Biaryl with directing groups

In the cross-coupling reaction, starting from the simple arene (with directing group), palladation by a Pd(II) salt would lead to the formation of the palladacyclic complex (Ar1Pd(II)L) (Scheme 3). After the transmetallation and reductive elimination processes, the biaryl product is obtained together with Pd(0). If the Pd(0) can be further oxidized to Pd(II) catalyst, a catalytic cycle will be formed. By accomplishing this, arenes (C-H) are used to replace the aryl halides (C-X). Similarly, arenes (C-H) can be used to replace the aryl metals (C-M). 

Shi and co-workers have developed various types of C—H bond functionalization and C—C bond formation. Recently, they reported a novel transformation to realize ortho-arylation of acetanilides with trialkoxyarylsilanes through direct C—H functionalization (Equation 11.34) [72]. Furthermore, they also demonstrated a novel method for the direct construction of biaryl C—C bonds via Pd(II)-catalyzed cross-coupling of (hetero)arenes and various arylboronic acids [73]. Various aromatic rings show good selectivity, even without directing groups, under mild conditions. 

Another intramolecular synthesis of carbazoles 270 employed amino biaryls 269 as the starting materials with 2-picolinic acid as a directing group to facilitate a net C—H amination reaction under copper catalysis in the presence of Mn02 and acetic acid. The directing group is removed spontaneously after the initial amination (140L2892). 

More commonly, the transition metal-catalyzed coupling of aryl halides with nonfunctionalized aromatic substrates has been used for the preparation of unsymmetrical biaryl systems. Different strategies have been developed over the last few years. One very elegant approach utilizes directing groups on aromatic substrates. The lone pair of the requisite heteroatom coordinates to the transition metal and promotes the arylation reaction via intermediary formation of a five-or six-membered metallacycle. 

The transformation from arenes into phenol acetates can be achieved with hypervalent iodine compounds (such as phenyliodonium acetate, PhI(OAc)2), with chromates, or under aerobic conditions. Ligands, like picolinic acids, stabilize the intermediate palladium(IV) salts. In the presence of Lewis acids or silver salts, biaryl formation takes place. The influence of different directing groups has recently been reviewed. For example, diaryl sulfones or sulfoxides having at least one heteroaryl attached can be oxidized to the corresponding aryl acetates (Scheme 5-194, Experimental Procedure below). ... 

Qudguiner s group enlisted a combination of directed metalation and a Pd-catalyzed crosscoupling reaction for the construction of heteroaryl natural products [49]. One example was the total synthesis of bauerine B (64), a -carboline natural product [50], Or/fio-lithiation of 2,3-dichloro-A-pivaloylaminobenzene (61) was followed by reaction with trimethylborate to provide boronic acid 62 after hydrolysis. The Suzuki reaction between 62 and 3-fluoro-4-iodopyridine led to the desired biaryl product 63 contaminated with the primary amine (ca. 30%), both of which were utilized in the total synthesis of bauerine B (64). Another p-carboline natural product, the antibiotic eudistomin T (65), and a few other hydroxy p-carbolines have also been synthesized in the same fashion [3,51]. 

The protected diol side-chain of 456 is introduced by asymmetric dihydroxylation and directs diastereoselectivity in the formation of 457 and 458 by lithiation. The most acidic position of 456, between the two methoxy groups, is first protected by silylation. Suzuki coupling of 459 with the boronic acid 460 gives the kinetic product 461—the more severe hindrance to bond rotation in this compound does not allow equilibration to the more stable atropisomer of the biaryl under the conditions of the reaction. 

However, a more exciting application of this reaction is the oxazoline-directed synthesis of axially chiral biaryls. The oxazoline system not only activates the ortho-methoxy group for nucleophilic displacement but also determines the stereochemical outcome of the reaction. This provides a convenient method for the introduction of axial-chirality. Meyers group continues their earlier lead on this subject with reports of the stereoselective synthesis of tetrasubstituted biphenyls 391,392 examples are shown in Table 8.29 (Scheme 8.154). The best... 

It is not possible to prepare biaryls containing a free carboxyl group directly by the diazo reaction. No biaryl is formed when (a) diazotized aniline and sodium benzoate, (b) diazotized anthranilic acid and aqueous sodium benzoate, or (c) diazotized anthranilic acid and benzene are used as components in the reaction.13 On the other hand, the reaction proceeds normally if methyl benzoate is used in reaction (a) or when methyl anthranilate replaces the anthranilic acid in (b) and in (c). The success of the diazohydroxide reaction appears to lie in the ability of the non-aqueous liquid to extract the reactive diazo compound from the aqueous layer.4 However, esters and nitriles can be prepared from esters of aromatic amino acids and cyanoanilines and also by coupling with esters of aromatic acids, and from the products the acids can be obtained by hydrolysis. By coupling N-nitrosoacetanilide with ethyl phthalate, ethyl 4-phenylphthalate (VIII) is formed in 37% yield. 

The presence of chelating groups in those complexes is necessary to stabilize the intermediate aryl-palladium complex for isolation but it does not seem necessary to cause palladation. The chelating group does, however, tremendously accelerate the palladation. Aromatic compounds reactive to electrophilic substitution apparently undergo palladation with palladium acetate in acetic acid solution fairly readily at 100 °C or above. Of course, the arylpalladium acetates presumably formed, are not stable under these conditions, and they decompose very rapidly into biaryls and palladium metal 34,35,36) ag do aryl palladium salts prepared by the exchange route 24>. If the direct palladation is carried out in the presence of suitable olefins, arylation can be achieved, so far, however, only in poor yields, arid with concurrent loss of stereospecificity and formation of isomers and other side products 37.38). 

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