2‐(Het)aryl‐N‐phosphorylpyrrolidines via Cyclization of Phosphorus Acid Amides: A Regioselective Approach

Abstract

A first successful synthesis of 2-(het)aryl-N-phosphorylpyrrolidines is reported starting from readily available N-(4,4-diethoxybutyl)amides of P(V) acids. A range of phenols and hydroxyl-substituted O-heterocycles may be employed into the reaction furnishing N-phosphorylated 2-(het)arylpyrrolidines with up to 90 % yield. The developed method permits a presence of sensitive to phosphorylation hydroxy groups and provides the easy and regioselective entry to target compounds. Pyrrolidine core is widespread in natural products [1,2] and synthetic drugs. [3] Phosphorus-containing pyrrolidine derivatives are of a special interest due to their various biological [4-8] and catalytic [9,10] properties. Among them, (pyrrolidin-1-yl) phosphoramidates are proposed for hepatitis C, [11] malaria and tuberculosis [12] treatment, possess anti-HIV [13-16] and antitumor [17,18] activity. Additionally, they employed as chiral ligands in various asymmetric reactions. Examples are metal-catalyzed stereoselective reduction of ketones, [19,20] ketimines [21] and alkenes, [22-24] various cycloadditions, [25-29] addition of boronic acids [30] and organotrifluoroborates [31] to alkenes, asymmetric ruthenium-catalyzed metallo-ene reaction [32] and Suzuki-Miyaura coupling. [33]

Enamine-mediated Mannich reaction of cyclicN,O-acetals and amido acetals: the multigram synthesis of pyrrolidine alkaloid precursors

“…During our prior research, we have shown that the N-substituted 4,4-diethoxybutan-1-amine derivatives also undergo the reaction with nucleophiles via 2-ethoxypyrrolidines as transient intermediates. [46][47][48] Thus, we employed sulfonylamides 2a and 2b in the reaction with ketones. Pleasingly, the reaction furnished the desired pyrrolidines 3ba-3bd.…”

The Highly Regioselective Synthesis of Novel Imidazolidin-2-Ones via the Intramolecular Cyclization/Electrophilic Substitution of Urea Derivatives and the Evaluation of Their Anticancer Activity

“…Nitrogen-containing aldehydes and acetals are widely used in the heterocycles synthesis [ 14 , 15 ]. Earlier, we have described the approach to 2-substituted pyrrolidine derivatives based on the in situ generation of a cyclic iminium ion from 4-aminobutanal acetals (4,4-diethoxybutan-1-amines) and its trapping by various nucleophiles [ 16 , 17 , 18 ]. Our preliminary studies indicate that N -(2,2-dialkoxyethyl) ureas are also capable of the formation of cyclic imidazolinium cations and the reaction results in cyclic urea derivatives—imidazolidinones or benzo [ d ] [1,3] diazepinones [ 19 ].…”