Crystal structure of 1-[(2S*,4R*)-6-fluoro-2-methyl-1,2,3,4-tetrahydroquinolin-4-yl]pyrrolidin-2-one

In the title compound, the 1,2,3,4-tetrahydropyridine ring of the quinoline moiety adopts a half-chair conformation while the pyrrolidine ring has an envelope conformation. In the crystal, molecules are linked by N—H⋯O and C—H⋯O hydrogen bonds, forming sheets lying parallel to (10), which are linked via C—H⋯F hydrogen bonds and C—H⋯π interactions, forming a three-dimensional structure.


Chemical context
Tetrahydroquinolines have been significant synthetic targets due to their ubiquitous distribution in natural products and as medicinal agents (Trost et al., 1991). They are potential anticancer agents and 2-aryl-4-(2-oxopyrrolidin-1-yl)-1,2,3,4tetrahydroquinolines have been reported to be inhibitors of HIV transcription. Furthermore, 2-methyl tetrahydroquinolines have also been found to exhibit high modulating activity in multidrug resistance (MDR) (Hiessbock et al., 1999). In view of their broad spectrum of medicinal properties and in continuation of our work on new quinoline-based therapeutic agents (Pradeep et al., 2014), we have synthesized the title compound and report herein on its spectroscopic and crystallographic characterization. ISSN 1600-5368

Structural commentary
The molecular structure of the title molecule is shown in Fig. 1. The relative configuration of the asymmetric centers is S for atom C2 and R for atom C4.
The pyrrolidine ring adopts an envelope conformation with the flap atom C15 deviating by 0.197 (2) Å from the mean plane defined by the atoms N12/C13/C14/C16. The pyrrolidine ring lies in the equatorial plane and its mean plane is perpendicular to the mean plane of the quinoline ring system, as indicated by the dihedral angle of 88.37 (9) . The N12-C13 distance [1.349 (3) Å ] is substantially shorter than the sum of the covalent radii [d cov : C-N = 1.47 Å and C N = 1.27 Å ; Holleman et al., 2007], which indicates partial double-bond character for this bond, resulting in a certain degree of charge delocalization. The C13 O1 bond length of 1.235 (3) Å confirms the presence of a keto group in the pyrrolidine moiety.
The conformation of the tetrahydropyridine ring and that of the pyrrolidine ring are similar to those observed in, for example, 1-[2-(2-furyl)-6-methyl-1,2,3,4-tetrahydroquinolin-4yl]pyrrolidin-2-one (Vizcaya et al., 2012 A view of the molecular structure of the title molecule, with the atom labelling. Displacement ellipsoids are drawn at the 50% probability level.

Figure 2
A viewed along the c axis of the crystal packing of the title compound. Hydrogen bonds are shown as dashed lines (see Table 1 for details; H atoms not involved in hydrogen bonding have been omitted for clarity). Table 1 Hydrogen-bond geometry (Å , ).

Figure 3
A viewed along the b axis of the crystal packing of the title compound. Hydrogen bonds are shown as dashed lines (see Table 1 for details; H atoms not involved in hydrogen bonding have been omitted for clarity).

Supramolecular features
In the crystal, molecules are linked by N-HÁ Á ÁO and C-HÁ Á ÁO hydrogen bonds, forming sheets lying parallel to (101); see Fig. 2 and Table 1. These two-dimensional networks are linked via C-HÁ Á ÁF hydrogen bonds and C-HÁ Á Á interactions, forming a three-dimensional structure (Table 1 and Fig. 3).
In all seven compounds, the tetrahydropyridine ring has a half-chair conformation, while in three molecules the pyrrolidine ring has an envelope conformation and in another three molecules a twist conformation. The orientation of the pyrrolidine ring with respect to the quinoline ring is very similar if one excludes the two compounds that have a substituent in the 5-position of the quinoline ring (Gutierrez et al., 2011a,b). The two mean planes are inclined to one another by dihedral angles varying from ca 79.98 to 89.59 , compared to 88.37 (9) in the title compound.

Synthesis and crystallization
A catalytic amount of SbF 3 (10 mol%) was added to a mixture of 4-flouroaniline (1 equivalent) and N-vinylpyrrolidone (2-3 equivalents) in acetonitrile (5-10 ml). The reaction mixture was stirred at ambient temperature (292 K) for 20-70 min. After completion of the reaction, as indicated by TLC using ethyl acetate/hexane as eluent, the solvent was removed under vacuo. The crude product was then quenched with water and the catalyst was decomposed by addition of the appropriate amount of sodium bicarbonate solution. It was then extracted with ethyl acetate (10 ml Â 5 times), dried and purified by column chromatography using ethyl acetate/hexane as eluent (petroleum ether/ethyl acetate 80:20 v/v). White crystals were obtained by slow evaporation of the solvent.
In the 1 H NMR spectrum of the title compound, the three quadrates at 1.60, 2.95 and 3.22 p.p.m. correspond to three protons at C 3 -H, C 5 0 -H and C 4 0 -H, respectively. A doublet at 5.24 p.p.m. corresponds to C 4 -H, a singlet at 5.62 p.p.m. corresponds to the -NH proton and the number of protons is in accordance with the obtained structure. Additional support to elucidate the structure was obtained from 13 C NMR (see the archived CIF for more details). The mass spectrum was recorded as additional evidence for the proposed structure: M+1 peak at m/z = 250.1.

Refinement
Crystal data, data collection and structure refinement details are summarized in Table 2. The NH H atom was located from a difference Fourier map and freely refined. The C-bound H atoms were fixed geometrically (C-H = 0.93-0.96 Å ) and allowed to ride on their parent atoms with U iso (H) = 1.5U eq (C) for methyl H atoms and = 1.2U eq (C) for other H atoms.

13
C NMR (400 MHz, DMSO-d 6 ): δ = 17. 6, 21.6, 30.6, 33.2, 41.6, 46.1, 47.2, 11.7, 114.4, 119.2, 142.9, 153.1, 155.4, 174.6 p.p.m.. MS (70 eV) m/z (%): 250.1 (M + , 99.63) HPLC Purity = 97.9%. Geometry. Bond distances, angles etc. have been calculated using the rounded fractional coordinates. All su's are estimated from the variances of the (full) variance-covariance matrix. The cell e.s.d.'s are taken into account in the estimation of distances, angles and torsion angles Refinement. Refinement on F 2 for ALL reflections except those flagged by the user for potential systematic errors. Weighted R-factors wR and all goodnesses of fit S are based on F 2 , conventional R-factors R are based on F, with F set to zero for negative F 2 . The observed criterion of F 2 > σ(F 2 ) is used only for calculating -R-factor-obs etc. and is not relevant to the choice of reflections for refinement. R-factors based on F 2 are statistically about twice as large as those based on F, and R-factors based on ALL data will be even larger.