The Stille Reaction

1 The Cu Catalyzed Stille Reaction - Synthesis of /V-Ethyl-A/-(phenyl-p-tolylmethyl)benzamide 

Different substrates for the Stille reaction have been used in two one-pot microwave-assisted hydrostannylation StUle-coupling sequences. High isolated 

A Stille-related paper reported different regioselectivities in a q clocarbo-palladation in which the multistep reaction described terminated in a Stille cross-coupling. Mechanistic studies with deuterium provided a background for a discussion of the different outcomes when alkynyl or vinyl stannanes were used. Microwave heating was found to increase the rate of the reaction with two vinyl stannanes and one heteroaromatic stannane as substrates [80]. 

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. 

The aryltrialkylstannanes as the key-Stille intermediates can be obtained by the following alternative reactions  

The latest approach to arylstannanes involves the reaction of aryl chlorides with sodium trimethylstannate under irradiation. Rossi s group has found that by simple 

The Pd(PPh3)2Cl2 and Pd(PPh3)4 catalysts in THF or dioxane as a reaction medium are the most common Stille reaction systems. Alternative methods for performing the reaction of aryltrialkylstannancs with different electrophilic substrates arc given in the Table 6. 

Sodium chloride has been used as an additive in the copper- and manganese-catalysed Stille reactions with aryl iodides in NMP [88]. 

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Advantages of the Stille reaction include neutral conditions under which the reaction takes place, often with full retention of stereochemistry, and compatibility with nearly all functional groups thus eliminating additional steps required for protection and deprotection. Conversely, a highly undesirable drawback is the use of toxic tin compounds and the ensuing difficult removal of these from the reaction mixture. 

Legros et al. (2001T2507) carried out the synthesis of acetylquinolines (e.g. 130) via Heck reaction of 3-bromoquinoline (70) and -butyl vinyl ether (Scheme 16) employing either Pd(dba)2 or Pd(OAc)a as the catalyst. In each case it was found that the Heck reaction for this synthesis gave better overall yields than using the Stille reaction (see Section IV.C). Another advantageous point in favor of the Heck is that it avoids the use of toxic stannane. 

As in case of other palladium-catalyzed reactions, the general mechanism of the Stille reaction is best described by a catalytic cycle—e.g. steps a) to c) ... 

The organotin compounds required for the Stille reaction are easy to prepare for a wide range of substituents, and are easy to handle. Many functional groups... 

Palladium-catalyzed carbon-carbon bond forming reactions like the Suzuki reac-tion as well as the Heck reaction and the Stille reaction, have in recent years gained increased importance in synthetic organic chemistry. In case of the Suzuki reaction, an organoboron compound—usually a boronic acid—is reacted with an aryl (or alkenyl, or alkynyl) halide in the presence of a palladium catalyst. 

Many types of functional groups are tolerated in a Suzuki reaction, and the yields are often good to very good. The presence of a base, e.g. sodium hydroxide or sodium/potassium carbonate, is essential for this reaction. The base is likely to be involved in more than one step of the catalytic cycle, at least in the transmetal-lation step. Proper choice of the base is important in order to obtain good results." In contrast to the Heck reaction and the Stille reaction, the Suzuki reaction does not work under neutral conditions. 

The Stille reaction has been employed by a number of researchers in the sy thesis of soluble PTV derivatives [130]. Alkyl-substituted PTVs were synthesiz... 

Scheme 30. Catalytic cycle for the Stille reaction direct coupling.

An important feature of the Stille reaction is that it is not particularly susceptible to steric effects. Indeed, vinyl triflate 120, despite its somewhat hindered nature, couples smoothly with the indicated vinylstannane in the presence of a catalytic amount of Pd(PPh3)4 and LiCl to give 1,3-diene 122 in 90% yield (see Scheme 32).49a As expected, vinyl triflate 119 is converted to the regioisomeric 1,3-diene 121 under identical conditions. 

Scheme 34. The Stille reaction in Evans s synthesis of (+)-A83543A (lepicidin) aglycon (131).

The palladium-catalyzed cyclization of compound 138 amply demonstrates the utility of the Stille reaction as a macrocyclization method (see Scheme 37). This efficient ring closure is just one of many examples disclosed by J.E. Baldwin and his group at Oxford.58 Interestingly, compound 138 can be employed as a stereoisomeric mixture of vinylstannanes because both stereoisomers converge on the same cyclized product. To rationalize this result, it was suggested that the configuration of the vinylstannane moiety is conserved in the cyclization, but that the macrocycle resulting from the (Z)-vinylstannane stereoisomer isomerizes to the thermodynamically favored trans product under the reaction condi-... 

Our general survey of palladium in organic synthesis must now come to an end. At the very least, we hope that our brief foray into this fascinating area conveys some of the vitality that characterizes research in this area. The remainder of this chapter will address the first total synthesis of rapamycin by the Nicolaou group. This work is predicated on a novel variant of the Stille reaction. 

The Stille reaction has developed as a popular protocol for the formation of C-C bonds due to the air- and moisture-stability as well as functional group compatibility of organotin compounds. Together with the Suzuki-Miyaura coupling it is one of the most powerful methods for the synthesis of molecules containing unsymmetrical biaryl moieties. However, despite its efficiency, this versatile reaction has slowly been displaced by other procedures that avoid the use of highly toxic organostannanes. 

The general catalytic cycle of the Stille reaction involves oxidative addition, transmetallation, and reductive elimination. 

The Stille reaction can be used with alkenyl stannanes, alkenyl halides, and triflates,196 and the reactions occur with retention of configuration at both the halide and stannane. 

The most problematic cases for the Stille reaction involve coupling saturated systems. The tendency for p-elimi nation of alkylpalladium compounds requires special conditions. Zh. v-(dialkylamino)cyclohexylphosphincs have shown considerable success... 

The Stille reaction has been successfully applied to a number of macrocyclic ring closures.207 In a synthesis of amphidinolide A, the two major fragments were coupled via a selective Stille reaction, presumably governed by steric factors. After deprotection the ring was closed by coupling the second vinyl stannane group with an allylic acetate.208... 

Figure 1.6 Recyclability of the catalyst in (BCN)Py.NTf2 (black) and (PCN)Py.NTf2 (hatched) in the Stille reaction between phenyltributylstannane and iodobenzene...

As mentioned previously, the Stille reaction can also be combined with an elec-trocyclization. Trauner and coworkers [99] used this approach for the synthesis of a part of SNF4435C (6/1-190) and its natural diastereomer. SNF4435C, which was isolated from the culture broth of an Okinawan strain of Streptomyces spectabilis, acts as an immunosuppressant and multidrug resistance reversal agent [100]. In order to form the annulated cyclobutane skeleton in 6/1-190, the vinyl iodide... 

The Stille reaction was one of the earliest transition-metal-catalyzed reactions to be reported with microwave-heating, and single-mode irradiation with very short re-... 

Some of the disadvantages of the Stille reaction, e. g. the low reactivity of some substrates, separation difficulties in chromatography, and the toxicity of tin compounds, have been ameliorated by recent efforts to improve the procedure. Curran has, in a series of papers, reported the development of the concept of fluorous chemistry, in which the special solubility properties of perfluorinated or partly fluorinated reagents and solvents are put to good use [45]. In short, fluorinated solvents are well known for their insolubility in standard organic solvents or water. If a compound contains a sufficient number of fluorine atoms it will partition to the fluorous phase, if such a phase is present. An extraction procedure would thus give rise to a three-phase solution enabling ready separation of fluorinated from nonfluorinated compounds. 

Oxazole compounds can also be produced by use of the Stille reaction. Clapham and Sutherland describe the use of tri-2-furylphosphine/Pd2(dba)3-catalyzed Stille coupling reactions (Scheme 12) to produce a range of oxazole-containing derivatives, including 58, with an 85% yield [56]. 

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). 

In a sequence analogous to the Suzuki reaction and annulation described in section 4.2.4, pyridine-containing tricyclic compounds have also been prepared via the Stille reaction and a ... 

Numerous stannanes have been coupled with halopyridines as electrophiles in the Stille coupling. One of the simplest of these is vinylstannane [82-84]. The Stille reaction of bromopyridine 95 with tributylvinyltin gave angustine (96) [84], an indolopyridine alkaloid. Bromopyridine 95 also took part in a three-component carbonylative-Stille coupling sequence to provide an entry to another indolopyridine alkaloid, naucletine (97) [84]. 

Methylation of halothiophenes 86 and 88 was accomplished via the Stille reaction with tetramethyltin to give methylated thieno[3,2- >]pyran 87 [74] and thienyldeoxyuridine 89 [75], respectively. Analogously, the coupling of an allyl chloride, chloromethylcephem 90 and 2-tri-n-butylstannylthiophene furnished 91, an intermediate for a C(3) thiophene analog of cephalosporin [76]. 

Liebeskind and associates converted 3,4-diisopropyl squarate (97) to stannylcyclobutenedione 98 via a 1,4-addition-elimination sequence. 98 was then coupled with 2-iodothiophene to afford substituted cyclobutenedione 99 [85]. In another case, 3-lithioquinuclidin-2-ene, generated from the Shapiro reaction of 3-quinuclidinone (100), was quenched with Bu3SnCl to afford a unique enamine stannane 101. The Stille reaction of stannane 101 and 5-bromo-2-formyl-thiophene then furnished 3-thienylquinuclidine 102 [86]. 

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