Theoretical Study of the [2+3] Cycloaddition of Nitrones to Nitriles—Influence of Nitrile Substituent, Solvent and Lewis Acid Coordination

Abstract

The [2+3] cycloaddition of nitrone PhCHdoublebondN(Me)O to nitriles RCtriplebondN (R=Me, Ph, CF(3)) was studied using quantum chemical calculations at the HF/6-31G* and B3LYP/6-31G* level of theory. With MeCN and PhCN, the reaction occurs through a concerted mechanism and leads selectively to Delta(4)-1,2,4-oxadiazolines rather than Delta(2)-1,2,5-oxadiazolines. Electron withdrawing substituents such as CF(3) at the nitrile provoke a non-synchronous bond formation, with the C-O bond being established on an earlier stage than the C-N bond. Additionally, the reaction becomes thermodynamically and kinetically more favourable. In the reaction of adducts of MeCN with BH(3) or BF(3) as model Lewis acids, the mechanism was found to change from fully concerted in the case of free MeCN towards a two-step reaction in the presence of BF(3), in which C-O bond formation occurs first. The BH(3)-mediated reaction occupies an intermediate stage where ring formation occurs in one-step but non-simultaneously, similar to the reaction of CF(3)CN. Interaction of the Lewis acid with the nitrile in the course of the reaction facilitates the cycloaddition by stabilizing transition states, intermediate and product rather than by activating the nitrile. The solvent influences the organic reaction mainly by lowering the energy of the reagents, thus leading to a higher activation barrier in a more polar solvent. In the Lewis acid mediated reaction, in contrast, the intermediate is strongly stabilised by a polar solvent and with that the synchronicity of the reaction changes in favour of a two-step mechanism.

[3+2] Cycloaddition of Oxaziridines with Nitriles: Synthesis of 2,3-Dihydro-1,2,4-Oxadiazoles

“…The reaction time could be shortened and the yield increased when the nitrile was used as the solvent itself, 21 as the temperature could be raised to 140°C (Table 1, entries 2, 4,9). Inspection of our results indicated that there were no substantial electronic effects of either the oxaziridine or the nitrile, as was reported with previous related systems.…”

“…Interestingly, the isomeric 4,5-dihydro-1,2,4oxadiazoles, which differ from the 2,3-dihydro-1,2,4-oxadiazoles only in the position of the ring double bond, have been studied in significantly more detail; numerous approaches for their synthesis 2 and subsequent application in various medical fields have been reported. 3 To date, the most common approaches for the synthesis of 2,3-dihydro-1,2,4-oxadiazoles is based on the cycloaddition reaction between nitrones and nitriles, [4][5][6][7][8][9] which proceeds with complete regiocontrol (Scheme 1).…”

Ligand discrimination in the reaction of nitrones with [PtCl2(PhCN)2]. Selective formation of mono-oxadiazoline and mixed bis-oxadiazoline complexes under thermal and microwave conditions

“…It was found that coordination of the nitrile to a Lewis acid changes the reaction mechanism from a concerted one involving an unpolar transition state to a two-step reaction, in which transition states and the intermediate are zwitterionic, highly polar species. 21 Thus, the stronger the Lewis acid, the more polar the transition states would be. In the initial bis-nitrile complex, all ligands are electron withdrawing and with this, the platinum center is expected to be more Lewis-acidic than in the mono-oxadiazoline complex, in which the oxadiazoline ligand rather acts as an electron donating ligand.…”

A Palladium(II) Center Activates Nitrile Ligands toward 1,3-Dipolar Cycloaddition of Nitrones Substantially More than the Corresponding Platinum(II) Center

“…Taking into account the significant increase of asynchronicity in CA of nitrones to ligated nitrile species as compared to CA of metalfree reactants, 14,18 the former type of cycloaddition resembles the nucleophilic addition to metal-activated nitriles. In this context, it is worth mentioning that a similar trend in reactivity upon alteration of metal centers was observed by Lippert and colleagues, 19 who studied the hydration of nitriles ligated to [M(en) 2 ] 2+ centers; the rate of the water addition found for M = Pd II was substantially higher than for M = Pt II .…”