Phenolic Ether Coupling

Coupling either at the ring or in the side-chain has been described under a variety of conditions. 

The styrenoid crown ether indicated, with lithium borofluoride in methanol contained in a Pyrex tube, upon irradiation under nitrogen with a 400w high pressure mercury lamp furnished a cyclobutane derivative in 82% yield (ref. 172). 

1-Methoxy-2-methylnaphthalene, with cobalt trifluoride in trifluoracetic acid upon refluxing for 12 hours afforded in 88% yield the 4,4 -dinaphthyl shown, which was also obtained from oxidation with lead tetra acetate, ferric chloride, thallium(lll) trifluoroacetate and mercuric trifluoroacetate (ref.173). 

Coupling simulutaneously with asymmetric synthesis has been reported by the use of a chiral leaving group. 

1-(1-Menthoxy)-2-oxazolinonaphthalene in tetrahydrofuran at -78 C added to 1 -lithionaphthalene (formed from 1 -bromonaphthalene in tetrahydrofuran at -78 to -42 C with sec-butyiiithium) followed by stirring of the mixture for 1 hour afforded the 2-(4,5-dihydro-4,4-dimethyloxazol-2-yl)-1,1 -binaphthyl, having 67% enantiomeric excess, in 80% yield (refs. 174,175). 

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Returning to phenol ether-phenol ether coupling, synthetic septicine (59) gave ( )-tylophorine (60) on treatment with thallium trifluoroacetate, and the same reagent converted synthetic julandine (61) to ( )-cryptopleurine (62 69%). In another synthesis of tylophorine the lactam (63) was transformed with va-... 

Electrooxidation is also viable for phenol ether-phenol ether coupling and has been thoroughly investigated. For example a range of compounds (65) with R = H or Me, Z = CH2 or O, = 1 or 2, reacted at the anode to give fair yields of the corresponding biaryls (66), together with spirodienone products (see Section 2.9.3.2). 

Phenol ethers show some, admittedly low, reactivity towards diazonium ions and also undissociated phenols (see Sec. 12.7). An instructive example of the reactivity of phenol ethers was reported by Ronaldson (1981). He found that 1,2-dimethoxy-benzene (veratrole) does not react with the 4-nitrobenzenediazonium ion, but the azo coupling product is formed when the more electrophilic 2,4-dinitrobenzenediazo-nium ion is used. 

Azo coupling reactions with phenol ethers give in some cases the expected arylazo-phenol ether. In others, however, hydrolysis of the ether bond is observed and the arylazophenol is isolated. This ambiguity has, to the best of our knowledge, never been investigated systematically. 

The key structural features of compound 1 are the chiral cis-diaryl benzox-athiin fused ring system, two phenols, and one phenol ether linkage with the pyrrolidinylethanol. Originally, SERM 1 was prepared by medicinal chemists from a key ketone intermediate 5 shown in Scheme 5.1. Compound 5 was prepared in four steps with rather low yield [4a], Among these steps, the high temperature de-methylation step and the use of extremely toxic MOM-C1 were not particularly suitable for scale-up. The ketone 5 was then brominated with PhMe3NBr3 (PTAB) and coupled with thiophenol 7 to produce adduct 8. The key step of the synthesis was the conversion of adduct 8 to cis-diaryl benzoxathiin 9 under the Kursanov-Parne reaction conditions (TFA/Et3SiH). This novel reaction allowed the formation... 

As seen in the retro-synthetic Scheme 5.3, intermediate 15 is useful for both routes. The choice of benzyl protection group was made based on the robust stability of benzyl phenol ethers toward most reactions and several possible avenues to remove it, although it was reported from Medicinal Chemistry that benzyl group removal via hydrogenolysis posed challenges in this compound. The choice of iodide substitution was born out of the known high reactivity of iodides in the Ullmann-type coupling reaction with alcohols and the robust stability of aryl iodides in many other common reactions. 

To satisfy his curiosity about dyeing processes, he took a summer course at the Badische Anilin- und Sodafabrik (BASF) in 1920. There he came into close personal and professional contact with P. Julius, the director of the BASF, who had been very interested in Meyer s work on the coupling of phenol ether. Julius wanted for his successor a scientist acquainted with the particulars of dyestuffs and having a sound knowledge of physical chemistry in addition to organic chemistry, and the position of director of... 

Even the doubly unsaturated hydrocarbons, such as butadiene, can be coupled with suitable diazo-compounds. Finally, not only phenols, but also phenol ethers, such as anisole, are capable of coupling (K. H. Meyer1). 

The anodic coupling of aryl ethers is reviewed in Ref. [180]. Aryl ethers are more selectively coupled than phenols for the following reasons The carbon-oxygen coupling is made impossible and the ortho-coupling and the oxidation to quinones become more difficult. A mixture of triflu-oroacetic acid (TFA) and dichloromethane proved to be the most suitable electrolyte [181]. TFA enhances the radical cation stability and suppresses the nucle-ophilicity of water. Of further advantage is the addition of alumina or trifluo-roacetic anhydride [182]. Table 12 compiles representative examples of the aryl ether coupling. 

Anodic C, C-coupling is a very powerful tool to synthesize cyclic compounds with high regio- and stereoselectivity. It involves inter- and intramolecular coupling of arylolefins, dienes, enolethers, phenol ethers, and aromatic amines and often opens a quick entry into complex natural products in a few steps. Although the mechanism is fully established in only a few cases, it does appear to involve the coupling of two radical cations at the site of their highest radical density and is further controlled by steric constraints. This important type of reaction is reviewed in Chap. 5 and in Refs. [89, 90]. 

Nonphenolic oxidative coupling of phenol ether derivatives using IBTA can also produce seven-membered N-containing heterocyclic compounds as exemplified by Eq. (45) [96JCS(CC)1481],... 

Under some conditions, phenolic ethers are dealkylated during coupling. However, the dealkylation follows the coupling step and is acid-catalyzed. Consequently, use of an excess of sodium acetate as a buffer or use of a nonaqueous medium obviates the dealkylation. 

Oxidative coupling of phenols and phenol ethers.2 This reaction can be conducted with ferric chloride supported on silica gel. 

Kita and Tohma found that exposure of p-substituted phenol ethers to [bis(tri-fluoroacetoxy)iodo]benzene 12 in the presence of some nucleophiles in polar, less nucleophilic solvents results in direct nucleophilic aromatic substitution [Eq. (84)] [156]. Involvement of a single-electron transfer (SET) from phenol ethers to A3-iodane 12 generating arene cation radicals was suggested by the detailed UV-vis and ESR studies. SET was involved in the oxidative biaryl coupling of phenol ethers by 12 in the presence of BF3-Et20 [157]. 

The use of hypervalent iodine reagents in carbon-carbon bond forming reactions is summarized with particular emphasis on applications in organic synthesis. The most important recent methods involve the radical decarboxylative alkylation of organic substrates with [bis(acyloxy)iodo]arenes, spirocyclization of para- and ortho-substituted phenols, the intramolecular oxidative coupling of phenol ethers, and the reactions of iodonium salts and ylides. A significant recent research activity is centered in the area of the transition metal-mediated coupling reactions of the alkenyl-, aryl-, and alkynyliodonium salts. 

In the intermolecular mode, this reaction has been utilized for the preparation of products 28 from various nucleophiles, including C-nucleophiles (e. g. (3-dicarbonyl compounds). A similar reaction in the intramolecular mode provides a powerful synthetic tool for the preparation of various polycyclic compounds via oxidative biaryl coupling [21,27 - 30]. Several examples of these C-C bond forming reactions are shown in Schemes 13-15. Specifically, various dibenzoheterocyclic compounds 30 have been prepared by the oxidation of phenol ether derivatives 29 with [bis(trifluoroacetoxy)iodo]benzene in the presence of BF3-etherate in dichloromethane (Scheme 13) [27-29]. 

Under similar conditions, the phenanthro-fused thiazoles, isoxazoles and pyrimidines 32 (Scheme 14) can be prepared by oxidative coupling of the respective phenol ethers 31 [31,32]. 

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