Stable nitroxides are functional components of many high-tech materials, such as energy storage and organoelectronics devices , catalysts , bioactive coatings and nanoparticles , organic radical contrast agents (ORCAs) for magnetic resonance imaging (MRI) , etc. For these applications, numerous nitroxides are incorporated into macromolecular or nanosized supramolecular structures, which modulate nitroxide properties. For example, the efficiency of ORCA (relaxivity) directly depends on the rotational correlation time of the radicals attached to the scaffold . Large structures in which rotation of the radical separately from the framework is impossible could be particularly promising. Rigid polycyclic fused systems with incorporated nitroxide moieties could be one of the possible ways to achieve the above feature.

We recently found that the reaction of sterically hindered 3-hydroxymethyl-2-ethynylpyrrolidine-1-oxyls with nucleophilic agents can lead to the formation of condensed systems involving the substituent at position 3 of the pyrrolidine ring . Alkynes are broadly used in the synthesis of various heterocyclic compounds, and participation of neighboring functional groups often leads to formation of complex polycyclic systems . In this study, we aimed to construct rigid tricyclic condensed systems with an integrated nitroxyl radical fragment from 3-substituted 2-ethynylpyrrolidine-1-oxyls. The desired tricyclic nitroxides were prepared via intramolecular Huisgen cycloaddition or via one-pot Michael addition–cyclocondensation reaction with hydrazine with subsequent intramolecular alkylation of the resulting pyrazoles.

Scheme 1: Synthesis of nitroxides 2a–f.

Terminal alkynes can be converted into propargylamines via A3-coupling reaction . In analogy to a literature procedure , heating of radical 2a in a mixture of dimethylamine, formalin, and tetrahydrofuran in the presence of copper(II) acetate afforded the corresponding dimethylamino derivative 2f.

Figure 1: X-ray structure of nitroxide 2d.

Scheme 2: Synthesis of mesyl 3a–f and triazole 4a–f derivatives.

The IR spectra of nitroxides 3a–f exhibit intense absorption bands in the ranges of 1354–1358 cm−1 and 1174–1178 cm−1, corresponding to the asymmetric and symmetric vibrations of the sulfonate group, respectively . The 1H NMR spectra of 3a,b,d–f (Zn/CF3COOH system in CD3OD) showed appearance of a singlet of methanesulfonate hydrogens in the region from 2.78 to 3.17 ppm. The NMR spectra were not recorded for 3c because of heavy resinification upon the sample preparation.

The literature data on reactivity of 5-azidopentyne derivatives in intramolecular Huisgen cycloaddition reactions are contradictory. Some authors successfully obtained 5-azidopentyne derivatives upon nucleophilic substitution at 80 °C in DMF, and additional heating at 170 °C was necessary for cyclization to triazoles to occur . However, there are also examples where the corresponding triazoles were isolated instead of 5-azidopentyne derivatives under the same conditions (DMF, 80 °C) .

Table 1: Reduction rate constants k2 and EPR spectral parameters of nitroxides 2a–f, 4a–f, 9c.

Figure 2: X-ray structures of nitroxides 4a–c.

Scheme 3: Synthesis of alkynones 6a,b.

In the IR spectra of 6a,b intense bands were observed at 2212–2214 and 1645–1647 cm−1, assigned to vibrations of the triple bond, and the conjugated carbonyl group, respectively. The elemental analyses data and high-resolution mass spectra (HRMS) of 6a,b were in agreement with the assigned structure.

Scheme 4: Synthesis of vinyl ether 8.

Figure 3: X-ray structures of nitroxides 8 and 9a.

Scheme 5: Synthesis of pyrazole derivatives 9a–c.

Treatment of 6b with hydrazine resulted in the formation of a condensed tricyclic ring system and nitroxide 9b was isolated in 42% yield. This nitroxide was alternatively prepared via mesylation of 9a. The yield of 9b in this reaction depends on excess of the reagent. Heating of 9a with five equivalents of MsCl and excess of DIPEA afforded 9b in 65% yield. When a 1.5-fold excess of mesyl chloride per hydroxy group was used, another nitroxide 9c was isolated in 26% yield along with 9b (43% yield).

Figure 4: Spin–spin coupling constants for reduced nitroxides 9a–c.

In this work we showed that formation of rigid tricyclic annulated systems from bifunctional nitroxides bearing alkynyl and another functional group in neighboring positions is feasible. The new tricyclic nitroxyl radicals of the pyrrolidine series annulated with 5,6-dihydro-4H-pyrrolo[1,2-c][1,2,3]triazole or 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole systems have been synthesized and characterized. Despite these nitroxides showed relatively low stability to reduction, the general strategy suggested here can be applied for the synthesis of various polycyclic systems with incorporated nitroxide.