Significant enhancement of both the rate and the chemoselectivity of iron-catalyzed oxidative coupling of phenols can be achieved in fluorinated solvents, such as 1,1,1,3,3,3-hexafluoropropan-2-ol (HFIP), 2,2,2-trifluoroethanol (TFE), and 1-phenyl-2,2,2-trifluoroethanol. The generality of this effect was examined for the cross-coupling of phenols with arenes and polycyclic aromatic hydrocarbons (PAHs) and of phenol with β-dicarbonyl compounds. The new conditions were utilized in the synthesis of 2'''-dehydroxycalodenin B in only four synthetic steps.

Significant enhancement of both the rate and the chemoselectivity of iron-catalyzedo xidative coupling of phenols can be achieved in fluorinated solvents,such as 1,1,1,3,3,3hexafluoropropan-2-ol (HFIP), 2,2,2-trifluoroethanol (TFE), and 1-phenyl-2,2,2-trifluoroethanol. The generality of this effect was examined for the cross-coupling of phenols with arenes and polycyclic aromatic hydrocarbons (PAHs) and of phenol with b-dicarbonyl compounds.T he new conditions were utilized in the synthesis of 2'''-dehydroxycalodenin Bi n only four synthetic steps.

O O X X X = Cl, Br, I Fe(ClO 4 ) 3 (10 mol%) 1,10-phenanthroline (10 mol%) t-BuOOt-Bu HFIP = 1,1,1,3,3,3-hexafluoropropan-2-ol HFIP r.t.X OH Abstract The iron-catalyzed oxidative cross-coupling of halophenols to α-substituted β-keto esters takes place through one of two modes: oxidative C-C coupling or oxidative C-O coupling. A mechanistic investigation revealed that the chemoselectivity of these reactions is determined by the electronic and steric properties of the two coupling partners.Oxidative cross-coupling reactions 1 of phenols based on iron chemistry 2 are attractive methods for assembling complex phenolic architectures from simple substrates. In this context, the classical approach to generating electrophilic phenoxyl radical species has two main drawbacks: it relies on stoichiometric amounts of metal oxidants, and it suffers from poor chemoselectivity. These drawbacks have been addressed by the introduction of cross-dehydrogenativecoupling (CDC) techniques, 3 mainly by Li and Pappo and their respective co-workers, who developed iron-catalyzed oxidative cross-coupling reactions of phenols with substrates having weak C-H bonds, such as β-keto esters, 4 α-substituted β-keto esters, 5 α-hydroxy ketones, 6 or conjugated alkenes. 7 These reactions offer direct entries to complex phenolic natural products. 4a,5,7a The iron-catalyzed oxidative cross-coupling reaction of phenols with α-substituted β-keto esters 5 is, however, limited to naphthols or electronrich phenols (Scheme 1, A). 5 Our group has recently introduced the use of fluoro alcohols 8 as solvents for CDC reactions and has shown that 1,1,1,3,3,3-hexafluoropropan-2-ol (HFIP), 2,2,2-trifluoroethanol (TFE), and 2,2,2-trifluoro-1-phenylethanol all have significant effects on the efficiency and selectivity of iron-catalyzed CDC of phenols. 9 With this improved set of conditions, a new window of reactivity has been opened, permitting substrates such as arenes (including polycyclic aromatic hydrocarbons) or β-diketones to act as legitimate coupling partners. 9 These substrates do not react with phenols under the commonly used CDC conditions [FeCl 3 (10 mol%), 1,10-phenanthroline (5 mol%), t-BuOOt-Bu (2.5 equiv), DCE, 70 °C].Our study revealed that the oxidation potential of phenols is reduced in fluoro alcohols and, consequently, electron-deficient phenols, which do not react in nonpolar solvents such as 1,2-dichloroethane or toluene, are easily oxidized to electrophilic phenoxyl radicals, even at 0 °C (Scheme 1, B). 9 For example, the oxidative cross-coupling of 4-bromophenol (1b) or 3-chlorophenol (1g) with ethyl 2-oxocyclopentanecarboxylate (2; Scheme 2, A) was not efficient under the usual CDC conditions, 5 but when the reactions were carried out in HFIP at 0 °C [Fe(ClO 4 ) 3 ·nH 2 O (10 mol%), 1,10-phenanthroline (10 mol%), t-BuOOH (2.5 equiv)], the corresponding polycyclic hemiacetals 3b and 3g were isolated in 64% and 38% yields, respectively.To extend the scope of the reaction under our new set of conditions, we treated phenol 1b with ethyl 2-methy...

Iron-Catalyzed Oxidative C-C and C-O Coupling of Halophenols to -Substituted -Keto Esters. -The chemoselectivity of these reactions is determined by both the electronic and steric properties of the two coupling partners. -(REGEV, A.; SHALIT, H.; PAPPO*, D.; Synthesis 47 (2015) 12, 1716-1725, http://dx.doi.org/10.1055/s-0034-1380360 ; Dep. Chem., Ben-Gurion Univ. Negev, Beer Sheva 84105, Israel; Eng.) -Toeppel

Phenols and naphthols are regioselectively coupled with 2‐oxocyclopentanoic acid ester (II), arenes (IV) and (VII), polyaromatic hydrocarbons, e.