Intermolecular Mizoroki-Heck Reactions

Asymmetric intermolecular Mizoroki—Heck reaction From phosphine/ phosphinite-nitrogen to phosphite-nitrogen hgands 12IJC572. Asymmetric palladium-catalyzed intramolecular Wacker-type cycliza-tions of unsaturated alcohols and amino alcohols to give O- and N-het-erocycles 13MOL6173. 

In 1990, Cabri el al. [40a] reported that the precursor Pd(OAc>2 associated with a biden-tate P P ligand as dppp (1,3-bis-diphenylphosphinopropane) appeared to be more efficient than PPhs in Mizoroki-Heck reactions performed from aryl Inflates and enol ethers (electron-rich alkenes) moreover, the regioselectivity in favour of the a-arylated alkenes was improved to 100%. Since that time, dppp associated with Pd(OAc)2 has been used extensively to catalyse Mizoroki-Heck reactions and to investigate the factors that control the regioselectivity [Ig, 40]. The chiral bidentate (7 )-Binap (2,2 -bis(diphenylphosphino)-1,1-binaphthyl) associated with Pd(OAc)2 has also been used by Shibasaki and coworkers [2b,d,41a] and Overman andPoon [41b] in intramolecular enantioselective Mizoroki-Heck reactions (also, see Link [2f] for an authorative review on the Overman-Shibasaki chemistry), as well as by Hayashi and coworkers [2a, 41c,d] to control the regioselectivity and enantioselectivity of intermolecular Mizoroki-Heck reactions performed from cyclic alkenes (see Schemes 1.3 and 1.2 (Z = O) respectively). 

There are two major realizations of the polar pathway in intermolecular Mizoroki-Heck reactions (1) enantioselective arylation of cyclic alkenes (Chapter 11) and (2) regioselective internal arylation of terminal alkenes (Chapter 3). 

Their role in the Mizoroki-Heck reaction is different. An analysis of published data shows that, in the intermolecular Mizoroki-Heck reaction, the use of carbene ligands is... 

Figure 3.2 Regiochemical outcome of the intermolecular Mizoroki-Heck reaction with mono-substituted alkenes.

This chapter provides a survey of the literature up to the end of 2007 dealing with the asymmetric intermolecular Mizoroki-Heck reaction, specifically focusing on ligand design for this important transformation. 

The first example of the asymmetric intermolecular Mizoroki-Heck reaction was reported by Hayashi and coworkers [8] in 1991. This involved the asymmetric arylation of 2,3-dihydrofuran (1) with aryl triflates using a palladium/(7 )-BINAP (BINAP = 2,2 -bis(diphenylphosphino)-l,F-binaphthyl) catalytic system (Scheme 11.4). 

Scheme 11.4 First catalytic asymmetric intermolecular Mizoroki-Heck reaction.

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). 

Keay and coworkers [22-24] synthesized the novel furan-derived diphosphine ligands, TetFuBINAP (29) and BlNAPFu (30) and applied them to the asymmetric intermolecular Mizoroki-Heck reaction of 2,3-dihydrofuran (1) and phenyl triflate (2) (Scheme 11.15). 

Scheme 11.24 Intermolecular Mizoroki-Heck reaction using ligands 60 and 61.

Grether and Waldmann [15] developed an enzyme-labile safety catch linker 1 tested in intermolecular Mizoroki-Heck reactions (Scheme 14.1). This linker releases alcohols and amines through enzymatic cleavage of the benzylamide moiety followed by snbsequent lactam formation. After a Mizoroki-Heck reaction performed on an immobilized iodoarene... 

In general, intermolecular Mizoroki-Heck reactions using immobilized alkenes are not as common as the variant that deals with solid-supported aryl halides, but we will come across another example in Section 14.2,3 on multicomponent Mizoroki-Heck reactions. 

The intermolecular Mizoroki-Heck reaction in macrocyclization of peptides was demonstrated by Byk et al. [207]. The reactions were done out in milligram scale with 15-25% yield. The Pd/C-catalysed Mizoroki-Heck reaction of aryl halides and butyl acrylate performed in an excellent manner. The catalyst could be reused five times without loss of activity [208]. Yields up to 90% could be achieved using bromoarenes and a catalyst loading of 1.5 mol% in a few minutes reaction time. 

Regiocontrol is a major challenge in intermolecular Mizoroki-Heck reactions, and usually results in a mixture of Unear and branched products (cf. Section 1.2.2.3 on directed Mizoroki-Heck chemistry). Both, Cabri et al. [14] and Hayashi et al. [15] showed that the nature of the ancillary Ugand L has a pronounced effect on the regioselectivity when palladium is Ugated by bidentate phosphines (Scheme... 

Over the course of the past decade, the intermolecular Mizoroki-Heck reaction has witnessed tremendous progress [9,10]. As a comprehensive survey of this area is certainly beyond the scope of this chapter, the decision was taken to include a few important developments, namely the activation of less-reactive aryl chlorides, waste-minimized processes, and novel catalyst systems. 

Over the past two decades, directed intermolecular Mizoroki-Heck reactions have been elaborated to remarkably high standards. Recently, Oestreich summarized the major advances in controlling both regio- and diastereoselectivity in these transformations [47]. With regards to the former aspect, the modular preparation of trisubstituted and tetrasubstituted alkenes is certainly a highlight within recent developments in Mizoroki-Heck chemistry [48],... 

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