Sonogashira protocol

In 2001 the first microwave-enhanced Sonogashira protocol including examples of heteroaromatic skeleta appeared. Trimethylsilylacetylene could be efficiently introduced on electron-rich and electron-deficient heteroaromatics as exemplified by thiophene and pyridine, respectively (Scheme 49) [68]. 

In order to minimize the formation of side products, PAM 4 can be assembled via an intramolecular approach [23]. The Sonogashira protocol [15] and conversion of masked iodides [24] comprises most of the chemistry involved in Scheme 7. Using these proven methods, diyne 16 and subsequently triyne 17 can be prepared quickly. lodination, desilylation, and intramolecular alkynylation with Pd(dba)2 under high dilution conditions furnished 4 as the sole product. 

Microwave-assisted Sonogashira protocols have also been used for the decoration or functionalization of various heterocyclic core structures. Some recent examples involving pyrazines [47], pyrimidines [66], and thiophenes [42] are shown in Scheme 6.32. 

Sonogashira protocol.The alkynylzinc reagent can also be prepared in situ form terminal alkynes by addition of ZnCl2 as a co-catalyst. ... 

Although the authors call this reaction a Castro-Stephens reaction, they point out that it is really a Linstrumelle modification of the Sonogashira protocol. 

Scheme 14 Aryl coupling of trimethylsilylacetylene via a palladium-catalyzed Sonogashira protocol...

The original Sonogashira protocol involves palladium-copper co-catalysis. Attempts have been made over the last few years to overcome some of the limitations in this method, specifically to eliminate the undesired dimerization of terminal alkynes. Various copper-free conditions have been developed in order to reduce the amount of diacetylene formation. The focus seems to have been on changing the ligand. 

The oxidation-labile TL 1.44 (102) was readily prepared from aminomethyl PS resin and used to decorate the aryl moiety with C-C coupling reactions (e.g. Heck, Stille, Suzuki, and Sonogashira protocols). Oxidation of the hydrazide moiety to acyl diazene [copper acetate or A -bromosuccinimide (NBS)] and nucleophilic cleavage (methanol or n-propylamine) produced the desired aryl products. 

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 problem of product contamination with phosphine-derived by-products has led others to investigate the use of phosphine alternatives in Sonogashira coupling reactions. N-heterocyclic carbenes (e.g. (9)) have found use in a wide variety of cross-coupling reactions, including the Sonogashira protocol. Similarly, Najera showed that oxime... 

Discoveries made in the late 1970s of electrical conductivity in conjugated polymers spawned a monumental interest in the study of these materials, which are ideally suited for synthesis via cross-coupling reactions. Yamamoto was the first to realize this possibility with a regiochemicahy defined synthesis of poly(/ -phenylene) formed via the Kumada-Corriu protocol. Since then, various cross-coupling reactions have been applied in condensation polymerization reactions,with the Suzuki and Sonogashira protocols gaining the most widespread use. 

A.ii.d. Comparison of Operational Simplicity. As mentioned earUer, the Sonogashira protocol is operationally somewhat simpler than the use of preformed alkynylmetals. This indeed is the main reason for considering first the Sonogashira protocol in cases where it is very satisfactory. When the starting terminal alkynes are prepared via alkynylmetal intermediates, however, the direct use of alkynylmetals would be more convenient, as demonstrated in a recent synthesis of xerulint (Scheme 4). 

Lavastre et al. [53] explored the synthesis of PAEs in a combichem setup. The diynes 13-20 were coupled in THF utilizing a Sonogashira protocol to the dibromides A-L to give 96 different PAEs (Scheme 6.13). The authors reported that the polymers J14,16, and 20 were fluorescent in thin film preparations, while 20H, J-L were fluorescent in dilute solution. The results for the thin films are not unexpected as it is... 

Since aryl triilates can easily be generated from corresponding phenols, Beller also developed a palladium-catalyzed carbonylative Sonogashira coupling of aryl triflates in 2010 [50]. This is the first carbonylative Sonogashira protocol that can apply aryl triflates as substrates. Various alkynones were produced in moderate to good yields under low pressure of CO (Scheme 5.21). A one-pot synthesis of enaminones was also achieved by running the reaction in the presence of primary amines. 

Scheme 9.46 One-pot synthesis of tolanes by a modified Sonogashira protocol involving in situ desilylation of an initially formed TMS-protected arylacetylene [130].

Acylation, vinylation, and ethinylation involving Pd(0)-catalyzed coupling reactions can be performed with halothiophenes, thiophene boronic acids, or thienyl stannanes following the classical Suzuki-Miyaura, Stille, or Sonogashira protocols [64]. 

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