Mizoroki-Heck reaction regioselectivity

The mechanisms of Mizoroki-Heck reactions performed from aryl derivatives are presented herein by highlighting how the catalytic precursors, the bases and the ligands may affect the structure and reactivity of intermediate palladium(O) or palladium(II) complexes in one or more steps of the catalytic cycle and, consequently, how they may affect the efficiency and regioselectivity of the catalytic reactions. 

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). 

Regioselectivity is one of the major problems of Mizoroki-Heck reactions. It is supposed to be affected by the type of mechanism ionic versus neutral, when the palladium is ligated by bidentate P P ligands. The ligand dppp has been taken as a model for the investigation of the regioselectivity. Cabri and Candiani [Ig] have reported that a mixture of branched and linear products is formed in Pd°(P P)-catalysed Mizoroki-Heck reactions performed from electron-rich alkenes and aryl halides (Scheme 1.26a) or aryl ttiflates in the presence of halide ions (Scheme 1.26b). This was rationalized by the so-called neutral mechanism (Scheme 1.27). The neutral complex ArPdX(P P) is formed in the oxidative addition of Pd°(pAp) yj Qj. Q aj.yj triflates in the presence of halides. The carbopalladation... 

Scheme 1.29 Textbook ionic mechanism for the regioselectivity of Mizoroki-Heck reactions.

In more recent studies by Xiao and coworkers [40m,n], Mizoroki-Heck reactions catalysed by Pd(OAc)2 associated with dppp and performed from the eleclron-rich alkene ( -butylvinyl ether) and aryl halides (without any halide scavenger, i.e. under the conditions of the textbook neutral mechanism of Scheme 1.27 proposed by Cabri and Candiani [Ig]) give a mixture of branched and linear products in DMF, whereas the branched product is exclusively produced in ionic liquids (in the absence of halide scavengers) in a faster reaction. Whatever the medium, the cationic complex ArPd5(dppp)+ is always the sole reactive complex with electron-rich alkene (Scheme 1.33) [53]. Consequently, the regioselectivity should not vary with the experimental conditions. 

Scheme 1.35 Mechanism which rationalizes the regioselectivity of Mizoroki-Heck reactions in DMF when P P= dppp (the C—C internal rotation in complexes 3+, 3 +, 4 and 4 is omitted for more clarity).

As established above, the regioselectivity of Mizoroki-Heck reactions performed in DMF is sensitive to the presence of coordinating anions such as hahde or acetate (Scheme 1.35). The carbopalladation step always proceeds from the more reactive cationic complex ArPd5"(dppp)+ (Schemes 1.35 and 1.36), not from neutral ArPdX(dppp), except for the reaction of ArPdl(dppp) with the most reactive methyl acrylate, performed in the absence of acetate ions (Schemes 1.34 and 1.37). 

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). 

It is vital to control the itt-complex formation and insertion steps in order to direct the regioselectivity of the Mizoroki-Heck reaction, in which the organic R group will be either added to the internal carbon of the monosubstituted alkene, yielding an a-product, or the terminal, providing trans- or cw-/6-products (Figure 3.1, steps 2-4 and Figure 3.2) [16,41]. 

Figure 3.34 Regioselective Mizoroki-Heck reaction of aiiyiic aicohoi and a heteroaryi chioride.

Returning to the classical Mizoroki-Heck reaction and regarding the regioselectivity of its intramolecular version, one particularly appreciated feature is the commonly... 

As seen before, regioselectivity in the intramolecular Mizoroki-Heck reaction can be controlled or directed by cautious choice of substrates and reaction conditions. In reality, the mechanism of the Mizoroki-Heck reaction is much more complex than the oversimplified... 

The last snbstrate substrncture encountered relatively often is of type K (Figure 6.5). Several groups used this substructure to prepare benzazepine derivatives [139-143]. Tietze et al. [144], could avoid isomerization of the double bond through optimization of the reaction conditions and lactam 200 could be obtained in a diastereo- and regioselective Mizoroki-Heck reaction in 55% yield (Scheme 6.58). 

A new trend in Mizoroki-Heck reactions is the apphcation of supported palladium catalysts with the aim of easy catalyst recycling and higher selectivity. The application of such catalysts results in a higher regioselectivity, which might be rationalized by the increased steric hindrance of the catalyst at the surface. Immobilization techniques use catalyst on a carrier, catalyst and ionic liquid on a carrier, ionic liquid and ligand on a carrier with and without catalyst, fixation of the base and the starting material. 

Another approach of regioselective Mizoroki-Heck reactions in ionic liquids is the synthesis of carbonyl compounds [51, 52]. Allylic alcohols (e.g. 12) react with iodoben-zene (5, X = I) via an enolic intermediate (e.g. 13) to the arylated carbonyl product 14 (Scheme 15.4 [52]), which was separated from the reaction mixture by extraction with diethyl ether. However, when choosing the appropriate reaction conditions (solvent and base), the corresponding allylic alcohols were obtained. If Pd(OAc)2 was applied in tetra-butylammonium acetate (as solvent and base) in the coupling of l-octen-3-ol with bromo-or iodobenzene, then selective formation (96 4) of allylic alcohols was achieved in 94% yield in 30 min reaction time at 70 °C [53]. 

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... 

Examples of Mizoroki-Heck cyclizations forming five-membered carbocycles are scarce for cycUc vinyl haUdes or triflates, presumably due to the strained reaction products. Grigg et al. [27] tested 31, a cyclic derivative of 4a (Scheme 5.2), giving regioselectively the... 

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