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DMSO/I2 CATALYSIS OF PARA C-C- BOND COUPLING OF PHENOLS AND ACETOPHENONES

The list of useful, high-yielding, environmentally-friendly, and inexpensive reactions catalyzed by DMSO/I2 continues to grow (for previous examples, see Synthesis Post articles from March 2017 and June, July, and October 2016). Wu and Wu recently published an account of a one pot method to reliably functionalize phenols at the para position.1 This C-C bond functionalization does not require protecting groups; it uses readily-available and inexpensive starting materials; the materials used are relatively environmentally benign and nontoxic; and it works with a wide range of substrates. The overall reaction and the optimized conditions are given in Equation 1. In this instance, HI interacts with DMSO to produce I2 which catalyzes the reaction.

Equation 1: DMSO/I2-catalyzed para-selective C-C bond coupling of an aryl-methyl ketone and a phenol.

Using this reaction, these researchers synthesized pharmaceutical candidates and natural products of interest (Scheme 1). In example (1) in Scheme 1, the pharmaceutical candidate NSC 115566 was synthesized in a 47% yield in a one-pot, two step sequence. In example (2) a fragment (the aglycone of sophodibenzoside) of a class of natural products containing a 4-hydroxybenzil moiety (sophodibenzosides) was readily synthesized on a gram scale in another one pot reaction. These two examples demonstrate the utility of this synthetic method.

Scheme 1: Synthesis of pharmaceutical compounds and natural products using the featured reaction.

As mentioned previously, HI reacts with DMSO to produce I2 in situ. Mechanistic studies allowed these researchers to propose the mechanism illustrated in Scheme 2. In this proposed mechanism, I2 activates the methyl group of acetophenone A to produce the iodinated acetophenone B.   The intermediate B undergoes a Kornblum-like oxidation to produce the ketoaldehyde C which is in equilibrium with its hydrate form. The coupling partner D is activated to become a better nucleophile by reaction with boric acid to produce E. This species E then attacks intermediate C, giving rise to intermediate F. Species E only reacts at the para position. This is thought to be due to steric constraints produced at the ortho positions due to the borate group. Intermediate F undergoes a final oxidation to produce a diketone, and workup cleaves the borate link, resulting in the product G.

Scheme 2: Proposed mechanism.

This is the first reported example of a para-selective C-C bond coupling reaction between phenols and acetophenones to produce 4-hydroxybenzyl derivatives. Additionally, this method adds to the growing list of useful transformations produced through DMSO/I2 catalysis.

 

References

  1. Xiang, J.-C.; Cheng, Y.; Wang, M.; Wu, Y.-D.; Wu, A.-X., Direct Construction of 4-Hydroxybenzils via Para-Selective C–C Bond Coupling of Phenols and Aryl Methyl Ketones. Organic Letters 2016, 18 (17), 4360-4363.
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