The present work deals with the synthesis of 2-cyano-N'-(3-(2-(2-cyanoacetyl) hydrazinyl) cyclohex-2-en-1-ylidene) acetohydrazide 3 that used as a key precursor in the manufacture of new heterocyclic derivatives, such as pyrazole, pyrane, pyridine and pyrole incorporating cyclohexene moiety via its reaction with a variety of nucleophilic and electrophilic reagents. The newly synthesized compounds were characterized by their elemental analyses (IR, 1H-NMR, 13C-NMR and Mass spectra) and assessed for their anti-microbial activity.
Research Article
Bis (2-Cyanoacetohydrazide) as Precursors for Synthesis of Novel Azoles / Azines and their Biological Evaluation
https://doi.org/10.21203/rs.3.rs-2327892/v1
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Hydrazide-Hydrazone
Pyrazole
Pyrane
Pyridine
Pyrole
Spectral data
Anti-microbial Activity
1,3-Cyclohexanedione and their related heterocyclic attracted our attention due to their derivatives pronounced biological activity. Their various applications include: antimalarials [1], plant growth promoters [2–4], herbicides [5–7] and other application [8, 9]. The present investigation aimed to synthesize and characterize newer pyrazole, pyrane, pyridine and pyrole incorporating cyclohexene moiety that have a specific biological activity. The literature survey reveals that pyrazole derivatives exist in various pharmaceutical formulations with anti-inflammatory effect [10] and other application [11–15]. Pyrane derivatives are used as anti-microbial [16], anti-cancer agents [17] and anti-fungal [18]. Additionally, pyridine derivatives have found to possess diverse pharmacological activities such as anti-cancer [19], anti-microbial [20, 21], anti-diabetic [22]. Moreover, the pyrole derivatives have received agreat deal of attention due to their pharmacological importance. Pyroles were reported to possess anti-microbial [23], anti-cancer [24] and anti-inflammatory effect [25].
The study reported in this article, involved cyanoethanoic acid hydrazide and its derivatives, which considered versatile reagents for the synthesis of a wide variety of heterocyclic compounds, due to their active methylene moiety and the β-functional nitrile moiety of the molecule is a favorable unit for addition reactions followed by cyclization or via cycloaddition with some electrophilic and nucleophilic reagents. Thus, the reaction of 1, 3-cyclohexanedione 1 with cyanoacetic acid hydrazide in glacial acetic acid solution at room temperature, due to the activity of 1, 3-dione and the methylene moiety at C2 one mole of cyanoacetic acid hydrazide condensed with carbonyl group while another mole reacted with enol form gave 2-cyano-N'-(3-(2-(2-cyanoacetyl)hydrazinyl)cyclohex-2-en-1-ylidene)acetohydrazide 3 [26, 27]. The structure of compound 3 was established and confirmed as the reaction product based on its elemental analyses and spectral data. The IR spectrum which revealed the presence of NH groups stretching at 3447 − 3224 cm− 1, the CN groups stretching at 2216 cm− 1 and revealed the carbonyl group at 1678 cm− 1. Also, the 1H-NMR spectrum showed characteristic singlet signals at δ = 8.52, 9.96 and 10.38 ppm for 3NH protons, a multiplet signals in the region of δ = 1.72–1.91 ppm due to the methylene group in the cyclohexene moiety, a multiplet signals at δ = 2.23–2.32 ppm corresponding to the hydrogens of the two methylene groups in the cyclohexene moiety and shows characteristic singlet signals at δ = 3.36, 3.95 and 5.54 ppm for two methylene groups and CH-cyclohexene, respectively. Moreover, the 13C-NMR spectrum of compound 3 shows the following signals at δ = 21.86, 24.70, 26.52, 26.63, 31.45, 86.93, 116.66, 116.88, 156.79, 160.20, 162.12, 164.67. The structure assigned for compound 3 was fully supported by its mass spectrum, which showed a molecular formula C12H14N6O2 (m/z % = 275, M++1, 1.01).
The proclivity of bis (2-cyanoacetohydrazide) derivative 3 towards some electrophilic reagents was investigated. Thus, the condensation of compound 3 with dimethylformamide-dimethylacetal (DMF-DMA) in dioxane produced a crylohydrazide derivative 4 as outlined in (scheme 1). The structure of compound 4 was confirmed from their elemental analyses and spectral data. The structure of compound 4 was mainly elucidated by the 1H-NMR spectra which showed a singlet signal at δ = 3.10 ppm assigned to the N (CH3)2, at δ = 3.13 ppm assigned to the N(CH3)2, at δ = 7.51 ppm assigned to CH-oleffinic and at δ = 7.72 ppm assigned to CH-oleffinic. The mass spectrum of compound 4 gave a strong peak at m/z = 384 (M+) corresponding to its molecular weight.
A crylohydrazide derivative 4 showed interesting reactivity towards binucleophilic reagent. So, when compound 4 was reacted with hydrazine hydrate afforded the 3-amino-N'-(3-(2-(3-amino-1H-pyrazole-4-carbonyl) hydrazinyl) cyclohex-2-en-1-ylidene)-1H-pyrazole-4-carbohydrazide 5. The structure of compound 5 was established and confirmed as the reaction product based on their elemental analyses and spectral data. The IR spectrum showed an absorption band in the region 3400, 3163 cm− 1 assignable for NH2/NH, in addition to disappearance of the cyano function group. Its 1H-NMR spectrum revealed new signal at δ = 7.12 ppm for CH-pyrazoles and a singlet signal at δ = 6.99 ppm assignable to the NH2 groups. Its mass spectrum showed a molecular ion peak at m/z = 358 (M+) corresponding to a molecular formula C14H18N10O2.
Cyclocondensation of hydrazide-hydrazone 3 with thioglycolic acid in boiling DMF, anhydrous ZnCl2 was added as a catalyst furnished the bis(2-(4-hydroxythiazol-2-yl) acetohydrazide) derivative 7 [26]. We first assumed that the reaction product is formed via the initial nucleophilic addition of the mercapto function to the nitrile group, followed by dehydration and subsequent tautomerization. The IR, 1H-NMR, 13C-NMR and Mass spectra are in agree in all respects with the proposed structure.
Reactivity of hydrazide-hydrazone derivative 3 towards aryl aldehyde was studied. Thus, benzaldehyde condensed with compound 3 afforded the corresponding arylidene derivative 8. The structure of compound 8 was based on its analytical and spectral data (see experimental section). Further evidence for the structure 8 was obtained through studying their chemical reactivity towards some chemical reagent. So, when compound 8 was reacted with hydrazine hydrate afforded the corresponding bis(3-amino-5-phenyl-1H-pyrazole-4-carbohydrazide) derivative 9. The structure of compound 9 was mainly elucidated by the 1H-NMR spectra which showed new singlet signal at δ = 5.90 ppm for NH2 groups [28, 29].
Furthermore, the behavior of hydrazide-hydrazone derivative 3 towards binucleophilic reagents was also investigated. Thus, the reaction of compound 3 with salicyladehyde in ethanol in the presence of a catalytic amount of piperidine afforded acyclic structure 10. The reaction probably takes place through condensation of the aldehydic group with the active methylene group. The presence of the nitrile groups in the IR spectra at 2222 cm− 1 revealed no cyclization process. Trials to cyclize compound 10 by nucleophilic attack of the hydroxyl group on the nitrile group succeeded under mild condition such as refluxing of 10 in dioxane in basic medium to afford 11. The absence of the nitrile function in the IR spectra confirms the cyclization process. Also, the 1H-NMR spectra of compound 11 reveal the CH-pyrane as a singlet signal at δ = 8.03 ppm [30, 31].
The behavior of hydrazide-hydrazone derivative 3 towards active methylene reagents was also investigated. Thus, a considerable approach for the synthesis of 4,6-diamino-1-((3-((4,6-diamino-3-cyano-2-oxopyridin-1(2H)-yl)amino)cyclohex-2-en-1-ylidene)amino)-2-oxo-1,2-dihydropyridine-3 –carbonitrile 12, 1-((3-((3-cyano-4,6-dimethyl-2-oxopyridin-1(2H)-yl)amino)cyclohex-2-en-1-ylidene) amino)-4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-carbonitrile 13 were fulfilled through interaction of hydrazide-hydrazone derivative 3 with malononitrile and acetylacetone, respectively. Assignment of the structure 12 for the reaction product was based on its correct analyses and compatible spectroscopic data, the 1H-NMR of the structure revealed a singlet signals at δ = 5.77, 6.20 ppm corresponding to NH2 groups. Also, a nice singlet signal at δ = 6.88 ppm this is due to CH-pyridine. Also, the mass spectrum of compound 12 agrees with the proposed structure, it showed a molecular ion peak at m/z = 406 (M+) in agreement with its molecular formula C18H18N10O2. While, the structure confirmation of 13 was assisted from their analytical and spectral data. The IR spectrum displayed characteristic an absorption band at 3448 cm− 1 related to NH group, an absorption band at 2220 cm− 1 related to the CN as well as the carbonyl group absorption band at 1627 cm− 1. In 1H-NMR spectrum two characteristic singlet signals at δ = 2.23, 2.31 ppm attributable to the four methyl groups, a singlet signal at δ = 6.20 ppm due to CH-pyridine moiety, the mass spectrum showed a molecular ion peak in accordance with the proposed structure [32, 33, 29]. Also, we converted the target compound 3 in to the corresponding 1-((3-((5-cyano-4-methyl-2,6-dioxo-3,6-dihydropyridin-1(2H)-yl)amino)cyclohex-2-en-1-ylidene) amino)-4-methyl-2,6-dioxo-1,2,5,6-tetrahydropyridine-3-carbonitrile 14. This was accomplished by fusion equimolar amounts of compound 3 and ethyl acetoacetate without solvent for about 12 hours. The structure of compound 14 was established and confirmed as the reaction product based on their elemental analyses and spectral data. The IR spectrum of 14 showed the presence of an NH stretching at 3426 cm− 1, one cyano group stretching at 2223 cm− 1 and one carbonyl group stretching at 1727 cm− 1. Also, the 1H-NMR and mass spectrum of the same product is in accordance with the proposed structure.
Hydrazide-hydrazone derivative 3 underwent Gewald thiophene synthesis via its reaction with malononitrile and elemental sulfur in refluxing ethanol containing TEA as a basic catalyst afforded the bis(3,5-diamino-4-cyanothiophene-2-carbohydrazide) derivative 15. The analytical and spectral data is consistent with the proposed structure. The IR spectrum of 15 displayed an absorption bands at 3423, 3197 cm− 1 for NH2/NH, an absorption band at 2203 cm− 1 for the nitrile group and the carbonyl absorption band at 1628 cm− 1. The structure of 15 was mainly elucidated by the 1H-NMR spectra which showed new two singlet signals at δ = 6.10 ppm and 6.60 ppm for NH2 protons. The mass spectrum of the same compound is in accordance with the proposed structure. It showed a very intense molecular ion peak at m/z 472 (M++2) and a few fragments agree the proposed structure.
On the other hand, the reaction of compound 3 with phenyl isothiocyanate and elemental sulfur afforded the 4-amino-N'-(3-(2-(4-amino-3-phenyl-2-thioxo-2,3-dihydrothiazole-5-carbonyl)-hydrazinyl)cyclohex-2-en-1-ylidene)-3-phenyl-2-thioxo-2,3-dihydrothiazole-5-carbohydrazide 16. The analytical and spectral data of compound 16 are consistent with the proposed structure [29, 32, 34]. Moreover, the reaction of compound 3 with cyclohexanone and elemental sulfur in the presence of TEA. The reaction led to the formation of bis(2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carbohydrazide) derivative 17. Formation of 17 took place according to reaction of cyclohexanone with methylene moiety and elemental sulfur (application of Gewald’s thiophene synthesis). The analytical and spectral data of 17 was in agreement with the proposed structure (see experimental section) [28, 35].
Next, we studied the reactivity of the hydrazide-hydrazone derivative 3 towards some electrophilic reagents under alkaline conditions. Thus, the reaction of compound 3 with acetonitrile dimer in refluxing ethanol in the presence of a catalytic amount of piperidine afforded bis(2-amino-4-cyano-5-methyl-1H-pyrrole-3-carbohydrazide) derivative 18. The structure of compound 18 was established and confirmed as the reaction product based on its elemental analyses and spectral data. The infrared spectrum revealed an absorption band at 3450 − 3207 cm− 1 for the amino groups, a sharp band at 2200 cm− 1 for the CN function and a strong band at 1641 cm− 1 for the carbonyl group. The 1H-NMR spectrum supports the proposed structure which reveals new a singlet signal at δ = 2.20 ppm for methyl groups and a singlet signal at δ = 6.39 ppm for NH2 protons. The mass spectrum of the same product is in accordance with the proposed structure, it showed a molecular ion peak at 434 (M+).
Our research deals with effective use of α, β-unsaturated ketones in the synthesis of 4H-pyrane derivatives. Thus, the reaction of chalcones with hydrazide-hydrazone derivative 3 in refluxing ethanol in the presence of piperidine to give substituted pyrane 19a,b. The structures of synthesized compounds were confirmed by (IR, 1H-NMR, 13C-NMR and mass spectra). The IR spectrum of compound 19a as an example was characterized by disappearance of the cyano group and showed an absorption band at υmax = 3416 − 3220, 2937 − 2860 and 1629 cm− 1 due to the amino, aliphatic and carbonyl function, respectively. The 1H-NMR spectrum supports the proposed structure. Which reveals new two doublets at δ = 3.66, 5.71 ppm characteristic for 4H-pyrane and = CH-pyrane, respectively. The mass spectrum of 19a showed a molecular ion peak m/z 690 (M+) with a base peak at m/z = 57 (100%) is consistent with the proposed structure.
On the other hand, 4-aryl-2-oxo-pyridine-3,5-dicarbonitrile derivatives 20a,b were synthesized in an excellent yield upon treatment of compound 3 with arylidinemalononitrile in the presence of piperidine as a catalyst. The products 20a,b are apparently formed via a Michael type addition of the active methylene group in compound 3 to the activated double bond in arylidinemalononitrile to form non-isolable intermediate through an intramolecular cyclization and subsequent tautomerization to give 20a,b. The structure of pyridine derivative 20 was confirmed from the elemental analyses and spectral data of the isolated product. The IR spectrum of 20a displayed stretching an absorption bands at 3419 − 3200, 2939, 2211, 1632 cm− 1 for the amino, aliphatic, cyano and the carbonyl function groups, respectively. Its 1H-NMR spectrum displayed new a singlet signal at δ = 5.70 ppm assignable to the NH2 protons and a singlet signal at δ = 10.30 ppm assignable to the NH proton. Moreover, an EI mass spectroscopic technique gave its correct molecular ion peak at m/z = 648 (M++2) [36, 37].
Moreover, proclivity of the active methylene group present in compound 3 towards diazonium salts was also investigated. Thus, the compound 3 could be readily coupled with aromatic diazonium salts to yield the corresponding aryl hydrazone derivatives 21a,b. The structure of 21 was established through microanalysis (IR, 1H-NMR and mass spectral data) and its chemical reactivity of this molecule towards some nucleophilic reagents. So, aryl hydrazononitriles 21a,b was reacted with hydroxylamine hydrochloride in ethanolic sodium acetate yielded amidooxime derivatives 22a,b that cyclized into amino triazole derivatives 23a,b by refluxing it in DMF/piperidine. The structures of 22 and 23 were supported based on its elemental analyses and spectral data. The IR spectrum of 22a as an example showed the appearance of an absorption bands at 3372 − 3183 cm− 1 for hydroxyl and amino groups and 1673 cm− 1 for the carbonyl group and the absence of the nitrile group in IR spectra confirms the addition process. The 1H-NMR and mass spectra of the latter reaction products are all consistent with the proposed structures. While, analytical and spectral data of compound 23a,b are in agreement with the proposed structure (see experimental section). Further elucidation of the structure 21 came from the reaction with hydrazine hydrate as binucleophilic reagent to give the amino pyrazole products 24. Analytical and spectral data of the product agree with the proposed structure [33, 35, 38–40].
In addition, the behavior of compound 3 towards diazonium salt of heterocyclic amine was also investigated. Thus, hydrazide-hydrazone derivative 3 coupled with diazonium salt derived from some heterocyclic amine to afford the respective hydrazone 25. The structure of the product 25 was determined from spectroscopic and elemental analyses.
bis(5-amino-2-oxo-7-Aryl-1,2,3,7-tetrahydropyrano[2,3-d]imidazole-6-carbohydrazide) derivatives 26a,b was synthesized in an excellent yield upon treatment of compound 3 with 5-benzylidene imidazolidine-2,4-dione in ethanol at reflux in the presence of piperidine. In a similar manner, cyclization of 2-(benzylidene cyclohexanones with substrate 3 under the same experimental conditions produced the corresponding bis(2-amino-4-Aryl-5,6,7,8-tetrahydro-4H-chromene-3-carbohydrazide) derivatives 27a,b. The formation of 27a,b can be understood in terms of the Michael type addition of the active methylene group in the substrate 3 to the activated double bond in the unsaturated cyclohexanone followed by cyclization of the resultant intermediate adducts. The structures of 26a,b and 27a,b were the final product and it were characterized with the help of its elemental analyses (IR, 1H-NMR and Mass spectra). The IR spectrum of compound 26a taken as a typical example of the series prepared revealed an absorption bands in the region 3421 − 3200 cm− 1 assignable for the NH2, in addition to disappearance of the cyano function band. Which suggest its participation in cyclization process. Its 1H-NMR spectrum displayed new a singlet signal at δ = 3.90 ppm assignable to the 4H-pyrane and a singlet signal at δ = 6.40 ppm assignable to the NH2 protons. Its mass spectrum showed a molecular ion peak at m/z = 650 (M+) corresponding to a molecular formula C32H30N10O6.
In Vitro Antimicrobial Activity
The anti-microbial activity of the synthesized compounds was tested against a panel of two Gram-negative bacteria (Escherichia coli, Pseudomonas aeuroginosa) and two Gram-positive bacteria (Staphylococcus aureus, Bacillus subtilis). The anti-fungal activities of the compounds were tested against two fungi (Candida albicans, Aspergillus flavus). Each of the compounds was dissolved in DMSO and solution of the concentration 1 mg/ml were prepared separately paper discs of Whatman filter paper were prepared with standard size (5 cm) were cut and sterilized in an autoclave. The paper discs soaked in the desired concentration of the complex solution were places aseptically in the petridishes containing nutrient agar media (agar 20g + beef extract 3g + peptone 5g) seeded with Escherichia coli, Pseudomonas aeuroginosa, Staphylococcus aureus, Bacillus subtilis, Candida albicans and Aspergillus flavus. The petridishes were incubated at 36 oC and the inhibition zones were recorded after 24h of incubation. Each treatment was replicated three times [41]. The antibacterial activity of a common standard antibiotic ampicillin and antifungal Clotrimazole was also recorded using the same procedure as above at the same concentration and solvents. The % activity index for the compound was calculated by the following formula.
Results in table (1) indicated that all the synthesized compounds had an obvious inhibitory effect against all tested microbial species. The synthesized compound 3 was the more sensitive compound with weakest anti-microbial activity and had similar effect on fungi and bacteria under this study. Despite the Gram-positive bacteria (Staphylococcus aureus) showed an activity index 66.7% and a diameter of inhibition zone (16mm) in response to synthesized compound 3, the other Gram-positive bacteria (Bacillus subtilis) showed the largest activity index of 91.3% and the largest diameter of inhibition zone (21mm). In face of that the two Gram-negative bacteria (Escherichia coli, Pseudomonas aeuroginosa) had lower values of activity index about 52% and 82.6% respectively. Despite its distinctive protective outer layer. In the other hand, the fungus (Candida albicans) showed no resistant to the three synthesized compounds 5, 23a, 24a that resulted in zero activity index and no inhibition zone. The synthesized compound 24a had the largest antimicrobial effect with 0% activity index in all species except 2mm diameter inhibition zone in Gram-positive bacteria (Bacillus subtilis) and 6mm in (Aspergillus flavus). Hence, the above results can indicate that the synthesized compound 24a had the highest antimicrobial activity which all microbial species under study cannot resist it followed by the compound 23a and the lowest antimicrobial activity belonging to the synthesized compound 3. All other compounds had a similar medium effect on all microbes.
It is worth noting that many of human infections are caused by Gram-negative bacteria which have an outer membrane that protect the bacterial cell against any foreign substance, in the other hand Gram-positive bacteria didn’t have this outer layer so it can be easily affected and destroyed by different antibiotic and antimicrobial compounds. In this study results indicated that all eleven synthesized compounds showed high microbial activity against Gram-negative, so it can penetrate its outer layer and inhibit its growth which helped in control them. Furthermore Gram-positive bacteria had great resistant against all 11 synthesized compound and all these compounds had weak effect on this type of bacteria. Moreover all these compounds had medium antimicrobial effect on fungi.
Minimum Inhibitory Concentration (Mic) Measurement:
The MIC was determined using the disc diffusion technique by preparing discs containing 1.9–1000µg/ml of each compound against gram negative Escherichia coli, Pseudomonas aeuroginosa and gram positive Staphylococcus aureus, Bacillus subtilis bacterial and Candida albicans, Aspergillus flavus as fungal and applying the protocol. The two fold dilutions of the solution were prepared. The microorganism suspensions at 10CFU/ml (colony forming unit/ml) concentrations were inoculated to the corresponding wells. The plates were incubated at 36°C for 24 h. for the bacteria. The standard antibiotic Ampicillin and Antifungal Clotrimazole was also recorded using the same procedure as above at the same concentration and solvents. At the end of the incubation period, the minimum inhibitory concentrations (MIC) values were recorded as the lowest concentration of the substance that had showed clear zone [42, 43]. Control experiments with DMSO and un-inoculated media were run parallel to the test compounds under the same condition.
Results in table (2) indicated that, synthesized compound 3 had the lowest concentration that can be resulted in the largest inhibition zone and the highest activity index according to table (1) followed by the compounds 19a and 12 respectively and clearly this made them the best compounds that can be used as strong antimicrobial agent with the minimum inhibitory concentrations. Furthermore, the synthesized compound 24a showed that it had no effect on the microbes under study and no clear zone appear despite we use a high concentration of it followed by the compound 23a, so both of them cannot be used as antimicrobial agents as it had very weak effect on microbes. All other synthesized compounds had medium antimicrobial effect with a medium minimum inhibitory concentrations.
Table (1)
Antibacterial and antifungal activities of synthesized compounds
| Compound | E. coli | P. aeuroginosa | S. aureus | B. subtilis | C. Albicans | A. flavus | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Diameter of inhibition zone (mm) | % Activity index | Diameter of inhibition zone (mm) | % Activity index | Diameter of inhibition zone (mm) | % Activity index | Diameter of inhibition zone (mm) | % Activity index | Diameter of inhibition zone (mm) | % Activity index | Diameter of inhibition zone (mm) | % Activity index | |
| 3 | 13 | 52 | 19 | 82.6 | 16 | 66.7 | 21 | 91.3 | 12 | 44.4 | 17 | 68 |
| 5 | 3 | 12 | 6 | 26.1 | 7 | 29.2 | 8 | 34.8 | NA | ---- | 4 | 16 |
| 7 | 2 | 8 | 5 | 21.7 | 4 | 16.7 | 7 | 30.4 | 3 | 11.1 | 9 | 36 |
| 9 | 4 | 16 | 8 | 34.8 | 9 | 37.5 | 10 | 43.5 | 13 | 48.1 | 18 | 72 |
| 11 | 7 | 28 | 10 | 43.5 | 11 | 45.8 | 13 | 56.5 | 9 | 33.3 | 12 | 48 |
| 12 | 9 | 36 | 16 | 69.6 | 14 | 58.3 | 19 | 82.6 | 12 | 44.4 | 15 | 60 |
| 15 | 6 | 24 | 10 | 43.5 | 10 | 41.7 | 11 | 47.8 | 6 | 22.2 | 11 | 44 |
| 17 | 7 | 28 | 13 | 56.5 | 12 | 50 | 15 | 65.2 | 8 | 29.6 | 12 | 48 |
| 19a | 10 | 40 | 17 | 73.9 | 13 | 54.2 | 18 | 78.3 | 10 | 37 | 14 | 56 |
| 23a | NA | ---- | 3 | 13 | 2 | 8.3 | 4 | 17.4 | NA | ---- | 2 | 8 |
| 24a | NA | ---- | NA | ---- | NA | ---- | 2 | 8.7 | NA | ---- | 6 | 24 |
| Amp. | 25 | 100 | 23 | 100 | 24 | 100 | 23 | 100 | NA | ---- | NA | ---- |
| Col. | NA | ---- | NA | ---- | NA | ---- | NA | ---- | 27 | 100 | 25 | 100 |
NA → No Activity.
Table (2)
Minimum inhibitory concentrations (MIC) for tested compounds
| Compound | E. coli | P. aeuroginosa | S. aureus | B. subtilis | C. Albicans | A.flavus |
|---|---|---|---|---|---|---|
| 3 | 1 | 1 | 2 | 1 | 4 | 1 |
| 5 | 64 | 64 | 32 | 32 | NA | 64 |
| 7 | 16 | 64 | 64 | 32 | 64 | 16 |
| 9 | 64 | 64 | 32 | 16 | 4 | 1 |
| 11 | 32 | 8 | 8 | 8 | 16 | 4 |
| 12 | 8 | 2 | 4 | 2 | 8 | 2 |
| 15 | 32 | 16 | 16 | 16 | 32 | 8 |
| 17 | 32 | 4 | 8 | 4 | 16 | 8 |
| 19a | 2 | 2 | 4 | 4 | 8 | 4 |
| 23a | NA | 32 | 16 | 64 | NA | 16 |
| 24a | NA | NA | NA | 16 | NA | 32 |
| Ampicillin | 0.5 | 2 | 1 | 4 | ---- | ---- |
| Clotrimazole | ---- | ---- | ---- | ---- | 2 | 1 |
NA → No Activity
In this work, 1,3-cyclohexanedione 1 reacted with cyanoacetic acid hydrazide to afford bis (2-cyanoaceto hydrazide) derivative 3. Cyanoacetic acid hydrazide and their analogues are especially important starting material for the synthesis of new biologically heterocyclic compounds. Our research deals with the effective use of bis (2-cyanoaceto hydrazide) derivative 3 in the synthesis of a variety of polyfunctionally azoles and (or) azines with biological interest.
ACKNOWLEDGEMENTS
The authors are very grateful to Prof. Dr. Mohamed. S. A. El-Gaby, Department of Chemistry, Faculty of Science, Al-Azhar University, Assiut, Egypt, for valuable support and reviewing this manuscript.
The melting points, the elemental analyses and the spectral data were recorded as reported in reference [44].
General synthesis of 2-cyano-N'-(3-(2-(2-cyanoacetyl)hydrazinyl)cyclohex-2-en-1-ylidene)acetohydrazide (3)
To a stirred solution of 2-cyanoaceto acid hydrazide 2 (0.02 mol, 5.48 g) in glacial acetic acid (10 mL) / ethanol (30 mL) and 1,3-cyclohexadione 1 (0.01 mol, 1.12 g) was added dropwise from 5-10 mins and reaction mixture was stirred at room temperature for about 12 hrs The separated solid was filtered off washed with ethanol, dried and recrystallized from ethanol to give(3) as paleyellow crystals: M.P.: 230-232 oC, yield: 2.65 g (96%). IR (KBr) (vmax/cm-1): 3447-3224 (NH), 2964-2945 (CH-aliphatic), 2216 (CN), 1678 (CO). MS (EI, 70 eV): m/z (%) = 275 (M++1). 1H NMR (400 MHz, DMSO-d6): d (ppm) 1.72-1.91 (m, 2H, CH2), 2.23-2.32 (m, 4H, 2CH2), 3.36 (s, 2H, CH2), 3.95 (s, 2H, CH2), 5.54 (s, 1H, CH-cyclohexene), 8.52 (s, 1H, NH), 9.96 (s, 1H, NH), 10.38 (s, 1H, NH). 13C NMR (100 MHz, DMSO-d6) d 21.86, 24.70, 26.52, 26.63, 31.45, 86.93, 116.66, 116.88, 156.79, 160.20, 162.12, 164.67. Anal. Calcd. for C12H14N6O2 (274): C, 52.55; H, 5.15; N, 30.64. Found: C, 52.62; H, 5.20; N, 30.70.
Synthesis of 2-cyano-N'-(3-(2-(2-cyano-3-(dimethylamino)acryloyl)hydrazinyl)-cyclohex-2-en-1-ylidene)-3-(dimethylamino)acrylohydrazide (4)
A mixture of 3 (0.01 mol, 2.74 g) and dimethylformamide-dimethylacetal (DMF-DMA) (0.02 mol) in dioxane (30 mL) was heated under reflux for 6 hrs after cooling, The separated solid was filtered off, dried and recrystallized from ethanol to give (3) as pale brown crystals: M.P.: 142-144 oC, yield: 3.25 g (84%). IR (KBr) (vmax/cm-1): 3381-3193 (NH), 2935-2870 (CH-aliphatic), 2203 (CN), 1646 (CO). MS (EI, 70 eV): m/z (%) = 384 (M+). 1H NMR (400 MHz, DMSO-d6): d (ppm) 1.77-1.80 (m, 2H, CH2), 2.08-2.48 (m, 4H, 2CH2), 3.10 (s, 6H, N(CH3)2), 3.13 (s, 6H, N(CH3)2), 5.15 (s, 1H, CH-cyclohexene), 7.51 (s, 1H, CH- Oleffinic), 7.72 (s, 1H, CH-Oleffinic), 8.34 (s, 1H, NH), 8.90 (s, 1H, NH), 11.45 (hump, 1H, NH).Anal. Calcd. for C18H24N8O2 (384): C, 56.24; H, 6.29; N, 29.15. Found: C, 56.30; H, 6.34; N, 29.21.
Synthesis of 3-amino-N'-(3-(2-(3-amino-1H-pyrazole-4-carbonyl)hydrazinyl)cyclohex-2-en-1-ylidene)-1H-pyrazole-4-carbohydrazide (5)
In ethanol (30 mL)compound 4 (0.5 gm) and hydrazine hydrate (3 mL) was refluxed for 12 hrs. Upon reaction completion the reaction mixture was allowed to cool and poured into water/ice. The separated solid was collected, washed well with water and recrystallized from the ideal solvent to afford (5) as brown crystals from ethanol: M.P.: 240-242 oC, yield: 2.25 g (63%). IR (KBr) (vmax/cm-1): 3400-3163 (NH2/NH), 2957 (CH-aliphatic), 1617 (CO). MS (EI, 70 eV): m/z (%) = 358 (M+). 1H NMR (400 MHz, DMSO-d6): d (ppm) 0.84-1.99 (m, 2H, CH2), 2.01-2.89 (m, 4H, 2CH2), 4.70 (s, 1H, CH- cyclohexene), 6.99 (s, 4H, 2NH2), 7.12 (s, 2H, CH-pyrazole), 7.24 (s, 2H, 2NH), 7.49-8.00 (hump, 3H, 3NH). Anal. Calcd. for C14H18N10O2 (358): C, 46.92; H, 5.06; N, 39.09. Found: C, 46.97; H, 5.13; N, 39.15.
Synthesis of 2-(4-hydroxythiazol-2-yl)-N'-(3-(2-(2-(4-hydroxythiazol-2-yl)acetyl)-hydrazinyl)-cyclohex-2-en-1-ylidene)acetohydrazide (7)
Thioglycolic acid (0.02 mol), compound 3 (0.01 mol, 2.74 g) were dissolved in DMF (20 mL) and anhydrous ZnCl2 (0.5 gm) was added as a catalyst. The reaction mixture was heated under reflux with stirring for about 10 hrs. Upon reaction completion the reaction mixture was allowed to cool and poured into water/ice and triturated with an excess of 10% sodium bicarbonate solution. The solid product obtained was recrystallized from ethanol to give (7) as brown crystals: M.P.: 152-154 oC, yield: 2.25 g (53%). IR (KBr) (vmax/cm-1): 3403-3200 (OH/NH), 2936 (CH-aliphatic), 1620 (CO). MS (EI, 70 eV): m/z (%) = 424 (M++2). 1H NMR (400 MHz, DMSO-d6): d (ppm) 0.84-1.91 (m, 2H, CH2), 2.09-2.99 (m, 4H, 2CH2), 3.18 (s, 2H, CH2), 3.37 (s, 2H, CH2), 4.50 (s, 1H, CH-cyclohexene), 7.32 (s, 2H, CH-thiazole), 8.18 (s, 1H, NH), 8.23 (s, 1H, NH), 8.35 (hump, 1H, NH), 11.50 (hump, 2H, 2OH). 13C NMR (100 MHz, DMSO-d6) d 21.90, 24.81, 34.90, 39.31, 39.52, 88.60, 128.92, 128.92, 144.73, 144.73, 157.0, 160.10, 162.20, 166.10, 171.84, 171.84.Anal. Calcd. for C16H18N6O4S2 (422): C, 45.49; H, 4.29; N, 19.89. Found: C, 45.55; H, 4.34; N, 19.95.
Synthesis of 2-cyano-N'-(3-(2-(2-cyano-3-phenylacryloyl)hydrazinyl)cyclohex-2-en-1-ylidene)-3-phenylacrylohydrazide (8)
A solution of 3 (0.01 mol, 2.74 g) in ethanol (30 mL) was treated with (0.02 mol, 2.12 g) of benzaldehyde and few drops of piperidine. The reaction mixture was heated under reflux for 6 hrs. the reaction mixture was left to cool at room temperature and poured into ice/water containing few drops of hydrochloric acid, and the formed solids was collected by filtration and recrystallized from ethanol to give (8) as red crystals: M.P.: 160-162 oC, yield: 3.85 g (85%). IR (KBr) (vmax/cm-1): 3429-3400 (NH), 3063 (CH-aromatic), 2936 (CH-aliphatic), 2191 (CN), 1626 (CO). MS (EI, 70 eV): m/z (%) = 451 (M++1). 1H NMR (400 MHz, DMSO-d6): d (ppm) 1.05-1.65 (m, 2H, CH2), 2.66-2.99 (m, 4H, 2CH2), 4.77 (s, 1H, CH- cyclohexene), 7.31-7.93 (m, 12H, CH-aromatic and CH- Oleffinic), 9.71 (s, 1H, NH), 9.93 (s, 1H, NH), 10.03 (s, 1H, NH). 13C NMR (100 MHz, DMSO-d6) d 22.65, 25.10, 32.40, 106.0, 106.0, 108.0, 118.60, 118.60, 128.20, 128.50, 128.50, 129.64, 129.64, 129.64, 129.64, 130.47, 130.47, 130.47, 130.47, 132.10, 132.10, 136.10, 136.10, 156.10, 159.50, 168.70.Anal. Calcd. for C26H22N6O2 (450): C, 69.32; H, 4.92; N, 18.66. Found: C, 69.40; H, 4.97; N, 18.72.
Synthesis of 3-amino-N'-(3-(2-(3-amino-5-phenyl-1H-pyrazole-4-carbonyl)hydrazinyl)-cyclohex-2-en-1-ylidene)-5-phenyl-1H-pyrazole-4-carbohydrazide (9)
A mixture of 8 (0.5 gm) and hydrazine hydrate (10 mL) was fused for 6 hrs after cooling poured into ice/water containing a few drops of hydrochloric acid. The formed solid was filtered, washed with water, and recrystallized from ethanol to give (9) as brown crystals: M.P.: 120-122 oC, yield: 4.25 g (83%). IR (KBr) (vmax/cm-1): 3506-3248 (NH2/NH), 3055 (CH-aromatic), 2958 (CH-aliphatic), 1625 (CO). MS (EI, 70 eV): m/z (%) = 510 (M+). 1H NMR (400 MHz, DMSO-d6): d (ppm) 0.75-1.83 (m, 2H, CH2), 2.20-2.45 (m, 4H, 2CH2), 4.70 (s, 1H, CH- cyclohexene), 5.90 (s, 4H, 2NH2), 7.74-7.79 (m, 10H, CH-aromatic), 8.40 (s, 1H, NH), 8.40 (s, 1H, NH), 10.30 (hump, 1H, NH), 12.50 (hump, 2H, 2NH). Anal. Calcd. forC26H26N10O2 (510):C, 61.17; H, 5.13; N, 27.43.Found: C, 61.22; H, 5.19; N, 27.50.
Synthesis of 2-cyano-N'-(3-(2-(2-cyano-3-(2-hydroxyphenyl)acryloyl)hydrazinyl)-cyclohex-2-en-1-ylidene)-3-(2-hydroxyphenyl)acrylohydrazide (10)
A mixture of compound 3 (0.01 mol, 2.74 g), salicyladehyde (0.02 mol) and piperidine (3 drops) in ethanol (30 mL) was heated under reflux for 12 hrs after cooling poured into ice/water containing a few drops of hydrochloric acid. The resulting precipitate was filtered off, dried, and recrystallized from ethanol to give (10) as orange crystals: M.P.: 170-172 oC, yield: 3.75 g (77%). IR (KBr) (vmax/cm-1): 3420-3380 (OH/NH), 2936 (CH-aliphatic), 2222 (CN), 1626 (CO). MS (EI, 70 eV): m/z (%) = 482 (M+). 1H NMR (400 MHz, DMSO-d6): d (ppm) 1.23-1.91 (m, 2H, CH2), 2.09-2.80 (m, 4H, 2CH2), 4.60 (s, 1H, CH- cyclohexene), 6.99-7.17 (m, 10H, CH-aromatic and CH-Oleffinic), 8.03 (s, 1H, NH), 8.05 (s, 1H, NH), 10.00 (s, 2H, 2OH), 10.20 (hump, 1H, NH).Anal. Calcd. for C26H22N6O4 (482): C, 64.72; H, 4.60; N, 17.42. Found: C, 64.79; H, 4.65; N, 17.47.
Synthesis of 2-imino-N'-(3-(2-(2-imino-2H-chromene-3-carbonyl)hydrazinyl)cyclohex-2-en-1-ylidene)-2H-chromene-3-carbohydrazide (11)
To a solution of compound 10 (0.5 gm) in dioxane (10 mL) containing a few drops of piperidine was heated under reflux for 24 hrs. The reaction mixture was allowed to cool. The separated solid was filtered off washed with water, dried and recrystallized from ethanol to give (11) as red crystals: M.P.: 218-220 oC, yield: 4.25 g (88%). IR (KBr) (vmax/cm-1): 3423-3217 (NH), 3050 (CH-aromatic), 2934 (CH-aliphatic), 1686 (CO). MS (EI, 70 eV): m/z (%) = 483 (M++1). 1H NMR (400 MHz, DMSO-d6): d (ppm) 1.22-1.92 (m, 2H, CH2), 2.20-2.80 (m, 4H, 2CH2), 4.19 (s, 1H, CH-cyclohexene), 6.99-7.96 (m, 8H, CH-aromatic), 8.03 (s, 2H, CH-pyrane), 8.60 (s, 1H, NH), 9.87 (s, 1H, NH), 10.51 (s, 2H, 2NH), 11.67 (s, 1H, NH). 13C NMR (100 MHz, DMSO-d6) d 22.47, 25.9, 27.3, 98.3, 114.3, 114.3, 115.1, 115.1, 118.3, 118.3, 123.5, 123.5, 129.7, 129.7, 129.9, 129.9, 131.4, 131.4, 155.2, 155.2, 157.2, 161.5, 161.5, 162.4, 167.2, 170.4. Anal. Calcd. forC26H22N6O4(482):C, 64.72; H, 4.60; N, 17.42.Found: C, 64.78; H, 4.66; N, 17.50.
General procedure for the Synthesis of (12,13)
To a solution of compound 3 (0.01 mol, 2.74 g), malononitrile (0.02 mol, 1.32 g) and (or) acetylacetone (0.02 mol) respectively in ethanol (20 mL) containing a few drops of piperidine, was added and reaction mixture was heated under reflux for 12 hrs then poured into ice/water containing a few drops of hydrochloric acid. The formed solid product was collected by filtration, dried and recrystallized from ethanol to give 12,13.
4,6-Diamino-1-((3-((4,6-diamino-3-cyano-2-oxopyridin-1(2H)-yl)amino)cyclohex-2-en-1-ylidene)amino)-2-oxo-1,2-dihydropyridine-3-carbonitrile (12)
It was obtained as brown crystals: M.P.: 180-182 oC, yield: 3.65 g (89%). IR (KBr) (vmax/cm-1): 3448-3330 (NH2/NH), 2950 (CH-aliphatic), 2196 (CN), 1631 (CO). MS (EI, 70 eV): m/z (%) = 406 (M+). 1H NMR (400 MHz, DMSO-d6): d (ppm) 1.61-1.83 (m, 2H, CH2), 2.09-2.59 (m, 4H, 2CH2), 3.56 (s, 1H, CH-cyclohexene), 5.77 (s, 4H, 2NH2), 6.20 (s, 4H, 2NH2), 6.88 (s, 2H, CH-pyridine), 8.50 (s, 1H, NH). 13C NMR (100 MHz, DMSO-d6) d 22.69, 24.86, 33.70, 44.20, 44.20, 55.49, 55.49, 98.15, 114.45, 114.45, 128.50, 128.50, 157.20, 163.10, 168.60, 168.60, 183.80, 183.80. Anal. Calcd. forC18H18N10O2 (406): C, 53.20; H, 4.46; N, 34.47.Found: C, 53.27; H, 4.52; N, 34.54.
1-((3-((3-Cyano-4,6-dimethyl-2-oxopyridin-1(2H)-yl)amino)cyclohex-2-en-1-ylidene)-amino)-4,6-dimethyl-2-oxo-1,2-dihydropyridine-3-carbonitrile (13)
It was obtained as brown crystals: M.P.: 218-220 oC, yield: 3.50 g (87%). IR (KBr) (vmax/cm-1): 3448 (NH), 2959-2838 (CH-aliphatic), 2220 (CN), 1627 (CO). MS (EI, 70 eV): m/z (%) = 402 (M+). 1H NMR (400 MHz, DMSO-d6): d (ppm) 1.55-1.91 (m, 2H, CH2), 2.23 (s, 6H, 2CH3), 2.31 (s, 6H, 2CH3), 2.37-2.43 (m, 4H, 2CH2), 4.60 (s, 1H, CH-cyclohexene), 6.20 (s, 2H, CH-pyridine), 9.05 (s, 1H, NH). 13C NMR (100 MHz, DMSO-d6) d 19.36, 19.36, 20.67, 20.67, 22.47, 25.72, 36.93, 99.50, 108.35, 108.35, 109.21, 109.21, 116.56, 116.56, 132.20, 132.20, 155.49, 155.49, 160.93, 161.44, 161.44, 196.52. Anal. Calcd. forC22H22N6O2 (402): C, 65.66; H, 5.51; N, 20.88.Found: C, 65.73; H, 5.57; N, 20.95.
Synthesis of 1-((3-((5-cyano-4-methyl-2,6-dioxo-3,6-dihydropyridin-1(2H)-yl)amino)-cyclohex-2-en-1-ylidene)amino)-4-methyl-2,6-dioxo-1,2,5,6-tetrahydro-pyridine-3-carbonitrile (14)
A mixture of compound 3 (0.01 mol, 2.74 g) and ethyl acetoacetate (0.02 mol) was fused for 12 hrs at 150 oC. The reaction mixture was allowed to cool, and then triturated with ethanol. The separated solid was filtered off washed with water, dried and recrystallized from ethanol to give (14) as brown crystals: M.P.: 170-172 oC, yield: 3.50 g (87%). IR (KBr) (vmax/cm-1): 3426 (NH), 2980-2935 (CH-aliphatic), 2223 (CN), 1727 (CO). MS (EI, 70 eV): m/z (%) = 402 (M+). 1H NMR (400 MHz, DMSO-d6): d (ppm) 0.90-1.70 (m, 2H, CH2), 2.23 (s, 6H, 2CH3), 2.27-2.43 (m, 4H, 2CH2), 2.78 (s, 4H, 2CH2), 5.98 (s, 1H, CH-cyclohexene), 7.28 (s, 1H, NH). Anal. Calcd. for C20H18N6O4 (406): C, 59.11; H, 4.46; N, 20.68.Found: C, 59.19; H, 4.53; N, 20.74.
Synthesis of 3,5-diamino-4-cyano-N'-(3-(2-(3,5-diamino-4-cyanothiophene-2-carbonyl)-hydrazinyl)cyclohex-2-en-1-ylidene)thiophene-2-carbohydrazide (15)
To a solution of compound 3 (0.01 mol, 2.74 g) in ethanol (20 mL) containing TEA (3 drops), elemental sulfur (0.02 mol, 0.64 g) was added followed by malononitrile (0.02 mol, 1.32 g). The reaction mixture was heated under reflux for 10 hrs then poured into ice/water containing a few drops of hydrochloric acid and the formed solid product was collected by filtration, dried and recrystallized from ethanol to give (15) as pale brown crystals: M.P.: 215-217 oC, yield: 3.90 g (83%). IR (KBr) (vmax/cm-1): 3423-3197 (NH2/NH), 2927 (CH-aliphatic), 2203 (CN), 1628 (CO). MS (EI, 70 eV): m/z (%) = 472 (M++2). 1H NMR (400 MHz, DMSO-d6): d (ppm) 0.78-1.80 (m, 2H, CH2), 2.08-2.46 (m, 4H, 2CH2), 5.76 (s, 1H, CH-cyclohexene), 6.10 (s, 4H, 2NH2), 6.60 (s, 4H, 2NH2), 7.31 (s, 1H, NH), 7.34 (s, 1H, NH), 11.78 (s, 1H, NH). 13C NMR (100 MHz, DMSO-d6) d 22.43, 25.7, 26.3, 83.2, 83.2, 99.8, 118.2, 118.2, 134.4, 158.3, 158.3, 158.7, 158.7, 160, 163.6, 163.7, 163.7, 170.2. Anal. Calcd. for C18H18N10O2S2 (470): C, 45.95; H, 3.86; N, 29.77. Found: C, 46.01; H, 3.94; N, 29.84.
Synthesis of 4-amino-N'-(3-(2-(4-amino-3-phenyl-2-thioxo-2,3-dihydrothiazole-5-carbonyl)-hydrazinyl)cyclohex-2-en-1-ylidene)-3-phenyl-2-thioxo-2,3-dihydro-thiazole-5-carbohydrazide (16)
To a solution of compound 3 (0.01 mol, 2.74 g) in ethanol (20 mL) containing TEA (3 drops), elemental sulfur (0.02 mol, 0.64 g) was added followed by phenyl isothiocyanate (0.02 mol). The reaction mixture was heated under reflux for 12 hrs then poured into ice/water containing a few drops of hydrochloric acid and the formed solid product was collected by filtration, dried and recrystallized from ethanol to give (16) as brown crystals: M.P.: 148-150 oC, yield: 4.95 g (81%). IR (KBr) (vmax/cm-1): 3423-3250 (NH2/NH), 2936 (CH-aliphatic), 1628 (CO). MS (EI, 70 eV): m/z (%) = 610 (M++2). 1H NMR (400 MHz, DMSO-d6): d (ppm) 0.84-1.91 (m, 2H, CH2), 2.09-2.90 (m, 4H, 2CH2), 4.60 (s, 1H, CH-cyclohexene), 5.70 (s, 4H, 2NH2), 7.31-7-65 (m, 10H, CH-aromatic), 8.30 (hump, 1H, NH), 9.20 (s, 1H, NH), 11.20 (hump, 1H, NH). Anal. Calcd. for C26H24N8O2S4 (608): C, 51.30; H, 3.97; N, 18.41. Found: C, 51.37; H, 4.05; N, 18.48.
Synthesis of 2-amino-N'-(3-(2-(2-amino-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carbonyl)-hydrazinyl)cyclohex-2-en-1-ylidene)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carbohydrazide (17)
To a solution of compound 3 (0.01 mol, 2.74 g) in ethanol (20 mL) containing TEA (3 drops), elemental sulfur (0.02 mol, 0.64 g) was added followed by cyclohexanone (0.02 mol). The reaction mixture was heated under reflux for 24 hrs then poured into ice/water containing a few drops of hydrochloric acid and the formed solid product was collected by filtration, dried and recrystallized from ethanol to give (17) as brown crystals: M.P.: 110-112 oC, yield: 4.25 g (85%). IR (KBr) (vmax/cm-1): 3420-3196 (NH2/NH), 2931-2857 (CH-aliphatic), 1624 (CO). MS (EI, 70 eV): m/z (%) = 500 (M++2). 1H NMR (400 MHz, DMSO-d6): d (ppm) 1.24-1.91 (m, 10H, 5CH2), 2.20-3.66 (m, 12H, 6CH2), 4.49 (s, 1H, CH-cyclohexene), 6.92 (s, 4H, 2NH2), 7.23 (s, 1H, NH), 7.31 (s, 1H, NH), 7.32 (s, 1H, NH). Anal. Calcd. for C24H30N6O2S2 (498): C, 57.81; H, 6.06; N, 16.85. Found: C, 57.87; H, 6.13; N, 16.92.
Synthesis of 2-amino-N'-(3-(2-(2-amino-4-cyano-5-methyl-1H-pyrrole-3-carbonyl)-hydrazinyl)-cyclohex-2-en-1-ylidene)-4-cyano-5-methyl-1H-pyrrole-3-carbohydrazide (18)
A mixture of compound 3 (0.01 mol, 2.74 g) and acetonitrile dimer (0.02 mol) in ethanol (20 mL) containing a few drops of piperidine was refluxed for 6 hrs. The reaction mixture was cooled and the solid so obtained was filtered off and recrystallized from ethanol to give (18) as brown crystals: M.P.: 190-192 oC, yield: 3.70 g (85%). IR (KBr) (vmax/cm-1): 3450-3207 (NH2/NH), 2931-2863 (CH-aliphatic), 2200 (CN), 1641 (CO). MS (EI, 70 eV): m/z (%) = 434 (M+). 1H NMR (400 MHz, DMSO-d6): d (ppm) 1.19-1.98 (m, 2H, CH2), 2.20 (s, 6H, 2CH3), 2.29-2.69 (m, 4H, 2CH2), 4.70 (s, 1H, CH-cyclohexene), 6.39 (s, 4H, 2NH2), 7.31 (s, 1H, NH), 7.60 (s, 1H, NH), 9.40 (s, 1H, NH), 13.00 (s, 2H, 2NH). Anal. Calcd. for C20H22N10O2 (434): C, 55.29; H, 5.10; N, 32.24. Found: C, 55.36; H, 5.16; N, 32.31.
General procedure for the Synthesis of (19a,b)
A mixture of 3 (0.01 mol, 2.74 g) and 3-phenyl-1-phenylprop-2-en-1-one, 3-(4-chlorophenyl)-1-phenylprop-2-en-1-one (0.02 mol) respectively in ethanol (30 mL) with a catalytic amount of piperidine was heated under reflux for 6 hrs. The reaction mixture was allowed to cool and poured into crushed ice then acidified with HCl. The separated solid was filtered off washed with water, dried and recrystallized from the ideal solvent to give 19a,b.
2-Amino-N'-(3-(2-(2-amino-4,6-diphenyl-4H-pyran-3-carbonyl)hydrazinyl)-cyclo-hex-2-en-1-ylidene)-4,6-diphenyl-4H-pyran-3-carbohydrazide (19a)
It was obtained as brown crystals from ethanol: M.P.: 212-214 oC, yield: 5.20 g (75%). IR (KBr) (vmax/cm-1): 3416-3220 (NH2/NH), 2937-2860 (CH-aliphatic), 1629 (CO). MS (EI, 70 eV): m/z (%) = 690 (M+). 1H NMR (400 MHz, DMSO-d6): d (ppm) 1.59-1.91 (m, 2H, CH2), 2.20-2.80 (m, 4H, 2CH2), 3.66 (d, 2H, 4H-pyrane), 4.60 (s, 1H, CH-cyclohexene), 5.71 (d, 2H, =CH-pyrane), 7.48-7.53 (m, 24H, CH-aromatic and 2NH2), 7.86 (s, 1H, NH), 8.21 (s, 1H, NH), 10.00 (hump, 1H, 1NH). 13C NMR (100 MHz, DMSO-d6) d 22.59, 25.80, 30.11, 31.48, 44.05, 44.05, 88.30, 88.30, 99.50, 99.50, 113.24, 127.10, 127.10, 127.10, 127.10, 127.73, 127.73, 128.38, 128.38, 128.38, 128.38, 128.57, 128.57, 128.57, 128.57, 129.23, 129.23, 129.23, 129.23, 129.86, 129.86, 130.11, 139.25, 139.25, 148.50, 148.50, 156.96, 160.10, 162.90, 166.30, 168.70, 192.90. Anal. Calcd. for C42H38N6O4 (690): C, 73.03; H, 5.54; N, 12.17. Found: C, 73.10; H, 5.60; N, 12.25.
2-Amino-N'-(3-(2-(2-amino-4-(4-chlorophenyl)-6-phenyl-4H-pyran-3-carbonyl)-hydr-azinyl)cyclohex-2-en-1-ylidene)-4-(4-chlorophenyl)-6-phenyl-4H-pyran-3-carbohydr-azide (19b)
It was obtained as pale brown crystals from ethanol: M.P.: 160-162 oC, yield: 4.80 g (63%). IR (KBr) (vmax/cm-1): 3423-3200 (NH2/NH), 2939-2859 (CH-aliphatic), 1633 (CO). MS (EI, 70 eV): m/z (%) = 760 (M++2). 1H NMR (400 MHz, DMSO-d6): d (ppm) 1.20-1.59 (m, 2H, CH2), 2.00-2.48 (m, 4H, 2CH2), 3.68 (d, 2H, 4H-pyrane), 4.60 (s, 1H, CH-cyclohexene), 5.70 (d, 2H, =CH-pyrane), 7.44-7.61 (m, 22H, CH-aromatic and 2NH2), 7.87 (s, 1H, NH), 8.20 (s, 1H, NH), 10.00 (hump, 1H, 1NH). Anal. Calcd. for C42H36Cl2N6O4 (758): C, 66.40; H, 4.78; N, 11.06. Found: C, 66.47; H, 4.85; N, 11.12.
General procedure for the Synthesis of (20a,b):
To a solution of 3 (0.01 mol, 2.74 g) in ethanol (30 mL) and 2-(4-chlorobenzylidene)malononitrile, 2-(4-methoxybenzylidene)malononitrile (0.02 mol) respectively were added. The reaction mixture was treated with a few drops of piperidine, and then refluxed for 6 hrs. The reaction mixture was allowed to cool and poured into crushed ice then acidified with HCl. The separated solid was filtered off washed with water, dried and crystallized from the proper solvent to give 20a,b.
6-Amino-1-((3-((6-amino-4-(4-chlorophenyl)-3,5-dicyano-2-oxopyridin-1(2H)-yl)-amino)-cyclohex-2-en-1-ylidene)amino)-4-(4-chlorophenyl)-2-oxo-1,2-dihydro-pyridine-3,5-dicarbonitrile (20a):
It was obtained as orange crystals from ethanol: M.P.: 142-144 oC, yield: 4.30 g (66%). IR (KBr) (vmax/cm-1): 3419-3200 (NH2/NH), 2939-2861 (CH-aliphatic), 2211 (CN), 1632 (CO). MS (EI, 70 eV): m/z (%) = 648 (M++2). 1H NMR (400 MHz, DMSO-d6): d (ppm) 1.77-1.85 (m, 2H, CH2), 2.21-2.78 (m, 4H, 2CH2), 4.70 (s, 1H, CH-cyclohexene), 5.70 (s, 4H, 2NH2), 7.23-7-63 (m, 8H, CH-aromatic), 10.30 (s, 1H, NH). 13C NMR (100 MHz, DMSO-d6) d 23.4, 26.2, 28.3, 77.9, 77.9, 101, 117.3, 117.3, 117.8, 117.8, 117.8, 117.8, 129.8, 129.8, 129.8, 129.8, 131, 131, 131, 131, 131.8, 131.8, 135.5, 135.5, 160.2, 160.2, 160.8, 161.3, 161.7, 161.7, 171.3, 171.3. Anal. Calcd. for C32H20Cl2N10O2 (646): C, 59.36; H, 3.11; N, 21.63. Found: C, 59.44; H, 3.17; N, 21.70.
6-Amino-1-((3-((6-amino-3,5-dicyano-4-(4-methoxyphenyl)-2-oxopyridin-1(2H)-yl)-amino)cyclohex-2-en-1-ylidene)amino)-4-(4-methoxyphenyl)-2-oxo-1,2-dihydro-pyridine-3,5-dicarbonitrile (20b):
It was obtained as pale yellow crystals from ethanol: M.P.: 170-172 oC, yield: 4.90 g (76%). IR (KBr) (vmax/cm-1): 3422-3224 (NH2/NH), 2938-2860 (CH-aliphatic), 2213 (CN), 1636 (CO). MS (EI, 70 eV): m/z (%) = 638 (M+). 1H NMR (400 MHz, DMSO-d6): d (ppm) 0.84-1.86 (m, 2H, CH2), 2.09-2.75 (m, 4H, 2CH2), 3.85 (s, 6H, 2OCH3), 4.60 (s, 1H, CH-cyclohexene), 5.71 (s, 4H, 2NH2), 7.06-7.47 (m, 8H, CH-aromatic), 10.30 (s, 1H, NH). Anal. Calcd. for C34H26N10O4 (638): C, 63.94; H, 4.10; N, 21.93. Found: C, 64.00; H, 4.18; N, 21.99.
General procedure for the Synthesis of (21a,b):
To a cold solution of 3 (0.01 mol, 2.74 g) in ethanol (20 mL) containing sodium acetate (3 g) was added with continuous stirring either of the appropriate substituted bezenediazonium salt (0.02 mol) [prepared by adding sodium nitrite (0.02 mol) in water to a cold solution of either of the appropriate substitute aniline in the appropriate amount of hydrochloric acid]. The reaction mixture was stirred for 1 hrs and the formed solid product, in each case, was collected by filtration, dried and recrystallized from the proper solvent to give 21a,b.
N-(4-chlorophenyl)-2-(2-(3-(2-(2-(2-(4-chlorophenyl)hydrazono)-2-cyanoacetyl)-hydrazinyl)-cyclohex-2-en-1-ylidene)hydrazinyl)-2-oxoacetohydrazonoyl cyanide (21a):
It was obtained as pale red crystals from ethanol: M.P.: 182-184 oC, yield: 3.20 g (58%). IR (KBr) (vmax/cm-1): 3449-3400 (NH), 3058 (CH-aromatic), 2992 (CH-aliphatic), 2217 (CN), 1656 (CO). MS (EI, 70 eV): m/z (%) = 552 (M++2). 1H NMR (400 MHz, DMSO-d6): d (ppm) 1.23-1.91 (m, 2H, CH2), 2.51-2.75 (m, 4H, 2CH2), 4.49 (s, 1H, CH-cyclohexene), 6.88-7.58 (m, 8H, CH-aromatic), 7.80 (s, 1H, NH), 8.20 (s, 1H, NH), 11.63 (s, 1H, NH), 11.80 (s, 2H, 2NH). Anal. Calcd. for C24H20Cl2N10O2 (550): C, 52.28; H, 3.66; N, 25.40. Found: C, 52.35; H, 3.72; N, 25.47.
2-(2-(3-(2-(2-Cyano-2-(2-(4-methoxyphenyl)hydrazono)acetyl)hydrazinyl)cyclohex-2-en-1-ylidene)hydrazinyl)-N-(4-methoxyphenyl)-2-oxoacetohydrazonoyl cyanide (21b):
It was obtained as red crystals from ethanol: M.P.: 160-162 oC, yield: 4.20 g (77%). IR (KBr) (vmax/cm-1): 3449-3200 (NH), 2937-2837 (CH-aliphatic), 2213 (CN), 1662 (CO). MS (EI, 70 eV): m/z (%) = 542 (M+). 1H NMR (400 MHz, DMSO-d6): d (ppm) 1.23-1.91 (m, 2H, CH2), 2.60-3.00 (m, 4H, 2CH2), 3.85 (s, 6H, 2OCH3), 4.18 (s, 1H, CH-cyclohexene), 6.70-7.36 (m, 8H, CH-aromatic), 7.88 (s, 1H, NH), 8.30 (s, 1H, NH), 10.80 (hump, 1H, NH), 13.20 (s, 2H, 2NH). Anal. Calcd. for C26H26N10O4 (542): C, 57.56; H, 4.83; N, 25.82. Found: C, 57.63; H, 4.90; N, 25.90.
General procedure for the Synthesis of (22a,b):
A mixture of compounds 21a,b (0.01 mol) and hydroxylamine hydrochloride (0.02 mol) in ethanol (20 mL), sodium acetate (2 gm) and water (3 drops) was heated at reflux for 12 hrs. The reaction mixture was allowed to cool and poured into crushed ice. The separated solid was filtered off washed with water, dried and recrystallized from the proper solvent to give 22a,b.
3-(2-(3-(2-(3-Amino-2-(2-(4-chlorophenyl)hydrazono)-3-(hydroxyimino)propanoyl)-hydrazinyl)-cyclohex-2-en-1-ylidene)hydrazinyl)-2-(2-(4-chlorophenyl)hydrazono)-N'-hydroxy-3-oxo-propanimidamide (22a):
It was obtained as pale brown crystals from ethanol: M.P.: 148-150 oC, yield: 3.90 g (63%). IR (KBr) (vmax/cm-1): 3372-3183 (OH/NH2/NH), 2928-2860 (CH-aliphatic), 1673 (CO). MS (EI, 70 eV): m/z (%) = 618 (M++2). 1H NMR (400 MHz, DMSO-d6): d (ppm) 1.24-1.65 (m, 2H, CH2), 2.51-2.64 (m, 4H, 2CH2), 3.35 (s, 1H, CH-cyclohexene), 5.87 (s, 2H, 2OH), 7.14-7.60 (m, 12H, CH-aromatic and 2NH2), 10.54 (s, 1H, NH), 11.18 (s, 1H, NH), 11.81 (s, 1H, NH), 12.81 (s, 2H, 2NH). Anal. Calcd. for C24H26Cl2N12O4 (616): C, 46.69; H, 4.24; N, 27.22. Found: C, 46.75; H, 4.30; N, 27.29.
3-(2-(3-(2-(3-Amino-3-(hydroxyimino)-2-(2-(4-methoxyphenyl)hydrazono)propanoyl)-hydr-azinyl)cyclohex-2-en-1-ylidene)hydrazinyl)-N'-hydroxy-2-(2-(4-methoxyphenyl)-hydrazono)-3-oxopropanimidamide (22b):
It was obtained as red crystals from ethanol: M.P.: 170-172 oC, yield: 4.40 g (72%). IR (KBr) (vmax/cm-1): 3423-3205 (OH/NH2/NH), 2935-2836 (CH-aliphatic), 1639 (CO). MS (EI, 70 eV): m/z (%) = 608 (M+). 1H NMR (400 MHz, DMSO-d6): d (ppm) 1.24-1.64 (m, 2H, CH2), 2.51-2.64 (m, 4H, 2CH2), 3.35 (s, 1H, CH-cyclohexene), 3.77 (s, 6H, 2OCH3), 5.74 (s, 2H, 2OH), 6.93-7.49 (m, 12H, CH-aromatic and 2NH2), 10.47 (s, 1H, NH), 11.04 (s, 1H, NH), 11.66 (s, 1H, NH), 12.81 (s, 2H, 2NH). Anal. Calcd. for C26H32N12O6 (608): C, 51.31; H, 5.30; N, 27.62. Found: C, 51.38; H, 5.36; N, 27.69.
General procedure for the Synthesis of (23a,b):
A solution of 22a,b (0.5 gm) in DMF (15 mL) containing a few drops of piperidine was heated at reflux for 24 hrs. The reaction mixture was allowed to cool and poured into crushed ice and acidified with HCl. The separated solid was filtered off washed with water, dried and recrystallized from the proper solvent to give 23a,b.
5-Amino-N'-(3-(2-(5-amino-2-(4-chlorophenyl)-2H-1,2,3-triazole-4-carbonyl)hydrazinyl)-cyclo-hex-2-en-1-ylidene)-2-(4-chlorophenyl)-2H-1,2,3-triazole-4-carbohydrazide (23a):
It was obtained as pale brown crystals from ethanol: M.P.: 136-138 oC, yield: 5.30 g (91%). IR (KBr) (vmax/cm-1): 3470-3419 (NH2/NH), 3050 (CH-aromatic), 2925-2856 (CH-aliphatic), 1656 (CO). MS (EI, 70 eV): m/z (%) = 582 (M++2). 1H NMR (400 MHz, DMSO-d6): d (ppm) 1.20-1.80 (m, 2H, CH2), 2.51-2.89 (m, 4H, 2CH2), 3.35 (s, 1H, CH-cyclohexene), 7.36-7.71 (m, 12H, CH-aromatic and 2NH2), 7.96 (s, 1H, NH), 8.28 (s, 1H, NH), 10.30 (hump, 1H, NH). Anal. Calcd. for C24H22Cl2N12O2 (580): C, 49.58; H, 3.81; N, 28.91. Found: C, 49.66; H, 3.88; N, 28.98.
5-Amino-N'-(3-(2-(5-amino-2-(4-methoxyphenyl)-2H-1,2,3-triazole-4-carbonyl)hydr-azinyl)-cyclohex-2-en-1-ylidene)-2-(4-methoxyphenyl)-2H-1,2,3-triazole-4-carbohydr-azide (23b):
It was obtained as brown crystals from ethanol: M.P.: 160-162 oC, yield: 3.40 g (59%). IR (KBr) (vmax/cm-1): 3470-3419 (NH2/NH), 3050 (CH-aromatic), 2928-2845 (CH-aliphatic), 1656 (CO). MS (EI, 70 eV): m/z (%) = 572 (M+). 1H NMR (400 MHz, DMSO-d6): d (ppm) 1.23-1.90 (m, 2H, CH2), 2.51-2.83 (m, 4H, 2CH2), 3.36 (s, 1H, CH-cyclohexene), 3.82 (s, 6H, 2OCH3), 7.09-7.92 (m, 12H, CH-aromatic and 2NH2), 7.96 (s, 1H, NH), 8.30 (s, 1H, NH), 11.31 (s, 1H, NH). Anal. Calcd. for C26H28N12O4 (572): C, 54.54; H, 4.93; N, 29.36. Found: C, 54.60; H, 4.99; N, 29.43.
General procedure for the Synthesis of (24a,b):
A mixture of compounds 21a,b (0.5 gm) and hydrazine hydrate (10 mL) was fused for 12 hrs. The reaction mixture was allowed to cool and poured into crushed ice containing a few drops of hydrochloric acid. The separated solid was filtered off washed with water, dried and recrystallized from the proper solvent to give 24a,b.
5-(2-(3-(2-(3-Amino-4-((4-chlorophenyl)diazenyl)-1H-pyrazol-5-yl)hydrazinyl)cyclo-hex-2-en-1-ylidene)hydrazinyl)-4-((4-chlorophenyl)diazenyl)-1H-pyrazol-3-amine (24a):
It was obtained as brown crystals from ethanol: M.P.: 178-180 oC, yield: 4.60 g (79%). IR (KBr) (vmax/cm-1): 3422-3200 (NH2/NH), 2937-2830 (CH-aliphatic). MS (EI, 70 eV): m/z (%) = 580 (M++2). 1H NMR (400 MHz, DMSO-d6): d (ppm) 1.24-1.91 (m, 2H, CH2), 2.09-2.38 (m, 4H, 2CH2), 4.70 (s, 1H, CH-cyclohexene), 6.00 (s, 4H, 2NH2), 7.30-8.40 (m, 11H, CH-aromatic and 3 NH), 12.60 (hump, 2H, 2NH). Anal. Calcd. for C24H24Cl2N14 (578): C, 49.75; H, 4.17; N, 33.84. Found: C, 49.82; H, 4.23; N, 33.90.
5-(2-(3-(2-(3-Amino-4-((4-methoxyphenyl)diazenyl)-1H-pyrazol-5-yl)hydrazinyl)cyclohex-2-en-1-ylidene)hydrazinyl)-4-((4-methoxyphenyl)diazenyl)-1H-pyrazol-3-amine (24b)
It was obtained as brown crystals from ethanol: M.P.: 140-142 oC, yield: 4.20 g (73%). IR (KBr) (vmax/cm-1): 3470-3204 (NH2/NH), 3050 (CH-aromatic), 2928 (CH-aliphatic). MS (EI, 70 eV): m/z (%) = 570 (M+). 1H NMR (400 MHz, DMSO-d6): d (ppm) 0.84-1.99 (m, 2H, CH2), 2.10-2.93 (m, 4H, 2CH2), 3.80 (s, 6H, 2OCH3), 4.80 (s, 1H, CH-cyclohexene), 6.88 (s, 4H, 2NH2), 7.07-7.72.40 (m, 11H, CH-aromatic and 3 NH), 8.33-8.47 (hump, 2H, 2NH). Anal. Calcd. for C26H30N14O2 (570): C, 54.73; H, 5.30; N, 34.37. Found: C, 54.80; H, 5.36; N, 34.45.
Synthesis of N-(3-amino-4-(p-tolyldiazenyl)-1H-pyrazol-5-yl)-2-(2-(3-(2-(2-(2-(3-amino-4-(p-tolyldiazenyl)-1H-pyrazol-5-yl)hydrazono)-2-cyanoacetyl)hydrazinyl)cyclohex-2-en-1-ylidene)-hydrazinyl)-2-oxoacetohydrazonoyl cyanide (25):
A cold suspension of aryl diazonium salts (0.02 mol) (prepared from 0.02 mol of heteroaromatic amine with the appropriate quantities of sodium nitrite and hydrochloric acid) was gradually added to a cold solution (0-5oC) of 3 (0.01 mol, 2.74 g) in ethanol (30 mL) containing anhydrous sodium acetate (1 g) with continuous stirring for 2 hrs. The resulting reaction product was filtered off, washed with water and recrystallized from ethanolto give (25) as brown crystals: M.P.: 208-210 oC, yield: 5.60 g (77%). IR (KBr) (vmax/cm-1): 3398-3303 (NH2/NH), 2919-2861 (CH-aliphatic), 2215 (CN), 1679 (CO). MS (EI, 70 eV): m/z (%) = 728 (M+). 1H NMR (400 MHz, DMSO-d6): d (ppm) 0.80-1.90 (m, 2H, CH2), 2.20-2.36 (m, 4H, 2CH2), 2.38 (s, 6H, 2CH3), 4.70 (s, 1H, CH-cyclohexene), 6.50 (s, 4H, 2NH2), 7.20-7.84 (m, 15H, CH-aromatic and 7NH). Anal. Calcd. for C32H32N20O2 (728): C, 52.74; H, 4.43; N, 38.44. Found: C, 52.81; H, 4.49; N, 38.50.
General procedure for the Synthesis of (26a,b, 27a,b):
A solution of 3 (0.01 mol, 2.74 g) in ethanol (30 mL) containing a few drops of piperidine was treated with (0.02 mol) of 5-benzylideneimidazolidine-2,4-dione, 5-(2,4-dichlorobenzylidene)imidazolidine-2,4-dione, 2-benzylidene-cyclohexan-1-one and 2-(4-methoxybenzylidene)cyclohexan-1-one respectively. The reaction mixture was heated under reflux for 6 hrs. The reaction mixture was left to cool at room temperature and poured into ice/water containing a few drops of hydrochloric acid, and the formed solids was collected by filtration, dried and recrystallized from the proper solvent to give 26a,b, 27a,b.
5-Amino-N'-(3-(2-(5-amino-2-oxo-7-phenyl-1,2,3,7-tetrahydropyrano[2,3-d]imidazole-6-carbonyl)hydrazinyl)cyclohex-2-en-1-ylidene)-2-oxo-7-phenyl-1,2,3,7-tetrahydro-pyrano[2,3-d]-imidazole-6-carbohydrazide (26a):
It was obtained as brown crystals from ethanol: M.P.: 220-222 oC, yield: 4.60 g (70%). IR (KBr) (vmax/cm-1): 3421-3200 (NH2/NH), 2925-2854 (CH-aliphatic), 1770, 1628 (2CO). MS (EI, 70 eV): m/z (%) = 650 (M+). 1H NMR (400 MHz, DMSO-d6): d (ppm) 0.84-1.91 (m, 2H, CH2), 2.09-3.00 (m, 4H, 2CH2), 3.90 (s, 2H, 4H-pyrane), 4.70 (s, 1H, CH-cyclohexene), 6.40 (s, 4H, 2NH2), 6.92-7-66 (m, 13H, CH-aromatic and 3NH), 10.70 (s, 2H, 2NH), 11.40 (s, 2H, 2NH). Anal. Calcd. for C32H30N10O6 (650): C, 59.07; H, 4.65; N, 21.53. Found: C, 59.14; H, 4.70; N, 21.58.
5-Amino-N'-(3-(2-(5-amino-7-(2,4-dichlorophenyl)-2-oxo-1,2,3,7-tetrahydropyrano[2,3-d]-imid-azole-6-carbonyl)hydrazinyl)cyclohex-2-en-1-ylidene)-7-(2,4-dichlorophenyl)-2-oxo-1,2,3,7-tetrahydropyrano[2,3-d]imidazole-6-carbohydrazide (26b):
It was obtained as pale brown crystals from ethanol: M.P.: 180-182 oC, yield: 5.20 g (66%). IR (KBr) (vmax/cm-1): 3423-3181 (NH2/NH), 3066 (CH-aromatic), 2935-2856 (CH-aliphatic), 1770, 1634 (2CO). MS (EI, 70 eV): m/z (%) = 788 (M++2). 1H NMR (400 MHz, DMSO-d6): d (ppm) 1.23-1.65 (m, 2H, CH2), 2.09-3.00 (m, 4H, 2CH2), 3.90 (s, 2H, 4H-pyrane), 4.49 (s, 1H, CH-cyclohexene), 6.48 (s, 4H, 2NH2), 7.31-7-73 (m, 9H, CH-aromatic and 3NH), 10.74 (s, 2H, 2NH), 11.40 (s, 2H, 2NH). Anal. Calcd. for C32H26Cl4N10O6 (786): C, 48.75; H, 3.32; N, 17.77. Found: C, 48.82; H, 3.40; N, 17.83.
2-Amino-N'-(3-(2-(2-amino-4-phenyl-5,6,7,8-tetrahydro-4H-chromene-3-carbonyl)-hydrazinyl)-cyclohex-2-en-1-ylidene)-4-phenyl-5,6,7,8-tetrahydro-4H-chromene-3-carbohydrazide (27a):
It was obtained as red crystals from ethanol: M.P.: 168-170 oC, yield: 4.40 g (68%). IR (KBr) (vmax/cm-1): 3446-3200 (NH2/NH), 2934-2862 (CH-aliphatic), 1628 (CO). MS (EI, 70 eV): m/z (%) = 646 (M+). 1H NMR (400 MHz, DMSO-d6): d (ppm) 1.19-1.91 (m, 10H, 5CH2), 2.57-2.98 (m, 12H, 6CH2), 3.68 (s, 2H, 4H-pyrane), 4.60 (s, 1H, CH-cyclohexene), 5.80 (s, 4H, 2NH2), 7.23-7-36 (m, 13H, CH-aromatic and 3 NH). Anal. Calcd. for C38H42N6O4 (646): C, 70.57; H, 6.55; N, 12.99. Found: C, 70.64; H, 6.61; N, 13.04.
2-Amino-N'-(3-(2-(2-amino-4-(4-methoxyphenyl)-5,6,7,8-tetrahydro-4H-chromene-3-carbonyl)-hydrazinyl)cyclohex-2-en-1-ylidene)-4-(4-methoxyphenyl)-5,6,7,8-tetra-hydro-4H-chromene-3-carbohydrazide (27b):
It was obtained as pale brown crystals from ethanol: M.P.: 180-182 oC, yield: 5.40 g (76%). IR (KBr) (vmax/cm-1): 3419-3200 (NH2/NH), 2937-2833 (CH-aliphatic), 1656 (CO). MS (EI, 70 eV): m/z (%) = 706 (M+). 1H NMR (400 MHz, DMSO-d6): d (ppm) 1.59-1.73 (m, 10H, 5CH2), 2.51-2.89 (m, 12H, 6CH2), 3.36 (s, 2H, 4H-pyrane), 3.81 (s, 6H, 2OCH3), 4.10 (s, 1H, CH-cyclohexene), 5.70 (s, 4H, 2NH2), 7.01-7-59 (m, 11H, CH-aromatic and 3 NH). Anal. Calcd. for C40H46N6O6 (706): C, 67.97; H, 6.56; N, 11.89. Found: C, 68.04; H, 6.63; N, 11.96.
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Scheme 1-7 is available in supplementary section.
No competing interests reported.