N-(2-Fluoro-2-propen-1-yl)-5-(trifluoromethyl)-2-pyridinecarboxamide

Abstract

Herein, the synthesis and crystallization of the unreported compound N-(2-fluoro-2-propen-1-yl)-5-(trifluoromethyl)-2-pyridinecarboxamide is achieved via amide coupling with a (2-fluoroallyl)ammonium salt. The structural properties are analyzed via single-crystal X-ray crystallography. Hydrogen bonding interactions between the amide groups and pyridine nitrogen atoms create a unique linear array of molecules in the crystal packing diagram. Furthermore, to validate the crystallographic data, the structural features of the compound are evaluated and compared to values reported in the literature.

1. Introduction

The small size and high electronegativity of the fluorine atom impart unique chemical and physical properties, making fluorine an essential tool for chemical research [1,2]. For example, it is estimated that fluorinated organic compounds make up 20% of pharmaceuticals and 40% of agrochemicals currently on the market, with these numbers gradually increasing [2,3]. Furthermore, organofluorine compounds have shown applications in materials science and biological imaging [4]. Among the many moieties containing C–F bonds, the trifluoromethylpyridine motif is one that is commonly incorporated in molecules with pharmaceutical and agrochemical applications [5]. For example, a 3-(trifluoromethyl)pyridyl group is present in Apalutamide (1, Figure 1), an FDA-approved androgen receptor inhibitor used to treat prostate cancer [5]. The same motif is seen even more extensively in agrochemicals such as the commercial fungicide Fluopicolide (2) [6]. Incorporation of the (trifluoromethyl)pyridyl group into organic synthesis could therefore assist in the development of new molecules of interest.

The monofluoroalkene represents another structural motif that has seen widespread application in drug design and materials chemistry [7]. Monofluoroalkenes are useful tools in medicinal chemistry as non-hydrolyzable isosteres of peptide bonds and mimics of enols (Figure 2) [8,9,10]. Studies have shown that monofluoroalkene-based peptide analogues can display enhanced hydrophobicity, a key factor that drives protein folding [8].

With both fluorinated motifs showing promise in chemical research, our group has pursued an interest in developing molecules featuring both a monofluoroalkene and a (trifluoromethyl)pyridyl group. These may be achieved via a one-pot amide coupling reaction between 5-(trifluoromethyl)-2-picolinic acid and (2-fluoroallyl)ammonium chloride 3 (Scheme 1). Potential applications of this synthetic route are highlighted by the fact that amide bond coupling is one of the most useful reactions in medicinal chemistry [11]. Due to the unique structure of amide 4, and the lack of similar structures in the published literature, the compound has been characterized exhaustively using X-ray crystallography in addition to standard techniques.

2. Results

2.1. Synthesis and Spectroscopy

5-(Trifluoromethyl)-2-pinolinic acid was converted into the corresponding acyl chloride by treatment with oxalyl chloride and catalytic DMF, then coupled with (2-fluoroallyl)ammonium chloride 3 in the presence of Et₃N to give amide 4 in a 36% yield (see the Supplementary Materials for more details). The product was purified by flash chromatography to give an off-white solid. NMR spectroscopy experiments (¹H, ¹³C{¹H} and ¹⁹F) were conducted to confirm the structure of the product. Furthermore, ¹³C DEPT-135 and ¹H–¹³C HMBC NMR spectroscopy experiments were performed to help assign carbon resonances. Finally, IR spectroscopy and high-resolution mass spectrometry were used to confirm formation of the desired product.

2.2. Crystal Structure of 4

A crystal of 4 suitable for X-ray diffraction was isolated by slow evaporation of dichloromethane from a saturated solution. This resulted in the vertical growth of a colourless plate. The data confirm that the structure of 4 (Figure 3) is in agreement with the spectroscopic data (vide infra).

2.2.1. Structural Commentary

The C=O bond length of 4 is 1.232(2) Å, and the fluoroalkene C–F bond refines to 1.3616(19) Å, which both fit expected values [12]. The methylene group on the N-allyl amide presents an N2–C7 bond length of 1.455(2) Å. The F–C–F bond angles in the trifluoromethyl group show a slight deviation from tetrahedral geometry, with the smallest angle being the F4–C10–F2 angle at 104.79(9)°. As expected, the sp²-hybridized carbon atoms of the alkene and the pyridine core adopt a trigonal planar geometry, and the alkene is perpendicular to the pyridine ring; these systems do not lie in the same plane. A bond angle of 123.83(15)° is seen between N1–C5–C4, which is likely due to the attachment of the amide group on C5 and the extended π-system [13]. As commonly seen with trifluoromethyl groups, the original model had large Fourier peaks between the fluorine atoms. Therefore, a two-part disorder model (87:13) was developed.

2.2.2. Supramolecular Features

The title compound 4 crystallizes in the monoclinic space group P2₁/c with Z’ = 1 and a crystal density of 1.575 g cm⁻³, which is not uncommon for fluorinated compounds. In the crystal, the dominating intermolecular forces are strong H-bonding interactions (N–H···O) between amide groups (Figure 4). The N–H···O distance is 2.123(19) Å, and the intermolecular N···O separation is 2.8483(19) Å (

Table 1. Summary of hydrogen bond distances (Å) that are shorter than the sum of the VdW radii.

Atoms	Length	Length—VdW	Symmetry Operation
N1···H7A	2.464	−0.396	½ − x, −½ + y, ½ − z
H2···O1	2.123	−0.577	½ − x, −½ + y, ½ − z

). This H-bonding interaction helps define the packing structure, which results in a linear array of molecules that alternate by 180°. The N–H···O bond angle that develops from the H-bonding interaction is reported as 138.7(19)°. Longer H-bonding interactions are seen between the nitrogen in the pyridine ring (N1) and one of the hydrogens on C7 (C–H···N = 2.464(14) Å). The fluorine atoms in the trifluoromethyl and fluoroalkene groups do not participate in hydrogen bonding due to the strict packing geometry and because fluorine is a weak hydrogen bond acceptor in organic compounds [14].

A unit cell diagram of the crystal highlights the lattice structure of 4 (Figure 5), revealing that there are four molecules in the cell. As discussed previously, the hydrogen bonding interactions develop parallel linear arrays of molecules that alternate by 180°. The steric bulk from the CF₃ group also benefits from this alternation, which allows for tighter packing. The unit cell possesses inversion centers on the faces of each plane and one in the center of the cell. There are two c-glide planes perpendicular to b at b = ¼ and ¾. Additionally, there are four 2₁ screw axes parallel to b at a = ¼ and ¾, and at c = ¼, ¾. These symmetry elements and the general positions are consistent with the space group P2₁/c.

2.2.3. Database Surve

Structures containing both 3-(trifluoromethyl)pyridyl and fluoroalkene motifs are scarce in the crystallographic literature; therefore, the fragments were analyzed separately. Similar (trifluoromethyl)benzamide structures (CSD (The Cambridge Structural Database, version 2025.1 [15]) refcodes PETJIJ [16] and HOGPIE [17]) crystallize in the monoclinic space groups P2₁/n and P2₁/c (No. 14), respectively. These structures also have dominating H-bonding interactions between the amide groups. PETJIJ has a N–H···O length of 2.053(18) Å and a N···O separation of 2.869 Å, which is slightly shorter than for 4, likely due to less steric bulk. Substituted pyridine-2-carboxamides such as AMETIX [18] and LESPUW [19] have comparable aromatic C–C bond lengths, and they also possess an enlarged N–C–C bond angle, as is seen in 4 (123.541(10)° and 123.099(9)°, respectively). The fluoroalkene C–F bond length in structures CUMHID [20] (1.367(9) Å) and KARYAG [21] (1.354(10) Å) correlates well with the C8–F1 bond length in 4. The disorder model in the CF₃ group compares well to other (3-trifluoromethyl)pyridyl groups. For compound 4, the C–F bond lengths for the primary disorder group were 1.3259(12), 1.3216(12) and 1.3217(12) Å. These values fall within the range of average values for similar structures, such as ERADUZ [22] (1.324(8) Å). The F–C–F bond angles in the primary disorder model of 4 are 106.54(9)°, 108.17(10)° and 104.79(9)° which are all slightly off from purely tetrahedral but consistent with the averages in ERADUZ (105.20(8)°). Overall, analysis of similar compounds in the literature showed agreement with the proposed structure of 4.

3. Experimental Section

3.1. General Considerations

Reactions were carried out under a nitrogen atmosphere. DCM was purified using an MBraun solvent purification system (SPS) and all other commercially available compounds were used as received. Vials (20 mL, Fisher Scientific) used to perform reactions were capped with Qorpak thermoset PTFE caps. Thin-layer chromatography (TLC) analysis of reaction mixtures was performed using Silicycle silica gel 60 Å, 230–400 mesh. ¹H, ¹³C{¹H} and ¹⁹F NMR spectra were recorded in CDCl₃ at room temperature using a Bruker Avance III (700 MHz for ¹H, 659 MHz for ¹⁹F, 176 MHz for ¹³C{¹H}) NMR spectrometer. ¹H and ¹³C{¹H} NMR chemical shifts are referenced to tetramethylsilane (δ = 0.00 ppm) and CDCl₃ (δ = 77.16 ppm), respectively. Multiplicities are reported using the following abbreviations: s = singlet, d = doublet, t = triplet, q = quartet, br s = broad signal, m = multiplet. Infrared spectra were recorded using an Agilent Cary 630 FT-IR spectrometer. High-resolution mass spectra were obtained on a Thermo Scientific Orbitrap Fusion mass spectrometer using electrospray ionization.

3.2. Synthesis of N-(2-fluoro-2-propen-1-yl)-5-(trifluoromethyl)-2-pyridinecarboxamide (4)

A 20 mL vial was charged with 5-(trifluoromethyl)-2-picolinic acid (86.0 mg, 0.450 mmol, 1.5 equiv) and DCM (3 mL). The solution was cooled to 0 °C in an ice bath, followed by the addition of oxalyl chloride (77 μL, 0.900 mmol, 3 equiv) and anhydrous DMF (6 μL, 0.078 mmol, 3 mol%). The reaction mixture was stirred for 15 min at 0 °C. The reaction mixture was then brought to room temperature and stirred for an additional 2 h. The solvent was removed under reduced pressure. In a new 20 mL vial, (2-fluoroallyl)ammonium chloride 3 (11.2 mg, 0.100 mmol, 1 equiv) was added, followed by DCM (6 mL) and triethylamine (46 μL, 0.300 mmol, 3 equiv). This new mixture was transferred slowly via syringe to the original reaction vial, which was then capped. The reaction mixture was stirred for 18 h at room temperature. The solvent was then removed under reduced pressure. The desired product (26.7 mg, 36%) was isolated as a white solid by flash chromatography using 20% ethyl acetate in hexanes. IR (ATR, diamond) ν = 3328, 2937, 1666, 1513, 1326, 1226, 1114, 1077, 864, 670 cm⁻¹; ¹H NMR (700 MHz, CDCl₃) δ 8.84 (s, 1H), 8.35 (d, 1H, J = 8.2 Hz), 8.26 (br s, 1H), 8.13 (dd, 1H, J = 8.2, 1.8 Hz), 4.75 (dd, 1H, J = 16.4, 3.3 Hz), 4.58 (dd, 1H, J = 48.3, 3.3 Hz), 4.23 (dd, 2H, J = 12.2, 6.1 Hz); ¹⁹F NMR (659 MHz, CDCl₃) δ −62.5 (s, 3F), −103.4 (ddt, 1F, J = 48.2, 16.3, 12.4 Hz); ¹³C{¹H} NMR (176 MHz, CDCl₃) δ 163.1 (C=O), 161.7 (d, J_C–F = 257 Hz, FC=CH₂), 152.3 (C–C=O), 145.5 (q, J_C–F = 3.9 Hz, HC=N), 135.0 (q, J_C–F = 2.7 Hz, HC=C–CF₃), 129.2 (q, J_C–F = 33.5 Hz, C–CF₃), 123.1 (q, J_C–F = 272 Hz, CF₃), 122.4 (HC=C–C=O), 92.3 (d, J_C–F = 18.1 Hz, H₂C=C), 40.0 (d, J_C–F = 33.7 Hz, H₂C–NH). HRMS calcd for C₁₀H₉F₄N₂O [M + H]⁺ 249.0646, found 249.0635.

A colorless X-ray quality crystal of 4 was grown by slow evaporation of a solution in DCM kept in a loosely capped 4 mL vial stored in the fridge.

3.3. X-Ray Diffraction Data of 4

X-ray diffraction data were collected at 100 K using a Rigaku Oxford SuperNova Duo/Pilatus 200 K X-ray Diffractometer [CuKα radiation (λ = 1.54184 Å)]. Data were collected and processed using CrysAlisPro (v1.171.42.94a & 109a) [23]. Using Olex2, the structure was solved with the ShelXT (2019) [24,25] structure solution program using intrinsic phasing and refined with olex2.refine.

Crystal data for C₁₀H₈F₄N₂O, M = 248.18 g mol⁻¹, colourless plate, crystal dimensions 0.33 × 0.14 × 0.091 mm, monoclinic, space group P2₁/n (No. 14), a = 4.96680(10), b = 9.06340(10), c = 23.3515(3) Å, β = 95.2200(10)°, V = 1046.83(3) ų, Z = 4, D_calc = 1.575 g cm⁻³, T = 100 K, 11,643 reflections collected, 2267 independent reflections (R_int = 0.0184). The final R₁ [I > 2σ(I)] was 0.0478 and ωR₂ [all data] was 0.1258, with a goodness of fit (F²) of 1.098.

3.4. X-Ray Structure Refinement of 4

A variety of refinement parameters were used in olex2.refine to provide a more accurate refinement model. An extinction correction and weights were applied in the refinement. H2, which is involved in H-bonding, was positionally refined but with the N2–H2 bond restrained to 0.88 Å. Large residual peaks around the trifluoromethyl group indicated that positional disorder was present. A two-part disorder model was developed, which resulted in lower residuals but induced large ellipsoids on the disordered CF₃ group. Therefore, a weak ISOR restraint was used to make the fluorine atoms approximately isotropic. Two different SADI restraints were used: First, a restraint (su = 0.005) was applied to equalize the F–F distances and keep both CF₃ groups approximately tetrahedral. Next, a second stronger SADI restraint (su = 0.001) was applied to the bonds between the fluorine atoms and C10 for C–F bond similarity. A RIGU restraint (su = 0.001) was also applied between the carbon–fluorine bonds of the disorder model to keep displacements in a reasonable direction. By applying these restraints, a suitable disorder model was developed that satisfies the geometric and electronic properties of the molecule and is crystallographically reasonable.