Pummerer s ketone

Parallel oxidations either electrochemically [117] or with iron([Il) salts [119] in water have also been made using l-alkyl-7-hydroxy-6-methoxytetrahydroisoquinO line salts as substrates. 4-Methy phenol is oxidised at a carbon anode in alkaline solution to give Pummerer s ketone 25 by the ortho-para coupling of two phenoxy radicals [120],... 

As a typical example of coupling reactions the oxidation of p-cresol (VII) to Pummerer s ketone (VIII) is presented in Figure 5, showing the mesomeric nature of the phenoxyl radical. According to Barton et al. 2) the ketone is formed by coupling at one 0-carbon atom and at one p-carbon atom and subsequent formation of an ether linkage. 

Figure 5. Formation of Pummerer s ketone VIII) from p-cresol VII)...

The photo-[4+2] cycloaddition of furan with Pummerer s ketone 102 [70,71] gives evidence for the intermediacy of the highly twisted enone intermediate 103, and a biradical cycloaddition pathway (Sch. 23). The structures of the endo and exo products 104 were confirmed by X-ray crystallography [72,73]. In a related comparison of cyclohexenone and cyclopentenone photochemistry, conditions that gave [4+2] adducts for the cyclohexenone produced only [2+2] adducts from cyclopentenone [74]. 

The pioneer in phenolate radical coupling was Pummerer. In 1925 he showed1 that one electron oxidation of />-cresol using potassium ferricyanide afforded a nicely crystalline ketonic dimer of the radical in up to 25 % yield. Pummerer s ketone, as it became known, was considered to result from the coupling of two p-cresol radicals to give the dienone 1. This then underwent spontaneous cyclization to furnish 2. As proof of the structure... 

Precursors such as reticuline 10 were synthesized labelled with 14C (O and N methyl groups) and with 3H in the aromatic nuclei. Labelling could also be done in the two 2-carbon bridges. We also synthesized from thebaine the key alkaloid 11 for the first time. Unlike the situation with Pummerer s ketone 11 did not close to 12 spontaneously. Later on, alkaloid 11 was isolated from a Brazilian plant. From correspondence with Prof. R. A. Barnes, we realized that the two were probably identical, which was confirmed by an exchange of specimens. So, we used thereafter the name salutaridine, given by our Brazilian colleagues. 

I was pleased with this result because the plant had clearly indicated to us that the original, and chemically available, pathway was not correct. Further thought then gave the real pathway. I was also pleased that so much beautiful chemistry (by nature) came from reflections on the erroneous formula of Pummerer s ketone. 

The reaction mixture was filtered to remove the enzyme particles and the solvent evaporated on a rotary evaporator yielding a yellow oil. The oil was dissolved in 100 mL diethyl ether and the low molecular weight phenolic products were extracted into an equal volume of 5% NaOH solution. The residual ether soluble fraction contained primarily Pummerer s ketone and higher molecular weight phenolics while the base-soluble fraction contained the p-cresol and the biscresol. Further purification was performed by preparative thin layer chromatography (TLC) (1 mm silica gel G plates, Analtech, Newark, DE) with a solvent system of diethyl ether heptane (2 1). Rf values were 0.81 for biscresol and 0.63 for Pummerer s ketone. 

Pummerer s ketone and its 1,2-dihydro derivatives reacted with CH(OMe)2 to give enaminones 143 and 144598. 

Finally, the reaction of the pyrrolidine dienamine of Pummerer s ketone 9, when treated with two equivalents of nitrosobenzene, leads regio- and diastereoselectively in very low yield to a single adduct 10 resulting from addition to the least hindered face, together with dimerization products 21. 

Phenols are quite sensitive to oxidation. On the one hand, they are easily oxidized to quinols and on further oxidation with, for example, iron(III) chloride, chromic acid or silver(I) oxide give p-quinones. However, under one-electron transfer conditions the phenoxide anion is oxidized to the phenoxyl radical. This shows free radical reactivity on the oxygen atom and at the ortho and para positions (Scheme 4.20a). The phenoxyl radical may readily dimerize. This is exemplified by the formation of Pummerer s ketone from p-cresol (Scheme 4.20b). 

An example of intcrmoiccular oxidative coupling with the new complex is the oxidation ofyj-cresol (3) to Pummerer s ketone (4) in 28% yield. 

Photochemical addition of furan to Pummerer s ketone (121) affords the two (4+2)-cycloadducts (122) and (123). The structures of both of these products has been established by X-ray crystallography. Spectroscopic studies on the enone (121) suggest that the triplet state is highly twisted and the authors suggest that the addition to furan results in the formation of two biradicals which lead to the observed products. No evidence for the involvement of a trans-ground state enone was obtained. ... 

Para-substituted phenols may still couple through the para position and products may be formed in good yield, especially if stable. Thus p-cresol gives Pummerer s ketone (9 63%) on treatment with silver... 

Lunarine (26), one of the typical neolignans, is biosynthesized by the ortho-para radical coupling between two molecules of p-hydroxycinnamic acid. In this connection, oxidative coupling reactions of 4-substituted phenols have been extensively stndied using thallium trifluoroacetate (TTFA), potassium ferricyanide (K3[Fe(CN)g]) and other reagents. p-Cresol (27) was also electrolyzed at a controlled potential (+0.25 V vi. SCE) in a basic medium to afford Pummerer s ketone 28 in 74% yield. The snggested mechanism is given in Scheme 4. 

Lunarine.— The biosynthesis of lunarine (109) has been studied in Lunaria biennis. Although [3 - C]phenylalanine was incorporated, [3 - C]tyrosine was not Consequently, phenylalanine is converted first into cinnamic acid, which is then hydroxylated. Oxidative coupling of p-hydroxycinnamic acid and cyclization would give (110), the analogue of Pummerer s ketone, and thence to... 

The selective oxidative phenolic orf/io-coupling reaction of simple methyl-substituted phenols turned out to be challenging [12]. When 2,4-dime thy Iphenol (1) is treated by conventional or electro-organic methods, not only the desired biphenol (2) is formed but rather a plethora of polycyclic architectures (Scheme 2) is observed. The major product is Pummerer s ketone (3) and related compounds with a wide structural diversity [13-16]. Application of a boron tether ameliorated the situation tremendously, and biphenol (2) was obtained as the major product [17, 18]. This templated anodic oxidation of 1 represents a multistep process but is suitable for the electro-organic synthesis of (2) on larger scale (see entry Electrosynthesis Using Template-Directed Methods ) [19]. 

Scheme 8.17. A pictorial representation of a pathway to Pummerer s ketone by the oxidation of 4-hydroxytolnene with basic iron(III) cyanide (ferricyanide, Fe(CN)6 ). The material prepared in the laboratory is racemic.

The simplest p-alkylphenol is p-cresol (35), which has a methyl substituent. One of the first detailed studies of the HRP-catalyzed oxidation of p-cresol was reported in 1976 [51]. Recently, a detailed in situ NMR analysis revealed details of the coupling mechanism of the p-cresol polymerization. NMR and H- H gCOSY 2D NMR analysis suggested that ortho-ortho coupling (43) is the dominant coupling mechanism at the initial stage of the polymerization. The consumption of dimer accelerated only after the complete conversion of the monomer in the reaction mixture. After a reaction time of about 75 min, the formation of Pummerer s ketone (44) was observed. These ketonic species are formed from ortho-para-coupled dimers by intramolecular Michael addition. They are probably not able to participate in the further polymerization process and remain as side products (Scheme 9) [76]. Experiments with 4-propylphenol have revealed that the formation of Pummerer s ketone may be suppressed at lower temperatures [112]. 

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