Synthesis of 2-Oxaadamantane Derivatives

1,3-Dichloroadamantanes in fuming nitric acid were converted to mixtures of 2-oxaadamantane derivatives whose structure was determined by two-dimensional NMR methods and X-ray analysis. The resulting compounds can be used in the design of highly complex molecules as subjects for studying biological activity.

Compounds containing an oxaadamantane fragment have been used in the synthesis of biologically active structures [5][6][7][8][9][10]. Conformationally rigid crown ethers have been obtained from oxaadamantane derivatives, and some of them were shown to bind alkali metal cations with a selectivity comparable to that of known crown ethers such as 15-crown-5 and 18-crown-6 [11,12].
Thus, the known methods for the synthesis of 2-oxa adamantane and its derivatives utilize mainly bicyclo[3.3.1]nonanes as initial compounds. These methods are sophisticated since the synthesis of initial SYNTHESIS OF 2-OXAADAMANTANE DERIVATIVES bicyclic structures is often quite laborious. In some cases, a common drawback of both strategies is the use of expensive reagents and solvents. In this connection, there is a need to find readily available substrates and reagents that would allow target 2-oxaadamantanes to be synthesized in a single step. Such substrates may be 1,3-dihaloadamantanes as they are synthetically available compounds convenient for the preparation of various functional derivatives.

RESULTS AND DISCUSSION
We previously showed that the reaction of 1,3-dichloroadamantane with fuming nitric acid, including in the presence of acetic anhydride, involves nitrolysis with the formation of 3-chloroadamantan-1-yl nitrate and adamantane-1,3-diyl dinitrate [44,45]. Change of the reaction conditions (no acetic anhydride, room temperature) led to the formation of a mixture of products having 2-oxaadamantane structure. The reaction of 1,3-dichloro-5,7-dimethyladamantane (1) with fuming nitric acid at room temperature gave a mixture of compounds 2-4 at a ratio of 66.1:32.6:1.3 after 3 h (according to the GLC data; Scheme 1). We succeeded in isolating pure compounds 2 and 3 by flash chromatography.
The product structure was determined by NMR spectroscopy using 1 H-13 C HMBC and 1 H-13 C HSQC techniques. The 1 H NMR spectrum of 2 showed a singlet at δ 0.96 ppm due to methyl protons. The singlet at δ 2.70 ppm was assigned to the OH proton, and methylene protons of the chloromethyl group resonated as a singlet at δ 3.44 ppm. The quaternary carbon atom bearing OH group gave a signal at δ C 96.5 ppm in the 13 C NMR spectrum. Protons of the chloromethyl group showed HMBC correlations with C 4 /C 10 and C 3 (δ C 42.8 and 76.4 ppm, respectively; Fig. 2). The structure of 2 was unambiguously proved by X-ray analysis of its single crystal which was grown from a solution in petroleum ether (Fig. 3). The mass spectrum of 2 showed the molecular ion peak (m/z 230).
In the 1 H NMR spectrum of 3, protons of the methyl groups resonated as two singlets at δ 0.97 and   1.07 ppm, and the OH proton signal was a broadened singlet at δ 3.19 ppm. Protons of the chloromethyl group appeared as two doublets at δ 3.52 and 3.73 ppm with a coupling constant 2 J of 11.7 Hz, and the CHCl proton gave a singlet at δ 3.96 ppm. The 13 C NMR spectrum of 3 showed a signal at δ C 95.8 ppm due to carbon atom linked to the hydroxy group, upfield signals at δ C 26.7 and 28.8 ppm due to methyl carbons, and a signal at δ C 66.0 ppm from the CHCl carbon atom. The 1 H-13 C HMBC spectrum of 3 ( Fig. 4) displayed correlations between the CHCl proton (δ 3.96 ppm) and C 3 , C 10 , C 5 , C 6 , and CH 2 Cl carbons (δ C 78.4, 37.2, 37.4, 42.0, and 49.8 ppm, respectively). The ClCH 2 proton resonating at δ 3.52 ppm was coupled with C 3 and C 4 (δ C 78.4 and 66.0 ppm, respectively), whereas no correlation with C 1 (δ C 95.8 ppm) was observed. The molecular ion peak (m/z 264) in the mass spectrum of 3 had a low intensity. The reaction proceeded through intermediate formation of 3-chloro-5,7-dimethyladamantan-1-yl nitrate (5) and 5,7-dimethyladamantane-1,3-diyl dinitrate (6) [44]. After 10 min from the reaction start, the fractions of 2-oxaadamantanes 2, 3, and 4 were 9.3, 4.8, and 0.6%, respectively (GLC), and the fraction of nitroxy derivatives amounted to 85.3%. By recrystallization of the obtained product mixture from methanol we isolated 5,7-dimethyladamantane-1,3-diyl dinitrate (6) whose structure was confirmed by 1 H and 13 C NMR spectra.
Presumably, protonation of 5 at the ONO 2 group, followed by elimination of nitric acid molecule, gives carbocation A which undergoes Grob fragmentation [47], and a sequence of subsequent transformations leads to the formation of 7-methylidenebicyclo[3.3.1]nonan-3-one (B). The latter adds liberated chlorine at the exocyclic double bond, and further reaction with HNO 3 , transannular cyclization, and elimination of nitronium cation yield compound 2 (Scheme 2). Hemiacetal 2 is likely to exist in equilibrium with its open ketone structure C. Its dehydration gives bicyclononene derivative D which undergoes electrophilic attack by chlorine generated via oxidation of chloride ion with fuming nitric acid. Cation E thus formed adds nitrate ion, and the subsequent cyclization furnishes dichloro derivative 3. Dichloride 3 can be converted to trichloride 4 according to a similar transformation sequence (Scheme 3).
The structure of hydroxy ketone C suggests an alter native mechanism of introduction of the second chlorine atom into molecule 2 through the enol form of C. However, the 1 H-13 C HMBC spectrum of 3 unambigu ously indicated the position of the second chlorine atom: as noted above, no correlation between the 4-H proton and C 1 was observed (Fig. 4).
The proposed mechanism of the transformation of dichloroadamantane 1 into 2-oxaadamantane deriva-   (7) was formed in addition to compounds 3 and 4. The structure of 7 was confirmed by 1 H and 13 C NMR spectra, including 2D NMR experiments.
The 13 C NMR spectrum of 7 contained carbonyl carbon signals at δ C 169.4 and 202.9 ppm. The 1 H-13 C HMBC spectrum clearly showed correlations between the 4-H protons (δ 2.17, 2.44 ppm; δ C 4 42.5 ppm) and C 3 (δ C 169.4 ppm), as well as between the aldehyde proton (δ 9.36 ppm) and C 7 (δ C 45.4 ppm). The latter in turn was coupled with protons of one methyl group resonating at δ 1.09 ppm and protons on C 6 and C 8 (Fig. 5). The other correlations also confirmed the proposed structure.
Under similar conditions, from 1,3-dichloroadamantane (8) as substrate we obtained a mixture of 2-oxaadamantane derivatives 9-11 which we failed to separate by flash chromatography or recrystallization (Scheme 4). After keeping the reaction mixture for 24 h, it contained 81% (GLC) of 4-chloro-3-chloromethyl-2-oxaadamantan-1-ol (10). Pure compound 10 was isolated from that mixture by recrystallization from carbon tetrachloride. In the 1 H NMR spectrum of 10, the 4-H proton resonated as a singlet at δ 4.33 ppm. Methylene protons of the chloromethyl group appeared as two doublets at δ 3.49 and 3.64 ppm with a coupling constant of 11.6 Hz. In the 13 C NMR spectrum of 10, the C 4 signal was located at δ C 60.5 ppm, and the signal at δ C 94.8 ppm was assigned to the quaternary carbon atom bearing the hydroxy group.

EXPERIMENTAL
The IR spectra were recorded on a Shimadzu IR Affinity-1 spectrometer (Japan). The 1 H and 13 C NMR spectra were recorded on a Jeol ECX-400 spectrometer (Japan) at 400 and 100 MHz, respectively, using tetramethylsilane as internal standard. The mass spectra (electron impact, 70 eV) were run on a Finnigan Trace DSQ instrument. The reaction mixtures were analyzed with a Thermo Scientific Focus gas chromatograph (USA) using a DB-5 capillary column, 30 m×0.32 mm (oven temperature programming from 80 to 340°C at a rate of 20 deg/min; injector temperature 250°C; carrier gas helium). Flash chromatography was performed using a Buchi Reveleris X2 system (Switzerland); sorbent silica gel (25-40 μm, 12 g), flow rate 20 mL/min. The melting points were measured in capillaries on an MPM-H2 melting point apparatus (Germany) and are uncorrected. Elemental analyses were carried out with a Euro Vector 3000 EA analyzer (Italy) using L-cystine as standard. The purity of the isolated compounds was no less than 96.0%.

and anti-4-chloro-3-(chloromethyl)-2-oxaada-
anti-4-Chloro-3-(chloromethyl)-2-oxaadamantan-1-ol (10). Fuming nitric acid, 5 mL (0.12 mol), was added with stirring at room temperature over a period of 5 min to a solution of 1 g (5 mmol) of 1,3-dichloroadamantane (8) in 0.5 mL of methylene chloride. The mixture was stirred for 24 h, poured onto crushed ice, and extracted with methylene chloride (4×10 mL). The combined extracts were successively washed with a solution of sodium bisulfite (2×10 mL), 10% aqueous sodium hydroxide (1×10 mL), and water, dried over anhydrous sodium sulfate, and evaporated under reduced pressure. The residue was recrystallized from carbon tetrachloride. Yield 0.46 g (40%), colorless crystals, mp 121-123°C. 1  X-Ray analysis of compound 2. Single crystals of 2 suitable for X-ray analysis were obtained by slow evaporation of its solution in petroleum ether at room temperature. The X-ray diffraction data were collected using a Stoe StadiVari Pilatus-100K diffractometer (Cu K α radiation). The structure was solved by the direct method and was refined by the full-matrix leastsquares method in anisotropic approximation for nonhydrogen atoms. All calculations were performed using SHELX [50], and the molecular structure was visualized by ORTEP [51]. The set of X-ray diffraction data for compound 2 was deposited to the Cambridge Crystallographic Data Centre (CCDC entry no. 1833287) [46].