Oxidation Sonogashira reactions

The coupling of terminal alkynes with aryl or alkenyl halides catalysed by palladium and a copper co-catalyst in a basic medium is known as the Sonogashira reaction. A Cu(I)-acetylide complex is formed in situ and transmetallates to the Pd(II) complex obtained after oxidative addition of the halide. Through a reductive elimination pathway the reaction delivers substituted alkynes as products. 

There are a number of procedures for coupling of terminal alkynes with halides and sulfonates, a reaction that is known as the Sonogashira reaction.161 A combination of Pd(PPh3)4 and Cu(I) effects coupling of terminal alkynes with vinyl or aryl halides.162 The reaction can be carried out directly with the alkyne, using amines for deprotonation. The alkyne is presumably converted to the copper acetylide, and the halide reacts with Pd(0) by oxidative addition. Transfer of the acetylide group to Pd results in reductive elimination and formation of the observed product. 

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. 

Advantage has been taken of the aforementioned observations in the synthesis of a terthiophene natural product, arctic acid (147) [123]. Pd-catalyzed carbonylation of bromobisthiophene 25, obtained from the Kumada coupling of 2-thienylmagnesium bromide and 2,5-dibromothiophene, gave bithiophene ester 144, which was converted to iodide 145 by reaction with iodine and yellow mercuric oxide. Subsequent propynylation of 145 was then realized using the Sonogashira reaction with prop-l-yne to give bisthienyl alkyne 146, which was subsequently hydrolyzed to 5 -(l-propynyl)-2,2 -bithienyl-5-carboxylic acid (147), a natural product isolated from the root of Arctium lappa. 

Akita and Ohta disclosed one of the earliest Sonogashira reactions of chloropyrazines and their A-oxides [24, 25]. The union of 2-chloro-3,6-dimethylpyrazine (23) and phenylacetylene led to 2,5-dimethyl-3-phenylethynylpyrazine (29). Subsequent Lindlar reduction of adduct 29 then delivered (Z)-2,5-dimethyl-3-styrylpyrazine (30), a natural product isolated from mandibular gland secretion of the Argentine ants, Iridomyrmex humilis. 

The standard Sonogashira reaction conditions were not successful for the coupling reaction of 3-chloropyrazine 1-oxide (40) and 1-hexyne. In contrast, treatment of 40 and 1-hexyne with Pd(Ph3P)4 and KOAc produced 3-(l-hexynyl)pyrazine 1-oxide (41), together with the co-dimeric product, (E)-enyne 42 [34]. Presumably, the co-dimerization product 42 resulted from the cis addition of 1-hexyne to adduct 41. 

The Sonogashira reaction of 2-chloropyrazine 1-oxide gave only recovered starting material. Pentylation and octylation of 2-chloropyrazine 1-oxide also failed [9]. Possible explanations for these results were either catalyst agglomeration or metal formation from pyrazinylpalladium... 

The mechanism of the Sonogashira reaction has not yet been established clearly. This statement, made in a 2004 publication by Amatore, Jutand and co-workers, certainly holds much truth [10], Nonetheless, the general outline of the mechanism is known, and involves a sequence of oxidative addition, transmetalation, and reductive elimination, which are common to palladium-catalyzed cross-coupling reactions [6b]. In-depth knowledge of the mechanism, however, is not yet available and, in particular, the precise role of the copper co-catalyst and the structure of the catalytically active species remain uncertain [11, 12], The mechanism displayed in Scheme 2 includes the catalytic cycle itself, the preactivation step and the copper mediated transfer of acetylide to the Pd complex and is based on proposals already made in the early publications of Sonogashira [6b]. 

Similar selectivities for the first cross-coupling have been observed for Suzuki and Sonogashira reactions. The Stille coupling of 3,4-diiodo-2,5-dimethylthiophene with 2-trimethylstannylthiazole stops at the monosubstitution stage. The reason for this selectivity might be that the carbon at the 3-position retards the oxidative addition and transmetalation at the adjacent 4-position. 

Yamamoto and Plenio introduced ferrocene units into PAEs and prepared redox-active PAEs 70 [107,109]. Yamamoto coupled l,l -diiodoferrocene to a diethynylarene by either a Sonogashira reaction or by utilizing alkynylgrignard reagents (Scheme 6.25). Plenio reported poly(l,3-ferrocenyleneethyny-lene)s 70d (Scheme 6.26) by a clever metallation strategy. Polymers 70 are structurally novel but have not found any applications. They might be useful as active layers in transistor-types due to their ease of oxidation. 

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