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At this point, the question of cross-coupling between different phenols arose, and this was regarded as a very difficult venture since any catalyst must promote the cross- coupling much faster than either of the corresponding homo-couplings.

Many groups attempted oxidative cross-coupling reaction between different two naphthols or phenols. 46

After Katsuki and coworkers discovered that ruthenium salen complexes could be used for aerobic oxidative homo-coupling of 2-naphthol,47 they found bis--hydroxo dimeric iron salan complex to be an excellent catalyst for not only

for homo-coupling of 2-naphthols but also for the cross-coupling of 2-naphthols.48 _In

2014, the Waldvogel group revealed the electrochemical methods for cross-coupling of phenols.14a Employing electrolytes with a high capacity for hydrogen bonding, a direct electrolysis in an undivided cell provided mixed 2,2'-biphenols with high selectivity.

And, more recently, Doron Pappo and coworkers developed an iron-catalyzed oxidative unsymmetrical biphenol coupling in 1,1,1,3,3,3-hexafluoro-2-propanol and postulated a

(46) For an alternate cross-coupling after our publication in 2014: (a) Elsler, B.; Schollmeyer, D.; Dyballa, K. M.; Franke, R.; Waldvogel, S. R. “Metal- and Reagent-Free Highly Selective Anodic Cross-Coupling Reaction of Phenols” Angew. Chem., Int. Ed. 2014, 53, 5210-5213. (b) Libman, A.; Shalit, H.; Vainer, Y.; Narute, S.; Kozuch, S.; Pappo, D. “Synthetic and Predictive Approach to Unsymmetrical Biphenols by Iron-Catalyzed Chelated Radical−Anion Oxidative Coupling” J. Am. Chem. Soc. 2015, 137, 11453-11460. (c) More, N. Y.; Jeganmohan, M. “Oxidative Cross-Coupling of Two Different Phenols: An Efficient Route to Unsymmetrical Biphenols” Org. Lett.2015, 17, 3042−3045.

( 47 ) Iried, R.; Masutani, K.; Katsuki, T. “Asymmetric Aerobic Oxidative Coupling of 2-Naphthol Derivatives Catalyzed by Photo-Activated Chiral (NO)Ru(II)-Salen Complex” Synlett 2000, 1433-1436.

(48) (a) Egami, H.; Matsumoto, K.; Oguma, T.; Kunisu, T.; Katsuki, T. “Enantioenriched Synthesis of C-1- Symmetric Binols: Iron-Catalyzed Cross-Coupling of 2-Naphthols and Some Mechanistic Insight” J. Am. Chem. Soc.2010, 132, 13633-13635. (b) Matsumoto, K.; Egami, H.; Oguma, T.; Katsuki, T. “What Factors Influence the Catalytic Activity of Iron-Salan Complexes for Aerobic Oxidative Coupling of 2-Naphthols?” Chem. Commun. 2012, 48, 5823-5825.

chelated radical−anion coupling mechanism.14b They determined oxidation potential (Eox) and the theoretical global nucleophilicity (N) parameters of various phenols to support their mechanism.

The intriguing finding that the Cr-Salen-Cy catalyst permits coupling at two different sites of a monomer stimulated us to study its behavior with different monomers especially if were possible to selectively coordinate one monomer to the catalyst in line with our putative model (Scheme 2.5). Initial studies showed a significant amount of cross-coupling when two different phenol substrates were employed in a 1:1 ratio (Scheme 2.6). More excitingly, as we switched to different coupling partners, the homo- coupling reactions were suppressed.

Scheme 2.14Initial Trials of Cross-Coupling Reaction

Changing the coupling partner to 2,6-di-tert-butylphenol (2.15) gave more cross- coupling product with higher selectivity. With 2,3,5-trimethylphenol (2.9), 2,6-di-tert-

butylphenol gave 50% of the para-ortho coupling product after 1 day at 50 °C. In a similar fashion, several other phenol substrates gave cross-coupling product selectively with moderate yield (Scheme 2.7). The same reaction conditions for the homo-coupling (50 °C, 0.05 M, 5 mol%) were used for the cross-coupling reaction. There was no side product, but the both phenol substrates remained unreacted. Reaction times longer than 2 days caused decomposition of both the starting phenols and the product.

With 2,6-di-tert-butylphenol (2.15), coupling partners with open ortho- and para- sites underwent reaction at the less sterically hindered position in a similar fashion in homo-coupling (Scheme 2.7). For example, 2,3,5-trisubstituted phenols and 3,5- disubstituted phenols coupled in the ortho position and gave ortho-para product (2.24, 2.25), whereas 2,5-disubstituted phenols coupled in para position to give the corresponding para-para bisphenols (2.26-2.29).

Scheme 2.15Cross-Coupling Reaction with 2,6-Di-tert-butylphenol

Additional screening of 2,6-disubstituted phenols revealed similar trends. 2,6- Dimethylphenol (2.31 and 2.32), 2,6-diisopropylphenol (2.33), and even unsymmetrical 2-methyl-6-tert-butylphenol (2.34–2.37) coupled in same way with various partners (Scheme 2.8). Notably, 2-methyl-6-tert-butylphenol gave high conversion, up to 77% at 70 °C; the other substrates either decomposed or coupled twice to form trimers with 2,6- di-tert-butylphenol at this temperature.

Scheme 2.16Cross-Coupling Reaction with 2,6-Disubstituted Phenols

For less reactive substrates, coupling could be induced at higher temperature (70 °C). However, the resultant dimeric product was more reactive in these cases than the original monomer leading to trimers (Scheme 2.9) with negligible amounts of dimer (less than 5%) in these cases. The second cross-coupling proceeded successively, and trimers were observed in fair yield (44–46%) along with unreacted starting materials after 2 days.

Scheme 2.17Trimer Formation in Cross-Coupling

There were some substrates where both dimer and trimer were observed indicating that the dimer product was not more reactive than the monomers. For example,

para-alkylphenol gave a mixture of dimer and trimer with 2,6-disubsituted phenols. Symmetric resorcinol also gave a mixture (Table 2.1). It was reasoned that if the reactivities of dimer and monomer were similar to each other, both products were observable. Since these formations of dimer and trimer were competitive, reactions were uncontrollable. Repeated trials to influence the outcome by adjusting the ratio between two products did not succeed. For example, slow addition of 2,6-di-tert-butylphenol during the reaction course did not suppress trimer formation, and excess addition of 2,6- di-tert-butylphenol also did not expedite trimer formation; in both case, dimer and trimer were observed forming at similar rates.

Table 2.5Dimer vs. Trimer

2,6-Disubstituted phenols (A, Scheme 2.10) were combined with phenols with only one open ortho-coupling site (B, Scheme 2.10) to render the ortho-para coupling products stable and prevent trimer formation by limiting the outcome to three coupling products: two homo-coupling products and one cross-coupling product (Scheme 2.10). The yields were excellent (up to 88%) due to the stability of the coupled product. However, in our system, there were examples that was inconsistent with Pappo’s postulation.14b For example, in product 2.46, 2,4-dimehtylphenol is both more nucleophilic and more oxidizable than 2,6-di-tert-butylphenol.

A range of naphthols was also effective in dimer formation with 2,6-disubstituted phenol providing products in good yield. Notably, even though there were two identical

coupling sites, 2,7-dihydroxynaphthalene did not form any trimer, but only dimer was observed with good yield (2.54, 82%).

Scheme 2.18Cross-Coupling Reaction

On the other hand, there were many challenging substrates in the cross-coupling reaction (Scheme 2.11). Electronic effects of phenol B played an important role in the reactivity of the cross-coupling. For example, amines (2.55 and 2.57) or vinyl groups (2.58) were not compatible with the cross-coupling reaction condition; no starting materials remained after overnight reaction and only decomposition was observed. 1- Naphthols (2.63 and 2.64) also failed to couple with 2,6-di-tert-butylphenol due to the

On the other hand, electron-withdrawing groups, such as formyl group (2.59), halide groups (2.60–2.62), or ester group (2.65), suppressed cross-coupling reaction with 2,6-di-tert-butylphenol. Only the diphenoquinone of 2,6-di-tert-butylphenol was observed along with the starting phenol substrates.

Unlike phenols with open sites in ortho position, phenols with open sites in the

para position were not as prone to oxidative coupling reaction with the chromium catalyst. After three days reaction at 80 °C, only 10% conversion was observed between 2,6-di-tert-butylphenol (2.15) and 2,6-dimethylphenol (2.17, Scheme 2.11). Again, when the cross-coupling did not happen for the substrates 2.66 and 2.67, the diphenoquinone of 2,6-di-tert-butylphenol and both unreacted substrates were observed.

Scheme 2.19Challenging Substrates in Cross-Coupling

The evidence from the present study that the scope of the cross-coupling reaction is different from that of the homo-coupling is noteworthy. For example, 2,6-disubstituted

phenol which also couples itself to give homo-coupling product is essential in the cross- coupling, whereas the coupling partner which cannot undergo a homo-coupling reaction under the present aerobic oxidation conditions, can undergo a cross-coupling reaction.