Mizoroki reductive arylations

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). 

Bulky ligands as above have also proved to be effective in other palladium-catalyzed reactions of aryl halides, e.g., amination [16-19], Suzuki-Miyaura reaction [20-22], Mizoroki-Heck reaction [23, 24], Migita-Kosugi-Stille reaction [25], and aryloxylation and alkoxylation [26-28] as well as the reaction with various carbon nucleophiles as described below. The ligands are considered to enhance both the initial oxidative addition of aryl halides and the reductive elimination of products [29, 30]. The effectiveness of the commercially available simple ligand, P(f-Bu)3, was first described for the amination by Nishiyama et al. [16]. 

In contrast to PPhs, P(c -Tol)3 cannot reduce Pd (OAc)2 to a Pd(0) complex, but a P,C-palladacycle, rran5-di(/r-acetato)-bis[o-(di-o-tolylphosphino)benzyl]dipaIladium (5) is formed via a cyclometallation [27, 55]. The palladacycle 5 is an efficient catalyst for Mizoroki-Heck reactions involving aryl bromides and activated aryl chlorides (i.e. substituted by EWGs) [lj,l,o,s-v, 27, 55]. When 5 is used as catalyst in C—N crosscoupling reactions, Louie and Hart wig [56] have established that the true catalyst is aPd(0) complex, Pd P(o-Tol)3 2 formed by reduction of the palladacycle by the nucleophile (a secondary amine as a hydride donor in the presence of a strong base). 

Kinetics data on the oxidative addition are scarce. In 2003, Roland and cowoikers [71] used PdX2(Cb )2 (X = I, Cl) as an efficient precursor for Mizoroki-Heck reactions performed from aryl bromides at moderate temperatures (Scheme 1.45). Since Pd (Cb )2 could not be isolated, its reactivity with aryl halides was followed by cyclic voltammetry, the transient Pd°(Cb )2 being generated in the electrochemical reduction of the precursors PdX2(Cb )2 in DMF (Scheme 1.45). The rate constants k of the oxidative addition of aryl halides to Pd (Cb )2 have been determined (Table 1.3) [71]. 

Crystallization of HPdCl(PR3)2 (R = fBu or Cy) reveals that the P-Pd-P angle is 161° in the bent HPdCl(P-f-Bu3)2 but 180° in HPdCl(PCy3)2, which is thus less prone to reductive elimination [83]. This explains why, when using the same base, P-f-Bus is more efficient than PCy3 for Mizoroki-Heck reactions performed from aryl chlorides [77]. 

The Mizoroki-Heck reaction is a subtle and complex reaction which involves a great variety of intermediate palladium complexes. The four main steps proposed by Heck (oxidative addition, alkene insertion, )3-hydride elimination and reductive elimination) have been confirmed. However, they involved a considerable number of different Pd(0) and Pd(Il) intermediates whose structure and reactivity depend on the experimental conditions, namely the catalytic precursor (Pd(0) complexes, Pd(OAc)2, palladacycles), the Ugand (mono- or bis-phosphines, carbenes, bulky monophosphines), the additives (hahdes, acetates), the aryl derivatives (ArX, ArOTf), the alkenes (electron-rich versus electron-deficient ones), which may also be ligands for Pd(0) complexes, and at least the base, which can play a... 

Some finer effects caused by additives were reported. Thus, the use of the pair rt-Bu4NOAc-KCl was used to control the selectivity of reductive elimination in the ary-lation of acrolein acetals (Scheme 2.7). Interestingly, a more usual reverse combination KOAc- -Bu4NC1 gave worse results with respect to selectivity [54, 55], which clearly shows that the Mizoroki-Heck reaction is often extremely sensitive towards subtle details of formulation of the catalytic system. As proposed by Cacchi and coworkers [54,68] for the -Bu4NOAc-KC1 cocktail [55-57], the coordination sphere of palladium is saturated to form an anionic complex 28 (28 29 + 30), in which palladium is not capable of coordinating to the aryl tt-system as in 31 (31 30, Scheme 2.7). 

In this section, only examples of Mizoroki-Heck reactions where a proper addition of the cr -aryl- or a -alkeny Ipalladium(II) complex to a double bond of an alkene or alkyne occurs are considered. As a consequence, an often-met deviation from the classic Mizoroki-Heck mechanism, the so-called cyclopalladation, will not be treated in further detail [12, 18]. However, as it is of some importance, especially in heterocycle formation and mainly because it will be encountered later during polycyclization cases, it shall be mentioned briefly below. Palladacycles are assumed to be intermediates in intramolecular Mizoroki-Heck reactions when j3-elimination of the formed intermediate cannot occur. These are frequently postulated as intermediates during intramolecular aryl-aryl Mizoroki-Heck reactions under dehydrohalogenation (Scheme 6.1). The reactivity of these palladacycles is strongly correlated to their size. Six-membered and larger palladacycles quickly undergo reductive elimination, whereas the five-membered species can, for example, lead to Mizoroki-Heck-type domino or cascade processes [18,19]. 

Brase and coworkers [29] also reported highly enantioselective desymmetrization of rran5-bicyclo[4.4.0]decadienes 81-84, which were prepared through Birch reduction of naphthalene, epoxidation and epoxide-opening reaction (Figure 13.11). The position of C=C double bonds also differed from the previous report [25], Although a Mizoroki-Heck reaction of aryl iodide 81 with the usual chiral ligands such as BINAP, DIOP i(2R,3R)- or (25,35)-0-isopropylidene-2,3-dihydroxy-l,4-bis(diphenylphosphino)butane)... 

The present section summarizes reductive Mizoroki-Heck-type arylations-that is, palladium-catalyzed hydroarylation reactions of alkenes-which are essentially limited to (hetero-)norbomenes (Section 7.3.2). It should be noted however, that only a handful of remarkable examples are known that are not based on the bicyclo[2.2.1]heptane framework (see Section 7.3.3). 

Scheme 7.35 Simplified catalytic cycle of reductive Mizoroki-Heck-type arylations.

Extension of the asymmetric hydroarylation to oxanorbornenes, as well as aza-norbornenes, was the obvious step forward. Fiaud et al. made several remarkable observations while examining the reductive Mizoroki-Heck-type arylation of the annulated 7-oxanorbornene 160 (Scheme 7.37) [100]. First, intermediate o-aUcyl... 

Reductive Mizoroki-Heck couplings of azanorbornenes would allow for short syntheses of the alkaloid epibatidine [102-104] and analogues thereof [104, 105]. Kaufmann et al. elaborated a straightforward one-step enantioselective access to N-protected epibatidine 165 (Scheme 7.38) [102,103]. Hydroarylation of 7-azanor-bornene 163 with functionalized aryl iodide 164 produced 165 in moderate yield with good enantiomeric excess [103]. Zhou et al. later tested a ligand similar to 158 (Figure 7.3) in the same reaction, and with a number of other heteronorbom-enes (49-85% ee) ]104]. 

Reductive Mizoroki-Heck-Type Arylation in Action... 

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