Ethyl 4-chloro-2-oxo-1,2,5,6,7,8-hexa­hydro­quinoline-3-carboxyl­ate

Rodriguez-Vega, G.; Aguirre, G.; Chávez, D.

doi:10.1107/S2414314619000166

organic compounds

IUCrDATA

ISSN: 2414-3146

Volume 4| Part 1| January 2019| x190016

https://doi.org/10.1107/S2414314619000166

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Ethyl 4-chloro-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxylate

Gibran Rodriguez-Vega,^a Gerardo Aguirre ^a and Daniel Chávez ^a ^*

^aTecnológico Nacional de México/Instituto Tecnológico de Tijuana, Centro de Graduados e Investigación en Química. Apartado Postal 1166, Tijuana, B.C., Mexico
^*Correspondence e-mail: dchavez@tectijuana.mx

Edited by J. Simpson, University of Otago, New Zealand (Received 21 November 2018; accepted 4 January 2019; online 8 January 2019)

In the title compound, C₁₂H₁₄ClNO₃, the aliphatic ring of the hexahydroquinoline system adopts a half-chair conformation while the ethyl carboxylate substituent is inclined to the hexahydroquinoline ring system by 85.1 (2)°. In the crystal, a pair of N–H⋯O hydrogen bonds form an inversion dimer. The structure is further stabilized by C—H⋯O and C—H⋯Cl hydrogen bonds, forming a three-dimensional network.

Keywords: crystal structure; quinoline derivative; human immunodeficiency virus (HIV).

CCDC reference: 1888738

Structure description

HIV or the human immunodeficiency virus is the virus that causes AIDS. HIV attacks the immune system by destroying CD4⁺ T lymphocytes, a cell type that is vital in fighting infections. The actual treatment consists of a group of several drugs known as anti-retroviral agents that inhibit proteins that are important for virus replication, including reverse transcriptase (Le Van et al., 2009 ). During work on the synthesis of promising compounds to be used as anti-retroviral agents, Medina-Franco and co-workers found that compounds maintaining a pyridinone core in the base structure showed activity in the inhibition of reverse transcriptase (Medina-Franco et al., 2007 ). As part of our ongoing research, we have synthesized another pyridin-2 (1H)-one analogue (Cabrera et al., 2015 ). In this work, we report the structure of the closely related title compound, again containing a hexahydroquinoline ring system.

The molecular structure of the title molecule is shown in Fig. 1. The hexahydroquinoline ring system is almost planar, r.m.s. deviation 0.1603 Å, with an angle of 4.86 (9)° between the best fit planes of the aromatic and half-chair aliphatic rings. The O1 and Cl1 substituents are very close to the mean plane of the aromatic ring. In contrast, the almost planar ester substituent, r.m.s. deviation 0.1108 Å, is almost orthogonal to the hexahydroquinoline ring system, at a dihedral angle of 89.45 (4)°.

Figure 1
The molecular structure of the title compound, showing the atom labelling. Displacement ellipsoids are drawn at the 50% probability level.

The 2-pyridinone unit participates in intermolecular N1—H1⋯O1ⁱ hydrogen bonding, forming an inversion dimer with a classical R₂²(8) ring motif, see Fig. 2 and Table 1. These hydrogen-bonding interactions form dimers that are reminiscent of those frequently observed in carboxylic acids. The structure is further consolidated by C—H⋯O hydrogen bonds and inversion-related C7—H7B⋯Cl1 contacts that generate R₂²(14) rings These additional contacts form a three-dimensional network with molecules stacked along b, see Fig. 3.

Table 1
Hydrogen-bond geometry (Å, °)

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
N1—H1⋯O1ⁱ	0.86	1.97	2.8280 (17)	176
C6—H6B⋯O2ⁱⁱ	0.97	2.47	3.379 (2)	155
C8—H8B⋯O1ⁱⁱ	0.97	2.60	3.492 (2)	153
C11—H11A⋯O2ⁱⁱⁱ	0.97	2.70	3.502 (2)	141
C7—H7B⋯Cl1^iv	0.97	2.85	3.7731 (19)	160
Symmetry codes: (i) -x, -y+2, -z+1; (ii) -x+1, -y+2, -z+1; (iii) $[-x+1, y-{\script{1\over 2}}, -z+{\script{1\over 2}}]$ ; (iv) -x+1, -y+1, -z+1.

Figure 2
Dimers formed by classical N—H⋯O hydrogen-bonding interactions, dashed lines.

Figure 3
The crystal packing of the title compound viewed along the b-axis direction.

Synthesis and crystallization

The synthesis of ethyl 4-chloro-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxylate used reagents and reagent-grade solvents, which were used without further purification. In a 100 mL round-bottom flask equipped with a magnetic stirrer was placed 1 g of ethyl 4-hydroxy-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxylate (4.22 mmol) and 3.84 g of benzyltriethylammonium chloride (4 eq) in 20 mL of acetonitrile. Under continuous stirring, 0.59 mL of the phosphoryl chloride (6.33 mmol, 1.5 eq) were added dropwise. The mixture was stirred at 40°C for 30 min and later at reflux for 8 h. Next the solvent was evaporated, 15 mL of cold water were added and the mixture stirred for 1 h. A precipitate was obtained, comprising a mixture of ethyl 4-chloro-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxylate (60%) and ethyl 2,4-dichloro-5,6,7,8-tetrahydroquinoline-3-carboxylate (40%). The product of interest was purified by column chromatography (dichloromethane/hexane, 2:1). NMR ¹H (CDCl₃), 400 MHz): δ 4.41 (q, J = 7.2 Hz, COOCH₂CH₃), 2.66 (br s, 2H, H-8), 2.53 (br s, 2H, H-5), 1.78 (m, 4H, H-6 and H-7), 1.38 (t, J = 7.2 Hz, COOCH₂CH₃). NMR ¹³C (CDCl₃, 100 MHz): δ 164.4, 160.6, 147.4, 146.1, 122.0, 113.8, 61.8, 27.1, 24.3, 22.2, 21.1, 14.1. EIME m/z (Rel. Ab): [M]⁺ 255 (42), [M]⁺+2 257 (14), 212 (19), 210 (60), 185 (27), 183 (100), 181 (51) amu.

Crystals of the title compound suitable for X-ray diffraction were obtained by dissolving 15 mg of ethyl 4-chloro-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxylate in 0.5 mL of chloroform and placing the solution in a glass vial. The solution was allowed to stand at room temperature for two days and the crystals formed were filtered.

Refinement

Crystal data, data collection and structure refinement details are summarized in Table 2.

Table 2
Experimental details

Crystal data
Chemical formula	C₁₂H₁₄ClNO₃
M_r	255.69
Crystal system, space group	Monoclinic, P2₁/c
Temperature (K)	100
a, b, c (Å)	5.7323 (3), 9.2537 (5), 21.6899 (12)
β (°)	91.168 (5)
V (Å³)	1150.30 (11)
Z	4
Radiation type	Mo Kα
μ (mm⁻¹)	0.33
Crystal size (mm)	0.32 × 0.23 × 0.09

Data collection
Diffractometer	Rigaku Oxford Diffraction SuperNova, Dual, Cu at zero, AtlasS2
Absorption correction	Multi-scan (CrysAlis PRO; Rigaku OD, 2015 $[Rigaku OD (2015). CrysAlis PRO. Rigaku Oxford Diffraction Ltd, Yarnton, England.]$ )
T_min, T_max	0.773, 1.000
No. of measured, independent and observed [I > 2σ(I)] reflections	13970, 3017, 2676
R_int	0.032
(sin θ/λ)_max (Å⁻¹)	0.690

Refinement
R[F² > 2σ(F²)], wR(F²), S	0.044, 0.101, 1.09
No. of reflections	3017
No. of parameters	155
H-atom treatment	H-atom parameters constrained
Δρ_max, Δρ_min (e Å⁻³)	0.86, −0.30
Computer programs: CrysAlis PRO (Rigaku OD, 2015 $[Rigaku OD (2015). CrysAlis PRO. Rigaku Oxford Diffraction Ltd, Yarnton, England.]$ ), SIR2004 (Burla et al., 2007 ), OLEX2 (Dolomanov et al., 2009 ), Mercury (Macrae et al., 2008 ) and publCIF(Westrip, 2010 ).

Structural data

CCDC reference: 1888738

Crystal structure: contains datablock I. DOI: https://doi.org/10.1107/S2414314619000166/sj4197sup1.cif

Structure factors: contains datablock I. DOI: https://doi.org/10.1107/S2414314619000166/sj4197Isup3.hkl

Supporting information file. DOI: https://doi.org/10.1107/S2414314619000166/sj4197Isup3.cml

checkCIF report

Computing details top

Data collection: CrysAlis PRO (Rigaku OD, 2015); cell refinement: CrysAlis PRO (Rigaku OD, 2015); data reduction: CrysAlis PRO (Rigaku OD, 2015); program(s) used to solve structure: SIR2004 (Burla et al., 2007); program(s) used to refine structure: OLEX2 (Dolomanov et al., 2009); molecular graphics: Mercury (Macrae et al., 2008); software used to prepare material for publication: publCIF(Westrip, 2010).

Ethyl 4-chloro-2-oxo-1,2,5,6,7,8-hexahydroquinoline-3-carboxylate top

Crystal data top

C₁₂H₁₄ClNO₃	F(000) = 536
M_r = 255.69	D_x = 1.476 Mg m⁻³
Monoclinic, P2₁/c	Mo Kα radiation, λ = 0.71073 Å
a = 5.7323 (3) Å	Cell parameters from 5245 reflections
b = 9.2537 (5) Å	θ = 2.4–28.8°
c = 21.6899 (12) Å	µ = 0.33 mm⁻¹
β = 91.168 (5)°	T = 100 K
V = 1150.30 (11) Å³	Block, translucent intense colourless
Z = 4	0.32 × 0.23 × 0.09 mm

Data collection top

Rigaku Oxford Diffraction SuperNova, Dual, Cu at zero, AtlasS2 diffractometer	3017 independent reflections
Radiation source: micro-focus sealed X-ray tube, SuperNova (Mo) X-ray Source	2676 reflections with I > 2σ(I)
Mirror monochromator	R_int = 0.032
Detector resolution: 5.1980 pixels mm^-1	θ_max = 29.4°, θ_min = 1.9°
ω scans	h = −7→7
Absorption correction: multi-scan (CrysAlisPro; Rigaku OD, 2015)	k = −12→11
T_min = 0.773, T_max = 1.000	l = −29→29
13970 measured reflections

Refinement top

Refinement on F²	Primary atom site location: structure-invariant direct methods
Least-squares matrix: full	Hydrogen site location: inferred from neighbouring sites
R[F² > 2σ(F²)] = 0.044	H-atom parameters constrained
wR(F²) = 0.101	w = 1/[σ²(F_o²) + (0.0349P)² + 1.0951P] where P = (F_o² + 2F_c²)/3
S = 1.09	(Δ/σ)_max = 0.001
3017 reflections	Δρ_max = 0.86 e Å⁻³
155 parameters	Δρ_min = −0.30 e Å⁻³
0 restraints

Special details top

Geometry. All esds (except the esd in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell esds is used for estimating esds involving l.s. planes.

Fractional atomic coordinates and isotropic or equivalent isotropic displacement parameters (Å²) top

	x	y	z	U_iso*/U_eq
Cl1	0.75996 (7)	0.62470 (5)	0.40163 (2)	0.01866 (12)
O1	0.0556 (2)	0.94748 (14)	0.42371 (5)	0.0162 (3)
O2	0.4402 (2)	0.87426 (15)	0.31021 (6)	0.0240 (3)
O3	0.2426 (2)	0.66734 (14)	0.32599 (5)	0.0162 (3)
N1	0.2608 (2)	0.87959 (15)	0.51040 (6)	0.0124 (3)
H1	0.169504	0.931850	0.532114	0.015*
C1	0.2208 (3)	0.87798 (18)	0.44748 (7)	0.0129 (3)
C2	0.3831 (3)	0.79147 (18)	0.41342 (7)	0.0130 (3)
C3	0.5600 (3)	0.72128 (18)	0.44430 (7)	0.0133 (3)
C4	0.5911 (3)	0.72343 (18)	0.50944 (7)	0.0123 (3)
C5	0.4335 (3)	0.80509 (18)	0.54128 (7)	0.0117 (3)
C6	0.4387 (3)	0.81981 (19)	0.61038 (7)	0.0145 (3)
H6A	0.281068	0.811392	0.625398	0.017*
H6B	0.496584	0.915069	0.621399	0.017*
C7	0.5925 (3)	0.7056 (2)	0.64185 (8)	0.0235 (4)
H7A	0.623150	0.732936	0.684420	0.028*
H7B	0.512014	0.613363	0.641614	0.028*
C8	0.8206 (3)	0.6912 (2)	0.60853 (8)	0.0226 (4)
H8A	0.920094	0.622654	0.630360	0.027*
H8B	0.899644	0.783933	0.608639	0.027*
C9	0.7836 (3)	0.64067 (19)	0.54209 (7)	0.0152 (3)
H9A	0.927464	0.652904	0.519912	0.018*
H9B	0.745109	0.538585	0.541940	0.018*
C10	0.3596 (3)	0.78524 (19)	0.34424 (7)	0.0141 (3)
C11	0.2272 (3)	0.6444 (2)	0.25915 (7)	0.0189 (4)
H11A	0.374809	0.608271	0.244386	0.023*
H11B	0.192908	0.734998	0.238396	0.023*
C12	0.0378 (4)	0.5373 (3)	0.24549 (9)	0.0325 (5)
H12A	0.024954	0.522164	0.201769	0.049*
H12B	−0.107534	0.573636	0.260352	0.049*
H12C	0.074284	0.447459	0.265581	0.049*

Atomic displacement parameters (Å²) top

	U¹¹	U²²	U³³	U¹²	U¹³	U²³
Cl1	0.01586 (19)	0.0218 (2)	0.0184 (2)	0.00599 (16)	0.00289 (14)	−0.00607 (16)
O1	0.0162 (5)	0.0169 (6)	0.0154 (5)	0.0053 (5)	−0.0006 (4)	−0.0014 (5)
O2	0.0338 (7)	0.0209 (7)	0.0173 (6)	−0.0080 (6)	0.0019 (5)	0.0014 (5)
O3	0.0198 (6)	0.0169 (6)	0.0118 (5)	−0.0038 (5)	0.0012 (4)	−0.0031 (5)
N1	0.0122 (6)	0.0118 (7)	0.0132 (6)	0.0027 (5)	0.0022 (5)	−0.0027 (5)
C1	0.0121 (7)	0.0123 (8)	0.0143 (7)	−0.0018 (6)	0.0009 (5)	−0.0020 (6)
C2	0.0138 (7)	0.0123 (8)	0.0131 (7)	−0.0008 (6)	0.0018 (5)	−0.0019 (6)
C3	0.0117 (7)	0.0105 (8)	0.0178 (7)	−0.0011 (6)	0.0041 (6)	−0.0038 (6)
C4	0.0106 (7)	0.0101 (8)	0.0161 (7)	−0.0012 (6)	0.0007 (5)	−0.0004 (6)
C5	0.0109 (7)	0.0095 (8)	0.0147 (7)	−0.0017 (6)	0.0005 (5)	0.0000 (6)
C6	0.0138 (7)	0.0168 (9)	0.0131 (7)	0.0011 (6)	0.0012 (5)	−0.0013 (6)
C7	0.0257 (9)	0.0263 (10)	0.0185 (8)	0.0054 (8)	0.0005 (7)	0.0019 (7)
C8	0.0214 (8)	0.0276 (11)	0.0188 (8)	0.0083 (8)	−0.0026 (6)	0.0018 (7)
C9	0.0135 (7)	0.0130 (8)	0.0190 (8)	0.0020 (6)	0.0007 (6)	0.0001 (6)
C10	0.0129 (7)	0.0148 (8)	0.0148 (7)	0.0024 (6)	0.0007 (5)	−0.0024 (6)
C11	0.0247 (8)	0.0211 (10)	0.0108 (7)	−0.0028 (7)	0.0009 (6)	−0.0031 (6)
C12	0.0376 (11)	0.0428 (14)	0.0168 (8)	−0.0178 (10)	−0.0057 (8)	−0.0007 (9)

Geometric parameters (Å, º) top

Cl1—C3	1.7357 (16)	C6—H6B	0.9700
O1—C1	1.248 (2)	C6—C7	1.528 (2)
O2—C10	1.205 (2)	C7—H7A	0.9700
O3—C10	1.336 (2)	C7—H7B	0.9700
O3—C11	1.4660 (19)	C7—C8	1.513 (3)
N1—H1	0.8600	C8—H8A	0.9700
N1—C1	1.379 (2)	C8—H8B	0.9700
N1—C5	1.370 (2)	C8—C9	1.526 (2)
C1—C2	1.442 (2)	C9—H9A	0.9700
C2—C3	1.367 (2)	C9—H9B	0.9700
C2—C10	1.505 (2)	C11—H11A	0.9700
C3—C4	1.421 (2)	C11—H11B	0.9700
C4—C5	1.375 (2)	C11—C12	1.495 (3)
C4—C9	1.508 (2)	C12—H12A	0.9600
C5—C6	1.505 (2)	C12—H12B	0.9600
C6—H6A	0.9700	C12—H12C	0.9600

C10—O3—C11	115.52 (13)	C8—C7—H7A	109.6
C1—N1—H1	117.2	C8—C7—H7B	109.6
C5—N1—H1	117.2	C7—C8—H8A	109.2
C5—N1—C1	125.60 (13)	C7—C8—H8B	109.2
O1—C1—N1	120.85 (14)	C7—C8—C9	111.90 (15)
O1—C1—C2	124.52 (14)	H8A—C8—H8B	107.9
N1—C1—C2	114.64 (14)	C9—C8—H8A	109.2
C1—C2—C10	119.09 (14)	C9—C8—H8B	109.2
C3—C2—C1	119.48 (14)	C4—C9—C8	111.98 (14)
C3—C2—C10	121.38 (14)	C4—C9—H9A	109.2
C2—C3—Cl1	118.33 (12)	C4—C9—H9B	109.2
C2—C3—C4	123.88 (14)	C8—C9—H9A	109.2
C4—C3—Cl1	117.80 (12)	C8—C9—H9B	109.2
C3—C4—C9	122.42 (14)	H9A—C9—H9B	107.9
C5—C4—C3	115.89 (14)	O2—C10—O3	124.98 (15)
C5—C4—C9	121.69 (14)	O2—C10—C2	123.85 (16)
N1—C5—C4	120.45 (14)	O3—C10—C2	111.15 (14)
N1—C5—C6	116.16 (13)	O3—C11—H11A	109.9
C4—C5—C6	123.39 (14)	O3—C11—H11B	109.9
C5—C6—H6A	109.1	O3—C11—C12	108.71 (14)
C5—C6—H6B	109.1	H11A—C11—H11B	108.3
C5—C6—C7	112.44 (14)	C12—C11—H11A	109.9
H6A—C6—H6B	107.8	C12—C11—H11B	109.9
C7—C6—H6A	109.1	C11—C12—H12A	109.5
C7—C6—H6B	109.1	C11—C12—H12B	109.5
C6—C7—H7A	109.6	C11—C12—H12C	109.5
C6—C7—H7B	109.6	H12A—C12—H12B	109.5
H7A—C7—H7B	108.2	H12A—C12—H12C	109.5
C8—C7—C6	110.10 (15)	H12B—C12—H12C	109.5

Cl1—C3—C4—C5	177.91 (12)	C3—C4—C5—N1	−0.7 (2)
Cl1—C3—C4—C9	−2.6 (2)	C3—C4—C5—C6	179.81 (15)
O1—C1—C2—C3	179.14 (16)	C3—C4—C9—C8	164.73 (16)
O1—C1—C2—C10	1.5 (2)	C4—C5—C6—C7	−15.1 (2)
N1—C1—C2—C3	−0.8 (2)	C5—N1—C1—O1	178.55 (15)
N1—C1—C2—C10	−178.38 (14)	C5—N1—C1—C2	−1.5 (2)
N1—C5—C6—C7	165.33 (15)	C5—C4—C9—C8	−15.8 (2)
C1—N1—C5—C4	2.3 (2)	C5—C6—C7—C8	44.9 (2)
C1—N1—C5—C6	−178.14 (15)	C6—C7—C8—C9	−62.2 (2)
C1—C2—C3—Cl1	−177.15 (12)	C7—C8—C9—C4	46.6 (2)
C1—C2—C3—C4	2.4 (3)	C9—C4—C5—N1	179.79 (15)
C1—C2—C10—O2	83.9 (2)	C9—C4—C5—C6	0.3 (2)
C1—C2—C10—O3	−97.36 (17)	C10—O3—C11—C12	−163.49 (16)
C2—C3—C4—C5	−1.6 (2)	C10—C2—C3—Cl1	0.4 (2)
C2—C3—C4—C9	177.91 (16)	C10—C2—C3—C4	179.91 (15)
C3—C2—C10—O2	−93.6 (2)	C11—O3—C10—O2	3.7 (2)
C3—C2—C10—O3	85.09 (19)	C11—O3—C10—C2	−174.97 (13)

Hydrogen-bond geometry (Å, º) top

D—H···A	D—H	H···A	D···A	D—H···A
N1—H1···O1ⁱ	0.86	1.97	2.8280 (17)	176
C6—H6B···O2ⁱⁱ	0.97	2.47	3.379 (2)	155
C8—H8B···O1ⁱⁱ	0.97	2.60	3.492 (2)	153
C11—H11A···O2ⁱⁱⁱ	0.97	2.70	3.502 (2)	141
C7—H7B···Cl1^iv	0.97	2.85	3.7731 (19)	160

Symmetry codes: (i) −x, −y+2, −z+1; (ii) −x+1, −y+2, −z+1; (iii) −x+1, y−1/2, −z+1/2; (iv) −x+1, −y+1, −z+1.

Funding information

GR-V acknowledge support from CONACyT in the form of graduate scholarships (grant Nos. 155029, INFRA-2011-3-173395, INFRA-2014-224405).

References

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