KO~tBu促进的有机叠氮和末端炔烃的环加成反应改进研究

文章系统研究了叔丁醇钾促进下芳基叠氮和取代苯乙炔的环加成反应。在等摩尔数的叔丁醇钾作用下,当溶剂为DMF时,反应效果最佳,产率高达92%。其他的芳基叠氮和苯乙炔的反应研究结果表明,芳基叠氮和苯乙炔在此环加成反应中具有良好的反应适应性。     

Click Chemistry合成1,2,3-三唑氨基酸衍生物

通过W ong叠氮转化和亲核取代反应,分别合成了叠氮苯丙氨酸、叠氮丙氨酸、苄基叠氮,采用上述叠氮化物与L-炔丙基甘氨酸进行C lick反应,合成了3个1,4-取代1,2,3-三唑氨基酸衍生物:2-氨基-3-[1-(1-羧基-2-苯乙基)-1H-1,2,3-三唑-4-基]丙酸、3,3-′(1H-1,2,3-三唑-1,4-基)双(2-氨基丙酸)和2-氨基-3-(1H-1,2,3-三唑-1-苄基-4-基)丙酸,收率分别是76%、62%和68%,产物结构经核磁共振波谱、质谱、红外光谱进行了表征。1,2,3-三唑氨基酸衍生物含双功能螯合基团,是很有潜力的fac-[188Re(CO)3(H2O)3]+放射性标记配体。     

The Efficient Copper(I) (Hexabenzyl)tren Catalyst and Dendritic Analogues for Green “Click” Reactions between Azides and Alkynes in Organic Solvent and in Water: Positive Dendritic Effects and Monometallic Mechanism

An easily synthesized, copper(I) (hexabenzyl)tren complex 1 is an efficient catalyst for the copper(I)‐catalyzed Huisgen‐type 1,3‐cycloaddition between azides and alkynes (CuAAC) reaction in toluene. Alternatively, a convenient procedure involves mixing copper(I) bromide (CuBr) with hexabenzyltren and the substrates in toluene which gives, for instance, 100% yield of triazole in 10 min using 0.1 equiv. catalyst with phenylacetylene and benzyl azide at room temperature. The toluene‐soluble catalyst 1 is recyclable and is applied, for example, to the CuAAC synthesis of an 81‐branched dendrimer that previously required the use of a stoichiometric amount of copper(II) sulfate (CuSO₄)+sodium ascorbate “catalyst”. Dendritic copper(I)‐centered analogues 2 and 3 of the first and second generations (G1 and G2, respectively) containing respectively 18 and 54 branch termini, including a 54‐branched water‐soluble metallodendrimer 5 , are also very efficient catalysts for the CuAAC reaction. With the metallodendritic Cu(I) derivatives 2 and 3 , the dendritic frame brings about steric protection against the well‐known inner‐sphere aerobic oxidation of Cu(I) to bis(μ‐oxo)‐bis‐Cu(II). The metallodendrimers 2 and 3 are also sometimes more efficient than the parent catalyst, as shown by kinetic studies. Catalysis in water without co‐solvent of the CuAAC reactions of water‐insoluble substrates was achieved under ambient conditions in good yields with the recyclable catalyst 5 . Efficient catalysis of the CuAAC reaction by these bulky Cu(I) metallodendrimers emphasizes the monometallic mechanism. The difference of kinetic behavior between 1 and CuBr+hexabenzyltren suggests, however, that whereas a monometallic mechanism is working for 1 , the mixture of CuBr+hexabenzyltren might involve the bimetallic mechanism proposed by Fokin and Finn.     

Intramolecular Azide‐Alkene 1,3‐Dipolar Cycloaddition/Enamine Addition(s) Cascade Reaction: Synthesis of Nitrogen‐Containing Heterocycles

A cascade intramolecular azide‐alkene 1,3‐dipolar cycloaddition/1,2 enamine and/or 1,4 enamine addition reaction sequence has been developed, and provides access to a variety of nitrogen containing heterocycles from readily available ω‐azido alkenes.     

Direct Metal-Free Transformation of Alkynes to Nitriles: Computational Evidence for the Precise Reaction Mechanism

Density functional theory calculations elucidated the precise reaction mechanism for the conversion of diphenylacetylenes into benzonitriles involving the cleavage of the triple C≡C bond, with N-iodosuccinimide (NIS) as an oxidant and trimethylsilyl azide (TMSN₃) as a nitrogen donor. The reaction requires six steps with the activation barrier ΔG^‡ = 33.5 kcal mol⁻¹ and a highly exergonic reaction free-energy ΔG_R = −191.9 kcal mol⁻¹ in MeCN. Reaction profiles agree with several experimental observations, offering evidence for the formation of molecular I₂, interpreting the necessity to increase the temperature to finalize the reaction, and revealing thermodynamic aspects allowing higher yields for alkynes with para-electron-donating groups. In addition, the proposed mechanism indicates usefulness of this concept for both internal and terminal alkynes, eliminates the option to replace NIS by its Cl- or Br-analogues, and strongly promotes NaN₃ as an alternative to TMSN₃. Lastly, our results advise increasing the solvent polarity as another route to advance this metal-free strategy towards more efficient processes.     

Alkynylboranes: A Practical Approach by Zinc‐Catalyzed Dehydrogenative Coupling of Terminal Alkynes with 1,8‐Naphthalenediaminatoborane

Under zinc Lewis acid catalysis, terminal alkynes coupled dehydrogenatively with 1,8‐naphthalenediaminatoborane [HB(dan)]. It is important to note that the resulting alkynylboranes with an C(sp) B(dan) bond are isolable by column chromatography on silica gel (SiO₂) and are usable as coupling partners for palladium‐ and copper‐catalyzed cross‐coupling reactions with (hetero)aryl halides.

     

Practical Methods for the Synthesis of Trifluoromethylated Alkynes: Oxidative Trifluoromethylation of Copper Acetylides and Alkynes

Two practical and complementary methods are reported for the synthesis of trifluoromethylated alkynes. The first one, a mix‐and‐stir process, is based on the oxidative trifluoromethylation of readily available and bench‐stable copper acetylides while the second one, which displays a broad substrate scope and has several advantages over existing procedures, is based on the oxidative copper‐catalyzed direct trifluoromethylation of terminal alkynes. Both reactions provide user‐friendly processes for the synthesis of trifluoromethylated acetylenes which can be easily obtained from readily available starting materials.

     

Rhodium‐Catalyzed Oxidative Cycloaddition of N‐tert‐Butoxycarbonylhydrazones with Alkynes for the Synthesis of Functionalized Pyrroles via C(sp3)–H Bond Functionalization

A rhodium(III)‐catalyzed cycloaddition of N‐tert‐butoxycarbonylhydrazones with internal alkynes was developed. The reaction features a regioselective α‐imino alkyl C(sp³)−H bond functionalization resulting in selective formation of highly functionalized NH‐free pyrroles. Our studies showed that utilizing the N‐tert‐butoxycarbonyl (N‐Boc) as the oxidizing directing group is critical for achieving the observed pyrrole formation versus the isoquinoline formation. To account for the pyrrole formation, we hypothesized that a prior tautomerization of the N‐Boc‐hydrazones to enamines should occur, followed by regioselective C(sp²)–H cleavage to form a putative five‐membered rhodacycle. Subsequent coupling of the rhodacycle with the alkynes would afford the pyrrole products.

     

An Efficient Bioorthogonal Strategy Using CuAAC Click Chemistry for Radiofluorinations of SNEW Peptides and the Role of Copper Depletion

The EphB2 receptor is known to be overexpressed in various types of cancer and is therefore a promising target for tumor cell imaging by positron emission tomography (PET). In this regard, imaging could facilitate the early detection of EphB2‐overexpressing tumors, monitoring responses to therapy directed toward EphB2, and thus improvement in patient outcomes. We report the synthesis and evaluation of several fluorine‐18‐labeled peptides containing the SNEW amino acid motif, with high affinity for the EphB2 receptor, for their potential as radiotracers in the non‐invasive imaging of cancer using PET. For the purposes of radiofluorination, EphB2‐antagonistic SNEW peptides were varied at the C terminus by the introduction of L ‐cysteine, and further by alkyne‐ or azide‐modified amino acids. In addition, two novel bifunctional and bioorthogonal labeling building blocks [¹⁸F]AFP and [¹⁸F]BFP were applied, and their capacity to introduce fluorine‐18 was compared with that of the established building block [¹⁸F]FBAM. Copper‐assisted Huisgen 1,3‐dipolar cycloaddition, which belongs to the set of bioorthogonal click chemistry reactions, was used to introduce both novel building blocks into azide‐ or alkyne‐modified SNEW peptides under mild conditions. Finally, the depletion of copper immediately after radiolabeling is a highly important step of this novel methodology.     

Click Functionalization of Gold Nanoparticles Using the Very Efficient Catalyst Copper(I) (Hexabenzyl)tris(2‐aminoethyl)‐ amine Bromide

Whereas previous “click” functionalization (Huisgen‐type copper‐catalyzed alkyne‐azide cycloaddition, CuAAC) of various gold nanoparticles (AuNP) had systematically proven to be very difficult, tedious, providing low yields with the use of high amounts of copper sulfate+sodium ascorbate – the classic Sharpless catalyst, the new catalyst copper(I) (hexabenzyl)tris(2‐aminoethyl)amine bromide, {[Cu(I)(Hexabenzyl)Tren]Br} is shown here to be very efficient for the introduction of a large variety of organic, organometallic, dendronic and polymeric molecular fragments of various sizes, topologies and hydrophilicities. Indeed, 0.1–0.15 equiv. of this catalyst in toluene was used in each reaction under ambient conditions for 8 to 48 h with good yields without AuNP aggregation. The new functional AuNP have been characterized by ¹H NMR, IR and UV‐vis. (plasmon band) spectroscopy, cyclic voltammetry (CV), dynamic light scattering (DLS) and transmission electron microscopy (TEM).     

Copper(I)‐Catalyzed Asymmetric 1,3‐Dipolar [3+4] Cycloaddition of Nitrones with Azoalkenes

The first copper(I)‐catalyzed asymmetric 1,3‐dipolar [3+4] cycloaddition of nitrones with azoalkenes has been developed, affording a variety of biologically important 1,2,4,5‐oxatriazepane derivatives in good yields with exclusive regioselectivities and excellent enantioselectivities.

     

Copper (I) Iodide‐Catalyzed One‐Step Preparation of Functionalized Allenes from Terminal Alkynes: Amine Effect

An efficient one‐step synthesis of functionalized allenes from readily available functionalized terminal alkynes and aldehydes by applying the effect of a dialkylamine has been developed. The protocol is catalyzed by copper(I) iodide and the dialkylamine is believed to play a very important role in the transformation.     

Copper(II)‐Catalyzed Asymmetric 1,3‐Dipolar [3+4] Cycloaddition and Kinetic Resolution of Azomethine Imines with Azoalkenes

An unprecedented copper(II)‐catalyzed enantioselective 1,3‐dipolar [3+4] cycloaddition of azomethine imines with in situ formed azoalkenes has been realized. This strategy provides a facile access to biologically important 1,2,4,5‐tetrazepine derivatives in high yield with exclusive regioselectivity and high stereoselectivity. Moreover, enantioenriched azomethine imines could be obtained via an efficient kinetic resolution using the same approach.

     

On the kinetics of the autoxidation of fats

The mechanism of fat autoxidation is elucidated from the rate data. All the data treated here and in an earlier publication follow the same basic rate equation, including the time function f(t) empirically derived for heterogeneous oxidation. Metals and glass (the wall of the reaction vessel) are catalysts. Depending on the state of the catalyst, f(t)=t² or f(t)=t. When f(t)=t, the kinetics are first-order as found for monolayer autoxidation, but in bulk phase they are complicated by a transient stage caused by the solubilization of O₂ into the hydroperoxide micelles produced in the exponential (“autocatalytic”) part of the oxidation. Certain additives, such as inhibitors, affect the catalyst and thereby f(t). The kinetics, as determined by O₂ consumption or by analysis of the remaining unreacted substrate, show the first oxidation step. It is unaffected by further chemical changes of the primary oxidation products,e.g., decomposition of hydroperoxides and trimerization in the autoxidation of 9,11-octadecadienoic acid methyl ester.     

The Competition Kinetics of Unbranched Chain Processes of Free-Radical Addition to Double Bonds of Molecules with the Formation of 1:1 Adducts

Abstract

Based on a kinetic model involving competing parallel reactions for free-radical addition to the double bond of a molecule with the formation of 1:1 adduct and participation of three radical types in the chain propagation, versions of the rate equation with 1 - 3 measurable parameters are derived. These versions make it possible to describe the nonmonotonic (with maximum) dependence of the formation rate of an addition product on concentration of the unsaturated compound. The unbranched chain process occurs in binary liquid systems comprising saturated and unsaturated components at comparable concentrations. Application of the competition kinetics of free-radical addition to oxidation of some hydrocarbons is discussed when the reaction that competes with chain propagation reactions involving the alkylperoxy radical RO₂ gives the cyclic alkylhydrotetraoxy radical [R(_?H)O₄H] as a less reactive radical inhibiting the chain process of formation of the main products of oxidation.     

Kinetics of the Interactions between Copper and Amyloid‐β with FAD Mutations and Phosphorylation at the N terminus

Mutations and post‐translational modifications of amyloid‐β (Aβ) peptide in its N terminus have been shown to increase fibril formation, yet the molecular mechanism is not clear. Here we investigated the kinetics of the interactions of copper with two Aβ peptides containing Familial Alzheimer's disease (FAD) mutations (English (H6R) and Tottori (D7N)), as well as with Aβ peptide phosphorylated at serine 8 (pS8). All three peptides bind to copper with a similar rate as the wild‐type (wt). The dissociation rates follow the order pS8>H6R>wt>D7N; the interconversion between the two coordinating species occurs 50 % faster for H6R and pS8, whereas D7N had only a negligible effect. Interestingly, the rate of ternary complex (copper‐bridged heterodimer) formation for the modified peptides was significantly faster than that for wt, thus leading us to propose that FAD and sporadic AD might share a kinetic origin for the enhanced oligomerisation of Aβ.     

Selective and Reversible 1,3-Dipolar Cycloaddition of 2-(2-Oxoindoline-3-ylidene)acetates with Nitrones in the Synthesis of Functionalized Spiroisoxazolidines

The 1,3-dipolar cycloaddition of 2-(2-oxoindoline-3-ylidene)acetates with functionalized aldo- and ketonitrones proceeds with good selectivity to provide new highly functionalized 5-spiroisoxazolidines. A characteristic feature of these reactions is reversibility that allows for the control of the diastereoselectivity of cycloaddition. The reduction of obtained adducts using zinc powder in acetic acid leads to 1,3-aminoalcohols or spirolactones. For a number of the spiro compounds obtained, anticancer activity was found.     

Molecular basis for the enhanced lipase-catalyzed N-acylation of 1-phenylethanamine with methoxyacetate

One of the commercial methods for preparing enantiopure amines is lipase-catalyzed kinetic resolution, although lipases catalyze aminolysis with only low activity. Interestingly, in 1997 Balkenhohl et al. used ethyl methoxyacetate instead of ethyl butyrate as an acylation reagent for the aminolysis of 1-phenylethanamine and increased the reaction rate more than a 100-fold. This method has been applied to other aminolysis reactions, but the molecular basis for the enhanced rate is not understood. A molecular-modeling study of the transition-state analogue for the aminolysis showed that an interaction between the beta-oxygen atom in methoxyacetate and the amine nitrogen atom might be a key factor in the rate enhancement. Other acylation reagents, such as methyl 3-methoxypropionate and methyl 4-methoxybutyrate, were chosen to test the influence of this interaction because these molecules can be spatially arranged to have similar interactions. The results were similar to that in the acylation with methoxyacetate. The initial aminolysis rates were improved (11-fold and sixfold, respectively) compared to that with butyrate. In contrast, alcoholysis with 1-phenylethanol afforded the same rate with all acyl donors.     

Copper-alginates: a biopolymer supported Cu(II) catalyst for 1,3-dipolar cycloaddition of alkynes with azides and oxidative coupling of 2-naphthols and phenols in water

Copper(II) ions immobilized onto a biopolymer (sodium alginate) is an effective heterogeneous catalyst for 1,3-dipolar cycloaddition of alkynes with azides and oxidative coupling of 2-naphthols and phenols in water to afford the 1,4-disubstituted 1,2,3-triazoles and biaryl compounds respectively in good yields. The catalyst was recovered quantitatively by simple filtration and reused for several times without significant loss of activity.     

Catalytic Asymmetric 1, 3‐Dipolar Cycloaddition Reaction of Nitrones with α′‐Phosphoric Enones by a Chiral Ligand‐ Copper(II) Triflate Complex

Using the C₂‐symmetric bis‐oxazoline copper(II) catalyst 6f as a chiral Lewis acid, α′‐phosphoric enones 2 undergo 1,3‐dipolar cycloaddition with nitrones 3 to provide isoxazolidines 4 with very high enantioselectivity and endo/exo selectivity.