Reaction Stille

2 Stille Reaction Stille coupling is a versatile C—C bond-forming reaction between stannanes and halides or pseudohalides. A Pd(0) or Pd(ll) catalyst was used 

Over the past decades, one of the most important families of natural products has attracted significant attention from synthetic chemists. Their structures contain a cyclic 

A Stille coupling reaction always takes place between two sp carbon atoms. For example, treatment of vinyl or aryl halides or triflates with vinyl or aryl organostan-nanes would lead to the formation of diene (or higher polyene) systems. A more useful application of the Stille reaction is when the diene generated serves as a transient intermediate which will undergo additional reactions and participate in the cascade sequence. 

Diels-Alder reaction, which ultimately generated panepophenanthrin in an impressive 75% overall yield. This impressive cascade seqnence was found to be rather efficient in terms of stereo- and regiochemical control, demonstrating the power of this biomimetic approach. 

The Stille reaction [41] is a general, selective, and multifaceted palladium-catalyzed reaction used to construct C—C bonds [42]. It proceeds via Pd-catalyzed coupling of organic electrophiles such as unsaturated halides, sulfonates, or triflates with functionalized organostannanes. Although it is nowadays considered a standard method in organic synthesis, recent modifications and variants of the Stille reaction have opened up a multitude of new and highly attractive synthetic possibilities. 

Eberlin and coworkers, [43] performed a ESI( + )-MS(/MS) investigation in which key Pd intermediates involved in the major steps of a real catalytic cyde of a Stille reaction were detected. The well-known working-model mechanism of the Stille [44] 

For the Stille reaction, on-line ESI( + )-MS(/MS) monitoring allowed interception and characterization of (a) the actual catalytically active species Pd(Ph3)2, (b) the oxidative addition product 60a as the corresponding ionic species 60b, and (c) the transmetalation intermediate 62a and two products of this process 63a and 64. Gas phase reductive elimination (for 65 ) was observed. Therefore, for the first time, most of the major intermediates of a Stille reaction were intercepted, isolated, and characterized. Using ESI(-)-MS, the counteranion I was the single species detected. 

The free Pd NPs in ILs were also used as catalysts for the Stille cross-couphng reactions of aryl bromides and chlorides [46]. In the absence of hgands, the IL-mediated free Pd NPs in the solvent of molten salt [Hept4N]Br can catalyze the Stille coupling of aryl bromides or chlorides and tributylphenyl stannane, and 85% yields can be achieved. 

Solvent Time (h) Catalyst Mass balance (%) Conversion (%) 

This chemistry was repeated with a traceless photolabile linker.60 The desired biphenyl was formed, but the couplings gave side products, and all yields of the desired biphenyl were lower than 30%. 

Chemistry similar to this was used in Ellman s paper to promote application of a silicon-based traceless linker.62 The full report on this work63 shows that both aliphatic and aromatic acid chlorides may be used in the coupling step. The same,approach is also shown to be successful with a germanium-based linker in place of the silicon. The couplings were typically performed for 1 h only, with equilibration time of a few minutes 

The copper-catalyzed coupling of polymer-bound aryl iodides with stannanes has also been demonstrated.64 

The Suzuki reaction was used in liquid crystal syntheses67 to modify the properties of a polymer by the introduction of aromatic groups to a boronic acid functionalized backbone. Palladium-catalyzed couplings have found wide use in this field.68,69 

A variety of conditions were tried for the coupling, and aqueous KOH in DME were found to be optimal. Although Pd(PPh3)4 and PdCl2(PPh3)2 worked equally well as catalysts, the latter was easier to handle, and this becomes an important issue when many reactions must be run to make a library. The resin-bound vinyl boronates 29, which would be produced if the order of addition of halides were different, were not stable with respect to deboration, and subsequent yields using this strategy were low. 

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Vinylation can also be done by Pd-catalysed cross-coupling in which one component is used as a halide or triflate and the other as a stannane (Stille reaction) or boronic acid (Suzuki reaction). Entry 9, Table 11.3, is an example of the use of a vinylstannane with a haloindole. lndole-3-boronic acids, which can be prepared by mcrcuration/boration, undergo coupling with vinyl triflates (Entry 10). 

Intramolecular Pd(0)-catalyzed Stille reaction of organotin reagents with electrophiles leading to C—C a-bond formation in synthesis of heterocycles, particularly, macrocyclic lactones 99JCS(P1)1235. 

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).

Scheme 36. Piers s annulation strategy based on the intramolecular Stille reaction.

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. 

In 2003 LJngstrOm and Samuelsson described the synthesis of a radiopharmaceutical for PET (positron emission tomography) using a microwave-assisted Stille reaction [25]. l-(2 -Deoxy-2 -fluoro- 6-D-arabinofuranosyl)-... 

J ,3J ,4J ,5J )-2,5-bis(benzyloxy)-3,4-dihydroxy-Nd -bis (lS)-2-methyl-l-[(methylamino)carbonyl]propyl hexanediamide is a C2-symmetric HIV-1 protease inhibitor [29]. Derivatization in the para positions of the benzyl-oxy groups via microwave-assisted Stille reaction on the corresponding di-brominated inhibitor smoothly yielded the desired heteroarylated derivatives (Scheme 10). Interestingly, the 1,3-thiazole derivative showed a higher antiviral activity on the wild type virus than the lead compound. The activity remained at the same level in the presence of seriun. Unfortimately, a low activity was observed on mutants. 

In the frame of a medicinal project at J J Pharmaceutical Research and Development aimed at designing new potent and selective glycogen synthase kinase-3/i (GSK-3/3) inhibitors, the C-3 derivatization of the 1-methyl-4-[l-alkyl-lff-indol-3-yl]-lff-pyrrole-2,5-dione scaffold was explored [31]. Microwave-assisted Stille reaction of 3-chloro-l-methyl-4-[l-alkyl-lff-indol-3-yl]-lH-pyrrole-2,5-diones with (2,4-dimethoxy-5-pyrimidinyl)(tributyl) stannane at 200 °C yielded in 6 min the desired 3,4-diaryl-lff-pyrrole-2,5-diones in moderate yields (Scheme 12). 

The synthesis of semiconducting polymers using microwave-assisted Stille reactions has also been studied [32]. The applied power was crucial for... 

For example, the sensitive imidoyl chloride moiety at the C-3 position of the pyrazinone scaffold is known to vmdergo Stille reactions with a variety of tetraaryltin reagents, generating the corresponding 3-substituted pyrazi-nones (Scheme 10) [26]. Furthermore, the transition-metal-catalyzed stannyl-ation at the C-3 position is also documented in the hterature, in view of cross-couphng with a variety of alkyl and (hetero)aryl hahdes [26]. However, this strategy is completely restricted to the C-3 position, while the Cl atom of C-5 position was found to be inert under these conditions. 

Scheme 11 Stille reactions under microwave irradiation...

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