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ZrOCl2·8H2O as an Efficient Catalyst for the Pseudo Four-Component Synthesis of Benzopyranopyrimidines

  • Received : 2012.12.31
  • Accepted : 2013.03.13
  • Published : 2013.04.20
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Abstract

An efficient and environmentally benign protocol for the pseudo four-component synthesis of benzopyranopyrimidines via condensation of salicylic aldehydes, malononitrile and various amines catalyzed by $ZrOCl_2{\cdot}8H_2O$ as an inexpensive and eco-friendly catalyst with high catalytic activity under solvent-free conditions is reported. This protocol provides a new and improved method for obtaining benzopyranopyrimidines in terms of good yields, simple experimental procedure and short reaction time.

Keywords

INTRODUCTION

The development of new methods for solvent-free organic synthesis involving multicomponent reactions is an important and attractive area of synthetic research.12 Organic reactions should be fast and facile and the target products should be easily separated and purified in high yields without the isolation of any intermediate.3 From this point of view, solvent-free multicomponent reactions4 find application as appealing methods to achieve these goals. Solventfree multicomponent reactions offer a wide range of possibilities for the efficient construction of highly complex molecules in a single step, thus avoiding complicated purification operations and allowing savings of both solvents and reagents.56

Functionalized nitrogen-heterocycles play a prominent role in medicinal chemistry and they have been intensively used as scaffolds for drug development. In this context fused pyrimidine derivatives are of particular interest because of their pharmacological profile.7 Some pyridopyrimidines are known as analgetics8 and CNS depressants, 9 while pyranopyrimidines exhibits antifungal and antibacterial activity.10 Several benzopyrano[2,3-d]pyrimidines were tested for their cytotoxic activity against a panel of cancer cell lines, and a number were shown to cause significant perturbation in cell cycle kinetics.11

The use of zirconium(IV) salts as an efficient Lewis acid for various transformations, has been well documented in the literature, because of their easy availability, moisture stability and low toxicity.12−14 Among the various types of Zr(IV) salts, particularly, ZrOCl2·8H2O has advantages of moisture stability, readily availability and easy handling.13 Also, the low toxicity of ZrOCl2·8H2O is evident from their LD50 [LD50 (ZrOCl2·8H2O, oral rat) = 3500 mg/kg].14 Therefore, the application of ZrOCl2·8H2O in organic synthesis is of renewed interest.

As part of our research aimed at developing new methods for the preparation of fused pyrimidine derivatives,15−17 recently, for the first time we have reported synthesis of benzopyrano[2,3-d]pyrimidines via pseudo four-component reaction of salicylic aldehyde, malononitrile and amine in the presence of LiClO4 in EtOH at room temperature for 24 h.18 Very recently, this multicomponent protocol has been developed by ionic liquid, [Bmim]BF4.19 Due to unique advantages of ZrOCl2·8H2O, the aim of our research described here was to develop the pseudo fourcomponent synthesis of benzopyrano[2,3-d]pyrimidines employing ZrOCl2·8H2O as an efficient and mild Lewis acid catalyst under solvent-free conditions (Scheme 1).

 

EXPERIMENTAL

General Procedure

A mixture of salicylic aldehydes (2 mmol), malononitrile (1 mmol), amines (1 mmol) and ZrOCl2·8H2O (30 mol%) was stirred at room temperature for 15 h (the progress of the reaction was monitored by TLC). After completion, the reaction mixture was washed with H2O (5 ml) and EtOH (5 ml) to afford pure product 4.

Scheme 1.

All the products are known and were fully characterized by a comparison with authentic samples (melting point) and IR spectra.18

2-(4-Morpholino-5H-chromeno[2,3-d]pyrimidin-2- yl)phenol (4c): White powder (90%); mp 196˗198 ℃. IR (KBr) (νmax/cm˗1): 3442. 1H NMR (300 MHz, DMSO-d6): δH 3.45 (4H, s, CH2), 3.77 (4H, s, CH2), 3.88 (2H, s, CH2- Ar), 6.84˗7.24 (7H, m, H-Ar), 8.18 (1H, bs, H-Ar), 12.99 (1H, s, OH). 13C NMR (75 MHz, DMSO-d6): δC 25.1, 48.5, 66.4, 97.8, 116.7, 117.5, 118.5, 119.1, 120.1, 124.9, 128.5, 129.0, 129.4, 133.2, 150.1, 160.2, 160.9, 163.4, 164.3. MS (EI, 70 eV) m/z (%): 361 (M+).

3-Methoxy-2-(6-methoxy-4-(piperidin-1-yl)-5H-chromeno[ 2,3-d]pyrimidin-2-yl)phenol (4d): White powder (91%); mp 195˗197 ℃. IR (KBr) (νmax/cm˗1): 3442. 1H NMR (300 MHz, DMSO-d6): δH 1.69 (6H, s, CH2), 3.12 (4H, bs, CH2), 3.76˗3.88 (8H, m, 2OCH3 and CH2-Ar), 6.53˗6.58 (2H, m, H-Ar), 7.71˗7.80 (2H, m, H-Ar), 7.17˗7.26 (2H, m, H-Ar), 10.93 (1H, s, OH). 13C NMR (75 MHz, DMSO-d6): δC 20.6, 24.4, 26.1, 49.4, 56.5, 56.7, 96.6, 104.2, 106.8, 109.1, 109.5, 110.0, 114.2, 128.6, 130.9, 151.4, 157.6, 158.7, 159.9, 160.7, 156.6. MS (EI, 70 eV) m/z (%): 419 (M+).

3-Methoxy-2-(6-methoxy-4-morpholino-5H-chromeno [2,3-d]pyrimidin-2-yl)phenol (4e): White powder (88%); mp 191˗193 ℃. IR (KBr) (νmax/cm˗1): 3437. 1H NMR (300 MHz, DMSO-d6): δH 3.42 (4H, s, 2CH2), 3.67˗3.73 (7H, m, 2CH2 and OCH3), 3.79˗3.84 (5H, m, OCH3 and CH2-Ar), 6.52 (2H, d, 3JHH = 7.0 Hz, H-Ar), 6.74 (2H, m, 3JHH = 8.0 Hz, H-Ar), 7.14˗7.26 (2H, m, H-Ar), 10.15 (1H, s, OH). 13C NMR (75 MHz, DMSO-d6): δC 20.4, 48.7, 56.1, 56.3, 66.5, 56.0, 97.4, 102.8, 106.4, 108.9, 109.0, 109.3, 115.5, 128.8, 130.4, 151.1, 157.2, 157.3, 158.8, 160.8, 164.0, 165.5. MS (EI, 70 eV) m/z (%): 421 (M+).

4-Bromo-2-(7-bromo-4-(piperidin-1-yl)-5H-chromeno [2,3-d]pyrimidin-2-yl)phenol (4g): White powder (81%); mp 187˗189 ℃. IR (KBr) (νmax/cm˗1): 3442. 1H NMR (300 MHz, DMSO-d6): δH 1.67 (6H, s, CH2), 3.41 (4H, s, CH2), 3.88 (2H, s, CH2-Ar), 6.81˗7.5 (5H, m, H-Ar), 8.19 (1H, bs, H-Ar), 13.2 (1H, bs, OH). MS (EI, 70 eV) m/z (%): 514 (M+). Due to very low solubility of the product 4h, we unable report the 13C NMR data for this product.

4-Bromo-2-(7-bromo-4-morpholino-5H-chromeno [2,3-d]pyrimidin-2-yl)phenol (4h): White powder (85%);mp 198˗200 ℃. IR (KBr) (νmax/cm˗1): 3416. 1H NMR (300 MHz, DMSO-d6): δH 3.47(4H, s, CH2), 3.78 (4H, s, CH2), 3.97 (2H, s, CH2-Ar), 6.84˗6.87 (1H, m, H-Ar), 7.12-7.15 (1H, m, H-Ar), 7.42˗7.48 (2H, m, H-Ar), 7.54 (1H, bs, H-Ar), 13.07 (1H, bs, OH). MS (EI, 70 eV) m/z (%): 519 (M+), 474 (38), 353 (30), 127 (90), 86 (100). Due to very low solubility of the product 4i, we unable report the 13C NMR data for this product.

2-(4-(Dimethylamino)-8-methoxy-5H-chromeno[2,3- d]pyrimidin-2-yl)-5-methoxyphenol (4i): White powder (77%); mp 174˗176 ℃. IR (KBr) (νmax/cm˗1): 3421. 1H NMR (300 MHz, DMSO-d6): δH 3.19 (6H, s, CH3), 3.77 (6H, s, CH3), 4.08 (2H, s, CH2-Ar), 6.43˗6.44 (1H, m, H-Ar), 6.50˗6.53 (1H, m, H-Ar), 6.71˗6.77 (2H, m, HAr), 7.2 (1H, d, 3JHH = 8.0 Hz, H-Ar), 8.14 (1H, d, 3JHH = 8.0 Hz, H-Ar), 13.53 (1H, s, OH). MS (EI, 70 eV) m/z (%): 379 (M+). Due to very low solubility of the product 4j, we unable report the 13C NMR data for this product.

5-Methoxy-2-(8-methoxy-4-(piperidin-1-yl)-5H-chromeno[ 2,3-d]pyrimidin-2-yl)phenol (4j): White powder (79%); mp 168˗170 ℃. IR (KBr) (νmax/cm˗1): 3400. 1H NMR (300 MHz, DMSO-d6): δH 1.65 (6H, s, CH2), 3.28 (2H, s, CH2), 3.28 (2H, s, CH2), 3.74 (6H, s, OCH3), 3.78 (2H, s, CH2-Ar), 6.39˗6.48 (2H, m, H-Ar), 6.66˗6.71 (2H, m, H-Ar), 7.51 (1H, d, 3JHH = 6 Hz, H-Ar), 8.11 (1H, d, 3JHH = 6 Hz, H-Ar), 13.33 (1H, s, OH). 13C NMR (75 MHz, DMSO-d6): δC 24.3, 24.5, 25.9, 49.1, 55.6, 55.8, 96.9, 101.5, 101.9, 106.7, 111.2, 111.7, 111.9, 129.8, 130.2, 150.9, 159.4, 160.9, 162.0, 163.4, 164.7. MS (EI, 70 eV) m/z (%): 419 (M+).

5-Methoxy-2-(8-methoxy-4-morpholino-5H-chromeno [2,3-d]pyrimidin-2-yl)phenol (4k): White powder (80%); mp 224˗226 ℃. IR (KBr) (νmax/cm˗1): 3442. 1H NMR (300 MHz, DMSO-d6): δH 3.45 (4H, s, CH2), 3.75 (10H, m, 2CH2 and 2OCH3), 3.87 (2H, s, CH2-Ar), 6.42˗6.51 (2H, m, H-Ar), 6.7˗6.76 (2H, m, H-Ar), 7.19˗7.22 (1H, m, HAr), 8.11˗8.14 (1H, m, H-Ar), 13.21 (1H, s, OH). 13C NMR (75 MHz, DMSO-d6): δC 24.5, 48.5, 55.7, 55.8, 66.4, 97.2, 101.5, 101.9, 106.9, 111.4, 111.6, 111.8, 129.9, 130.3, 150.7, 159.5, 160.9, 161.9, 163.5, 164.4. MS (EI, 70 eV) m/z (%): 421 (M+).

 

RESULTS AND DISCUSSION

Initially, the reaction of 2-hydroxybenzaldehyde (1a, 2 mmol), malononitrile (2, 1 mmol) and dimethylamine (3a, 1 mmol) as a simple model substrate in the presence of ZrOCl2·8H2O in different solvents and under solvent-free conditions at room temprature was investigated to optimize the reaction conditions. It was found that the reaction under solvent-free conditions after 15 h resulted in higher isolated yield (Table 1). Similarly, the molar ratio of ZrOCl2·8H2O was studied with the optimum amount being 30 mol% (entry 6). When this reaction was carried out without ZrOCl2·8H2O the yield of the expected product was trace (entry 9).

Table 1.Screening of the reaction conditions

Using the optimized conditions, the generality of this reaction was examined using several types of salicylic aldehydes 1a−d and amines 3a−c. In all cases, the reactions gave the corresponding products in good isolated yield (Table 2). These reactions proceeded very cleanly under mild conditions at room temperature, and no side reactions were observed.

Another advantage of this approach could be related to the reusability of catalyst. We found that the catalyst could be separated from the reaction mixture simply by washing with water and reused after washing with CH2Cl2 and dried at 60 ℃. The reusability of the catalyst was checked by the reaction of salicylaldehyde, malononotrile and dimethyl amine under optimized reaction conditions. The results show that the catalyst can be used effectively three times without any loss of its activity (Table 2, entry 1). Therefore, the recyclability of catalyst makes the process economically and potentially viable for commercial applications.

A possible mechanism for the formation of 4 is proposed in Scheme 2. It is reasonable to assume that product 4 results from initial Knoevenagel condensation reaction of salicylic aldehyde 1 and malonontrile 2 followed by subsequent Pinner reaction (5−6). Next, the cyano group of intermediate 6 can be attacked by the amine 3 to produce intermediate 7. Finally, amine 7 reacts with another molecule of salicylic aldehyde 1 followed by proton transfer to afford the product 4 (Scheme 2).

Table 2.aIsolated yield after recycling of catalyst

Scheme 2.

 

CONCLUSION

In conclusion, we have demonstrated that ZrOCl2·8H2O can be used as green and reusable catalyst for efficient synthesis of (5H-benzopyrano[2,3-d]pyrimidin-2-yl)phenols under solvent-free conditions. Moreover, the cheapness, easy availability of the reagent, easy and clean workup makes this method attractive for organic chemist.

References

  1. Martins, M. A. P.; Frizzo, C. P.; Moreira, D. N.; Buriol, L.; Machado, P. Chem. Rev. 2009, 109, 4140. https://doi.org/10.1021/cr9001098
  2. Tanaka, K.; Toda, F. In Solvent-free Organic Synthesis; Wiley-VCH GmbH: 2003.
  3. Bagley, M. C.; Lubinu, M. C. Top. Heterocycl. Chem. 2006, 31.
  4. Multicomponent Reactions; Zhu, J., Bienayme, H., Eds.; Wiley-VCH: Weinheim, Germany, 2005.
  5. Ramon, D. J.; Yus, M. Angew. Chem. 2005, 117, 1628. https://doi.org/10.1002/ange.200460548
  6. Nandi, G. C.; Samai, S.; Kumar, R.; Singh, M. S. Tetrahedron Lett. 2009, 50, 7220. https://doi.org/10.1016/j.tetlet.2009.10.055
  7. Baraldi, P. G.; Tabrizi, M. A.; Gessi, S.; Borea, P. A. Chem. Rev. 2008, 108, 238. https://doi.org/10.1021/cr0682195
  8. Sharma, R.; Goyal, R. D.; Praskash, L. Indian J. Chem. Sect. B 1992, 31. 719.
  9. Noda, K.; Nakagawa, A.; Yamagata, K.; Mujata, S.; Ide, H. JPN Patent 75−157. Chem. Abstr. 1976, 85, 5675p.
  10. Ahluwalia, V. K.; Batla, R.; Khurana, R.; Kumar, R. Indian J. Chem. Sect. B 1990, 29. 1141.
  11. Hadfield, J. A.; Pavlidis, V. H.; Perry, P. J.; McGown, A. T. Anti-Cancer Drugs 1999, 10, 591. https://doi.org/10.1097/00001813-199907000-00011
  12. Firouzabadi, H.; Jafarpour, M. J. Iran. Chem. Soc. 2008, 5, 159. https://doi.org/10.1007/BF03246110
  13. Ghosh, R.; Maiti, S. Chakraborty, A. Tetrahedron Lett. 2005, 46. 147. https://doi.org/10.1016/j.tetlet.2004.10.164
  14. Mirkhani, V.; Mohammadpoor-Baltork, I.; Moghadam, M.; Tangestaninejad, S.; Abdollahi-Alibeik, M.; Kargar, H. Appl. Catal. A: Gen. 2007, 325, 99. https://doi.org/10.1016/j.apcata.2007.03.016
  15. Dabiri, M.; Arvin-Nezhad, H.; Khavasi, H. R.; Bazgir, A. Tetrahedron 2007, 63. 1770. https://doi.org/10.1016/j.tet.2006.12.043
  16. Dabiri, M.; Azimi, S. C.; Khavasi, H. R.; Bazgir, A. Tetrahedron 2008, 64. 7307. https://doi.org/10.1016/j.tet.2008.05.063
  17. Jadidi, K.; Ghahremanzadeh, R.; Bazgir, A. Tetrahedron 2009, 65. 2005. https://doi.org/10.1016/j.tet.2009.01.013
  18. Ghahremanzadeh, R.; Amanpour, T.; Bazgir, A. Tetrahedron Lett. 2010, 51. 4202. https://doi.org/10.1016/j.tetlet.2010.06.014
  19. Gupta, A. K.; Kumari, K.; Singh, N.; Raghuvanshi, D. S.; Singh, K. N. Tetrahedron Lett. 2012, 53. 650. https://doi.org/10.1016/j.tetlet.2011.11.116

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