Stille-coupling

Stille coupling was also developed in tlie early 1980s and is similar to Suzuki coupling in its sequence. It is used to couple aryl or vinyl halides or triflates with organotin compounds via oxidative addition, transmetallation, and reductive elimination. The oxidative addition reaction has tlie same requirements and preferences as discussed earlier for tlie Heck and Suzuki reactions. The reductive elimination results in formation of tlie new carbon-carbon bond. The main difference is that tlie transmetallation reaction uses an organotin compound and occurs readily without the need for an oxygen base. Aryl, alkenyl, and alkyl stannanes are readily available. Usually only one of tlie groups on tin enters into 

Coupling of an aryl triflate with an arylstannane is a good mediod for the preparation of biaryls and other bis-aromatic species of all types. Coupling of vinyl groups takes place with retention of stereochemistry. Furdiermore transfer of die allyl group occurs smoothly. 

This is very robust chemistry that works very well with enol tridates. Intramolecular reactions have been used to close rings of many sizes, including large rings. 

The use of (Me3Sn)2 provides a unique way to convert vinyl and aryl halides into die very tin reagents needed for subsequent Stille couplings  

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. 

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. 

In 2002, Nikolaides et al. reported the coupling of quinolinyl-8-triflate with Et4Sn to synthesize 8-ethylquinoline in 74% yield (2002SC2027). 

Palladium-catalyzed cross-coupling reaction of organostannanes with organic halides, triflates, etc. For the catalytic cycle, see Kumada coupling on page 345. 

Milstein, D. StiUe, 1. K. J. Am. Chem. Soc. 1978, 100, 3636. John Kenneth Stille (1930-1989) was bom in Tncson, Arizona. He developed the reaction bearing his name at Colorado State University. At the height of his career, StiUe nnfortunately died of an airplane accident returning from an ACS meeting. 

Farina, V. Krishnamurphy, V. Scott, W. J. Org. React. 1997, 50, 1-652. (Review). For an exceUent review on the intramolecular Stille reaction, see, Duncton, M. A. J. Pattenden, G. J. Chem. Soc., Perkin Trans. 1 1999, 1235. (Review). 

Samuelsson, L. Langstrom, B. J. Labelled Comd. Radiopharm. 2003, 46, 263. MitcheU, T. N. Organotin Reagents in Cross-Coupling Reactions. In Metal-Catalyzed Cross-Coupling Reactions (2nd edn) De Meijere, A. Diederich, F. eds., 2004, 1, 125-161. WUey-VCH Weinheim, Germany. (Review). 

Palladium-catalyzed intramolecular cross-coupling reaction of bis-aryl halides using ditin reagents. 

Name Reactions, 4th ed., DOI 10.1007/978-3-642-01053-8 246, Springer-Verlag Berlin Heidelberg 2009 

Mascitti, V. Stille Coupling. In Name Reactions for Homologations-Part 1 Li, J. J., Corey, E. J., Eds. Whey Sons Hoboken, NJ, 2009, pp 133-162. (Review). 

Name Reactions A Collection of Detailed Mechanisms and Synthetic Applications, DOI 10,1007/978-3-319-03979-4 264, Springer International Publishing Switzerland 2014 

For an excellent review on the intramolecular Stille reaction, see, Duncton, M. A. J. Pattenden, G. J. Chem. Soc., Perkin Trans. 11999,1235. 

In total synthesis papers, most reported Stille reactions involving oxazoles occur remotely to the oxazole ring. Most papers detailing direct Stille reaction of an oxazole ring are methodology papers. Williams showed that 2-phenylsulfonyl-5-stannyloxazole is a competent coupling partner with a vinyl iodide in a Stille reaction, and Taylor utilized a series of 2-chlorooxazoles as coupling partners for Stille reaction with 

Medicinally relevant, Doi, Takahashi and co-workers derivatized the tris-oxazole subunit of the antiproliferative telomestatin with a Stille reaction (as well as Suzuki reaction and Pd-catalyzed amination reaction) utilizing a 5 -bromooxazole 

The reaction between an organic electrophile 1 and an organostannane 2 mediated by a transition metal catalyst (originally palladium) to form a new sigma carbon carbon bond is referred to as the Stille cross-coupling reaction (equation 1). 

Commonly used organic electrophiles involve C(sp ) hybridized carbon as coupling partners like in acid chlorides, (hetero)aryl halides (Cl, Br, I) and triflates, alkenyl halides and triflates activated C(sp ) hybridized carbon like allyl halides and acetates, benzyl halides are also used. Recently the use of unactivated alkyl halides has also been reported. Aryl sulphonyl chlorides and arenediazonium salts have also been used as organic eletrophiles. 

Organotin reagents involving C(sp ) or C(sp) hybridized carbons, like in alkenyl, aryl, heteroaryl, alkynyl organostannanes, are the most widely used. Examples of use of allyl and alkyl organotin compounds are also reported. The relative order of ligand transfer from the organostannane is alkynyl alkenyl aryl allyl benzyl alkyl. 

The catalyst used is often palladium (0) (like Pd(PPh3)4, Pd2(dba)3), or a source of palladium (II) (like Pd(OAc)2, BnPdCl(PPh3)2 to name a few that gets reduced to the active species palladium(O) in situ. Methods using other metals like manganese, copper, and nickel have been reported the latter has been applied for instance in the successful Stille coupling of unreactive aryl chlorides as well as in the coupling of unactivated primary and secondary alkyl halides.  

The Stille coupling is usually carried out in a dipolar solvent (like DMF, DMSO or NMP) or in an ethereal solvent (like THE or dioxane). 

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The Suzuki coupling of arylboronic acids and aryl halides has proven to be a useful method for preparing C-aryl indoles. The indole can be used either as the halide component or as the boronic acid. 6-Bromo and 7-bromoindolc were coupled with arylboronic acids using Pd(PPh3)4[5]. No protection of the indole NH was necessary. 4-Thallated indoles couple with aryl and vinyl boronic acides in the presence of Pd(OAc)j[6]. Stille coupling between an aryl stannane and a haloindole is another option (Entry 5, Table 14.3). 

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). 

Together with reactions named after Heck and Suzuki, the Stille reac-tion belongs to a class of modern, palladium-catalyzed carbon-carbon bond forming reactions. The palladium-catalyzed reaction of an organotin compound 2 with a carbon electrophile 1 is called Stille coupling. 

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 ... 

Scheme 5.2-19 Pd-catalyzed Stille coupling of a-iodoenones with vinyl and aryl stannanes in...

A distinguishing feature of the Nicolaou synthesis of rapamycin is the use of a palladium-mediated tandem inter-/intramolecular Stille coupling to construct rapamycin s 31-membered macrolide ring and conjugated triene moiety. This maneuver was unprecedented in the macrolide field,9 and it can be applied to a fully deprotected seco substrate (vide infra). 

Scheme 32. Stille couplings of regioselectively generated enol triflates with a vinylstannane.

Scheme 37. Baldwin s approach to y-oxo-a,/ -unsaturated macrocycles by intramolecular Stille coupling.

Our strategy is based on the premise that the 31-membered ring and the conjugated triene array of the natural product could be fashioned simultaneously by a tandem inter-/intramolecular Stille coupling. Moreover, the mild conditions under which Stille couplings can be performed fueled hopes that the crucial stitching cycliza-tion could be conducted on a fully deprotected seco bis(vinyl iodide) (see 145, Schemes 40 and 54) the stitching cyclization would thus be the final operation in the synthesis. 

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... 

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