Arylstannanes Stille reactions

Palladium-catalyzed cross coupling of resin bound iodopyridine with a boronic acid (Suzuki reaction) (12) or with an alkenyl-, alkynyl-, or arylstannane (Stille reaction) (13) was effected by treatment of resin 5 with 4 equivalents of the boronic acid or stannane, 8 equivalents of K2CO3 (Suzuki reaction only), and catalytic Pd(PPh3)4 in DMF at 50 C for 20 hours. (14) Best results were achieved by running each reaction twice, with an intermediate wash of the resin, in order to drive the reaction to conq>letion. The corresponding Pd-catalyzed amination (Buchwald reaction) (15) worked well in protocol development but the reaction failed with the 3 amines attenpted during actual library preparation. 

Porco s pathway to complete the synthesis of (- )-kinamycin C (3) is shown in Scheme 3.8. The arylstannane 34 and the a-bromoenone 35 were efficiently coupled by a Stille reaction using tris(dibenzylideneacetone)dipalladium and triphenylarsine... 

An early attempt to use the Stille reaction on solid support is detailed in a paper from 1994 by Deshpande.57 In this, an aryl iodide linked to Rink amide or Wang resin is coupled to a number of vinyl and one arylstannanes (Scheme 23). The protocol used only 5 mol % Pt dba and proceeded in typically 90% yield at 45°C. Interestingly, the reactions were simply left to stand (rather than being shaken) overnight. 

The scope and limitations of Pd(0)-mediated coupling reactions between aromatic halides linked to a polystyrene resin and boronic acid derivatives (Suzuki coupling) or arylstannanes (Stille coupling) have been reported. For all the reactions, the conditions were optimized and evaluated with various reagents. In most cases, products were obtained in excellent yields upon cleavage from the solid support (Eq. (63)) [101]. 

Much of the recent interest in the arylstannanes, particularly the aryltrialkylstannanes, however, derives from their use in the Stille reaction in which an aryl-C bond is generated by reaction with a halide or sulfonate RX, where R = vinyl, allyl, benzyl, or aryl, to give Ar-R under catalysis by palladium68 or another transition metal.69-72 The reactions are very tolerant of various functional groups, and are finding wide application in organic synthesis, and are considered in Section 22.2. 

The first Stille reactions on halopyridazines were described by Draper and Bailey in 1995 [48]. They successfully coupled 6-substituted 3-iodopyridazincs (151) with arylstannanes in refluxing THF or DMF at 80°C using Pd(PPh3)2Cl2 as the precatalyst. 

Besides halopyridazines, pseudohalopyridazines have been used as substrates for Stille reactions [29]. 6-Methylpyridazin-3-yl trifluoromethanesulfonate (96) reacted with arylstannanes using a procedure based on Stille s original conditions for aryl triflates. Although 3-methyl-6-(2-thienyl)pyridazine was obtained in a good yield (77%) under these conditions, trialkyl(phenyl)stannanes reacted only very slowly in comparison with tributyl(2-thienyl)stannane. Trimethyl(phenyl)stannane and tributyl (phenyl) stannane gave 3-methyl-6-phenylpyridazine in only 22 and 6% yield, respectively. 

Moreover, copper(l) halides or manganese(ll) bromide efficiently catalysed the Stille reaction of arylstannanes with aryl halides without any palladium catalyst added [87,88]. In contrast to MnBr2, manganese(II) chloride was proved as a less effective catalyst, whereas manganese(II) iodide-mediated reactions failed to give any cross-coupled products [88]. The latter achievements dramatically extend the economy of the Stille reaction since the use of, generally very expensive, palladium chemicals is completely avoided. 

In this section, we refer to some Stille reactions that serve as representative examples. As noted before, the Stille reaction is compatible with boronic esters. " Therefore, the Stille cross-coupling provides a simple method for homologation of aryl-and 1-alkenylboronic esters (Scheme 5-60). Since the carbon-boron bond is inert to transmetalation in the absence of a base and oxidative addition of the carbon iodide bond is faster than that of the carbon bromine bond, the arylation of iodoboranes with arylstannanes selectively occurs at the carbon iodo bond without affecting the other onej l In addition. Scheme 5-60 also shows a Stille reaction having a multitude of functional groups such as being present in a modified nucleotide. ... 

Innumerable aryl- and heteroarylstannanes take part in Stille couplings with halopyridines. In one such example, the union of arylstannane 106 and 4-bromopyridine furnished arylpyridine 107 [90], Arylstannane 106 was prepared from the Pd-catalyzed reaction of hexabutylditin with iodoarene 105, which arose from aminobenzolactam 104 via a Sandmeyer reaction. 

The Stille coupling of 2-chloro-5-tributylstannylpyridine with an enantiopure 2-iodo-cyclohexenon (7.29.) derivative formed the basis of the total synthesis of (+)-epibatidine. The reaction is a nice example of the chemical inertness of arylstannanes and the mildness of the coupling conditions. Both the enone moiety and the chiral ally lie centre remained untouched in the process. The effective coupling required the use of a soft ligand, triphenylarsine and the addition of copper(I) iodide as co-catalyst.40... 

There are a number of commonly used reactions of this type and many are named after the chemists who discovered them. They differ, among other things, in the exact nature of the metallic component. One of the first to be developed extensively was the Stille coupling, which specifically involves the coupling of an arylstannane with an aryl halide or triflate under the action of palladium catalysis (Scheme 10.19). 

When 1,2-diiodoalkenes were subjected to the coupling reaction monofunctionalization occurred successfully and the new C-C bond was formed preferentially at the less hindered iodide [160]. Migita-Kosugi-Stille coupling occurs preferably at iodide and bromide leaving fluoride intact - treatment of fluoroethenyl iodide [161] and bromide [162] with arylstannane in the presence of palladium catalyst afforded the corresponding ethenyl fluoride products, respectively. 

The first application of arylstannanes was presented by Stille who demonstrated the transferability of an aryl group from tetraphenyltin [50]. This approach was generalised by the improved preparation of arylstannanes from trialkylstannanes and aryl halides followed by their Pd(0) catalysed coupling with aryl halides [51]. Similarly to aryl halides, aryl triflates also react with arylstannates to give biphenyls [52]. Electron-rich aryl triflates are especially suitable coupling reagents in the synthesis of unsymmetrical biaryls [53]. Symmetrical biaryls can be easily obtained by the reaction of an aryl triflate with 0.5 eg. of hexamethyldistannane. 

Stille coupling. The many examples describing applications of this C-C bondforming method attest to its versatility. A comprehensive study of the coupling of arylstannanes with sulfonates has appeared. Of course, various combinations of aryl/aryl, aryl/vinyl, and vinyl/vinyl couplings are equally possible. PhsAs is often added to the reaction media, and in other cases Cul acts as a cocatalyst. 

The aryltrialkylstannanes obtained by above described methods affected the Stille cross-coupling reactions whose efficacy is presented through the following examples where arylstannanes 172-176 were reacted with aryl halides 25, 177, 178 and iodobenzene giving biaryls 179-183 in respective yields [77], Scheme 25. 

In 2003, when the second edition appeared, it was clear that the Stille chemistr/ had really come of age, as shown by the increasing number of applications of palladium-catalyzed cross-coupling reactions of vinyl- and arylstannanes in natural product synthesis and in advanced organic synthesis. In the past decade, these types of applications, of course, remained very important and, in addition, the use of allylstannanes in palladium-catalyzed coupling reactions received much attention. Cross-coupling of allylstannanes with imines also forwarded the area of asymmetric catalysis. 

Vinyl triflates can easily be converted to the corresponding vinylstannanes by reaction with (Me3Sn)2 using the catalytic system originally developed by Stille and colleagues (Scheme Aromatic triflates also undergo the stannylation to form arylstannanes. 

Diaryl ketones are important scaffolds in biologically active compoimds, and although several synthetic pathways are available in solution, their application in solid phase synthesis is rare. Yun et aL [85] have developed a high-throughput synthesis of diaryl ketones via a Stille carbonylation on solid phase. Immobilized arylstannanes 39 were subjected to Stille coupling with aryl halides in presence of carbon monoxide (Scheme 23). Not only did the reaction afford products of high yield and purity, but it was also tolerant towards most functional groups. 

Some palladium-catalyzed reactions of organotins, such as carbostannylations, are not related to the Stille cross-coupling. The history of the transition-metal-cata-lyzed carbostarmylation [148] began with alkynylstannylation of alkynes catalyzed by a palladium-iminophosphine complex [149]. Thus, alkynylstannanes added to a carbon-carbon triple bond of various acetylenes, conjugated ynoates and propar-gyl amines and ethers in the presence of a catalytic amount of a palladium-iminophosphine complex [150]. The reaction also proceeded with arynes to afford ortho-substituted arylstannanes, which could further be converted into 1,2-substituted arenes via carbon-carbon bond-forming reactions [151]. 

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