Open Access

Synthesis and crystal structures of 2-methyl-4-aryl-5-oxo-5H-indeno [1,2-b] pyridine carboxylate derivatives

  • Ramesh Pandian1, 2,
  • Edayadulla Naushad3,
  • Vinodhkumar Vijayakumar4,
  • Günther H Peters5 and
  • Ponnuswamy Mondikalipudur Nanjappagounder1Email author
Contributed equally
Chemistry Central Journal20148:34

https://doi.org/10.1186/1752-153X-8-34

Received: 20 February 2014

Accepted: 9 May 2014

Published: 29 May 2014

Abstract

Background

Hantzsch 1,4-dihydropyridines (Hantzsch1,4-DHP) have been extensively utilized as the analogs of nicotinamide adenine dinucleotide (NADH) coenzyme to study the mechanism and various redox processes. During the redox processes 1,4-DHP systems undergo transformation into the corresponding pyridine derivatives through oxidation. Consequently, the interest in this aromatization reaction, investigation of a wide range of 1, 4-DHPs continues to attract the attention of researchers. Herein, we report the preparation of pyridine derivatives and the crystal structures determined by X-ray crystallographic methods.

Results

The crystal structures and conformational studies of two organic compounds, namely ethyl 2-methyl-4-phenyl-5-oxo-5H-indeno [1,2-b] pyridine-3-carboxylate (I) and ethyl 2-methyl-4-(4 chlorophenyl)-5-oxo-5H-indeno [1,2-b] pyridine-3-carboxylate (II) are reported. The terminal ethyl group of the compound I is disordered over two positions with the refined occupancies of 0.645 & 0.355 and C8 one dimensional zig-zag chain running along 101 direction through C-H…O type of intermolecular interactions. In the compound II, C-H…O interactions connect the molecules to form an R22 (16) dimer running along 011 direction.

Conclusion

The crystal structures ethyl 2-methyl-4-phenyl-5-oxo-5H-indeno [1,2-b] pyridine-3-carboxylate and ethyl 2-methyl-4-(4 chlorophenyl)-5-oxo-5H-indeno [1,2-b] pyridine-3-carboxylate have been investigated in detail. The terminal ethyl group of compound I is disordered. In compound II, the substitution of Cl atom in the phenyl ring alters the configuration of carboxylate group with respect to the pyridine indane ring.

Background

Hantzsch 1,4-dihydropyridines (Hantzsch1,4-DHP) have been extensively utilized as the analogs of nicotinamide adenine dinucleotide (NADH) coenzyme to study the mechanism and the synthetic potential of various redox processes [1, 2]. Hantzsch 1,4-DHP based drugs such as nifedipine and niguldipine are widely used as calcium channel blockers for the treatment of cardiovascular disorders including angina, hypertension and cardiac arrhythmias [3]. During the redox processes and in the course of drug metabolism [4], 1,4-DHP systems are oxidatively transformed into the corresponding pyridine derivatives. Consequently, this aromatization reaction continues to attract the attention of researchers to establish a general protocol applicable to a wide range of 1,4-dihydropyridines. A number of methods and reagents have been reported recently in the literature for this purpose [514].

Some of these methods suffer from disadvantages such as the use of strong or toxic oxidants, the requirement of severe conditions or need excess of the oxidants. Other drawbacks are the long reaction times, production of by-products, the lower yields of products and/or the requirement of tedious work-up procedures.

N-Bromosuccinimide (NBS) is a versatile reagent for the oxidation of primary and secondary alcohols, α-hydroxycarboxylic acids [15], α-hydroxycarboxylic esters [16], hydrazines and hydrazones [15]. In addition, NBS is preferred for allylic bromination. While hydroxy acids like malic acid, tartaric acid, citric acid etc. are converted to aldehydes and ketones, polyhydric alcohols (glycol, glycerol and hexitols) are quantitatively decomposed to carbon dioxide and water [17] with NBS. NBS also promotes reactions of sterically hindered cresols via p-benzoquinone methide [18].

Having synthesized a number of 1, 4-dihydropyridines derived from indane-1,3-dione, we have dehydrogenated them to the corresponding pyridines. The reagent of the choice for effecting dehydrogenation is NBS in methanol (Schemes 1 and 2). This reagent was earlier employed to effect dehydrogenation of simple dihydropyridines [19].
Scheme 1

Synthesis scheme of the dihydropyridines.

Scheme 2

Synthesis scheme of the compounds I and II.

Experimental

The title compounds reported in the present work were prepared by the following procedure [19, 20].

Preparation of 4a-b

To an alcoholic solution (50 mL) of indane-1,3-dione 2 (0.01 mol), appropriate aromatic aldehydes 1a-b (0.01 mol), ethyl acetoacetate 3 (0.01 mol), ammonium acetate (0.02 mol) and a drop of piperidine were added and the mixture was refluxed for 1 hr. The reaction mixture was concentrated to half of its original volume and allowed to cool in an ice-chest. The solid 4a-b thus separated was filtered, washed with ice cold aqueous ethanol and crystallized from petroleum ether (60–80°C)-chloroform (1: 1) (Scheme 1).

Preparation of 5a-b

To a solution of ethyl 2-methyl-4-aryl-5-oxo-1H,4H-indeno [1,2-b] dihydropyridine-3-carboxylate 4a-b (0.5 g, 1.87 mmol) in methanol (10.0 mL), N-bromosuccinimide (0.33 g, 1.87 mmol) was added and the reaction mixture was stirred at room temperature. The colour of the solution changes immediately and the reaction proceeds instantaneously within five minutes. The course of the reaction was monitored by TLC. The reaction mixture was diluted with water (50 mL) and extracted with chloroform (3 × 20 mL). The organic layer was separated, dried over anhydrous sodium sulfate and filtered (Scheme 2). Evaporation of the solvent afforded the products ethyl 2-methyl-4-phenyl-5-oxo-5H-indeno [1,2-b] pyridine-3-carboxylate (Scheme 3) or ethyl 2-methyl-4-(4-chlorophenyl)-5-oxo-5H-indeno [1,2-b] pyridine-3-carboxylate respectively in excellent yields (Scheme 4). For compound (5a): Yield 96%; M.p. 212˚C. For compound (5b): Yield 89%; M.p. 198˚C.
Scheme 3

Scheme showing the structural formula of compound I.

Scheme 4

Scheme showing the structural formula of compound II.

Results and Discussion

In both the compounds, the indenopyridine ring is almost planar, with r.m.s deviation of 0.035(2) Å [C3] and 0.087(2) Å [C11] for compounds I and II, respectively. The keto atom O substituted in the indenopyridine in both the molecules are slightly out of plane [0.048(2) & 0.217(1) Å for I & II]. The substitution of the Cl atom in the phenyl ring plays a vital role while packing the molecules in the unit cell and promotes the change of conformation of the carboxylate group. This is evidenced from the torsion angle values of [C10-C11-15-O2] and [C12-C11-C15-O2] 114.5(2)° & -63.5(2)° for (I) and −74.9(2)° & 114.0(1)° for (II), respectively. The terminal ethyl group in compound I is disordered over two positions with refined occupancies of 0.645 & 0.355. The phenyl ring and indenopyridine rings are oriented by an angle of 67.8(1)˚ in compound (I) which is almost similar in compound (II) amounting the value of 55.2(1)˚. The overall conformations in both the molecules are similar as can be seen from the superimposed rmsd value 0.154 Å (Figure 1). Both the structures are stabilized by C-H…O type of intra and intermolecular interactions. In compound I, molecules at (x, y, z) and (x + 1/2, −y − 1/2, z + 1/2) are linked through intermolecular C20-H20…O1 hydrogen bond to form a C8 zig-zag chain (Figure 2) running along 101 direction [21]. The combination of C5-H5…O3 and C22-H22…O1 intermolecular hydrogen bonds, lead to the formation of a R22 (16) ring motif chain running along [0 1 1] direction (Figure 3), observed in compound II.
Figure 1

The conformation of both the molecules, as seen from the superimposition of the planar indenopyridine rings.

Figure 2

Figure showing the intermolecular hydrogen bonds resulting in C8 zig-zag motif in compound (I).

Figure 3

Figure showing the intermolecular hydrogen bonds resulting in R 2 2 (16) ring motifs chain running along 0 1 1 direction in compound (II).

X-ray Crystallography

Single crystal X-ray intensity data for the compounds (I) and (II) were collected using a Bruker Kappa APEX II area-detector diffractometer with MoKα (0.71073 Å) radiation at room temperature (293 K). The data reduction was carried out using the program SAINT [22]. The absorption corrections were applied using the Multi-scan method using SADABS program [23]. The structures of both the compounds were solved by direct methods using SHELXS97 [24] and all the non-hydrogen atoms were refined anisotropically by full-matrix least-squares on F2 taking all the unique reflections using SHELXL97 [24]. The hydrogen attached with carbon atoms were placed in their calculated positions and included in the isotropic refinement using the riding model with C–H = 0.93 Å (−CH) or 0.97 Å (−CH2) Å or 0.96 Å (−CH3) Å with Uiso (H) = 1.2Ueq (parent C atom). The crystal data, experimental conditions and structure refinement parameters for the compounds (I) and (II) are presented in Table 1. Table 2 gives the geometry of the intra and intermolecular interactions. The molecular structure of compounds (I) and (II) with the atom numbering scheme using ORTEP3 [25] are given in Figure 4 and Figure 5, respectively. The least-squares plane, geometrical and puckering parameters of both the compounds were calculated using PLATON software package [2628].
Table 1

The crystal data, experimental conditions and structure refinement parameters for the compounds (I) and (II)

Parameters

Compound (I)

Compound (II)

Empirical formula

C22H17NO3

C22H16ClNO3

Formula weight

343.37

377.81

Wavelength

0.71073 Å

Crystal system, space group

Monoclinic, P21/n

Triclinic, P-1

Unit cell dimensions

a = 7.5078(5) Å

a = 9.7750(8) Å; α = 113.199(2)˚

b = 21.0935(15) Å

b = 9.8262(4) Å; β = 102.572(3)˚

c = 11.5058(3) Å

c = 10.8687(5) Å; γ = 99.791(3)˚

β = 104.876(2)˚

Volume

1761.1(2) Å3

897.65(9) Å3

Z, Calculated density

4, 1.295 g/cm3

2, 1.398 g/cm3

Absorption coefficient

0.086 mm−1

0.236 mm−1

F (000)

720

392

Crystal size

0.23 × 0.20 × 0.19 mm3

0.22 × 0.18 × 0.17 mm3

Theta range for data collection

1.93 to 30.48˚

2.15 to 30.99˚

Limiting indices

−10 ≤ h ≤ 10, −30 ≤ k ≤ 30, −15 ≤ l ≤ 16

−13 ≤ h ≤ 14, −14 ≤ k ≤ 14, −15 ≤ l ≤ 15

Reflections collected/unique

5323/2998

5580/4173

[R (int) = 0.032]

[R (int) = 0.0261]

Completeness

99.4%

97.5%

Absorption correction

Multi-scan

Refinement method

Full-matrix least-squares on F2

Data/restraints/parameters

2998/0/238

5580/0/244

Goodness-of-fit on F2

1.008

1.051

Final R indices [I > 2σ (I)]

R1 = 0.0574, wR2 = 0.1494

R1 = 0.0464, wR2 = 0.1334

R indices (all data)

R1 = 0.1047, wR2 = 0.1819

R1 = 0.0638, wR2 = 0.1470

Extinction coefficient

0.0098(18)

0

Largest diff. peak and hole

0.333 and −0.240 e.Å−3

0.393 and −0.332 e.Å−3

Table 2

The geometry of the hydrogen bonds (Å, ˚)

D-HA

D (D-H)

D (HA)

D (DA)

<(DHA)

Compound (I)

C (20) -H (20)…O (1)i

0.93

2.40

3.232(3)

149

Compound (II)

C (14)-H (14A)…O (2)

0.96

2.44

3.132(2)

128

C (5)-H (5)…O (3)ii

0.93

2.60

3.472(2)

157

C (22)-H (22)…O (1)iii

0.93

2.58

3.458(2)

157

C (16) -H (16A)…Cg(3)iv

0.97

2.72

3.566(2)

146

Symmetry transformations used: (i) x + 1/2, −y − 1/2, z + 1/2; (ii) x, y-1, z-1; (iii) 1-x,-y,-z;(iv) -x,-y,-1-z; Cg3 centroid atom of the ring (C2-C7).

Figure 4

ORTEP plot of compound (I) showing with atoms ellipsoids are drawn at 40% probability level.

Figure 5

ORTEP plot of compound (II) showing with atoms ellipsoids drawn at 40% probability level.

Conclusions

The title compounds were synthesized, crystallized and the crystal structures have been determined by single-crystal X-ray diffraction methods. The terminal ethyl group of the compound I is disordered over two positions with the refined occupancies of 0.645 & 0.355. C-H…O intermolecular hydrogen bond builds up a one dimensional zig-zag chain running along 101 directions. In compound II, C-H…O hydrogen bonds connect the molecules to form a R22 (16) dimer chain running along 011 direction.

Notes

Declarations

Acknowledgements

One of the authors NE is grateful to Mother Teresa Women’s University, Kodaikanal, Tamilnadu-India and DST-CURIE programme for their encouragement and providing facilities for doing this research work. NE also put forth his heartfelt thanks to his guide Dr. P. Ramesh (Late) for the encouragement and motivation of the research work. PR thanks Prof. Kyeong Kyu Kim, Laboratory of Structural Biology, Department of Molecular Cell Biology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon 440–746, South Korea and the National Research Foundation of Korea for the financial support in the form of postdoctoral fellowship (2012K2A4A1034867 and 2011–0030915).

Additional material

Crystallographic data (excluding structure factors) for the structures of compounds (I) and (II) reported in this paper have been deposited with the Cambridge Crystallographic Data Centre as supplementary publication numbers, CCDC 996464 and CCDC 996465, respectively. Copies of the data can be obtained free of charge, on application to CCDC, 12 Union Road, Cambridge CB2 1 EZ, UK. (fax: +44-(0)1223-336033 or email: deposit@ccdc.cam.ac.uk).

Authors’ Affiliations

(1)
Centre of Advanced Study in Crystallography and Biophysics, University of Madras
(2)
Laboratory of Structural Biology, Department of Molecular Cell Biology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine
(3)
Department of Chemistry, Mother Teresa Women’s University
(4)
Department of Life Sciences and Chemistry, Roskilde University
(5)
Department of Chemistry, Technical University of Denmark

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