‐, and alkoxy‐substituted sulfone nucleophiles. These transition‐metal‐free reactions complement the metal‐catalyzed versions in terms of substitution patterns, simplicity, and reaction conditions.     

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.     

Bridge‐Clamp Bis(tetrazine)s with [N]8 π‐Stacking Interactions and Azido‐s‐Aryl Tetrazines: Two Classes of Doubly Clickable Tetrazines

Click chemistry at a tetrazine core is useful for bioorthogonal labeling and crosslinking. Introduced here are two new classes of doubly clickable s‐aryl tetrazines synthesized by Cu‐catalyzed cross‐coupling. Homocoupling of o‐brominated s‐aryl tetrazines leads to bis(tetrazine)s structurally characterized by tetrazine cores arranged face‐to‐face. [N]₈ π‐stacking interactions are essential to the conformation. Upon inverse electron demand Diels–Alder (iEDDA) cycloaddition, the bis(tetrazine)s produce a unique staple structure. The o‐azidation of s‐aryl tetrazines introduces a second proximal intermolecular clickable function that leads to double click chemistry opportunities. The stepwise introduction of fluorophores and then iEDDA cycloaddition, including bioconjugation to antibodies, was achieved on this class of tetrazines. This method extends to (thio)etherification, phosphination, trifluoromethylation and the introduction of various bioactive nitrogen‐based heterocycles.     

Iron‐Mediated Electrophilic Amination of Organozinc Halides using Organic Azides

A wide range of alkyl‐, aryl‐ and heteroarylzinc halides were aminated with highly functionalized alkyl, aryl, and heterocyclic azides. The reaction proceeds smoothly at 50 °C within 1 h in the presence of FeCl₃ (0.5 equiv) to furnish the corresponding secondary amines in good yields. This method was extended to peptidic azides and provided the arylated substrates with full retention of configuration. To demonstrate the utility of this reaction, we prepared two amine derivatives of pharmaceutical relevance using this iron‐mediated electrophilic amination as the key step.     

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.     

An Enolate‐Mediated Organocatalytic Azide–Ketone [3+2]‐Cycloaddition Reaction: Regioselective High‐Yielding Synthesis of Fully Decorated 1,2,3‐Triazoles

An enolate‐mediated organocatalytic azide–ketone [3+2]‐cycloaddition (OrgAKC) reaction of a variety of enolizable arylacetones and deoxybenzoins with aryl azides was developed for the synthesis of fully decorated 1,4‐diaryl‐5‐methyl(alkyl)‐1,2,3‐triazoles in excellent yields with high regioselectivity at 25 °C for 0.5–6 h. This reaction has an excellent outcome with reference to reaction rate, yield, regioselectivity, operation simplicity, and availability of substrates and catalyst. This reaction has advantages over the previously known metal‐mediated reactions.     

Copper‐Catalyzed N‐Arylation of Polysubstituted Pyridines Synthesized by the Novel Reaction of N‐Sulfonyl Ketenimine and Malononitrile‐Trichloroacetonitrile Adduct

In this study, we synthesized some new derivatives of N‐(4‐amino‐5‐cyano‐6‐(trichloromethyl)pyridin‐2‐yl)alkyl sulfonamides in the presence of a copper catalyst. A one‐pot reaction system was used, and four components participated in the process. These four components were sulfonyl azides, terminal alkynes, malononitrile, and trichloroacetonitrile. The reaction rate was increased by the use of copper (I) iodide as the catalyst and tetrahydrofuran was used as the solvent. We achieved the final compounds in moderate to good yields. Moreover, we converted “NH₂” side group to N‐aryl by the use of various aryl halide analogs in acetonitrile as the solvent, under mild reaction and at the room temperature.     

Norbornene derivatives from a metal‐free,strain‐promoted cycloaddition reaction: New building blocks for ring‐opening metathesis polymerization reactions

The preparation of new ring opening metathesis polymerization (ROMP) monomers using a 1,3‐dipolar cycloaddition between aryl azides and norbornadiene is described. Various norbornenetriazolines, obtained through a solvent‐and catalyst‐free reaction, can subsequently be incorporated into polymer backbones through ROMP reactions. Furthermore, thermal decomposition of the triazoline moiety can allow for further polymer functionalization. © 2015 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2015 , 53, 2357–2362     

Cathepsin B‐Specific Metabolic Precursor for In Vivo Tumor‐Specific Fluorescence Imaging

Recently, metabolic glycoengineering with bioorthogonal click reactions has focused on improving the tumor targeting efficiency of nanoparticles as delivery vehicles for anticancer drugs or imaging agents. It is the key technique for developing tumor‐specific metabolic precursors that can generate unnatural glycans on the tumor‐cell surface. A cathepsin B‐specific cleavable substrate (KGRR) conjugated with triacetylated N‐azidoacetyl‐d ‐mannosamine (RR‐S‐Ac₃ManNAz) was developed to enable tumor cells to generate unnatural glycans that contain azide groups. The generation of azide groups on the tumor cell surface was exogenously and specifically controlled by the amount of RR‐S‐Ac₃ManNAz that was fed to target tumor cells. Moreover, unnatural glycans on the tumor cell surface were conjugated with near infrared fluorescence (NIRF) dye‐labeled molecules by a bioorthogonal click reaction in cell cultures and in tumor‐bearing mice. Therefore, our RR‐S‐Ac₃ManNAz is promising for research in tumor‐specific imaging or drug delivery.     

A Novel ‘Domino‐Click Approach’ to Unsymmetrical Bis‐1H‐1,2,3‐triazoles

Aryl azides 1 were treated with allenylmagnesium bromide ( 2 ) to generate 1,5‐disubstituted butynyl‐1H‐1,2,3‐triazoles 3 in a domino fashion, which upon Cu^I‐catalyzed 1,3‐dipolar cycloaddition with aryl azides 4 afforded novel bis‐1H‐1,2,3‐triazoles 5 in quantitative yields (Scheme 1 and Table).     

Synthesis and formulation of self-immolative PEG-aryl azide block copolymers and click-to-release reactivity with trans-cyclooctene

Self-immolative aryl azides can react with trans-cyclooctenes (TCO), triphenylphosphines or hydrogen sulfide (H₂S) to activate prodrugs, imaging probes and drug delivery systems. To date, the synthesis of polymers containing these aryl azide self-immolative linkers and their reactivity with a strained alkene (i.e., in a bioorthogonal reaction) has not been explored. Also, due to the instability of aryl azides towards light and high temperatures, the polymerization methods compatible with aryl azides are limited. Through systematic investigation of the reversible addition-fragmentation chain transfer (RAFT) and atom transfer radical polymerization (ATRP) methods, a self-immolative PEG-aryl azide block copolymer (PEG₄₅-b-ABOC₂₈ 2 ) and a non-responsive 4-fluoroaryl block copolymer (PEG₄₅-b-FBOC₂₄ 3 ) was prepared. ATRP provided the desired polymers in a highly controlled manner, whereas the RAFT conditions led to higher levels of aryl azide polymer degradation. The ATRP derived polymers 2 and 3 were formulated into nanoparticles of approximately 200 nm diameter, and particle triggering was demonstrated by the [3+2]-cycloaddition reaction of TCO with PEG₄₅-b-ABOC₂₈ 2 in solution (pure polymer) and as a formulated nanoparticle. Preliminary in vitro cell viability studies suggested that the stimuli-responsive aryl azide polymers/nanoparticles are not cytotoxic up to 200 μg/ml concentrations.     

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.     

An Efficient Palladium and Bis(2‐pyridylmethyl)amine‐based System for Suzuki‐Miyaura Cross‐Coupling under Aqueous and Aerobic Condition

A novel PdCl₂/bis(2‐pyridylmethyl)amine‐based ligand ( 1 ) catalytic system, which is water‐soluble and air‐stable, has been successfully synthesized and applied for Suzuki‐Miyaura cross‐coupling reaction. In the presence of catalytic amount of PdCl₂/ 1 system, arylboronic acids can couple with a wide range of aryl halides, including aryl bromides and aryl chlorides. The reactions proceed under mild conditions to give excellent yields, and a wide range of functionalities is tolerated.     

[FeIII(F20‐tpp)Cl] Is an Effective Catalyst for Nitrene Transfer Reactions and Amination of Saturated Hydrocarbons with Sulfonyl and Aryl Azides as Nitrogen Source under Thermal and Microwave‐Assisted Conditions

[Fe^III(F₂₀‐tpp)Cl] (F₂₀‐tpp=meso‐tetrakis(pentafluorophenyl)porphyrinato dianion) is an effective catalyst for imido/nitrene insertion reactions using sulfonyl and aryl azides as nitrogen source. Under thermal conditions, aziridination of aryl and alkyl alkenes (16 examples, 60–95 % yields), sulfimidation of sulfides (11 examples, 76–96 % yields), allylic amidation/amination of α‐methylstyrenes (15 examples, 68–83 % yields), and amination of saturated C? H bonds including that of cycloalkanes and adamantane (eight examples, 64–80 % yields) can be accomplished by using 2 mol % [Fe^III(F₂₀‐tpp)Cl] as catalyst. Under microwave irradiation conditions, the reaction time of aziridination (four examples), allylic amination (five examples), sulfimidation (two examples), and amination of saturated C? H bonds (three examples) can be reduced by up to 16‐fold (24–48 versus 1.5–6 h) without significantly affecting the product yield and substrate conversion.     

An Efficient Copper‐Catalyzed One‐Pot Synthesis of 1‐Aryl‐1,2,3‐triazoles from Arylboronic Acids in Water under Mild Conditions

A convenient method for one‐pot two‐step 1,3‐dipolar cycloadditon reaction of arylboronic acid, sodium azide followed with terminal alkynes in the presence of 2‐pyrrolecarbaldiminato‐Cu(II) complexes catalyst is reported. Various 1‐aryl‐1,2,3‐triazoles were prepared in 63%–97% yields in water at 30°C without any additives and avoiding the isolation of unstable aryl azides.