Crystal structure of ethyl 2,4-di­chloro­quinoline-3-carboxyl­ate

Cabrera, A.; Miranda, L.D.; Reyes, H.; Aguirre, G.; Chávez, D.

doi:10.1107/S2056989015020587

organic compounds

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Volume 71| Part 12| December 2015| Page o939

https://doi.org/10.1107/S2056989015020587

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Crystal structure of ethyl 2,4-dichloroquinoline-3-carboxylate

Alberto Cabrera,^a Luis D. Miranda,^b Héctor Reyes,^a Gerardo Aguirre ^a and Daniel Chávez ^a ^*

^aCentro de Graduados e Investigación en Química del Instituto, Tecnológico de, Tijuana, Apdo. Postal 1166, 22500, Tijuana, B.C., Mexico, and ^bInstituto de Química, Universidad Nacional Autónoma de, México, Circuito, Exterior, S. N., Ciudad Universitaria, Coyoacán, México, D. F. 04510, Mexico
^*Correspondence e-mail: dchavez@tectijuana.mx

Edited by G. S. Nichol, University of Edinburgh, Scotland (Received 9 July 2015; accepted 30 October 2015; online 14 November 2015)

In the crystal structure of the title compound, C₁₂H₉Cl₂NO₂, the mean planes through the quinoline and carboxylate groups have r.m.s. deviations of 0.006 and 0.021 Å, respectively, and form a dihedral angle of 87.06 (19)°. In the crystal, molecules are linked via very weak C—H⋯O hydrogen bonds, forming chains, which propagate along the c-axis direction.

Keywords: crystal structure; quinnoline; human immunodeficiency virus (HIV); hydrogen bonding.

CCDC reference: 1434378

1. Related literature

For the potential of related compounds in anti-HIV treatment, see: Maartens et al. (2014 ); Hopkins et al. (2004 ). For a related structure, see: Reyes et al. (2013 )

2. Experimental

2.1. Crystal data

C₁₂H₉Cl₂NO₂
M_r = 270.10
Monoclinic, P 2₁ /c
a = 8.5860 (4) Å
b = 19.9082 (11) Å
c = 7.1304 (4) Å
β = 100.262 (1)°
V = 1199.32 (11) Å³
Z = 4
Mo Kα radiation
μ = 0.53 mm⁻¹
T = 298 K
0.50 × 0.25 × 0.16 mm

2.2. Data collection

Bruker APEXII CCD area-detector diffractometer
6785 measured reflections
2197 independent reflections
1833 reflections with I > 2σ(I)
R_int = 0.024

2.3. Refinement

R[F² > 2σ(F²)] = 0.035
wR(F²) = 0.094
S = 1.05
2197 reflections
156 parameters
H-atom parameters constrained
Δρ_max = 0.22 e Å⁻³
Δρ_min = −0.21 e Å⁻³

Table 1
Hydrogen-bond geometry (Å, °)

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
C7—H7⋯O1ⁱ	0.93	2.69	3.586 (3)	162
Symmetry code: (i) $[x+1, -y+{\script{3\over 2}}, z+{\script{1\over 2}}]$ .

Data collection: APEX2 (Bruker, 2012 ); cell refinement: SAINT (Bruker, 2012); data reduction: SAINT; program(s) used to solve structure: SHELXTL (Sheldrick, 2015 ); program(s) used to refine structure: SHELXL2013 (Sheldrick, 2015); molecular graphics: SHELXTL; software used to prepare material for publication: SHELXTL.

Supporting information

CCDC reference: 1434378

Crystal structure: contains datablocks I, global. DOI: https://doi.org/10.1107/S2056989015020587/nk2231sup1.cif

Structure factors: contains datablock I. DOI: https://doi.org/10.1107/S2056989015020587/nk2231Isup2.hkl

Supporting information file. DOI: https://doi.org/10.1107/S2056989015020587/nk2231Isup3.cml

checkCIF report

Chemical context top

The HIV (human immunodeficiency virus) is responsible of the acquired immunodeficiency syndrome (AIDS). The actual treatment consists of a group of several drugs known as anti-retrovirals which inhibit important proteins for virus replication, including reverse transcriptase (Maartens et al., 2014).

As part of the synthesis of promising compounds as anti-retrovirals, Stammers and coworkers, maintaining as base structure a quinolone core, found compounds that showed activity in the inhibition of the reverse transcriptase. They obtained a dibromide quinolone in C2/C4 as an intermediate. After that, they were able to remove the C2 bromine in an acetic acid solution and finally, the C4 bromine was substituted by alkyl-sulfurated compounds to get the final molecules which have been proven activity against HIV (Hopkins et al., 2004),

As part of our ongoing research, we have synthesized different pyridin-2 (1H)-one analogues (Reyes et al., 2013). In this work, we developed a methodology to obtain derivatives of quinolone, with saturated and unsaturated amines in in C4 with ethyl 4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxilate as a starting material. Chlorination of the quinolone core results in the dichlorinated compound ethyl 2,4-dichloroquinoline-3-carboxylate with a yield of 70% and a crystal structure was obtained. The intermediate of interest, the ethyl 4-chloro-2-oxo-1,2-dihydroquinoline-3-carboxylate, was obtained after treatment of the dichlorinated compound with an acetic acid solution following the methodology described by Stammers (Hopkins et al., 2004) in >98% yield (see experimental section in supplementary material).

The structure of the compound is shown in Fig. 1. The two aromatic rings of quinoline are fused almost coaxially, with a dihedral angle between their planes of C8—C9—C10—C4= 179.21 (14)^o. The carboxylate group is in an antiperiplanar conformation to the quinoline with a torsion angle C12—O2—C11—C3 = -179.39 (15)°, and bonded to the quinoline over the plane C3—C11—O2 by 110.46 (14)^o. The deviation of the bond length values for C2—Cl1= 1.745 (2) and C4— Cl 2= 1.7248 (16) from the standard values can be attributed for the sp2 hybridization of the quinoline ring. In the crystal, molecules are linked via O1—H7 intermolecular hydrogen bonds forming chains propagating along the c axis direction. (Fig. 2).

Synthesis and crystallization top

The synthesis of ethyl 2,4-dichloroquinoline-3-carboxylate and ethyl 4-chloro-2-oxo-1,2-dihydroquinoline-3-carboxylate includes 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 500 mg of ethyl 4-hydroxy-2-oxo-1,2-dihydroquinoline-3-carboxylate (2.15 mmol) and 1.96 g of benzyltriethylammonium chloride in 15 mL of acetonitrile. Under continuous stirring, 0.88 mL of the phosphoryl chloride (9.46 mmol) was added drop by drop. The mixture was stirred at 40^o C for 30 min and later at reflux for 1 h. Then, the solvent was evaporated and 15 mL of cold water was added and stirred for 1 h. Then a precipitate was obtained corresponding to a mixture of ethyl 2,4-dichloroquinoline-3-carboxylate and ethyl 4-chloro-2-oxo-1,2-dihydroquinoline-3-carboxylate. The precipitate was dissolved in 3 mL of dichloromethane-methanol (1:1, v/v). Partial evaporation leads to crystals (not suitable for X-ray diffraction) of ethyl 4-chloro-2-oxo-1,2-dihydroquinoline-3-carboxylate (0.65 mmol, 30%). The rest corresponded to ethyl 2,4-dichloroquinoline-3-carboxylate (1.5 mmol, 70%). The latter compound was placed in a round bottom flask of 50 mL containing acetic acid (10 mL) and water (5 mL). The mixture was stirred under reflux for 24 h. After cooling, the product was extracted with ethyl ether to afford ethyl 4-chloro-2-oxo-1,2-dihydroquinoline-3-carboxylate (>98%).

Ethyl 2,4-dichloroquinoline-3-carboxylate: m.p. 83-85 °C. ¹H RMN (DMSO-d6): δ 8.27 (dd, J = 8.3, 0.6 Hz, H-5), 8.09 (dd, J = 8.3, 0.6 Hz, H-8), 8.03 (ddd, J = 7.7, 6.9, 1.4 Hz, H-7), 7.89 (ddd, J = 7.7, 6.9, 1.4 Hz, H-6) 4.51 (q, J = 7.1 Hz, COOCH₂CH₃), 1.39 (t, J = 7.1 Hz, COOCH₂CH₃). ¹³C RMN (DMSO-d6): δ 163.5, 147.2, 144.7, 141.1, 133.7, 130.2, 129.1, 127.1, 124.9, 124.3, 63.4, 14.3. IEMS m/e (int. rel): [M]⁺ 269 (32), [M]⁺+2 271 (21), [M]⁺+4 273 (3), 241 (26), 223 (100), 195 (17), 161 (28) amu.

Crystals of the title compound suitable for X-ray diffraction were obtained by dissolving 15 mg of ethyl 2,4-dichloroquinoline-3-carboxylate in 0.5 mL of ethanol-di-ethyl ether (1:1, v / v) and placing the solution in a glass vial. The solution was allowed to stand at room temperature for 7 days and the crystals formed were filtered.

Refinement details top

The C-bound H atoms were positioned geometrically and refined using a riding model with d(C—H) = 1.00 Å, U_iso = 1.2Ueq(C) for Csp³—H, d(C—H) = 0.99 Å, U_iso = 1.2Ueq(C) for CH₂ groups, d(C—H) = 0.95 Å, U_iso = 1.2Ueq(C) for aromatic C—H.

Related literature top

For the potential of related compounds in anti-HIV treatment, see: Maartens et al. (2014); Hopkins et al. (2004). For a related structure, see: Reyes et al. (2013)

Structure description top

For the potential of related compounds in anti-HIV treatment, see: Maartens et al. (2014); Hopkins et al. (2004). For a related structure, see: Reyes et al. (2013)

Synthesis and crystallization top

Refinement details top

Computing details top

Data collection: APEX2 (Bruker, 2012); cell refinement: SAINT (Bruker, 2012); data reduction: SAINT (Bruker, 2012); program(s) used to solve structure: SHELXTL (Sheldrick, 2015); program(s) used to refine structure: SHELXL2013 (Sheldrick, 2015); molecular graphics: SHELXTL (Sheldrick, 2015); software used to prepare material for publication: SHELXTL (Sheldrick, 2015).

Figures top

	Fig. 1. The asymmetric unit of the title compound with displacement ellipsoids drawn at the 50% probability level.
	Fig. 2. Crystal packing viewed along the a axis. The intermolecular C—H···O hydrogen bonds are shown as dashed lines.

Ethyl 2,4-dichloroquinoline-3-carboxylate top

Crystal data top

C₁₂H₉Cl₂NO₂	F(000) = 552
M_r = 270.10	D_x = 1.496 Mg m⁻³
Monoclinic, P2₁/c	Mo Kα radiation, λ = 0.71073 Å
a = 8.5860 (4) Å	Cell parameters from 4843 reflections
b = 19.9082 (11) Å	θ = 2.4–25.4°
c = 7.1304 (4) Å	µ = 0.53 mm⁻¹
β = 100.262 (1)°	T = 298 K
V = 1199.32 (11) Å³	Prism, colourless
Z = 4	0.50 × 0.25 × 0.16 mm

Data collection top

Bruker APEXII CCD area-detector diffractometer	R_int = 0.024
Detector resolution: 0.83 pixels mm^-1	θ_max = 25.4°, θ_min = 2.1°
ω scans	h = −10→10
6785 measured reflections	k = −23→23
2197 independent reflections	l = −8→8
1833 reflections with I > 2σ(I)

Refinement top

Refinement on F²	Hydrogen site location: inferred from neighbouring sites
Least-squares matrix: full	H-atom parameters constrained
R[F² > 2σ(F²)] = 0.035	w = 1/[σ²(F_o²) + (0.052P)² + 0.1257P] where P = (F_o² + 2F_c²)/3
wR(F²) = 0.094	(Δ/σ)_max = 0.001
S = 1.05	Δρ_max = 0.22 e Å⁻³
2197 reflections	Δρ_min = −0.21 e Å⁻³
156 parameters	Extinction correction: SHELXL2013 (Sheldrick, 2015), Fc^*=kFc[1+0.001xFc²λ³/sin(2θ)]^-1/4
0 restraints	Extinction coefficient: 0.010 (2)

Crystal data top

C₁₂H₉Cl₂NO₂	V = 1199.32 (11) Å³
M_r = 270.10	Z = 4
Monoclinic, P2₁/c	Mo Kα radiation
a = 8.5860 (4) Å	µ = 0.53 mm⁻¹
b = 19.9082 (11) Å	T = 298 K
c = 7.1304 (4) Å	0.50 × 0.25 × 0.16 mm
β = 100.262 (1)°

Data collection top

Bruker APEXII CCD area-detector diffractometer	1833 reflections with I > 2σ(I)
6785 measured reflections	R_int = 0.024
2197 independent reflections

Refinement top

R[F² > 2σ(F²)] = 0.035	0 restraints
wR(F²) = 0.094	H-atom parameters constrained
S = 1.05	Δρ_max = 0.22 e Å⁻³
2197 reflections	Δρ_min = −0.21 e Å⁻³
156 parameters

Special details top

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

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

	x	y	z	U_iso*/U_eq
Cl1	0.85142 (7)	0.95554 (3)	0.67524 (10)	0.0847 (2)
Cl2	0.49224 (5)	0.73357 (2)	0.59388 (7)	0.05637 (19)
O1	0.48324 (17)	0.90370 (7)	0.44065 (18)	0.0701 (4)
O2	0.48524 (14)	0.89699 (6)	0.75480 (17)	0.0565 (3)
N1	0.96891 (17)	0.83536 (9)	0.7101 (2)	0.0567 (4)
C2	0.8376 (2)	0.86809 (9)	0.6757 (2)	0.0514 (4)
C3	0.68405 (18)	0.84036 (8)	0.6379 (2)	0.0435 (4)
C4	0.67539 (18)	0.77181 (8)	0.6378 (2)	0.0415 (4)
C5	0.8137 (3)	0.66071 (10)	0.6754 (3)	0.0621 (5)
H5	0.7187	0.6372	0.6505	0.075*
C6	0.9535 (3)	0.62696 (13)	0.7135 (3)	0.0816 (7)
H6	0.9531	0.5802	0.7143	0.098*
C7	1.0976 (3)	0.66121 (14)	0.7514 (3)	0.0838 (8)
H7	1.1918	0.6371	0.7779	0.101*
C8	1.1014 (2)	0.72928 (13)	0.7498 (3)	0.0705 (6)
H8	1.1981	0.7516	0.7748	0.085*
C9	0.9593 (2)	0.76660 (10)	0.7105 (2)	0.0511 (5)
C10	0.81366 (19)	0.73162 (9)	0.6738 (2)	0.0451 (4)
C11	0.5396 (2)	0.88399 (9)	0.5963 (2)	0.0478 (4)
C12	0.3434 (2)	0.93853 (11)	0.7367 (3)	0.0674 (5)
H12A	0.2575	0.9182	0.6481	0.081*
H12B	0.3638	0.9828	0.6897	0.081*
C13	0.3010 (3)	0.94358 (13)	0.9279 (3)	0.0858 (7)
H13A	0.2721	0.9000	0.9681	0.129*
H13B	0.2133	0.9738	0.9235	0.129*
H13C	0.3900	0.9602	1.0166	0.129*

Atomic displacement parameters (Å²) top

	U¹¹	U²²	U³³	U¹²	U¹³	U²³
Cl1	0.0773 (4)	0.0613 (3)	0.1107 (5)	−0.0197 (3)	0.0034 (3)	−0.0015 (3)
Cl2	0.0445 (3)	0.0641 (3)	0.0597 (3)	−0.01024 (19)	0.0070 (2)	−0.0018 (2)
O1	0.0713 (9)	0.0848 (10)	0.0506 (8)	0.0213 (7)	0.0009 (7)	0.0096 (7)
O2	0.0498 (7)	0.0681 (8)	0.0529 (7)	0.0183 (6)	0.0129 (6)	0.0081 (6)
N1	0.0395 (8)	0.0795 (11)	0.0508 (9)	−0.0050 (7)	0.0070 (6)	−0.0022 (8)
C2	0.0455 (10)	0.0606 (11)	0.0475 (10)	−0.0066 (8)	0.0064 (8)	−0.0016 (8)
C3	0.0393 (9)	0.0544 (10)	0.0367 (8)	0.0011 (7)	0.0069 (7)	0.0000 (7)
C4	0.0377 (8)	0.0548 (10)	0.0325 (8)	−0.0016 (7)	0.0073 (6)	−0.0002 (7)
C5	0.0719 (13)	0.0630 (12)	0.0520 (11)	0.0133 (10)	0.0128 (9)	0.0027 (9)
C6	0.0980 (19)	0.0785 (15)	0.0680 (14)	0.0429 (14)	0.0143 (13)	0.0066 (11)
C7	0.0768 (16)	0.118 (2)	0.0564 (13)	0.0554 (16)	0.0110 (11)	0.0060 (13)
C8	0.0445 (11)	0.120 (2)	0.0476 (11)	0.0239 (11)	0.0085 (8)	−0.0009 (11)
C9	0.0412 (9)	0.0793 (13)	0.0337 (9)	0.0101 (8)	0.0090 (7)	−0.0001 (8)
C10	0.0451 (9)	0.0608 (11)	0.0301 (8)	0.0100 (8)	0.0088 (7)	0.0016 (7)
C11	0.0440 (9)	0.0499 (9)	0.0481 (10)	−0.0006 (7)	0.0042 (8)	0.0018 (8)
C12	0.0544 (11)	0.0706 (12)	0.0778 (13)	0.0229 (10)	0.0136 (10)	0.0079 (11)
C13	0.0641 (14)	0.1089 (19)	0.0878 (16)	0.0215 (13)	0.0227 (12)	−0.0130 (14)

Geometric parameters (Å, º) top

Cl1—C2	1.745 (2)	C6—C7	1.396 (4)
Cl2—C4	1.7248 (16)	C6—H6	0.9300
O1—C11	1.195 (2)	C7—C8	1.356 (4)
O2—C11	1.323 (2)	C7—H7	0.9300
O2—C12	1.459 (2)	C8—C9	1.413 (3)
N1—C2	1.287 (2)	C8—H8	0.9300
N1—C9	1.371 (3)	C9—C10	1.414 (2)
C2—C3	1.411 (2)	C12—C13	1.476 (3)
C3—C4	1.367 (2)	C12—H12A	0.9700
C3—C11	1.500 (2)	C12—H12B	0.9700
C4—C10	1.417 (2)	C13—H13A	0.9600
C5—C6	1.360 (3)	C13—H13B	0.9600
C5—C10	1.412 (3)	C13—H13C	0.9600
C5—H5	0.9300

C11—O2—C12	116.84 (14)	C9—C8—H8	119.8
C2—N1—C9	117.06 (15)	N1—C9—C8	118.38 (18)
N1—C2—C3	126.55 (18)	N1—C9—C10	122.85 (15)
N1—C2—Cl1	116.62 (14)	C8—C9—C10	118.77 (19)
C3—C2—Cl1	116.83 (14)	C5—C10—C9	119.45 (16)
C4—C3—C2	116.09 (15)	C5—C10—C4	124.43 (17)
C4—C3—C11	122.35 (14)	C9—C10—C4	116.12 (16)
C2—C3—C11	121.55 (15)	O1—C11—O2	125.64 (16)
C3—C4—C10	121.33 (15)	O1—C11—C3	123.90 (16)
C3—C4—Cl2	119.25 (12)	O2—C11—C3	110.46 (14)
C10—C4—Cl2	119.42 (13)	O2—C12—C13	107.24 (16)
C6—C5—C10	119.7 (2)	O2—C12—H12A	110.3
C6—C5—H5	120.2	C13—C12—H12A	110.3
C10—C5—H5	120.2	O2—C12—H12B	110.3
C5—C6—C7	121.2 (2)	C13—C12—H12B	110.3
C5—C6—H6	119.4	H12A—C12—H12B	108.5
C7—C6—H6	119.4	C12—C13—H13A	109.5
C8—C7—C6	120.5 (2)	C12—C13—H13B	109.5
C8—C7—H7	119.7	H13A—C13—H13B	109.5
C6—C7—H7	119.7	C12—C13—H13C	109.5
C7—C8—C9	120.4 (2)	H13A—C13—H13C	109.5
C7—C8—H8	119.8	H13B—C13—H13C	109.5

Hydrogen-bond geometry (Å, º) top

D—H···A	D—H	H···A	D···A	D—H···A
C7—H7···O1ⁱ	0.93	2.69	3.586 (3)	162

Symmetry code: (i) x+1, −y+3/2, z+1/2.

Hydrogen-bond geometry (Å, º) top

D—H···A	D—H	H···A	D···A	D—H···A
C7—H7···O1ⁱ	0.93	2.69	3.586 (3)	162.2

Symmetry code: (i) x+1, −y+3/2, z+1/2.

Acknowledgements

We gratefully acknowledge support for this project by Consejo Nacional de Ciencia y Tecnología (CONACyT Grant 155029). AC and HR acknowledge support from CONACyT in the form of graduate scholarships.

References

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