Sonogashira coupling reaction development

A rapid MW-assisted palladium-catalyzed coupling of heteroaryl and aryl boronic acids with iodo- and bromo-substituted benzoic acids, anchored on TentaGel has been achieved [174]. An environmentally friendly Suzuki cross-coupling reaction has been developed that uses polyethylene glycol (PEG) as the reaction medium and palladium chloride as a catalyst [175]. A solventless Suzuki coupling has also been reported on palladium-doped alumina in the presence of potassium fluoride as a base [176], This approach has been extended to Sonogashira coupling reaction wherein terminal alkynes couple readily with aryl or alkenyl iodides on palladium-doped alumina in the presence of triphenylphosphine and cuprous iodide (Scheme 6.52) [177]. 

Similar three-component reactions based on in situ activation of alkynes by a Sonogashira coupling reaction have also been developed by Muller and co-workers... 

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... 

Catalyst development for Pd-catalyzed Sonogashira coupling reactions. 

Besides cycloadditions, cross-coupling reactions were applied to the site-specific modification of DNA. In addition to Sonogashira couplings, we developed a selective variant of the Suzuki-Miyaura coupling reaction that allows the one-step postsynthetic modification of commercially available iodo-modified DNA with a variety of boronic acids to form functional DNA derivatives (in this case, photoswitchable derivatives) [16a]. This methodology shortened the synthetic pathway to such modified DNA by 10 synthetic steps. Recent work identified Stille-Migita coupling as a much milder and potentially very useful reaction (Krause and Jaschke, to be published). 

Cationic phosphine ligands containing guanidiniumphenyl moieties were originally developed in order to make use of their pronounced solubility in water [72, 73]. They were shown to form active catalytic systems in Pd-mediated C-C coupling reactions between aryl iodides and alkynes (Castro-Stephens-Sonogashira reaction) [72, 74] and Rh-catalyzed hydroformylation of olefins in aqueous two-phase systems [75]. 

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. 

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 ... 

Aryl hydrazide-based linker 79 was developed as a traceless handle that released products under mild oxidative conditions (Scheme 42) [91]. Polymeric bound p-iodophenylhydrazide was subjected to a variety of Pd°-catalyzed coupling reactions (Heck, Suzuki, Sonogashira, and Stille). Oxidation with Cu(OAc)2 in MeOH and pyridine released the final products in 50-96% yield. 

Transition metal-catalyzed transformations are of major importance in synthetic organic chemistry [1], This reflects also the increasing number of domino processes starting with such a reaction. In particular, Pd-catalyzed domino transformations have seen an astounding development over the past years with the Heck reaction [2] - the Pd-catalyzed transformation of aryl halides or triflates as well as of alkenyl halides or triflates with alkenes or alkynes - being used most often. This has been combined with another Heck reaction or a cross-coupling reaction [3] such as Suzuki, Stille, and Sonogashira reactions. Moreover, several examples have been published with a Tsuji-Trost reaction [lb, 4], a carbonylation, a pericyclic or an aldol reaction as the second step. 

Recent developments in palladium-catalyzed coupling reactions have arisen in the pyrimidine field as well. The Sonogashira coupling of bromopyrimidine 85 with alkynes 86 produced pyrimidines 87, important intermediates reported by Hart and co-workers in their approach to the cylindrospermopsin substructure . 

In addition, Rollin et al.26 have also developed a new modified Sonogashira cross-coupling reaction of OZTs, in which copper(i) is used in catalytic amount, allowing the formation of C-C bonds to produce alkynyloxazoles (Scheme 65). 

The Pd-catalyzed C-C coupling (Sonogashira coupling) was applied to polymer synthesis about 20 years ago [23-25], and has especially been developed for the synthesis of n-conjugated poly(aryleneethynylene)s (PAEs) (for reviews, see refs. [16,26-33]). Recently other synthetic routes for PAEs were also developed, e.g., the alkyne metathesis method [28, 34] and the coupling reaction of =C-MR3 with R X (M=Si [35, 36] or Sn [37, 38]). In this review, we are concerned with the synthesis and chemical properties of PAEs with heteroaromatic rings. 

Other successful examples of catalysts containing NHC ligands are found in palladium- and nickel-catalyzed carbon-carbon bond formations. The catalyst development with these metals has focused in particular on Heck-type reactions, especially the Mizoroki-Heck reaction itself [Eq. (42)] and various cross coupling reactions [Eq. (43)], e.g., the Suzuki-Miyaura reaction ([M] = and the Kumada-Corriu reaction ([M] = MgBr). " Related reactions like the Sonogashira coupling [Eq. (44)]326-329 Buchwald-... 

The Sonogashira coupling of haloazines can be effected by a series of catalyst systems. Recently a lot effort was devoted to the development of a recyclable catalyst system. Kotschy and co-workers recently reported the use of palladium on charcoal as a convenient palladium source for this process, which allows for the separation and reuse of the catalyst at the end of the reaction (7.35.), The authors also demonstrated that, in spite of the absence of any substantial catalyst leaching, the catalytic activity of the reused Pd/C decreases on each run,49 a surprising phenomenon which was attributed to the dissolution and reprecipitation of the active catalyst in the course of the process. Pd(OH)2 on charcoal exhibited a similar activity in the Sonogashira coupling of bromopyridines.50... 

Few methods have been devised as alternatives to the palladium-catalysed Sonogashira couplings. In response to this, Wang and co-workers have developed a microwave heated and purely copper-catalysed version of this reaction using 10% Cul58. As shown in Scheme 2.21, high yields were achieved after just 10 min of heating in a commercial multi-mode microwave oven. 

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