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Synthesis of Six and Seven-membered Heterocyclic Molecules Containing an Adamantyl Fragment and an X-ray Crystal Structure of (E)-N-(adamantan-1-yl)-1-(3-nitrophenyl)methanimine

Our work included a synthesis of three new imine derivatives—1,3-thiazinan-4-one, 1,3-oxazinan-6-one and 1,3-oxazepin-4,7-dione—which contained an adamantyl fragment. These were produced via the condensation of the Schiff`s base (E)-N-(adamantan-1-yl)-1-(3-aryl)methanimine with 3-mercaptopropanoic acid; 3-chloropropanoic acid; and maleic, citraconic anhydride, respectively. These new imines were prepared via the condensation of adamantan-1-ylamine and 3-nitro-, 3-bromobenzaldehyde in n-BuOH. We obtained a good yield of products. FTIR, 1 H NMR spectroscopy and C.H.N.S analysis were used to diagnostic the products. The molecular structure of (E)-N-(adamantan-1-yl)-1-(3-nitrophenyl)methanimine was confirmed by X-ray crystallography analysis.


Introduction:
The molecular skeleton of adamantane and its derivative molecules are of current interest to researchers in molecular technology. Adamantan-1ylamine and its derivatives are amines containing adamantyl fragment in the form of three fused cyclohexane rings in a chair conformation (1), and adamantane is the monomer of the diamond lattice (2). The adamantyl group has been found to be an important component in the development of many drug treatments (3). For example, the addition of adamantyl moiety to an active pharmaceutical molecule leads to improvements in an array of therapeutic drugs (4), and adamantan-1-ylamine was the first anti-viral treatment to be developed (5). This development led to the synthesis and testing of hundreds of adamantylamine derivatives for different bioactivities, especially for cancer drugs. The synthesis and study of the bioactivity of (E)-N-(adamantan-1-yl)-1- (3-aryl) methanimine derivatives have been undertaken via the condensation of two components of adamantan-1ylamine together with various aromatic aldehydes in the presence of acetic acid, and some of the synthesized compounds have been reported to inhibit acetylcholinesterase (ACHE) and to have anti-microbial, anti-cancer impacts in vitro and antiinflammatory (6)(7)(8)(9)(10)(11).
Furthermore, azomethine (imine) compounds are reactive intermediaries for organic synthesis in a number of diverse fields (12,13).

Materials and Methods:
All materials and solvents were supplied by Sigma-Aldrich Chemical Co. (Germany) and Romil Co. (UK). Melting point temperatures were measured using the Stuart SMP-10 apparatus. FTIR and 1 H NMR spectra were recorded using the Bruker-Tensor 27 and Bruker-300 MHz spectrometers, respectively (with DMSO-d 6 and CDCl 3 as a solvents and TMS as internal standard). Microelemental analysis was performed by using a thermo scientific flash 2000 series analyser, whilst X-ray diffraction was measured using a STOE StadiVari Pilatus100K diffractometer. The progress of reactions were monitored by TLC Silica gel 60G F254 (Sigma-Aldrich) using eluent chloroform/acetone (6:1) and benzene/methanol (7:1) as mobile phase under iodine vapour.
The general procedure for synthesizing (E)-N-(adamantan-1-yl)-1-(3-aryl)methanimine (1a,b) 1a was synthesized using a simple procedure with comparing (6) A solution of 0.013 mol adamantan-1ylamine in 20 mL butanol was added to a 0.013 mol solution of suitable 3-substituted benzaldehyde in 15 mL butanol. The mixture was heated for 1-1.5 hours with stirring at the boiling point of the solvent. The solvent was evaporated, and the residual product was re-crystallized from i-PrOH.

The general procedure for synthesizing 3-(adamantan-1-yl)-2-(3-aryl)-1,3-thiazinan-4-one (5a,b)
A 0.01 mol solution of compound 1a and b was mixed with 15 mL dry 1,4-dioxane, and a convenient solution of 0.01 mol 3mercaptopropanoic acid in 10 mL dry 1,4-dioxane in the presence of a small portion of anhydrous ZnCl 2 . This was then refluxed for 22-24 hours with vigorous stirring. The solvent was vaporized and the residual solid was washed with a 5% solution NaHCO 3 and then with distilled water. The obtained product was dried and re-crystallized from EtOH.

Results and Discussion:
The 277 also be provided in the following reaction equation 1. (1a,b) FTIR and 1 H NMR data for compounds (1a,b) is shown in Figs. 1, 2, 3 and 4. FTIR: all spectra exhibited evanescence in the stretching vibration bands of groups -NH 2 and C=O for amine and aldehydes, respectively with characteristic stretching vibration bands of the azomethine group (C=N) at 1638 and 1631 cm -1 , stretching vibration bands at range 3052 and 3092 cm -1 for C-H aromatic , and stretching vibration bands at range 2811-2906 cm -1 for C-H aliphatic . 1 H NMR data: all spectra exhibited singlet and multiplet signals of the adamantyl group (3H, s, 3СН), (12H, m, 6СН 2 ) at the range δ 1.63-2.13 ppm, and protons for the CH=N group displayed a singlet signal at δ 8.29 and 8.58 ppm, and displayed singlet, doublet , doublet and triplet of protons (H 2 , H 6 , H 4, H 5 aromatic ), respectively in an phenyl group at the range δ 7.40-8.47 ppm. The forming imine derivatives (1a,b) was carried out according to mechanism in literature (19). The nitrogen of amine attacks to the carbonyl group by nucleophilic addition to produce hemiaminal and then the leaving of a water molecule to give the target compound. See Scheme 1. FTIR spectra of compounds (2a,b-5a,b) revealed the disappearance of absorption bands of -C=N azomethines and C=O anhydrides, and the appearance of a stretching vibrations of C-H aromatic at 3010-3085 cm -1 and C-H aliphatic at 2811-2915 cm -1 . The stretching vibrations of the C=O lactone and C=O lactam groups were confirmed by a strong absorption band observed at the ranges 1722-1730 cm -1 and 1663-1704 cm -1 respectively, whilst the stretching vibrations of the CO-N, CO-O and C-S-C groups appeared at the frequency ranges of 1490-1529 cm -1 , 1332-1340 cm -1 and 832-883 cm -1 , respectively. These data was displayed selective spectra in Figs. 5, 6 and 7. The proposed mechanisms of formation 1,3-oxazepin-4,7-one (2a,b and 3a,b), 1,3-oxazinan-6-one (4a,b) and 1,3thiazinan-4-one (5a,b) derivatives were explained in literatures (16,21,24). The forming mechanism (2a,b and 3a,b) compounds included a cycloaddition reaction (2+5) to produce cyclic seven membered by nucleophilic acts of the ion pair of electrons in an imine group towards the electrophilic center of carbonyl group of the cyclic anhydride to make cyclic four and five membered as a transition state [a] which was recycled intramolecular by concerted, breaking and forming cyclic seven membered to make the target compound [b] without forming intermediate. See doublet-doublet signals at ranges of 6.11-6.33 ppm and 4.12-4.14 ppm, respectively. Whilst protons of the (=СНCO-N) group in compounds 3a,b were observed as doublet signal at range of 6.02-6.06 ppm, the protons of the methyl group showed singlet signal at δ 2.13 and 2.14 ppm. The protons of the (СН 2 -N) and (СН 2 -CO) groups in compounds 4a,b displayed a broad singlet signals at ranges of 3.06-3.65 ppm and 2.09-2.10 ppm, respectively. These data was displayed selective spectra in Figs.
The X-ray diffraction intensity for compound 1a was measured using a STOE StadiVari Pilatus100K diffractometer (26), λ(CuKα) = 1.5418 Å, using the ω-scanning technique. The data for the X-ray diffraction were processed by the WinGX suite (27), with the SHELX-97 program package being used to perform all subsequent calculations (28). The crystal structure was determined using the direct method, then refined with anisotropic displacement parameters for all nonhydrogen atoms. The hydrogen atoms were placed geometrically and refined isotropically using a riding model. The drawing of the structure was prepared using the MERCURY CSD 3.1 program (29). The bond length for (N1-C11) is 1.258 (3) Å, which is normal for double bond of (N=C), and the arrangement around this bond is trans (30). The structure displayed no hydrogen bonds. The details of the crystal data are provided in Tables 5-7.    dmitryalbov@mail.ru) for their support in performing the (C.H.N.S and 1 H NMR) analysis and the X-ray crystallography analysis.