Directed Intermolecular Arylations

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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In 2006 Fagnou described the direct intermolecular arylation of perfluoro benzene derivatives via the proposed proton-transfer pathway (Scheme 6). The reaction shows complete inversion of reactivity relative to the electrophilic C-H activation pathway and is thought to proceed via a concerted arene-metallation and C-H bond cleaving process, which depends on the acidity of the C-H bond being cleaved. 

Several papers describing the direct intermolecular a-arylation of ketones proceed by mechanism D were published in 1997 [46-48]. Only a single example had been disclosed in a patent by the year [49]. The authors found that aryl iodides react with benzyl ketones in the presence of PdCl2 using CS2CO3 as base (Eq. 8) [46,50]. Bromobenzenes can also be used for this reaction when a phosphine ligand is added. 

The direct intermolecular a-arylation of relatively less acidic ketones with aryl halides, which proceeds by mechanism B, was reported concurrently in 1997 by the groups of Miura, Buchwald, and Hartwig [35-37]. The intramolecular version was also described by Muratake and coworkers in the same year [38,39], while some intermolecular vinylation reaction had been reported [40, 41]. Taking advantage of this, the reaction of carbonyl compounds and related substrates has been studied extensively. Now a variety of ketones are known to be arylated by using appropriate ligands and bases [42-46]. The reaction usually takes place at a less hindered a position (Eqs. 5-7) [19,20]. 

As described above, appropriately functionalized aromatic substrates such as phenols and aromatic carbonyl compounds undergo intermolecular arylation directly and regioselectively on treatment with aryl halides in the presence of palladium catalysts. As illustrated in Scheme 3, which is a proposed general... 

Patel and co-workers presented an efficient and regioselective protocol for the synthesis of 2-aryl-2H-benzotriazoles 48 with the help of Pd/TBHP combinations (Scheme 7.29) [88]. The ligand-directed intermolecular azidation via ortho sp -C-H functionalization of azobenzenes followed by intramolecular cyclization leads to the construction of 2-aryl-2H-benzotriazoles 48. This method provides an alternatively concise approach for the synthesis of 2-aryl-2H-benzotriazoles. 

Fagnou et al. reported the synthesis of mukonine (11) starting from methyl vanillate (644). This synthesis uses both a palladium(0)-catalyzed intermolecular direct arylation and an intramolecular cyclization reaction. Triflation of methyl vanillate (644) afforded the aryl triflate 645. Using a Buchwald-Flartwig amination protocol, the latter was subjected to direct arylation with 2-chloroaniline (646) to furnish the corresponding diarylamine 647. Finally, intramolecular cyclization of 647 afforded mukonine (11). To date, this is the best synthesis (three steps, 75% overall yield) available for mukonine based on commercially available methyl vanillate (644) (582) (Scheme 5.45). 

Palladium(0)-catalyzed cross-coupling of aryl halides and alkenes (i.e., the Heck reaction) is widely used in organic chemistry. Oxidative Heck reactions can be achieved by forming the Pd -aryl intermediate via direct palladation of an arene C - H bond. Intramolecular reactions of this type were described in Sect. 4.1.2, but considerable effort has also been directed toward the development of intermolecular reactions. Early examples by Fu-jiwara and others used organic peroxides and related oxidants to promote catalytic turnover [182-184]. This section will highlight several recent examples that use BQ or dioxygen as the stoichiometric oxidant. 

The consecutive formation of o-hydroxybenzophenone (Figure 3) occurred by Fries transposition over phenylbenzoate. In the Fries reaction catalyzed by Lewis-type systems, aimed at the synthesis of hydroxyarylketones starting from aryl esters, the mechanism can be either (i) intermolecular, in which the benzoyl cation acylates phenylbenzoate with formation of benzoylphenylbenzoate, while the Ph-O-AfCL complex generates phenol (in this case, hydroxybenzophenone is a consecutive product of phenylbenzoate transformation), or (ii) intramolecular, in which phenylbenzoate directly transforms into hydroxybenzophenone, or (iii) again intermolecular, in which however the benzoyl cation acylates the Ph-O-AfCL complex, with formation of another complex which then decomposes to yield hydroxybenzophenone (mechanism of monomolecular deacylation-acylation). Mechanisms (i) and (iii) lead preferentially to the formation of p-hydroxybenzophenone (especially at low temperature), while mechanism (ii) to the ortho isomer. In the case of the Bronsted-type catalysis with zeolites, shape-selectivity effects may favor the formation of the para isomer with respect to the ortho one (11,12). 

In order to determine whether energy migration makes a significant contribution to the photophysical behavior of P2VN and PS in dilute miscible blends, it is instructive to calculate the expected exdmer-to-monomer fluorescence quantum yield ratio in the absence of energy migration. To do so, it is first necessary to assume that intermolecular and non-adjacent intramolecular EFS are absent. In addition, the adjacent intramolecular EFS are assumed to be frozen into the aryl vinyl polymer and must be excited by direct absorption of a photon. Since the absorption spectrum of an EFS is no different from that of non-EFS chromophores, then the calculated fraction of rings within EFS is sufficient to determine the fluorescence ratio. 

In comparison to the cyclization reactions shown above, intermolecular Meerwein arylations are often more difficult to conduct. Since the aryl radical addition to the alkene is no longer favored by the close proximity of the reacting centers, the probability for a direct recombination of the aryl radical with scavengers Y is significantly increased (Scheme 17). To maintain the desired reaction course from 44 to 45 including steps (1) and (2) [89, 90], Meerwein arylations have for a long time mostly been conducted with activated alkenes, such as acrylates (R = COOR ), vinylketones (R = COR ), styrenes (R = Ph), or conjugated dienes [91,92]. These types of alkenes are known for fast addition of aryl radicals. 

An intermolecular version of the arylation of carbamates has been recently published by Hartwig et al. (Eq. (21)) [132]. His group showed that reactions catalyzed by a combination of Pd(OAc)2 and P( -Bu)3 formed /V-aryl carbamates from aryl bromides or chlorides and f-butylcarbamate as substrate. Again, the reaction conditions were not as mild as those for amination, but were similar to those of the intramolecular reactions. For the intermolecular reactions, the use of sodium phenox-ide as base was crucial. Reactions using Cs2C03 showed low conversions. Those involving NaO-r-Bu as base rapidly formed a gel, presumably from the deproto-nated carbamate, and also showed little or no conversion. The products of these reactions serve as conveniently protected anilines, and r-butylcarbamate can be considered one type of ammonia surrogate. In addition, the products of these reactions are suitable for subsequent directed metalation procedures [100]. 

Ando and coworkers conducted isotope effect studies (entry 11) on the direct displacement reaction of benzyl arenesulfonates with dimethylaniline (DMA)38. They found that an electron-withdrawing substituent in the substrate (Y = 3-Br) caused the TS to shift to a later position along the reaction coordinate, which is consistent with that predicted by the Thornton rule (or anti-Hammond effect). The anilinolysis of phenylethyl arenesulfonates (entries 12 and 13) proceeds also by an SN2 mechanism. The reaction was found to proceed by a dissociative SN2 mechanism with a relatively small degree of aryl participation. The fraction of the phenonium ion intermediate captured by the aniline nucleophile in the aryl-assisted pathway has been shown to increase with a stronger nucleophile, and a four-center TS in an intermolecular SNi mechanism is suggested for the aryl-assisted pathway39,40. Under the same reaction conditions, benzylamine nucleophiles react at a rate ca two times faster than that of anilines. 

Organolanthanide-catalyzed intermolecular hydrophosphination is a more facile process than intermolecular hydroamination. The reaction of alkynes, dienes, and activated alkenes with diphenylphosphine was achieved utilizing the ytterbium imine complex 9 (Fig. 8) as catalyst [185-188]. Unsymmetric internal alkynes react regioselectively, presumably due to an aryl-directing effect (48) [186]. 

One class of transformations that illustrate the striking difference in reactivity between heteroarenes and carbocyclic arenes is the heteroaryl Heck reaction, in which an aryl or heteroaryl halide is coupled directly with a heteroaromatic compound to afford a biaryl product (formally a C—H bond functionalization process). Intermolecular Heck reactions involving the functionalization of aromatic carbocycles with aryVheteroaryl halides are rare [70], whereas heterocycles including thiophenes, furans, thiazoles, oxazoles, imidazoles. 

Perfluoroarenes were also found to be highly reactive coupling partners in intermolecular direct arylation [68, 69]. A wide range of aryl halides can be employed, including heterocycles such as pyridines, thiophenes, and quinolines. A fluorinated pyridine substrate may also be cross-coupled in high yield and it was also found that the site of arylation preferentially occurs adjacent to fluorine substituents when fewer fluorine atoms are present. Interestingly, the relative rates established from competition studies reveal that the rate of the direct arylation increases with the amount of fluorine substituents on the aromatic ring. In this way, it is inversely proportional to the arene nucleophilicity and therefore cannot arise from an electrophilic aromatic substitution type process (Scheme 7). 

The intermolecular direct arylation of simple benzenes was also evaluated [12]. Under conditions established for the fluorinated substrates, none of the desired cross-coupled product was formed. With the goal of increasing the amount of soluble base in the reaction mixture, varying amounts of different carboxylic acids were added. Both the amount and the type of acid was found to influence significantly the reaction outcome, with larger acids used in substoichiometric amounts providing superior outcomes. For example, as the steric bulk is increased from acetic acid to pivalic acid, an increase in conversion is noted. Under optimal conditions, addition of 30 mol% pivalic acid results in 100% conversion of the aryl bromide and an 82% isolated yield of benzene direct arylation is obtained. To rationalize the reactivity, it was proposed that the potassium pivalate may behave as... 

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