Sonogashira transmetallation

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. 

More recently, a study with di- and mono-carbene Pd(II) complexes has demonstrated that the Sonogashira coupling of activated and non-activated aryl iodides can be carried out in an aqueous, aerobic medium and in the absence of amines. These results suggest that the moisture-sensitive copper-acetylide may not be present in this particular transformation, and that a Pd-acetyhde could be formed by deprotonation of the coordinated alkyne instead of transmetallation [130]. 

It is speculated that an alkynylcopper species, which undergoes the transmetalation process more readily, is generated during the reaction with the aid of an amine. The aliphatic amine also serves as a reducing agent to generate Pd(0). For recent reviews on the Sonogashira reaction, see references [60] and [61]. 

Oxidative addition of Pd(0) to a c/s-dihaloethylene gives an intermediate that can undergo 3-halide elimination. The C-Br or C-I bond is more prone to undergo (3-elimination than the much stronger C-Cl bond. The transmetallation and reductive elimination steps of the Sonogashira coupling have more time to occur when a C-Cl bond is (3 to Pd than when a C-Br or C-I bond is (3 to Pd. 

Another alternate to the Sonogashira coupling was reported by Blum and Molander, where sodium tetraalkynylaluminatcs were coupled with bromoazines and bromoazoles in the presence of a palladium-triphenylphosphine catalyst system. 5-Bromopyrimidine coupled with the TMS-acetylide, for example, to give the cthynylpyrimidinc in excellent yield (7.41.),59 The transmetalating reagents were prepared in situ by the reaction of the appropriate acetylene derivative with sodium aluminiumhydride. 

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. 

The mechanism of the Sonogashira cross-coupling follows the expected oxidative addition-reductive elimination pathway. However, the structure of the catalytically active species and the precise role of the Cul catalyst is unknown. The reaction commences with the generation of a coordinatively unsaturated Pd species from a Pd " complex by reduction with the alkyne substrate or with an added phosphine ligand. The Pd " then undergoes oxidative addition with the aryl or vinyl halide followed by transmetallation by the copper(l)-acetylide. Reductive elimination affords the coupled product and the regeneration of the catalyst completes the catalytic cycle. 

One can imagine that the Sonogashira coupling proceeds by a catalytic cycle very similar to the Stille coupling. The transmetallation step of the Stille coupling is replaced with a ligand substitution reaction, in which a deprotonated alkyne displaces X- from the Pd(II) complex. The alkyne may be deprotonated by the Et3N that is present in the reaction mixture. 

The problem with this scenario is that alkynes are more acidic than most hydrocarbons (pK 25), but they are not sufficiently acidic to be deprotonated by amines (p/temperature required for the Sonogashira coupling from >100 °C to room temperature. The Cul may convert the alkyne (RC=CH) to a copper(I) acetylide (RC=C-Cu), a species that can undergo transmetallation with Pd(II). Of course, now the question is, How is RC=C-H converted to RC=C-Cu The alkyne may form a tt complex with Cu, and this complex may be deprotonated (E2-like elimination) to give the Cu acetylide, which can transmetallate with Pd. 

Scheme 12.22 shows the generally accepted mechanism for Sonogashira coupling. It features three interconnecting cycles.150 Cycle a lies at the heart of the mechanism and should by now be quite familiar. Cycle b shows a plausible scheme for converting Pd(II) complexes, the usual form of the precatalyst, to Pd(0). Other mechanisms for this reduction may apply, however, especially since tertiary amine bases are commonly present in the reaction (see Section 12-3-2). Cycle c connects with cycle a, and it suggests how Cu catalyzes the formation of the Cu-alkyne, which then transmetalates with Pd. 

In the next chapter we will discuss the use of alkynes as nucleophiles. From the reaction mechanism for Sonogashira reactions, the in situ-formed alkynylcopper intermediate should do transmetalation with palladium center and followed by reductive elimination, which is similar to the carbonylative reactions described in this chapter. 

Despite all the synthetic developments, relatively little detailed mechanistic work has been performed on Sonogashira carbonylations until the present. The generally accepted mechanism is shown in Scheme 5.25. The typical reaction begins with the oxidative addition of ArX to a palladium(0) complex to form an aryl palladium(II) intermediate. The subsequent insertion of CO leads to the respective palladium acyl complex. Transmetallation, and finally reductive elimination, releases the product and a new catalytic cycle can be started. Notably, all species passing through the cycle are believed to be in a reversible equilibrium. 

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