Oxidative phenolic coupling alternatives

Alternatives to Oxidative Phenolic Coupling 1 The Fuchs Approach... 

Here is another alternative to oxidative phenolic coupling. Kathy Parker and her group (Brown University) described a synthesis of morphine that focuses on the same key bonds as seen in the Fuchs synthesis, but using totally different chemistry. The Parker plan was, once again, to construct the key C-N bond late in the synthesis from an intermediate of type 64. Parker also focused on initial construction of the same C-C bonds, but this time using a free radical addition-addition-elimination sequence beginning with a radical of type 65. The precursor of this radical (see 78 on Morphine-11) was to be an aryl bromide. This bromide was to be assembled from diol 66 and aryl bromide 67, structures that are similar to the pieces used in the Fuchs synthesis (49 and 54). 

Mulzer s elegant synthesis of morphine is characterized by a stepwise elaboration of the ring motives in the natural product. While the biosynthetic pathway comprises an oxidative phenolic coupling, Mulzer employed a highly efficient Friedel-Crafts acylation to estabhsh the C12—C13 bond. Additionally, the implementation of observations from degradation studies represents an interesting alternative strategy to the exploitation of biomimetic pathways for natural product synthesis. 

A simplification of the classical Baker-Venkataraman 3-step route uses DBU to effect a one-pot synthesis of 2,8-disubstituted chromones <97SYN195>. Solid state phenol coupling of a 2 -hydroxyacetophenone is the key step in a total synthesis of the natural atropisomer of a biflavone <97JOC7222>. An alternative approach involves an asymmetric intramolecular oxidative coupling to produce the biaryl precursor <97TL1087>. 

An alternative electrochemical method has recently been used to obtain the standard potentials of a series of 31 PhO /PhO- redox couples (13). This method uses conventional cyclic voltammetry, and it is based on the CV s obtained on alkaline solutions of the phenols. The observed CV s are completely irreversible and simply show a wave corresponding to the one-electron oxidation of PhO-. The irreversibility is due to the rapid homogeneous decay of the PhO radicals produced, such that no reverse wave can be detected. It is well known that PhO radicals decay with second-order kinetics and rate constants close to the diffusion-controlled limit. If the mechanism of the electrochemical oxidation of PhO- consists of diffusion-limited transfer of the electron from PhO- to the electrode and the second-order decay of the PhO radicals, the following equation describes the scan-rate dependence of the peak potential ... 

The one-step hydroxylation ofbenzene represents an attractive alternative pathway for the direct synthesis of phenol and many studies are performed using different processes among which the photocatalytic reaction [45,46]. One of the main problem is the low selectivity of the process due to the higher reactivity of phenol towards the oxidation than benzene with the formation of oxidation by-products. In order to avoid these secondary products and to obtain the separation of the phenol from the oxidant reaction environment the use of a membrane system coupled with the photocatalytic process seems a useful solution. 

Important synthetic thrusts in this area have been described. The mechanism of the transformation (4) -> (6) which proceeds in 35 % yield [80 % from (5)] has been shown to require both phenolic hydroxy-groups in (4) unblocked and therefore must involve pp-coupling and further oxidation to the intermediate (5). The high yield may be due to the adoption of a favourable conformation and anion-radical exchange in the precursor of (S). An alternative indoline structure was eliminated from consideration as an intermediate since it... 

Phenolic oxidative coupling of the benzylisoquinoline (85) gave the aporphine (86) which led to the non-phenolic thalicsimidine upon O-methylation. Alternatively, oxidative coupling of (87) gave rise to a mixture of dienones (88) which on acid-catalysed dienone-phenol rearrangement furnished the aporphines (89) and... 

In the recent past, the focus of new developments was on alternative phenol processes that overcome the disadvantage of the coupled product acetone in the cumene oxidation process. These processes are based on the oxidation of benzene with nitrous oxide or hydrogen peroxide [7]. The main research on the cumene oxidation process is process intensification by improving the oxidation reaction and improved process and reactor design. 

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