Coupling Sonogashira

The Sonogashira reaction allows for the direct cross-coupling of terminal alkynes with aryl halides under mild conditions through use of catalytic bis(triphenylphosphine)-palladium dichloride and Cul as the co-catalyst in the presence of an aliphatic amine. The formation of diphenylacetylene exemplifies the original Sonogashira reaction conditions  

The greatest application of the Sonogashira coupling is of course the Larock indole synthesis, which is reviewed in Section 3.3 in this chapter. A Sonogashira coupling was carried out between protected phenyliodide and alkyne. With JV-methanesulfonyl protection, the coupling product spontaneously cyclized to the indole, which was converted into an indole-based insulin mimic. 

The Sonogashira coupling was applied to the synthesis of an indole-containing KDR kinase inhibitor by tandem Sonogashira coupling/5-ew /o-i%-cyclization as a key step.  

Reproduced from Futner DA, Shearouse WC. Merdonza ST, Mack J. Solvent-free Sonrogashira coupling reaction via high speed ball milling. Green Chem 2009 11 1821-5. With permission from the Royal Society of Chemistry. 

70 CHAPTER 2 Carbon-Carbon Bond-Forming Reactions 

Entry X R Copper-Free Yield (%) Cu BalF Yield (%) Cu Ball+Cu Vial Yield (%) 

Entry Aryl Iodide Acetylene Conversion (%) Selectivily to Product (%) 

The Inamoto group [44] has reported that the NHC-based pincer complex 30 is an effective catalyst for the cross-coupHng of aryl haUdes and butyl acrylate (Eq. (5.33)). This catalytic system is appHcable to aryl iodides, aryl bromides, and activated aryl chlorides, and compatible with functional groups including nitrile, ketone, and aldehyde. Notably, the reaction of 4-bromobenzonitrile can be retarded by a drop of mercury, suggesting that the catalytic system may be heterogeneous. 

Mitsudo, Tanaka, and coworkers [79] have reported an air-stable cationic bis(oxazohne)-based nickel pincer complex 51 as a catalyst for the coupling of phenyl iodide and butyl acrylate (Eq. (5.34)). Stopping the reaction after 24 h gives the cross-coupling product in 25% yield, which is less than half of the yield for a 48 h reaction. This indicates an induction period during the catalytic reaction, possibly due to the conversion of 51 to a true catalytic species. 

Ghosh and co-workers synthesised a number of modified versions of the PEPPSI pre-catalysts, employing pyridine rather than 3-chloropyridine and 

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Because the Sonogashira coupling process outlined in Scheme 18 is initiated by the in situ reduction of palladium(n) to palladium(o), it would be expected that palladium(o) catalysts could be utilized directly. Indeed, a catalytic amount of tetrakis(triphenylphosphine)-... 

Scheme 19. The Sonogashira coupling in Nicolaou s synthesis of (12S)-HETE (78).

Scheme 20. Sonogashira couplings in Magnus s calicheamicin/esperamicin model study.

Scheme 21. The Sonogashira coupling reaction in Nicolaou s dynemicin A model study.

Scheme 22. Schreiber s approach to dynemicin A system 86 by a tandem Sonogashira coupling/Diels-Alder reaction.

Carbon-carbon bond formation reactions and the CH activation of methane are another example where NHC complexes have been used successfully in catalytic applications. Palladium-catalysed reactions include Heck-type reactions, especially the Mizoroki-Heck reaction itself [171-175], and various cross-coupling reactions [176-182]. They have also been found useful for related reactions like the Sonogashira coupling [183-185] or the Buchwald-Hartwig amination [186-189]. The reactions are similar concerning the first step of the catalytic cycle, the oxidative addition of aryl halides to palladium(O) species. This is facilitated by electron-donating substituents and therefore the development of highly active catalysts has focussed on NHC complexes. 

We synthesized uniform CU2O coated Cu nanoparticles from the thermal decomposition of copper acetylacetonate, followed by air oxidation. We successfully used these nanoparticles for the catalysts for Ullmann type amination coupling reactions of aryl chlorides. We synthesized core/shell-like Ni/Pd bimetallic nanoparticles from the consecutive thermal decomposition of metal-surfactant complexes. The nanoparticle catalyst was atom-economically applied for various Sonogashira coupling reactions. 

Synthesis of Ni/Pd bimetallic core/shell nanoparticles and their applications to Sonogashira coupling reactions... 

Ni/Pd nanoparticles and similar sized Pd nanoparticles for the following Sonogashira coupling reactions using equal amount of palladium in the reaction mixtures. As expected, the Ni/Pd... 

A copper-free Sonogashira coupling reaction in ionic liquids and its application to a microflow system for efficient catalyst recycling, Org. Lett. 4, 10 (2002) 1691-1694. 

Beneficial Micro Reactor Properties for Sonogashira Couplings... 

Sonogashira Couplings Investigated in Micro Reactors Organic synthesis 46 [OS 46) Copper-free Son<%ashira reaction... 

Table 4.7 Sonogashira coupling of aryl halides with terminal acetylenes in the presence of PdCbiPPhj) catalyst [120].

Scheme 6.40 Sonogashira coupling with iV-carbamoyl-substituted NHC-Pd (11) complexes...

Scheme 6.42 Sonogashira coupling with alkyl bromides...

More recently, a study with di- and mono-carbene Pd(II) complexes has demonstrated that the Sonogashira coupling of activated and non-activated aryl iodides can be carried out in an aqueous, aerobic medium and in the absence of amines. These results suggest that the moisture-sensitive copper-acetylide may not be present in this particular transformation, and that a Pd-acetyhde could be formed by deprotonation of the coordinated alkyne instead of transmetallation [130]. 

Concerning other metals, Sonogashira coupling products have also been observed in the reaction of Ag(l)-carbenes [133] and Au(I)-supported carbenes [134] in low to moderate yields, but only under harsh conditions (more than 100°C). In this regard, NHC based catalysts for Sonogashira reactions have been supported on different materials that include clays [135], polymers [136] and peptides [137]. 

The coupling of terminal alkynes with organic halides, known as the Castro-Stephens-Sonogashira reaction, has wide applications in synthesis. The most widely used method is the Sonogashira coupling, using a combination of palladium and copper as the catalyst.13 Recently,... 

Besides palladium catalysts, nickel was also found to be an effective catalyst for the Sonogashira reaction in aqueous media. Recently, Beletskaya et al. reported a Ni(PPh3)2Cl2/CuI-catalyzed Sonogashira coupling reaction of terminal acetylenes with aryl iodides in aqueous dioxane in high yields (Eq. 4.19).39... 

There are many other transition-metal catalyzed coupling reactions that are based on organic halides in aqueous media. One example is the coupling of terminal alkyne with aryl halides, the Sonogashira coupling, which has been discussed in detail in the chapter on alkynes (Chapter 4). An example is the condensation of 2-propynyl or allyl halides with simple acetylenes in the presence of copper salts. 

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