Experimental and Theoretical Studies on the Functionalization Reactions of 4-Benzoyl-1,5-Diphenyl-1H-Pyrazole-3-Carboxylic Acid and Acid Chloride with 2,3-Diaminopyridine
1
Department of Chemistry, Erciyes University, 38039, Kayseri, Turkey
2
Department of Chemistry, Kocaeli University, 41300, Izmit, Turkey
*
Author to whom correspondence should be addressed.
Molecules 2005, 10(3), 559-571; https://doi.org/10.3390/10030559
Submission received: 17 July 2004
/
Revised: 28 December 2004
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Accepted: 4 January 2005
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Published: 31 March 2005
Abstract
:The 1H-pyrazole-3-carboxylic acid 2 was converted in good yield (69%) into the corresponding 1H-pyrazole-3-carboxamide 5 via reaction of the acid chloride 3 with 2,3-diaminopyridine (4). A different product, the 3H-imidazo[4,5-b] pyridine derivative 6, was formed from the reaction of 3 with 4 and base in benzene for 5 hours. The structures of the synthesized compounds were determined spectroscopically. The mechanism of the reaction between 3 and 4 was examined theoretically.
Introduction
The cyclocondensation reaction of 1,3-dicarbonyl compounds with oxalyl chloride represents a convenient synthesis of furan-2,3-dione systems [1,2,3], which constitute an important group of oxygen-containing heterocyclic starting materials. This synthesis has been widely explored during the last few decades [4,5,6,7] and furan-2,3-diones of type 1 have been used successfully for a long time in the syntheses of various heterocycles [8,9]. Convenient synthetic methods, mechanisms of the reactions, and semi-empirical (AM1 and PM3) and ab initio (DFT) calculations on the interaction of 4-benzoyl-5-phenyl-2,3-dihydro-2,3-furandione (1) with several semicarbazones, ureas, thioureas and anilides have been reported recently [10,11,12,13,14,15]. The reaction of furan-2,3-dione with various phenylhydrazones and phenylhydrazine leads to pyrazole-3-carboxylic acid and pyridazinones [16,17,18,19].
Pyrazole derivatives are in general well-known nitrogen-containing heterocyclic compounds, and various procedures have been developed for their syntheses [20,21,22,23]. The chemistry of pyrazole derivatives have been the subject of much interest due to their importance for various applications and their widespread potential and proven biological and pharmacological activities such as anti-inflammatory, antipyretic, analgesic, antimicrobial, antiviral, antitumor, antifungal, pesticidal, anti-convulsant, antihistaminic, antibiotics, anti-depressant, and CNS regulant activities [24,25,26,27,28,29,30,31,32]. In view of these important properties, we decided both to prove the reproducibility of the reaction of 4-benzoyl-1,5-diphenyl-1H-pyrazole-3-carboxylic acid (2) and acid chloride (3) with a diamine binucleophile 4 and to extend our investigations related to the preparation of new heterocycles, which include two pyrazole rings or 3H-imidazo[4,5-b] pyridine rings in their structure. We are now reporting the reaction mechanism, synthesis and characterization of the 1H-pyrazole-3-carboxamide 5 and 3H-imidazo[4,5-b]pyridine derivative 6 which were formed by the reaction of the pyrazole-3-carboxylic acid 2 or the pyrazole-3-carboxylic acid chloride 3 with 2,3-diaminopyridine (4) (see Scheme 1).
Scheme 1.
Results and Discussion
Compound 3 reacts with 2,3-diaminopyridine (4) in two ways, thus yielding the 1H-pyrazole-3-carboxamide derivative 5 or the 3H-imidazo[4,5-b] pyridine derivative 6. The substituted 2,3-furandione 1 and 1H-pyrazole-3-carboxylic acid 2, as well as 1H-pyrazole-3-carboxylic acid chloride 3, which are important starting materials in the synthesis of the target heterocycles, were prepared using the literature procedures [1,16,17]. Compound 5 was synthesized in good yield by refluxing 2,3-diaminopyridine (4) and a two-fold molar excess of the pyrazole-3-carboxylic acid 2 or the pyrazole-3-carboxylic acid chloride 3 in benzene, without opening of the pyrazole ring (see Scheme 1). The reactions were performed together with catalytic amounts of an acid (in the case of 2) or a base (in the case of 3), for 5-10 hours, by the usual chemical method (for details, see the Experimental section). Addition of binucleophile 4 to the acid 2 or acid chloride 3 usually starts with nucleophilic attack at the acid or acid chloride moieties in these compounds. Therefore, the newly obtained product 5 arises from the sequential attacks of the diamine 4 at the acid chloride moieties of two respective molecules of 3, followed by elimination of hydrogen chloride (in the case of 2, by elimination of water). The first step corresponds to the nucleophilic addition of one of 2,3-diaminopyridine’s amino groups (N9) to the electrophilic sp2-hybridized carbon atom (C6) of the 1H-pyrazole-3-carboxylic acid chloride (See Figure 1).
Figure 1.
The total self-consistent field energy of reacting molecules (3+4), which are far from each other (C6-N9 = 3.65 Å), is –1931.018 a.u. for RHF/STO-3G method. TS1 is the result of the C6-N9 bond formation for the account of proton transfer to chlorine atom. The C6-N9, C6-Cl8, and Cl8-H10 bond lengths for TS1 become 1.61 Å, 2.34 Å, 1.97 Å. (see Table 1.)
| Atoms/Bonds | 3-4 | TS1 | IN(1) | ||||||
| AM1 | RHF STO-3G | RHF 3-21G | AM1 | RHF STO-3G | AM1 | RHF STO-3G | RHF 3-21G | ||
| INTERATOMIC DISTANCES (in Å) | C6-N9 | 3.11 | 3.65 | 3.22 | 1.55 | 1.61 | 1.38 | 1.38 | 1.35 |
| C6- O7 | 1.23 | 1.21 | 1.19 | 1.24 | 1.21 | 1.24 | 1.25 | 1.22 | |
| C6-Cl8 | 1.73 | 1.82 | 1.85 | 2.23 | 2.34 | 4.49 | 3.49 | 4.12 | |
| N9-H10 | 1.00 | 1.03 | 1.00 | 1.07 | 1.06 | 3.79 | 2.68 | 3.44 | |
| N10-H11 | 1.00 | 1.03 | 1.00 | 1.02 | 1.04 | 1.00 | 1.04 | 1.00 | |
| N9-C12 | 1.41 | 1.44 | 1.38 | 1.46 | 1.48 | 1.42 | 1.45 | 1.41 | |
| C12-C14 | 1.40 | 1.44 | 1.39 | 1.39 | 1.43 | 1.40 | 1.44 | 1.37 | |
| C12-N13 | 1.36 | 1.34 | 1.31 | 1.36 | 1.34 | 1.36 | 1.35 | 1.30 | |
| N15-H16 | 1.00 | 1.03 | 1.00 | 1.00 | 1.03 | 1.00 | 1.03 | 1.00 | |
| N15-H17 | 1.00 | 1.03 | 1.00 | 1.00 | 1.03 | 1.00 | 1.03 | 1.00 | |
| C6-C5 | 1.46 | 1.50 | 1.45 | 1.49 | 1.52 | 1.49 | 1.52 | 1.50 | |
| C5-C4 | 1.45 | 1.43 | 1.41 | 1.45 | 1.42 | 1.45 | 1.44 | 1.43 | |
| C5-N1 | 1.39 | 1.33 | 1.30 | 1.36 | 1.33 | 1.36 | 1.33 | 1.30 | |
| Cl8-H10 | 4.32 | 5.37 | 4.39 | 2.00 | 1.97 | 1.30 | 1.45 | 1.33 | |
| Frequencies(cm-1) | -351 | -281 | |||||||
| Atoms/Bonds | 3-4 | TS1 | IN(1) | ||||||
| AM1 | RHF STO-3G | RHF 3-21G | AM1 | RHF STO-3G | AM1 | RHF STO-3G | RHF 3-21G | ||
| CHARGES (in electronoc units ē) | N1 | -0.01 | -0.12 | -0.34 | -0.01 | -0.20 | -0.01 | -0.12 | -0.32 |
| C4 | -0.17 | -0.06 | -0.33 | -0.24 | -0.05 | -0.22 | -0.07 | -0.49 | |
| C5 | -0.16 | 0.05 | 0.37 | -0.14 | 0.08 | -0.14 | 0.05 | 0.35 | |
| C6 | 0.34 | 0.28 | 0.44 | 0.41 | 0.37 | 0.40 | 0.36 | 0.99 | |
| O7 | -0.26 | -0.19 | -0.53 | -0.35 | -0.24 | -0.32 | -0.26 | -0.63 | |
| Cl8 | -0.06 | -0.18 | 0.05 | -0.56 | -0.69 | -0.23 | -0.53 | -0.40 | |
| N9 | -0.31 | -0.41 | -0.95 | -0.10 | -0.32 | -0.32 | -0.38 | -1.06 | |
| H10 | 0.19 | 0.17 | 0.33 | 0.31 | 0.32 | 0.23 | 0.27 | 0.31 | |
| H11 | 0.19 | 0.19 | 0.37 | 0.25 | 0.27 | 0.26 | 0.26 | 0.42 | |
| C12 | 0.05 | 0.18 | 0.74 | -0.06 | 0.17 | 0.06 | 0.18 | 0.78 | |
| N13 | -0.18 | -0.27 | -0.78 | -0.10 | -0.22 | -0.13 | -0.24 | -0.75 | |
| N15 | -0.32 | -0.40 | -0.96 | -0.32 | -0.39 | -0.32 | -0.38 | -1.03 | |
| H16 | 0.20 | 0.20 | 0.35 | 0.21 | 0.19 | 0.21 | 0.18 | 0.38 | |
| H17 | 0.17 | 0.16 | 0.32 | 0.19 | 0.19 | 0.18 | 0.18 | 0.34 | |
The resulting SCF energy value is –1930.967 a.u. for an intermediate product IN(1). In theoretical chemistry, the reaction intermediates and transition states can be strictly distinguished by the use of vibrational analysis. For TS1 one imaginary frequency was found at –281 cm-1. Molecule 4 approaches the molecular plane of 3 at an angle of 107.1o. Torsion angle of H9-N8-C6-C4 being equal to -111o is not coplanar. When the bond length of C6 - N9 becomes 1.38 Å, IN(1) is formed. Torsion angle of H9-N8-C6-C4 becomes 168o and approximates to the coplanar one. When the bond C6 - N9 is formed, new charge redistribution is seen. The negative charge on the N9 (RHF/STO-3G) decreases from –0.41 to –0.38 ē, positive charge on the C6 atom and negative charges on the O7 and Cl8 atoms increase. In this way, a substantial polarization of bonds formed by the atom C6 can be observed.
The calculations were done by using semi-empirical AM1 and ab initio methods. Ab initio calculations were carried out by using two different basis sets that differ in the polarization functions, namely, STO-3G and 3-21G. When the ab initio method is used instead of AM1, this causes electron redistribution and changes in bond lengths. The latter are also changed, when the same method but a different basis set is used. For example, the C6-O7 bond length at 3-4 is 1.23 Å for AM1, 1.21 Å for RHF/ STO-3G, and 1.19 Å for RHF/3-21G.
Figure 2.
The use of different methods and different basis sets displays a little difference in atomic charges calculated. When the number of functions in the basis set grows, the calculations show a considerable redistribution of electron density on bonds. Because of polarization, the negative charge increase on the N1, N9, N13, N15, C4, O7 atoms, and positive charges increase on the C12 and hydrogen atoms.
Figure 3.
In the second step of the reaction, nucleophilic addition of the other amino group (N15) of IN1 to the sp2-hybridized carbon atom (C19) of the second electrophilic 1H-pyrazole-3-carboxylic acid chloride happens. In this way the compound 5 was obtained. For the transitional state TS2, its interatomic distances are determined as RN15-C19 = 1.54 Å, RN15-H16 = 1.10 Å, RC21-Cl18 = 2.40 Å, RC18-H19 = 1.90 Å (see Table 2).
| Atoms/Bonds | IN(1) | TS25 | 5 | |
|---|---|---|---|---|
| INTERATOMIC DISTANCES (in Å) | C14-N15 | 1.40 | 1.44 | 1.41 |
| N15-H17 | 1.00 | 1.02 | 1.00 | |
| N15-H16 | 1.00 | 1.10 | 3.12 | |
| N15-C19 | 2.89 | 1.54 | 1.38 | |
| C19-O20 | 1.23 | 1.23 | 1.25 | |
| C21-Cl18 | 1.74 | 2.40 | 3.79 | |
| Cl18-H19 | 3.04 | 1.90 | 1.30 | |
| C19-C21 | 1.46 | 1.47 | 1.48 | |
| C21-N23 | 1.37 | 1.37 | 1.36 | |
| C21-C22 | 1.45 | 1.45 | 1.45 | |
| C12-N9 | 1.42 | 1.39 | 1.40 | |
| N9- C6 | 1.39 | 1.40 | 1.39 | |
| N9-H11 | 1.00 | 1.04 | 1.00 | |
| C6-O7 | 1.24 | 1.24 | 1.24 | |
| C6- C5 | 1.48 | 1.28 | 1.48 | |
| Frequencies(cm-1) | -274 | |||
| CHARGES (in electronoc units ē) | Atoms/Bonds | 5I | TS2 | 5 |
| N1 | -0.04 | -0.04 | -0.03 | |
| N2 | -0.16 | -0.07 | -0.06 | |
| C4 | -0.20 | -0.18 | -0.19 | |
| C5 | -0.09 | -0.11 | -0.10 | |
| C6 | 0.46 | 0.39 | 0.40 | |
| O7 | -0.37 | -0.30 | -0.34 | |
| N9 | -0.45 | -0.33 | -0.30 | |
| H11 | 0.33 | 0.32 | 0.26 | |
| C12 | 0.12 | 0.22 | 0.16 | |
| N13 | -0.19 | -0.18 | -0.17 | |
| C14 | 0.01 | -0.20 | -0.05 | |
| N15 | -0.47 | -0.10 | -0.33 | |
| H16 | 0.26 | 0.32 | 0.22 | |
| H17 | 0.25 | 0.22 | 0.26 | |
| Cl18 | -0.09 | -0.65 | -0.22 | |
| C19 | 0.38 | 0.40 | 0.40 | |
| O20 | -0.28 | -0.28 | -0.37 | |
| C21 | -0.14 | -0.13 | -0.13 | |
| C22 | -0.20 | -0.18 | -0.20 | |
| N23 | -0.02 | -0.01 | -0.04 |
The structure of compound 5 was confirmed, besides elemental analysis, by IR and NMR spectroscopic techniques. These results are in full agreement with similar findings for substituted 1H-pyrazole-3-carboxamides [16,17,18]. The formation of 5 was supported by the results of both analytical and spectroscopic measurements, particularly by the presence of four characteristic absorption bands (FT IR: 1686.93 cm-1, 1670.68 cm-1) for carbonyl (amidic and benzoyl) groups. The broad absorption band of NH⇌OH groups was at 3433.64 cm-1 [16,17,18,37], and the skeleton bands of benzene or pyrazole rings, together with N-H bending vibrations, were observed at 1596.77, 1581.34, 1518.19, 1499.38, 1448.28 cm-1 (C...C, C...N). Important structural information about 5 can be obtained from its 13C-NMR spectrum. The 13C-NMR peaks were found to be at 197.68 (t, 3J = 4.6 Hz, Ph-C=O), 172.20 (s, -NH-C=O), 160.92 (s, -NH-C=O), 158.04 (C-2’, pyr.), 147.21, 146.35, 145.65 (C-3, C-3’, C-5, C-5’ exchangeable), 141.46, 141.03 (N-Ph), 137.18-129.82 (C-Ph), 127.11-124.26 ppm (C-4, C-4’). Final confirmation of structure 5 was derived from its 1H-NMR spectrum: δ is equal to 10.40 ppm (s, OH, tautomeric proton), 9.58 ppm (s, NH) and 8.21-7.18 ppm for a set of signals for aromatic protons [37].
In order to make the reaction selective, we had to determine the parameters, or, in other words, the reaction pathways, that could lead to such results. At this point, the reaction of 3 with 4 in boiling benzene for 5 hours with no catalytic amounts of pyridine or triethylamine gave another product, 2-(4-benzoyl-1,5-diphenyl-1H-pyrazol-3-yl)-3H-imidazo[4,5-b]pyridine-1,4-diiumdichloride (6), which was also obtained in 49% yield by stirring at room temperature for 3-4 days (see Scheme 1). Thus, compound 3 reacts with 2,3-diaminopyridine (4) in two ways and yields either the 1H-pyrazole-3-carboxamide derivative 5 or the 3H-imidazo[4,5-b] pyridine derivative 6. These results were confirmed by TLC using authentic specimens of 5 or 6 and identified by elemental and spectral data. A Beilstein test gave a green colour for compound 6. The FT-IR spectra of 6 showed broad bands for the imidazole N-H bond in the ν 3484.56, 3175.22 cm-1 region and also for two =N+-H groups at 2727.32 cm-1. The characteristic absorption bands for the carbonyl groups of 6 were observed at 1668.15 cm-1 [37]. The 1H-NMR peaks were found at δ = 10.12 (broad, NH imidazole and =N+-H imidazole or pyridine). The results of MS measurements and other structural data for the compound 6 are given in the Experimental section.
Scheme 2.
The moderate to excellent yield of the reaction can be explained by the chemical behavior of acid chlorides, similar to the behavior of the compound 3 towards N-nucleophiles [16,17,18]. The formation of 6 can easily be explained by a nucleophilic attack on the carbonyl group of the acid chloride 3. It appears, that this process can be followed by elimination of a molecule of hydrogen chloride, formation of IN(1) as mentioned above, and elimination of a molecule of water, to give tautomers of 6, whose formation is rationalized in Scheme 2.
The elimination of water molecule may occur in two states. First, a new bond C6-N15 is formed, being accompanied by the proton H17 transfer to the O6 atom. Transitional state TS2 formation happens under C6-N15 = 1.81 Å, C6-N9 = 1.52 Å, C6-O7 = 1.27 Å, O7-H17 = 1.69 Å for STO-3G basis set. The intermediate product is being formed under C6-N15 = 1.50 Å, C6-N9 = 1.47 Å, C6-O7 = 1.42 Å, O7-H17 = 0.99 Å (see Table 3). Imaginary frequency for TS2 is –1854 cm-1 that indicates a substantial change in its structure.
Table 3.
Conformational and electron characteristics of intermediates, transition states and product.
| Atoms/Bonds | IN(1) | TS26 | IN(2) | |||||||
| AM1 | RHFSTO-3G | RHF3-21G | AM1 | RHFSTO-3G | RHF3-21G | AM1 | RHFSTO-3G | RHF3-21G | ||
| INTERATOMIC DISTANCES (in Å) | C6-N9 | 1.38 | 1.45 | 1.36 | 1.51 | 1.52 | 1.46 | 1.51 | 1.47 | 1.44 |
| C6-O7 | 1.25 | 1.22 | 1.21 | 1.33 | 1.27 | 1.33 | 1.44 | 1.42 | 1.42 | |
| N10-H11 | 0.99 | 1.03 | 1.00 | 1.00 | 1.03 | 1.00 | 1.00 | 1.03 | 0.99 | |
| N9-C12 | 1.42 | 1.45 | 1.42 | 1.41 | 1.42 | 1.36 | 1.42 | 1.44 | 1.38 | |
| C12-N13 | 1.36 | 1.35 | 1.31 | 1.36 | 1.35 | 1.31 | 1.35 | 1.33 | 1.29 | |
| C12-C14 | 1.45 | 1.41 | 1.41 | 1.46 | 1.45 | 1.40 | 1.46 | 1.41 | 1.41 | |
| C14-N15 | 1.38 | 1.44 | 1.37 | 1.44 | 1.45 | 1.44 | 1.42 | 1.43 | 1.38 | |
| N15-H16 | 0.99 | 1.03 | 1.00 | 1.01 | 1.03 | 1.01 | 1.00 | 1.03 | 1.00 | |
| N15-H17 | 0.99 | 1.03 | 0.99 | 1.10 | 1.04 | 1.05 | 2.40 | 2.48 | 1.00 | |
| C6-C5 | 1.49 | 1.52 | 1.50 | 1.51 | 1.53 | 1.49 | 1.52 | 1.54 | 1.50 | |
| C5-C4 | 1.45 | 1.43 | 1.42 | 1.45 | 1.43 | 1.41 | 1.45 | 1.43 | 1.41 | |
| C5-N1 | 1.36 | 1.33 | 1.30 | 1.36 | 1.33 | 1.30 | 1.36 | 1.33 | 1.30 | |
| O7-H17 | 3.42 | 4.06 | 5.58 | 1.70 | 1.69 | 1.65 | 0.97 | 0.99 | 0.97 | |
| N15-C6 | 3.00 | 3.24 | 2.81 | 1.59 | 1.81 | 1.63 | 1.51 | 1.50 | 1.45 | |
| Frequencies(cm-1) | 2031 | -1854 | -1804 | |||||||
| Atoms/Bonds | IN(1) | TS26 | IN(2) | |||||||
| AM1 | RHFSTO-3G | RHF3-21G | AM1 | RHFSTO-3G | RHF3-21G | AM1 | RHFSTO-3G | RHF3-21G | ||
| CHARGES (in electronoc units ē) | N1 | -0.01 | -0.16 | -0.33 | -0.02 | -0.12 | -0.40 | -0.01 | -0.17 | -0.40 |
| C4 | -0.23 | -0.06 | -0.41 | -0.23 | 0.08 | -0.34 | -0.22 | -0.22 | -0.38 | |
| C5 | -0.13 | 0.04 | 0.36 | -0.10 | 0.06 | 0.46 | -0.10 | 0.06 | 0.53 | |
| C6 | 0.39 | 0.29 | 0.91 | 0.35 | 0.28 | 0.76 | 0.30 | 0.31 | 0.76 | |
| O7 | -0.30 | -0.24 | -0.58 | -0.59 | -0.30 | -0.74 | -0.34 | -0.30 | -0.68 | |
| N9 | -0.33 | -0.36 | -1.02 | -0.26 | -0.38 | -0.97 | -0.26 | -0.34 | -0.94 | |
| H11 | 0.26 | 0.21 | 0.40 | 0.23 | 0.27 | 0.39 | 0.23 | 0.20 | 0.38 | |
| C12 | 0.06 | 0.17 | 0.73 | 0.13 | 0.15 | 0.89 | 0.04 | 0.18 | 0.79 | |
| N13 | -0.11 | -0.25 | -0.71 | -0.16 | -0.26 | -0.78 | -0.14 | -0.26 | -0.77 | |
| C14 | 0.01 | 0.10 | 0.33 | -0.20 | 0.06 | 0.17 | -0.09 | 0.07 | 0.34 | |
| N15 | -0.33 | -0.38 | -1.01 | -0.12 | -0.38 | -1.01 | -0.26 | -0.36 | -1.01 | |
| H16 | 0.21 | 0.19 | 0. 37 | 0.23 | 0.23 | 0.42 | 0.22 | 0.20 | 0.39 | |
| H17 | 0.18 | 0.17 | 0.34 | 0.30 | 0.20 | 0.27 | 0.23 | 0.20 | 0.39 | |
In the second stage of the reaction, final product 6 is obtained. In the transition state TS3, bond lengths are 1.60 Å for C6-O7, 1.47 Å for N15-C6 1.26 Å for N10-H11. When the N15-C6 bond is formed, C6-O7 bond is broken simultaneously.
Conclusions
In this study, dicarboxamide derivative 5 was prepared in good yield (69%) without opening the pyrazole ring by the nucleophilic substitution reaction of a two-fold molar excess of compounds 2 or 3 and 2,3-diaminopyridine. The reaction of 3 with 4 in benzene with no catalytic amounts of triethylamine led to the formation of another product 6, besides 5. The structures of compounds 5 and 6 were confirmed by elemental analyses and spectroscopic data.
Figure 4.
The changes that occurred in some of the bond lengths during the IN(1) and product 6 formation (the lengths were determined by AM1 method) are shown in Figure 4. While IN(1) is being formed, C6-Cl8 and N9-H10 bonds are broken and C6-N9 and Cl8-H10 bonds are formed. In the same way, during the formation of product 6, C6-O7 and N15-H17 bonds are broken and N15-C6 and O7-H17 bonds are formed. As is seen from Figure 4, some important changes in the charges of atoms occur both under the formation and breakage of the bonds, at the time when IN(1) and product 6 are being formed. As an example, the charge density on chlorine atom is -0.06ē in 3+4 reactants, -0.56ē in TS1, -0.23ē in product. During the formation of product 6, charge density on carbon atom is 0.39ē in IN(1), 0.35ē in TS2, 0.30ē in IN(2), 0.2 ē in TS3, and 0.09ē in product 6. Thus, in this paper we have presented a theoretical and experimental study of the preparation of either product 5 or 6.
Experimental
General
Melting points were determined on an Electrothermal 9200 apparatus and are uncorrected. Microanalyses were performed on a Carlo Erba Elemental Analyser Model 1108. The IR spectra were recorded on a Jasco FT-IR spectrometer model 460, using KBr pellets. The 1H- and 13C-NMR spectra were obtained on Varian Gemini 200 instrument with CDCl3 as solvent and TMS as internal standard. Mass spectra were measured on a Shimadzu GC/MS-QP 5050A spectrometer, using DI method with EI. After completion of the reactions, solvents were evaporated with rotary evaporator (Buchi RE model 111). All experiments were followed with TLC using DC Alufolien Kieselgel 60 F254 (Merck) and a Camag TLC lamp (254/366 nm). Solvents were dried by refluxing with the appropriate drying agent and distilled before use. All other reagents were purchased from Merck, Fluka, Aldrich, Sigma and Acros Chemical Co. and used without further purification. All computations were done by the Gaussian 03W program. Quantum chemical calculations were done by means of semi-empirical AM1 and ab initio methods. The STO-3G and 3-21G basis sets were used throughout. Geometries were fully optimized with STO-3G and 3-21G basis sets in the frameworks of the methods used. All stationary points were characterized as minima or transition states by vibrational frequency calculations at the same level of theory as geometry optimization. In addition, intrinsic reaction coordinate (IRC) calculations for transition states were also performed.
4-Benzoyl-1,5-diphenyl-N-(2-{[(4-benzoyl-1,5-diphenyl-1H-pyrazol-3-yl)carbonyl]amino}pyridin-3-yl)-1H-pyrazole-3-carboxamide (5).
Compound 5 was prepared by two methods as follows:
Method A. From 1H-pyrazole-3-carboxylic acid (2). Appropriate amounts of 4-benzoyl-1,5-diphenyl-1H-pyrazole-3-carboxylic acid (2, 0.50 g, 1.80 mmoles, easily obtained from 4-benzoyl-5-phenyl-2,3-dihydrofuran-2,3-dione and phenylhydrazine [1,16,17]) and 2,3-diaminopyridine (4) were dissolved in benzene (30 mL) in a molar ratio of 2:1 and heated with stirring under reflux together with catalytic amounts of sulfuric acid for 10 hours. The solution was then cooled to 5 oC in a refrigerator and a precipitate was formed. After suction filtration, the crude product was recrystallized from methanol and dried over P2O5 to give 0.18 g (33%) of 5; m.p. 250 oC (white crystals); IR: 3434 (b, NH⇌OH), 1687, 1671 (s, C=O), 1597, 1581, 1518, 1499 cm-1 (C...C, C...N, aromatic rings); 1H-NMR: δ 10.40 (s, 1H, OH, tautomeric proton), 9.58 (s, 1H, NH), 8.21-7.18 ppm (m, 33H, Ar-H); 13C-NMR: δ 197.68 (t, 3J = 4.6 Hz, Ph-C=O), 172.20 (s, -NH-C=O), 160.92 (s, -NH-C=O), 158.04 (C-2’, pyr.), 147.21, 146.35, 145.65 (C-3, C-3’, C-5, C-5’ exchangeable), 141.46, 141.03 (N-Ph), 137.18, 136.77, 131.91, 131.72, 131.07, 130.78, 130.40, 130.24, 129.82, (C-Ph), 127.11, 125.39, 125.12 124.83, 124.26 (C-4, C-4’), 116.94, 114.60, 111.44 ppm; Anal. Calcd. for C51H35N7O4: C, 75.64; H, 4.36; N, 12.11. Found: C, 75.81; H, 4.41; N, 12.07.
Method B. From 1H-pyrazole-3-carboxylic acid chloride (3). Appropriate amounts of the acid chloride 3 (0.50 g, 1.30 mmoles) and 2,3-diaminopyridine (4, molar ratio 2:1) were dissolved in benzene (30 mL) and refluxed together with catalytic amounts of triethylamine for 5 hours. The solvent was evaporated and the remaining oily residue was treated with petroleum ether to give a crude product that was recrystallized from methanol and dried over P2O5 to yield 0.36 g (69%) of 5, with an m.p. and TLC identical to those of the product obtained as described above.
2-(4-Benzoyl-1,5-diphenyl-1H-pyrazol-3-yl)-3H-imidazo[4,5-b]pyridine-1,4-diiumdichloride (6).
This compound was obtained by method B with a reflux time of 5 hours, and with no catalytic amounts of triethylamine. After cooling the solution to room temperature, the precipitate formed was filtered off and recrystallized from 2-propanol, yield 0.32 g (49%); m.p. 221 oC; IR: 3485, 3175 (b, NH⇌OH), 2727 (b, =N+-H), 1668 (s, C=O), 1624, 1596, 1577, 1515, 1496, 1459 cm-1 (C...C, C...N, aromatic rings); 1H-NMR: δ 10.12 (b, 1H, NH imidazole and 2H, =N+-H), 8.42-6.86 ppm (m, 18H, Ar-H); 13C-NMR: δ 196.76 (Ph-C=O), 154.02 (C-2’, pyr.), 151.63, 148.92 (C-3’, C-5’), 138.32, 137.35, 134.08, 132.97, 132.25, 131.87, 131.20, 130.58 (N-Ph, C-Ph), 127.63, 126.84 (C-4’), 116.04, 115.73 ppm; GC/MS: m/z = 514.3 [M+], 512.3, 502.4, 501.3, 485.4, 484.3, 470.3, 460.3, 459.3, 442.4, 441.3, 440.3, 431.3, 413.3, 412.3, 368.3, 354.3, 353.3, 352.3, 351.2, 349.2, 334.2, 333.2, 324.3, 323.1, 306.2, 305.2, 295.2, 293.2, 248.2, 247.0, 219.2, 218.2, 216.8, 205.9, 203.8, 190.6, 190.5, 181.2, 180.0, 179.2, 178.2, 177.1, 176.0, 165.1, 160.0, 152.2, 150.2, 147.2, 136.1, 135.1, 120.1, 119.0, 108.1, 107.1, 106.1, 105.0, 93.0, 91.0, 89.1, 81.1, 79.0, 78.1, 77.0, 71.0, 66.1, 64.0, 63.0, 55.1, 53.0, 52.0, 51.0; Anal. Calcd. for C28H21N5OCl2: C, 65.38; H, 4.11; N, 13.61. Found: C, 65.35; H, 4.09; N, 13.29.
Acknowledgements
Financial support from the Research Center of Erciyes University, is gratefully acknowledged.
References and Notes
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Yıldırım, I.; Kandemirli, F.; Demir, E. Experimental and Theoretical Studies on the Functionalization Reactions of 4-Benzoyl-1,5-Diphenyl-1H-Pyrazole-3-Carboxylic Acid and Acid Chloride with 2,3-Diaminopyridine. Molecules 2005, 10, 559-571. https://doi.org/10.3390/10030559
AMA Style
Yıldırım I, Kandemirli F, Demir E. Experimental and Theoretical Studies on the Functionalization Reactions of 4-Benzoyl-1,5-Diphenyl-1H-Pyrazole-3-Carboxylic Acid and Acid Chloride with 2,3-Diaminopyridine. Molecules. 2005; 10(3):559-571. https://doi.org/10.3390/10030559
Chicago/Turabian StyleYıldırım, Ismail, Fatma Kandemirli, and Elif Demir. 2005. "Experimental and Theoretical Studies on the Functionalization Reactions of 4-Benzoyl-1,5-Diphenyl-1H-Pyrazole-3-Carboxylic Acid and Acid Chloride with 2,3-Diaminopyridine" Molecules 10, no. 3: 559-571. https://doi.org/10.3390/10030559
