Synthesis, Characterization, and Single Crystal Structure of 4-(3-methoxy-4-(prop-2-yn-1-yloxy)phenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarbonitrile

Contents

1 Introduction
1.1 Experimental
1.3 X-ray Diffraction Data
1.4 Experimental Details
1.5 Crystal Structure Images
1.6 Packing diagram of the molecules when viewed down the b axis.
1.7 Representative spectrums
1.8 References

Acknowledgement

Firstly, I would like to thank Prof. Anamik Shah, Department of Chemistry, Saurashtra University for giving me an opportunity to carry out work in his laboratory under his guidance. His wide knowledge in the field of Chemistry research and X-Ray logical way of thinking has been of great value for me to accomplish this chapter work. I am deeply grateful to the Institute for the trust and support that they gave me in order to study in Single Crystal X-Ray Instrumentation, SCX-mini model, Rigaku Company at National Facility for Drug Discovery Complex, Department of Chemistry, Saurashtra University, Rajkot, India.

I owe my special thanks to my beloved wife, Bhawati Gauni Mehariya. My special gratitude is due to my parents, my sisters and their families for their loving support, inspiration to do my best in all matters of life. To them I dedicate this Chapter.

Krunal Mehariya

1 Introduction

The ability of 1,4-Dihydropyride and its derivatives represent an important class of heterocycles. The synthesis of novel 1,4-Dihydropyride derivatives have gained more importance in recent decades such as, multi drug resistance (mdr) reversal in tumor cell [¹ -² ], antitubercular ³, potential immunomodulating ⁴ as well. Dihydropyridine core a vital class of Ca+2 channel blockers such as Nifedipin and Amlodipine, which are clinically effective in hypertension ⁵. 1,4-Dihydropyridines were first successfully synthesized by Hantzsch ⁶ using a aldehydes, ammonia and ketoester, under reflux in methanol or ethanol which takes longer time with low yields[⁷ -⁸ ].

Over the few years, an increasing interest has been persistent on the synthesis of dicyano substitutions on C3 and C5 positions of DHP ring [⁹ -¹⁰ ].

1.1 Experimental

1.1.1 Analysis Protocol

The melting point was determined in an open capillary melting point apparatus. The IR was recorded on Shimadzu FTIR-8400 spectrometer (KBr Pellet method, 400–4000 cm-1). 1H and 13C NMR spectrum was recorded on a Bruker AC 400 MHz using TMS as an internal standard and DMSO-d6 as solvent (chemical shifts are in ppm and coupling constant J in Hz). Mass spectrum was obtained using a Jeol SX 102/DA-6000 spectrometer (for FAB). TLC was performed on 0.25 mm pre-coated silica gel plates (Merck 60 F254) by using ethyl acetate/hexane (1:9) as the eluents.

1.1.2 Reaction Scheme of (3-methoxy-4-(prop-2-yn-1yloxy)phenyl)-2,6-dimethyl-1,4dihydropyridine-3,5-dicarbonitrile

Abbildung in dieser Leseprobe nicht enthalten

1.1.3 Preparation of (3-methoxy-4-(prop-2-yn-1yloxy)phenyl)-2,6-dimethyl-1,4dihydropyridine-3,5-dicarbonitrile

The present work, reports synthesis and crystal structure of 4-(3-methoxy-4-(prop-2-yn-1yloxy)phenyl)-2,6-dimethyl-1,4dihydropyridine-3,5-dicarbonitrile (3) studied in this work was synthesized from a 3-methoxy-4-(prop-2-yn-1 yloxy) benzaldehyde (1) with (Z)-3-aminobut-2-enenitrile in glacial acetic acid solvent at 60 °C for 30 minute. Reaction was completed as monitored by TLC, the reaction product was filtered to obtain crude product. The precipitate was filtered and recrystallized with ethanol to get pure product. The physical and spectral data of compound are as follow: colorless crystal, yield 90% ; m.p. 180-182 °C.

1.2 Spectral Discussion

1.2.1 IR Spectra

IR spectra of the synthesized compounds were recorded on Shimadzu FT-IR 8400 model using KBr Powder method. Various functional groups present were identified by characteristic frequency obtained for them. Aromatic -CH bond stretching and bending frequencies showed between 3060-3040 cm-1 and 1610-1420 cm-1 respectively. The –CH bond stretching and bending frequencies for –CH3 and –CH2 group were obtained near 2960-2890 cm-1 and 1460-1380 cm-1. The stretching frequency of the characteristic band of secondary N-H group showed in the region of 3500-3210 cm-1 with a deformation due to in plane bending at 1660-1570 cm-1. C-O stretching frequency showed at 1230-1140 cm-1. Characteristic frequency of -C≡N bond showed at 2250-2210 cm-1. Characteristic frequency of C-N stretching showed near 1360-1290 cm-1.

1.2.2 Mass Spectra

Mass spectra of the synthesized compounds were recorded on Shimadzu GC-MS-QP- 2010 model using Direct Injection Probe technique. The molecular ion peak was found in agreement with molecular weight of the respective compound.

1.2.3 1H NMR Spectra

1H NMR spectra of the synthesized compounds were recorded on Bruker Avance II 400 MHz NMR Spectrometer by making a solution of samples in DMSO-d6/CDCl3 solvent using tetramethylsilane (TMS) as the internal standard unless otherwise mentioned. Number of protons identified from 1H NMR spectra and their chemical shift (δ ppm) were in the agreement of the structure of the molecule. J values were calculated to identify o, m and p coupling. In some cases, aromatic protons were obtained as multiplet. Interpretations of representative spectra are discussed as under.

1.2.4 13C NMR Spectra

13C NMR spectra of the synthesized compounds were recorded on Bruker Avance II 400 MHz NMR Spectrometer by making a solution of samples in DMSO- d6 /CDCl3 solvent using tetramethylsilane (TMS) as the internal standard unless otherwise mentioned. Types of carbons identified from NMR spectrum and their chemical shifts (δ ppm) were in the agreement with the structure of the molecule.

1.2.5 Spectral Analysis of (3-methoxy-4-(prop-2-yn-1yloxy)phenyl)-2,6-dimethyl-1,4dihydropyridine-3,5-dicarbonitrile

MS (EI) (m/z): 319; IR (KBr pellet, ν; cm-1): 3340 (-NH starching), 3217 (Ar C=C-H starching), 2206 (C≡N starching), 1666 (N-H bend), 1597, 1504, 1427 (Ar C=C starching), 1427 (-CH bending –CH2), 1375 (C-H bend –CH3), 1340 (C-N sec amine vib), 1118 (C-O starching), 864 (-CH overlap); 1H NMR (400 MHz, δ, ppm, DMSO– d 6): 9.50 (s, 1H, CH), 7.06-7.04 (d, 1H, J = 8.04 Hz, Ar-H), 6.87 (s, 1H, Ar-H), 6.80-6.78 (d, 1H, j = 7.84, Ar-H), 4.79 (s, 2H, CH2), 4.36 (s, 1H, CH), 3.77 (s, 3H, CH3), 3.41 (s, 1H, NH), 2.04 (s, 6H, 2 × CH3); 13C NMR (100 MHz, δ, ppm) 149.11, 146.44, 145.90, 137.75, 119.63, 119.35, 114.13, 111.52, 82.75, 79.33, 78.26, 55.95, 17.73.

1.2.6 Preparation of Single Crystals of (3-methoxy-4-(prop-2-yn-1yloxy)phenyl)-2,6-dimethyl-1,4dihydropyridine-3,5-dicarbonitrile

The Single spot compound of (3-methoxy-4-(prop-2-yn-1yloxy)phenyl)-2,6-dimethyl-1,4dihydropyridine-3,5-dicarbonitrile (500 mg) was taken in 20 mL glacial acetic acid and heated to 60 ºC for 10-15 minutes till it dissolved. 200 mg Charcoal was added and further it was heated up to 60 ºC for 5-10 minutes. The hot solution was filtered through Celite pad covered by wattmann 41 filter paper. The solution was allowed to cool gradually and kept in a stoppered 100 conical flask slightly opened. The crystals were grown up due to thin layer evaporation.

1.3 X-ray Diffraction Data for (3-methoxy-4-(prop-2-yn-1yloxy)phenyl)-2,6-dimethyl-1,4dihydropyridine-3,5-dicarbonitrile

A colorless block crystal of C19H17N3O2 having approximate dimensions of 0.550 × 0.300 × 0.300 mm was mounted on a glass fiber. All measurements were made on a Rigaku SCX mini diffractometer using graphite monochromated Mo-Kα radiation. The crystal-to-detector distance was 52.00 mm.

The crystallographic data analysis reveals that crystallizes in the triclinic crystal system, space group, a = 9.1875(8) Å, b = 10.0894(9) Å, c = 10.4209(9) Å, α = 84.555(3)°, β = 73.300(3)°, and γ = 67.740(3)°, Z = 2, V= 856.2(2) Å3, ρcalc= 1.239 g/cm3, space group P-1 (#2). Data Reduction of the 8679 reflections that were collected, 3873 were unique (Rint = 0.0174); equivalent reflections were merged.

Data were collected and processed using Crystal Clear ¹¹. The linear absorption coefficient, µ, for Mo-Kα radiation is 0.824 cm-1. An empirical absorption correction was applied which resulted in transmission factors ranging from 0.834 to 0.976. The data were corrected for Lorentz and polarization effects.

The structure was solved by direct methods ¹² and expanded using Fourier techniques. The non-hydrogen atoms were refined anisotropically. Hydrogen atoms were refined using the riding model. The final cycle of full-matrix least-squares refinement ¹³ on F2 was based on 3873 observed reflections and 217 variable parameters and converged. The standard deviation of an observation of unit weight4 was 1.60. Unit weights were used. The maximum and minimum peaks on the final difference Fourier map corresponded to 0.39 and -0.34 e /Å3, respectively.

Neutral atom scattering factors were taken from Cromer and Waber ¹⁴. Anomalous dispersion effects were included in Fcalc ¹⁵ ; the values for Δf' and Δf" were those of Creagh and McAuley ¹⁶.

The values for the mass attenuation coefficients are those of Creagh and Hubbell ¹⁷. All calculations were performed using the Crystal Structure ¹⁸ crystallographic software package except for refinement, which was performed using SHELXL-97 ¹⁹.

1.4 Experimental Details

A. Crystal Data

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B. Intensity Measurements

Abbildung in dieser Leseprobe nicht enthalten

C. Structure Solution and Refinement

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[...]

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⁷. Zenouz, A. M.; Oskuie, M. R.; Mollazadeh, S.; Synthesis of novel asymmetrical 1,4-dihydropyridine derivatives. Synth. Commun. 2005, 35(22), 2895-2903.

⁸. Zenouz, A. M.; Oskuie, M. R.; Mollazadeh, S.; Synthesis of novel asymmetrical 1,4-dihydropyridine derivatives. Synth. Commun. 2005, 35(22), 2895-2903.

⁹. Zenouz, A. M.; Allahverdi, S. S.; Raissossadat, M.; Sadeghi, Q. Synthesis of the C-2 functionalized 1,4- dihydropyridines. Asian J. Chem. 2005, 17(4), 2639- 2643.

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¹¹. CrystalClear: Rigaku Corporation, 1999. CrystalClear Software User's Guide, Molecular Structure Corporation,(c) 2000.J.W.Pflugrath (1999) Acta Cryst. D55, 1718-1725.

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¹³. Least Squares function minimized: (SHELXL97) o2-Fc2)2 where w = Least Squares weights.

¹⁴. Standard deviation of an observation of unit weight: - o2-Fc2)2/(No-Nv)]1/2 Where: No = number of observations, Nv = number of variables

¹⁵. Cromer, D. T. & Waber, J. T.; "International Tables for X-ray Crystallography", Vol. IV, The Kynoch Press, Birmingham, England, Table 2.2 A (1974).

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¹⁷. Creagh, D. C. & McAuley, W.J .; "International Tables for Crystallography", Vol C, (A.J.C. Wilson, ed.), Kluwer Academic Publishers, Boston, Table 4.2.6.8, pages 219-222 (1992).

¹⁸. Creagh, D. C. & Hubbell, J.H..; "International Tables for Crystallography", Vol C, (A.J.C. Wilson, ed.), Kluwer Academic Publishers, Boston, Table 4.2.4.3, pages 200-206 (1992).

¹⁹. CrystalStructure 4.0: Crystal Structure Analysis Package, Rigaku Corporation (2000-2010). Tokyo 196-8666, Japan.