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Article

An Efficient Synthesis of 5-Alkoxycarbonyl-4-aryl-3,4-dihydropyrimidin-2(1H)-ones Catalyzed by KSF Montmorillonite

1
Department of Chemistry, Wenzhou Normal College, Wenzhou 325003, China
2
Department of Chemistry, Lanzhou University, Lanzhou 730000, China
*
Author to whom correspondence should be addressed.
Molecules 2000, 5(12), 1240-1243; https://doi.org/10.3390/51201240
Submission received: 21 September 2000 / Revised: 27 October 2000 / Accepted: 8 November 2000 / Published: 18 December 2000

Abstract

:
A mild and efficient catalytic method for synthesis of 5-alkoxycarbonyl-4-aryl-3, 4- dihydropyrimidin-2(1H)-ones using KSF montmorillonite as catalyst is described.

Introduction

4-Aryl-3,4-dihydropyrimidin-2(1H)-ones 4 (“Biginelli compounds”, DHPMs) have been reported to possess diverse biological activities such as antiviral, antibacterial, antihypertensive and anti-tumor effects [1,2,3]. More recently, DHPMs have emerged as the integral backbones of several calcium channel blockers [4]. Furthermore, several marine alkaloids with interesting biological activities containing the dihydropyrimidine-5-carboxylate core have been isolated [5]. Consequently a great need still exists for versatile and simple processes whereby compounds 4 may be formed under very mild conditions. However, Biginelli’s initial one-pot method of refluxing a β-keto ester 1, aryl aldehyde 2 and urea 3 with a catalytic amount of acid frequently afforded low (20-60%) yields of the desired target molecules 4 [6]. This has led to the recent disclosure of several improved reaction protocols for the synthesis of DHPMs, either by modification of the classical one-pot Biginelli approach itself [7,8,9,10], or by the development of novel, but more complex multistep strategies [11,12]. In addition, several combinatorial approaches towards DHPMs 4 have been reported [13,14].
Montomorillonite clays have been widely used in organic synthesis due to their ready availability, ease of set up and of work up, mild experimental condition and high yield and selectivity. Recently, Bigi [15] reported that the Biginelli reaction could be performed under solventless conditions using KSF montmorillonite, although the procedures described suffer limitations such as long reaction times and moderate yields. Our group has exploited the catalytic potential of montomorillonite for various synthetic organic transformations [16]. While optimizing the reaction conditions of the Biginelli reaction, we found that treatment of β-keto ester, aryl aldehyde and urea with KSF montmorillonite in methanol afforded DHPMs in good to excellent yields (Table 1).
Molecules 05 01240 i001

Results and Discussion

Our results show that it is necessary to control the molar ratio of the reactant. When the molar ratio of β-keto ester (1): aryl aldehyde (2): urea (3) is 1:1:1.2, our method produced higher yields. The same reaction when run in methanol gave better yields than in tetrahydrofuran. A variety of montomorillonites, including montomorillonite K 10 and montomorillonite KSF showed catalytic activity for Biginelli reaction, although montomorillonite KSF reagent proved superior to montomorillonite K 10.
Our approach not only preserved the simplicity of Biginelli’s one-pot reaction, but also consistently provided excellent yields of dihydropyrimidinones 4, regardless of the keto ester or aldehyde substituents tested. Montmorillonite KSF has many advantages over catalysts like BF3•OEt2/CuCl such as ease of handling, low cost and elimination of metal wastes (use of an environmentally-friendly catalyst). When compared to Bigi’s conditions (Table 1), our method consistently produced higher yields and required shorter reaction times. Detailed work on the mechanism of the transformation is still in progress.

Conclusions

We have presented a mild and effecient catalytic method for synthesis of 5-alkoxycarbonyl-4-aryl-3, 4- dihydropyrimidin-2(1H)-ones using KSF montmorillonite as catalyst.

Experimental

General

Melting points were determined using a XT 4A melting point apparatus and were uncorrected. The 1H- and 13C-NMR spectra were acquired on a Bruker Avance 300 spectrometer in DMSO with TMS as internal standard. IR spectra were recorded on a Nicolet Axatar IR 360 spectrometer. Elemental analysis data were taken on a Perkin-Elmer 240C elemental analytical instrument.

Syntheses

A mixture of β-keto ester (20mmol), aryl aldehyde (20mmol), urea (24mmol) and montmorillonite KSF (0.6g) was refluxed in dry methanol (15mL), The completion of the reaction was monitored vide tlc. Montomorillonite KSF filtered off and methanol was removed under reduced pressure. The product was crystallised from ethanol. The results were summarized in Table 1. All the products except entry 1 are known compounds, which were satisfactorily characterised by melting point, 1H-NMR, 13C-NMR and IR spectra.
Entry 1 ( 88% yield) mp 213-4°C, IR(KBr) 3245, 3114, 2981, 2942, 1725, 1706, 1650 cm−1; 1H-NMR (DMSO-d6) δ9.13 ( s,1H ), 7.66 ( d, J=3.11Hz, 1H ), 7.09 ( m, 4H ), 5.08 (d, J=3.11Hz, 1H ), 3.95 ( q, J=7.03Hz, 2H ), 2.23 ( s, 3H ), 2.21 ( s, 3H ), 1.08 ( t, J=7.03Hz, 3H); 13C-NMR (DMSO-d6) δ165.5, 152.3, 148.2, 142.1, 136.4, 129.0, 126.3, 99.6, 59.3, 53.8, 20.8, 17.9, 14.2. Anal. Calcd for C15H18N2O3: C, 65.67; H, 6.61; N, 10.21. Found: C, 65.42; H, 6.65; N, 10.16.

References

  1. McKinstry, D. W.; Reading, E. H. J. Frankin Inst. 1944, 237, 422–431.
  2. Matsuda, T.; Hirao, I. Nippon Kagaku Zasshi 1965, 86, 1195–1197.
  3. Kato, T. Japn. Kokai Tokkyo Koho JP 1984, 59, 190,974.
  4. Takatani, T.; Takasugi, H.; Kuno, A.; Inoue, Z. Japn. Kokai Tokkyo koho JP 1987, 62, 252,775.
  5. Overman, L. E.; Rabinowitz, M. H.; Renhowe, P. A. J. Am. Chem. Soc. 1995, 117, 1657–2658.
  6. Biginelli, P. Gazz. Chim. Ital. 1893, 23, 360.
  7. Hu, E. H.; Sidler, D. R.; Dolling, U. H. J. Org. Chem. 1998, 63, 3454–3457.
  8. Kappe, C. O.; Falsone, F. S. Synlett 1998, 718.
  9. Kappe, C. O.; Kumar, D.; Varma, R. S. Synthesis 1999, 10, 1799–1803.
  10. Lu, J.; Ma, H. Synlett 2000, 1, 63–64.
  11. O’Reilly, B. C.; Atwal, K. S. Heterocycles 1987, 26, 1185.
  12. Shutalev, A. D.; Kishko, E. A.; Sivova, N.; Kuznetsov, A. Y. Molecules 1998, 3, 100.
  13. Studer, A.; Hadida, S.; Ferrito, R.; Kim, S. Y.; Jeger, P.; Wipf, P.; Curran, D. P. Science 1997, 275, 823. [PubMed]
  14. Lewandowski, K.; Murer, P.; Svec, F.; Frechet, J. M. J. Chem. Soc. Chem. Commun. 1998, 2237.
  15. Bigi, F.; Carloni, S.; Frullanti, B.; Maggi, R.; Sartori, G. Tetrahedron Letters 1999, 40, 3465–3468.
  16. Lin, H. X.; Zhang, L. X.; Cheng, L. S. Chin. Chem. Lett. 1999, 10(11), 915–916.
  • Samples Availability: Samples are available from the authors.
Table 1. Experimental results and physical data of dihydropyrimidinones 4.
Table 1. Experimental results and physical data of dihydropyrimidinones 4.
entryR1R2R3Yield(%)m.p. (°C) (literature) [7]
AaBbCcDd
1EtMeMe88 213-4
2EtMeCl93569276214-5(213-5)
3EtMeNO2895491 209-11(208-11)
4EtMeOMe82378579200-2(201-3)
5EtMeH92719482205-6(202-4)
6EtPhH80107075158-9(157-9)
7MeMeH904288 211-3(209-12)
a Method A: New reaction conditions(montomorillonite KSF in methanol, reflux 8-10h). b Method B: Classical Biginelli conditions (cat.H2SO4 in EtOH, reflux 18h) [6] c Method C: Hu improved conditions (BF3·OEt2/CuCl in THF, reflux 18h) [7] d Method D: Bigi improved conditions (montmorillonite KSF without solvent at 130°C for 48h) [15]

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MDPI and ACS Style

Lin, H.; Ding, J.; Chen, X.; Zhang, Z. An Efficient Synthesis of 5-Alkoxycarbonyl-4-aryl-3,4-dihydropyrimidin-2(1H)-ones Catalyzed by KSF Montmorillonite. Molecules 2000, 5, 1240-1243. https://doi.org/10.3390/51201240

AMA Style

Lin H, Ding J, Chen X, Zhang Z. An Efficient Synthesis of 5-Alkoxycarbonyl-4-aryl-3,4-dihydropyrimidin-2(1H)-ones Catalyzed by KSF Montmorillonite. Molecules. 2000; 5(12):1240-1243. https://doi.org/10.3390/51201240

Chicago/Turabian Style

Lin, Haixia, Jinchang Ding, Xianten Chen, and Ziyi Zhang. 2000. "An Efficient Synthesis of 5-Alkoxycarbonyl-4-aryl-3,4-dihydropyrimidin-2(1H)-ones Catalyzed by KSF Montmorillonite" Molecules 5, no. 12: 1240-1243. https://doi.org/10.3390/51201240

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