Sonogashira reaction developments

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]. 

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. 

Although the Sonogashira reaction is normally performed with a copper cocatalyst, a copper-free, one-pot procedure for direct coupling with l-aryl-2-trimethylsilylacetylenes has been developed <2005T2697>. The procedure uses a mixture of palladium acetate and tri(o-tolyl)phosphine as catalyst in the presence of tetra- -butylammonium chloride... 

Removal of the tri-wo-propylsilyl (TIPS) and tm-butyldimethylsilyl (TBS) protecting groups could be accomplished concomitantly with TBAF in tetrahydrofuran at 0 °C, but here competing elimination of the secondary bromide was observed. Better overall yields and cleaner conversion was observed when TBS ether was cleaved with 5 % aqueous HF in acetonitrile at 0 °C followed by removal of the acetylenic TIPS with TBAF under milder conditions of -78 °C.10 The diastereomers are not separated before the desilylation process therefore even a 3 1 mixture of E- and Z-enyne is obtained. Prelaureatin 4 and its F-isomer 17 are likewise goals in natural product synthesis. Crimmins and co-workers developed an own synthetic route to 4. The reaction sequence is similar up to aldehyde 55. Afterwards a Z-vinyl-iodide is selectively formed and the alkyne is introduced via a Sonogashira reaction. 

Van der Eycken s group developed a silver(I)-mediated synthesis of substituted furo[2,3-6]pyrazines.53 Starting from -methoxybenzyl-protected 3,5-dichloropyr-azine-2(l//)-ones 26 (Scheme 5.13), after a regioselective microwave-assisted Sonogashira reaction with various terminal alkynes, the cycloisomerization reaction could occur using AgOTf (2 mol%) with trifluoroacetic acid (TFA, 5 equiv) to yield... 

Cu-catalyzed alkynation of L Pd and cross-coupling with R -X, has developed into a widely used method for forming new C-C bonds between alkynyl and aryl or vinyl groups. This transformation is now called Sonogashira cross-coupling. Equation 12.72 shows a typical example of the Sonogashira reaction.146... 

Yamanaka and associates developed a method for the synthesis of 2-butylindole from the Sonogashira adduct of ethyl 2-bromophenylcarbamate and 1-hexyne [97, 98]. Extension of that method to pyridines led to the synthesis of pyrrolopyridines [99]. However, the method was not applicable to the synthesis of pyrrolo[2,3-6/]pyrimidines. They then developed an alternative route involving an initial S Ar displacement at the 4-position of 4,5-dihalopyrimidine followed by a Sonogashira coupling at the 5-position [100]. Thus, 5-iodopyrimidine 200 was obtained from an S Ar displacement at the 4-position of a 4-chloro-5-iodo-2-methylthiopyrimidine (199). The subsequent Sonogashira reaction of 200 with trimethylacetylene at 80°C resulted in adduct 201, which spontaneously cyclized to pyrrolo[2,3-6/]pyrimidine 202. 

However, the real breakthrough in this area is due to the development of catalysis by transition metals, with the Heck, Suzuki, Sonogashira reactions and other related coupling process. ... 

Methods to form fluorescein and rhodamine dyes typically feature high-temperature condensation reactions that are not readily adapted to form small libraries of derivatives. Burgess and co-workers developed borylation, Suzuki, and Sonogashira reactions involving bromo derivatives of fluorescein and rhodamine [86]. Organoboron compounds, biaryls, and alkynes were readily synthesized by... 

Interesting is the development of concept of copper-free Sonogashira reaction in which Cul catalyst was not used (Scheme 2.15). In these reactions, coupUng products 47 in various yields were still obtained (Table 2.14), probably due to the presence of trace amounts of copper in palladium reagent. When copper catalyst-free reaction was carried out with copper milling balls as a source of copper, yields increased to 31-88% (Table 2.15). Finally, copper vials in combination with copper balls as a source of copper afforded respectable yields in the range of42-90% (Table 2.16). 

Probably the first industrial application of the Sonogashira reaction was in the production of Terbinafin 148, an anti-fungal agent developed by Sandoz (now Novartis) [99]. This was the cornerstone of a second generation process that consisted of less steps and was both more environmentally friendly and more economic than the first generation process. The new process was invented by chemists from Banyu Pharmaceutical and licensed by Sandoz [100]. Further... 

In the original synthesis of Pemetrexed 41 which was developed by Taylor at Princeton University vide infra), a Sonogashira coupling was used to couple the other half of the molecule directly on the iodo-pyrrolopyrimidine [41], However, since this latter intermediate was hard to make a different synthesis was developed by Lilly (see also Scheme 10) for which a C-4 fragment needed to be coupled to methyl 4-bromobenzoate. In Scheme 10 we have seen the use of the Heck reaction on but-3-ene-l-ol for this coupling, but in fact the Sonogashira reaction on but-3-yn-l-ol has also been described by Lilly (Scheme 40) [ 107]. It is a classical variant that uses... 

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