Sulfoxide-mediated oxidative cross-coupling of phenols†

A metal-free, oxidative coupling of phenols with various nucleophiles, including arenes, 1,3-diketones and other phenols, is reported. Cross-coupling is mediated by a sulfoxide which inverts the reactivity of the phenol partner. Crucially, the process shows high selectivity for cross-versus homo-coupling and allows efficient access to a variety of aromatic scaffolds including biaryls, benzofurans and, through an iterative procedure, aromatic oligomers.


Introduction
Metal-catalyzed cross-coupling, involving an aryl halide and an organometallic partner, is a powerful tool for biaryl synthesis (Scheme 1A). 1 However, oxidative, C-H/C-H couplings, involving non-prefunctionalized partners, have recently come to the fore as an attractive alternative (Scheme 1B). 2 Their development remains a challenge, as the reactivity of one partner must be inverted, and known processes are compromised by the requirement for expensive, supply risk, metal oxidants or metal catalysts. 2 The development of selective, metal-free C-H/C-H coupling reactions is, therefore, an important goal. 3 Phenols, in particular unsymmetrical phenol-derived biaryls, are ubiquitous in nature, biomaterials and ligand collections for catalysis. 4 Approaches to these compounds generally require multiple stepsprefunctionalization of partners or manipulation of protecting groupsand/or the use of metals. 5 Metal-free oxidative coupling of unprotected phenols is therefore of interest, however, avoiding homocoupling is a challenge (Scheme 1C). 6 Nevertheless, metal-free cross-coupling of phenols has been described, most notably using electroorganic synthesis 7 or hypervalent iodine reagents, 8 amongst other approaches 9 (Scheme 1D).
We proposed that sulfoxides 10,11 could be used to invert the reactivity of a phenol partner, thus providing an alternative approach to their oxidative coupling (Scheme 1E). Capture of phenols by sulfoxides will deliver aryloxysulfonium intermediates I that are electrophilic and capable of coupling with various nucleophiles (e.g. Ar 2 ). 12-14 The major challenge in such an approach is the avoidance of homocoupling. 13 Furthermore, alternative Pummerer chemistry of the sulfoxide 15 and rearrangement of sulfonium intermediates I 9a,10,16 must be by-passed.
anhydride (TFAA), before subsequent addition of 2a (1.5 equivalents), to give the product of cross-coupling 3a in 91% isolated yield (see the ESI † for optimisation).

Iterative coupling of three nucleophiles
Intrigued by the formation of the triaryl products 3ab 0 and 3ac 0 (Scheme 2), we considered an iterative process that would allow the sequential, metal-free, oxidative coupling of phenols with two different nucleophilic partners (Scheme 4). For example, 4methoxy phenol was rst coupled with 1,2,4-trimethoxybenzene to afford 3ab. Subsequent treatment of 3ab with 1,3-dimethoxybenzene gave the unsymmetrical, diarylated phenol 7a in 68% yield. 1,3-Diphenylpropane-1,3-dione could also be used as the third nucleophilic partner and gave C7-arylated benzofurans 7c and 7h. 19 Mechanistic studies Based on the above results, and our previous studies, 10,13 a possible mechanism for the oxidative cross-coupling is shown in Scheme 5A. 13 Activation of sulfoxide 4a with TFAA gives acyloxysulfonium salt II and interrupted Pummerer reaction with a phenol coupling partner gives aryloxysulfonium salt I. Subsequent attack of the second partner, at the ortho or para position of the rst, results in C-C bond formation and expulsion of 3-methylbenzothiophene. The control experiments in Scheme 5B highlight the important role of the hydroxy group in the rst partner and suggest that activation of the phenol occurs via intermediate I. However, we were unable to detect or isolate this intermediate and further studies are needed to conrm the exact mechanism for phenol activation. Scheme 5C shows that the order in which the two nucleophilic partners are combined can be critical, suggesting that rapid and irreversible, aryloxysulfonium salt formation takes place between the activated sulfoxide I and the rst phenol partner, and that aryloxysulfonium salt intermediates have very different reactivities. 20

Conclusions
In summary, a metal-free, sulfoxide-mediated, oxidative crosscoupling unites phenols and various nucleophilic partners, including phenols, 1,3-diketones and arenes. The capture and inversion of reactivity of the rst nucleophilic partner, using an interrupted Pummerer reaction, prior to coupling with the second nucleophile, is key to the cross-coupling. Homocoupling is not observed and alternative Pummerer and rearrangement processes are avoided. Iterative sulfoxide-mediated couplings allow the construction of polyaryl compounds.

Conflicts of interest
There are no conicts to declare.