New spirocyclic nitroxides of 2,5-dihydroimidazole series flanked by two mesogenic fragments

N / C-Hydroxylated spirofused derivatives of 2,5-dihydroimidazole which were synthesized by condensation of 4-(4-hydroxyphenyl)cyclohexanone with aryl hydroxylaminoalkyl ketones in the presence of ammonia were determined to be trans-ee -isomers of 1,4-cyclohexane framework by NMR spectroscopy. Oxidation of the cyclic hydroxylamino moiety followed by acylation of the phenolic hydroxyl group with 4-alkyloxybenzoic acid chlorides led to the corresponding spirocyclic nitroxides bearing two mesogenic fragments.


Introduction
The rapid development of synthetic chemistry of stable nitroxyl radicals (aminoxyls) has led to significant advances in the field of their practical importance.They have proven to serve as (i) very effective stoichiometric and catalytic oxidants for alcohols, enolates, electron-rich olefins, carbanions, etc., 1,2 (ii) key agents for nitroxide-mediated radical polymerization, 1 and (iii) structural units for creating single molecular magnets 3 and ferromagnetics. 4Another aspect of their use is the creation of advanced paramagnetic liquid crystalline (LC) materials based on them. 5In fact, it attracted a great deal of attention because the obtained materials could exhibit unique magnetic interactions and unconventional magneto-electric or magneto-optical properties. 6[9][10] This type of organic radicals has shown a set of prominent physical properties in the LC state such as generation of a sort of spin glass-like inhomogeneous ferromagnetic interactions under weak magnetic fields, 9,10 possibility of the second harmonic generation, 11 and existence of two bistable states in ferroelectric LC phase. 12,13n connection with these aforesaid studies, it seems to be promising to synthesize a new type of all-organic paramagnetic LC materials bearing a nitroxide fragment in heterocyclic core such as 2,5-dihydroimidazole. Insertion of the second imine type of nitrogen atom being effective binding site can provide additional features and advantages in development of new soft materials, such as pH-sensitive LC droplets 14 or self-organized nanoparticles in LC medium.15,16 The introduction of a spirocyclic fragment as a building block into the molecule structure has been a subject of considerable interest.Tschierske and Vögtle et al. succeed in the synthesis of a number of calamitic LCs on the basis of mono-and dispiro derivatives of cyclobutanes, cyclopentanes and cyclohexanes.[17][18][19][20][21][22] Interesting results were obtained in the preparation ferroelectric LC`s on the basis of triangular structures (3+3+3) 23,24 and gem-difluoro derivatives of spirocyclopropanes (3+6+3), 25 which showed chiral smectic SmA* and SmC* phases in different conditions.
This report is a continuation of the researches on the synthesis of spirocyclic mono-and biradicals of azole series which can show mesogenic properties [26][27][28] and serve as spin probes for diamagnetic LCs by ESR spectroscopy. 29,30In this work we describe an approach to the synthesis of stable spirocyclic nitroxides 2-4 with a 2,5-dihydroimidazole structure (Figure 1).Despite the fact that a great number of LC molecules are often not ideal calamitics and have bulky substitutients near the lateral and terminal atoms, 31 we have tried to choose for our investigation such model compounds which satisfied the requirement of rod-like configuration.First, we performed the molecular modeling (see Experimental) for the structure with heterocyclic 2,5-dihydroimidazole core spirofused with cyclohexane moiety possessing 4-(aroyloxy)phenyl substituent on the C4 position.Analysis of obtained data for model diastereomers A and B revealed that A is Z-shaped while B can meet the requirement to be rodlike molecule (Figure 2).Thus, we decided to prepare the target radicals using 1,4-bifunctional derivative of cyclohexane as the starting compound.An approach to the synthesis of functionally substituted spirocyclic radicals of 2,5-dihydroimidazole series includes condensation of the corresponding 2hydroxylamino ketones with cycloalkanones in the presence of ammonia followed by oxidation of intermediate 1-hydroxy-2,5-dihydroimidazoles [32][33][34][35] .Produced in such manner 3-imidazoline nitroxide radicals would be relatively inert toward many common chemical agents 36 and could be modified on available functional groups without destruction of radical center.Condensation of commercially available 4-(4-hydroxyphenyl)cyclohexanone ( 7) with 2-hydroxylamino ketones 5 and 6 in methanol saturated with ammonia at ambient temperature gave imidazolines 8 and 9 with 70% and 97% yield, respectively.© ARKAT-USA, Inc. Scheme 1. Synthesis of nitroxides 2a-g and 3a-g.
The spatial molecular structure (3D-structure) depends on the conformation of "a central" cyclohexane fragment spirofused with an imidazoline ring due to the linearity of the substituents.Based on the chemical shift and coupling constants in the 1 H NMR spectrum of compound 9, the proton H8 was assigned to the axial position and geminal to it 4-hydroxyphenyl substituent to equatorial.However, determination of configuration spirofused imidazoline cycle to the cyclohexane ring was a nontrivial task.To solve this problem, the NOESY and ROESY spectral information of 2,5-dihydroimidazole 9 was used together with the results of quantum chemical conformational analyses of its two possible stereoisomers.Consequently, 13 conformers were found for both isomers (excluding enantiomers originating from the chirality of twist and sp 3 nitrogen atom) due to the conformation of the cyclohexane ring and the spatial arrangement of two aromatic rings 37 .These data suggest that the equatorial position of NOH fragment in 2,5dihydroimidazole as compared to the axial one has advantage by ca. 2 kcal/mol (according to DFT calculations).Comparison of spatial structures of low-energy conformers with ROESY data allowed us to identify 9 as the trans-ee-isomer (see Fig. 3).Similarly, compound 8 is assumed to take a trans-ee-isomer.An analogous substituent conformation was shown in a recent work by Serrano et al 38 for 4'-substituted cyclohexane-5-spirohydantoins which was consistent with that obtained by the X-ray crystallographic analysis.Thus, condensation of 2-hydroxylamino ketones with 4-substituted cyclohexanone in the presence of ammonia turned out to proceed with high stereoselectivity to furnish an A type isomer, apparently, more thermodynamically stable product.Oxidation of imidazolines 8 and 9 with manganese dioxide in chloroform -methanol solution gave the corresponding radicals 10 and 11 with 88% and 49% yields, respectively.To perform acylation, phenoxide anions of nitroxides 10 and 11 were successfully generated with potassium tert-butoxide as a base.These anions were reacted with 4-alkoxybenzoic acid chlorides 12a-g to give the target nitroxides 2a-g and 3a-g.
For the synthesis of nitroxide 4 with two different mesogenic acyl groups (n ≠ m), radical 11 was initially treated with one equiv of tert-BuOK and then one equiv of 4-octyloxybenzoic acid chloride (12a) was added to the reaction mixture to give monoacyl derivative 13 in 28% yield after the starting radical 11 were separated chromatographically.To characterize the product 13, it was reduced by Zn/NH4Cl to give the hydroxylamine 14.Comparison of NMR 1 H and 13 C spectra of 14 with 9 verified the monoacylation at the more acidic phenolic group (Scheme 2).Reaction of nitroxide 13 with 4-nonyloxybenzoic acid chloride (12b) afforded the target radical 4 possessing two different mesogenic acyl groups in 21% yield.both sides of spirofused heterocyclic and cyclohexane frameworks.On the basis of NMR studies, trans-ee configuration of substituents in 1,4-cyclohexane ring was established.As a consequence, none of the obtained nitroxides demonstrated mesomorphous behavior due to nonlinearity of molecules.

Experimental Section
General.Analytical and spectroscopic studies were performed in the Chemical Service Center of collective use of the SB RAS.Melting points and DSC-thermograms were obtained by FP 81 HT «METTLER TOLEDO» device.IR spectra were recorded on a Vector-22 Bruker spectrometer in KBr. 1 H and 13 C NMR spectra were recorded on Bruker AV-300, AV-400 and AV-600 spectrometers for solutions of compounds in CDCl3+CD3OD, CD3OD, DMSO-d6, chemical shifts were recorded in parts per million (ppm) relative to internal standard residual solvent signals -CDCl3 (δH 7.24 ppm, δC 77.36 ppm), CD3OD (δH 3.34 ppm, δC 49.00 ppm), DMSO-d6 (δH 2.50 ppm, δC 39.50 ppm).Structures of compounds were established by conventional oneand two-dimensional NMR spectra.Mixed time 0.2 s for NOESY and ROESY of compound 8 was used.ESR spectra of radicals were recorded on a Bruker 300 spectrometer for 10 -4 M chloroform solutions.Reactions were monitored by TLC on silica gel with Sorbfil UV-254 plates.The silica gel utilized for column chromatography (CC) was purchased from ACROS, 0.060-0.200mm.All chemicals and solvents were commercial reagent quality and used without further purification unless otherwise stated.Dry tetrahydrofuran (THF) was obtained by distillation over LiH/CaH2 mixture.4-(4-Hydroxyphenyl)cyclohexanone was purchased from Aldrich.2-Hydroxylamino ketones 5, 6 were prepared by analogy with patent .4-Alkoxyphenyl benzoic acids 40 were obtained by literature procedure.The initial set of conformers for compounds A, B and 9 was obtained by using ChemAxon's Marvin (conformers plugin) 41 , Verachem Vconf 42 and Confab 43 , then structures were optimized by RM1 44 with the MOPAC2012 program 45 , and for 9 by the density functional theory (functional PBE 46 , basis L1 (Λ01 47 , cc-pVDZ analog), with the PRIRODA program 47 ).The chemical shifts were calculated by GIAO/DFT/PBE (basis L22 (L22, cc-pCVTZ analog), with the PRIRODA program.For quantum chemical calculations, we used the cluster of the Information Computation Center, Novosibirsk State University 48 .All results of DFT calculations are available 37 .

Figure 3 .
Figure 3. Optimized molecular structure of major trans-ee-conformer 9 by DFT/PBE/L1 (see Experimental) calculations.The red arrows indicate the ROESY cross-peaks; solid arrows indicate strong effects and dashed arrowsweak ones.