Catalytic, Enantioselective Synthesis of Cyclic Carbamates from Dialkyl Amines by CO₂-Capture: Discovery, Development, and Mechanism

Abstract

Cyclic carbamates are a common feature of small molecule therapeutics, offering a constrained hydrogen bond acceptor that is both polar and sterically small. Methods for their preparation most often focus first on aminoalcohol synthesis and then reaction with phosgene or its equivalent. This report describes an enantioselective synthesis of cyclic carbamates in which carbon dioxide engages an unsaturated basic amine, facilitated by a bifunctional organocatalyst designed to stabilize a carbamic acid intermediate while activating it toward subsequent enantioselective carbon-oxygen bond formation. Six-membered cyclic carbamates are prepared in good yield with high levels of enantioselection, as constrained 1,3-amino alcohols featuring a chiral tertiary alcohol carbon. Spectroscopic analysis (NMR, DOSY) of various substrate-reagent combinations provides insight into the dominant species under the reaction conditions. Two peculiar requirements were identified to achieve highest consistency: a ‘Goldilocks’ amount of water and the use of a non-crystalline form of the ligand. These atypical features of the final protocol notwithstanding, a diverse range of products could be prepared. Their functionalizations illustrate the versatility of the carbamates as precursors to enantioenriched small molecules.

Recent Advances in the Chemical Fixation of Carbon Dioxide: A Green Route to Carbonylated Heterocycle Synthesis

“…NHAr Cl R (1) HCl R (1) NHAr O R (1) O N N Bu Cl H N O R (1) R (1) Ar These last two reactions have been employed also for larger cyclic carbamates than oxazolidinones. Very recently, an enantioselective cyclization was developed to prepare six-membered cyclic carbamates from homoallylic amines (Scheme 25) [182]. The catalyst was studied in order to have Brønsted basicity enough to avoid amine to form an achiral carbamate salt intermediate.…”

Bypassing the Inertness of Aziridine/CO2 Systems to Access 5‐Aryl‐2‐Oxazolidinones: Catalyst‐Free Synthesis Under Ambient Conditions

“…All of the reported methods require the use of a catalyst unless high CO 2 pressure or supercritical carbon dioxide is employed . Thus, unsaturated amines, haloamines, and amino‐alcohols have been investigated for their cyclization reactions with CO 2 to afford 2‐oxazolidinones; even three‐component systems may be effective, and in this regard, several epoxide/amine, alkyne/amine, and alkene/amine combinations have been considered. Repo and co‐workers demonstrated that a series of N ‐aryl‐2‐oxazolidinones are accessible from the one‐pot carboxylation of aniline/1,2‐dibromoethane in organic solvents under mild conditions .…”

The interpretation of small molecule diffusion coefficients: Quantitative use of diffusion-ordered NMR spectroscopy

“…While additional spectral information concerning the acid's diffusion coefficient is lost, the deduction proved robust and suggested a 1:1 complex between the Brønsted acid and substrate base. This methodology has subsequently been successfully used in a number of fields, particularly by Day and Weaver to help confirm their successful synthesis of 2,3,5,6-tetrafluoro-4-(nitromethyl)pyridine [155] and by Yousefi et al to confirm the stoichiometry of complexes formed during carbon dioxide capture/cyclization reactions performed using chiral Brønsted acid catalysts [156].…”