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Synthesis and DFT studies of novel aminoimidazodipyridines using 2-(3H- imidazo[4,5-b]pyrid-2-yl)acetonitrile as an efficient key precursor

Novel 9-aminoimidazo[1,2-a:5,4-b']dipyridine-6,8-dicarbonitriles were prepared via the Michael addition reaction of readily accessible 2-(3H-imidazo[4,5-b]pyrid-2-yl)acetonitrile with arylidenemalononitriles. The regioselectivity of the reaction was supported by theoretical calculations at the DFT level. In contrast, the reaction of the appropriate bis-arylidenemalononitrile with 2-(3H-imidazo[4,5-b]pyrid-2-yl)acetonitrile under similar reaction conditions gave the corresponding bis[2-(3H-imidazo[4,5-b]pyrid-2-yl)acrylonitriles].


Introduction
Imidazo [4,5-b]pyridines are important classes of heterocyclic compounds that possess diverse pharmacological properties including anticancer, 1 antimicrobial, 2 anti-inflammatory, 3 and antiviral activities. 4,5 Moreover, N-fused polyheterocycles display also a wide range of biological activities. 6 In particular, imidazo[1,2-a:5,4-b']dipyridines exhibit interesting anticancer 7 and antiviral 8 activities. Some examples of biologically active compounds containing an imidazo[1,2-a:5,4-b']dipyridine such as (CF02334) 1, a selective inhibitor of the cytopathic effect (CPE) caused by bovine viral diarrhea 8 and anti-human prostate cancer 2 7 are outlined in Figure 1. In addition, the development of simple and efficient synthetic routes to novel heterocyclic compounds represents a great challenge in organic synthesis. In this respect, the Michael addition reaction has attracted much attention in the last decades as an effective strategy for the synthesis of heterocycles and their fused derivatives under mild reaction conditions. 9,10 Moreover, due to their promising nonlinearoptical (NLO) properties, imidazo [1,2-a]pyridine and their corresponding fused derivatives have a diverse range of applications in material chemistry. In this respect, many of these derivatives have been used as multiple fluorescent chemosensors, in an electron transport layer of an organic light emitting device, as biomarkers of hypoxic tumor cells, and as a receptor in fluorescent high-affinity ligand in dopamine D3. [11][12][13][14] In connection with the increasing interest of adoption of new synthetic methods in drug discovery, and in continuation to our recent applications of carbon-Michael [15][16][17][18] as well as aza-Michael 16 addition reactions as powerful tools for the synthesis of nitrogen containing heterocycles and their corresponding bisheterocycles, 15,17,[19][20][21][22][23][24][25][26] we report herein our investigation on the reactivity of 2-(3H-imidazo [4,5-b]pyrid-2yl)acetonitrile towards arylidenemalononitriles and bis-arylidenemalononitriles aiming at synthesizing novel mono-and bis-imidazo[1,2-a:5,4-b']dipyridine-6,8-dicarbonitriles. In addition, a theoretical density functional theory (DFT) study aims to determine the more stable regioisomer of the two possible expected isomeric products from the mentioned reactions as well as to investigate the efficacy of the target compounds as suitable candidate for NLO material.
The reactivity of compound 10 towards substituted cinnamonitriles was then investigated. Compound 10 (a Michael donor) has two nucleophilic centers (NH group and CH2) at which the Michael addition to the Michael acceptor 11 can initiate. Thus, two regioisomeric products are possible by the reaction of compound 10 with the activated double bond reagents 11 via routes A and B (Schemes 3 & 4). Route A involves the initial nucleophilic addition of CH2 of compound 10 to -carbon of the activated double bond of 11 followed by cyclization that involves the NH group to afford 9-amino-7-arylimidazo[1,2-a:5,4-b']dipyridine-6,8dicarbonitrile 12 through intermediates 14 and 15 (Scheme 4). Route B encompasses the initial addition of the NH group of the compound 10 to the activated double bond of 11 followed by cyclization involving CH2 of 10 to give 7-amino-9-arylimidazo[1,2-a:5,4-b']dipyridine-6,8-dicarbonitrile 13 through intermediates 16 and 17 (Scheme 4). The structures of the expected products 12 or 13 could not be determined based on spectral analyses as both of them give similar data. For example, the IR spectrum of the compound produced from the reaction of 10 with 11a showed the presence of amino group at ν(N-H) 3456 and 3317 cm -1 as well as characteristic nitrile band at ν(C≡N) 2214 cm -1 . Its 1 H NMR spectrum revealed the amino group at δ 8.89 as a broad signal. Unfortunately, these data can agree with both structures 12 and 13. reaction of 20 with 19, with identical physical and spectral data with that prepared from the reaction of 10 and 11a, supports the reaction proceeded via route A and not via route B.

Scheme 5.
Alternative methods for the synthesis of compound 12a.
The regioselective formation of 12 was also supported by theoretical calculations at DFT level (cf. Molecular orbital calculations).
In searching for the optimal reaction conditions, the reaction was carried out in different solvents as well as in the presence of a variety of bases. Firstly, we tried EtOH as a solvent and DABCO, pyridine, KOH, TEA and piperidine as bases. Among the different bases, the use of piperidine gave the cleanest products and best yields. The reaction was also examined in different solvents including dioxane, dichloromethane, acetonitrile, water and DMF heated at reflux in each case. The reaction proceeded in most solvents but with different degrees of conversion; EtOH was the best solvent in terms of reaction time and yield. The reactions were completed in 3-5 h, while prolonged heating did not improve the reaction yield. On the other hand, no traces of products were obtained at room temperature. The reactivity of compound 10 towards heteromethylenemalononitriles was also investigated aiming at synthesizing novel imidazo A similar pathway has been reported. 34 The structures of compounds 25a-d were supported by comparison of their physical data with authentic samples prepared from the reaction of one equivalent of bisaldehydes 27 with two equivalents of 2-(3H-imidazo[4,5-b]pyrid-2-yl)acetonitrile (10) in EtOH in the presence of catalytic piperidine (Scheme 9). The constitutions of compounds 25 were established based on spectral data. Thus, the 1 H NMR spectrum of compound 25a as a representative example revealed two singlet signals at δ 4.63 and 8.59 for the OCH2 groups and the ylidene H-atoms, respectively. Moreover, it revealed the NH group as broad singlet at 13.63 ppm.

Geometry of compounds 12 and 13
Geometry structures of the expected products 12 and 13 and their intermediates 14 and 16 were optimized at the B3LYP/6-311G** level and the results are given in Table 1. The reaction of 10 with 11 can lead to the formation of the regioisomer 12, via intermediate 14 through the attack of the active CH2 of 10 (C14) on CH groups of 11 (C12). On the other hand, the regioisomer 13 can arise via initial attack of NH of 10 on CH of 11 to give intermediate 16 as seen in Fig. 2 (cf. supporting information). The energy of regioisomer 13 was 7.15 kcal/mol higher than that of 12, i.e., the structure of 12 was more stable. Also, the intermediate 16 has energy of 5.52 kcal/mol higher than that of 14. Therefore, this study supports the regioselective formation of 12 from the reaction of 10 with 11. The planarity of 12 can be estimated from the values of the dihedral angles. Compound 12 has a non-planar structure where the phenyl ring rotates out of the plane. This is can be indicated from the dihedral angles of the phenyl ring attached to C13-C24, especially the angles (<C13-C11-C12-N17), (<C13-C14-C16-N18) and (<C11-C13-C24-C29) which are -176.879°, -179.389° and 123.976° (Table 1, cf. supporting information). Where these angles are far from 0° or 180°. This also can be verified from the bond angel (<C14-C13-C24) which has the value of 119.117° (Table 1).

Ground state properties and Global reactivity descriptors
The energy difference between the HOMO and LUMO, Eg, of compounds 10, 11 and 12 occur in the range 5.28-3.32 eV. The energy gap of compound 10 is the maximum (5.28 eV) while that for compound 12 has the minimum (3.32 eV) value ( Table 2). As a result, charge transfer and polarization can easily occur with more reactivity within 12 than 10 and 11. The electronegativity, χ, chemical hardness, η, global softness, S, chemical potential, , were calculated using HOMO and LUMO energies and were recorded in Table 2, Fig. 3 (cf. supporting information). Compound 10 has the lowest η and maximum S value which means that the charge transfer occurs easily in this compound and it has a lower chemical hardness. Large Eg gaps are representative of the hardness of the molecule, while smaller Eg gaps are representative for soft and reactive molecules. The accumulated data in Table 2 showed that the HOMO of 12 is less stable than that of the other compounds and has lower IP value. The electron affinities values are of the order: 10 < 12 < 11. The processed reactivity parameters are shown in Table 2 which revealed that compound 10 has the lowest η and minimum S values. This indicated that it has lower chemical hardness. The 3-D distribution of frontier MOs, HOMO and LUMO of 10, 11 and 12 are presented in Fig. 2. The calculated values of EHOMO and ELUMO of 12 are -6.1690 and -2.8478 eV, respectively, thus the energy gap value Eg is 3.3212 eV. It can be regarded from Fig. 3 that the HOMO and LUMO of 12 are mainly allocated over the whole molecule. The partial frontier molecular orbital compositions and the energy levels of 12 in the ground state are recorded in Table 2 and Fig. 3. The frequency calculations for compound 12a (Figure 4, cf. supporting information) were performed using B3LYP/6-31G(d,p). The data obtained are comparable with that theoretically calculated (Exp. 3456, 3317, 2214; Calc. 3470, 3240, 2212 cm -1 ) cf. experimental section. TD-DFT calculations for compound 12a (Figure 5, cf. supporting information) were brought out at the same level of theory [B3LYP/6-31G(d,p)] to clarify the origin of the electronic spectra, using the polarizable continuum solvation method, PCM, PCM-TD-DFT. The theoretical spectrum of 12a is characterized by five bands at 361 (3.4316 eV), 308 (4.0224 eV), 286 (4.3248 eV), 262 (4.7280 eV) and 245 nm (5.0405 eV). Theoretical IR and UV spectra of 12a using B3LYP6-31G(d,p) are mentioned in supplementary material.

Non-linear optical properties (NLO)
The circulation of the atomic charges in the chelates is also valuable in the determination of the magnitude and direction of the moment vector which depends on the centers of negative and positive charges. The dipole moment, the mean polarizability, the anisotropy of the polarizability and the first-order hyperpolarizability for compounds 10, 11 and 12 were calculated using the same level and the obtained values are tabulated in Table 3. The table also includes the experimental values of urea. The considered dipole moment values of 10, 11 and 12 in the gas phase are 4.4076, 6.6808 and 5.3942 D, respectively. The analyzed values of the polarizability of 10, 11 and 12 have the range 1.09-7.02×10 -24 (esu). Compound 11 has the lowest calculated value and 12 has 7.02×10 -24 . Compared with urea 35 as a reference substance, all the studied chelates have higher polarizability and first-order hyperpolarizability. The polarizabilities and first-order hyperpolarizabilities are reported in atomic units (a.u.), the calculated values have been changed into electrostatic units (esu) using conversion factor of 0.1482×10 -24 esu for α and 8.6393×10 -33 esu for . Urea is used as standard example in non-linear optical studies. In this study, urea is chosen as a reference material as there were no experimental values of NLO properties for the new derivatives. The extent of the molecular hyperpolarizability (˂ ˃) is one of the key factors in non-linear optical system. The calculated (˂ ˃) values for compounds 10, 11 and 12 are ~6, ~60, and ~6, times greater than that of urea, respectively. Therefore, all the studied compounds reveal considerable polarizability and first-order hyperpolarizability and are projected to be successful encouraged for NLO materials.

Conclusions
We developed a simple and an efficient method for the preparation of novel 9-aminoimidazo[1,2-a:5,4b']dipyridine-6,8-dicarbonitriles via the Michael addition reaction that involves 2-(3H-Imidazo[4,5-b]pyrid-2yl)acetonitrile (as Michael donor) and the appropriate arylidenemalononitriles (as Michael acceptor). Also, we managed to synthesize bis[2-(3H-imidazo[4,5-b]pyrid-2-yl)acrylonitriles] through the reaction of 2-(3Himidazo[4,5-b]pyrid-2-yl)acetonitrile with bis-arylidenemalononitriles under similar reaction conditions. The theoretical calculations were carried out using Gaussian 09 W package with Gauss View 5. The analysis includes bond lengths, bond angles, molecular electrostatic potential maps, description of the important frontier molecular orbital surfaces of the compounds. The optimized molecular structure of the compounds was obtained at B3LYP/6-311G**. The regioisomer 13 has higher energy than that of 12. This gives further confirmation for the formation of the more stable regioisomer 12. The polarizability and hyperpolarizabilities parameters of the compounds indicated that they are suitable candidate for NLO material.