α-Oximono-esters as precursors to heterocycles – generation of oxazinone N-oxides and cycloaddition to alkene dipolarophiles

Abstract

Preparation of a series of terminally and internally substituted δ-alkenyl and δ-alkynyl esters 6,7 and 9, potential precursors to oxazin-2-one nitrones, has been attempted. Condensation between pyruvic or benzoylformic acid and the appropriate alcohol proceeded smoothly in some cases whilst allylic transposition was a major feature in other casesmost especially during reactions with α-vinylbenzyl alcohol. Oximation of pyruvic acid derivatives furnished E-oxime isomers whilst benzoylformic acid derivatives afforded mixed geometrical isomers. The E-oxime of 4a 1 carrying an internal Me group undergoes facile thermal cyclisation affording nitrones 1c and 1d in good yield. Oximes E-5a,b with a terminal methyl substituent on the alkene moiety furnish nitrone only under the influence of an external electrophile [PhSeBr/AgBF 4 ]. A terminal Ph substituent on 5c,d prohibits formation of the cyclic dipole irrespective of reaction conditions, and whilst 5d reacts to afford a bicyclic isoxazolofuranone 13 by an IOOC reaction (intramolecular oxime olefin cyclisation) 5c remains thermally inert. Finally δ-alkynyl oximes 9c,d also failed to cyclise. The regio-and stereochemical characteristics of the cycloadditions between the new dipoles and electron poor olefinic dipolarophiles have been investigated. The conditions needed for reaction were rather forcing since the dipoles are somewhat stabilised by the adjacent alkoxycarbonyl group. All reactions proceeded regiospecifically to give adducts with 5-substituted isoxazolidine rings whilst diastereoselectivity varied with the choice of dipolarophile and the steric demands of the nitrone substituents. The phenylselenyl dipole 10a could not be trapped by any dipolarophiles bar dimethyl acetylenedicarboxylate.

Synthesis of Unsaturated Precursors for Parahydrogen-Induced Polarization and Molecular Imaging of 1-13C-Acetates and 1-13C-Pyruvates via Side Arm Hydrogenation

“…Moreover, we report the preparation of pure (from organic solvent) compounds, which is desirable for PHIP-SAH hyperpolarization. We also note that the overall yields for compounds 9a and 9b were lower than those previously reported for 9a ( 62 ) because here neat liquid (vs solutions) was prepared as the final product. The additional achievement of the reported work is the synthesis of 13 C-labeled compounds in pure form.…”

“…Pyruvic acid esters 8a , 8b , and 9a , 62 9b were obtained by the reaction of pyruvic acid 2a or labeled 1- 13 C-pyruvic acid 2b with small excess of allyl alcohol 3 or propargyl alcohol 4 in the presence of a p -toluenesulfonic acid ( Scheme 4 ). All reactions were refluxed with the Dean–Stark adapter with benzene as a solvent.…”

ParaHydrogen Induced Polarization of 13C carboxylate resonance in acetate and pyruvate

“…On the basis of the results obtained on propargylic ester of acetate, propargyl alcohol was used to prepare the unsaturated ester of pyruvic acid 2-propynyl-2-oxopropanoate (8) 32 (naturally abundance [1-13 C] pyruvate). According to the reported phase transfer procedure 33 , hydrogenation of the ester was carried out in a chloroform (90%)-methanol (10%) mixture and was followed by the addition of an aqueous basic solution (NaOD 1 M).…”

An investigation of structure-reactivity relationships of δ-alkenyl oximes; competitive thermal reactions leading to cyclic nitrones and/or N-unsubstituted bicyclic isoxazolidines

“…An IOOC approach to the synthesis of lactam-fused isoxazolidines has previously been demonstrated with substrates bearing an amido functionality tethered either directly 7b or more remotely 23 to the alkene bond affording isomeric 5,5-bicycles illustrated, respectively, by 11 and 2a.…”