The Stille Coupling

Collum 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). 

Arenediazonium chlorides and hydrogen sulfates react with tetram-ethyltin in aqueous acetonitrile in the presence of a catalytic amount of palladium acetate to give high yields of substituted toluenes. One-pot hydrostannylation/Stille couplings with catalytic amounts of 

There are many other transition-metal catalyzed coupling reactions that are based on organic halides in aqueous media. One example is the coupling of terminal alkyne with aryl halides, the Sonogashira coupling, which has been discussed in detail in the chapter on alkynes (Chapter 4). An example is the condensation of 2-propynyl or allyl halides with simple acetylenes in the presence of copper salts. 

Examples involving the use of organomercury reagents as nucleophiles in aqueous media are also known. Bergstrom studied the synthesis of C-5-substituted pyrimidine nucleosides in aqueous media via a mercurated intermediate using Li2PdCl4 as a catalyst (Eq. 6.42).  

Mertes investigated the coupling of the 5-mercuriuridines with styrenes in aqueous media resulting in alkylation of the uracil nucleotides. Carbon alkylation of C-5 on the uracil ring in the ribo- and deoxyri-bonucleosides and nucleotides was obtained in high yields by this method. A similar reaction was used by Langer et al. in the synthesis of 5-(3-amino)allyluridine and deoxyuridine-5 -triphosphates (AA-UTP and AA-dUTP) (6.12)  

Since the first reported use in the late 1970s, the Stille coupling has been widely used for the coupling of both aromatic and vinylic systems.  

The phosphine or other ligand that is used to stabilise the palladium(O) catalyst can have a dramatic effect on the rate of the reaction. Both tri(2-furyl)phosphine and triphenylarsine can be used in place of the more normal triphenylphosphine in reactions where this ligand gives poor yields. Indeed, the protocol for the Stille reaction between vinyl trifiate 14 and organostannane 15 contained in this chapter (Protocol 2) is an excellent example of this. The reaction was originally reported not to proceed. However, with triphenylarsine, Roth and co-workers have obtained excellent yields under mild conditions, without the need for added LiCl.  

The Stille reaction, which represents over 50% of all 1992 cross-coupling 

Stille Coupling of 4-t-butyl-cyclohexen-1-yloxytriflate (Structure 14) with p-(trifiuoromethyl)phenyltributyltin (Structure 15) 

Caution Triphenyiarsine is very toxic. All procedures should be carried out in an efficient fume hood. Disposable vinyl or latex gloves and safety glasses should be worn. 

This aUows the cross-coupling of an aryUialide (2) with an aryltrialkyl stannane in presence of a boronic ester. The latter remains unreactive because it would need to be hydrolyzed to a boronate to be suited for Pd-mediated couplings. Progression in a couphng cycle would further require OH , CO , or F , not present under the used StiUe couphng conditions [178,179]. The Stille conditions proved very useful for affording many aryl-aryl [1, 4, 180, 181, 182], vinyl-aryl [9, 161, 183, 184] and also aUcyl-aryl [185] compounds bearing hydrolytically labile moieties. The commonly used reactivities of aryl or vinyl halide components are like those in the 

Suzuki coupling, e.g., I(OH)Ots [186] I Br or OTF. Diaryl iodonium salts were also reported to couple with various staimanes at r.t. catalyzed by Cul, and therefore have reactivity similar to other formal iodine(I) species [30]. Several extremely effective catalysts are air stable Pd2dba3-CHCl3, Pd(OAc)2, and Pd(PhCN)2Cl2 in conjunction with AsPh3 [4, 9, 10, 75, 187, 188, 189] other co-catalysts, such as trifurylphosphine PPh3 in the absence of Cu salts, were much less effective [75, 

Coupling reactions promoted by cuprous thiophenecarboxylate were also reported to take place at or below room temperature at high rates. However, they seem to be restricted to aryl hahdes bearing NO2 ortho to the hahde [190]. 

Some Stille couphngs have been accelerated by Cu co-catalysis. The role of the copper herein is to scavenge 16-electron tin species [191] formed after dissociation of strong ligands such as phosphines [192], Mechanishc studies by Casado et al. 

Alkyl scrambling due to fhe transfer of fhe wrong alkyl group from fhe stannyl derivative onto fhe aryl species 

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The conversion of 3 to 8 is summarized in Scheme 2. The trityl group (too large and too acid sensitive for the ensuing steps) was removed from N, and both N s were protected by Cbz (benzyloxycarbonyl) groups. Protection of the tertiary OH specifically as the robust TBS (f-butyldimethylsilyl) group was found to be necessary for the sequence involving the electrophilic aromatic substitution step, 5 to 6, and the Stille coupling steps (6 + 7 —> 8). 

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). 

Interestingly, 4-quinolinyl triflate 103 underwent the Stille coupling smoothly with 3-tributylstannylindole 104 to deliver indolylquinoline 105 in 92% yield in the presence of Pd2(dba)3-AsPh3 in the absence of LiCl (94TL2405). It is possible that this transmetallation is facilitated by the softer ligand AsPh3. 

An intramolecular variant of the Stille coupling is suitable for the construction of macrocycles. An example is the ring-closing step to form a 14-membered lactone ring 8 in a synthesis of zearalenone as reported by Stille et al. ... 

The mechanism " of the Suzuki reaction is closely related to that of the Stille coupling reaction, and is also best described by a catalytic cycle ... 

The synthesis of the key intermediate aldehyde 68 is outlined in Schemes 19-21. The two hydroxyls of butyne-l,4-diol (74, Scheme 19), a cheap intermediate in the industrial synthesis of THF, can be protected as 4-methoxybenzyl (PMB) ethers in 94% yield. The triple bond is then m-hydrostannylated with tri-n-butyl-tin hydride and a catalytic amount of Pd(PPh3)2Cl238 to give the vinylstannane 76 in 98 % yield. Note that the stereospecific nature of the m-hydrostannylation absolutely guarantees the correct relative stereochemistry of C-3 and C-4 in the natural product. The other partner for the Stille coupling, vinyl iodide 78, is prepared by... 

Polymerization using the Stille coupling, the cross-coupling of aryl-alkenyl halides with organotins in the presence of palladium catalysts (Scheme 9.10),13 appeared in 1989 (Scheme 9.11).14 The low nucleophilicity of organotins makes it possible to use functionalized monomers for the polymerization.15... 

Scheme 6.37 The Stille coupling under Nolan conditions...

The Stille coupling reaction is very versatile with respect to the functionality that can be carried in both the halide and the tin reagent. Groups such as ester, nitrile, nitro, cyano, and formyl can be present, which permits applications involving masked functionality. For example, when the coupling reaction is applied to l-alkoxy-2-butenylstannanes, the double-bond shift leads to a vinyl ether that can be hydrolyzed to an aldehyde. 

Reductive cyclization of 2-formyl-2 -nitrobiaryl compounds gives phenanthridine derivatives.136 The Stille coupling of nitroarylstannanes with 2-bromobenzaldehyde are used for the preparation of the requisite 2-formyl-2 -nitrobiaryls. Subsequent treatment of biphenyl derivatives with zinc dust in acetic acid gives the phenanthridine derivatives as shown in Eq. 10.80.137... 

Compounds 575, obtained by the Stille coupling reaction, react with PTAD to give high yields of the Diels-Alder products 576 obtained with good to excellent asymmetric induction (Equation 81) <1995SL1264>. 

Among the many applications of fluorous chemistry is the Stille coupling of tin reagents with fluorinated tags in which the products and excess of the tin-containing reagents can be conveniently removed from the reaction mixture, and recycled. Un-... 

Similarly, Lehn and co-workers reported the Stille coupling of stannane 91 with bromoanthracene 92 to provide aminopyrimidine 93 after deprotection <00T6701>. These 2-aminopyrimidines were utilized in molecular recognition studies. 

Bailey described the first application of the Stille coupling to pyrroles, and one of the earliest examples of any such reaction involving heterocycles [66]. Lithiation of IV-methylpyrrole and quenching with trimethylstannyl chloride gives 2-(trimethylstannyl)pyrrole (76), and palladium-catalyzed coupling with iodobenzene affords l-methyl-2-phenylpyrrole (46) in good yield. 

As a synthetic route to the grossularine natural products, Hibino and Potier independently studied the Stille coupling of ethyl 3-iodo-2-indolylcarboxylate, and / -protected analogs, with imidazolylstannanes [188-192], An example is illustrated for 180 to 182 [191]. During the course of their studies in this area, Hibino and co-workers discovered an interesting case of cine-substitution, which seems to be the first such example in heterostannane reactions [190]. 

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). 

Interestingly, adduct 89, resulting from the Stille coupling of a pyridylstannane 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]. 

Other tin reagents have found use in Pd-catalyzed cross-couplings with halopyridines as well. The Stille coupling of 3-iodopyridine with ethoxy(tributylstannyl)acetylene gave rise to 3-ethoxyethynylpyridine (100), which was then hydrolyzed to the corresponding ethyl 3-pyridylacetate (101) [88], Carbamoylstannane 102 was prepared by sequential treatment of lithiated piperidine with carbon monoxide and trimethyltin chloride. Stille coupling of carbamoylstannane 102 and 3-bromopyridine provided a unique entry to amide 103 [89],... 

A Stille coupling of a bromopyridine on solid support was described by Snieckus group [101]. Merrifield resin 119 was esterified with 3-bromopyridine-5-carboxylic acid to afford ester 120. The Stille coupling of ester 120 on a solid support led to the expected hetero phenylpyridine 121, which was then cleaved via basic hydrolysis to produce 122. Snieckus work has the potential for application to combinatorial chemistry and high throughput screening. 

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