Palladium intermolecular arylations

Hartwig has reported an intramolecular/intermolecular process affording the 3-aryloxindoles 105 (Scheme 32).115 The intermolecular arylation of acetanilide derivative 104 is slower than the intramolecular arylation to form the oxindole. Thus, the overall transformation starts with cyclization followed by intermolecular arylation of indole. In order to slow down the intermolecular process and speed up the intramolecular reaction, chloroarene and bromine-substituted acetanilide precursors are used according to their respective reactivity with palladium(O) in the oxidative addition process. 

Palladium-catalyzed arylation of olefins and the analogous alkenylation (Heck reaction) are the useful synthetic methods for carbon-carbon bond formation.60 Although these reactions have been known for over 20 years, it was only in 1989 that the asymmetric Heck reaction was pioneered in independent work by Sato et al.60d and Carpenter et al.61 These scientists demonstrated that intramolecular cyclization of an alkenyl iodide or triflate yielded chiral cyclic compounds with approximately 45% ee. The first example of the intermolecular asymmetric Heck reaction was reported by Ozawa et al.60c Under appropriate conditions, the major product was obtained in over 96% ee for a variety of aryl triflates.62... 

Palladium chemistry of heterocycles has its idiosyncrasies stemming from their different structural properties from the corresponding carbocyclic aryl compounds. Even activated chloroheterocycles are sufficiently reactive to undergo Pd-catalyzed reactions. As a consequence of a and y activation of heteroaryl halides, Pd-catalyzed chemistry may take place regioselectively at the activated positions, a phenomenon rarely seen in carbocyclic aryl halides. In addition, another salient peculiarity in palladium chemistry of heterocycles is the so-called heteroaryl Heck reaction . For instance, while intermolecular palladium-catalyzed arylations of carbocyclic arenes are rare, palladium-catalyzed arylations of azoles and many other heterocycles readily take place. Therefore, the principal aim of this book is to highlight important palladium-mediated reactions of heterocycles with emphasis on the unique characteristics of individual heterocycles. 

Larock, R. C. Yum, E. K. Yang, H. Palladium-catalyzed intermolecular arylation of function-ally-substituted cycloalkenes by aryl iodides. Tetrahedron 1994, 50, 305-321. 

The palladium-catalyzed arylation and alkenylation of olefins, which were first discovered in the 1970 s by Heck (7,2) and Mizoroki (3) and have been often called the "Heck reaction", are versatile synthetic means for making a carbon-carbon bond. These reactions have been extensively used for organic synthesis during the past two decades (4-7). However, no reports on the "asymmetric Heck reaction" have been appeared until very recently. Shibasaki reported an asymmetric intramolecular cyclization of alkenyl iodides to give c/j-decalin derivatives of 80-91% ee (8-10). Overman reported an intramolecular cyclization of alkenyl triflate, giving a chiral quaternary carbon center of 45% ee (77). We report herein the first example of intermolecular asymmetric Heck-type arylation of cyclic olefins catalyzed by (7 )-BINAP-coordinated palladium complexes (Scheme 1) (12,13). 

Several reports on the application of the intermolecular arylation of primary alkylamines have appeared. For example, the reaction of primary amines with chloro 1,3 azoles has been used to produce the H-l-antihistaminic norastemizole [153]. As shown in Eq. (32), the palladium chemistry is dictated by the steric properties of the amines. This property creates selectivity that complements the thermal chemistry, which is dictated by amine nucleophilicity. These researchers have also shown that this high selectivity for arylation of primary over secondary amines with catalysts containing BINAP as ligand allows for the rapid assembly of other multiamino-based structures [154]. 

Since the pioneering work by Beletskaya and co-workers [8] the intra- and (more commonly) intermolecular arylation of alkenes has been shown to proceed very smoothly in aqueous medium in the presence of palladium acetate. At the beginning, the methodology seemed to be limited to aryl iodides under a strong influence of the base it was shown that the presence of potassium acetate instead of carbonate yielded lower reaction temperatures and higher rates (Eq. 4). 

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... 

Arylation with palladium involves the metal in its divalent state. It has been applied in ring closure reactions [58,59] and intermolecular arylation [60]. In these cases, the mechanism is of the second type, the proton is abstracted by a base... 

After the intermolecular palladium-catalyzed arylation of enolates had been discovered by the research groups of Buchwald, Hartwig, and Miura [63], it was an obvious idea to explore a stereoselective variant that was based on the reliable Evans auxiliaries, while catalytic, enantioselective protocols (cf. Section 5.2) were developed at the same time. However, only relatively moderate diastereoselectivity in the formation of arylation products 133 was achieved when the silyl ketenimine (S)-132 derived from Af-propionyl oxazolidinone was coupled with aryl bromides under palladium catalysis, as disclosed by Hartwig and Liu [64]. The additive zinc(ll) f-butoxide permitted to lower the temperature to 25 °C so that the diastereoselectivity could be enhanced (Scheme 4.26). The authors noticed that Ley s chiral dioxanone 134 proves itself as an auxiliary that induced excellent diastereoselectivity and led to the formation of arylated compounds 135 in very high diastereomeric ratios. The chiral auxiliary group was readily removed by treatment with chlorotrimethylsUane and methanol, so... 

The intermolecular arylation of nonactivated electron-deficient aromatic substrates is possible by means of a palladium-catalyzed protocol. Fagnou and coworkers reported the arylation of pentafluorobenzene in excellent yield as shown in Scheme 12.38 [126]. The authors employed different halides as coupling partner for the fluorinated species and were even able to convert chlorides into the corresponding adducts in good yield (57% isolated yield when p-methyl chlorobenzene was used). Additionally, different mono-, di-, and trifluorides were converted to biaryl products. 

In 2001, Mauleon et al. reported an unusual palladium-cascade arylation of a,P-unsaturated phenyl sulfones 23 under Heck reaction conditions [12]. Contrary to the work of Fuchs and others [13], Mauledn et al. described the intermolecular reaction of a,P-unsaturated sulfones with a large excess of iodobenzene (or / -substituted iodoarenes) in the presence of Ag COj as base, which occurred mainly through a complex cascade reaction in which three molecules of iodobenzene and one molecule of vinyl sulfone were involved, forming fused polycyclic compounds 25 rather than the Heck trisubstituted olefin expected. The authors propose a mechanism involving Heck reaction and C-H activation pathways (Scheme 6.5). 

Lamaty and coworkers described a straightforward combination of three Pd-cata-lyzed transformations first, an intermolecular nucleophilic substitution of an al-lylic bromide to form an aryl ether second, an intramolecular Heck-type transformation in which as the third reaction the intermediate palladium species is intercepted by a phenylboronic acid [124]. Thus, the reaction of a mixture of 2-iodophenol (6/1-253), methyl 2-bromomethylacrylate 6/1-254 and phenylboronic acid in the presence of catalytic amounts of Pd(OAc)2 led to 3,3-disubstituted 2,3-di-hydrobenzofuran 6/1-255 (Scheme 6/1.66). In addition to phenylboronic acid, several substituted boronic acids have also been used in this process. 

The first palladium-catalyzed formation of aryl alkyl ethers in an intermolecular fashion occurred between activated aryl halides and alkoxides (Equation (28)), and the first formation of vinyl ethers occurred between activated vinyl halides and tin alkoxides (Equation (29)). Reactions of activated chloro- and bromoarenes with NaO-Z-Bu to form /-butyl aryl ethers occurred in the presence of palladium and DPPF as catalyst,107 while reactions of activated aryl halides with alcohols that could undergo /3-hydrogen elimination occurred in the presence of palladium and BINAP as catalyst.110 Reactions of NaO-/-Bu with unactivated aryl halides gave only modest yields of ether when catalyzed by aromatic bisphosphines.110 Similar chemistry occurred in the presence of nickel catalysts. In fact, nickel catalysts produced higher yields of silyl aryl ethers than palladium catalysts.108 The formation of diaryl ethers from activated aryl halides in the presence of palladium catalysts bearing DPPF or a CF3-subsituted DPPF was also reported 109... 

Chang et al. reported a mild tandem intramolecular hydroamination of yne amines to form an endo-adduct intermediate, which reacts with electron-deficient azides to produce cyclic amidines <06JA12366>. Selected examples of an interesting synthetic route to tropene derivatives 165 via a dual hydroamination strategy is shown below. This one-step reaction makes use of a palladium catalyst and takes place by sequential intermolecular hydroamination of cycloheptatriene with aryl, heteroaryl, and primary alkyl amines to generate intermediate 166, followed by transannular intramolecular hydroamination <06JA8134>. 

Palladium-catalyzed cyclization reactions with aryl halides have been used to synthesize pyrazole derivatives. V-Aryl-lV-(c>-bromobenzyl)hydrazines 26 participated in a palladium-catalyzed intramolecular amination reaction to give 2-aryl-2W-indazoles 27 . Palladium-catalyzed cascade intermolecular queuing-cyclocondensation reaction of o-iodophenol (28) with dimethylallene and aryl hydrazines provided pyrazolyl chromanones 29 <00TL7129>. A novel one-pot synthesis of 3,5-disubstituted-2-pyrazolines 32 has been achieved with an unexpected coupling-isomerization sequence of haloarene 30, propargyl alcohol 31, and methylhydrazine <00ACIE1253>. 

Arylative or silylative cyclizations of allenyl aldehydes or ketones have been reported (Equations (101) and (102)).459,459a The intermolecular process, that is, three-component coupling reaction of aldehydes, allenes, and arylboronic acids, is catalyzed by palladium as well (Equation (103)).46O 46Oa These reactions are proposed to proceed through nucleophilic attack of the allylpalladium intermediates to the carbonyl groups. 

Recently, synthesis of aryl ketones by a combination of palladium-catalyzed C-H activation of arenes and intermolecular carbopalladation of nitriles has been reported (Equation (119)).474... 

Palladium chemistry involving heterocycles has its unique characteristics stemming from the heterocycles inherently different structural and electronic properties in comparison to the corresponding carbocyclic aryl compounds. One example illustrating the striking difference in reactivity between a heteroarene and a carbocyclic arene is the heteroaryl Heck reaction (vide infra, see Section 1.4). We define a heteroaryl Heck reaction as an intermolecular or an intramolecular Heck reaction occurring onto a heteroaryl recipient. Intermolecular Heck reactions of carbocyclic arenes as the recipients are rare [12a-d], whereas heterocycles including thiophenes, furans, thiazoles, oxazoles, imidazoles, pyrroles and indoles, etc. are excellent substrates. For instance, the heteroaryl Heck reaction of 2-chloro-3,6-diethylpyrazine (1) and benzoxazole occurred at the C(2) position of benzoxazole to elaborate pyrazinylbenzoxazole 2 [12e]. 

The use of cyclic alkenes as substrates or the preparation of cyclic structures in the Heck reaction allows an asymmetric variation of the Heck reaction. An example of an intermolecular process is the addition of arenes to 1,2-dihydro furan using BINAP as the ligand, reported by Hayashi [23], Since the addition of palladium-aryl occurs in a syn fashion to a cyclic compound, the 13-hydride elimination cannot take place at the carbon that carries the phenyl group just added (carbon 1), and therefore it takes place at the carbon atom at the other side of palladium (carbon 3). The normal Heck products would not be chiral because an alkene is formed at the position where the aryl group is added. A side-reaction that occurs is the isomerisation of the alkene. Figure 13.20 illustrates this, omitting catalyst details and isomerisation products. 

Salcedo A, Neuville L, Rondot C, Retailleau P, Zhu J (2008) Palladium-catalyzed domino intramolecular A-arylation/intermolecular C-C bond formation for the synthesis of functionalized benzodiazepinediones. Org Lett 10 857-860... 

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. 

Li and Yue also reported the intermolecular palladium catalyzed cross coupling reactions of bromo quinoxalines 214 and 216 with aryl boronic acids and heterocyclic stannanes, respectively <99TL4507>. The Suzuki couplings (i.e., 214 215) required the use of a... 

With its (9r/ (9-(cu-phenylalkynyl) group, the iodoarene 156 in the presence of a palladium catalyst initiates the cascade process with an intramolecular carbopalladation this is followed by an intermolecular insertion, for example, into the double bond of the 3-azanorborn-5-en-l-one 157 and terminated by ortho-2XX,2Jz of the norbornyl-type cr-palladium intermediate on the previously terminal aryl group to yield the two regioisomeric hexacyclic systems 158 and 159 in a ratio of 1 1 (Scheme 39). ... 

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