Pd/Cu-catalyzed cross-coupling

Pd/Cu-catalyzed cross-coupling of organohalides with terminal alkynes. Cf. Cadiot-Chodkiewicz coupling and Castro-Stephens reaction. The Castro-Stephens coupling uses stoichiometric copper, whereas the Sonogashira variant uses catalytic palladium and copper. 

Scheme 2. Mechanism of the Sonogashira reaction for Pd/ Cu-catalyzed cross-coupling of sp2-C halides with terminal acetylenes.

K. Sonogashira, Development of Pd—Cu Catalyzed Cross-Coupling of Terminal Acetylenes with sp2-Carbon Halides, J. Organomet. Chem. 653, 46 49 (2002). 

Sonogashira K (2002) Development of Pd-Cu catalyzed cross-coupling of terminal acetylenes with sp -carbon halides. J Organomet Chem 653(l-2) 46 9... 

As shown in the following scheme, a SEM-ether derived phenyl acetylene was treated with PtClj in the presence of CO to give a benzo[4>]furan, which was first subjected to desilylation, followed by Pd-catalyzed intramolecular etherification, affording the tetracyclic skeleton of pterocarpane family of phytoalexins <05JA15024>. A similar type of synthetic transformation was so applied to make a key intermediate in the total synthesis of vibsanol <05JA15022>. 2,3-Disubstituted benzo[h]furans were prepared under very mild reaction conditions by the Pd/Cu-catalyzed cross-coupling of various o-iodoanisoles and terminal... 

Copper Reactants. Application of the Pd/Cu-catalyzed cross-coupling, the Sonogashira reaction, with monosubstituted or protected acetylene gives rise to a variety of ethynyl-heteroarenes (Schenae 27). Reactions with trimethylsilylacetylene or phenylacetylene in... 

The most commonly used form of the Pd/Cu-catalyzed cross-coupling reaction is that in which an aromatic iodide is coupled with a terminal alkyne. The reaction takes place readily at room temperature and is often complete in a few hours. The reaction of iodides is very reliable and proceeds readily without vigorous purification of substrates and without use of dry or freshly distilled solvents. The presence of a Cu species is essential for the coupling to proceed at room temperature. Cul is most often used but CuBr has been used successfully. Generally, commercial grade Cul is perfectly adequate in this procedure. The... 

Selective and stepwise couplings of polyiodobenzene with tenninal acetylenes are also reported. In the course of the synthesis of rigid, benzene-centered, star-like porphyrin arrays, triply coupled derivative 75 has been prepared by Pd/Cu-catalyzed cross-coupling reactions with different terminal acetylenes under normal conditions from 1,3,5-triiodobenzene 74 in a stepwise manner (Scheme 29). ... 

On the other hand, even the recently prepared Herrmann-Beller catalystf still requires higher temperatures for efficient coupling rates of the Heck reaction. Interestingly, the complexation of chloroarenes with the Cr(CO)3 fragment activates the arene-chlorine bond considerably toward the oxidative addition. Thus, Cr(CO)3 complexed chloroarenes react about 15 times faster than iodoarenes in Pd-catalyzed cross-couphng reactions under mild conditions, in particular in Pd/Cu-catalyzed cross-couplings with terminal acetylenes in refluxing THF and/or tertiary amines (Scheme 36). ... 

Pd/Cu-catalyzed cross-coupling reactions of sp -C halides with terminal acetylenes have been shown to be highly useful and established reactions for the synthesis of eneyne compounds. 

Recent developments of Pd/Cu-catalyzed cross-coupling such as low-temperature coupling, use of long-lived paUadacycle catalysts, and coupling reactions in aqueous media were described. Although there have been tremendous developments in Pd-catalyzed systems for Heck-type reactions in the last decade, successful approaches toward the cross-coupUng reaction with terminal acetylenes are rare. 

Several examples of the application of Pd/Cu-catalyzed cross-coupling for synthesis of alkynyl ketones, terminal acetylenes, enediyne macrocycles, and enediyne polymers are given. 

The PPEs [14, 35, 36], which are dehydrogenated analogs of the poly(p-phenylene vinylene) s, display desirable optoelectronic properties that have found extensive use as emissive materials [37, 38]. PPE preparation is dominated by the Sonogashira Pd/Cu-catalyzed cross-coupling of aryl haUdes and terminal alkynes [39]. However, polymerizations under these conditions rarely achieve a high molecular weight, and defects such as diyne formation and alkyne crosshnking in the polymer backbone are endemic [14, 40]. Alkyne metathesis was envisioned as a complementary method to PPE synthesis, with much success. 

B.iii. Pd/Cu-Catalyzed Cross-Coupling Reactions of Organic Halides or Triflates with Terminal Acetylenes... 

Pd/Cu-catalyzed cross-coupling of organohalides with terminal alkynes. Cf. Castro-Stephens reaction. 

We outlined the rapid syntheses of oligo(2-alkyl-l,4-phenylene-ethynylene)s via an iterative divergent/convergent approach that needed only three sets of reaction conditions for the entire iterative synthetic sequence an iodination, a protodesilylation, and a Pd/Cu-catalyzed cross coupling. The syntheses were conducted in solution and on a polymer support. At each stage in the iteration, the length of the framework doubled. Equations were derived... 

Compounds 118 and 120 were synthesized by Pd/Cu-catalyzed cross couplings reactions (Scheme 3.46). Surprisingly, each of these compounds was... 

Likewise, compounds 122 and 124 were synthesized (Scheme 3.47). Again, these compounds were produced in a straightforward fashion by Pd/Cu-catalyzed cross couplings. 

The preparation of resin-bound alkyne 29 followed a parallel synthesis. The subsequent split-and-pool synthesis of individual oligomers was performed in micro-reactors, specifically MacroKans, " with unique identification system. Resin-bound monomer 29 sealed in MacroKans were subjected to a Pd/Cu-catalyzed cross-coupling with monomers 30a-e in EtjN. This catalyst (Pd(dba)j/PPh/CuI) solution was pre-mixed with stirring at 70 °C for 2 h prior to use. The suspended MacroKans were heated in a screw cap tube at 65 °C for 44-48 h. At the completion of the coupling reaction, the MacroKans were collected and washed according to a literature procedure. 

The next step was to pool one (or more) of each resin-bound dimers 30a-e for another split combinatorial approach with monomers 3a-e. Resin-bound dimmers 30a-e were deprotected with a solution TBAF in THF to give the corresponding resin-bound alkynes, following a subsequent Pd/Cu-catalyzed cross-coupling with monomers 3a-e to afford a library of 25 different polymer-supported trimers 31a-e - 35a-e (Scheme 3.73). 

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