Synthesis and Crystal Structure of N-(2-(1,3,4-oxadiazol-2-yl)phenyl)-2,3-dimethylaniline①

Ali Soulozi Seye Hami Reza Shojaei Ali Ramazani Katarzyna Ślepokura Taeusz Lisa (Department of Chemistry, Urmia Branh, Islami Aza University, P. O. Box 969, Urmia, Iran) (Department of Physis, Urmia Branh, Islami Aza University, P. O. Box 969, Urmia, Iran) (Department of Chemistry, Zanjan Branh, Islami Aza University, P. O. Box 49195-467, Zanjan, Iran) (Faulty of Chemistry, University of Wroław, 14 Joliot-Curie St., 50-383 Wroław, Polan)

1 INTRODUCTION

1,3,4-Oxadiazoles are an important class of heterocyclic compounds with broad spectrum of biological activities[1-3]. Substituted 1,3,4-oxadiazoles have revealed anticancer[4-5], antitumor[6], anti-HIV[7-8], antibacterial[9], antimycobacterial[10-19],antifungal[20], anti-inflammatory[21,22], analgesic[23],anticonvulsant[24], antitubercular[25-27], antiurease[28],antioxidant[29]and insecticidal[30]properties.

Several methods have been reported in literature for the synthesis of 1,3,4-oxadiazoles. These protocols are multistep in nature. The most general method involves the cyclization of diacyl hydrazides with a variety of reagents, such as SOCl2, POCl3, or H2SO4, usually under harsh reaction conditions. Few reliable and operationally simple examples have been reported for the one-pot synthesis of 1,3,4-oxadiazoles, especially from readily available carboxylic acids and acid hydrazides[31-35].

In recent years, several synthetic methods have been reported for the preparation of (N-isocyanimino)triphenylphosphorane (CNNPPh3). There are several reports on the use of 2 in the synthesis of metal complexes[36-37]. However, the application of 2 in synthesizing organic compounds is rather rare[38-51].

As part of our ongoing program to develop efficient and robust methods for the preparation of heterocyclic compounds[38-51], we sought to examine the reaction of 2-aminobenzoic acid (1) with (N-isocyanimino)triphenylphosphorane (2) (Scheme 1).In this paper, we describe the synthesis and crystal structure of N-(2-(1,3,4-oxadiazol-2-yl)phenyl)-2,3-dimethylaniline.

2 EXPERIMENTAL

2.1 Reagents and physical measurements

Starting materials and solvents were obtained from Merck (Germany) and Fluka (Switzerland) and were used without further purification. TLC and NMR indicated that there is no side product.Melting points were measured on an Electrothermal 9100 apparatus and uncorrected. IR spectra were measured on a Shimadzu IR-460 spectrometer.1H and13C NMR spectra were measured (CDCl3solution) with a Bruker DRX-300 AVANCE spectrometer at 300.13 and 75.467 MHz, respec-tively.Elemental analyses were performed using a Heraeus CHN-O-Rapid analyzer. Flash chromato-graphy columns were prepared from Merck silica gel powder.

2.2 Preparation of the title compound

To a magnetically stirred solution of (N-isocyanimino)triphenylphosphorane 2 (0.302 g, 1 mmol) in dry CH2Cl2(8 mL) was added dropwise a mixture of 2-(2,3-dimethylphenyl)aminobenzoic acid 1 (0.241 g, 1 mmol) in dry CH2Cl2(7 mL) over 15 min. The mixture was stirred for 6 h at r. t. The solvent was removed under reduced pressure and the viscous residue was purified by flash column chromatography (silica gel:petroleum ether-ethyl acetate(10:2)). The solvent was removed under reduced pressure and the product 5 was obtained as light yellow crystals. Yield: 89%, m. p.: 118.1～119.5 ℃.Elemental Anal. Calcd. (%) for C16H15N3O (265.31):C, 72.43; H, 5.70; N, 15.84. Found (%): C, 71.87; H,5.63; N, 15.91. MS m/z: 41:48%; 43:81%, 57:42%,77:67%, 91:30%, 149:33%; 167:21%; 180:45%;194:100%; 208:62%; 223:65%; 241:58%; 265:59%;266:15%. IR (KBr): v 3316.38, 3138.46, 2930.77,1615.38, 1584.62, 1507.69, 1453.85, 1323.08,1276.92, 746.15 cm-1.1H NMR (CDCl3, 300 MHz):2.23 (s, 3H, CH3), 2.33 (s, 3H, CH3), 6.77～6.88 (m,2H, arom), 7.05～7.31 (m, 4H, Ar-H), 7.87 (d,3JHH= 7.8 Hz, 1H, Ar-H), 8.45 (s, 1H, oxadiazole), 9.11(s, 1H, NH).13CNMR (CDCl3, 62.5 MHz): δ 113.6,116.8, 123.4, 126.0, 127.1, 128.3, 132.8 (7CH, Ar-CH), 105.8, 138.3, 138.6, 146.2 (4C, Ar-C), 151.0(1CH, oxadiazole), 164.7 (1C, oxadiazole).

Single crystals of the title compound were prepared by using the branch tube method in nhexane/ethyl acetate (10:1) solvent at 45 ℃ during a week. The yellow crystals were filtered off, washed with cold n-hexane and dried at r. t.

2.3 Computational details

The structure of 5 was optimized using DFT,along with the B3LYP functional and the 6-31G basis set. At this stage, we would like to recall that,compared with experiment or benchmark theoretical results, the B3LYP predictions for bond lengths and bond angles are generally superior to the MP2 ones[52]. Indeed, the B3LYP approach is known to provide structural as well as harmonic vibrational frequencies of quality comparable to the CCSD(T)level[53]. The above described calculations have been performed using the Gaussian 03 package of programs[54].

2.4 Crystal structure determination

Data collection for X-ray structure determination of compound 5 was performed on an Xcalibur PX four-circle diffractometer (ω and φ scan) with an Onyx CCD detector equipped with graphite-monochromatized MoKα radiation. The data were collected at 120(2) K using an Oxford Cryosystems cooler.Data were corrected for Lorentz and polarization effects. Data collection, cell refinement, data reduction and analysis, and empirical (multi-scan) absorption correction were carried out with the Xcalibur PX software, CRYSALIS CCD and CRYSALIS RED,respectively[55]. The structure was solved by direct methods with the SHELXS-97[56], and refined by a full-matrix least-squares technique on F2using SHELXL-2013[56]with anisotropic thermal parameters for the non-H-atoms. The H atoms were found in difference Fourier maps, and in the final refinement cycles the C-bonded H atoms were repositioned in their calculated positions and refined using a riding model, with C–H = 0.95～0.98 Å, and with Uiso(H) = 1.2Ueq(C) for the CH groups or 1.5Ueq(C) for CH3. The N-bonded H atoms were refined freely. The structure plots were prepared with DIAMOND[57].

Crystal data for 5. C16H15N3O, Mr= 265.31,yellow plate, crystal size 0.18 × 0.13 × 0.04 mm3,triclinic, space group P1 (No. 2), a = 7.813(3), b =11.341(3), c = 16.125(4) Å, α = 93.89(3), β =101.92(3), γ = 107.51(3)°, V = 1320.2(7) Å3, T =120(2) K, Z = 4, Dc= 1.335 g·cm-3, F(000) = 560, μ= 0.09 mm-1(for MoKα, λ = 0.71073 Å), Tmin=0.960, Tmax= 1.000, 14490 reflections measured,7395 unique (Rint= 0.047), 3474 observed (I ＞2σ(I)), θ range 4.30～30.00°, index ranges –10≤h≤8, –15≤k≤15, –22≤l≤22, parameters = 373,restraints = 0, R = 0.065, wR = 0.134 (observed refl.),R = 0.150, wR = 0.148 (all data), GOOF = 1.01,(Δρ)max= 0.65 and (Δρ)min= –0.28 e·Å-3.

3 RESULTS AND DISCUSSION

Mefenamic acid (1) and (N-isocyanimino)triphenylphosphorane (2) in dichloromethane undergo a smooth 1:1 addition reaction at r. t. to produce N-(2-(1,3,4-oxadiazol-2-yl)phenyl)-2,3dimethylaniline(5) and triphenylphosphine oxide (6) (Scheme 1).The reaction proceeds smoothly and cleanly under mild conditions and no side reactions were observed.The mechanism of the reaction between 1 and 2 has not been established experimentally. However, a possible explanation is proposed in Scheme 1. On the basis of the well established chemistry of isocyanides, it is reasonable to assume that the protonation of zwitterionic isocyanide 2 by 1, followed by quenching of the cationic center by the conjugate base of the acid, can generate the iminophosphorane 4. Intramolecular aza-Wittig reaction of 4 leads to the formation of 5 and 6. The structure of 5 was confirmed by IR,1H, and13C NMR spectroscopy,mass spectrometry, and single-crystal X-ray structure determination.

Scheme 1. Chemical synthesis of the title compound

The asymmetric unit of the crystal of compound 5 contains two molecules of N-(2-(1,3,4-oxadiazol-2-yl)phenyl)-2,3-dimethylaniline (denoted as A and B),the structures of which are shown in Fig. 1. Two planar fragments of the molecules, i.e. [2-(1,3,4-oxadiazol-2-yl)phenyl]amino group (r.m.s. deviations of fitted atoms = 0.026 Å and 0.029 Å for A and B) and 2,3-dimethylphenyl, are almost perpendicular to each other (inclined at about 81.25(5)°and 89.00(5)° for A and B). In both [2-(1,3,4-oxadiazol-2-yl)phenyl]amino fragments, the maximum deviation from the least-squares planes is observed for atom O(1) (0.050(2) Å in A and 0.052(2) Å in B),which was also observed for the analogues of 5,namely 2-(1,3,4-oxadiazol-2-yl)aniline[39]and its 2-carbonyl derivative 5-(2-aminophenyl)-1,3,4-oxadiazol-2(3H)-one[58].

As a consequence of the formal sp2hybridization of atom N(3), atoms H(3) and C(31) are almost coplanar with the (1,3,4-oxadiazol-2-yl)phenyl group,which is reflected in the values of C(31)–N(3)–C(4)–C(3) torsion angles, amounting to−176.42(19)° and 174.2(2)° for A and B, respectively, and revealing the E conformation about the partially double N(3)–C(4) bond. The sums of the angles about N(3) are 360(2)° in A and 360(3)° in B,which are typical for a planar, trigonal environment with a sp2-hybridized atom. Two N–C bond distances involving N(3) atom, i.e. N(3)–C(4) (1.365(3) Å for A and 1.373(3) Å for B) and N(3)–C(31)(1.451(3) and 1.461(3) Å for A and B, respectively;see Table 1) reveal their different nature and the partial double-bond character of N(3)–C(4) bond.Both molecules adopt the same E conformation with respect to this bond. As a consequence, both amine H atoms point towards N(2) atoms and form with them intramolecular N–H··N hydrogen bonds with S(6) motifs, as shown in Fig. 1. It is possible that these hydrogen bonds may be assisted by resonance.

Table 1. Selected Geometric Parameters (X-ray and Theoretical; Å, °) for 5

Fig. 1. X-ray structures of two crystallographically independent molecules of 5 (denoted as A and B),showing the atom-numbering scheme and intramolecular N–H··N hydrogen bonds forming S(6) motifs (thick orange dashed lines), as well as the C–H··π contact between the molecules(thin blue dashed line). Displacement ellipsoids are drawn at the 30% probability level

However, molecules A and B are different conformers regarding the N(3)–C(31) bond and orientation of 2,3-dimethylphenyl ring, which is illustrated in Fig. 2 and confirmed by the values of C(4)–N(3)–C(31)–C(32) torsion angles of −82.0(3)° for A and 91.0(3)° for B.

As seen in Table 2, the adjacent molecules of 5 in the crystal lattice interact with each other mainly via C–H··π contacts. One of them, C(8A)–H(8A)··π[Cg(1)] shown in Fig. 1, is formed between the phenyl rings of [2-(1,3,4-oxadiazol-2-yl)phenyl]amino fragments from two crystallographically independent molecules A and B. Another two C–H··π interactions to the C(3)～C(8) rings, namely C(35A)–H(35A)··Cg(2)iand C(35B)–H(35B)··Cg(1)i, along with symmetry-independent C(8A)–H(8)··Cg(1)contact, link each molecule with three neighbors to form a ribbon along the a-axis in a manner shown in Fig. 3. The inter-ribbon contacts are provided by π··π stacking interactions between the C(31)～C(36)rings of both A and B molecules. The ribbon at (x, y,z) interacts with two other, related by the action of the centers of symmetry, i.e. at (ii) ˉx+2, ˉy+1, ˉz and (iii) ˉx+1, ˉy, ˉz+1, with the centroid separations of 3.678(2) Å for Cg(3)··Cg(3)iiand 3.849(2)Å for Cg(4)··Cg(4)iiiand the interplanar spacing of 3.5012(9) and 3.5337(9) Å, respectively, giving centroid offsets of 1.125 and 1.526 Å, respectively(Cg(3) and Cg(4) are the centroids of C(31A)～C(36A) and C(31B)～C(36B) rings). This gives rise to the double-layers parallel to the (011) plane.

Fig. 2. Comparison of the molecular structures of the two crystallographically independent molecules in 5: A (violet) and B (lime), showing two different orientations of 2,3-dimethylphenyl ring. The common reference points are O(1), N(1) and N(2)

Fig. 3. Arrangement of molecules A and B in the crystal of 5 within the ribbon along the a-axis Dashed lines show intramolecular N–H∙∙N (thick orange) and intermolecular

C–H∙∙π (thin blue) contacts. Symmetry code is given in Table 2.

Table 2. Hydrogen Bond and C–H··π Lengths (Å) and Bond Angles (°) for 5

4 CONCLUSION

In summary, we have found a new method for the one-pot synthesis as well as characterization of 5 from 1 and 2 in fairly moderate yield in neutral conditions. Crystal structure of product 5 was determined by X-ray single-crystal diffraction. X-ray structural analysis of product 5 contains two molecules of the same formula with one (molecule B) in vertical and the other (molecule A) in horizontal position. If comparing the two molecules of A and B with each other, the difference will be on the orienttation of 2,3-dimethyl phenyl ring, although the other parts are identical. The optimazation of 5 in bond lengths, bond angles and torsion angles was obtained by Density Functional Theory (DFT) calculations at the B3LYP/6-31G level. The theoretical and expermental comparison indicates that the theoritical data, to a great extent, are similar with the experimental values.

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