Dimethyl 4-(4-hy­droxy­phen­yl)-2,6-dimethyl-1,4-dihydro­pyridine-3,5-dicarboxyl­ate

Chun-Hua Zhang; Jing-Min Zhao; Bao-Guo Chen

doi:10.1107/S1600536811032521

. 2011 Aug 17;67(Pt 9):o2362–o2363. doi: 10.1107/S1600536811032521

Dimethyl 4-(4-hydroxyphenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate

Chun-Hua Zhang ^a,^*, Jing-Min Zhao ^b, Bao-Guo Chen ^a

PMCID: PMC3200733 PMID: 22064645

Abstract

The title molecule, C₁₇H₁₉NO₅, was prepared by a Hantzsch dihydropyridine synthesis from 4-hydroxybenzaldehyde, methyl acetoacetate and NH₄HCO₃. In the molecular structure of the title compound, the dihydropyridine ring adopts a flattened boat conformation and the plane of the base of the boat forms a dihedral angle of 80.8 (2)° with the aromatic six-membered ring. The packing is stabilized by strong intermolecular N—H⋯O_carbonyl, O_hydroxy—H⋯O_carbonyl and weak intramolecular C—H⋯O hydrogen bonds.

Related literature

For background to the bioactivity and synthesis of 1,4-dihydropyridines, see: Yang et al. (2010 ▶); Davies et al. (2005 ▶); Warrior et al. (2005 ▶); Ko & Yao (2006 ▶); Rose & Draeger (1992 ▶). For related structures, see: Bai et al. (2009 ▶); Fun et al. (2009 ▶); Thenmozhi et al. (2009 ▶). For hydrogen-bond definitions, see: Desiraju & Steiner (1999 ▶). For the synthetic method, see: Tamaddon et al. (2010 ▶).

Experimental

Crystal data

C₁₇H₁₉NO₅
M _r = 317.33
Monoclinic,
a = 13.245 (3) Å
b = 9.3480 (19) Å
c = 13.754 (3) Å
β = 110.14 (3)°
V = 1598.8 (6) Å³
Z = 4
Mo Kα radiation
μ = 0.10 mm⁻¹
T = 293 K
0.20 × 0.10 × 0.10 mm

Data collection

Nonius CAD-4 diffractometer
Absorption correction: ψ scan For semi-empirical (using intensity measurements) absorption, see: North et al. (1968 ▶) T _min = 0.981, T _max = 0.990
4588 measured reflections
2931 independent reflections
1212 reflections with I > 2σ(I)
R _int = 0.104
3 standard reflections every 200 reflections intensity decay: 1%

Refinement

R[F ² > 2σ(F ²)] = 0.074
wR(F ²) = 0.081
S = 1.00
2931 reflections
209 parameters
1 restraint
H-atom parameters constrained
Δρ_max = 0.16 e Å⁻³
Δρ_min = −0.17 e Å⁻³

Data collection: CAD-4 EXPRESS (Enraf–Nonius, 1994 ▶); cell refinement: CAD-4 EXPRESS; data reduction: XCAD4 (Harms & Wocadlo, 1996 ▶); program(s) used to solve structure: SHELXS97 (Sheldrick, 2008 ▶); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008 ▶); molecular graphics: SHELXTL (Sheldrick, 2008 ▶); software used to prepare material for publication: SHELXTL.

Supplementary Material

Crystal structure: contains datablock(s) I, global. DOI: 10.1107/S1600536811032521/zl2397sup1.cif

e-67-o2362-sup1.cif^{(24.9KB, cif)}

Structure factors: contains datablock(s) I. DOI: 10.1107/S1600536811032521/zl2397Isup2.hkl

e-67-o2362-Isup2.hkl^{(143.9KB, hkl)}

Supplementary material file. DOI: 10.1107/S1600536811032521/zl2397Isup3.mol

Supplementary material file. DOI: 10.1107/S1600536811032521/zl2397Isup4.cml

Additional supplementary materials: crystallographic information; 3D view; checkCIF report

Table 1. Hydrogen-bond geometry (Å, °).

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
N1—H1A⋯O4ⁱ	0.86	2.10	2.936 (4)	164
O1—H1B⋯O2ⁱⁱ	0.82	1.92	2.742 (4)	179
C7—H7A⋯O2	0.98	2.39	2.781 (5)	103
C7—H7A⋯O5	0.98	2.32	2.717 (5)	103
C12—H12A⋯O3	0.96	2.06	2.790 (5)	131
C13—H13A⋯O4	0.96	2.26	2.818 (5)	116

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Symmetry codes: (i) Inline graphic ; (ii) .

supplementary crystallographic information

Comment

In recent years, much attention has been focused on the synthesis of 1,4-dihydropyridine derivatives because of their presence in numerous natural products along with a wide spectrum of their physiological activities (Yang et al., 2010). For example, some dihydropyridines have calcium modulatory properties (Rose & Draeger, 1992), antibacterial activity (Davies et al., 2005), or fungicidal activity (Warrior et al., 2005), to name just a few. Because of the biological importance associated with these compounds, numerous methods had been developed for the synthesis of 1,4-dihydropyridine derivatives, which include the use of microwaves, ionic liquids, refluxing at high temperature, metal triflates, and iodine (Ko & Yao, 2006). However, the use of high temperatures, expensive metal precursors, catalysts that are harmful to the environment, and long reaction times limit the use of many of these methods. Herein, we report a mild and catalyst-free synthesis based on a variation of the commonly used Hantzsch dihydropyridine synthesis (Tamaddon et al., 2010), and the crystal structure of the resultant title compound is presented. Compared to the classical method involving the three-component coupling of an aldehyde with ethyl acetoacetate, and ammonia in acetic acid or in refluxing alcohol, the reation was conducted in water and avoided the use of catalysts, so it was very environmentally benign. Moreover, the workup is very simple and can give the product in high yield after simple filtration.

In the molecular structure of the title compound (Fig. 1), atoms C7 and N1 deviate from the mean plane of atoms C8/C9/C10/C11 in the same direction, by 0.45 (0) and 0.18 (7) Å, respectively, so the heterocyclic ring adopts a boat conformation. In addition, the phenol ring substituent is almost perpendicular to the plane of the atoms C8/C9/C10/C11, with a dihedral angle between them of 80.8 (2)°. The methyl groups are nearly coplanar with the aformentioned plane of the atoms C8/C9/C10/C11, with the methyl C atoms C12 and C13 deviating from the mean plane by 0.12 (4) and 0.22 (2) Å, respectively. The average C—N bond lengths of the title compound are with 1.353 (9) Å similar to those of its phenyl substituted 1,4-dihydropyridine derivative (Bai et al., 2009) which has average C—N bond lenghts of 1.376 (8) Å, its 4-methoxyphenyl substituted 1,4-dihydropyridine derivative (Thenmozhi et al., 2009) which has average C—N bond lenghts of 1.377 (4) Å, and its 4-methylphenyl substituted 1,4-dihydropyridine derivative (Fun et al., 2009) which has average C—N bond lenghts of 1.385 (7) Å.

The crystal packing of the title compound is stabilized by strong intermolecular N—H···O_carbonyl and O_hydroxyl—H···O_carbonyl hydrogen bonds (Desiraju & Steiner, 1999), N1—H1A···O4ⁱ and O1—H1B···O2ⁱⁱ, and by several weaker intramolecular C—H···O hydrogen bonds, C7—H7A···O2, C7–H7A···O5, C12—H12A···O3, C13—H13A···O4 (see Table 1 for numerical values and symmetry operators).

Experimental

The title compound was obtained according to a reported method (Tamaddon et al., 2010). A mixture of 4-hydroxybenzaldehyde (2 mmol), methyl acetoacetate (4 mmol), and NH₄HCO₃ (2 mmol) was stirred in water (2 mL) under reflux. After completion of the reaction (TLC monitoring), the mixture was diluted with cold water (20 mL) and filtered to obtain the precipitated product which was further purified by recrystallization. Single crystals suitable for X-ray diffraction were obtained by slow evaporation of an ethanol solution. IR (KBr) v/cm^-1: 3327, 2960, 1685, 1652; ¹H NMR (300 MHz, DMSO-d6) δ/ppm: 9.05 (s, 1H, NH), 8.77 (s, 1H, OH), 6.91 (d, 2H, ArH, J = 7.8 Hz), 6.56 (d, 2H, ArH, J = 7.8 Hz), 4.77 (s, 1H, H4), 3.55 (s, 6H, 2COOCH₃), 2.25 (s, 6H, 2CH₃); MS (ESI) m/z: 318.1 [M+H]⁺, 340.1 [M+Na]⁺, 356.0 [M+K]⁺; Anal. Calcd for C₁₇H₁₉NO₅: C, 64.34; H, 6.03; N, 4.41; found: C, 64.46; H, 6.09; N, 4.33.