Sonogashira coupling reaction reactivity

Based on these results, conditions for alkyl-Sonogashira coupling reactions were developed. Primary alkyl halides reacted with terminal alkynes catalyzed by 5 mol% of complex 24a and Cul in the presence of substoichiometric amounts of Nal for bromides or Bu4NI for alkyl chlorides (entry 29) [73]. The latter serves to catalyze the in situ generation of more reactive alkyl iodides under the reaction conditions. The internal alkyne products were isolated in 57-89% yield. The Sonogashira coupling can also be combined to the Kumada reaction described above. a,o)-Chloroalkyl bromides underwent the Kumada coupling first selectively... 

A potentially interesting development is the microwave-assisted transition-metal-free Sonogashira-type coupling reaction (Eq. 4.10). The reactions were performed in water without the use of copper(I) or a transition metal-phosphine complex. A variety of different aryl and hetero-aryl halides were reactive in water.25a The amount of palladium or copper present in the reaction system was determined to be less than 1 ppm by AAS-MS technique. However, in view of the recent reassessment of a similarly claimed transition-metal-free Suzuki-type coupling reaction, the possibility of a sub-ppm level of palladium contaminants found in commercially available sodium carbonate needs to be ruled out by a more sensitive analytical method.25 ... 

Palladium(0)-catalyzed coupling reactions - i. e. the Heck and Sonogashira reactions, the carbonylative coupling reactions, the Suzuki and Stille cross-coupling reactions, and allylic substitutions (Fig. 11.1) - have enabled the formation of many kinds of carbon-carbon attachments that were previously very difficult to make. These reactions are usually robust and occur in the presence of a wide variety of functional groups. The reactions are, furthermore, autocatalytic (i.e. the substrate regenerates the required oxidation state of the palladium) and a vast number of different ligands can be used to fine-tune the reactivity and selectivity of the reactions. 

A systematic survey of the Sonogashira coupling of 2-halopyrimidines under mild conditions revealed that, in line with the expectations, the iodopyrimidines give excellent yield, while the reactivity of bromopyrimidines is mediocre and chloropyrimidines hardly react (7.37.).52 These results have, of course only limited relevance as increase of the reaction temperature might drive the coupling of the latter halopyrimidines to completion too. An example of the increased reactivity of chlorodiazines... 

Unlike other cross-coupling reactions, for which the scope has rapidly expanded in recent years, the range of electrophilic substrates that can be used successfully in the Sonogashira protocol is still rather limited. Vinylic substrates (iodides, bromides, chlorides, triflates, and more recently tosylates) typically yield the best results. For aromatic substrates, iodides and triflates are preferred over bromides, which in turn give far better yields than aryl chlorides. This latter aspect of the reaction is particularly frustrating when one considers the recent advances in the activation of aryl chloride substrates for reactivity in other cross-coupling protocols. ... 

The order of reactivity of aryl or alkenyl halides in Pd-catalyzed crosscouplings is I > Br > Cl. The preparation of enediynes by a Sonogashira coupling, however, is usually carried out with cw-dichloroethylene as the substrate yields are considerably poorer when cfs-dibroniocthylcnc is used instead. Why (Hint The key intermediate may be more prone to undergo what side reaction when the dibromide or diiodide is used )... 

Pd-catalyzed Sonogashira cross-coupling reaction (Sonogashira et al., 1975) on 4-bromo or on more reactive iodo-substituted dipicolinic frameworks whereby either the dialkyl (methyl, ethyl) ester or diamide forms can be used (Picot et al., 2008b Platas-Iglesias et ah, 2001). While the bromo derivatives led to deceptively low yields (<45%), the less stable... 

Alkenyliodonium salts have been used as highly reactive reagents for Heck-type olefination [39, 971], Sonogashira-type coupling with alkynes [965, 972] and similar other palladium-catalyzed cross-coupling reactions [966, 973, 974]. In a specific example, (Z)-p-fiuoro-a,p-unsaturated esters 721 were stereoselec-tively synthesized from (Z)-2-fluoro-l-alkenyliodonium salts 720 by the Pd-catalyzed methoxycarbonylation reaction (Scheme 3.288) [974]. This reaction proceeds at room temperature and is compatible with various functional groups on the substrate. 

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