Biaryl ether

Alkenyl ethers Biaryl iodide Aryl bromides Aryl triflates... 

Carbon-oxygen bonds are formed by the Ullmann reaction (- coupling of aryl halides with copper) which has been varied in alkaloid chemistry to produce diaryl ethers instead of biaryls. This is achieved by the use of CuO in basic media (T. Kametani, 1969 R.W. Dos-kotch, 1971). 

The pharmacological versatility of this general substitution strategy is further illustrated by diazonium coupling of 14 with 2-nitrobenzenediazonium chloride to produce biarylal-dehyde 18. Formation of the oxime with hydroxylamine is followed by dehydration to the nitrile. Reaction with anhydrous methanolic hydrogen chloride leads to imino ether and addition-elimination of ammonia leads to the antidepressant amid-ine, nitrafudam (20). ... 

Zhn and coworkers have developed SwAr-based macrocyclizadon via biaryl ether formation. The first example of SivAr-based macrocyclizadon for synthesis of model carboxylate-binding pocket C-O-D rings of vancomycin was reported in 1994 fScheme 9.3. ... 

Fagnou and co-workers reported on the use of a palladium source in the presence of different phosphine ligands for the intramolecular direct arylation reaction of arenes with bromides [56]. Later, they discovered that new conditions employing palladium complex 27 promoted the direct arylation of a broad range of aryl chlorides to form six- and five-membered ring biaryls including different functionalities as ether, amine, amide and alkyl (Scheme 7.11) [57]. 

The key synthetic challenges in the target molecule 1 were the chiral 2-arylpyrrolidine fragment, the densely functionalized benzimidazole ring, and the hindered biaryl ether linkage. 

The highly selective nitration of 6 set the stage for the installation of the benzimidazole as well as solving the problem of the biaryl ether formation, which would have been a challenge for existing transition metal-catalyzed technologies. 

In connection with another project being developed we needed large quantities of a biaryl phenol or biaryl aryl methyl ether which was being prepared by a Suzuki coupling reaction (Scheme 6). 

Transmetallation of aiyl halide (VIII) with n-butyl lithium and treating it with readily available and inexpensive 3-ethoxycyclohexen-l-one followed by acid work-up would provide enone (XI) (Scheme 8). Enone (XI) can be then aromatized to phenol (X) or any other biaryl alkyl ether. By using this protocol, 3-ethoxycyclohexen-l-one is a synthon for 3-hydroxyphenyl boronic acid. The bulk price of 3-ethoxycyclohexen-l-one is 85/kg compared to 3500 for the boronic acid, thereby significantly reducing the cost to prepare biaryl (X). 

Several microwave-assisted protocols for soluble polymer-supported syntheses have been described. Among the first examples of so-called liquid-phase synthesis were aqueous Suzuki couplings. Schotten and coworkers presented the use of polyethylene glycol (PEG)-bound aryl halides and sulfonates in these palladium-catalyzed cross-couplings [70]. The authors demonstrated that no additional phase-transfer catalyst (PTC) is needed when the PEG-bound electrophiles are coupled with appropriate aryl boronic acids. The polymer-bound substrates were coupled with 1.2 equivalents of the boronic acids in water under short-term microwave irradiation in sealed vessels in a domestic microwave oven (Scheme 7.62). Work-up involved precipitation of the polymer-bound biaryl from a suitable organic solvent with diethyl ether. Water and insoluble impurities need to be removed prior to precipitation in order to achieve high recoveries of the products. 

Biaryl ethers are a well-known motif in medicinal chemistry. The reaction of p-nitrophenol with 2,4-dichloropyrimidine was performed in a mixture of acetone and water from which the product precipitated after completion. Work-up and isolation of the product was therefore very simple. We also observed the formation of a by-product (depend-... 

Mechanistic studies carried out by the Buchwald group97,98 on the key C-O bond formation step in these reactions have reinforced the importance of the properties of the ligand, and have led to the adoption of a variety of more sterically hindered ligands (e.g., 23, 24, 27, 29, and 30), which have given improved results for the preparation of biaryl ethers (Equation (15)),89 /-butyl aryl ethers,99 and aryl ethers of primary alcohols.100... 

The most prominent application of the Ru-arene chemistry has been for the preparation of biaryl ethers in the syntheses of portions of vancomycin,467 ristocetin (Equation (127)),462,468-473 and teicoplanin (see also Section 10.14.1.2).474-476 Additional applications477-479 have included the syntheses of the macrocyclic biaryl ether-containing compounds K-13480,481 and OF4949-III,481,482 several macrocyclic depsipeptides,483,484 and poly(phenylene oxide) polymers.485... 

FortnagelP, WittichRM, Harms H, Schmidt S (1989) New bacterial degradation of the biaryl ether structure. Naturwissenshaften 76 523-524... 

Zhu and co-workers used S Ar reactions to create the biaryl ether bond in their synthesis of cyclopeptide alkaloids [55-57] (Scheme 5). The electrophile in this case is an aryl fluoride, often additionally activated by an electron-withdrawing group such as a nitro group. The necessity of such an activation auxiliary obviously has a negative impact on general applicability of this method. 

Scheme 5 Macrocyclic biaryl ether formation by S Ar reaction in synthetic studies towards RP-66453 (25)...

Total synthesis of complex (macrocyclic) natural products using fast and flexible strategies and diversity-oriented synthesis of natural product-like macrocycles are important research topics in our laboratory. The following sections describe the total synthesis of epothilone D and epothilone D5 analogues, DOS of cyclopeptide alkaloid analogues, of biaryl ether macrocycles, and of steroid/peptide hybrid macrocycles, respectively. 

Key components for the synthesis of biaryl ether macrocycles were diisonitriles 98 and 101. The former was synthesized in two steps (61% yield) from commercially available diamine 97 by bisformamide formation and subsequent dehydration with phosphorus oxychloride (Scheme 16). Starting ma-... 

Encouraged by the success of MUMBIs to synthesize biaryl ether macrocycles, we endeavored to combine this methodology with experience in steroid synthesis to obtain very large macrocycles with both peptide and steroid moieties (Fig. 21). These molecules bear no direct resemblance to any known natural products, but they do display a high degree of structural... 

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