Chinese Chemical Letters  2017, Vol. 28 Issue (5): 943-948   PDF    
DABCO-catalyzed multi-component domino reactions for green and efficient synthesis of novel 3-oxo-3H-benzo[a]pyrano[2, 3-c] phenazine-1-carboxylate and 3-(5-hydroxybenzo[a]phenazin-6-yl) acrylate derivatives in water
Razieh Mohebata, Afshin Yazdani-Elah-Abadib, Malek-Taher Maghsoodloub, Nourallah Hazerib     
a Young Researchers and Elite Club, Yazd Branch, Islamic Azad University, Yazd, Iran;
b Department of Chemistry, Faculty of Science, University of Sistan and Baluchestan, P. O. Box 98135-674, Zahedan, Iran
Abstract: An efficient, convenient and environmentally benign procedure for the synthesis of novel 3-oxo-3H-benzo[a]pyrano[2, 3-c]phenazine-1-carboxylate and 3-(5-hydroxybenzo[a]phenazin-6-yl)acrylate derivatives has been developed by domino three-component condensation reaction between 2-hydroxynaphthalene-1, 4-dione, benzene-1, 2-diamines and acetylenic esters in the presence of a catalytic amount of DABCO as an expedient, eco-friendly and reusable base catalyst in water. This green process produces biologically and pharmacologically significant heterocycles in a one-pot single operation and offers considerable advantages such as:operational simplicity, short reaction time, high yields, reusability of catalyst, absence of any tedious workup or purification and avoids hazardous reagents/solvents.
Key words: Multi-component domino reactions (MDRs)     DABCO     Acetylenic esters     Benzo[a]phenazin derivatives     Green chemistry    
1. Introduction

Synthesis of polyfunctionalized heterocyclic compounds from readily available starting materials in a cost and time effective manner has been received significant attention in organic synthesis due to their extensive applications in pharmaceuticals, agrochemicals and in materials sciences [1-3]. In this area, multicomponent domino reactions (MDRs), in which more than two components are combined in a single synthetic operation, have been extensively used as a powerful strategy in the synthesis of complex heterocyclic molecules due to their advantages such as higher productivity, simple procedures, facile execution, lower costs, minimum waste production, structural diversity, shorter reaction times, environmentally friendliness, atom economy, high selectivity and allowing savings of both solvents and reagents [4-7].

Furthermore, replacement of hazardous solvents with environmentally benign solvents [8-10] is one of the major focus areas of green chemistry. Organic solvents used in most of the synthetic organic chemistry evaporate into the atmosphere with destructive effects on the environment and ozone layer [11]. Thus, aqueous phase organic synthesis has attracted the attention of chemists as it overcomes the harmful effects associated with the organic solvents and is environmentally benign. Moreover, using water as the medium, surfactants can be used to build micelles and provide better chemical yields and shorter reaction times due to its strong hydrogen bonding ability, hydrophobic effects and high polarity [12-14].

As mentioned, functionalized heterocyclic compounds play significant roles in the drug discovery process, and analysis of drugs [15, 16]. Among them, phenazine systems are nitrogencontaining heterocycles that are found in natural and synthetic products [17-20] and they have been demonstrated to possess a myriad of biological functions, including antimalarial [21, 22], trypanocidal [23], fungicidal [24, 25], antiplatelet [26], and antitumour [27] activities. For example, pyridophenazinediones and pyridazinophenazinedione derivatives have shown the antitumor activity [28, 29].

As part of our research on the development of new synthetic methods in heterocyclic chemistry and our interest in acetylenic ester-based MCRs [30-36], in this paper, we would like to report new sequence of a one-pot, three-component condensation reaction between 2-hydroxynaphthalene-1, 4-dione 1, benzene-1, 2-diamines 2 and acetylenic esters 4, 5 in the presence of DABCO as an efficient, non-toxic and reusable solid base catalyst for the synthesis of novel 3-oxo-3H-benzo[a]pyrano[2, 3-c]phenazine-1-carboxylate and 3-(5-hydroxybenzo[a]phenazin-6-yl)acrylate derivatives 6, 7 in aqueous medium at 50 ℃ (Scheme 1).

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Scheme 1. One-pot, three-component domino synthesis of novel 3-oxo-3H-benzo [a]pyrano[2, 3-c]phenazine-1-carboxylate and 3-(5-hydroxybenzo[a]phenazin-6-yl)acrylate derivatives in the presence of DABCO as catalyst.

2. Results and discussion

Considering the importance of phenazine derivatives, we were willing to find a practical and general method for their synthesis in high yields and purities and also, owing to the development of efficient and environmentally friendly synthetic procedures is always desirable, we decided to peruse whether those phenazines could be prepared by condensation of 2-hydroxynaphthalene-1, 4-dione, benzene-1, 2-diamines and acetylenic esters in the absence of any organic solvent.

In order to investigate the optimizing reaction conditions for the synthesis of 3-oxo-3H-benzo[a]pyrano[2, 3-c]phenazine-1-carboxylates, we carried out the three-component domino reaction between 2-hydroxynaphthalene-1, 4-dione 1 (1 mmol), benzene-1, 2-diamine 2a (1 mmol) and dimethyl acetylenedicaboxylate 4 (1 mmol) in ethanol as a model. Initially, to minimize the formation of byproducts, the 2-hydroxynaphthalene-1, 4-dione and benzene-1, 2-diamine were refluxed in EtOH until in less than 10 min an orange solid of benzo[a]phenazine 3a was formed without using any catalyst. Next, dimethyl acetylenedicaboxylate was added and the mixture was heated in EtOH under reflux. The desired product 6a was not obtained when the reaction was carried out in EtOH for 4 h under reflux and catalyst-free conditions (Table 1, entry 1). However, 6a was obtained in 81% yield when the reaction was conducted in the presence of triethylamine (20 mol%) in EtOH (Table 1, entry 2). Several bases were evaluated in the reaction as catalyst, including Et3N, pyridine, isoquinoline, Ph3P, DBU and DABCO; these were all added in substoechiometric amount (20 mol%) and the reactions were carried out in EtOH under reflux conditions. DABCO showed excellent catalytic activity in terms of reaction time as well as yield of the product (Table 1, entry 7). Then, water was appraised to determine the impact of the solvent on the reaction yields. Water due to its strong hydrogen bonding ability, hydrophobic effects and high polarity showed better performance in comparison with ethanol and gave the higher product yield (Table 1, entry 8). We then evaluated the amount of catalyst required for this transformation. An increase in the amount of DABCO more than 20 mol% showed no remarkable improvement in the yield, whereas the yield was reduced by decreasing the amount of DABCO to 10 mol% (Table 1, entries 8-10). Finally, the reaction was performed at different temperatures to determine the optimum reaction temperature. The reaction was conducted with 20 mol% DABCO in water at r.t., 50, 70 and 100 ℃, and the desired product 6a was formed in yields of trace, 94%, 91% and 95% (Table 1, entries 8 and 11-13), respectively.

Table 1
Optimization of reaction conditions of compound 6a.a

After extensive screening, we found that the optimized best yields and time profiles were obtained with 20 mol% of DABCO in H2O at 50 ℃, which furnished the corresponding methyl 3-oxo-3H-benzo[a]pyrano[2, 3-c]phenazine-1-carboxylate 6a in 94% yield within 2 h (Table 1, entry 12).

Using these optimized conditions, we turned our attention to investigate the scope and general applicability of this methodology by carrying out the synthesis of 3-oxo-3H-benzo[a]pyrano[2, 3-c] phenazine-1-carboxylates using different benzene-1, 2-diamines and various electron defficient acetylenic esters (Table 2).

Table 2
Domino one-pot three-component synthesis of 3-oxo-3H-benzo[a]pyrano[2, 3-c] phenazine-1-carboxylate derivatives.a

All the reactions were complete in 2-3 h and resulted in the formation of the target structures (Scheme 1, Table 2, entries 1-6) in high yields using the DABCO as environment-friendly catalyst [37] and this domino reaction was efficiently promoted using benzene-1, 2-diamine with reduced reaction times and increased yields rather than other benzene-1, 2-diamines and dimethyl acetylenedicaboxylate with less steric hindrance reacted rapidly and gave higher yields in comparison with diethyl acetylenedicaboxylate.

On the next step, in order to achieve 3H-benzo[a]pyrano[2, 3-c] phenazin-3-one derivatives, we carried out the reaction between 2-hydroxynaphthalene-1, 4-dione 1 (1 mmol), benzene-1, 2-diamine 2a (1 mmol) and methyl propiolate 5 (1 mmol) in the presence of triethylamine (20 mol%) as catalyst in aqueous medium under reflux. In the event we did not observe the expected MDR product 8; instead the reaction afforded the corresponding 3-(5-hydroxybenzo[a]phenazin-6-yl)acrylate derivatives 7 with three-component domino reaction (Scheme 2).

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Scheme 2. Synthesis of methyl 3-(5-hydroxybenzo[a]phenazin-6-yl)acrylate.

Then, to prepare 3-(5-hydroxybenzo[a]phenazin-6-yl)acrylate derivatives in a more efficient way, and to minimize the reaction time and the amount of catalyst required, the three-component domino reaction between 2-hydroxynaphthalene-1, 4-dione 1 (1 mmol), benzene-1, 2-diamine 2a (1 mmol) and methyl propiolate 5 (1 mmol) in water was selected as a model system. After broad screening, we found that the optimized best yields and time profiles were obtained with 10 mol % of DABCO in H2O at 50 ℃, which furnished the corresponding methyl 3-(5-hydroxybenzo[a] phenazin-6-yl)acrylate 7a in 92% yield within 2 h proceed efficiently (Table 3, entry 10).

Table 3
Optimization of reaction conditions of compound 7a.a

Using these optimized reaction conditions, the scope and efficiency of the reaction were explored for the synthesis of a wide variety of 3-(5-hydroxybenzo[a]phenazin-6-yl)acrylate derivatives. The results are summarized in Table 4.

Table 4
Domino one-pot three-component synthesis of 3-(5-hydroxybenzo[a]phenazin-6-yl)acrylate derivatives.a

The isolated products 6 and 7 were fully characterized on the basis of IR, NMR and MS spectroscopy and elemental analysis.

Reusability of catalyst is a significant feature in green organic synthesis. Our findings revealed that DABCO was a recoverable catalyst. For this purpose, we investigated the recycling of the catalyst in aqueous medium at 50 ℃ using a selected model reaction of 2-hydroxynaphthalene-1, 4-dione, benzene-1, 2-diamine and dimethyl acetylenedicaboxylate in the presence of DABCO as homogeneous catalyst (Table 2, entry 1). After completion of the reaction, then reaction mixture was cooled to room temperature. Then, 5 mL of water was added to the mixture and filtered for separation of the crude product. The separated product was washed twice with water (2 × 5 mL). The resulting product subsequently recrystallized from hot ethanol to give the pure solid. In order to recover the catalyst, since DABCO is soluble in water, the filtrate was extracted with diethyl ether. The aqueous layer (including DABCO) was separated, and its solvent was evaporated under reduced pressure and DABCO was recovered and reused.

As shown in Fig. 1, the recovered catalyst works with the same performance up to 2nd run, while in the 3rd, 4th and 5th runs product yield gets reduced slightly that may be due to little weight loss of catalyst during each recovery process.

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Figure 1. The reusability of the catalyst (20 mol%) in the synthesis of 6a in water at 50 ℃ (2 h).

In order to determine the catalytic behavior of DABCO, the suggested mechanism for the formation of the products 6 and 7 is shown in Scheme 3. On the basis of this mechanism, at first, 2-hydroxynaphthalene-1, 4-dione 1 tautomrizes to intermediate 9. The primary condensation of 4-hydroxy-1, 2-naphthoquinone 9 with benzene-1, 2-diamine 2 obtain benzo[a]phenazin-5-ol 3. Then, based on nucleophilicity of DABCO, the nucleophilic addition of DABCO to the acetylenic ester 4 or 5 and subsequent protonation in the presence of compound 3 gives intermediates 10 or 11, followed by attack of the anion on the cation part of intermediates 10 or 11 to form the intermediates 12 or 13. Intramolecular lactonization of the intermediate 12 leads to produce compound 6 and also, intermediate 13 followed by a tautomeric proton shift leads to the formation of desired product 7.

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Scheme 3. Plausible mechanism based on nucleophilicity of DABCO for the synthesis of 3-oxo-3H-benzo[a]pyrano[2, 3-c]phenazine-1-carboxylate and 3-(5-hydroxybenzo[a] phenazin-6-yl)acrylate derivatives.

3. Conclusion

In summary, we have described a novel domino threecomponent coupling reaction leading to selective and highyielding 3-oxo-3H-benzo[a]pyrano[2, 3-c]phenazine-1-carboxylate and 3-(5-hydroxybenzo[a]phenazin-6-yl)acrylate derivatives from readily avaible starting materials in aqueous medium. This protocol also offers several advantages such as convenient one-pot operation, high atom economy, easy work-up, short reaction time, use of DABCO as a highly reactive, non-toxic and reusable catalyst and avoidance of conventional volatile organic solvents that make it a green, economically cost-effective and attractive process for the synthesis of these heterocycles. Furthermore, our work is expected to exhibit interesting pharmacology activities and may act as potential drug candidates, since phenazine and pyran motifs have a vast range of biological activity.

4. Experimental 4.1. Chemistry

All melting points were determined on an Electrothermal 9100 apparatus and are uncorrected. IR spectra were recorded on a shimadzu IR-470 spectrometer. Elemental analyses for C, H, and N were performed using a Heraeus CHN-O-Rapid analyzer at Iranian Central Research of Petroleum Company. Mass spectra were recorded on an Agilent Technology (HP) spectrometer operating at an ionization potential of 70 eV. The 1H NMR and 13C NMR spectra were recorded on a Bruker DRX-300 and 400 Avanve instrument with CDCl3 and DMSO-d6 as solvent and using TMS as internal reference at 300, 400, 75, and 100 MHz, respectively. Thinlayer chromatography (TLC) was performed on silica-gel Polygram SILG/UV 254 plates. All reagents and solvent were purchased from Merck and Aldrich and used without further purification.

4.2. General procedure for the synthesis of novel 3-oxo-3H-benzo[a] pyrano[2, 3-c]phenazine-1-carboxylate and 3-(5-hydroxybenzo-[a] phenazin-6-yl)acrylate derivatives (6, 7)

Initially, a mixture of 2-hydroxynaphthalene-1, 4-dione 1 (1 mmol), benzene-1, 2-diamine 2 (1 mmol), DABCO (20 or 10 mol%) and water (10 mL) was placed in a 50 mL round-bottomed flask mounted over a magnetic stirrer. The contents were stirred magnetically in an oil-bath maintained at 50 ℃ until in less than 10 min benzo[a]phenazin-5-ol 3 was formed. Then, dialkyl acetylenedicarboxylate 4 (1 mmol) or alkyl propiolate 5 (1 mmol) was added to the above reaction mixture which was heated further at the same temperature for an appropriate time as shown in Tables 2 and 4. Upon completion of the reaction, monitored by TLC, the reaction mixture was allowed to cool to room temperature. Then, 5 mL of water was added to the mixture and filtered for separation of the crude product. The separated product was washed twice with water (2 × 5 mL). The solid crude product subsequently recrystallized from hot ethanol to give the pure product 6 and 7. Some spectral and analytical data are presented below, others are deposited in Supporting information.

Methyl 3-oxo-3H-benzo[a]pyrano[2, 3-c]phenazine-1-carboxylate (6a): Brown powder; yield 0.334 g (94%), mp 243-245 ℃; IR (KBr, cm-1): νmax 1729 (C═O); 1H NMR (400 MHz, CDCl3): δ 4.18 (s, 3H, OCH3), 6.61 (s, 1H, CH), 7.86 -7.94 (m, 4H, Ar-H), 8.11 -8.13 (m, 1H, Ar-H), 8.30 -8.32 (m, 1H, Ar-H), 8.56 -8.58 (m, 1H, Ar-H), 9.31 -9.33 (m, 1H, Ar-H); 13C NMR (100 MHz, CDCl3): δ 52.9 (OCH3), 108.5 (CH), 113.9, 123.5, 125.0, 125.5, 128.7, 129.7, 130.3, 130.6, 130.8, 131.0, 132.0, 137.9, 139.7, 141.2, 141.5, 146.9 and 155.5 (17Colefinic and Carom), 159.2 and 166.9 (2C═O); MS (m/z, %): 356 (M+, 74), 297 (100), 241 (67), 125 (19), 97 (62), 57 (83); Anal. Calcd. for C21H12N2O4: C, 70.78; H, 3.39; N, 7.86. Found: C, 70.96; H, 3.51; N, 8.01.

Methyl 12-methyl-3-oxo-3H-benzo[a]pyrano[2, 3-c]phenazine-1-carboxylate (6c): Yellow powder; yield 0.342 g (92%), mp 234- 236 ℃; IR (KBr, cm-1): νmax 1721 (C═O); 1H NMR (400 MHz, CDCl3): δ 2.51 (s, 3H, CH3), 4.19 (s, 3H, OCH3), 6.64 (s, 1H, CH), 7.90-7.96 (m, 3H, Ar-H), 7.99 (td, 1H, J1 = 6.0 Hz, J2 = 1.2 Hz, Ar-H), 8.36 -8.39 (m, 1H, Ar-H), 8.65 -8.67 (m, 1H, Ar-H), 9.42 -9.44 (m, 1H, Ar-H); 13C NMR (100 MHz, CDCl3): δ 22.5 (CH3), 52.7 (OCH3), 108.3 (CH), 113.1, 123.9, 124.5, 125.6, 128.7, 129.7, 130.5, 131.6, 131.7, 132.9, 133.1, 137.3, 139.9, 140.3, 140.4, 143.4 and 155.2 (17Colefinic and Carom), 159.9 and 166.2 (2C═O); MS (m/z, %): 370 (M+, 100), 311 (92), 284 (90), 188 (14), 127 (36), 69 (64): Anal. Calcd. for C22H14N2O4: C, 71.35; H, 3.81; N, 7.56. Found: C, 71.57; H, 3.69; N, 7.70.

Methyl 11-nitro-3-oxo-3H-benzo[a]pyrano[2, 3-c]phenazine-1-carboxylate (6e): Yellow powder; yield 0.353 g (88%), mp 260- 262 ℃; IR (KBr, cm-1): νmax 1747, 1726 (2C═O); 1H NMR (300 MHz, DMSO-d6): δ 4.11 (s, 3H, OCH3), 6.97 (s, 1H, CH), 7.88-8.04 (m, 2H, Ar-H), 8.28 -8.44 (m, 2H, Ar-H), 8.57-8.68 (m, 1H, Ar-H), 8.83 (s, 1H, Ar-H), 9.12 -9.18 (m, 1H, Ar-H); 13C NMR (75 MHz, DMSO-d6): δ 52.8 (OCH3), 108.3 (CH), 112.9, 121.5, 123.6, 125.9, 128.3, 129.7, 129.8, 130.8, 131.6, 131.8, 132.2, 137.4, 139.8, 141.1, 141.6, 147.8 and 155.2 (17Colefinic and Carom), 159.2 and 166.4 (2C═O); MS (m/z, %): 401 (M+, 2), 311 (60), 284 (100), 255 (59), 127 (26), 69 (90); Anal. Calcd. for C21H11N3O6: C, 62.85; H, 2.76; N, 10.47. Found: C, 62.76; H, 2.99; N, 10.41.

Methyl 3-(5-hydroxybenzo[a]phenazin-6-yl)acrylate (7a): Yellow powder; yield 0.304 g (92%), mp 134-136 ℃; IR (KBr, cm-1): νmax 1714 (C═O); 1H NMR (300 MHz, CDCl3): d 3.84 (s, 3H, OCH3), 5.52 (d, 1H, J = 6.6 Hz, CH), 6.00 (d, 1H, J = 12.0 Hz, CH), 7.37 -7.50 (m, 1H, Ar-H), 7.87 -7.90 (m, 3H, Ar-H), 8.14 -8.36 (m, 3H, Ar-H), 9.41 (d, 1H, J = 6.0 Hz, Ar-H), 11.80 (s, 1H, OH); 13C NMR (75 MHz, CDCl3): d 51.6 (OCH3), 105.2, 108.4, 122.3, 125.4, 127.2, 128.7, 129.0, 129.5, 129.7, 129.9, 130.2, 131.6, 140.7, 141.3, 142.8, 143.5, 150.7, and 156.3 (18Colefinic and Carom), 166.8 (C═O); MS (m/z, %): 330 (M+, 34), 271 (100), 217 (35), 190 (14), 89 (13), 43 (28); Anal. Calcd. for C20H14N2O3: C, 72.72; H, 4.27; N, 8.48. Found: C, 72.80; H, 4.05; N, 8.57.

Methyl 3-(5-hydroxy-9-methylbenzo[a]phenazin-6-yl)acrylate (7c): Yellow powder; yield 0.306 g (89%), mp 146-148 ℃; IR (KBr, cm-1): νmax 1706 (C═O); 1H NMR (300 MHz, DMSO-d6): δ 2.72 (s, 3H, CH3), 3.74 (s, 3H, OCH3), 5.54 (d, 1H, J = 6.6 Hz, CH), 6.03 (dd, 1H, J1 = 12.0 Hz, J2 = 8.1 Hz, CH), 7.83-7.96 (m, 3H, Ar-H), 8.13 -8.30 (m, 3H, Ar-H), 9.20 -9.23 (m, 1H, Ar-H), 11.53 (s, 1H, OH); 13C NMR (75 MHz, DMSO-d6): δ 22.5 (CH3), 52.0 (OCH3), 105.5, 108.5, 122.2, 125.3, 127.2, 128.1, 128.9, 129.1, 129.6, 129.7, 129.9, 131.6, 132.9, 140.1, 141.4, 142.8, 150.6 and 156.1 (18Colefinic and Carom), 166.4 (C═O); MS (m/z, %): 344 (M+, 45), 271 (64), 217 (23), 149 (46), 105 (15), 57 (100); Anal. Calcd. for C21H16N2O3: C, 73.24; H, 4.68; N, 8.13. Found: C, 73.48; H, 4.83; N, 8.06.

Methyl 3-(5-hydroxy-10-nitrobenzo[a]phenazin-6-yl)acrylate (7e): Brown powder; yield 0.319 g (85%), mp 265 -267 ℃; IR (KBr, cm-1): νmax 1710 (C═O); 1H NMR (300 MHz, DMSO-d6): d 3.78 (s, 3H, OCH3), 5.59 (d, 1H, J = 6.6 Hz, CH), 6.13 (dd, 1H, J1 = 12.0 Hz, J2 = 5.4 Hz, CH), 7.82-7.93 (m, 2H, Ar-H), 8.23-8.38 (m, 3H, Ar-H), 8.69 -8.75 (m, 1H, Ar-H), 9.05 (d, 1H, J = 5.1 Hz, Ar-H), 11.84 (s, 1H, OH); 13C NMR (75 MHz, DMSO-d6): δ 51.9 (OCH3), 103.2, 106.1, 121.2, 122.8, 125.4, 127.5, 129.5, 129.8, 130.1, 130.5, 130.6, 131.3, 131.5, 140.7, 141.6, 145.7, 147.1 and 155.9 (18Colefinic and Carom), 166.1 (C═O); MS (m/z, %): 375 (M+, 24), 291 (100), 245 (42), 182 (23), 83 (22), 43 (44); Anal. Calcd. for C20H13N3O5: C, 64.00; H, 3.49; N, 11.20. Found: C, 64.08; H, 3.57; N, 11.23.

Acknowledgments

We gratefully acknowledge financial support from the Research Council of Young Researchers and Elite Club of the Islamic Azad University of Yazd and University of Sistan and Baluchestan.

Appendix A. Supplementary data

Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.cclet.2016.12.042.

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