New Azacycles by One‐Pot Three‐Component Hantzsch‐Like Synthesis of Tetra(hexa)azacyclopenta[a]anthracenes, Tetraazaindeno[5,4‐b]fluorenes, and Oxatetraazacyclopenta[m]tetraphenes

Abstract

New Azacycles by One‐Pot Three‐Component Hantzsch‐Like Synthesis of Tetra(hexa)azacyclopenta[a]anthracenes, Tetraazaindeno[5,4‐b]fluorenes, and Oxatetraazacyclopenta[m]tetraphenes (H. Butenschön, I. A. Abdelhamid et al.) #OpenAccess

Multicomponent reactions (MCRs) are envisaged as an entry point for the synthesis of heterocyclic compounds with interesting biological activities. An efficient approach to annelated tetra(hexa)azacyclopenta[a]anthracenes, tetraazaindeno[5,4‐b]fluorenes, and oxatetraazacyclopenta[m]tetraphene was accomplished using a three‐component reaction involving 7‐amino‐2‐methyl‐3‐phenylpyrazolo[1,5‐a]pyrimidin‐5‐one with aromatic aldehydes and the corresponding active 1,3‐dicarbonyl compounds (namely, dimedone, 1,3‐dimethylbarbituric acid, 1,3‐indanedione, and 4‐hydroxycoumarine). The reactions were conducted in glacial acetic acid at reflux for 5 h to give the desired products in good yields (62–83 %). The chemical constitutions of all new products were confirmed spectroscopically.

An efficient approach to annelated tetra(hexa)azacyclopenta[a]anthracenes, tetraazaindeno[5,4‐b]fluorenes, and oxatetraazacyclopenta[m]tetraphene was accomplished via the one pot three‐component reaction involving 7‐amino‐2‐methyl‐3‐phenylpyrazolo[1,5‐a]pyrimidin‐5‐one with aromatic aldehydes and the corresponding active 1,3‐dicarbonyl compounds (namely, dimedone, 1,3‐dimethylbarbituric acid, 1,3‐indanedione, and 4‐hydroxycoumarine)

Introduction

Multicomponent reactions (MCRs) represent an attractive and efficient rapid access to important organic compounds.[ ¹ , ² , ³ , ⁴ , ⁵ ] Among these, the Hantzsch reaction is one of the most frequently used multicomponent reactions for producing 1,4‐dihydropyridines (1,4‐DHPs), which have a wide range of biological and pharmacological effects, including antituberculosis, ^[6] anticancer, ^[7] anticonvulsant, ^[8] antiviral, ^[9] anti‐inflammatory, ^[10] anti‐Alzheimer, ^[11] and anticonvulsant ^[12] activities. Numerous FDA‐approved drugs based on the 1,4‐dihydropyridine moiety like nisoldipine, amlodipine, and felodipine were introduced as calcium channel blockers for treatment of hypertension (Figure 1). ^[13] Besides, pyrazolo[1,5‐a]pyrimidines indicated a wide range of biological activities that include CRF‐1 receptor antagonists, ^[14] KDR kinase inhibitors, ^[15] antischistosomal, ^[16] and antiproliferative agents. ^[17] Zaleplone, an FDA‐approved sedative/hypnotic for short term treatment of insomnia, is a pyrazolo[1,5‐a]pyrimidine derivative (Figure 1). ^[18] In addition, due to their remarkable photophysical properties, pyrazolo[1,5‐a]pyrimidines received noticeable interest in material science as promising fluorophores.[ ¹⁹ , ²⁰ , ²¹ , ²² ] In continuation of our interest in enamine chemistry,[ ²³ , ²⁴ ] Hantzsch[ ²⁵ , ²⁶ , ²⁷ , ²⁸ ] and Michael addition reactions,[ ²⁹ , ³⁰ , ³¹ , ³² , ³³ , ³⁴ ] in this contribution, we describe the full details of our investigation on the syntheses of novel annelated tetra(hexa)azacyclopenta[a]anthracenes, tetraazaindeno[5,4‐b]fluorenes, and oxatetraazacyclopenta[m]tetraphene derivatives.

Figure 1.

Some FDA‐approved dihydropyridine ^[13] and pyrazolo[1,5‐a]pyrimidine ^[18] based drugs.

Results and Discussion

Recently, we reported the synthesis of 7‐amino‐2‐methyl‐3‐phenylpyrazolo[1,5‐a]pyrimidin‐5(4H)‐one 3 from the reaction of 3‐methyl‐4‐phenyl‐1H‐pyrazol‐5‐amine 1 with 3‐(3,5‐dimethyl‐1H‐pyrazol‐1‐yl)‐3‐oxopropanenitrile 2 in toluene under reflux conditions (Scheme 1). ^[23] Besides, we studied the utility of 3 as a precursor for the synthesis of the new symmetric ring system heptaza‐dicyclopenta[a,j]anthracenes I (Figure 2). ^[23] In an effort to develop efficient syntheses of novel heterocycles, here, we show how compound 3 may be used as starting material for a novel series of aza‐polycyclic aromatic compounds (II) through the unsymmetric Hantzsch reaction of one mole equivalent of 3 with one mole equivalent of both, aldehydes and active methylene compounds (Figure 2).

Scheme 1.

Synthesis of 7‐aminopyrazolo[1,5‐a]pyrimidin‐5(4H)‐one 3. ^[23]

Figure 2.

Structure of the targeted symmetric and unsymmetric Hantzsch products. ^[23]

Initially, we conducted the reaction of the 7‐amino‐2‐methyl‐3‐phenylpyrazolo[1,5‐a]pyrimidin‐5‐one 3 with aromatic aldehydes 4 and dimedone 5 in a trial to prepare a novel series of tetraazacyclopenta[a]anthracenes 6 (IUPAC name: pyrazolo[5′,1′:2,3]pyrimido[4,5‐b]quinoline‐5,7‐diones). Thus, the cyclo‐condensation reaction of the substituted aldehydes 4 with one mole equivalent of both 7‐amino‐2‐methyl‐3‐phenylpyrazolo[1,5‐a]pyrimidin‐5‐one 3 and dimedone 5 in the presence of acetic acid directly leads to the formation of the target products 6 a‐d in 66–78 % yield (Scheme 2). As a representative example, the constitution of compound 6 a was confirmed on the basis of its spectral data. Thus, the IR spectra featured the presence of NH groups with a broad absorption band at $\tilde{\nu }$ 3266 cm⁻¹. In addition, the spectra indicated two sharp bands at $\tilde{\nu }$ 1653 and 1631 cm⁻¹ corresponding to the ketonic and amidic carbonyl groups, respectively. The ¹H NMR spectrum of 6 a showed three singlets at δ 0.91, 1.03, and 2.33 ppm assigned to the three methyl groups. In addition, it indicated an AB line system as two pairs of doublets at δ 2.05–2.27 ppm (J=−16.0 Hz) and δ 2.59–2.78 ppm (J=−17.5 Hz) related to diastereotropic protons H10 and H8, respectively. In addition, it featured a singlet at δ 4.98 ppm assigned to H6. It also revealed signals assigned to the aryl protons as multiplets at δ 7.07–7.39 ppm. Absorptions of the two NH groups appeared as two broad signals at δ 10.30 and 11.80 ppm, respectively.

Scheme 2.

Synthesis of pyrazolo[5′,1′:2,3]pyrimido[4,5‐b]quinoline‐5,7‐diones 6 a‐d.

Replacing dimedone 5 with 1,3‐dimethylbarbituric acid 7, which has two additional nitrogen atoms, afforded the hexaazacyclopenta[a]anthracenes 8 in 75–82 % yield. Thus, the three‐component reaction of aldehydes 4, 1,3‐dimethylbarbituric acid 7 and 7‐amino‐2‐methyl‐3‐phenylpyrazolo[1,5‐a]pyrimidin‐5‐one 3 in glacial acetic under reflux conditions gave 1,4,8,10,11,11b‐hexaazacyclopenta[a]anthracene‐5,7,9‐triones 8 a‐c (Scheme 3).

Scheme 3.

Synthesis of 1,4,8,10,11,11b‐hexaazacyclopenta[a]anthracene‐5,7,9‐triones 8 a‐c.

In contrast, the replacement of dimedone by 1,3‐indanedione 9 leads to additional annulation to pentacyclic structure 10 (tetraazaindeno[5,4‐b]fluorene). This finding warrants interest, because compounds with an indenopyridine moiety show a wide range of bioactivities including calcium antagonistic, ^[35] antidepressant,[ ³⁶ , ³⁷ ] and antihistamine activities.[ ³⁶ , ³⁷ ] They also act as NK‐1 and dopamine receptor ligands. ^[38] Thus, under the same reaction conditions, the cyclocondensation reaction of aldehydes with both 3 and 1,3‐indandione 9 proceeded smoothly, and a new series of indeno[2′,1′:5,6]pyrido[3,2‐e]pyrazolo[1,5‐a]pyrimidine‐5,7‐diones 10 was obtained (Scheme 4). Surprisingly, in the presence of an electron‐withdrawing nitro group in 4, the reaction yields the non‐oxidized product 10 d in high yield, while the other derivatives directly afford the readily oxidized products 10 a‐c. It is noteworthy to mention that these compounds can be considered as 1,4,12,12b‐tetraazaindeno[5,4‐b]fluorene analogues.

Scheme 4.

Synthesis of indeno[2′,1′:5,6]pyrido[3,2‐e]pyrazolo[1,5‐a]pyrimidine‐5,7‐diones 10 a‐d

Encouraged by the above results, our study was extended to include the synthesis of chromeno[3′,4′:5,6]pyrido[3,2‐e]pyrazolo[1,5‐a]pyrimidine‐5,7(4H)‐dione derivatives 12 via the cyclocondensation of aldehydes 4 with both 4‐hydroxycoumarin 11 and 3. These ring systems can be regarded as 1,4,8,13,13b‐oxatetraazacyclopenta[m]tetraphene analogues (Scheme 5). In contrast to the three‐component reaction incorporating 1,3‐indanedione (Scheme 4), only partially oxidized products 12 a‐d could be obtained under the same reaction condition even at prolonged reaction times under reflux conditions (up to 12 h).

Scheme 5.

Synthesis of chromeno[3′,4′:5,6]pyrido[3,2‐e]pyrazolo[1,5‐a]pyrimidine‐5,7(4H)‐diones 12 a‐d.

As indicated in Scheme 6, we propose a plausible pathway for these transformations based on the Hantzsch reaction‘s classical mechanism. Generally, the reaction pathway involves the initial acid‐catalyzed enamine addition of 3 to the aldehyde 4 to yield intermediate 13 which loses water to form the unstable ylidene 14. The ylidene 14 then reacts with one equivalent of an active methylene compound (5, 7, 9, or 11) yielding the intermediate 15, which cyclizes into 16. The intermediate 15 loses water and becomes deprotonated, producing the final isolable product 6, 8, 10, or 12 respectively. (Scheme 6).

Scheme 6.

A proposed mechanism for the synthesis of compounds 6, 8, 10, and 12.

As a part of our sequential work on spirocyclic oxindoles,[ ³⁹ , ⁴⁰ , ⁴¹ , ⁴² , ⁴³ , ⁴⁴ , ⁴⁵ ] we modified the structures by replacing the aldehydes with isatin 17 to achieve the concept of molecular hybridization ^[46] to improve their medicinal efficacy and overcome drug resistance.[ ⁴⁷ , ⁴⁸ , ⁴⁹ , ⁵⁰ ] Thus, the reaction of isatin 17 and 7‐amino‐2‐methyl‐3‐phenylpyrazolo[1,5‐a]pyrimidin‐5‐one 3 with either dimedone 5 or indan‐1,3‐dione 9 leads to the formation of the spirocyclic oxindoles of the respective tetraazacyclopenta[a]anthracene 18 or tetraazaindeno[5,4‐b]fluorene 19 (Scheme 7). The constitutions of the obtained products were confirmed by inspection of their spectral data.

Scheme 7.

Synthesis of spirocyclic compounds 18 and 19.

We believe that more effort is still needed in order to further broaden the scope of reaction of 7‐amino‐2‐methyl‐3‐phenylpyrazolo[1,5‐a]pyrimidin‐5‐one 3 especially in Hantzsch‐like reactions for the purpose of elaboration of interesting new ring systems. The bioactivity and the photophysical properties of the synthesized tetra(hexa)azacyclopenta[a]anthracenes 6 and 8, tetraazaindeno[5,4‐b]fluorenes 19, and oxatetraazacyclopenta[m]tetraphene 12 derivatives as new ring systems are currently under investigation.

Conclusion

We have reported the first efficient route for the synthesis of new annelated ring systems including tetra(hexa)azacyclopenta[a]anthracenes 6 and 8, tetraazaindeno[5,4‐b]fluorenes 10, and oxatetraazacyclopenta[m]tetraphene 12 derivatives using a three‐component one pot reaction. The sequence involves the reaction of one mole equivalent of 7‐aminopyrazolo[1,5‐a]pyrimidin‐5‐one 3 with one mole equivalent of both aldehydes and active methylene reagents.

Experimental Section

General: Melting points were measured with a Stuart melting point apparatus and are uncorrected. The IR spectra were recorded using a FTIR Bruker–vector 22 spectrophotometer as KBr pellets. The ¹H and ¹³C NMR spectra were recorded in DMSO–d₆ as solvent with a Bruker AVS 400 instrument (¹H: 400.1 MHz, ¹³C: 100.6 MHz) or a Varian Gemini NMR spectrometer (¹H: 300 MHz, ¹³C: 75 MHz). Chemical shifts δ refer to δ _TMS=0.00 ppm or to residual solvent signals. The multiplicities of the ¹³C signals in some compounds were determined by ATP measurements. Due to poor solubilities, ¹³C NMR spectral data for compounds 8a, 8c, 10a, 10b, 10c, 12b, and 12d are not provided. Mass spectra were recorded with a Shimadzu GCMS–QP–1000 EX mass spectrometer in EI (70 eV) model. The elemental analyses were performed at the Microanalytical center, Cairo University. All solvents and reagents was supplied by Sigma‐Aldrich and used as received. 7‐Amino‐2‐methyl‐3‐phenylpyrazolo[1,5‐a]pyrimidin‐5(4H)‐one 3 was synthesized according to the reported literatures. ^[23]

General procedure (GP) for the synthesis of compounds 6, 8, 10, 12, 18 and 19: A mixture of 7‐amino‐2‐methyl‐3‐phenylpyrazolo[1,5‐a]pyrimidin‐5(4H)‐one 3 ^[23] (0.24 g, 1 mmol), aromatic aldehyde 4 (1 mmol) or isatin 17 (0.15 g, 1 mmol), and the cyclic 1,3‐dicarbonyl compound (dimedone 5, 1,3‐dimethylbarbituric acid 7, 1,3‐indanedione 9, or 4‐hydroxycoumarine 11) (1 mmol) was heated in glacial acetic acid (15 mL) at reflux for 5 h. The solvent was evaporated under reduced pressure and the residue was treated with aq. NaHCO₃ solution (2 n, 25 mL). The collected crude products were purified by crystallization from EtOH/dioxane mixture (2 : 1, v/v, 15 mL).

2,9,9‐Trimethyl‐3,6‐diphenyl‐6,9,10,11‐tetrahydropyrazolo[5′,1′:2,3]pyrimido[4,5‐b]quinoline‐5,7(4H,8H)‐dione (6 a): GP. Yellow powder (0.34 g, 75 %). Mp >300 °C. IR (KBr): $\tilde{\nu }$ 3266 (br, 2NH), 1663, 1631 (2CO) cm⁻¹. ¹H NMR (400 MHz, DMSO‐d₆): δ 0.91 (s, 3H, CH ₃), 1.04 (s, 3H, CH ₃), 2.05–2.27 (AB line system, ² J=−16.0 Hz, 2H, CH ₂), 2.49 (s, 3H, pyrazole CH ₃), 2.59–2.78 (AB line system, ² J=−17.5 Hz, 2H, CH ₂), 4.98 (s, 1H, CH), 7.07–7.42 (m, 10H, ArH), 10.37 (br s, 1H, NH), 11.79 (br s, 1H, NH) ppm. ¹³C NMR (100 MHz, DMSO‐d₆): δ 13.5 (CH₃), 27.1 (CH₃), 32.6 (CH₃), 34.1 (CH), 39.3 (CH₂), 50.6 (CH₂), 87.9 (C), 92.8 (C), 102.8 (C), 111.8 (C), 126.4 (CH), 127.0 (CH), 128.1 (CH), 128.2 (CH), 128.9 (CH), 129.6 (CH), 130.8 (C), 139.5 (C), 146.8 (C), 15.3 (C), 146.6 (C), 160.1 (CO), 173.4 (C), 195.0 (CO) ppm. MS (EI, 70 eV): m/z 450 [M]⁺. Anal. calcd. for C₂₈H₂₆N₄O₂: C 74.65; H 5.82; N 12.44. Found: C 74.41; H 5.63; N 12.65.

2,9,9‐Trimethyl‐6‐(4‐nitrophenyl)‐3‐phenyl‐6,9,10,11‐tetrahydropyrazolo[5′,1′:2,3]pyrimido[4,5‐b]quinoline‐5,7(4H,8H)‐dione (6 b): GP. Yellow powder (0.39 g, 78 %). Mp >300 °C. IR (KBr): $\tilde{\nu }$ 3346 (br, 2NH), 1667 (br, 2CO) cm⁻¹. ¹H NMR (400 MHz, DMSO‐d₆): δ 0.91 (s, 3H, CH ₃), 1.05 (s, 3H, CH ₃), 2.05–2.28 (AB line system, ² J=−17.8 Hz, 2H, CH ₂), 2.34 (s, 3H, CH ₃), 2.62–2.78 (AB line system, ² J=−17.6 Hz, 2H, CH ₂), 5.08 (s, 1H, CH), 7.30–8.11 (m, 9H, ArH), 10.55 (br s, 1H, NH), 11.67 (br s, 1H, NH) ppm. ¹³C NMR (100 MHz, DMSO‐d₆): δ 13.5 (CH₃), 27.2 (CH₃), 29.3 (CH₃), 32.6 (C), 35.0 (CH), 40.6 (CH₂), 50.5 (CH₂), 86.5 (C), 100.9 (C), 110.9 (C), 123.6 (CH), 127.1 (CH), 128.9 (CH), 129.6 (CH), 129.7 (CH), 139.9 (C), 146.1 (C), 146.3 (C), 150.9 (C), 151.0 (C), 154.2 (C), 160.0 (CO), 169.9 (C), 195.1 (CO) ppm. MS (EI, 70 eV): m/z 495 [M]⁺. Anal. calcd. for C₂₈H₂₅N₅O₄: C 67.87; H 5.09; N 14.13. Found: C 67.65; H 5.22; N,14.40.

6‐(Benzo[d][1,3]dioxol‐5‐yl)‐2,9,9‐trimethyl‐3‐phenyl‐6,9,10,11‐tetrahydropyrazolo[5′,1′:2,3]pyrimido[4,5‐b]quinoline‐5,7(4H,8H)‐dione (6 c): GP. Yellow powder (0.3 g, 66 %). Mp 270–272 °C. IR (KBr): $\tilde{\nu }$ 3419 (br, 2NH), 1627, 1592 (2CO) cm⁻¹. ¹H NMR (400 MHz, DMSO‐d₆): δ 0.94 (s, 3H, CH ₃), 1.04 (s, 3H, CH ₃), 2.07‐2.26 (AB line system, ² J=−17.6 Hz, 2H, CH ₂), 2.33 (s, 3H, pyrazole CH ₃), 2.58–2.77 (AB line system, ² J=−17.2 Hz, 2H, CH ₂), 4.90 (s, 1H, CH), 5.90 (s, 1H, OCH ₂O), 6.67–7.43 (m, 8H, ArH), 10.34 (br s, 1H, NH), 11.58 (br s, 1H, NH) ppm. ¹³C NMR (100 MHz, DMSO‐d₆): δ 13.5 (CH₃), 27.2 (CH₃), 29.4 (CH₃), 32.6 (C), 33.8 (CH), 40.6 (CH₂), 50.7 (CH₂), 92.9 (C), 101.1 (CH₂), 102.9 (C), 108.1 (CH), 108.9 (CH), 111.9 (C), 120.9 (CH), 127.0 (CH), 128.9 (CH), 129.7 (CH), 130.9 (C), 139.4 (C), 145.8 (C), 147.1 (C), 150.2 (C), 150.5 (C), 160.1 (C), 168.3 (C), 195.0 (CO) ppm. MS (EI, 70 eV): m/z 494 [M]⁺. Anal. calcd. for C₂₉H₂₆N₄O₄: C 70.43; H 5.30; N 11.33. Found: C 70.20; H 5.62; N 11.15.

2,9,9‐Trimethyl‐3‐phenyl‐6‐(p–tolyl)‐6,9,10,11‐tetrahydropyrazolo[5′,1′:2,3]pyrimido[4,5‐b]quinoline‐5,7(4H,8H)‐dione (6 d): GP. Yellow powder (0.36 g, 77 %). Mp >300 °C. IR (KBr): $\tilde{\nu }$ 3444, 3414 (2NH), 1665, 1634 (2CO) cm⁻¹, ¹H NMR (400 MHz, DMSO‐d₆): δ 0.91 (s, 3H, CH ₃), 1.04 (s, 3H, CH ₃), 2.04–2.22 (AB line system, ² J=−15.9 Hz, 2H, CH ₂), 2.19 (s, 3H, tolyl CH ₃), 2.34 (s, 3H, pyrazole CH ₃), 2.50‐2.72 (AB line system, ² J=−17.0 Hz, 2H, CH ₂), 4.93 (s, 1H, CH), 6.98–7.42 (m, 9H, ArH), 10.32 (br s, 1H, NH), 11.80 (br s, 1H, NH) ppm. ¹³C NMR (100 MHz, DMSO‐d₆): δ 13.4 (CH₃), 21.0 (CH₃), 21.5 (CH₃), 27.1 (CH₃), 29.5 (CH), 32.6 (C), 33.6 (CH), 40.8 (CH₂), 50.6 (CH₂), 102.8 (C), 112.0 (C), 126.9 (CH), 128.0 (CH), 128.8 (CH), 128.9 (CH), 129.6 (CH), 130.9 (C), 139.4 (C), 143.9 (C), 150.1 (C), 150.5 (C), 160.0 (C), 172.4 (CO), 195.0 (CO) ppm. MS (EI, 70 eV): m/z 464 [M]⁺, Anal. calcd. for C₂₉H₂₈N₄O₂: C 74.98; H 6.08; N 12.06. Found: C 74.87; H 6.35; N 12.34.

2,8,10‐Trimethyl‐3,6‐diphenyl‐4,6,11,11 b‐tetrahydro‐1,4,8,10,11,11 b‐hexaaza‐5H‐cyclopenta[a]anthracene‐5,7,9(8H,10H)‐trione (8 a): GP. Yellow powder (0.35 g, 75 %). Mp >300 °C. IR (KBr): $\tilde{\nu }$ 3360 (br, 2NH), 1647, 1579 (br, 3CO) cm⁻¹. ¹H NMR (300 MHz, DMSO‐d₆): δ 1.91 (s, 3H, CH ₃), 2.29 (s, 6H 2CH ₃), 5.81 (s, 1H, CH), 7.10‐7.40 (m, 10H, ArH), 11.57 (br, 2H, 2NH) ppm. MS (EI, 70 eV): m/z 466 [M]⁺. Anal. calcd. for C₂₆H₂₂N₆O₃: C 66.94; H 4.75; N 18.02. Found: C 66.68; H 4.51; N 17.83.

6‐(4‐Chlorophenyl)‐2,8,10‐trimethyl‐3‐phenyl‐4,6,11,11 b‐tetrahydro‐1,4,8,10,11,11 b‐hexaaza‐5H‐cyclopenta[a]anthracene‐5,7,9(8H,10H)‐trione (8 b): GP. Yellow powder (0.38 g, 76 %). Mp >300 °C. IR (KBr): $\tilde{\nu }$ 3404 (br, 2NH), 1653, 1581 (br, 3CO) cm⁻¹. ¹H NMR (300 MHz, DMSO‐d₆): δ 1.90 (s, 3H, CH ₃), 2.30 (s, 6H, 2CH ₃), 5.81 (s, 1H, CH), 7.03‐7.41 (m, 9H, ArH), 11.60 (br s, 2H, 2NH) ppm. ¹³C NMR (75 MHz, DMSO‐d₆): δ 12.9 (CH₃), 20.3 (CH₃), 20.8 (CH₃), 34.0 (CH), 79.7 (C), 87.9 (C), 101.6 (C), 126.2 (CH), 126.3 (CH), 128.2 (CH), 128.3 (CH), 129.1 (CH), 130.5 (C), 133.6 (C), 135.8 (C), 136.1 (C), 149.4 (C), 148.8 (C), 151.4 (C), 160.9 (CO), 171.7 (CO), 173.9 (CO) ppm. MS (EI, 70 eV): m/z 500 [M]⁺. Anal. calcd. for C₂₆H₂₁ClN₆O₃: C 62.34; H 4.23; N 16.78. Found: C 62.60; H 4.52; N 16.45.

2,8,10‐Trimethyl‐6‐(4‐nitrophenyl)‐3‐phenyl‐4,6,11,11 b‐tetrahydro‐1,4,8,10,11,11 b‐hexaaza‐5H‐cyclopenta[a]anthracene‐5,7,9(8H,10H)‐trione (8 c): GP. Yellow powder (0.42 g, 82 %). Mp 288–290 °C. IR (KBr): $\tilde{\nu }$ 3425, 3332 (2NH), 1690, 1646, 1611 (3CO) cm⁻¹. ¹H NMR (300 MHz, DMSO‐d₆): δ 1.89 (s, 3H, CH ₃), 2.30 (s, 6H, 2CH ₃), 5.91 (s, 1H, CH), 7.28‐8.12 (m, 9H, ArH), 11.60 (br, 2H, 2NH) ppm. MS (EI, 70 eV): m/z 511 [M]⁺. Anal. calcd. for C₂₆H₂₁N₇O₅: C 61.05; H 4.14; N 19.17. Found: C 61.27; H 4.39; N 18.98.

2‐Methyl‐3,6‐diphenyl‐4H‐indeno[2′,1′:5,6]pyrido[3,2‐e]pyrazolo[1,5‐a]pyrimidine‐5,7‐dione (10 a): GP. Yellow powder (0.35 g, 77 %). Mp >300 °C. IR (KBr): $\tilde{\nu }$ 3426 (NH), 1723, 1686 (2CO) cm⁻¹. ¹H NMR (300 MHz, DMSO‐d₆): δ 2.35 (s, 3H, CH ₃), 7.28‐8.04 (m, 14H, ArH), 11.80 (br s, 1H, NH) ppm. MS (EI, 70 eV): m/z 454 [M]⁺. Anal. calcd. for C₂₉H₁₈N₄O₂: C 76.64; H 3.99; N 12.33. Found: C 76.95; H 4.16; N 12.57.

6‐(4‐Chlorophenyl)‐2‐methyl‐3‐phenyl‐4H‐indeno[2′,1′:5,6]pyrido[3,2‐e]pyrazolo[1,5‐a]pyrimidine‐5,7‐dione (10 b): GP. Yellow powder (0.40 g, 81 %). Mp >300 °C. IR (KBr): $\tilde{\nu }$ 3447 (NH), 1675, 1617 (2CO) cm⁻¹. ¹H NMR (300 MHz, DMSO‐d₆): δ 2.31 (s, 3H, CH ₃), 7.33‐8.00 (m, 13H, ArH), 11.80 (br s, 1H, NH) ppm. MS (EI, 70 eV): m/z 488 [M]⁺. Anal. calcd. for C₂₉H₁₇ClN₄O₂: C 71.24; H 3.50; N 11.46. Found: C 71.09; H 3.18; N 11.60.

2‐Methyl‐3‐phenyl‐6‐(p–tolyl)‐4H‐indeno[2′,1′:5,6]pyrido[3,2‐e]pyrazolo[1,5‐a]pyrimidine‐5,7‐dione (10 c): GP. Yellow powder (0.36 g, 78 %). Mp 238–240 °C. IR (KBr): $\tilde{\nu }$ 3408 (NH), 1658 (br, 2CO) cm⁻¹. ¹H NMR (300 MHz, DMSO‐d₆): δ 2.32 (s, 3H, CH ₃), 2.42 (s, 3H, CH ₃), 7.20–7.97 (m, 13H, ArH), 11.60 (br s, 1H, NH) ppm. MS (EI, 70 eV): m/z 468 [M]⁺. Anal. calcd. for C₃₀H₂₀N₄O₂: C 76.91; H 4.30; N 11.96. Found: C 76.75; H 4.51; N 11.73.

2‐Methyl‐6‐(4‐nitrophenyl)‐3‐phenyl‐6,12‐dihydro‐4H‐indeno[2′,1′:5,6]pyrido[3,2‐e]pyrazolo[1,5‐a]pyrimidine‐5,7‐dione (10 d): GP. Orange powder (0.42 g, 83 %). Mp 292–294 °C. IR (KBr): $\tilde{\nu }$ 3397, 3344 (2NH), 1662 (br, 2CO) cm⁻¹. ¹H NMR (300 MHz, DMSO‐d₆): δ 2.40 (s, 3H, CH ₃), 5.02 (s, 1H, CH), 7.28‐8.27 (m, 13H, ArH) 11.80 (br, 2H, 2NH) ppm. ¹³C NMR (75 MHz, DMSO‐d₆): δ 12.8 (CH₃), 34.6 (CH), 82.8 (C), 93.0 (C), 108.8 (C), 120.4 (CH), 121.4 (CH), 123.1 (CH), 126.5 (CH), 128.3 (CH), 129.1 (CH), 129.2 (CH), 130.1 (CH), 132.1 (C), 132.2 (CH), 135.7 (C), 136.0 (C), 140.5 (C), 145.5 (C), 145.9 (C), 150.5 (C), 152.4 (C), 154.1 (C), 159.1 (CO), 168.3 (CO) ppm. MS (EI, 70 eV): m/z 501 [M]⁺. Anal. calcd. for C₂₉H₁₉N₅O₄: C 69.46; H 3.82; N 13.97. Found: C 69.22; H 3.52; N 13.71.

2‐Methyl‐3,6‐diphenyl‐6,13‐dihydro‐7H‐chromeno[3′,4′:5,6]pyrido[3,2‐e]pyrazolo[1,5‐a]pyrimidine‐5,7(4H)‐dione (12 a): GP. Yellow powder (0.35 g, 74 %). Mp 248–250 °C. IR (KBr): $\tilde{\nu }$ 3430, 3329 (2NH), 1656, 1615 (2CO) cm⁻¹. ¹H NMR (300 MHz, DMSO‐d₆): δ 2.32 (s, 3H, CH ₃), 5.81 (s, 1H, CH), 7.17‐7.86 (m, 14H, ArH), 12.10 (br s, 1H, NH), 14.6 (br s, 1H, NH) ppm.¹³C NMR (75 MHz, DMSO‐d₆): δ 12.9 (CH₃), 35.6 (CH), 49.2 (C), 71.9 (C), 88.1 (C), 104.5 (C), 116.0 (CH), 120.4 (CH), 120.5 (CH), 123.6 (CH), 124.1 (CH), 125.6 (CH), 126.3 (CH), 126.6 (CH), 128.0, (CH), 128.4 (CH), 129.3 (C), 130.0 (C), 132.2 (C), 135.6 (C), 138.1 (C), 149.2 (C), 150.6 (CO), 160.9 (CO), 163.5 (C) ppm. MS (EI, 70 eV): m/z 472 [M]⁺. Anal. calcd. for C₂₉H₂₀N₄O₃: C 73.72; H 4.27; N 11.86. Found: C 73.40; H 4.50; N 11.65.

6‐(4‐Chlorophenyl)‐2‐methyl‐3‐phenyl‐6,13‐dihydro‐7H‐chromeno[3′,4′:5,6]pyrido[3,2‐e]pyrazolo[1,5‐a]pyrimidine‐5,7(4H)‐dione (12 b): GP. Yellow powder (0.40 g, 80 %). Mp 292–294 °C. IR (KBr): $\tilde{\nu }$ 3407 (br, 2NH), 1644 (br, 2CO) cm⁻¹. ¹H NMR (300 MHz, DMSO‐d ₆): δ 2.35 (s, 3H, CH ₃), 5.10 (s, 1H, CH), 7.50–8.46 (m, 13H, ArH), 10.30 (br s, 1H, NH), 11.83 (br s, 1H, NH) ppm. MS (EI, 70 eV): m/z 506 [M]⁺. Anal. calcd. for C₂₉H₁₉ClN₄O₃: C 68.71; H 3.78; N 11.05. Found: C 68.50; H 3.95; N 11.29.

2‐Methyl‐3‐phenyl‐6‐(p–tolyl)‐6,13‐dihydro‐7H‐chromeno[3′,4′:5,6]pyrido[3,2‐e]pyrazolo[1,5‐a]pyrimidine‐5,7(4H)‐dione (12 c): GP. Yellow powder (0.38 g, 79 %), Mp >300 °C. IR (KBr): $\tilde{\nu }$ 3396 (NH), 1706, 1638 (2CO) cm⁻¹. ¹H NMR (400 MHz, DMSO‐d₆): δ 2.24 (s, 3H, CH ₃), 2.36 (s, 3H, CH ₃), 5.01 (s, 1H, CH), 7.07–8.86 (m, 14H, ArH and NH), 11.80 (br s, 1H, NH) ppm. ¹³C NMR (100 MHz, DMSO‐d₆): δ 13.6 (CH₃), 21.0 (CH₃), 33.8 (CH), 93.5 (C), 103.2 (C), 103.8 (C), 113.3 (C), 126.9 (CH), 127.0 (CH), 128.2 (CH), 128.96 (CH), 128.98 (CH), 129.2 (CH), 129.65 (CH), 129.7 (CH), 129.8, (CH), 130.9 (C), 136.4 (C), 139.6 (C), 141.8 (C), 150.8 (C), 150.9 (C), 152.6 (C), 160.1 (CO), 160.4 (CO), 169.8 (C) ppm. MS (EI, 70 eV): m/z 486 [M]⁺. Anal. calcd. for C₃₀H₂₂N₄O₃: C, 74.06; H, 4.56; N, 11.52. Found: C, 74.16; H, 4.43; N, 11.33.

6‐(2,4‐Dichlorophenyl)‐2‐methyl‐3‐phenyl‐6,13‐dihydro‐7H‐chromeno[3′,4′:5,6]pyrido[3,2‐e]pyrazolo[1,5‐a]pyrimidine‐5,7(4H)‐dione (12 d): GP. Off‐white powder (0.36 g, 66 %). Mp >300 °C. IR (KBr): $\tilde{\nu }$ 3359, 3218 (2NH), 1723, 1655 (2CO) cm⁻¹. ¹H NMR (300 MHz, DMSO‐d₆): δ 2.40 (s, 3H, CH ₃), 4.60 (s, 1H, CH), 7.50–7.67 (m, 12H, ArH), 11.26 (br s, 1H, NH), 11.90 (br s, 1H, NH) ppm. MS (EI, 70 eV): m/z 540 [M]⁺. Anal. calcd. for C₂₉H₁₈C_l2N₄O₃: C 64.34; H 3.35; N 10.35. Found: C 64.12; H 3.60; N 10.67.

2′,9′,9′‐Trimethyl‐3′‐phenyl‐9′,10′‐dihydro‐4′H‐spiro[indoline‐3,6′‐pyrazolo[5′,1′:2,3]pyrimido[4,5‐b]quinoline]‐2,5′,7′(8′H,11′H)‐trione (18): GP. Red brown powder (0.38 g, 78 %). Mp >300 °C. IR (KBr): $\tilde{\nu }$ 3404, 3241 (br, 3NH), 1706, 1661 (br, 3CO) cm⁻¹. ¹H NMR (300 MHz, DMSO‐d₆): δ 0.95 (s, 3H, CH ₃), 1.03 (s, 3H, CH ₃), 1.95 (m, 2H, CH ₂), 2.14 (m, 2H, CH ₂), 2.34 (s, 3H, pyrazole CH ₃), 6.65–7.43 (m, 9H, ArH), 10.14 (s, 1H, NH), 10.41 (s, 1H, NH), 11.46 (br s, 1H, NH) ppm. ¹³C NMR (100 MHz, DMSO‐d₆): δ 14.4 (CH₃), 27.0 (CH₃), 28.9 (CH₃), 32.4 (C), 42.8 (CH₂), 48.8 (CH₂), 51.1 (C), 87.2 (C), 103.4 (C), 108.4 (CH), 11.3 (C),120.9 (CH), 123.3 (CH), 127.3 (C), 127.8 (CH), 129.0 (CH), 129.7 (2CH), 136.4 (C), 139.8 (C), 144.1 (C), 150.9 (C), 151.1 (C), 163.4 (CO), 169.1 (C), 180.1 (CO), 194.0 (CO) ppm. MS (EI, 70 eV): m/z 491 [M]⁺. Anal. calcd. for C₂₉H₂₅N₅O₃: C 70.86; H 5.13; N 14.25. Found: C 70.65; H 5.04; N 14.11.

2‐Methyl‐3‐phenylspiro[indeno[2′,1′:5,6]pyrido[3,2‐e]pyrazolo[1,5‐a]pyrimidine‐6,3′‐indoline]‐2′,5,7(4H,12H)‐trione (19): GP. Red brown powder (0.36 g, 76 %). Mp >300 °C. IR (KBr): $\tilde{\nu }$ 3450 (br), 3370 (3NH), 1698, 1658 (br, 3CO) cm⁻¹. ¹H NMR (300 MHz, DMSO‐d₆): δ 2.38 (s, 3H, CH ₃), 6.78–8.22 (m, 13H, ArH), 10.45 (br s, 1H, NH), 11.52 (br s, 2H, 2NH) ppm. ¹³C NMR (75 MHz, DMSO‐d₆): δ 13.5 (CH₃), 51.4 (C), 87.3 (C), 108.4 (C), 109.0 (CH), 109.6 (CH), 110.7 (C), 120.4 (CH), 121.6 (CH), 123.9 (CH), 127.0 (CH), 127.2 (CH), 128.8 (CH), 129.0 (CH), 129.8 (C), 130.8 (CH), 131.1 (C), 133.0 (CH), 134.9 (C), 136.0 (C), 136.6 (C), 142.5 (C), 143.3 (C), 151.2 (C), 156.2 (CO), 159.6 (C), 179.0 (CO), 190.3 (CO) ppm. MS (EI, 70 eV): m/z 497 [M]⁺. Anal. calcd. for C₂₉H₂₅N₅O₃: C 72.43; H 3.85; N 14.08. Found: C 72.29; H 3.67; N 14.02.

Supporting Information Summary

Copies of ¹H and ¹³C NMR spectra of the synthesized compounds are available in the supplementary material.

Conflict of interest

The authors declare no conflict of interest.

Supporting information

As a service to our authors and readers, this journal provides supporting information supplied by the authors. Such materials are peer reviewed and may be re‐organized for online delivery, but are not copy‐edited or typeset. Technical support issues arising from supporting information (other than missing files) should be addressed to the authors.

Supporting Information

Abdelmoniem A. M., Ramadan M. A., Ghozlan S. A. S., Butenschön H., Abdelhamid I. A., ChemistryOpen 2023, 12, e202300009.

Data Availability Statement

The data that support the findings of this study are available in the supplementary material of this article.