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Acta Crystallogr Sect E Struct Rep Online. 2009 August 1; 65(Pt 8): o1748.
Published online 2009 July 4. doi:  10.1107/S1600536809024945
PMCID: PMC2977273

3,5-Bis(ethoxy­carbon­yl)-2,6-dimethyl-1,4-dihydro­pyridine-4-carboxylic acid

Abstract

The title mol­ecule, C14H19NO6, was synthesized by the reaction of glyoxylic acid, ethyl acetoacetate and NH4HCO3. In the crystal structure, the dihydro­pyridine ring adopts an asymmetric boat-type conformation with the C atom bearing the carboxyl group showing a signficantly larger deviation [0.325 (2) Å] from the base plane then the N atom [0.137 (2) Å]. One of the ethyl groups is disordered over two positions with occupancies of 0.741 (10) and 0.259 (10). The crystal is stabilized by strong inter­molecular hydrogen bonds. N—H(...)O inter­actions form infinite chains in the a direction. O—H(...)O hydrogen bonds form typical carboxylic acid dimers, which link the N—H(...)O chains into a ladder-type double chain.

Related literature

For the electrophysiological activity of 1,4-dipyridine derivatives, see: Fleckenstein (1977 [triangle]); Cutshall et al. (2002 [triangle]). For their biological activity, see: Triggle et al. (1980 [triangle]); Fossheim et al. (1982 [triangle]); Heinrich et al. (2004 [triangle]); Henry (2004 [triangle]).

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Object name is e-65-o1748-scheme1.jpg

Experimental

Crystal data

  • C14H19NO6
  • M r = 297.30
  • Triclinic, An external file that holds a picture, illustration, etc.
Object name is e-65-o1748-efi1.jpg
  • a = 7.445 (4) Å
  • b = 9.864 (5) Å
  • c = 11.908 (2) Å
  • α = 104.10 (3)°
  • β = 97.808 (9)°
  • γ = 111.658 (10)°
  • V = 763.2 (6) Å3
  • Z = 2
  • Mo Kα radiation
  • μ = 0.10 mm−1
  • T = 291 K
  • 0.36 × 0.30 × 0.28 mm

Data collection

  • Rigaku SCXmini diffractometer
  • Absorption correction: multi-scan (CrystalClear; Rigaku, 2005 [triangle]) T min = 0.960, T max = 0.970
  • 6950 measured reflections
  • 2969 independent reflections
  • 2241 reflections with I > 2σ(I)
  • R int = 0.029

Refinement

  • R[F 2 > 2σ(F 2)] = 0.063
  • wR(F 2) = 0.197
  • S = 1.08
  • 2969 reflections
  • 199 parameters
  • 2 restraints
  • H-atom parameters constrained
  • Δρmax = 0.29 e Å−3
  • Δρmin = −0.24 e Å−3

Data collection: CrystalClear (Rigaku, 2005 [triangle]); cell refinement: CrystalClear; data reduction: CrystalClear; program(s) used to solve structure: SHELXS97 (Sheldrick, 2008 [triangle]); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008 [triangle]); molecular graphics: SHELXTL (Sheldrick, 2008 [triangle]); software used to prepare material for publication: SHELXTL.

Table 1
Hydrogen-bond geometry (Å, °)

Supplementary Material

Crystal structure: contains datablocks I, New_Global_Publ_Block. DOI: 10.1107/S1600536809024945/kj2129sup1.cif

Structure factors: contains datablocks I. DOI: 10.1107/S1600536809024945/kj2129Isup2.hkl

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

Acknowledgments

The authors thank Jiangsu Planned Projects for Postdoctoral Research Funds (grant No. 0802003B) and Professor Dr Rengen Xiong.

supplementary crystallographic information

Comment

The development of new methods for the synthesis of 1,4-dipyridine derivatives is a motive for the current research because of their presence in numerous natural products along with a wide spectrum of their electrophysiological activities (Fleckenstein, 1977; Cutshall et al., 2002). Pyridine 1,4-derivatives and their complexes have been studied for their fungicidal and antibacterial effects, antiviral drugs, as well as calcium antagonists (Triggle et al., 1980; Fossheim et al., 1982; Heinrich et al., 2004; Henry, 2004).

Here we report the structure of 3,5-di(ethoxycarbonyl)-1,4-dihydro-2,6-dimethylpyridine-4- carboxylic acid (Fig. 1). In the crystal structure, the dihydropyridine ring adopts a asymmetric boat-type conformation with C1 showing a signficantly larger deviation from the base plane C3/C4/C5/C6 [0.325 (2) Å] then N1 [0.137 (2) Å]. The ethyl group labeled by C9 and C10 is disordered over two positions with occupancies of 0.741 (10) and 0.259 (10). The crystal is stabilized by strong intermolecular hydrogen bonds (Table 1). Interactions of type N—H···O form infinite chains in the a-direction. The O—H···O hydrogen bonds form typical carboxylic acid dimers which link the N—H···O chains into a ladder-type double chain (Fig. 2).

Experimental

Glyoxylic acid (50% in water, 6 mmol), ethyl acetoacetate (12 mmol) and NH4HCO3 (6 mmol) were mixed in a 50 ml flask. After the mixture had been stirred for 6 h at 293 K, the crude product was obtained with yield of 65%. Single crystals suitable for X-ray structure analysis were obtained by the slow evaporation of a dimethylformamide solution in air.

Refinement

H atoms, with exception of H2D bonded to O2, were placed on calculated positions (N—H = 0.86 Å; C—H = 0.96–0.98 Å for Csp2 and Csp3 atoms, respectively), assigned fixed Uiso values [Uiso = 1.2 Ueq(Csp2/N) and 1.5 Ueq(Csp3)] and allowed to ride. H2D was found with O—H = 0.97 Å in the difference electron density map. The ethyl group labeled by C9 and C10 is disordered over two positions with occupancies of 0.741 (10) and 0.259 (10), and all disordered atoms were subjected to a rigid bond restraint. The minor disorder component was refined with isotropic displacement parameters.

Figures

Fig. 1.
The molecular structure of the title compound, showing the atomic numbering scheme with 30% probability displacement ellipsoids. All disorder components are shown.
Fig. 2.
The crystal packing of the title compound, viewed down the b axis, showing chains along the [100] direction. Hydrogen bonds are shown as dashed lines. The hydrogen atoms except for H1D and H2D are omitted. Only major disorder components are shown.

Crystal data

C14H19NO6Z = 2
Mr = 297.30F(000) = 316
Triclinic, P1Dx = 1.294 Mg m3
Hall symbol: -P 1Mo Kα radiation, λ = 0.71073 Å
a = 7.445 (4) ÅCell parameters from 2034 reflections
b = 9.864 (5) Åθ = 2.3–27.5°
c = 11.908 (2) ŵ = 0.10 mm1
α = 104.10 (3)°T = 291 K
β = 97.808 (9)°Block, colourless
γ = 111.658 (10)°0.36 × 0.30 × 0.28 mm
V = 763.2 (6) Å3

Data collection

Rigaku SCXmini diffractometer2969 independent reflections
Radiation source: fine-focus sealed tube2241 reflections with I > 2σ(I)
graphiteRint = 0.029
Detector resolution: 13.6612 pixels mm-1θmax = 26.0°, θmin = 3.0°
ω scansh = −9→9
Absorption correction: multi-scan (CrystalClear; Rigaku, 2005)k = −12→12
Tmin = 0.960, Tmax = 0.970l = −14→14
6950 measured reflections

Refinement

Refinement on F2Primary atom site location: structure-invariant direct methods
Least-squares matrix: fullSecondary atom site location: difference Fourier map
R[F2 > 2σ(F2)] = 0.063Hydrogen site location: inferred from neighbouring sites
wR(F2) = 0.197H-atom parameters constrained
S = 1.08w = 1/[σ2(Fo2) + (0.115P)2 + 0.1066P] where P = (Fo2 + 2Fc2)/3
2969 reflections(Δ/σ)max < 0.001
199 parametersΔρmax = 0.29 e Å3
2 restraintsΔρmin = −0.24 e Å3

Special details

Experimental. 1H NMR (DMSO-d6, p.p.m.): δ 1.17 (t, J = 7.0 Hz, 6H, CH2CH3), 2.21 (s, 6H, Me), 4.07 (m, J = 7.0 Hz, 4H, CH2CH3), 4.58 (s, 1H, CH), 8.84 (s, 1H, NH), 11.89 (S, 1H, OH). 13 C NMR (DMSO-d6, p.p.m.): δ 14.72 (CH2CH3), 18.39 (CH3), 39.71 (CH in dihydropyridine ring), 59.55 (CH2), 97.68, 146.27 (quaternary C in dihydropyridine ring), 167.33 (CO), 175.02 (COOH).
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.
Refinement. Refinement of F2 against ALL reflections. The weighted R-factor wR and goodness of fit S are based on F2, conventional R-factors R are based on F, with F set to zero for negative F2. The threshold expression of F2 > σ(F2) is used only for calculating R-factors(gt) etc. and is not relevant to the choice of reflections for refinement. R-factors based on F2 are statistically about twice as large as those based on F, and R- factors based on ALL data will be even larger.

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

xyzUiso*/UeqOcc. (<1)
C10.5752 (3)0.3833 (2)0.24556 (18)0.0403 (5)
H1A0.48910.40290.29680.048*
C20.5338 (3)0.4308 (2)0.13568 (18)0.0418 (5)
C30.7927 (3)0.4825 (2)0.31506 (19)0.0471 (5)
C40.9329 (3)0.4276 (3)0.29898 (19)0.0482 (5)
C50.6783 (3)0.1670 (2)0.19748 (19)0.0447 (5)
C60.5295 (3)0.2141 (2)0.21075 (17)0.0403 (5)
C71.1547 (3)0.5129 (3)0.3518 (3)0.0700 (7)
H7A1.18580.61680.39800.105*
H7B1.22230.51360.28870.105*
H7C1.19740.46270.40260.105*
C80.8460 (4)0.6388 (3)0.3946 (2)0.0691 (7)
C90.7022 (9)0.7955 (6)0.5064 (4)0.0796 (16)0.742 (10)
H9A0.83400.85140.56090.096*0.742 (10)
H9B0.60410.77520.55320.096*0.742 (10)
C100.6670 (9)0.8858 (5)0.4323 (6)0.109 (2)0.742 (10)
H10D0.67210.98020.48240.164*0.742 (10)
H10E0.53790.82810.37710.164*0.742 (10)
H10F0.76780.90850.38870.164*0.742 (10)
C110.6588 (4)0.0046 (3)0.1497 (3)0.0639 (7)
H11A0.5206−0.06590.12830.096*
H11B0.7320−0.01780.21000.096*
H11C0.7114−0.00590.08040.096*
C120.3169 (3)0.1123 (2)0.18269 (19)0.0439 (5)
C130.0631 (4)−0.1451 (3)0.1230 (3)0.0734 (8)
H13A−0.0118−0.12800.05880.088*
H13B0.0062−0.13150.19130.088*
C140.0555 (5)−0.3023 (3)0.0839 (4)0.0916 (11)
H14A−0.0808−0.37680.06180.137*
H14B0.1301−0.31770.14820.137*
H14C0.1121−0.31420.01640.137*
C9'0.7854 (18)0.8432 (14)0.4818 (12)0.065 (4)*0.258 (10)
H9'A0.88950.88310.55510.078*0.258 (10)
H9'B0.83640.89100.42380.078*0.258 (10)
C10'0.5997 (16)0.8597 (14)0.5033 (11)0.070 (4)*0.258 (10)
H10A0.63120.96620.54170.105*0.258 (10)
H10B0.54590.80090.55380.105*0.258 (10)
H10C0.50300.82270.42830.105*0.258 (10)
N10.8729 (2)0.2761 (2)0.23053 (18)0.0502 (5)
H1D0.96200.24840.20730.060*
O10.5162 (3)0.35326 (19)0.03480 (14)0.0690 (5)
O20.5283 (3)0.56518 (19)0.15897 (15)0.0760 (6)
H2A0.51440.58650.09690.114*
O31.0104 (4)0.7427 (3)0.4291 (3)0.1314 (12)
O40.6867 (3)0.6538 (2)0.42828 (16)0.0787 (6)
O50.1878 (2)0.16074 (18)0.18443 (16)0.0603 (5)
O60.2733 (2)−0.03741 (17)0.15535 (18)0.0639 (5)

Atomic displacement parameters (Å2)

U11U22U33U12U13U23
C10.0385 (10)0.0393 (10)0.0487 (11)0.0212 (8)0.0147 (8)0.0137 (8)
C20.0404 (10)0.0340 (10)0.0518 (12)0.0200 (8)0.0104 (8)0.0091 (9)
C30.0447 (11)0.0448 (11)0.0502 (12)0.0201 (9)0.0089 (9)0.0117 (9)
C40.0402 (11)0.0529 (12)0.0527 (12)0.0210 (9)0.0110 (9)0.0169 (10)
C50.0443 (11)0.0453 (11)0.0554 (12)0.0265 (9)0.0186 (9)0.0191 (9)
C60.0391 (10)0.0404 (10)0.0485 (11)0.0221 (9)0.0143 (8)0.0159 (9)
C70.0421 (12)0.0737 (17)0.0839 (18)0.0226 (12)0.0055 (11)0.0162 (14)
C80.0668 (16)0.0540 (14)0.0696 (16)0.0268 (13)−0.0015 (12)−0.0009 (12)
C90.102 (4)0.070 (3)0.062 (2)0.047 (3)0.017 (2)−0.004 (2)
C100.120 (4)0.052 (2)0.130 (5)0.029 (3)0.012 (4)0.007 (3)
C110.0567 (14)0.0494 (13)0.0981 (19)0.0345 (12)0.0273 (13)0.0212 (13)
C120.0423 (11)0.0406 (11)0.0555 (12)0.0228 (9)0.0169 (9)0.0160 (9)
C130.0475 (13)0.0486 (14)0.124 (2)0.0173 (11)0.0306 (14)0.0259 (15)
C140.0775 (19)0.0460 (14)0.148 (3)0.0191 (14)0.043 (2)0.0279 (17)
N10.0374 (9)0.0496 (10)0.0691 (12)0.0240 (8)0.0191 (8)0.0161 (9)
O10.1177 (15)0.0498 (9)0.0501 (10)0.0486 (10)0.0179 (9)0.0143 (8)
O20.1359 (18)0.0542 (10)0.0573 (10)0.0630 (12)0.0200 (10)0.0166 (8)
O30.0760 (15)0.0632 (14)0.184 (3)0.0120 (12)−0.0075 (16)−0.0318 (16)
O40.0949 (14)0.0754 (13)0.0623 (11)0.0545 (11)0.0071 (10)−0.0064 (9)
O50.0400 (8)0.0500 (9)0.0941 (13)0.0261 (7)0.0178 (8)0.0163 (8)
O60.0432 (8)0.0396 (8)0.1140 (14)0.0194 (7)0.0259 (9)0.0266 (9)

Geometric parameters (Å, °)

C1—C61.510 (3)C10—H10E0.9600
C1—C21.524 (3)C10—H10F0.9600
C1—C31.528 (3)C11—H11A0.9600
C1—H1A0.9800C11—H11B0.9600
C2—O11.217 (3)C11—H11C0.9600
C2—O21.304 (2)C12—O51.222 (2)
C3—C41.357 (3)C12—O61.332 (2)
C3—C81.472 (3)C13—O61.462 (3)
C4—N11.383 (3)C13—C141.483 (4)
C4—C71.505 (3)C13—H13A0.9700
C5—C61.363 (3)C13—H13B0.9700
C5—N11.378 (3)C14—H14A0.9600
C5—C111.508 (3)C14—H14B0.9600
C6—C121.465 (3)C14—H14C0.9600
C7—H7A0.9600C9'—C10'1.499 (15)
C7—H7B0.9600C9'—O41.649 (12)
C7—H7C0.9600C9'—H9'A0.9700
C8—O31.204 (3)C9'—H9'B0.9700
C8—O41.348 (3)C10'—H10A0.9600
C9—O41.432 (4)C10'—H10B0.9600
C9—C101.461 (8)C10'—H10C0.9600
C9—H9A0.9700N1—H1D0.8600
C9—H9B0.9700O2—H2A0.8200
C10—H10D0.9600
C6—C1—C2111.10 (16)H10E—C10—H10F109.5
C6—C1—C3111.42 (16)C5—C11—H11A109.5
C2—C1—C3108.83 (16)C5—C11—H11B109.5
C6—C1—H1A108.5H11A—C11—H11B109.5
C2—C1—H1A108.5C5—C11—H11C109.5
C3—C1—H1A108.5H11A—C11—H11C109.5
O1—C2—O2122.4 (2)H11B—C11—H11C109.5
O1—C2—C1122.99 (17)O5—C12—O6122.05 (19)
O2—C2—C1114.51 (17)O5—C12—C6122.53 (19)
C4—C3—C8121.5 (2)O6—C12—C6115.42 (17)
C4—C3—C1119.72 (19)O6—C13—C14106.9 (2)
C8—C3—C1118.72 (19)O6—C13—H13A110.3
C3—C4—N1119.07 (18)C14—C13—H13A110.3
C3—C4—C7127.0 (2)O6—C13—H13B110.3
N1—C4—C7113.86 (19)C14—C13—H13B110.3
C6—C5—N1118.93 (18)H13A—C13—H13B108.6
C6—C5—C11127.8 (2)C13—C14—H14A109.5
N1—C5—C11113.28 (17)C13—C14—H14B109.5
C5—C6—C12125.35 (19)H14A—C14—H14B109.5
C5—C6—C1120.07 (18)C13—C14—H14C109.5
C12—C6—C1114.31 (16)H14A—C14—H14C109.5
C4—C7—H7A109.5H14B—C14—H14C109.5
C4—C7—H7B109.5C10'—C9'—O497.3 (9)
H7A—C7—H7B109.5C10'—C9'—H9'A112.3
C4—C7—H7C109.5O4—C9'—H9'A112.3
H7A—C7—H7C109.5C10'—C9'—H9'B112.3
H7B—C7—H7C109.5O4—C9'—H9'B112.3
O3—C8—O4122.4 (3)H9'A—C9'—H9'B109.9
O3—C8—C3125.8 (3)C9'—C10'—H10A109.5
O4—C8—C3111.8 (2)C9'—C10'—H10B109.5
O4—C9—C10107.7 (4)H10A—C10'—H10B109.5
O4—C9—H9A110.2C9'—C10'—H10C109.5
C10—C9—H9A110.2H10A—C10'—H10C109.5
O4—C9—H9B110.2H10B—C10'—H10C109.5
C10—C9—H9B110.2C5—N1—C4123.75 (16)
H9A—C9—H9B108.5C5—N1—H1D118.1
C9—C10—H10D109.5C4—N1—H1D118.1
C9—C10—H10E109.5C2—O2—H2A109.5
H10D—C10—H10E109.5C8—O4—C9121.9 (3)
C9—C10—H10F109.5C8—O4—C9'97.6 (5)
H10D—C10—H10F109.5C12—O6—C13117.96 (17)
C6—C1—C2—O1−17.2 (3)C1—C3—C8—O3−158.8 (3)
C3—C1—C2—O1105.9 (2)C4—C3—C8—O4−160.1 (2)
C6—C1—C2—O2166.01 (18)C1—C3—C8—O422.5 (3)
C3—C1—C2—O2−70.9 (2)C5—C6—C12—O5−172.2 (2)
C6—C1—C3—C425.8 (3)C1—C6—C12—O51.8 (3)
C2—C1—C3—C4−97.1 (2)C5—C6—C12—O68.0 (3)
C6—C1—C3—C8−156.7 (2)C1—C6—C12—O6−177.98 (17)
C2—C1—C3—C880.4 (2)C6—C5—N1—C413.9 (3)
C8—C3—C4—N1175.1 (2)C11—C5—N1—C4−166.0 (2)
C1—C3—C4—N1−7.5 (3)C3—C4—N1—C5−14.1 (3)
C8—C3—C4—C7−2.6 (4)C7—C4—N1—C5163.9 (2)
C1—C3—C4—C7174.8 (2)O3—C8—O4—C90.8 (5)
N1—C5—C6—C12−178.35 (18)C3—C8—O4—C9179.6 (3)
C11—C5—C6—C121.5 (4)O3—C8—O4—C9'15.3 (6)
N1—C5—C6—C18.0 (3)C3—C8—O4—C9'−165.9 (5)
C11—C5—C6—C1−172.2 (2)C10—C9—O4—C889.7 (5)
C2—C1—C6—C595.5 (2)C10'—C9'—O4—C8172.6 (8)
C3—C1—C6—C5−26.0 (3)O5—C12—O6—C132.0 (3)
C2—C1—C6—C12−78.8 (2)C6—C12—O6—C13−178.2 (2)
C3—C1—C6—C12159.62 (17)C14—C13—O6—C12173.7 (2)
C4—C3—C8—O318.6 (5)

Hydrogen-bond geometry (Å, °)

D—H···AD—HH···AD···AD—H···A
N1—H1D···O5i0.862.173.018 (2)167
O2—H2A···O1ii0.821.822.641 (2)176

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

Footnotes

Supplementary data and figures for this paper are available from the IUCr electronic archives (Reference: KJ2129).

References

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  • Fleckenstein, A. (1977). Annu. Rev. Pharmacol. Toxicol.17, 149–166. [PubMed]
  • Fossheim, R., Svarteng, K., Mostad, A., Roemming, C., Shefter, E. & Triggle, D. J. (1982). J. Med. Chem.25, 126–131. [PubMed]
  • Heinrich, T., Burschka, C., Warneck, J. & Tacke, R. (2004). Organometallics, 23, 361–366.
  • Henry, G. D. (2004). Tetrahedron, 60, 6043–6061.
  • Rigaku (2005). CrystalClear Rigaku Corporation, Tokyo, Japan.
  • Sheldrick, G. M. (2008). Acta Cryst. A64, 112–122. [PubMed]
  • Triggle, A. M., Shefter, E. & Triggle, D. J. (1980). J. Med. Chem.23, 1442–1445. [PubMed]

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