Indium-mediated formation of propargyl ketones from aldehydes or acyl chlorides

Propargyl ketones were prepared from aldehydes via an indium-mediated alkynylation reaction followed by an indium-mediated Oppenauer oxidation. They were also obtained via an indium-mediated alkynylation of the relevant acyl chlorides.     

Ethynyl benziodoxolones for the direct alkynylation of heterocycles: structural requirement, improved procedure for pyrroles, and insights into the mechanism

This report describes a full study of the gold-catalyzed direct alkynylation of indoles, pyrroles, and thiophenes using alkynyl hypervalent iodine reagents, especially the study of the structural requirements of alkynyl benziodoxolones for an efficient acetylene transfer to heterocycles. An improved procedure for the alkynylation of pyrroles using pyridine as additive is also reported. Nineteen alkynyl benziodoxol(on)es were synthesized and evaluated in the direct alkynylation of indoles and/or thiophenes. Bulky silyl groups as acetylene substituents were optimal. Nevertheless, transfer of aromatic acetylenes to thiophene was achieved for the first time. An accelerating effect of a methyl substituent in both the 3- and 6-position of triisopropylsilylethynyl-1,2-benziodoxol-3(1H)-one (TIPS-EBX) on the reaction rate was observed. Competitive experiments between substrates of different nucleophilicity, deuterium labeling experiments, as well as the regioselectivity observed are all in agreement with electrophilic aromatic substitution. Gold(III) 2-pyridinecarboxylate dichloride was also an efficient catalyst for the reaction. Investigations indicated that gold(III) could be eventually reduced to gold(I) during the process. As a result of these investigations, a π activation or an oxidative mechanism are most probable for the alkynylation reaction.     

Autotandem Catalysis: Inexpensive and Green Access to Functionalized Ketones by Intermolecular Iron-Catalyzed Amidoalkynylation/Hydration Cascade Reaction via N-Acyliminium Ion Chemistry

Iron-based catalysts were applied in cascade-type reactions for the synthesis of different carbonyl compounds. The reactions proceeded by a new iron-catalyzed cascade of alkynylation/hydration by using both the σ- and π-Lewis acid properties of iron salts. The alkynylation reactions of several endo and exocyclic acetoxylactams were achieved with three different catalysts including FeCl₃ ⋅ 6H₂O, FeCl₃, and Fe(OTf)₃ showing the efficiency of σ-Lewis acidity of iron (III) salts in catalyzing the alkynylation reaction. We also demonstrated that the reaction sequence could be shortened by the direct use of hydroxylactams, leading to an environmentally friendly protocol, avoiding the need to perform unnecessary lengthy steps. A combination of the hard/soft iron Lewis acid properties was then used to implement an unprecedented tandem intermolecular alkynylation/intramolecular hydration sequence allowing expedient access to a new carbonyl structures from trivial materials.     

Palladium-catalyzed oxidative alkynylation of heterocycles with terminal alkynes under air conditions

Pd-Catalyzed oxidative alkynylation of azoles with terminal alkynes was developed via simultaneous activation of both heterocyclic sp(2) C-H and alkynyl sp C-H bonds. The choice of palladium catalyst source and external base resulted in being important factors for performing the reaction with high efficiency and selectivity, and air was successfully utilized as an environmental oxidant in the present alkynylation procedure.     

亚胺及其类似物的催化不对称炔基化反应新进展

手性炔丙胺是天然产物和药物活性分子不对称全合成中常用的关键中间体,亚胺及其类似物的不对称炔基化反应可以为该砌块提供高效高对映选择性的合成路径;此外通过合理的底物和反应设计,亚胺的不对称炔基化反应还能作为一系列串联反应的起点,来合成多种结构新颖的含氮杂环化合物.因此,亚胺及其类似物的高效高对映选择性炔基化反应得到合成化学家们持续关注.按照底物类型,主要分为醛亚胺的不对称炔基化和酮亚胺的不对称炔基化两大部分,介绍了亚胺及其类似物的不对称炔基化反应在过去十年中的研究进展.对这些反应的机理、优势与不足之处以及该反应在合成中的应用进行简要讨论,从而为拓展该反应在合成中的应用提供一些有益参考和借鉴.     

Palladium-catalyzed oxidative alkynylation of arene C–H bond using the chelation-assisted strategy

Palladium-catalyzed alkynylation of arene C–H bonds with (triisopropylsilyl)acetylene was developed for the first time under oxidative conditions in the present study. Among various type of directing groups examined, the N-phenyl-2-aminopyridine skeleton was shown to be most effective and selective for the Pd-catalyzed direct alkynylation reaction, and the desired alkynylated products were obtained in moderate to good yields.     

Palladium-Catalyzed Decarboxylative Alkynylation of α-Acyloxyketones by C(sp3)−O Bond Cleavage

Palladium-catalyzed decarboxylative alkynylation of α-acyloxyketones triggered by C(sp³)−O bond cleavage is disclosed. The decarboxylation strategy featuring a neutral reaction condition enabled an unprecedent catalytic alkynylation of a ketone enolate. The reaction was applied to a variety of substrates, giving desired products in good yields. We successfully obtained X-ray crystallography of a new palladium–enolate intermediate that was synthesized by a reaction of [Pd(cod)(CH₂TMS)₂] with XPhos and α-acyloxyketone at room temperature, indicating facile C(sp³)−O bond disconnection.     

Radical Monofluoroalkylative Alkynylation of Olefins by a Docking–Migration Strategy

A radical‐mediated monofluoroalkylative alkynylation of alkenes is disclosed for the first time. The reaction demonstrates a remarkably broad substrate scope in which both activated and unactivated alkenes are suitable starting materials. The concurrent addition of an alkynyl and a monofluoroalkyl group onto an alkene proceeds through a docking–migration sequence, affording a vast array of valuable fluoroalkyl‐substituted alkynes. Many complex natural products and drug derivatives are readily functionalized, demonstrating that this method can be used for late‐stage alkynylation.     

Meerwein-Ponndorf-Verley alkynylation of aldehydes: essential modification of aluminium alkoxides for rate acceleration and asymmetric synthesis

A novel carbonyl alkynylation has been accomplished based on utilization of the Meerwein-Ponndorf-Verley (MPV) reaction system. The success of the MPV alkynylation crucially depends on the discovery of the remarkable ligand acceleration effect of 2,2'-biphenol. For example, the alkynylation of chloral (2c) with the aluminium alkoxide 6(R = Ph), prepared in situ from Me(3)Al, 2,2'-biphenol and 2-methyl-4-phenyl-3-butyn-2-ol (1a) as an alkynyl source, proceeded smoothly in CH(2)Cl(2) at room temperature to give the desired propargyl alcohol 3ca in almost quantitative yield after 5 h stirring. The characteristic feature of this new transformation involving no metal alkynides can be visualized by the fact that the alkynyl group bearing keto carbonyl was transferred successfully to aldehyde carbonyl without any side reactions on keto carbonyl. Although the use of (S)-1,1[prime or minute]-bi-2-naphthol and its simple analogues was found to be unsuitable for inducing asymmetry in this reaction, design of new chiral biphenols bearing a certain flexibility of the biphenyl axis led to satisfactory results in terms of enantioselectivity as well as reactivity.     

Iridium-Catalyzed β-Alkynylation of Aliphatic Oximes as Masked Carbonyl Compounds and Alcohols

An Ir-catalyzed C(sp³)−H alkynylation of aliphatic ketones, aldehydes, and alcohols was achieved by using the corresponding oxime derivatives and a Ir^III catalyst. This general reaction is selective towards primary C(sp³)−H bonds and can be used for the late-stage C−H alkynylation of complex molecules.     

Enantioselective alkynylation of ketones with trimethoxysilylalkynes using lithium binaphtholate as a catalyst

Chiral lithium 3,3′-diphenylbinaphtholate successfully catalyzed the alkynylation of ketone with trimethoxysilylalkyne, affording chiral tertiary propargylic alcohols in high chemical yields and high enantioselectivities. The present reaction could be extended to the alkynylation of acetylpyridine, which afforded a biologically active pyridyl propargylic alcohol in good enantioselectivity.     

Ligand‐Enabled Alkynylation of C(sp3)−H Bonds with Palladium(II) Catalysts

The palladium(II)‐catalyzed β‐ and γ‐alkynylation of amide C(sp³)−H bonds is enabled by pyridine‐based ligands. This alkynylation reaction is compatible with substrates containing α‐tertiary or α‐quaternary carbon centers. The β‐methylene C(sp³)−H bonds of various carbocyclic rings were also successfully alkynylated.     

Systematic synthesis of Bis-THF ring cores in annonaceous acetogenins

Systematic synthesis of bis-THF ring cores, synthetic intermediates of adjacent bis-THF annonaceous acetogenins, has been achieved by asymmetric alkynylation and subsequent stereodivergent THF ring formation. The asymmetric alkynylation of alpha-tetrahydrofuranic aldehyde with (S)-3-butyne-1,2-diol derivatives gave good yields of erythro- and threo-adducts with very high diastereoselectivity. These adducts were converted into four types of bis-THF cores via two kinds of one-pot THF ring formation. [reaction: see text]     

Iridium‐Catalyzed β‐Alkynylation of Aliphatic Oximes as Masked Carbonyl Compounds and Alcohols

An Ir‐catalyzed C(sp³)?H alkynylation of aliphatic ketones, aldehydes, and alcohols was achieved by using the corresponding oxime derivatives and a Ir^III catalyst. This general reaction is selective towards primary C(sp³)?H bonds and can be used for the late‐stage C?H alkynylation of complex molecules.     

The first Cu- and amine-free Sonogashira-type cross-coupling in the C-6-alkynylation of protected 2′-deoxyadenosine

The Sonogashira cross-coupling reaction offers a convenient route to C(sp)-C(sp²) bond formation. Although the Sonogashira reaction has traditionally been carried out in the presence of Pd catalyst and a co-catalyst of Cu(I) salt, the use of Cu(I) salt is often not efficient because it leads to the formation of unwanted side-products. This has prompted interest in recent years in the development of Cu-free Sonogashira cross-coupling reaction conditions. In addition, the development of Cu-free Sonogashira cross-coupling conditions for the alkynylation of nucleoside derivatives remains largely unexplored. Herein, we demonstrate that Cu- and amine-free Sonogashira-type cross-coupling lead to successful alkynylation of aryl bromides and heteroaryl bromides. For the first time, we have extended this method for the alkynylation of protected 2′-deoxyadenosine at the C-6 position.     

Efficient ruthenium and copper cocatalzyed five-component coupling to form dipropargyl amines under mild conditions in water

Dipropargyl amines are synthesized by a double direct alkynylation of primary followed by secondary imines formed in situ during an efficient, five-component, one-pot coupling reaction cocatalyzed by ruthenium and copper in water.     

Visible Light-Enabled sp3-C−H Functionalization with Chloro- and Bromoalkynes: Chemoselective Route to Vinylchlorides or Alkynes

An unprecedented direct atom-economic chemo- and regioselective hydroalkylation of chloroalkynes and an sp³-C−H alkynylation of bromoalkynes was achieved. The reaction partners are unfunctionalized ethers, alcohols, amides, and even non-activated hydrocarbons. We found that a household fluorescent bulb was able to excite a diaryl ketone, which then selectively abstracts a H-atom from an sp³-C−H bond. The product of a formal alkyne insertion into the sp³-C−H bond was obtained with chloroalkynes, providing valuable vinyl chlorides. The photo-organocatalytic hydrogen atom transfer strategy gives rise to a broad range of diversely functionalized olefins. When bromoalkynes are applied in the presence of a base, a chemoselectivity switch to an alkynylation is observed. This reaction can even be performed for the alkynylation of unactivated sp³-C−H bonds, in this case with a preference of the more substituted carbon. Accompanying quantum chemical calculations indicate a vinyl radical intermediate with pronounced linear coordination of the carbon radical center, thus enabling the formation of both diastereoisomers after H-atom abstraction, suggesting that the (Z)-diastereoisomer is preferred, which supports the experimentally observed (E/Z)-distribution.     

Copper-catalyzed decarboxylative coupling of aryl halides with alkynyl carboxylic acids performed in water

Most alkynes are volatile liquids, which are relatively difficult to use and to transport. In contrast, alkynyl carboxylic acids offer a stable and attractive alternative for the alkynylation reactions. Here, we employed alkynyl carboxylic acids as reaction partners for the alkynylation of aryl halides. Copper-catalyzed decarboxylative coupling, including various challenging aryl bromides with phenylpropiolic acid, was performed in water without using co-solvents with good yields. Our approach provides a low-loading, low-cost, stable and environmentally friendly copper catalyst system for decarboxylative coupling.     

Synthesis of C3-symmetric tris(beta-hydroxy amide) ligands and their Ti(IV) complex-catalyzed enantioselective alkynylation of aldehydes

[reaction: see text]. A series of new chiral C3-symmetric tris(beta-hydroxy amide) ligands have been synthesized via the reaction of 1,3,5-benzenetricarboxylic chloride and optically pure amino alcohols (up to 96% yield). The asymmetric catalytic alkynylation of aldehydes with these new C3-symmetric chiral tris(beta-hydroxy amide) ligands and Ti (O(i)'Pr)4 was investigated. Ligand 4c synthesized from (1R,2S)-(-)-2-amino-1,2-diphenylethanol is effective for the enantioselective alkynylation of various aldehydes, and high enantioselectivity was obtained with aromatic aldehydes and alpha,beta-unsaturated aldehyde (up to 92% ee).