Heck-Mizoroki reaction sequences

Much of the chemistry of organic transition metal compounds becomes more understandable if we are able to follow the mechanisms of the reactions that occur. These mechanisms, in most cases, amount to nothing more than a sequence of reactions, each of which represents a fundamental reaction type that is characteristic of a transition metal complex. Let us examine three of the fundamental reaction types now. In each instance we shall use steps that occur when an alkene is hydrogenated using a catalyst called Wilkinsons catalyst. In Section G.7 we shall examine the entire hydrogenation mechanism. In Section G.8 we shall see how similar types of steps are involved in the Heck—Mizoroki reaction. 

The Heck-Mizoroki reaction has also been heavily applied in one-pot sequential reaction sequences. The topic of sequential, domino, consecutive, or tandem catalytic reactions is a very timely subject, as at its core is efficiency, economy, and waste minimization in organic synthesis. In 2010 [59], one of us published a review of this topic which explains the current state of play and includes relevant references on the subject. However, the topic is still rather murky in terms of definitions, and this is something that we feel needs urgent attention. The Heck-Mizoroki is a very suitable transformation for inclusion in a sequential catalytic process, given that it leads to the formation of C=C units, a common functionality for further catalytic transformation. 

For nongroup-selective examples, one of the first reports of an enantioselective intramolecular Mizoroki-Heck reaction was a polyene cyclization (Scheme 12.22) [23b], The trienyl triflate 5 underwent two intramolecular cyclization reactions to give the tricycle 6 in high yield and 45% ee. A cascade intramolecular Mizoroki-Heck-hydride capture sequence was used in the synthesis of retinoid derivatives from aryl iodide 100 to give benzofuran 101 in 80-81% ee [49]. Poor enantioselectivity was observed when neutral reaction conditions were employed. 

An impressive reaction sequence for the modular synthesis of tetraarylated alkenes involving two directed Mizoroki-Heck reactions is outlined in Scheme... 

The Mizoroki-Heck reaction is a metal catalysed transformation that involves the reaction of a non-functionalised olefin with an aryl or alkenyl group to yield a more substituted aUcene [11,12]. The reaction mechanism is described as a sequence of oxidative addition of the catalytic active species to an aryl halide, coordination of the alkene and migratory insertion, P-hydride elimination, and final reductive elimination of the hydride, facilitated by a base, to regenerate the active species and complete the catalytic cycle (Scheme 6.5). 

The first example of an enantioselective intramolecular cascade Mizoroki-Heck-cyanation sequence was recently reported which included the reaction of amide 104 (Scheme 12.24) [33], The cyanide source employed was potassium ferro(II)cyanide, which has been utilized for the palladium-catalysed cyanation of aryl halides. The proposed reaction pathway for the Mizoroki-Heck-cyanation involves capture of a a-alkylpalladium intermediate. Previous examples of enantioselective Mizoroki-Heck cyclization-anion capture most often involve trapping of the 7r-allylpalladium complexes in group-selective reactions. Reaction conditions were surveyed for the Mizoroki-Heck cyanation sequence. It was found that Pd(dba)2 afforded better enantioselectivities than Pd(OAc)2 with Ag3P04 as the additive. Using PMP under neutral conditions led to racemic product. To improve the enantioselectivity, several bidentate ligands were screened, and the ligand DIFLUORPHOS 54a was found to give the best enantioselectivity. 

Shibasaki and coworkers [40] also demonstrated the use of soft carbanionic nucleophiles, initially sodium dimethyl malonate, in cascade asymmetric Mizoroki-Heck cyclization- j -allyl trapping sequences. This conversion succeeds with various soft carbanionic nucleophiles to provide functionalized bicyclo[3.3.0]octane derivatives 55 in excellent yields (72-92%) and up to 94% ee (Scheme 16.13). The enantioselectivity of these Mizoroki-Heck reactions is significantly diminished in the absence of NaBr a speculative rationale to account for the effect of the NaBr additive has been advanced [40]. 

The use of carbanionic nucleophiles in the Mizoroki-Heck cyclization-/ -allyl nucleophilic trapping sequence allowed for streamlined access to the triquinane core common to various members of the capnellene family of natural products. For example, Shibasaki and coworkers obtained diquinane 57 in 77% yield and 87% ee by Mizoroki-Heck cy-clization of trienyl triflate 47 in the presence of malonate nucleophile 56 Scheme 16.14). It is notable that two new C-C bonds and three stereocentres are generated in this reaction. Eleven additional steps were used to convert intermediate 57 to ( )-A ( Ecapnellene (58). This first catalytic asymmetric total synthesis ( )-A d2). j pjjgjjgjjg achieved in 19 steps and 20% overall yield from commercially available materials. A related approach has recently been employed to prepare intermediates en route to capnellenols 53 and 54 (Scheme 16.12) [41]. 

The identification of novel ways to incorporate an asymmetric intramolecular Mizoroki-Heck reaction as part of a cascade cyclization sequence has led to attractive approaches for assembling complex polycyclic molecules. Keay and coworkers [54] reported the use of a double Mizoroki-Heck cyclization as the pivotal step in the asymmetric total synthesis of xestoquinone (93), a reduced congener of halenaquinone (Scheme 16.20). In this step, naphthyl triflate 90 was cyclized with Pd2(dba)3 (dba = dibenzylideneace-tone), (5 )-BINAP and 1,2,2,6,6-pentamethylpiperidine (PMP) in toluene at 110°C to give pentacyclic product 92 with impressive efficiency and moderate enantioselectivity. This conversion proceeds by initial asymmetric 6-exo Mizoroki-Heck cyclization to form the central six-membered carbocycle and install the benzylic quaternary stereocentre. The first cyclization event is followed by a second Mizoroki-Heck reaction in which neopentyl... 

Equation 14.4 shows how a Buchwald-Hartwig amination can be combined with a Mizoroki-Heck reaction in a tandem sequence... 

In Scheme 26.24, examples of an RCM/isomerization/tautomerization sequence by Yoshida et al. are shown [30]. After RCM of 4-methylene-l,7-octadien-3-ones 81, synthesis of phenols 83 was accomplished by Rh-catalyzed isomerization of the carbon-carbon double bond of the RCM products 82 from exo to endo, followed by spontaneous tautomerization. The same group also showed that the Mizoroki-Heck reaction could be used as an alternative to the isomerization described above (Scheme 26.25) [30]. In the presence of a catalytic amount of Pd(OAc)2, RCM product 82... 

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