Transition Metal-Catalyzed Oxidations. 11.Para-selective chlorination and bromination of phenols with tert-butyl hydroperoxide and TiX(OiPr)3

Abstract

Selectivity is a major goal in modern synthetic chemistry [2]. This goal is relatively difficult to achieve in some electrophilic aromatic substitutions especially in the halogenation of phenols. Mixtures of ortho-and para-substitution products are usually formed which are often difficult to separate. We now report on surprisingly clean chlorinations and brominations with interesting para-position selectivity in the reactions of phenols with tert-butyl hydroperoxide (TBHP) in the presence of halogenated transitionmetal alkoxides such as TiX(OiPr) 3 (X = Cl or Br; for a review on TBHP oxidations see [3]). The halogenating power of the TiX n (OiPr) m /TBHP system and the selectivities involved have not yet been systematically investigated. Pertrifluoroacetic acid is known to generate hypochlorite ions in the reaction with TiCl 4 that chlorinate phenol (1) with moderate ortho-selectivity (56:22) [4]. A reverse, but also very poor para-selectivity (67.5:25) is obtained when meta-chloroperbenzoic acid is used in presence of HCl [5].Our preliminary chlorination experiments of 2-methylphenol (2) in dichloromethane at room temperature with TiCl(OiPr) 3 /TBHP gave low yields but an interesting paraselectivity encouraging further studies. The reaction was finally (see Experimental for details) conducted in THF at -30 ° C with 0.1 molar solutions of the phenols 1-3. Increasing the chlorine content of the titanium catalyst or the addition of lithium or magnesium chloride did not improve Abstract. Mononuclear phenols 1-4 are chlorinated or brominated with high para-selectivity and in good yields to the the conversions that were in the range of 90 -95% by GC analysis after 20 h of reaction time at -30 °C. The corresponding para-chlorination products 5, 7 and 9 were the only products detected by GC analysis; the isolated yields were 62, 58, and 47%, respectively [6]. For comparison, the most successful reagents for regioselective para-chlorination are listed in Table 1. With exception of a recent procedure of Hirano et al. [7] using sodium chlorite and a manganese(III)-salen complex in the chlorination of anisol some orthochlorination products (3 -8.7%) were always formed in the described procedures.Next, we turned our attention to the bromination of the phenols 1-4. Initially, we observed that bromination products halides 5-11 with the TiX n (OiPr) m /TBHP system (X = Cl or Br).