Heck reaction substituent effects

The selectivity in the Heck reaction of allylic alcohol 111 is interesting, and the factors that lead to the observed preference for (3-hydride elimination toward nitrogen in this system are unclear, although a combination of steric effects and stereoelectronic factors (i.e., alignment of C-H and C-Pd bonds, nN a c H interactions) is likely involved. Examination of related examples from the literature (Scheme 4.20) reveals no clear trend. Rawal and Michoud examined substrate 115, which lacks the influence of both the amine and hydroxyl substituents and also seems to favor (3-hydride elimination within the six-membered ring over formation of the exocyclic olefin under standard Heck conditions [18a]. However, under... 

In one case, the intermolecular Heck reaction of 3-pyridyltriflate with ethyl acrylate was accelerated by LiCl to give 159 [127,128], Here, both electronic and steric effects all favored p-substitution. In another case, however, electronic effects prevailed and complete a-substitution was observed. In the presence of an electron-donating substituent (i.e., a protected amine), 3-bromopyridine 160 was coupled with f-butoxyethylene to give 3-pyridyl methyl ketone 162 [126]. The regiochemistry of the Heck reaction was governed by inductive effects, leading to intermediate 161. 

The second Heck reaction involves a naphthyl iodide (Ar2 = 2-naphthyl) but the initial mechanism is much the same. However, the enol ether has two diastereotopic faces syn or anti to the aromatic substituent (Ar1) introduced in the first step. Palladium is very sensitive to steric effects and generally forms less hindered complexes where possible. Thus coordination of the palladium(II) intermediate occurs on the face of the enol ether anti to Ar1. This in turn controls all the subsequent steps, which must be syn, leading to the trans product. The requirement for syn p-hydride elimination also explains the regiochemical preference of the elimination. In this cyclic structure there is only one hydrogen (green) that is syn the one on the carbon bearing the naphthyl substituent is anti to the palladium and cannot be eliminated.. ... 

Scheme 1 shows the desired Heck reaction of alkoxy-DSB 1 with 2. The formation of 3 is accompanied by two destructive pathways the reductive debromination of 1 to 4 as a side reaction and the protodesilylation to 5 as a subsequent reaction. Particularly the latter limits the reaction conditions in terms of time and temperature. The phosphine is a decisive factor in this system consisting of three reactions a fine-tuning of the reaction conditions is possible via electronic and steric effects of the substituents in the phosphine electron-rich trialkylphosphines 6 and 7 strongly favor the reduction. Fast coupling reactions were observed with tris-o-tolylphosphine 8, the chelating diphosphine dppe 9 being even more efficient in terms of turnover, yield, and suppression of side reactions. Compared with Heck reactions of polycyclic or electron-deficient arenes with 2 [21, 22], the yield of 3 is only moderate. The reactivity of bromo-distyrylbenzenes 1 and 12 -14 in the coupling reaction is controlled by the substituents on the opposite side of the n-system (Fig. 1, Table 2) a compensation for the electron-donating alkoxy groups by a cyanide (13) or exchange of donors with electronically neutral alkyl side chains strongly improves the yields.

A solvent-free approach has been used to scale up a Heck reaction to the 1 mol level. Again, this study was preceded by optimization and investigation of substituent effects. However, on 0.5-1.0 molar scale under solvent-free conditions, the reaction was markedly exothermic, self-heating to 150 °C from the 100 °C set point. It is important to stress the importance of taking every precaution when performing reaction under solvent-free conditions on larger scales. In this case, the reaction mixture was heated slowly, and an over-sized flask was used. 

Substituent Effects on Hydwpalladation and Carbopalladation. As repeatedly mentioned earlier, Pd(II) species are electrophilic. So, hydropalladation and carbopalladation as well as other addition reactions of Pd(II) complexes are accelerated by electron-donating substituents in Tr-compounds. Any substituents can also exert steric and some other kinds of effects as well. So, the overall substituent effects are the sum of all these factors, of which electronic and steric effects are usually the most dominant ones. The rates of the Heck reaction of various alkenes decrease in the following order CH2=CH2 > CH2=CHOAc > CH2=CHMe > CH2=CHPh > CH2=CMePh. 

However, some cases are known in which electronic effects of substituents strongly influence the ontcome of the intramolecnlar Heck reaction. The example presented in Scheme 3 is especially illustrative the bisamide underwent a monocychzation to give a highly substituted indole, whereas the corresponding dimethoxy-substituted starting material did not react at all. ... 

A common ground that is explicitly or implicitly defended in the majority of studies on Mizoroki-Heck reactions is that the limiting stage for the whole cycle is the oxidative addition step. By this criterion, the most important substrates, aryl halides, are subdivided into very reactive (aryl iodides and electron-deficient aryl bromides), less reactive (all other aryl bromides and electron-deficient aryl chlorides) and very unreactive (all other aryl chlorides). As evident as this classification may seem, it is not based on any solid proof. Indeed, if it were really so important, the oxidative addition step should have been characterized by very strong dependence on substituent effects in these substrates. However, this has not been observed in either Mizoroki-Heck reactions or in any other palladium-catalysed reaction of aryl hahdes. The Hammett reaction constant values p, whenever measured, are rather modest in valne [5]. Such values could hardly have accounted for the well-known enormous distance between the reactivity of, for example, a typical activated substrate 7 and a typical deactivated substrate 8 (Figure 2.1). 

Orr/zc- em-Dihalovinylanilines 278 were also used in another example of a Buchwald-Hartwig-type/Mizoroki-Heck reaction for the synthesis of 2-vinylic indoles 279 (Scheme 8.69). Lautens and coworkers [140] recently illustrated a domino coupUng under Jeffery s condition where the aniline nitrogen undergoes an amination step followed by a Mizoroki-Heck coupling with various alkenes. In this process, electronic factors and steric hindrance of the different substituents had only a small effect on the yield however, in the formation of 3-substituted indoles using this method only very poor yields were obtained. The procedure can also be performed in an intramolecular mode leading to tricycUc compounds such as pyridino and azepino indoles 281 and 282 (Scheme 8.69). 

R, and ligands on the palladium, and the dominance of meta over para substitution is an electronic effect of the substituent on the cleaving carbon—hydrogen bond. In a variation of the Heck reaction, it has been shown that arylsulfinic acids may be substituted by alkenes in the presence of a palladium acetate catalyst, with copper... 

Because Pd(II) salts, like Hgtll) salts, can effect electrophilic metallation of the indole ring at C3, it is also possible to carry out vinylation on indoles without 3-substituents. These reactions usually require the use of an equiv. of the Pd(ll) salt and also a Cu(If) or Ag(I) salt to effect reoxidation of the Pd. As in the standard Heck conditions, an EW substitution on the indole nitrogen is usually necessary. Entry 8 of Table 11.3 is an interesting example. The oxidative vinylation was achieved in 87% yield by using one equiv. of PdfOAcfj and one equiv. of chloranil as a co-oxidant. This example is also noteworthy in that the 4-broino substituent was unreactive under these conditions. Part B of Table 11.3 lists some other representative procedures. 

Without the alkoxy substituent on the olefin, steric effects prevail. The Heck adduct 164 was isolated when 2-chloro-3-pivaloylamidopyridine (163) was allowed to react with an excess of styrene [129], Steric effects can play a major role in the regioselectivity of these reactions. 

En route to the synthesis of mensacarcin (104), a polyfunctionalized hexahy-droanthracene, showing cytostatic and cytotoxic activity, Tietze et al. [49] devised a Mizoroki-Heck cyclization for the formation of the tricyclic core. Several substrates with different protecting groups and substitution patterns were tested, out of which 102 turned out to be the best, affording 103 in 94% yield under optimized reaction conditions (102 103, Scheme 5.20). A similar strategy was pursued by Banerjee and coworkers [50] for the synthesis of tetrahydroanthracenes leading to umbrosone (107). Variation of the substituents in 105 had a minor effect, the reactions proceeded smoothly in 84-86% yield (105 106), and subsequent elimination of H2O provided the tetrahydroanthracene core. When diene 108 was employed the aromatic system in 109 was directly installed by double-bond migration (108 109). 

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