Phenol-coupling reactions products

In the first of these, the key step in the synthetic sequence involves an oxidative phenol coupling reaction patterned after the biosynthesis of the natural product. Preparation of the moiety that is to become the aromatic ring starts by methyla-tion of phloroglucinol (5) with methanolic hydrogen chloride to give the dimethyl ether (6). Treatment of that intermediate with sulfuryl chloride introduces the chlorine atom needed in the final product (7). 

Toward the industrial production of 34, Node and co-workers improved the yield of this phenolic coupling reaction using the suitably protected norbella-dine-type derivative (154) [115] (Scheme 25). 

Deposition from coal products. Deposits could form in heat exchangers and have been identified as being in part at least, products of phenolic coupling reactions [Gayla et al 1986]... 

Other early applications of hypervalent iodine reagents in natural products are the total syntheses of bioactive alkaloids, by Szantay s and White s groups in early 1980s, such as salutaridine (Scheme 6), (-)-codeine, and 6a-epipretazettine [35-37]. Although these involved pioneering studies on phenolic coupling reactions, they had not received much attention because of their low yields of the chemical processes (up to 32% yield). 

The manifold possibilities for the elaboration of structurally intriguing natural products via the aforementioned oxidative aryl-aryl coupling reactions emphasize the importance of phenolic coupling reactions in the biosynthesis of tyrosine-derived alkaloids. This important reaction not only plays a significant role in the biosynthesis of benzyltetrahydroisoquinoline alkaloids but also for the construction of phenethylisoquinoline alkaloids and Amaryllidaceae constituents, discussed in the following sections. 

All major pathways toward tyrosine-derived secondary metabolites discussed within the biosynthetic section of this chapter are summarized in Scheme 12.16. The great structural diversity of this important class of natural products arises from a very limited set of chemical transformations. Except for the extremely simple catecholamines and phenyl-ethylamines, tyrosine-derived alkaloids are generally formed via condensation of two aromatic substrates, facultatively followed by a Pictet-Spengler-type ring closing reaction. Next, the key oxidative phenolic coupling reaction then introduces stractural complexity and serves as convenient tool for the elaboration of different alkaloid frameworks. 

Discussion. The formation of coloured compounds by coupling phenols with diazotised primary aromatic amines has long been recognised as a method of determining phenols, and procedures have been evolved whereby the phenol solution is titrated with a diazonium solution which has been calibrated against known concentrations of the phenol. The resultant reaction products are coloured, but many are only sparingly soluble in water and organic solvents and do not therefore lend themselves to colorimetric determination. 

Light can effect the coupling of phenols. For example, Joschek and Miller (22) found that phenoxyphenols could be produced in the flash photolysis of phenol, but although sought, no dioxin was detected in the reaction products. 

The ketone 15 was eventually prepared by Grignard addition to Weinreb amide 21, as shown in Scheme 5.5. The Weinreb amide 21 was prepared from p-iodobenzoic acid (20). The phenol of readily available 3-hydroxybenzaldehyde (22) was first protected with a benzyl group, then the aldehyde was converted to chloride 24 via alcohol 23 under standard conditions. Preparation of the Grignard reagent 25 from chloride 24 was initially problematic. A large proportion of the homo-coupling side product 26 was observed in THF. The use of a 3 1 mixture of toluene THF as the reaction solvent suppressed this side reaction [7]. The iodoketone 15 was isolated as a crystalline solid and this sequence was scaled up to pilot plant scale to make around 50 kg of 15. 

---