Asymmetric Mizoroki-Heck reaction

The palladium-catalysed Mizoroki-Heck reaction is the most efficient route for the vinyla-tion of aryl/vinyl halides or triflates. This reaction, in which a C—C bond is formed, proceeds in the presence of a base (Scheme 1.1) [1, 2], Nonconjugated alkenes are formed in reactions involving cyclic alkenes (Scheme 1.2) [le, 2a,c,e,g] or in intramolecular reactions (Scheme 1.3) [2b,d-g] with creation of stereogenic centres. Asymmetric Mizoroki-Heck reactions may be performed in the presence of a chiral ligand [2], The Mizoroki-Heck reaction has been intensively developed from a synthetic and mechanistic point of view, as expressed by the impressive number of reviews and book chapters [1,2]. 

The o-aminophenyl-directed asymmetric Mizoroki-Heck reaction can also be applied to intramolecular reactions [30]. For example, when alkenyl iodide 63 is subjected to palladium catalyst, Mizoroki-Heck cyclization furnishes 64 with almost complete diastereose-lectivity (Figure 7.21). An asymmetric reaction utihzing an enantiomerically pure sulfoxide unit is also possible. 

Ligand Design for Intermolecular Asymmetric Mizoroki-Heck Reactions... 

Scheme 11.3 Inter- and intra-molecular asymmetric Mizoroki-Heck reactions.

For this reason, two general types of asymmetric Mizoroki-Heck reaction, as illustrated in Scheme 11.3, have been the subject of most investigations ... 

Scheme 11.6 Mechanism of intermolecular asymmetric Mizoroki-Heck reaction of 2,3-dihydrofuran (1).

While 2,3-dihydrofuran (1) was the initial test substrate of choice for the intermolecular asymmetric Mizoroki-Heck reaction, the reaction was also applied to 2,3-dihydropyrrole 12, which shows similar patterns of both regio- and stereoselectivity to 2,3-dihydrofuran (1) [16], The intermolecular Mizoroki-Heck reaction with substituted 2,3-dihydropynole 12 and aryl triflates 13 gave mixtures of the 2-aryl-2,3-dihyropym)les 14 and the 2-aryl-2,5-dihydropyrroles 15, with the 2,3-product being the major product formed with a 74% ee (Scheme 11.9). 

Shibasaki and coworkers [18] carried out the intermolecular asymmetric Mizoroki-Heck reaction with dihydrodioxepines 20 using the palladium-(50-BlNAP catalytic system (Scheme 11.11). The product 21 was obtained in yields up of to 86% and with up to 75% ee. When the aryl group on the triflate 13 was changed, the enantioselectivity was not found to vary appreciably. 

Scheme 11.8 Intermolecular asymmetric Mizoroki-Heck reaction of hypervalent alkenylio-dinium salt 10.

Scheme 11.12 A new substrate for the intermolecular asymmetric Mizoroki-Heck reaction.

While BDSfAP (5) has been one of the most successful ligands employed in the intermolecular asymmetric Mizoroki-Heck reaction, many other diphosphine ligands have also been synthesized and tested. Sannicolo and coworkers [20] synthesized novel thiophene-derived axially chiral diphosphine ligands 24 and 25 and applied these to the intermolecular Mizoroki-Heck reactiou of 2,3-dihydrofuran (1) (Scheme 11.13). 

Scheme 11.13 Intermolecular asymmetric Mizoroki-Heck reaction using thiophene diphosphine ligands.

Ligand Design for intermolecular Asymmetric Mizoroki-Heck Reactions 415... 

To date, the large majority of asymmetric Mizoroki-Heck reactions reported have utilized palladium complexes of BINAP (5). However, since their first application to the asymmetric Mizoroki-Heck reaction, P,N ligands have proven successful and have thus received a greater amount of attention recently [30], The phosphinooxazoline PJSl ligands 41-45 developed independently by the groups of Pfaltz [31], Williams [32] and Hehnchen [33] have shown dramatic improvement in enantioselectivity in a number of asymmetric transformations, including the intermolecular asymmetric Mizoroki-Heck reaction [34]. 

Scheme 11.20 Selected examples of Intermolecular asymmetric MIzoroki-Heck reactions using ligand 42.

Pfaltz and coworkers [43] developed P,N ligands 73 and 74 derived from pyridine and quinoline. They reasoned that oxazoline and pyridine/quinoline ligands, since they have different electronic effects, would induce different patterns of reactivity and selectivity in the asymmetric Mizoroki-Heck reaction. In the reaction of phenyl triflate (2) with... 

Furthermore, these ligands were tested in the phenylation of cis- and trans-crotyl alcohols 79. This was the first reported asymmetric Mizoroki-Heck reaction of an acyclic alkene. Using phenyl trifiate (2) resulted in no conversion after 3 days, whereas the reaction proceeded with good conversions (up to 76%) when phenyl iodide (80) was used, albeit with low enantiomeric excess (up to 17%) (Scheme 11.26). 

Dai et al. [55] reported the only example of P,0 ligands applied to the asymmetric Mizoroki-Heck reaction. The atropisomeric amide-derived ligands 88 were applied to the reaction of phenyl triflate (2) and 2,3-dihydrofuran (1). Conversions were low (<30%) in all cases, although moderate enantioselectivity was observed (52% ee, ligand 88a). 

Ligand Design for Intermolecuiar Asymmetric Mizoroki-Heck Reactions 431... 

Scheme 12.1 Representative intramolecular asymmetric Mizoroki Heck reaction types.

The suggestion is then made that the stereoconlrolling step in asymmetric Mizoroki-Heck reactions is oxidative addition (via dynamic kinetic resolution) rather than alkene association or migratory insertion. The implication is that only substrates capable of a dynamic kinetic resolution may cyclize with high enantioselectivity. This would limit the substrate scope of the asymmetric intramolecular Mizoroki-Heck reaction. While the dynamic kinetic resolution during the oxidative addition may be a component of the overall stereoselectivity, it does not rule out contributions from later events in the mechanistic pathway and does not explain the effect of additives on selectivity. What has been shown is that the axial chirality of the o-iodoanilides (as with any enantioenriched isomer of a chiral precursor) influences the stereochemical outcome of their reactions. 

Figure 13.3 Neutral and cationic pathways for the asymmetric Mizoroki-Heck reaction.

Figure 13.4 Optimization of the asymmetric Mizoroki-Heck reaction of an alkenyl iodide.

In 1992, Feringa and coworkers developed an efQcient intramolecular asymmetric Mizoroki-Heck reaction of prochiral cyclohexadienones 37 to tricyclic compound 40. This transformation required inversion of the C2 stereocentre in intermediate 38 by enolization (38-> 39) in order to make a synperiplanar C—H bond available for the subsequent syn fi-hydride elimination (39-> 40) (Figure 13.8) [21a]. Upon this asymmetric Mizoroki-Heck reaction, the stereogenic centre is not created at the site of the C—C bond formation, but... 

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