Diethyl 4-(1H-imidazol-2-yl)-2,6-dimethyl-1,4-di­hydro­pyridine-3,5-di­carboxyl­ate

Yoo, M.; Koh, D.

doi:10.1107/S2414314620000346

organic compounds

IUCrDATA

ISSN: 2414-3146

Volume 5| Part 1| January 2020| x200034

https://doi.org/10.1107/S2414314620000346

Open

access

Diethyl 4-(1H-imidazol-2-yl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate

Miri Yoo ^a and Dongsoo Koh ^a ^*

^aDepartment of Applied Chemistry, Dongduk Women's University, Seoul 136-714, Republic of Korea
^*Correspondence e-mail: dskoh@dongduk.ac.kr

Edited by M. Bolte, Goethe-Universität Frankfurt, Germany (Received 10 January 2020; accepted 13 January 2020; online 17 January 2020)

In the title compound, C₁₆H₂₁N₃O₄, the 1,4-dihydropyridine ring adopts a flattened boat conformation, with the imidazole substituent in an axial orientation [dihedral angle between ring planes = 82.9 (6)°]. In the crystal structure, pairs of N—H⋯O and N—H⋯N hydrogen bonds with graph-set notation R₂²(14) connect the molecules into chains running along the c-axis direction.

Keywords: crystal structure; 1,4-dihydropyridine; N—H⋯O hydrogen bonds; N—H⋯N hydrogen bonds.

CCDC reference: 1977288

Structure description

Hantzsch 1,4-dihydropyridines (1,4-DHPs) have shown broad biological activities which include calcium channel blocker (Schaller et al., 2018 ), antimycobacterial (Lentz et al., 2016 ), anticonvulsant (Prasanthi et al., 2014 ) and anti-tubercular (Khoshneviszadeh et al., 2009 ) activities. According to our recent report, they show anti-cancer activities in HCT116 human colon cancer cell lines (Ahn et al., 2018 ). We report herein the synthesis and crystal structure of the title compound (Fig. 1).

Figure 1
The molecular structure of the title compound, showing the atom-labelling scheme with displacement ellipsoids drawn at the 30% probability level.

In the title compound, the 1,4-dihydropyridine (C1–C5/N1) ring is twisted slightly from planarity, with a maximum deviation of 0.178 (1) Å at C3 (r.m.s. deviation = 0.113 Å). The dihedral angle formed between the plane of the 1,4-dihydropyridine (C1–C5/N1) and imidazole (C10–C12/N2–N3) rings is 82.9 (6)°. One of the carbonyl groups (C13=O3) lies on the same side as the methyl group at C16 with the other carbonyl group (C7=O1) on the opposite side. In the crystal, pairs of N—H⋯O and N—H⋯N hydrogen bonds with graph-set notation R₂²(14) connect the molecules into chains running along the c-axis direction (Table 1, Fig. 2).

Table 1
Hydrogen-bond geometry (Å, °)

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
N1—H1⋯N3ⁱ	0.87	2.05	2.913 (3)	175
N2—H2⋯O1ⁱⁱ	0.87	2.18	2.979 (3)	152
Symmetry codes: (i) -x, -y+1, -z+1; (ii) -x, -y+1, -z.

Figure 2
Part of the crystal structure with two intermolecular hydrogen bonds (blue and yellow dashed lines) are shown. For clarity, only those H atoms involved in hydrogen bonding are shown.

Synthesis and crystallization

Methyl acetoacetate (20 mmol) and 1H-imidazole-2-carbaldehyde (10 mmol) were dissolved in 30 ml of ethanol to give a clear solution. To the mixture, ammonium acetate (10 mmol) was added and the reaction mixture was heated at 365 K for 5 h. After completion of the reaction (monitored by TLC), the mixture was cooled to room temperature to produce a solid product. This solid was recrystallized from ethanol solution to obtain single-crystal of the title compound in 61% yield.

Refinement

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

Table 2
Experimental details

Crystal data
Chemical formula	C₁₆H₂₁N₃O₄
M_r	319.36
Crystal system, space group	Triclinic, P $[\overline{1}]$
Temperature (K)	223
a, b, c (Å)	8.127 (7), 8.411 (9), 12.536 (10)
α, β, γ (°)	105.36 (4), 96.52 (2), 94.77 (3)
V (Å³)	815.1 (13)
Z	2
Radiation type	Mo Kα
μ (mm⁻¹)	0.10
Crystal size (mm)	0.28 × 0.21 × 0.14

Data collection
Diffractometer	PHOTON 100 CMOS
Absorption correction	Multi-scan (SADABS; Bruker, 2012 )
T_min, T_max	0.974, 0.987
No. of measured, independent and observed [I > 2σ(I)] reflections	33431, 3920, 3144
R_int	0.041
(sin θ/λ)_max (Å⁻¹)	0.667

Refinement
R[F² > 2σ(F²)], wR(F²), S	0.049, 0.142, 1.06
No. of reflections	3920
No. of parameters	212
H-atom treatment	H-atom parameters constrained
Δρ_max, Δρ_min (e Å⁻³)	0.32, −0.23
Computer programs: APEX2 and SAINT (Bruker, 2012), SHELXS97 (Sheldrick, 2008 ), SHELXL2014 (Sheldrick, 2015 ), SHELXTL (Sheldrick, 2008) and publCIF (Westrip, 2010 ).

Structural data

CCDC reference: 1977288

Crystal structure: contains datablock I. DOI: https://doi.org/10.1107/S2414314620000346/bt4088sup1.cif

Structure factors: contains datablock I. DOI: https://doi.org/10.1107/S2414314620000346/bt4088Isup2.hkl

Supporting information file. DOI: https://doi.org/10.1107/S2414314620000346/bt4088Isup3.cml

checkCIF report

Computing details top

Data collection: APEX2 (Bruker, 2012); cell refinement: SAINT (Bruker, 2012); data reduction: SAINT (Bruker, 2012); program(s) used to solve structure: SHELXS97 (Sheldrick, 2008); program(s) used to refine structure: SHELXL2014 (Sheldrick, 2015); molecular graphics: SHELXTL (Sheldrick, 2008); software used to prepare material for publication: publCIF (Westrip, 2010).

Diethyl 4-(1H-imidazol-2-yl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate top

Crystal data top

C₁₆H₂₁N₃O₄	Z = 2
M_r = 319.36	F(000) = 340
Triclinic, P1	D_x = 1.301 Mg m⁻³
a = 8.127 (7) Å	Mo Kα radiation, λ = 0.71073 Å
b = 8.411 (9) Å	Cell parameters from 9982 reflections
c = 12.536 (10) Å	θ = 2.5–28.3°
α = 105.36 (4)°	µ = 0.10 mm⁻¹
β = 96.52 (2)°	T = 223 K
γ = 94.77 (3)°	Block, colourless
V = 815.1 (13) Å³	0.28 × 0.21 × 0.14 mm

Data collection top

PHOTON 100 CMOS diffractometer	3144 reflections with I > 2σ(I)
φ and ω scans	R_int = 0.041
Absorption correction: multi-scan (SADABS; Bruker, 2012)	θ_max = 28.3°, θ_min = 2.5°
T_min = 0.974, T_max = 0.987	h = −10→10
33431 measured reflections	k = −11→11
3920 independent reflections	l = −16→16

Refinement top

Refinement on F²	0 restraints
Least-squares matrix: full	Hydrogen site location: inferred from neighbouring sites
R[F² > 2σ(F²)] = 0.049	H-atom parameters constrained
wR(F²) = 0.142	w = 1/[σ²(F_o²) + (0.0734P)² + 0.2436P] where P = (F_o² + 2F_c²)/3
S = 1.06	(Δ/σ)_max < 0.001
3920 reflections	Δρ_max = 0.32 e Å⁻³
212 parameters	Δρ_min = −0.23 e Å⁻³

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
N1	0.18302 (15)	0.47356 (14)	0.46454 (9)	0.0280 (3)
H1	0.1979	0.5159	0.5367	0.034*
C1	0.21728 (16)	0.57673 (16)	0.39890 (11)	0.0251 (3)
C2	0.16729 (15)	0.52079 (16)	0.28644 (10)	0.0232 (3)
C3	0.04796 (16)	0.36033 (15)	0.23758 (10)	0.0229 (3)
H3	0.0781	0.3040	0.1637	0.028*
C4	0.06773 (16)	0.24414 (16)	0.31144 (11)	0.0253 (3)
C5	0.12622 (16)	0.30616 (17)	0.42189 (11)	0.0261 (3)
C6	0.3103 (2)	0.74263 (19)	0.46493 (12)	0.0374 (4)
H6A	0.4280	0.7424	0.4580	0.056*
H6B	0.2959	0.7626	0.5430	0.056*
H6C	0.2669	0.8296	0.4363	0.056*
C7	0.21403 (16)	0.60658 (17)	0.20487 (11)	0.0258 (3)
O1	0.15784 (14)	0.55990 (13)	0.10544 (8)	0.0368 (3)
O2	0.32952 (13)	0.73897 (13)	0.24786 (8)	0.0333 (3)
C8	0.3728 (2)	0.83898 (19)	0.17506 (13)	0.0387 (4)
H8A	0.2719	0.8672	0.1369	0.046*
H8B	0.4361	0.7785	0.1186	0.046*
C9	0.4771 (3)	0.9939 (2)	0.24842 (16)	0.0521 (5)
H9A	0.4123	1.0534	0.3030	0.078*
H9B	0.5110	1.0643	0.2028	0.078*
H9C	0.5754	0.9640	0.2867	0.078*
C10	−0.13059 (16)	0.39732 (15)	0.21997 (10)	0.0231 (3)
N2	−0.20049 (15)	0.42932 (16)	0.12553 (10)	0.0315 (3)
H2	−0.1525	0.4293	0.0669	0.038*
C11	−0.36104 (19)	0.4617 (2)	0.13918 (13)	0.0384 (4)
H11	−0.4397	0.4889	0.0878	0.046*
C12	−0.38247 (19)	0.4467 (2)	0.24119 (13)	0.0373 (3)
H12	−0.4814	0.4613	0.2730	0.045*
N3	−0.23804 (14)	0.40668 (16)	0.29244 (9)	0.0302 (3)
C13	0.00797 (18)	0.06611 (17)	0.26232 (12)	0.0308 (3)
O3	0.02408 (19)	−0.04606 (14)	0.30548 (11)	0.0556 (4)
O4	−0.07121 (14)	0.03801 (12)	0.15720 (9)	0.0360 (3)
C14	−0.1454 (2)	−0.13100 (19)	0.10123 (14)	0.0406 (4)
H14A	−0.2060	−0.1768	0.1517	0.049*
H14B	−0.0586	−0.2015	0.0776	0.049*
C15	−0.2623 (2)	−0.1240 (2)	0.00188 (14)	0.0441 (4)
H15A	−0.3471	−0.0535	0.0264	0.066*
H15B	−0.3149	−0.2350	−0.0377	0.066*
H15C	−0.2006	−0.0790	−0.0475	0.066*
C16	0.1393 (2)	0.2112 (2)	0.50829 (13)	0.0372 (4)
H16A	0.0529	0.1174	0.4870	0.056*
H16B	0.1256	0.2835	0.5803	0.056*
H16C	0.2479	0.1716	0.5132	0.056*

Atomic displacement parameters (Å²) top

	U¹¹	U²²	U³³	U¹²	U¹³	U²³
N1	0.0361 (6)	0.0299 (6)	0.0185 (5)	0.0004 (5)	0.0041 (4)	0.0086 (4)
C1	0.0256 (6)	0.0272 (6)	0.0237 (6)	0.0016 (5)	0.0050 (5)	0.0090 (5)
C2	0.0240 (6)	0.0247 (6)	0.0222 (6)	0.0008 (5)	0.0045 (5)	0.0088 (5)
C3	0.0280 (6)	0.0228 (6)	0.0186 (6)	0.0010 (5)	0.0044 (5)	0.0068 (4)
C4	0.0273 (6)	0.0246 (6)	0.0269 (6)	0.0043 (5)	0.0060 (5)	0.0111 (5)
C5	0.0268 (6)	0.0288 (7)	0.0265 (6)	0.0045 (5)	0.0061 (5)	0.0130 (5)
C6	0.0467 (9)	0.0365 (8)	0.0239 (7)	−0.0088 (7)	0.0006 (6)	0.0055 (6)
C7	0.0272 (6)	0.0277 (6)	0.0236 (6)	0.0010 (5)	0.0049 (5)	0.0092 (5)
O1	0.0488 (6)	0.0388 (6)	0.0221 (5)	−0.0082 (5)	0.0029 (4)	0.0124 (4)
O2	0.0368 (6)	0.0343 (5)	0.0292 (5)	−0.0092 (4)	0.0029 (4)	0.0144 (4)
C8	0.0481 (9)	0.0347 (8)	0.0352 (8)	−0.0084 (7)	0.0090 (7)	0.0158 (6)
C9	0.0616 (12)	0.0394 (9)	0.0509 (10)	−0.0158 (8)	0.0143 (9)	0.0092 (8)
C10	0.0296 (6)	0.0211 (6)	0.0170 (6)	−0.0020 (5)	0.0001 (5)	0.0055 (4)
N2	0.0356 (6)	0.0397 (7)	0.0216 (6)	0.0011 (5)	0.0005 (4)	0.0147 (5)
C11	0.0332 (8)	0.0492 (9)	0.0336 (8)	0.0043 (7)	−0.0072 (6)	0.0180 (7)
C12	0.0272 (7)	0.0506 (9)	0.0353 (8)	0.0071 (6)	0.0013 (6)	0.0144 (7)
N3	0.0274 (6)	0.0424 (7)	0.0228 (6)	0.0058 (5)	0.0034 (4)	0.0119 (5)
C13	0.0350 (7)	0.0270 (7)	0.0325 (7)	0.0034 (5)	0.0064 (6)	0.0113 (5)
O3	0.0870 (10)	0.0298 (6)	0.0494 (7)	−0.0010 (6)	−0.0086 (7)	0.0200 (5)
O4	0.0481 (6)	0.0242 (5)	0.0332 (6)	−0.0033 (4)	0.0001 (5)	0.0083 (4)
C14	0.0466 (9)	0.0245 (7)	0.0461 (9)	−0.0043 (6)	0.0013 (7)	0.0065 (6)
C15	0.0401 (9)	0.0456 (9)	0.0402 (9)	−0.0039 (7)	0.0046 (7)	0.0040 (7)
C16	0.0491 (9)	0.0376 (8)	0.0299 (7)	0.0046 (7)	0.0038 (6)	0.0187 (6)

Geometric parameters (Å, º) top

N1—C1	1.3777 (19)	C9—H9B	0.9700
N1—C5	1.385 (2)	C9—H9C	0.9700
N1—H1	0.8700	C10—N3	1.3221 (19)
C1—C2	1.364 (2)	C10—N2	1.3558 (19)
C1—C6	1.508 (2)	N2—C11	1.375 (2)
C2—C7	1.464 (2)	N2—H2	0.8700
C2—C3	1.532 (2)	C11—C12	1.347 (2)
C3—C10	1.513 (2)	C11—H11	0.9400
C3—C4	1.520 (2)	C12—N3	1.383 (2)
C3—H3	0.9900	C12—H12	0.9400
C4—C5	1.357 (2)	C13—O3	1.214 (2)
C4—C13	1.476 (2)	C13—O4	1.350 (2)
C5—C16	1.506 (2)	O4—C14	1.452 (2)
C6—H6A	0.9700	C14—C15	1.496 (3)
C6—H6B	0.9700	C14—H14A	0.9800
C6—H6C	0.9700	C14—H14B	0.9800
C7—O1	1.2239 (19)	C15—H15A	0.9700
C7—O2	1.3434 (19)	C15—H15B	0.9700
O2—C8	1.4473 (19)	C15—H15C	0.9700
C8—C9	1.506 (2)	C16—H16A	0.9700
C8—H8A	0.9800	C16—H16B	0.9700
C8—H8B	0.9800	C16—H16C	0.9700
C9—H9A	0.9700

C1—N1—C5	123.55 (12)	H9A—C9—H9B	109.5
C1—N1—H1	118.2	C8—C9—H9C	109.5
C5—N1—H1	118.2	H9A—C9—H9C	109.5
C2—C1—N1	118.86 (13)	H9B—C9—H9C	109.5
C2—C1—C6	128.14 (12)	N3—C10—N2	110.72 (13)
N1—C1—C6	113.00 (13)	N3—C10—C3	126.17 (12)
C1—C2—C7	124.90 (13)	N2—C10—C3	123.10 (12)
C1—C2—C3	120.01 (11)	C10—N2—C11	107.57 (12)
C7—C2—C3	115.05 (12)	C10—N2—H2	126.2
C10—C3—C4	111.44 (10)	C11—N2—H2	126.2
C10—C3—C2	111.01 (12)	C12—C11—N2	105.92 (13)
C4—C3—C2	110.65 (12)	C12—C11—H11	127.0
C10—C3—H3	107.9	N2—C11—H11	127.0
C4—C3—H3	107.9	C11—C12—N3	110.26 (14)
C2—C3—H3	107.9	C11—C12—H12	124.9
C5—C4—C13	121.28 (13)	N3—C12—H12	124.9
C5—C4—C3	120.13 (13)	C10—N3—C12	105.53 (13)
C13—C4—C3	118.36 (13)	O3—C13—O4	121.56 (14)
C4—C5—N1	119.54 (12)	O3—C13—C4	127.60 (15)
C4—C5—C16	126.95 (14)	O4—C13—C4	110.84 (12)
N1—C5—C16	113.51 (13)	C13—O4—C14	116.62 (12)
C1—C6—H6A	109.5	O4—C14—C15	106.98 (14)
C1—C6—H6B	109.5	O4—C14—H14A	110.3
H6A—C6—H6B	109.5	C15—C14—H14A	110.3
C1—C6—H6C	109.5	O4—C14—H14B	110.3
H6A—C6—H6C	109.5	C15—C14—H14B	110.3
H6B—C6—H6C	109.5	H14A—C14—H14B	108.6
O1—C7—O2	122.36 (12)	C14—C15—H15A	109.5
O1—C7—C2	123.54 (13)	C14—C15—H15B	109.5
O2—C7—C2	114.06 (12)	H15A—C15—H15B	109.5
C7—O2—C8	117.63 (12)	C14—C15—H15C	109.5
O2—C8—C9	106.51 (14)	H15A—C15—H15C	109.5
O2—C8—H8A	110.4	H15B—C15—H15C	109.5
C9—C8—H8A	110.4	C5—C16—H16A	109.5
O2—C8—H8B	110.4	C5—C16—H16B	109.5
C9—C8—H8B	110.4	H16A—C16—H16B	109.5
H8A—C8—H8B	108.6	C5—C16—H16C	109.5
C8—C9—H9A	109.5	H16A—C16—H16C	109.5
C8—C9—H9B	109.5	H16B—C16—H16C	109.5

C5—N1—C1—C2	11.5 (2)	C3—C2—C7—O2	−174.61 (11)
C5—N1—C1—C6	−168.01 (13)	O1—C7—O2—C8	7.2 (2)
N1—C1—C2—C7	−171.32 (12)	C2—C7—O2—C8	−175.03 (12)
C6—C1—C2—C7	8.1 (2)	C7—O2—C8—C9	169.35 (14)
N1—C1—C2—C3	11.18 (19)	C4—C3—C10—N3	32.28 (17)
C6—C1—C2—C3	−169.38 (13)	C2—C3—C10—N3	−91.54 (16)
C1—C2—C3—C10	96.34 (14)	C4—C3—C10—N2	−149.20 (12)
C7—C2—C3—C10	−81.40 (14)	C2—C3—C10—N2	86.98 (15)
C1—C2—C3—C4	−27.93 (17)	N3—C10—N2—C11	0.37 (16)
C7—C2—C3—C4	154.33 (11)	C3—C10—N2—C11	−178.36 (12)
C10—C3—C4—C5	−98.67 (15)	C10—N2—C11—C12	−0.51 (17)
C2—C3—C4—C5	25.35 (17)	N2—C11—C12—N3	0.48 (19)
C10—C3—C4—C13	75.95 (15)	N2—C10—N3—C12	−0.07 (16)
C2—C3—C4—C13	−160.02 (12)	C3—C10—N3—C12	178.60 (12)
C13—C4—C5—N1	179.24 (12)	C11—C12—N3—C10	−0.26 (18)
C3—C4—C5—N1	−6.29 (19)	C5—C4—C13—O3	−11.3 (2)
C13—C4—C5—C16	−0.2 (2)	C3—C4—C13—O3	174.13 (16)
C3—C4—C5—C16	174.29 (13)	C5—C4—C13—O4	169.00 (12)
C1—N1—C5—C4	−14.2 (2)	C3—C4—C13—O4	−5.56 (17)
C1—N1—C5—C16	165.30 (13)	O3—C13—O4—C14	3.9 (2)
C1—C2—C7—O1	−174.51 (14)	C4—C13—O4—C14	−176.41 (12)
C3—C2—C7—O1	3.1 (2)	C13—O4—C14—C15	165.03 (13)
C1—C2—C7—O2	7.8 (2)

Hydrogen-bond geometry (Å, º) top

D—H···A	D—H	H···A	D···A	D—H···A
N1—H1···N3ⁱ	0.87	2.05	2.913 (3)	175
N2—H2···O1ⁱⁱ	0.87	2.18	2.979 (3)	152

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

Funding information

The authors acknowledge financial support from the Basic Science Research Program (award No. NRF-2019R1F1A1058747).

References

Ahn, S., Lee, Y., Park, J., Lee, J., Shin, Y., Lee, Y., Koh, D. & Lim, Y. (2018). Med. Chem. 14, 851–862. CrossRef CAS PubMed Google Scholar
Bruker (2012). APEX2, SAINT and SADABS, Bruker AXS Inc. Madison, Wisconsin, USA. Google Scholar
Khoshneviszadeh, M., Edraki, N., Javidnia, K., Alborzi, A., Pourabbas, B., Mardaneh, J. & Miri, R. (2009). Bioorg. Med. Chem. 17, 1579–1586. Web of Science CrossRef PubMed CAS Google Scholar
Lentz, F., Hemmer, M., Reiling, N. & Hilgeroth, A. (2016). Bioorg. Med. Chem. Lett. 26, 5896–5898. Web of Science CrossRef CAS PubMed Google Scholar
Prasanthi, G., Prasad, K. V. S. R. G. & Bharathi, K. (2014). Eur. J. Med. Chem. 73, 97–104. Web of Science CrossRef CAS PubMed Google Scholar
Schaller, D., Gündüz, M. G., Zhang, F. X., Zamponi, G. W. & Wolber, G. (2018). Eur. J. Med. Chem. 155, 1–12. Web of Science CrossRef CAS PubMed Google Scholar
Sheldrick, G. M. (2008). Acta Cryst. A64, 112–122. Web of Science CrossRef CAS IUCr Journals Google Scholar
Sheldrick, G. M. (2015). Acta Cryst. C71, 3–8. Web of Science CrossRef IUCr Journals Google Scholar
Westrip, S. P. (2010). J. Appl. Cryst. 43, 920–925. Web of Science CrossRef CAS IUCr Journals Google Scholar

This is an open-access article distributed under the terms of the Creative Commons Attribution (CC-BY) Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original authors and source are cited.