Carbonylative Sonogashira annulation sequence: One-pot synthesis of 4-quinolone and 4H-chromen-4-one derivatives

Carbonylative Sonogashira annulation sequence for one pot synthesis of 4-quinolone and 4H-chromen-4-one has been developed in presence of Pd-NHC catalyst. Substituted 2-iodoaniline and 2-iodophenol independently underwent in the carbonylative Sonogashira annulation reaction with a variety of acetylenes to result in 4-quinolone and flavone derivatives respectively in good to excellent yield. Moreover, this protocol does not require toxic CO gas, high catalyst loading and any expensive salt/additive. Herein we, for the first time, are using Mo(CO)₆, as solid CO source for the one pot synthesis of flavone derivatives via carbonylative Sonogashira annulation reaction.     

One-pot approach to access 2H-pyran-2-ones bearing an amino group via the Pd-catalyzed Sonogashira coupling of (Z)-3-iodovinylic esters followed by intramolecular iodocyclization

A one‐pot sequence of Sonogashira coupling and iodocyclization afforded novel amino-containing trisubstituted 2H-pyran-2-ones in good yields. This transformation proceeds via 1) synthesis of an ynenoic ester intermediate by a Sonogashira coupling reaction with an N-substituted (Z)-3-iodovinylic ester; 2) intramolecular iodocyclization of the latter intermediate under mildly basic conditions. The flexibility of this strategy enables the efficient syntheses of a variety of substituted 2H-pyran-2-ones.     

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.     

Copper-free Sonogashira cross-coupling reaction catalyzed by polymer-supported N-heterocyclic carbene palladium complex

A core-shell type of polymer-supported N-heterocyclic carbene (NHC) palladium catalyst was applied to Sonogashira cross-coupling reactions without copper cocatalyst under ambient atmosphere. This supported NHC-palladium complex efficiently catalyzed the copper-free Sonogashira reaction of various aryl iodides and bromides with terminal alkynes; the reaction exhibited high dependency on the temperature and the amount of base as well as its nature. In addition, this heterogeneous catalyst exhibited good reusability for the copper-free Sonogashira reaction.     

Efficient access to materials-oriented aromatic alkynes via the mechanochemical Sonogashira coupling of solid aryl halides with large polycyclic conjugated systems

Sonogashira coupling represents an indispensable tool for the preparation of organic materials that contain C(sp)–C(sp²) bonds. Improving the efficiency and generality of this methodology has long been an important research subject in materials science. Here, we show that a high-temperature ball-milling technique enables the highly efficient palladium-catalyzed Sonogashira coupling of solid aryl halides that bear large polyaromatic structures including sparingly soluble substrates and unactivated aryl chlorides. In fact, this new protocol provides various materials-oriented polyaromatic alkynes in excellent yield within short reaction times in the absence of bulk reaction solvents. Notably, we synthesized a new luminescent material via the mechanochemical Sonogashira coupling of poorly soluble Vat Red 1 in a much higher yield compared to those obtained using solution-based conditions. The utility of this method was further demonstrated by the rapid synthesis of a fluorescent metal–organic framework (MOF) precursor via two sequential mechanochemical Sonogashira cross-coupling reactions. The present study illustrates the great potential of Sonogashira coupling using ball milling for the preparation of materials-oriented alkynes and for the discovery of novel functional materials.

Using a high-temperature ball-milling technique, a practical mechanochemical protocol for the Sonogashira cross-coupling of polyaromatic halides was achieved, which provides efficient access to materials-oriented aromatic alkynes.     

Cyclization and rearrangement products from coupling reactions between terminal o-alkynylphenols or o-ethynyl(hydroxymethyl)benzene and 6-halopurines

Cyclization reactions on 6-[(2-hydroxyphenyl)ethynyl]purines, 6-[(2-hydroxymethylphenyl)ethynyl]purines and 6-[(2-hydroxyphenyl)propyn-1-yl]purines have been studied. 6-(2-Benzofuryl)purines are readily available via a one-pot Sonogashira coupling-cyclization between 6-iodopurine and 2-ethynylphenol. When the same reaction was performed with o-(hydroxymethyl)ethynylbenzene, 6-[isobenzofuran-1(3H)-ylidenemethyl]purine was formed, mainly as the (E)-isomer. Acid catalyzed isomerization of the (E)-compound afforded the (Z)-isomer. The latter compound was also formed from a two-step reaction; Sonogashira coupling with O-silylated alkyne followed by deprotection and subsequent 5-exo cyclization. Sonogashira coupling between 6-halopurines and 2-propynylphenol gave only the alkyne coupling product and no cyclization took place. However, the Sonogashira product was unexpectedly rearranged to 6-(3-phenoxypropa-1,2-dienyl)purines under basic conditions. Theoretical calculations demonstrated that the allenes are more stable than their alkyne isomers.     

Synthesis of novel 8-(het)aryl-6H-pyrano[4′,3′:4,5]thieno[3,2-b]pyridines by 6-endo-dig cyclization of Sonogashira products and halolactonizations with Cu salts/NXS. Preliminary antitumor evaluation

Novel 8-(het)aryl-6H-pyrano[4′,3′:4,5]thieno[3,2-b]pyridines were prepared in good to high yields by a tandem one-pot procedure of Sonogashira coupling and 6-endo-dig lactonization from 3-bromothieno[3,2-b]pyridine-2-carboxylic acid and (het)arylalkynes. Sonogashira coupling products were also prepared from the corresponding methyl ester giving in the same reaction the corresponding 6-endo-dig compounds as minor products. The Sonogashira phenyl ester product gave cyclization with electrophiles only in low to moderate yields. Nevertheless, halolactonizations using Cu(I) or (II) salts/N-halosuccinimides (NXS) from either the phenyl ester or the carboxylic acid derivatives occurred in good to high yields. The growth inhibition potential of the compounds was evaluated using human tumor cell lines, HCT-15 (colorectal adenocarcinoma) and NCI-H460 (non-small cell lung cancer) and studies of apoptosis induction were performed for the three most promising compounds in HCT-15?cells. Two of them caused almost 40% of cell death by apoptosis when tested at their 1.5?×?GI₅₀ concentrations. The tricyclic lactone with a F atom in the meta position showed to be the most promising one.     

Recent advances in Sonogashira reactions

The coupling of aryl or vinyl halides with terminal acetylenes catalysed by palladium and other transition metals, commonly termed as Sonogashira cross-coupling reaction, is one of the most important and widely used sp(2)-sp carbon-carbon bond formation reactions in organic synthesis, frequently employed in the synthesis of natural products, biologically active molecules, heterocycles, molecular electronics, dendrimers and conjugated polymers or nanostructures. This critical review focuses on developments in the Sonogashira reaction achieved in recent years concerning catalysts, reaction conditions and substrates (352 references).     

Enantioselective Dearomative Difunctionalization of Indoles by Palladium-Catalyzed Heck/Sonogashira Sequence

Palladium-catalyzed enantioselective dearomative arylalkynylation of N-substituted indoles, through a Heck/Sonogashira sequence, was established using a new BINOL-based phosphoramidite as the chiral ligand. A wide range of 2,3-disubstituted indolines, bearing vicinal quaternary and tertiary stereocenters, were efficiently constructed in one step with excellent enantioselectivities (up to 97 % ee) and diastereoselectivities (>20:1).     

A guide to Sonogashira cross-coupling reactions: the influence of substituents in aryl bromides, acetylenes, and phosphines

The conversion-time data for 168 different Pd/Cu-catalyzed Sonogashira cross-coupling reactions of five arylacetylenes (phenylacetylene; 1-ethynyl-2-ethylbenzene; 1-ethynyl-2,4,6-R(3)-benzene (R = Me, Et, i-Pr)) and Me(3)SiCCH with seven aryl bromides (three 2-R-bromobenzenes (R = Me, Et, i-Pr); 2,6-Me(2)-bromobenzene and three 2,4,6-R(3)-bromobenzenes (R = Me, Et, i-Pr)) with four different phosphines (P-t-Bu(3), t-Bu(2)PCy, t-BuPCy(2), PCy(3)) were determined using quantitative gas chromatography. The stereoelectronic properties of the substituents in the aryl bromides, acetylenes, and phosphines were correlated with the performance in Sonogashira reactions. It was found that the nature of the most active Pd/PR(3) complex for a Sonogashira transformation is primarily determined by the steric bulk of the acetylene; ideal catalysts are: Pd/P-t-Bu(3) or Pd/t-Bu(2)PCy for sterically undemanding phenylacetylene, Pd/t-BuPCy(2) for 2- and 2,6-substituted arylacetylenes or Me(3)SiCCH and Pd/PCy(3) for extremely bulky acetylenes and aryl bromides. Electron-rich and sterically demanding aryl bromides with substituents in the 2- or the 2,6-position require larger amounts of catalyst than 4-substituted aryl bromides. The synthesis of tolanes with bulky groups at one of the two aryl rings is best done by placing the steric bulk at the arylacetylene, which is also the best place for electron-withdrawing substituents.     

Chemical Labeling of 5-Iodo-2′-deoxyuridine with 4-Ethynyl-N-ethyl-1,8-naphthalimide Using Copper-Free Sonogashira Cross-Coupling in Aqueous Medium

The utility of Sonogashira cross-coupling reactions in organic synthesis is indisputable. However, the palladium catalytic Sonogashira reaction in mild condition is still in its infancy. Here, we reported the synthesis of a fluorescent nucleoside analog by using a copper-free Sonogashira cross-coupling reaction in a satisfactory yield. This reaction occurred at 37 °C in the open air and aqueous medium, and avoided the toxicity of Cu(I). The mild Sonogashira reaction provided the possibility of fluorescent labeling of nucleoside mimics in living cells.

[Supplementary materials are available for this article. Go to the publisher's online edition of Synthetic Communications® for the following free supplemental resource(s): Full experimental and spectral details.]     

两种新型丁二炔衍生物的合成

以3,5-二溴-1-｛3-（十二烷氧基）-2-［（十二烷氧基）甲基］丙氧基｝苯和2-甲基-3-丁炔-2-醇为原料,经选择性Sonogashira偶联反应,Sonogashira偶联反应和去硅保护基反应制得中间体--3-乙炔基-5-（3-甲基-3-羟基)-丁炔基-1-（3-十二烷氧基）-2-｛［（十二烷氧基）甲基］丙氧基｝苯（6）; 6经改良的Glaser偶联反应(CuI为催化剂,Et₃N为溶剂)合成了一个新型的丁二炔衍生物（1）。 6与2,2′-［（2,5-二碘-1,4-亚苯基）双（氧基）］双（四氢-2H-吡喃）经Sonogashira偶联,脱 THP保护基和改良的Glaser偶联反应合成了一个新型的丁二炔衍生物（2）。中间体,1和2的结构经¹H NMR, ¹³C NMR和MALDI-TOF-MS表征。     

原位生成的水溶性Salen-Pd配合物催化微波促进水中的C-C偶联反应

将一种水溶性Salen,N,N’-双[（5-磺酸基-2-羟基）苄基]缩N,N’-二甲基-1,2-乙二胺（L）与醋酸钯原位生成水溶性Salen-Pd配合物,该水溶性钯配合物应用于催化微波加热的水中的Heck和Sonogashira碳-碳偶联反应.在优化反应条件之后,对溴苯衍生物与乙烯衍生物的Heck偶联反应以及溴苯衍生物与苯乙炔及其衍生物之间的Sonogashira偶联反应进行了考察.发现,在优化的反应条件下,无论是Heck反应,还是Sonogashira偶联反应,都能得到很好的收率.在有机物分离之后,水相继续循环使用4次,在水相的前3次循环使用时,都获得了不错的收率.     

Aryl alkynylation versus alkyne homocoupling: unprecedented selectivity switch in Cu, phosphine and solvent-free heterogeneous Pd-catalysed couplings

Sonogashira reaction and oxidative dimerisation of terminal alkynes are among the most relevant and attractive C-C bond forming transformations in the metallo-catalysed cross-coupling scenario. Often, the homocoupling reactions of substituted acetylenic derivatives are concomitant to the Sonogashira pathway and time-consuming optimization procedures are required in order to reach satisfactory levels of selectivity. In this paper, the potential of a class of Pd-complexes loaded to mesoporous silica gel in promoting the Sonogashira reaction between aryl acetylenes and iodoarenes is underlined. This family of heterogeneous organo-palladium systems allows the desired cross-coupled compounds to be isolated in excellent yield under very mild conditions. In fact, the absence of organic solvents, copper(I) co-catalyst and phosphane ligands, (which are easily oxidisable and whose preparation has a heavy environmental impact), in conjunction with the low catalyst loading ([Pd] 0.1-1 mol%) and its recoverability, stresses the environmental benefits of the protocol. The Sonogashira/homocoupling selectivity proved to be function of the haloarene employed. As a matter of fact, while iodoarenes bearing EWG (electron withdrawing groups) on the phenyl ring underwent smoothly the Sonogashira pathway, electron-rich iodobenzenes showed opposite behaviour by mainly furnishing the homocoupling product. The use of bromoarenes provided solely the homocoupling product in excellent yield without themselves being consumed. This is despite that fact that the catalysts used activate bromoarenes equally as well as iodoarenes in both Heck and Suzuki systems. Kinetic investigations revealed a highly temperature-dependent profile, which indicates strongly that the reaction takes place at the surface. Finally, the full heterogeneous character of the catalytically active species as well as the reusability of the immobilised Pd-complex were confirmed by hot-filtration test and by multiple reuses of the supported catalyst in subsequent Sonogashira cross-couplings.     

Enantioselective Dearomative Difunctionalization of Indoles by Palladium‐Catalyzed Heck/Sonogashira Sequence

Palladium‐catalyzed enantioselective dearomative arylalkynylation of N‐substituted indoles, through a Heck/Sonogashira sequence, was established using a new BINOL‐based phosphoramidite as the chiral ligand. A wide range of 2,3‐disubstituted indolines, bearing vicinal quaternary and tertiary stereocenters, were efficiently constructed in one step with excellent enantioselectivities (up to 97 % ee) and diastereoselectivities (>20:1).     

Synthesis of Potentially Biologically Active 6‐(1,3‐Butadiynyl)purines

1,3‐Alkadiynyl(trimethyl)silanes were prepared by the Negishi or Sonogashira reactions of bromoethynyl(trimethyl)silane with several terminal alkynes in 34–75% yield. However, the direct Hiyama coupling of these compounds with 6‐iodopurine derivatives has not been successful. Therefore, a modified Sonogashira reaction using TBAF or CsF for in situ removal of the trimethylsilyl group has been utilized. This methodology afforded the desired 6‐(1,3‐butadiynyl)purines in 47–87% yield.     

Palladium nanoparticles embedded in improved mesoporous silica: a pH‐triggered phase transfer catalyst for Sonogashira reaction

An efficient and reusable pH‐responsive mesoporous silica nanocomposite shuttle‐supported palladium catalyst was synthesized, which efficiently promotes the Sonogashira reaction in water‐based biphasic systems. This catalyst of shell‐embedded palladium nanoparticles is highly dispersed in organic phase in a pH range from 9 to 10 just like a homogeneous catalyst, and can be separated and reused like a heterogeneous one by adjusting the pH value of the aqueous medium. In addition, Sonogashira reactions can be performed without a copper co‐catalyst. Copyright © 2015 John Wiley & Sons, Ltd.     

Di(2-pyridyl)methylamine-palladium dichloride complex covalently anchored to a styrene-maleic anhydride co-polymer as recoverable catalyst for C-C cross-coupling reactions in water

A new polymer-supported di(2-pyridyl)methylamine-palladium dichloride complex covalently anchored to a styrene-alt-maleic anhydride co-polymer is prepared. This complex catalyzes Heck, Suzuki and Sonogashira cross-coupling reactions in neat water with similar efficiency than the monomeric complex. The turnover number (TON) of this polymer reaches up to 10⁴ for Heck reactions, whereas for Suzuki and Sonogashira couplings TONs up to 10⁵ are achieved. There is low leaching of palladium after filtration of the polymer and the activity remains almost constant after fourth and five reaction cycles especially in Sonogashira reactions. In the case of the Suzuki reaction Pd nanoparticles are dispersed into the polymer after the first cycle according to TEM images and 2.4% of Pd are found by ICP-OES in the corresponding filtrate. Alternatively, these palladium-catalyzed reactions can also be performed under microwave heating. These couplings take place with better efficiency with polymer-supported di(2-pyridyl)methylamine-palladium dichloride complex than with the polyurea-encapsulated Pd EnCat™ 40.     

Sonogashira反应研究的最新进展

对Sonogashira反应的最新研究进展作了综述. 详细地介绍了Sonogashira 反应的最新优化、联串化、绿色化以及非Pd催化的Sonogashira反应等, 同时还综述了Sonogashira反应的机理研究.     

Synthesis of new ethynylbipyridine-linked mono- and bis-tetrathiafulvalenes: electrochemical, spectroscopic, and Ru(II)-binding studies

Two new ethynylbipyridine-linked mono- and bis-tetrathiafulvalene (TTF) derivatives, together with a Ru(II) complex, were synthesized using Sonogashira coupling reactions and characterized by UV/vis spectroscopy and cyclic voltammetry. They display a clear electrochemically amphoteric behavior consisting of two reversible single-electron oxidation waves (typical for TTF derivatives) and one reversible single-electron reduction wave (bpy) and act as donor-acceptor (D-A) systems. Furthermore, for the Ru(II) complex, a quite intense fluorescence originating from the ³MLCT state is observed.