tert-Butyl (6-(3-(3-Fluorophenyl)ureido)hexyl)carbamate

Abstract

The title compound, tert-butyl (6-(3-(3-fluorophenyl)ureido)hexyl)carbamate, was synthesized and characterized by NMR, MS, elemental analysis, and single-crystal X-ray diffraction. This urea can serve as a framework for the preparation of unsymmetrical diureas or compounds containing both urea and thiourea groups.

1. Introduction

It is known that 1,3-disubstituted ureas are potent inhibitors of human soluble epoxide hydrolase (sEH) [1,2,3,4,5]. Such compounds are currently undergoing clinical (EC 5026, Figure 1) and preclinical (AMHDU, Figure 1) trials and may become a good alternative to opioid analgesics [6,7]. We have previously shown that symmetrical compounds containing two urea groups and two lipophilic fragments linked by an aliphatic spacer are capable of inhibiting soluble epoxide hydrolase in the picomolar concentration range [8]. However, from the point of view of synthetic chemistry, the described method is suitable for obtaining only symmetrical compounds, the properties of which are not always suitable for their use as drugs.

Therefore, the development of methods for the synthesis of unsymmetrical diureas and carbamates [9] is an urgent task. The present study is focused on the preparation and identification of tert-butyl (6-(3-(3-fluorophenyl)ureido)hexyl)carbamate, which can serve as a framework for the preparation of unsymmetrical diureas.

2. Results and Discussion

The idea was to use a Boc-protected diamine at one of its amino groups. Such a diamine is commercially available, but can also be easily prepared in the laboratory [10]. In our experience, dry ether is a good solvent for the synthesis of 1,3-disubstituted ureas, since the latter usually dissolve poorly in it. Compounds 1 and 2 dissolved well in ether, which determined our choice (Scheme 1). However, after 8 h of synthesis, despite the almost complete conversion of the initial compounds (according to TLC data), no urea precipitate was observed. Then, we added 1N HCl to the reaction mass and stirred the reaction mass until the ether was completely removed (about 1 h). During the evaporation of the ether, a precipitate of urea 3 was formed at the phase boundary.

The synthesis was repeated one more time with a similar yield. However, an unusual result was obtained in the third repetition. The synthesis was carried out by an undergraduate volunteer, who, due to attending classes, was unable to isolate the product after 8 h, and the reaction mass stood for two days. After this, precipitation in the form of large colorless crystals was discovered (Figure S3). The crystals were good enough for X-ray diffraction analysis without additional recrystallization. Apparently, over the extra 40 h, the ether took water from the atmosphere since the flask was not sealed, which led to the precipitation of urea. And since the process of ether saturation with water proceeded slowly, crystals of the correct shape grew.

The molecular structure of tert-butyl (6-(3-(3-fluorophenyl)ureido)hexyl)carbamate (3) was determined by single-crystal X-ray diffraction (SC XRD). According to the SC XRD data, 3 crystallizes in the monoclinic Pn space group with a unique complex molecule in an asymmetric unit. The molecule comprises four parts: a main six-membered carbon chain C(8)-C(13), a 3-fluorophenyl ring attached to N(1) (N,N′-disubstituted urea fragment), and a Boc-protecting group bonded to N(3) (Figure 2). All bond lengths and angles are within normal ranges (Tables S2 and S3 in the Supplementary Section). The general molecular conformation is a consequence of the twist of each terminal substituent to the main disubstituted aliphatic diamine. The dihedral angles between the mean plane of the 3-fluorophenyl group (atoms C(1)–C(6)) and the carboxylic group (atoms O(2)–C(14)–O(3)–C(15)) are 56.78(10)°. The orientation of the Boc-protecting group relative to the main chain gives a torsion angle of C(14)-N(3)-C(13)-C(12) = −118.7(2)°.

Crystal structure packing analysis revealed that molecules of 3 form layers and relatively strong intermolecular contacts due to the presence of hydrogen bonds N–H…O in the supramolecular structure, which can be classified as a classic type H-bonds based on the geometrical parameters (Table S4, Figure 3 and Figures S4 and S5). In the absence of stronger discoverable intermolecular interactions, these hydrogen bonds explain the molecular conformation and lead to the overall structure of the crystal.

3. Materials and Methods

The ¹H and ¹³C NMR spectra were taken with a Bruker DPX 300 machine (Bruker AXS GmbH, Karlsruhe, Germany) at a frequency of 300 and 75 MHz in DMSO-d₆ solution with TMS as the standard. The J values are given in Hz. The MS spectrum was measured on a Finnigan MAT INCOS^TM 50 (Thermo Fisher Scientific, Waltham, MA, USA) using electron impact ionization (EI). The elemental analysis was performed on a Perkin-Elmer Series II 2400 Elemental Analyzer (Perkin Elmer Inc., Waltham, MA, USA). The TLC analysis was carried out on Merck silica gel chromatography plates with the fluorescent indicator F₂₅₄ (1.05554); the sorbent Silica 60; a layer thickness of 200 µm; a pore size of 60 Å; a particle size of 10–12 µm; and organic polymer as a binder (Merck KGaA, Darmstadt, Germany). The melting points were measured on a Büchi M-565 (Büchi Labortechnik AG, Flawil, Switzerland), and the average values of three independent experiments were recorded. The solvents and reagents were purchased from commercial sources.

3.1. X-Ray Crystallography

The single-crystal X-ray data for 3 were collected using a Bruker D8 Venture Photon II four-circle diffractometer (Bruker, Billerica, MA, USA) in ω-scan mode (Cu Kα radiation, λ = 1.54178 Å) at the Center for Collective Use of the Kurnakov Institute RAS (Moscow, Russia). The raw data were indexed and integrated with the APEX3 program suite (Bruker AXS Inc., Madison, WI, USA, 2016). The experimental intensities were corrected for absorption effects using SADABS [11]. The crystal structure was solved using direct methods [12] and refined via full-matrix least-squares on F² [13] using the OLEX2 structural data visualization and analysis program suite [14]. All non-hydrogen atoms were refined with anisotropic thermal parameters. The C–H hydrogen atoms were placed in the calculated positions and refined using a riding model with dependent isotropic thermal parameters, with U_iso(H) = 1.5U_eq(C) for the methyl groups and with U_iso(H) = 1.2U_eq(C) for other hydrogen atoms, while N–H hydrogen atoms were located in difference-Fourier maps and refined independently. The crystallographic data and structure refinement details for 3 are given in Table S1. CCDC entry 2,426,014 contains the supplementary crystallographic data for this paper. These data are provided free of charge by the Cambridge Crystallographic Data Centre: ccdc.cam.ac.uk/structures (accessed on 21 February 2025). The corresponding CIF files are also available as Supporting Information.

Crystal data for 3: C₁₈H₂₈FN₃O₃, M = 353.43, Pn, a = 5.07017(8) Å, b = 22.1104(4) Å, c = 8.60307(14) Å, β = 102.0417(7)°, V = 943.21(3) ų, Z = 2, d_calc = 1.244 g/cm³. A colorless single-crystal prism with dimensions of 0.20 × 0.12 × 0.08 mm was selected, and the intensities of 14,672 reflections were collected (μ = 0.756 mm⁻¹, θ_max = 74.515°). After the merging of equivalence reflections and absorption corrections, 3691 independent reflections (R_int = 0.0355) were used for the structure solution and refinement. The final R factor R₁ was 0.0328 [for 3594 reflections with F² > 2σ(F²)], wR₂ was 0.0884 (for all reflections), S was 1.093, and the largest diff. peak and hole were 0.219 and −0.213 e/ų, respectively.

3.2. Synthesis of tert-Butyl (6-(3-(3-Fluorophenyl)ureido)hexyl)carbamate (3)

Into a flat-bottom flask equipped with magnetic stirrer were added 1130 mg (5.23 mmol) of tert-butyl (6-aminohexyl)carbamate (1), 16 mL of anhydrous Et₂O, 700 mg (5.11 mmol) of 3-fluorophenyl isocyanate = (2), and 730 mg (7.22 mmol, 1 mL) of Et₃N. The resulting mixture was left to be stirred for 8 h at rt. Then, 15 mL of 1 N HCl was added, followed by the formation of white precipitate. After stirring for another 1 h, the precipitate was filtered off, washed with 30 mL of distilled water and dried in vacuo. The resulting crude tert-butyl (6-(3-(3-fluorophenyl)ureido)hexyl)carbamate (3) was purified by crystallization from ethanol. Alternatively, the reaction mass could be left for 48 h to acquire colorless crystals of 3 suitable for X-Ray diffraction analysis. Pure tert-butyl (6-(3-(3-fluorophenyl)ureido)hexyl)carbamate (3): 1050 mg, 2.97 mmol, 58% yield (for both methods), white solid. Mp = 99.2 °C. Mass spectrum, m/z (I_rel. %): 353 (1.5% [M]⁺), 252 (18%), 137 (30% [OCN-Ph-F]⁺), 111 (100% [H₂N-Ph-Fl]⁺). ¹H NMR (CDCl₃), δ, ppm: 1.23–1.29 (m, 4H, 2CH₂), 1.35–1.43 (m, 13H, 2CH₂, 3CH₃), 2.91 (q, 2H, J = 6.5 Hz, CH₂-NH-C(O)NH), 3.07 (q, 2H, J = 6.7 Hz, CH₂-NH-C(O)O), 6.18 (t, 1H, J = 5.7 Hz, NH-CH₂), 6.66 (tdd, 1H, J = 8.5, 2.6, 0.9 Hz, 4-H Ph), 6.72 (br.t, 1H, NH-C(O)O), 7.01 (ddd, 1H, J = 8.2, 2.0, 0.9 Hz, 6-H Ph), 7.21 (td, 1H, J = 8.2, 6.9 Hz, 5-H Ph), 7.45 (dt, 1H, J = 12.3, 2.3 Hz, 2-H Ph), 8.61 (s, 1H, NH-Ph). ¹³C NMR (CDCl₃), δ, ppm: 26.5 (2C, 2CH₂), 28.7 (3C, 3CH₃), 29.9 (1C, CH₂), 30.1 (1C, CH₂), 39.4 (1C, CH₂-NH-C(O)O), 40.3 (1C, CH₂-NH-CO-NH), 77.7 (1C, C(CH₃)₃), 104.7 (d, 1C, J = 26.6 Hz, 4-C Ph), 107.5 (d, 1C, J = 21.2 Hz, 2-C Ph), 113.7 (1C, 6-C Ph), 130.5 (d, 1C, J = 9.7 Hz, 5-C Ph), 143.0 (d, 1C, J = 11.4 Hz, 1-C Ph), 155.4 (1C, NH-CO-NH), 156.0 (1C, NH-C(O)O), 162.9 (d, 1C, J = 240.1 Hz, C-F). Calc. for C₁₈H₂₈FN₃O₃: C 61.17; H 7.99; N 11.89. Found: 61.20; H 8.00.; N 11.85. M = 353.44.

4. Conclusions

In this work, we described the preparation of a new compound, tert-butyl (6-(3-(3-fluorophenyl)ureido)hexyl)carbamate, and identified it with ¹H and ¹³C NMR, MS, and single-crystal X-ray diffraction.