Studies toward the Synthesis of 4-(2-R-ethyl)amino-2,2,5,5-tetramethyl-3-imidazoline 1-Oxyls. Nucleophilic Substitution of Bromide in theN-Alkyl Chain of the 1,2,4-Oxadiazol-2-one Precursor

Abstract

A synthetic approach to access the new nitroxides of the amidine type exhibiting pH-dependent EPR spectra through substitution of a halide in the exo-N-halogenoalkyl chain of 1-(2-bromoethyl)-6-oxyl-5,5,7,7-tetramethyltetrahydroimidazo[1,5-b][1,2,4]oxadiazol-2-one is reported. In this approach, an oxycarbonyl moiety of the oxadiazolone heterocycle plays the role of a "protecting group" for the amidine functionality. A nucleophilic cleavage of the oxadiazolone heterocycle under mild nonbasic conditions, applicable to substrates bearing substituents vulnerable to attack by strong basic nucleophiles, is elaborated. The approach allows for the new amidine nitroxides bearing various functional groups (e.g., such as CN, N3, NH2, COOEt) to be synthesized. A series of nitroxides obtained through the Staudinger/intermolecular aza-Wittig reaction of the azido derivative is also described. The nitroxides synthesized here were found to have pH-dependent two-component EPR spectra indicative of a slow, on the EPR time scale, R* left arrow over right arrow R*H+ chemical exchange, and pKa values ranging from 2.8 to 12.5 units. The guanidine derivatives synthesized in this work show the highest pKa values (pKa = 10.2 and 12.5, respectively) ever reported for the nitroxide pH-probes of a "basic type".

Synthesis of N'-substituted amidines through the cleavage an oxadiazolone heterocycle by weakly basic nucleophiles. Effect of the nature of the nucleophile and of the nucleophile/substrate molar ratio

“…In each of these examples the reaction can reach completion using less than an equivalent amount of the nucleophile just by increasing the reaction time. The results of the experiments reported fully agree with our previously proposed scheme of nucleophilic opening of an oxadiazolone ring which implies a recovery of the nucleophile in the reaction [14].…”

“…The presence of the dimethylcarbonate was not recorded in the reaction mixture. Instead, there was observed an increase in the amount of CO 2 in the reaction mixture over time (an exact quantitative measurement was not carried out) and this supports Scheme 4A [14] (see Experimental section).…”

“…We have recently found that the use of NaN 3 and KBr in DMSO or DMF leads to opening of an oxadiazolone ring in high yields under mild conditions (~ 55ºC) without affecting functional groups such as an ester which are sensitive to the action of the basic nucleophiles NaOH and MeONa [14]. We also found a marked difference in the reactivity of azide and bromide ions in the splitting reaction of the oxadiazolone ring.…”

“…In this case the yield of the reaction product does not differ from that using KCN [14] but the reaction time is decreased eightfold. One of the possible schemes of conversion of the oxadiazolone to the amidine under nucleophilic reagent conditions has been discussed by us before [14]. The scheme is based on heterolytic cleavage of the C-N bond of the oxadiazolone fragment and it implies a recovery of the nucleophile in the reaction (Scheme 4A).…”

“…In our work we have used as substrate the cycloadduct 4, the ester group of which (as previously shown) is stable to the conditions for ring splitting by such nucleophiles as NaN 3 or KBr [14]. The nucleophilic reagents used were NaN 3 , NaCN, KF, KBr, KCl, and NaNO 2 .…”