Efficient Preparation of α-Ketoacetals

Abstract

The Weinreb amides 2a,b were prepared from the α,α-dimethoxyacetic acids 1c,d. A number of representative nucleophilic additions (RMgX and RLi) on 2 afforded α-ketoacetals 3a–j in 70–99% yield. These compounds represent a versatile arrangement of functional groups of significant synthetic value, as demonstrated in the synthesis of (±)-salbutamol.

Reductive Amination in the Synthesis of Pharmaceuticals

“…Zepeda et al showed that salbutamol can be obtained by reacting acetal 7.2.a with t BuNH 2 in the presence of sodium borohydride (Scheme ). As a result, salbutamol was obtained in 81% yield (85 mg of the product, 11% RME).…”

PTSA-Catalyzed Reaction of Alkyl/Aryl Methyl Ketones with Aliphatic Alcohols in the Presence of Selenium Dioxide: A Protocol for the Generation of an α-Ketoacetals Library

“…7 Ayala-Mata and group employed Weinreb amides as a starting material for the synthesis of α-ketoacetals (Scheme 1b). 8 More recently, we have reported the synthesis of phenylglyoxal diethylacetals via the reaction of aromatic ketones with triethylorthoformate in the presence of H 2 SeO 3 catalyzed by BF 3 ·Et 2 O (Scheme 1c). 9 This method, though simple is limited by the use of triethylorthoformate as the sole source of alkoxide nucleophile.…”

“…For instance the α-ketoacetals are a key intermediate in the synthesis of various biological active compounds such as chiral α-hydroxy acetals, chiral α-amino acetals, chiral auxiliaries, and cyanosilylation and also for the construction of important heterocycles . Several methods have been described for the preparation of α-ketoacetals. − Goswami et al, reported the synthesis of aliphatic α-ketoacetals starting from ketones via a two step procedure using SeO 2 . , Tiecco and co-workers reported the synthesis of α-ketoacetals catalyzed by diphenyldiselenide and an excess of ammonium peroxydisulfate under reflux conditions (Scheme a) . Ayala-Mata and group employed Weinreb amides as a starting material for the synthesis of α-ketoacetals (Scheme b) .…”

“…Several methods have been described for the preparation of α-ketoacetals. − Goswami et al, reported the synthesis of aliphatic α-ketoacetals starting from ketones via a two step procedure using SeO 2 . , Tiecco and co-workers reported the synthesis of α-ketoacetals catalyzed by diphenyldiselenide and an excess of ammonium peroxydisulfate under reflux conditions (Scheme a) . Ayala-Mata and group employed Weinreb amides as a starting material for the synthesis of α-ketoacetals (Scheme b) . More recently, we have reported the synthesis of phenylglyoxal diethylacetals via the reaction of aromatic ketones with triethylorthoformate in the presence of H 2 SeO 3 catalyzed by BF 3 ·Et 2 O (Scheme c) .…”

Unusual Tandem Oxidative C–C Bond Cleavage and Acetalization of Chalcone Epoxides in the Presence of Iodine in Methanol

“…The 2,4-disubstituted phenyl ring took longer time for completion (Table 3, entry 6). This reaction has a potential to generate key intermediates α,α-dimethoxy acetophenones which find application in the synthesis 15 of chiral cyanohydrins, nicotine derivatives, chiral sulfoxides, α-hydroxy acetals, chiral 1,2-diols, and myretnalderived chiral auxillaries. We have reported an unusual observation of oxidative cleavage of the C-C bond in chalcone epoxides followed by acetalization with methanol to form α,α-dimethoxyacetophenones, when chalcone epoxides are reacted with iodine in methanol.…”