Synthesis , characterization and crystal structure of pentyl 2-( 1 H-indole-2-carboxamido ) benzoate

Article history: Received November 21, 2018 Received in revised form November 21, 2018 Accepted December 28, 2018 Available online December 28, 2018 Pentyl 2-(1H-indole-2-carboxamido)benzoate (5) is obtained in good yield as stable crystals by reaction of pentyl 2-amino benzoate (6) with indole-2-carbonyl chloride acid (7) in the presence of pyridine. The crystal structure of 5 confirms the presence of intramolecular hydrogen bonding (N-H...O) which produces a six-membered ring, and the molecules are linked together by intermolecular hydrogen forces (N-H...O). © 2019 by the authors; licensee Growing Science, Canada.


Introduction
Heterocyclic moieties are present in a wide variety of drugs, due to their remarkable medicinal properties.2][3][4] Amide bond formation utilizes either the reaction of carboxylic acid derivatives with amines in the presence of bases, such as triethylamine or pyridine.These reactions are called indirect amidation. 5Alternatively, direct amidation utilizes reactions of free carboxylic acid with amines through thermal direct reaction or by using a metal-catalyst. 6In continuation of our further search for new derivatives of heterocyclic moieties, [2][3][4]7 we report herein the synthesis and full characterization of compound 5 (Fig. 1).

Results and Discussion
Compound 5 was prepared by reacting 6 with 7 in dry chloroform and in the presence of dry pyridine which was employed as base and catalyst, as shown in Scheme 1. Fischer esterification of 2aminobenzoic acid with 1-pentanol, in the presence of sulfuric acid, afforded compound 6.It is worthy to mention that the reaction of isatoic anhydride with 1-pentanol produced 6. 8 On the other hand, compound 7 was used rather than the indole-2-carboxylic acid itself, since it is more reactive towards nucleophilic acyl substitution reaction, in particular, if the nucleophile (such as aromatic amine) is weak.Pyridine was employed in this type of reaction to trap the evolved hydrogen chloride gas by forming pyridinium chloride salt, which also helps in the conversion of 7 into more reactive species (pyridium adduct) towards nucleophilic acyl substitution reaction.This approach of synthesis has many advantages such as good yield is usually obtained and milder experimental conditions can be used.In contrast to other methodologies that used ester derivatives instead of acyl halides as reactant, strong base (e.g. sodium alkoxide) in refluxing DMF for long time is usually preferred and the yield is even low.On the other hand, coupling agent should be employed when carboxylic acid itself is acting as a starting material to form the amide group.In 1 H NMR spectrum of 5, signals of aliphatic protons have been observed in the range 0.8 -5 ppm, while the signals of two protons in both N-H groups were highly deshielded (11-12 ppm) in deuterated DMSO solvent due to intra-hydrogen bonding with solvent molecules.On the other hand, the carbon atom of the amide group resonates, as expected, at 160.1 ppm in 13 C-NMR spectrum; other peaks are observed in the expected ranges.The results of DEPT experiments are in conformity with the proposed structure, four methylene groups (CH2) show down peaks at four different positions.Further, the mass spectrum of compound 5 displays the correct molecular ion peaks for which the measured HRMS data are in good agreement with the calculated values.Elemental analysis data assures the purity of the product.

Description of the Crystal Structure
Single X-ray crystallography measurements show that 5 crystallizes in the monoclinic system, with space group P21/m and crystallographic data are listed in Table 1.The asymmetric unit of 5 (Fig. 2) contains one molecular unit.Crystal structure of 5 reveals the presence of intramolecular N-H…O bond [O(2)…H(2) 1.918, N(2)…H(2) 0.859 Å, N(2)-H(2)…O(2) 139.2°].As expected, the bond length of C(10A)-O(1), in the amide group, is slightly longer than that of C(11A)-O(2), in the ester group, (1.220 compared to 1.204 Å); this is due to the resonance effect in the amide group.
Intramolecular hydrogen bonding forms six-membered ring, in which the amide NH group is considered as proton donor and the oxygen atom of the carbonyl of the ester group as proton acceptor.The indolic NH proton is involved in intermolecular hydrogen bonding to the oxygen atom (of the amide group) of an adjacent molecule leading to a polymeric chain structure (Fig. 3

Conclusions
The target compound 5 has been successfully prepared in reaction which follows the mechanism of nucleophilic acyl substitution of acyl chloride (7) and aromatic primary amine (6).Hydrogen-bond donor (N-H) and hydrogen-bond acceptor (C=O) functional groups were incorporated into its structure.The structure of the target product was fully characterized.Further, X-ray structural analyses of 5 shows that there are intra and inter hydrogen bonding forces.
(HPLC grade Acros).Compound 7 was prepared according to the published procedure. 3Chloroform (Labchem) was purified by stirring under anhydrous sodium sulfate overnight then distilled.NMR analysis was done using Bruker-Avance III 500 MHz spectrometers with TMS as the internal standard.Coupling constant (J) values are given in Hertz (Hz).High resolution mass spectra (HRMS) were measured (in positive ion mode) using electrospray ion trap (ESI) technique by collision-induced dissociation on a BrukerAPEX-4 (7 Tesla) instrument.The FT-IR measurements (500-4000 cm -1 ) were recorded using ThermoNicolet 670 FT-IR spectrophotometer.Thin Layer Chromatography (TLC) was performed using Merck aluminum plates pre-coated with silica gel PF254; (20 x 20) cm x 0.25 mm, and detected by visualization of the plate under UV lamp (ƛ = 254 nm).Melting point was measured with an SMP 10 Stuart apparatus.Elemental analysis was obtained using Euro Vector Elemental analyzer model EUROEA3000 A, (Redavalle), Italy.Single-crystal X-ray diffraction data were collected using an Oxford Diffraction XCalibur, equipped with (Mo) X-ray Source (λ = 0.71073 Å) at 293(2) K.

Crystallographic Data
Crystals of 5 were obtained by slow evaporation of a CH2Cl2 solution of 5. Data collection, reduction, and cell refinement were performed using the software package CrysAlisPro. 9Analytical absorption corrections were applied using spherical harmonics implemented in SCALE3 (ABSPACK) scaling algorithm.Crystal structure was solved by direct methods, using the program OLEX2, followed by Fourier synthesis, and refined on F 2 with SHELXL-97. 10Anisotropic least-squares refinement of non-H atoms was applied.All crystallographic plots were obtained using the Diamond program. 11A summary of the crystallographic data and structure refinement parameters is given in Table 1.