Synthesis of Imidates: TFA-Mediated Regioselective Amide Alkylation Using Meerwein’s Reagent

Abstract

Regioselective O-alkylation of an amide to form the corresponding imidate is a common synthetic problem, often resulting in varying amounts of N-alkylation. Screening existing methods for converting amides to imidates gave inconsistent or irreproducible results, sometimes affording N-alkylamide as the major product. A simple and reliable protocol for amide O-alkylation with complete regioselectivity has been designed, and its scope and efficiency demonstrated on a number of substrates.

An Efficient Synthesis of (±)-Dehaloperophoramidine

“…The yield for this step was, however, far from optimal with only 42% (72% brsm) of the desired product being isolated, the low yield being a consequence of considerable amounts of the corresponding bis N -Ts product being formed. The efficiency of the desymmetrization could be improved to 75% by instead forming the monoimidate using Meerwein’s reagent and a catalytic amount of TFA . It is believed that the improved selectivity of the monoalkylation is ascribed to the slow conformational equilibria of the cyclohexene moiety in 7 , which is evident from the broad peaks in its 1 H NMR spectrum.…”

“…In the event, compound 15 was treated with Meerwein’s salt in the presence of catalytic amounts of TFA to furnish imidate 16 in good yield (Scheme ). Removal of the N -Ts group, using SmI 2 and pyrrolidine in THF/H 2 O, provided compound 17 in excellent yield. However, deprotection of the benzyl groups through hydrogenation proved to be problematic.…”

“…The efficiency of the desymmetrization could be improved to 75% by instead forming the monoimidate using Meerwein's reagent and a catalytic amount of TFA. 16 It is believed that the improved selectivity of the monoalkylation is ascribed to the slow conformational equilibria of the cyclohexene moiety in 7, which is evident from the broad peaks in its 1 H NMR spectrum. Alkylation of the equatorial carboxamide moiety is believed to be more favored than alkylation of the axial one for steric reasons.…”

Highly diastereo- and enantioselective organocatalytic synthesis of new heterocyclic hybrids isoindolinone-imidate and isoindolinone-phthalide

“…According to the first experiments (Table 1), Cinchonaalkaloid based phase transfer catalysis was less effective than tertiary amine base organocatalysis (entries 1,3 vs entries 2,4), while 2-formyl benzonitrile was more promising than 2formyl methylbenzoate, giving a good er of 92/8 with high diastereoselectivity (dr>20/1) and good yields in the presence of 10 mol% of 7 (Entry 4). Despite the longer synthetic pathway, the use of 2-formyl benzonitrile has the additional advantage of allowing the access to another class of interesting heterocycles 5 with the imidate functionality, 12 which was then conveniently converted into the phthalide 3 by hydrolysis. The screening of conditions, performed with catalyst 7, led to the identification of xylene as the best solvent for this system, and after the optimization of medium concentration, a very good 95/5 er was obtained (Entry 6).…”

Catalytic I2-moist DMSO-mediated synthesis of valuable α-amidohydroxyketones and unsymmetrical gem-bisamides from benzimidates

“…Hence, they can cover a wide range of strategies to provide homo atomic and hetero atomic couplings. [10][11][12] Based on this fundamental science, recently synthetic chemists have reported interesting breakthroughs regarding some biologically important molecules. 13,14 Herein, we describe a highly proficient synthetic protocol for the simultaneous two bond-forming cross-coupling reaction of benzimidate skeletons (1) with acetophenone analogues to provide α-amidohydroxyketones (3, eqn (2), Scheme 1).…”