Stille coupling additives

The Stille reaction of 2-chloro-3,6-diisopropylpyrazine (7) and 2-chloro-3,6-diisopropylpyrazine 4-oxide (9) with tetra(p-methoxyphenyl)stannane (readily prepared in situ from the corresponding Grignard reagent and SnCU) led to the corresponding arylation products 8 and 10, respectively [9]. Additional Stille coupling reactions of chloropyrazines and their N-oxides have been carried out with tetraphenyltin [10] and aryl-, heteroaryl-, allyl- and alkylstannanes [11]. 

The Stille coupling of an aryl triflate normally calls for the addition of at least one equivalent of LiCl. Presumably, the transmetallation is facilitated by replacing triflate with CP at the palladium intermediate generated from oxidative addition. As Stille demonstrated in 1988, 4-quinolinyl triflate 100 was coupled with phenylstannane 101 in the presence of Pd(Ph3P)4 and LiCl in refluxing 1,4-dioxane to furnish biaryl 102, which was used as an intermediate for the first total synthesis of antibiotic amphimedine (88JA4051). 

Table 1. The reasons for the apparent breakdown of the original principle have included chemical interaction between one couple and an intermediate species of the other, changes produced in the structure of the electrode surface and, most common of all, adsorption on the surface of a component of one couple that affected the electrode kinetics of the other. The underlying problem in these cases has been the untenable premise that each couple acts quite independently of the other and is not affected by the other s presence. However, as many of these studies have shown, the premise of additivity still applies whenever the interactions have been allowed for by carrying out the electrochemical experiments in an appropriate fashion. The validity of adding or superimposing electrochemical curves can therefore be considerably extended by restating the principle as follows ...

Collum129 reported that while the Stille coupling can proceed without using a phosphine ligand, the addition of a water-soluble ligand improved the yield of the reaction. Water-soluble aryl and vinyl halides were coupled with alkyl-, aryl-, and vinyltrichlorostannane derivatives in this way (Eq. 6.39). 

The following two schemes exemplify the synthesis of piperidines via 1,4-addition of amines. In the first scheme below, a one-pot Stille coupling/double Michael addition, starting from readily available vinyl stannanes, is used to generate piperidinones 174 <06SL547>. An example of the reduction of piperidinone 174 to piperidine 175 is also highlighted. 

Note The amount of crosslinker solution to be transferred is dependent on the level of activation desired. Suitable activation levels can be obtained for the following proteins by adding the indicated quantities of the sulfo-SMCC solution. The degree of sulfo-SMCC modification often determines whether the carrier will maintain solubility after activation and coupling to a hapten. Multimeric KLH in particular, is sensitive to the amount of crosslinker addition. KLH usually retains solubility at about 0.1-0.2 times the mass of crosslinker added to BSA. This level of addition still results in excellent activation yields, since KLH is significantly larger than most of the other protein carriers. 

The Stille coupling of a-iodo enones is sluggish under standard conditions. Significant rate enhancement was observed for the Stille reaction of 2-chloro-5-tributylstannylpyridine and a-iodo enone 76 using triphenylarsine as the soft palladium ligand and Cul as the co-catalyst [63], Oxygenated functionalities did not affect the efficiency of the reaction provided both Ph3As and Cul were added. Additional manipulations of 77 resulted in the synthesis of (+)-epibatidine (78). 

With respect to the coupling reactions of stannylthiazoles with aryl halides, the union of 4-chlorobromobenzene and 2-tributylstannylthiazole constructed arylthiazole 53 [37]. The Stille reaction of 3-bromobenzylphosphonate (54) and 2-tributylstannylthiazole led to heterobiaryl phosphonate 55, which may be utilized as a substrate in a Wadsworth-Homer-Emmons reaction or a bioisosteric analog of a carboxylic acid [38], The phosphonate did not interfere with the reaction. In addition, the coupling of 5-bromo-2,2-dimethoxy-l,3-indandione (56) and 2-tributylstannylbenzothiazole resulted in adduct 57, which was then hydrolyzed to 5-(2 -benzothiazolyl)ninhydrin [39]. 

Stille couplings also have been exploited in the synthesis of the aromatic macrocyclic core of diazonamide A (2) [5, 20]. Pattenden s group utilized the Pd-catalyzed coupling between the 3-stannyl substituted indole 23 and the 3-bromooxazole 24 to provide a particularly expeditious route to the ring system 25 [20]. In addition, Harran s group secured the connection between bromooxazole 12 and vinylstannane 26 also using a Stille coupling [5]. 

The mechanism is the same as a regular Stille coupling, except that coordination of CO and insertion into the Pd-C bond intervenes between the oxidative addition and transmetallation steps At some point the TfO- group on Pd is exchanged for a Cl- group. 

A new C-C bond is formed between a nucleophilic C-Sn and an electrophilic C-Br. This Stille coupling proceeds through the standard oxidative addition, transmetallation, reductive elimination process characteristic of Pd-catalyzed cross-couplings. The mechanism was discussed in the text (Section 6.3.4). 

The use of soluble dendrimers with phospine ligands experienced a rapid growth and was also transferred to several other dendrimer scaffolds [64—66]. Many reactions, such as hydrogenation, hydrovinylation, Stille coupling, Knoeve-nagel condensation and Michael addition were reported (Tab. 7.2) [73, 74]. 

In addition to all the good features of the Stille couplings, there are a few problems with the use of RSnMles or RSn(n-Bu)3 in aqueous solutions. These compounds are rather volatile and water-insoluble but this can be overcome with the aid of co-solvents. However, the products of the reaction still contain alkyltin species which are toxic and environmentally unacceptable. Furthermore, only one of the four Sn-C units take active part in the... 

Maraval et al 39) synthesized core- and periphery-functionalized ruthenium and palladium dendritic diphosphines (Fig. 12) that were applied in three reactions (Stille coupling, Knoevenagel condensation, and diastereoselective Michael addition). The catalyst was recovered by using the precipitation strategy. 

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