Adamantane-Functionalized Phthalimide Scaffold: Pathways to Supramolecular Interactions and Drug Discovery

Abstract

Herein, the synthesis of a novel adamantanyl-functionalized phthalimide scaffold is demonstrated. The novel compound could be used as a precursor for various synthetic pathways owing to the generic use of adamantane substituents as the driving force for supramolecular interactions with macrocycles and N-substituted phthalimide derivatives as a core structure in numerous drugs. The adamantanyl-functionalized phthalimide scaffold contains bromide groups on the C4 and C5 positions of the benzene ring, effectively allowing further facile modifications of the scaffold. The structure was fully characterized including single-crystal X-ray crystallography. The crystal structure shows an adamantane moiety at an angle of 115.57(7)° to the phthalimide core, hence sterically freeing the adamantane unit for host–guest interactions.

1. Introduction

Adamantane is a polycyclic hydrocarbon with fused chair cyclohexane rings with remarkable properties due to its lipophilicity and rigid structure [1]. It was only after Siewerth et al. illustrated a facile synthetic method for adamantane that it received greater attention from the materials and pharmaceutical industries [2,3]. As a result of the sustained interest in adamantane derivatives, amantadine (1-aminoadamantane) became the first derivative to exhibit potent anti-influenza properties and an antiviral activity against rubella viruses [4,5]. Remarkably, research in adamantane-based materials has extended far and wide to areas such as drug delivery [6,7,8,9], transitional metal catalysis [10,11,12], metal–organic frameworks, supramolecular chemistry and surface recognition [13,14,15].

Due to its rigid structure and high symmetry, the adamantane moiety can form strong and directional supramolecular inclusion complexes with macrocyclic host molecules such as cucurbiturils and cyclodextrins [6,7]. For instance, Kim et al. reported a highly removable homogeneous transition metal catalyst in aqueous media via host–guest interactions between an adamantanyl moiety and β-cyclodextrin [12]. Using modified ligands to retrieve metal catalysts from reaction mixtures has immense industrial applications. The pharmaceutical industries rely on the association equilibrium constant of about K = 5.2 × 10⁴ M⁻¹ of adamantane-β-cyclodextrin complexes to purify products through supramolecular interactions [16].

Given the myriad of applications for adamantanyl-decorated materials in drug design, catalysis, separation and new materials, we report the synthesis and structural analysis of a novel adamantanyl-functionalized phthalimide scaffold, 2-[(adamantan-1-yl)methyl]-5,6-dibromo-1H-isoindole-1,3(2H)-dione, or AdBr. In this work, the structure of AdBr was characterized by NMR spectroscopy, FTIR spectroscopy, single-crystal X-ray diffraction and elemental analysis. The AdBr scaffold could potentially be modified via Buckwald–Hartwig amination or other synthetic strategies to obtain new materials such as N-heterocyclic compounds [17,18,19].

2. Materials and Methods

1,2-Dimethyl-4,5-dibromobenzene (XyBr) and 4,5-dibromo phthalic acid (AcidBr) were synthesized as previously reported [20,21]. All other materials were of reagent quality and of HPLC grade and used as received. ¹H and ¹³C{¹H} NMR spectra were obtained using a Bruker 300 MHz spectrometer. Chemical shifts δ (in ppm) for ¹H and ¹³C NMR were referenced to SiMe₄ using the residual protio-solvent as an internal standard. For ¹H NMR: CDCl₃, 7.26 ppm. For ¹³C NMR: CDCl₃, 77.16 ppm. Coupling constants (J) were expressed in hertz (Hz). Infrared spectra were recorded with 1 cm^–1 resolution on a Shimadzu IRAffinity-1S spectrometer. Elemental analyses were performed at Atlantic Microlab, Inc. (Norcross, GA, USA). All reactions were performed under an inert N₂ atmosphere using standard Schlenk. All subsequent experiments were performed under ambient conditions using standard benchtop techniques.

2.1. Preparation of 4,5-Dibromo Phthalic Acid (AcidBr)

4,5-Dibromo o-xylene 200.00 mg (0.76 mmol) was dispersed in a 3.6 mL pyridine and 6.0 mL water mixture. Then, 473.00 mg KMnO₄ (2.99 mmol, 3.95 eq) was added to it and refluxed for 2 h. After, 945.00 mg of KMnO4 was added seven times (6.62 g total), and the reaction was set to continue refluxing overnight. After 16 h, the mixture was filtered while hot, and the residue was washed with hot water. The filtrate was reduced under vacuum to remove the pyridine, and the remaining solution was acidified with conc. HCl to form a white precipitate which was filtered and dried. Yield 208.00 mg, 85%. Due to the limited solubility of the product in the organic solvent, a satisfactory NMR spectrum could not be obtained. ATR-IR: v 3091 (vw), 2904 (vw), 2791 (vw), 2616 (vw), 2516 (vw), 1700 (s), 1515 (w), 1408 (w), 1289 (m), 1239(s), 1158 (w), 1077 (m), 876 (m), 816 (w), 776 (m), 701(w), 607 (vw).

2.2. Preparation of 2-[(Adamantan-1-yl)Methyl]-5,6-Dibromo-1H-Isoindole-1,3(2H)-Dione (AdBr)

4,5-Dibromo phthalic acid (AcidBr) 722.00 mg (2.24 mmol) and 1-adamantanemethyl ammonium salt 450.70 mg (2.24 mmol) were placed in 100 mL RBF equipped with a stir bar. Then, 15.0 mL acetic acid was added and refluxed at 120 °C for 16 h. The mixture was allowed to cool to RT, and 10.0 mL of water was added to it. The precipitate formed was filtered and washed with methanol (10 mL × 3) in a centrifuge tube. The precipitate was dried in vacuo to afford a gray solid (650.00 mg, 1.44 mmol, 64%). MP, 245.8–247.0 °C. ¹H NMR (300 MHz, CDCl₃): δ 8.10 (s, 2H), 3.39 (s, 2H), 1.99 (s, 3H), 1.63–1.54 (m,12H). ¹³C NMR (300 MHz, CDCl₃): δ 167.18, 131.79, 131.27, 128.40, 50.16, 40.79, 36.66, 35.58, 28.21. ATR-IR: v 3089 (vw), 2909 (m), 2840 (w), 1764 (w), 1706 (s), 1355 (s), 1253 (w), 1137 (w), 1088 (m), 990 (m), 903 (w), 856 (m), 743 (s), 611 (m), 581 (s). Anal. Calc. for C₁₉H₁₉Br₂NO₂: C, 50.36; H, 4.23; N, 3.09. Found: C, 50.22; H, 4.25; N, 3.08.

2.3. Crystal Structure Data Acquisition

A specimen of C₁₉H₁₉Br₂NO₂ (AdBr), with approximate dimensions of 0.256 × 0.312 × 0.452 mm, was used for the X-ray crystallographic analysis. The X-ray intensity data were measured. The integration of the data using a triclinic unit cell yielded a total of 40,110 reflections at a maximum θ angle of 33.18° (0.65 Å resolution), of which 6439 were independent (average redundancy 6.229, completeness = 98.7%, R_int = 1.69%, R_sig = 1.07%), and 6143 (95.40%) were greater than 2σ(F²). The final cell constants of a = 7.3485(3) Å, b = 8.0912(4) Å, c = 15.0118(7) Å, α = 100.7690(10)°, β = 102.3410(10)°, γ = 93.5710(10)° and volume = 851.72(7) ų are based upon the refinement of the XYZ centroids of reflections above 20 σ(I). The calculated minimum and maximum transmission coefficients (based on crystal size) were 0.7672 and 1.0000.

The structure was solved and refined using the Bruker SHELXTL Software Package, using the space group P-1, with Z = 2 for the formula unit, C₁₉H₁₉Br₂NO₂. The final anisotropic full-matrix least squares refinement on F² with 217 variables converged at R1 = 1.61% for the observed data, and wR2 = 4.13% for all data. The goodness of fit was 1.088. The largest peak in the final difference electron density synthesis was 0.663 e⁻/ų, and the largest hole was −0.346 e⁻/ų, with an RMS deviation of 0.057 e⁻/ų. On the basis of the final model, the calculated density was 1.767 g/cm³ and F(000), 452 e⁻.

3. Results and Discussion

3.1. Synthesis and Spectroscopy

As the first step towards constructing an adamantanyl-functionalized phthalimide scaffold, we pursued the bromination of o-xylene to yield 1,2-dimethyl-4,5-dibromobenzene (XyBr) (Scheme 1), as reported [20]. XyBr was subsequently oxidized with KMnO₄ in the water/pyridine mixture to form the corresponding 4,5-dibromo phthalic acid (AcidBr) which could not be characterized with a ¹H NMR spectroscope due to its poor solubility [21]. However, FTIR analysis indicated a very broad trough at 3000 cm⁻¹ due to O-H stretching, and a carbonyl peak at 1706 cm⁻¹ which proves that the methyl groups are oxidized to carboxylic acids.

Interestingly, while there are numerous examples of N-substituted phthalimide derivatives due to the role of their structural unit in various drugs [22], examples of 2-[(adamantan-1-yl)methyl]-5,6-dibromo-1H-isoindole-1,3(2H)-dione (AdBr) with a dibromo group are rare [23,24]. As a result, we devised a novel strategy for the straightforward synthesis of an adamantanyl-functionalized phthalimide scaffold which contains bromide groups on the C4 and C5 positions of the benzene ring, effectively allowing further facile modifications of the scaffold. In order to synthesize AdBr (Scheme 1), AcidBr was reacted with 1-adamantanemethylamine hydrochloride [25] in acetic acid for 16 h under reflux conditions. 1-Adamantanemethylamine was selected because it is less bulky around the amine group compared to 1-adamantaneamine. The methylene spacer in the adamantylmethyl substituent allows host molecules such as β-cyclodextrin to form a supramolecular complex with the adamantanyl moiety with minimal steric interference from the phthalimide core.

After TLC showed completion of the reaction, the desired product was obtained by adding water to the reaction mixture and filtering the precipitate formed, which was a gray solid. However, when recrystallized in a chloroform/pentane mixture, a white crystal was formed. ¹H-NMR showed characteristic adamantane peaks from 1.99 to 1.54 ppm, with the methylene peak resonating at 3.39 ppm as a singlet. In contrast, the methylene peak of 1-adamantanemethylamine hydrochloride showed a quartet at 2.66 ppm [25]. When compared to XyBr, the aromatic protons shifted downfield to 8.10 ppm, indicating the successful appendage of 1-adamantanemethylamine (Figure 1).

¹³C-NMR further proved the synthesis of AdBr by showing a characteristic peak of carbonyl carbon at 167.18 ppm and methylene carbon at 50.16 ppm (Figure 2). The FTIR spectrum of AdBr (Figure 3) indicated a characteristic carbonyl peak at 1706 cm⁻¹ and stronger C-H stretching at 2904 cm⁻¹ and 2830 cm⁻¹ compared to XyBr and AcidBr. The stronger C-H stretching in AdBr relative to its precursors indicates the successful functionalization with the adamantane moiety which has significant aliphatic C-H bonds.

3.2. Crystallography

Diffraction-quality single crystals of AdBr were obtained from a saturated solution of chloroform through gradual diffusion of pentane vapor at room temperature. After 24 h, large white crystals were observed and subjected to crystallographic analysis. The crystal system was determined to be triclinic, and the space group was of the P-1 type. The N1-C9-C10 bond angle was 115.57(7)°, which suggests the adamantane moiety is not in the same plane as the phthalimide unit (see supporting information). The adamantane moiety was almost perpendicular to the phthalimide core, and this observation was also reported by Basaric et al. [24]. The orientation of the adamantanyl unit is suitable for interaction with host macrocycles for formation of an inclusion complex without steric interference from the phthalimide unit (Figure 4). Furthermore, the carbonyl bond distance for O1-C7 was 1.2104(11) Å, which is within the reported range of 1.201–1.235 Å [26,27,28]. The twinned nature of the AdBr molecule in the unit cell of the crystal structure suggests a Br–Br halogen interaction, which could be the driving force for crystallization [29,30].

4. Conclusions

The synthesis of a novel adamantanyl-functionalized phthalimide scaffold was demonstrated. The scaffold has bromide groups on the C4 and C5 positions of the benzene ring, effectively allowing further facile modifications toward the potential synthesis of new drugs and supramolecular materials. The single-crystal X-ray diffraction structure of AdBr further confirmed the NMR, FTIR and elemental analysis results.