Stereoselective and Regioselective Reaction of Cyclic Ortho Esters with Phenols

Abstract

Cyclic ortho esters undergo stereoselective and regioselective reaction with phenols when treated with BF(3) x OEt(2) at low temperatures. Attack of the phenol on the ortho ester occurs at an open carbon para to electron-donating groups on the phenol ("C-addition") or at the phenolic hydroxyl group ("O-addition") depending on the nature of the cation formed from reaction of the ortho ester and BF(3) x OEt(2). Products resulting from O-addition undergo reversion to a mixture of starting phenol, C-addition product, and O-addition product if treated with BF(3) x OEt(2) at room temperature, but C-addition products are stable under the same conditions. X-ray structural analysis of the C-addition compound indicates that its stereochemistry is opposite to that observed in reaction of similar ortho esters with chloride from TMSCl. However, the stereochemistry of the reaction can be rationalized by the ability of the ortho ester to isomerize via an intermediate benzylic cation and examination of the preferred trajectory of attack of the nucleophile on the intermediate oxonium ion.

Lewis Acid-Promoted Regio- and Diastereoselective Cross-Coupling of Aryl-Substituted 1,2-Diols and Boronic Acids

“…The large coupling constant value ( J 2H–3H = 9.9 Hz) between C(2) and C(3) in trans -(±)- 13 indicates that the relative configuration of the major diastereomer must be syn , whereas the small constant value ( J 2H–3H = 3.6 Hz) between C(2) and C(3) in cis -(±)- 13 indicates that the relative configuration of the minor diastereomer must be anti . In addition, by comparison of the spectral data of syn -(±)- 10r (Scheme ) with those reported by Bozell and co-workers, we confirmed the relative configuration of the major and minor products syn - and anti -(±)- 10a , demonstrating that this reaction occurs with overall retention of configuration at the benzylic stereocenter. The relative configurations of the other major products were assigned by analogy.…”

“…Not surprisingly, extensive synthetic endeavors have been devoted to this approach. One of the most notable methods involves the generation of resonance-stabilized benzylic carbenium ions derived from benzylic alcohols catalyzed by Brønsted or Lewis acids (eq 1, Scheme ) ,− and aryl-substituted cyclic orthoesters in the presence of BF 3 ·OEt 2 (eq 2, Scheme ), followed by the introduction of an arene nucleophile in an S N 1-type process. However, the scope reported for each method is notably limited to electron-rich arenes as nucleophiles, and their facial selectivity at the benzylic carbon center depends on the electron demand of the aromatic substituents.…”

Synthetic Uses of Phenols

“…Although the classical reaction of alkali metal phenoxides with alkyl halides generally takes place at the oxygen atom, C-alkylation occurs in some cases depending on solvent, counter cation and heterogeneity of the reaction system 117 . The regio-and stereoselectivity of the phenol alkylation was examined using a chiral ortho-ester under acidic conditions (equation 30) 118 . The Cand O-alkylation is controlled by the electronic nature of the substituent on the orthoester; an electron-rich aryl group induces the C-alkylation.…”

Sc(OTf)3-catalyzed diastereoselective Friedel–Crafts reactions of arenes and hetarenes with 3-phenylglycidates

“…3-arylglycidates), diastereoselective access to β,β-diaryl-α-acetoxypropionates from cyclic ortho-esters was reported by Bozell et al 9 They invoked a free carbocation intermediate, which was postulated to be attacked by the nucleophile in a Felkin-Anh type transition state.…”