Anion-Controlled Synthesis of Novel Guanidine-Substituted Oxanorbornanes

Abstract

The cycloaddition of simple alkyl-substituted guanidine derivatives is an interesting approach toward polycyclic superbases and guanidine-based organocatalysts. Due to the high nucleophilicity of guanidines, an aza-Michael reaction with dienophiles is more common and presents a huge obstacle in achieving the desired synthetic goal. Our preliminary investigations indicated that the proton could act as a suitable protecting group to regulate the directionality of the reaction. To investigate the role of the protonation state and type of anion, the reactivity of furfuryl guanidines with dimethyl acetylenedicarboxylate was explored. Furfuryl guanidines showed a strong reaction dependence on the nucleophilicity of the counterion and the structure of guanidine. While the reaction of DMAD with the guanidinium halides provided products of an aza-Michael addition, Diels–Alder cycloaddition occurred if non-nucleophilic hexafluorophosphate salts were used. Depending on the structure and the reaction conditions, oxanorbornadiene products underwent subsequent intramolecular cyclization. A tendency toward intramolecular cyclization was interpreted in terms of the pKa of different positions of the guanidine functionality in oxanorbornadienes. New polycyclic guanidines had a slightly decreased pKa in acetonitrile and well-defined geometry suitable for the buildup of selective sensors.

A DFT Investigation of the Reactivity of Guanidinium Salts in Tandem aza-Michael Addition/Intramolecular Cyclization

“…A computational approach to the analysis of the tandem AMA/CYC reaction was started by considering the thermodynamics of the hydrogen halide transfer from guanidinium halide to DMAD. The assumed mechanism of the reaction is initiated by the halide attack on DMAD followed by proton abstraction from the guanidinium cation as we proposed recently [23]. The overall reaction is shown in Figure 1.…”

“…Their relative energies (Grel) and the Gibbs energies of the reactions (ΔrG) were calculated using five selected DFT methods. Two commonly employed density functionals were considered as very good (M06-2X [27]) and poor (B3LYP [28][29][30][31]) performers in the reaction [23]. Relative ratios are calculated from the 1 H NMR spectra of the reaction mixtures.…”

“…The results are given in Figure 2. Since in our previous paper, B3LYP correctly identified the isolated imidazolidinone derivatives 2-4 (Figure 1) as the most stable isomers of six possible products [23], we wanted to test its performance in spite of its known shortcomings, primarily from the viewpoint of the relative energies of the isomeric structures. The obtained results for the stability of tautomers are generally consistent across the employed methods.…”

“…Recently, we have found that guanidinium hydrohalides formed products of aza-Michael addition/cyclization (AMA/CYC) much like those obtained by the reaction of neutral guanidines with DMAD [23]. Unexpected reactivity was tentatively attributed to the initial deprotonation of guanidinium cation by halomaleic or halofumaric anions formed in situ by the addition of halide anions to DMAD.…”

“…Besides rationalization of the origin of the structural diversity of products, the accuracy of the DFT methods to predict the product ratios is also assessed. Structures of various products obtained by AMA/CYC tandem reaction of guanidinium salts 1a-1c with DMAD [23]. Relative ratios are calculated from the 1 H NMR spectra of the reaction mixtures.…”