Cross-Coupling with Terminal Acetylene

The application of aqueous mono- and biphasic techniques, both in the presence of hydrophilic phosphine ligands, and in phosphine-less mode, was investigated in detail, and turned out to be quite successful. 

The reaction of both water-soluble and water-insoluble aryl iodides with hydrophilic propargyl alcohol shows the best results if run in the presence of both TPPMS and PhaP ligands, with the former being more important to achieve good yields of cross-coupling product, and the latter behaving like a typical promoter additive [58]  

For water-insoluble acetylenes the reaction can be readily and conveniently carried out in a heterogeneous system containing water, K2CO3 and 10mol% BU3N in the presence of the hydrophobic catalyst PdCl2(PPh3)2 [59]  

Acetylene itself can be used in cross-coupling using the method described. The use of water, however, enables one to add calcium carbide to the reaction mixture to generate C2H2 in situ, thus allowing the hazards of handling gaseous acetylene to be avoided. This approach opens the route to a one-pot procedure for the assembly of disubstituted unsymmetrical acetylenes by 

Neither the triphosphate residue nor the dye fragment interfered with the reaction, in sharp contrast with the commonly used processes in organic solvents, in which such fragile groups have no chance to survive [7]. 

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A particularly interesting application of this protocol, in conjunction with the direct cross-coupling with terminal acetylenes is shown in Scheme 5-2. Here, the first coupling occurs between the alkynyltin reagent 50 and the cyclized palladium intermediate 49 and is followed by the second direct coupling with the terminal acetylene 52 at the vinyl bromide moiety to yield unsymmetrical cyclic dienediyne 53 [32]. 

This protocol and the Pd-Cu-catalyzed direct cross-coupling with terminal acetylenes (Section 5.3.5) directly complement each other. The following examples, which cannot be applied to the latter, give normal coupling products only by Stille method [Eqs. 17-20] [28-31]. This method is especially useful for the cross-coupling reactions of organometallic complexes with cyclopentadienyl ligand that are sensitive to amines [Eq. 19] [30]. 

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). ... 

Cross-coupling of terminal acetylenes used as nucleophiles with aryl or alkenyl halides (referred to as the Sonogashira-Hagihara, or SH, reaction) is a versatile method of synthesis for acetylenic compounds, which are rapidly gaining importance as advanced new materials and building blocks for implementing unusual molecular architectures. 

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... 

The same catalytic system was used for cross-coupling of terminal acetylenes with o-iodophenols and anilines giving the cyclization products, 2-substituted furanes and indoles, in high yields (Scheme 26). ... 

C. Cross-Coupling of Halogenopyrazoles with Terminal Acetylenes and Their Copper(I) Salts (Tables X to XV)... 

Similarly, the limitations and peculiarities of the cross-coupling of pyrazolyl-halides with terminal acetylenes have been fully and systematically studied by Russian chemists (86TH1 97TH1). 

A similar phenomenon was observed for 3-amino- and5-amino-4-iodopyrazoles. The anomalous reaction in which the products of oxidative coupling of terminal acetylenes (up to 90%) are present along with the products of deiodination (up to 90%) has been described for the first time [99JCS(P1 )3713] and will be considered below in the part related to cross-coupling of 4-iodopyrazoles. 

In spite of the common conception that Ni catalysts are useless in the Sonogashira reaction, NiCl2(PPh3) has been disclosed as being able to catalyze the cross-coupling of aryl iodides with terminal acetylenes in aqueous dioxane, in the presence of Cul.147... 

So far, no systematic work has been done on the use of recyclable, solid-phase catalysts in cross-coupling reactions. Most of the examples have been obtained for cross-couplings with either arylboronic acids or terminal acetylenes. It should be noted, however, that due care should be exercised when interpreting results on the cross-coupling of arylboronic acids with aryl iodides, as this extremely facile reaction can be catalyzed by practically any palladium-containing material, including trivial Pd black,481 e.g., as a sediment on the reaction vessel. Therefore, this reaction cannot serve as a reliable test for comparison between different catalytic systems. 

Substituted propargylic carbonates react with terminal acetylenes in the presence of a catalytic amount of Pd(PPh3)4 and Cul to produce Sonogashira-type cross-coupling products (Eq. 9.114) [84]. Presumably, the reaction proceeds through an allenylpalladium complex. Addition of a salt, such as KBr, increased the yield of the coupling product. Only tetrasubstituted allenes could be obtained by this procedure. 

Methyl 2,3-alkadienoates undergoes cross-coupling reactions with terminal acetylenes to give enynes in a highly regioselective manner (Scheme 16.94) [100],... 

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