Synthesis of diverse dihydropyrimidine-related scaffolds by fluorous benzaldehyde-based Biginelli reaction and post-condensation modifications

  1. Bruno Piqani and
  2. Wei Zhang

Department of Chemistry, University of Massachusetts Boston, 100 Morrissey Boulevard, Boston, MA 02125, USA

  1. Author email
  2. Corresponding author email

This article is part of the Thematic Series "Multicomponent reactions".

Guest Editor: T. J. J. Müller
Beilstein J. Org. Chem. 2011, 7, 1294–1298. https://doi.org/10.3762/bjoc.7.150
Received 10 Jun 2011, Accepted 23 Aug 2011, Published 16 Sep 2011

Abstract

Dihydropyrimidinones and dihydropyrimidinethiones generated from the Biginelli reactions of perfluorooctanesulfonyl-attached benzaldehydes are used as common intermediates for post-condensation modifications such as cycloaddition, Liebeskind–Srogl reaction and Suzuki coupling to form biaryl-substituted dihydropyrimidinone, dihydropyrimidine, and thiazolopyrimidine compounds. The high efficiency of the diversity-oriented synthesis is achieved by conducting a multicomponent reaction for improved atom economy, under microwave heating for fast reaction, and with fluorous solid-phase extractions (F-SPE) for ease of purification.

Keywords: Biginelli reaction; dihydropyrimidine; diversity-oriented synthesis; fluorous; Suzuki coupling

Introduction

Dihydropyrimidinone and dihydropyrimidine derivatives have broad biologically activities. Many synthetic samples have been studied as antibacterial, antiviral, antihypertensive, and anticancer agents [1], and the natural products containing these heterocyclic moieties have been studied as new leads for AIDS therapies [2]. The Biginelli reaction of a β-keto ester, an aldehyde, and urea is considered as one of the most efficient ways to synthesize dihydropyrimidinones [3]. This acid-catalyzed reaction can be conducted under conventional or microwave heating [4,5]. Reported in this paper is a diversity-oriented synthesis of biaryl-substituted dihydropyrimidinone 5, thiazolopyrimidine 6, and dihydropyrimidine 7 compounds (Scheme 1). The perfluorooctanesulfonyl-attached benzaldehydes 1 were used as a key component for the Biginelli reactions [6]. The Biginelli products 4 were used as a common intermediate for post-condensation reactions including cycloaddition, Liebeskind–Srogl reaction and Suzuki coupling to form three different heterocyclic skeletons. The high efficiency of the diversity-oriented synthesis was achieved by conducting fast, microwave-heated reactions and simple fluorous solid-phase extractions (F-SPE) for purification [7]. The perfluorooctanesulfonyl group served as a phase tag for F-SPE and also as a convertible linker for the Suzuki coupling to introduce biaryl functionality to the heterocyclic skeletons [8-12].

[1860-5397-7-150-i1]

Scheme 1: Synthesis of diverse dihydropyrimidine-related compounds.

Result and Discussion

Fluorous benzaldehydes 1 were prepared by the reaction of phenols with perfluorooctanesulfonyl fluoride, by following the reported procedure [13]. Compounds 1 were used as a limiting agent to react with urea/thiourea 2 and acetylacetone 3 for the Biginelli reactions. The reactions were promoted by Yb(OTf)3 as a catalyst [14,15], acetonitrile as a solvent, and under microwave irradiation at 120 °C for 20 min. This optimized condition was developed after other solvents, including water, EtOH and toluene, and different microwave reaction temperatures (100–130 °C) and times (10–20 min) were explored. The Biginelli products were separated from the reaction mixtures by F-SPE eluted with fluorophobic 80:20 MeOH/H2O and then fluorophilic 100% MeOH or acetone [7]. The fluorous Biginelli products were collected from the MeOH fraction to give dihydropyrimidinones 4a–d and dihydropyrimidinethiones 4e,f in 85–95% yields (Table 1). The Biginelli products 4a–e were used for Suzuki coupling reactions to remove the fluorous linker and introduce the biaryl functional group. The coupling reactions were promoted by microwave heating at 140 °C for 30 min with Pd(pddf)Cl2 as a catalyst, Cs2CO3 as a base, and 4:4:1 acetone/toluene/H2O as a solvent [13]. Dihydropyrimidinones 4a–d gave the expected products 5a–h in 51–68% yield after F-SPE and flash chromatography purification. However, no reactions occurred with the dihydropyrimidinethiones 4e,f under these reaction conditions.

Table 1: Biginelli reactions followed by Suzuki reactions of dihydropyrimidinones and dihydropyrimidinethiones.

[Graphic 1]
R1 R2 X F-Sulfonyl position 4 (yield) R3 5 (yield)
CH3 CH3 O meta 4a (91%) p-OCH3 5a (67%)
          H 5b (56%)
CH3 OCH3 O meta 4b (95%) p-OCH3 5c (57%)
          H 5d (51%)
CH3 CH3 O para 4c (90%) p-OCH3 5e (68%)
          H 5f (62%)
CH3 OCH3 O para 4d (88%) p-OCH3 5g (58%)
          H 5h (60%)
H CH3 S meta 4e (89%) H -
H OCH3 S meta 4f (85%) H -

Since dihydropyrimidinethiones 4e,f failed to give Suzuki coupling products, our next effort was to convert them to thiazolopyrimidine through cyclocondensation with chloroacetone [16,17]. The reaction was performed in water under microwave heating at 120 °C for 30 min to afford thiazolopyrimidines 8a and 8b in 89% and 85% yields, respectively, after F-SPE. Suzuki reactions of 8a and 8b with four boronic acids yielded 5-biaryl-5H-thiazolo[3,2-a]pyrimidines 6a–h in 55–64% yields after F-SPE and flash chromatography purifications (Table 2).

Table 2: Synthesis of biaryl-substituted thiazolopyrimidines.

[Graphic 2]
4 R2 8 R3 6 (yield)
4e CH3 8a (89%) H 6a (61%)
      p-OCH3 6b (64%)
      m-Cl 6c (56%)
      p-CH3 6d (62%)
4f OCH3 8b (85%) H 6e (58%)
      p-OCH3 6f (55%)
      m-Cl 6g (63%)
      p-CH3 6h (55%)

Dihydropyrimidinethione 4f was used for the Liebeskind–Srogl coupling reaction with a phenylboronic acid to convert to 2-aryl-1,6-dihydropyrimidine 9 [18-20]. The reaction was performed following a literature procedure [21] and was catalyzed by Pd(PPh3)4 and copper(I) thiophene-2-carboxylate (CuTC) under microwave heating at 100 °C for 25 min to afford aryl-substituted dihydropyrimidine 9 in 76% yield. This compound was then subjected to Suzuki coupling reactions with four boronic acids to yield 2-aryl-6-biaryl substituted dihydropyrimidines 7a–d after F-SPE and flash chromatography purifications (Table 3).

Table 3: Synthesis of 2-aryl-6-biaryl-substituted dihydropyrimidines.

[Graphic 3]
R3 7 (yield)
H 7a (45%)
p-OCH3 7b (48%)
m-Cl 7c (31%)
p-CH3 7d (48%)

Conclusion

We have developed a new application of perfluorooctanesulfonyl-attached benzaldehydes for the diversity-oriented synthesis of heterocyclic scaffolds. The intermediates obtained from the Biginelli reaction were used for post-condensation modifications to afford biaryl-substituted dihydropyrimidinone, dihydropyrimidine, and thiazolopyrimidine compounds. A set of reaction and separation techniques such as multicomponent reactions, microwave heating, and F-SPE was employed to increase the synthetic efficiency. The fluorous sulfonyl group not only served as a phase tag for F-SPE separation, but also as a cleavable linker for the Suzuki coupling reactions.

Experimental

Typical Biginelli reaction procedure: Synthesis of 5-acetyl-4-(4- (perfluorooctylsulfonyloxy)phenyl)-1,6-dimethyl-3,4-dihydropyrimidin-2(1H)-one (4c)

A solution of p-perfluorooctanesulfonyl benzaldehyde 1 (1.2 g, 2.0 mmol), methylurea 2 (0.18 g, 2.4 mmol), methyl acetoacetate 3 (0.35 g, 3.0 mmol) and Yb(OTf)3 (124 mg, 0.2 mmol) in 2 mL of acetonitrile was heated in a Biotage Initiator microwave synthesizer at 120 °C for 20 min. The resulting mixture was purified by F-SPE eluted with 40 mL of 80:20 MeOH/H2O and then 40 mL of acetone. The acetone fraction was concentrated to give 4c (1.3 g) in 90% yield.

Typical Suzuki reaction procedure: Synthesis of 5-acetyl-4-(4'-methoxy-[1,1'-biphenyl]-3-yl)-1,6-dimethyl-3,4-dihydropyrimidin-2(1H)-one (5a)

A solution of 4a (75 mg, 0.1 mmol), 4-methoxyphenylboronic acid (23 mg, 0.15 mmol), Cs2CO3 (81 mg, 0.25 mmol) and Pd(dppf)Cl2 (16 mg, 0.02 mmol) in 3 mL of 4:1:4 acetone/H2O/toluene was heated in a Biotage Initiator microwave synthesizer at 140 °C for 30 min. The resulting mixture was purified by flash chromatography to give 5a (24 mg) in 67% yield.

Typical procedure for cyclocondensation of 4e,f. Synthesis of methyl 3,7-dimethyl-5-(3-(perfluorooctylsulfonyloxy)phenyl)-5H-thiazolo[3,2-a]pyrimidine-6-carboxylate (8b)

A solution of 3,4-dihydropyrimidinethione 4f (0.76 g, 1 mmol), chloroacetone (185 mg, 1.5 mmol) in 2 mL water was heated in Biotage Initiator microwave synthesizer at 120 °C for 30 min. The resulting mixture was purified by F-SPE eluted with 30 mL of 80:20 MeOH/H2O and then 30 mL of acetone. The acetone fraction was concentrated to give 8b (0.67 g) in 85% yield.

Typical LiebeskindSrogl reaction procedure. Synthesis of methyl 4-methyl-6-(3-(perfluorooctylsulfonyloxy)phenyl)-2-phenyl-1,6-dihydropyrimidine-5-carboxylate (9)

A solution of 3,4-dihydropyrimidinethione 4f (152 mg, 0.20 mmol), phenylboronic acid (82 mg, 0.3 mmol), CuTC (95 mg, 0.6 mmol), and Pd(PPh3)4 (3 mol %) in 2 mL THF was heated in Biotage Initiator microwave synthesizer at 100 °C for 25 min. The mixture was purified by F-SPE eluted with 30 mL of 80:20 MeOH/H2O and then 30 mL of acetone. The acetone fraction was concentrated to give 9 (0.85 g) in 76% yield.

Supporting Information

Supporting Information File 1: LC–MS, 1H NMR and 13C NMR data and spectra for compounds 4c, 5a, 6b, 7b, 8b, 9.
Format: PDF Size: 3.9 MB Download

Acknowledgments

This work was supported by the Healey grant from University of Massachusetts Boston. We would like to thank Dave York for his participation in some initial experiments of this project.

References

  1. Kappe, C. O. Acc. Chem. Res. 2000, 33, 879–888. doi:10.1021/ar000048h
    Return to citation in text: [1]
  2. Kappe, C. O. Eur. J. Med. Chem. 2000, 35, 1043–1052. doi:10.1016/S0223-5234(00)01189-2
    Return to citation in text: [1]
  3. Biginelli, P. Gazz. Chim. Ital. 1893, 23, 360–416.
    Return to citation in text: [1]
  4. Kappe, C. O.; Stadler, A. Org. React. 2004, 63, 1–116. doi:10.1002/0471264180.or063.01
    Return to citation in text: [1]
  5. Kappe, C. O. The Biginelli Reaction. In Multicomponent Reactions; Zhu, J.; Bienaymé, H., Eds.; Wiley-VCH: Weinheim, Germany, 2005; pp 95–120.
    Return to citation in text: [1]
  6. Studer, A.; Jeger, P.; Wipf, P.; Curran, D. P. J. Org. Chem. 1997, 62, 2917–2924.
    Return to citation in text: [1]
  7. Zhang, W.; Curran, D. P. Tetrahedron 2006, 62, 11837–11865. doi:10.1016/j.tet.2006.08.051
    Return to citation in text: [1] [2]
  8. Larhed, M.; Hallberg, A. J. Org. Chem. 1996, 61, 9582–9584. doi:10.1021/jo9612990
    Return to citation in text: [1]
  9. Larhed, M.; Hoshino, M.; Hadida, S.; Curran, D. P.; Hallberg, A. J. Org. Chem. 1997, 62, 5583–5587. doi:10.1021/jo970362y
    Return to citation in text: [1]
  10. Kadam, A.; Zhang, Z.; Zhang, W. Curr. Org. Synth. 2011, 8, 295–309. doi:10.2174/157017911794697259
    Return to citation in text: [1]
  11. Zhang, W. Chem. Rev. 2009, 109, 749–795. doi:10.1021/cr800412s
    Return to citation in text: [1]
  12. Zhang, W. Comb. Chem. High Throughput Screening 2007, 10, 219–229.
    Return to citation in text: [1]
  13. Zhang, W.; Chen, C. H.-T.; Lu, Y.; Nagashima, T. Org. Lett. 2004, 6, 1473–1476. doi:10.1021/ol0496428
    Return to citation in text: [1] [2]
  14. Kappe, C. O.; Dallinger, D. Nat. Rev. Drug Discovery 2006, 5, 51–63. doi:10.1038/nrd1926
    Return to citation in text: [1]
  15. Dallinger, D.; Kappe, C. O. Nat. Protoc. 2007, 2, 1713–1721. doi:10.1038/nprot.2007.224
    Return to citation in text: [1]
  16. Wang, X.-C.; Quan, Z.-J.; Zhang, Z.; Liu, Y.-J.; Ji, P.-Y. Lett. Org. Chem. 2007, 4, 370–373. doi:10.2174/157017807781212139
    Return to citation in text: [1]
  17. Quan, Z.-J.; Zhang, Z.; Wang, J.-K.; Wang, X.-C.; Liu, Y.-J.; Ji, P.-Y. Heteroat. Chem. 2008, 19, 149–152. doi:10.1002/hc.20386
    Return to citation in text: [1]
  18. Liebeskind, L. S.; Srogl, J. J. Am. Chem. Soc. 2000, 122, 11260–11261. doi:10.1021/ja005613q
    Return to citation in text: [1]
  19. Villalobos, J. M.; Srogl, J.; Liebeskind, L. S. J. Am. Chem. Soc. 2007, 129, 15734–15735. doi:10.1021/ja074931n
    Return to citation in text: [1]
  20. Prokopcová, H.; Kappe, C. O. J. Org. Chem. 2007, 72, 4440–4448. doi:10.1021/jo070408f
    Return to citation in text: [1]
  21. Prokopcová, H.; Kappe, C. O. Angew. Chem., Int. Ed. 2009, 48, 2276–2286. doi:10.1002/anie.200802842
    Return to citation in text: [1]

© 2011 Piqani and Zhang; licensee Beilstein-Institut.
This is an Open Access article under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
The license is subject to the Beilstein Journal of Organic Chemistry terms and conditions: (http://www.beilstein-journals.org/bjoc)

 
Back to Article List

Other Beilstein-Institut Open Science Activities

Keep Informed

RSS Feed

Subscribe to our Latest Articles RSS Feed.

Subscribe

Follow the Beilstein-Institut

LinkedIn

Twitter: @BeilsteinInst