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

Scott A Steiger; Anthony J Monacelli; Chun Li; Janet L Hunting; Nicholas R Natale

doi:10.1107/S1600536814013294

. 2014 Jun 18;70(Pt 7):o791–o792. doi: 10.1107/S1600536814013294

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

Scott A Steiger ^a, Anthony J Monacelli ^b, Chun Li ^b, Janet L Hunting ^b, Nicholas R Natale ^a,^*

PMCID: PMC4120632 PMID: 25161575

Abstract

The title compound, C₂₅H₂₇NO₄, has a flattened dihydropyridine ring. The benzene and phenyl rings are synclinal to one another, forming a dihedral angle of 49.82 (8)°; the axis of the biphenyl rings makes an 81.05 (9)° angle to the plane of the dihydropyridine ring. In the crystal, N—H⋯O hydrogen bonds link the molecules into chain motifs running along the a-axis direction. The chains are cross-linked by C—H⋯O interactions, forming sheet motifs running slightly off the (110) plane, together with an intermolecular interaction between head-to tail biphenyl groups, thus making the whole crystal packing a three-dimensional network. Intramolecular C—H⋯O hydrogen bonds are also observed.

Related literature

For general structure–activity relationship studies of 1,4-dihydropyridines (DHPs) as calcium channel modulators, see: Bossert et al. (1981 ▶); Triggle (2003 ▶). For binding studies of DHPs to multiple drug resistant protein 1 (MDR1), see: Abe et al. (1995 ▶); Cole et al. (1989 ▶); Tasaki et al. (1995 ▶); Vanhoefer et al. (1999 ▶); Tolomero et al. (1994 ▶); Cindric et al. (2010 ▶). graphic file with name e-70-0o791-scheme1.jpg

Experimental

Crystal data

C₂₅H₂₇NO₄
M _r = 405.47
Triclinic,
a = 7.3431 (3) Å
b = 10.6075 (4) Å
c = 13.8449 (6) Å
α = 85.762 (3)°
β = 88.124 (3)°
γ = 73.530 (2)°
V = 1031.25 (7) Å³
Z = 2
Mo Kα radiation
μ = 0.09 mm⁻¹
T = 100 K
0.15 × 0.14 × 0.13 mm

Data collection

Bruker SMART BREEZE CCD diffractometer
Absorption correction: multi-scan (SADABS; Bruker, 2012 ▶) T _min = 0.919, T _max = 1.000
19956 measured reflections
4752 independent reflections
2983 reflections with I > 2σ(I)
R _int = 0.072

Refinement

R[F ² > 2σ(F ²)] = 0.062
wR(F ²) = 0.149
S = 1.02
4752 reflections
279 parameters
H atoms treated by a mixture of independent and constrained refinement
Δρ_max = 0.43 e Å⁻³
Δρ_min = −0.37 e Å⁻³

Data collection: APEX2 (Bruker, 2012 ▶); cell refinement: SAINT (Bruker, 2012 ▶); data reduction: SAINT; program(s) used to solve structure: SHELXS97 (Sheldrick, 2008 ▶); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008 ▶); molecular graphics: OLEX2 (Dolomanov et al., 2009 ▶); software used to prepare material for publication: OLEX2 (Dolomanov et al., 2009 ▶).

Supplementary Material

Crystal structure: contains datablock(s) I. DOI: 10.1107/S1600536814013294/zl2590sup1.cif

e-70-0o791-sup1.cif^{(28.3KB, cif)}

Structure factors: contains datablock(s) I. DOI: 10.1107/S1600536814013294/zl2590Isup2.hkl

e-70-0o791-Isup2.hkl^{(260.6KB, hkl)}

Click here for additional data file.^{(8.3KB, cml)}

Supporting information file. DOI: 10.1107/S1600536814013294/zl2590Isup3.cml

Additional supporting information: crystallographic information; 3D view; checkCIF report

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

D—H⋯A	D—H	H⋯A	D⋯A	D—H⋯A
C21—H21⋯O2ⁱ	0.95	2.50	3.256 (3)	137
C6—H6A⋯O3ⁱⁱ	0.98	2.59	3.452 (3)	147
C19—H19⋯O1	0.95	2.51	3.227 (3)	132
C13—H13B⋯O2	0.98	2.11	2.857 (3)	131
C8—H8A⋯O2ⁱⁱⁱ	0.99	2.55	3.344 (3)	137
N1—H1⋯O3ⁱⁱ	0.91 (3)	2.03 (3)	2.938 (3)	173 (2)

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

Acknowledgments

SS and NRN thank the National Institutes of Health for grants NINDS P20RR015583 Center for Structural and Functional Neuroscience (CSFN) and P20 RR017670 Center for Environmental Health Sciences (CEHS).

supplementary crystallographic information

S1. Comment

Hantzsch 1,4-dihydropyridines (DHPs) are an extensively studied class of compounds that are known predominantly for their L-type voltage gated calcium channel modulation. (Bossert et al. 1981, Triggle 2003) There have been extensive structure-activity relationship (SAR) studies done on DHPs that have revealed the basic structural requirements for robust binding affinity to calcium channels. (Triggle 2003) Other studies in the field have shown that DHPs bind to multiple receptors, most notably the multiple drug resistant protein 1 (MDR1) (Abe et al. 1995, Cole et al. 1989, Tasaki et al. 1995, Vanhoefer et al. 1999, Tolomero et al. 1994, Cindric et al. 2010). Using established SAR more selective compounds can be designed for greater selectivity resulting in more clinically relevant compounds.

The title compound, C₂₅H₂₇NO₄, has very similar structural features as other DHPs. Such features include a flattened boat conformation of the 1,4-DHP ring and two ester groups coplanar to the double bonds in the 1,4-DHP, with one carbonyl being cis and the other carbonyl being trans to the double bonds (Figure 1). Although the phenyl group attached at C(3) is still orthogonal to the bottom [C(1)—C(2)—C(4)—C(5)] of the 1,4-DHP ring [81.05 (9)°], it twists away from the N(1)—C(3) at an angle of 47.77 (8)°. The next phenyl ring twists again, with 49.82 (8)° from the center phenyl group, and becomes almost orthogonal to the N(1)—C(3) axis [12.97 (9)°]. Intermolecular hydrogen bonds between N(1) – H(1) and O(3), together with the intermolecular C(6) – H(6) ··· O(3) interactions, link the molecules into chain motifs running along the a axis (Figure 2). Two intermolecular C – H ··· O interactions both from O(2) cross link the molecules into sheet motifs running slightly off the 110 plane (Figure 3). These interations form a three-dimensional network in the cyrstal packing (Figure 4). There are two intramolecular H-bonds observed in the molecule, C(19) – H(19) ··· O(1) and C(13) – H(13B) ··· O(2).

S2. Experimental

S2.1. Synthesis and crystallization

An oven-dried 100 mL round bottom flask was charged with 1.90g of biphenyl-4-carbaldehyde, 2.86 g of ethyl acetoacetate, 2.49 mL of 14.8M ammonium hydroxide, and a magenetic stir bar. The mixture was taken up in 50 mL of absolute ethanol, and the round bottom flask was fitted with a dean stark trap and heated to reflux while stirring. Reaction progress was monitored via TLC. Once the reaction was complete, excess solvent was removed via rotary evaporation. The solution was then purified via a silica column chromatography. The product was re-crystallized into white to yellow crystalline clumps with hexane and dichloromethane (yield = 1.24g , 3.06 mmol, 29.31%).

S2.2. Refinement

Crystal data, data collection and structure refinement details are summarized in Table 1. The methyl H atoms were constrained to an ideal geometry, with C – H = 0.98 Å and U_iso(H) = 1.5U_eq(C), and were allowed to rotate freely about the C – C bonds. The rest of the H atoms were placed in calculated positions with C – H = 0.95 ~ 1.00 Å and refined as riding on their carrier atoms with U_iso(H) = 1.2U_eq(C). The positions of amine H atoms were determined from difference Fourier maps and refined freely along with their isotropic displacement parameters. One low-angle reflection was omitted from the refinement because its observed intensity was much lower than the calculated value as a result of being partially obscured by the beam stop.