HETEROCYCLES

Short Paper | Regular issue | Vol. 91, No. 1, 2015, pp. 105-112
Received, 3rd November, 2014, Accepted, 3rd December, 2014, Published online, 25th December, 2014.
DOI: 10.3987/COM-14-13118

■ Ga(OTf)3 Catalyzed Synthesis of 3,4-Dihydropyrimidin-2(1H)-ones

Jingjing Xia* and Kehua Zhang

Materials and chemical engineering, Anhui Jianzhu University, Anhui Jianzhu University 230601, China

Abstract

Gallium(III) triflate was used to catalyze Biginelli-like reactions under solvent-free condition to obtain dihydropyrimidione derivatives in good to excellent yields and short reaction time.

Dihydropyrimidinones (DHPMs) has attracted increasing attentions in organic and medicinal chemistry due to their versatile pharmacological and therapeutic properties, such as calcium channel modulators, α1a adrenoaceptor-selective antagonists,1-3 anticancer drugs to inhibit kinesin motor proteins,4,5 Rho-kinase inhibitors,6 anti-HIV activity7 and so on.
The first synthesis of DHPMs was reported by an Italian chemist, Pietro Biginelli, in 1893 through a simple one-pot, three-component condensation reaction of urea, ethyl acetoacetate and an aromatic aldehyde.8 The Biginelli reaction was not widely applied until the early 1990s as the increasing requirement of biological active compounds, which made this multicomponent reaction attractive. In the past years, this reaction has gained much more attention and several modified procedures have been reported in order to improve its efficiency. Lewis acids catalyzed DHPMs synthesis is one of the most widely used methods, such as BF3.OEt2,9 FeCl3.6H2O,10 LaCl3,11 Yb(OTf)3,12 Cu(OTf)2,13 InBr3,14 Zr(NO3)3,15 BiCl3,16 Mn(OAc)3,17 CaCl2,18 I2,19 ZrOCl2,20 montmorillonite KSF,21 LiBr22 etc. Although extensive investigations have devoted to improve the efficiency of Biginelli reaction, we, here, provide a relatively simple operation and environmental friendly reaction condition to carry out Biginelli reaction.
As a water-compatible strong Lewis acid, Ga(OTf)3 has been widely used to catalyze organic reactions,23 such as Beckmann rearrangements,24 Friedel–Crafts reactions,25,26 aldoxime dehydration,27,28 regioselective rearrangements of 2-substituted vinylepoxides,29 asymmetric Mukaiyama aldol reactions,30 constructions of fused-bicyclolactones,31 and so on. Herein, we report a new utility of gallium(III) triflate catalyzed neat Biginelli reaction. Compared to other methods reported in the literature, gallium(III)-promoted reactions are straightforward, giving good to excellent yields. Moreover, this reaction condition can also expand to cycloketones, giving a novel transformation for the synthesis of dihydropyrimidinones.

Initially, the reaction conditions were screened by exploring a typical Biginelli reaction of ethyl acetoacetate, benzaldehyde and urea with catalyzed Ga(OTf)3 in various solvents, as collected in Table 1. 10 mol% Ga(OTf)3 was employed to catalyze this reaction under various solvents, such as THF, DCM, acetonitrile, ethanol and toluene. THF and DCM gave trace amount of the desired product after refluxing for 12 hours, which might be attributed to the low boiling points of the solvents (Table 1, entries 1 and 3). Low yields were also obtained in toluene and acetonitrile solutions (Table 1, entries 2 and 4). Ethanol can give a relatively better yield of 88% (Table 1, entry 5). However, when this reaction was carried out without solvent at 90 oC, 98% yield product can be obtained within 0.5 h (Table 1, entry 6). The yield was a little bit lower (90%) when the catalyst amount was reduced to 5 mol% (Table 1, entry 7).

With the best reaction condition (Table 1, entry 6) in hand; the reaction scope was explored to different aldehydes, alkyl acetoacetates and urea or thiourea. The collected results were presented in Table 2. First of all, different benzaldehydes with both electron donating (–OMe) and electron withdrawing (–NO2 and –F) groups were investigated, giving high yield (> 90%) within less than one hour (Table 2, entries 1–5 and 9–11). Alkyl aldehydes were also explored (Table 2, entries 7 and 8), but with relatively low yields of 84% and 82%, respectively. Thioureas can also be applied in this reaction condition (Table 2, entries 12 and 13) with good yields.

The successful scope investigation mentioned above (Table 2) prompted us to further expand the versatility of Biginelli reaction by replacing alkyl acetoacetate to cycloketones. Although Pan group has reported the one-pot multicomponent Biginelli reactions between cycloalkanones, urea or thiourea, and aldehydes catalyzed by TMSCl,32 a combination solvent of DMF/MeCN was used. Liu group mentioned a solvent and catalyst free reaction condition, but the aldehydes were only restricted for aromatic aldehydes and no cycloketones were investigated.33 In this reaction, Ga(OTf)3 catalyzed cycloketones, urea and aldehydes were also succeeded under solvent-free conditions with moderate to high yields (Table 3). Benzaldehydes with both electron donating (–Me and –OMe) and electron withdrawing (–NO2) groups were tested with good yields (Table 3, entries 1–5 and 7). A seven-membered ring ketone, cycloheptanone, was also tried with a 83% yield (Table 3, entry 6).

In conclusion, Ga(OTf)3 can effectively catalyze Biginelli reaction of alkyl acetoacetates (or cycloketones), aldehydes and urea or thiourea under solvent-free conditions. The functional group diversity, environmental friendly condition, high yield and mild reactions conditions will promote this reaction with wide applications.

EXPERIMENTAL
All chemicals (AR grade) were obtained from commercial resources and used without further purification. 1H NMR (400 MHz) spectra were recorded on a Varian Mercury MHz spectrometer in CDCl3 with TMS as the internal standard. All products are known and they were also identified by melting point, which were determined using XT-4 apparatus and are not corrected. High-resolution mass spectra (HRMS) were obtained using a GCT-TOF instrument.

General procedure for the synthesis of DHPMs
To a mixture of alkyl acetoacetate (or cycloketone) (1.0 mmol), aldehyde (1.0 mmol, for cycloketones: 2.0 mmol) and urea (or thiourea) (1.2 mmol), 0.1 equivalent Ga(OTf)3 was added. The mixture was stirred at 90 oC for appropriate time. After reaction completed by TLC analysis, water was added and the product was extracted with EtOAc. The organic layer was dried over anhydrous Na2SO4 and evaporated. The residue was recrystallized from methanol or ethanol to obtain pure products.

NMR and HR-MS for part of the compounds:
Ethyl 6-methyl-2-oxo-4-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxylate (4a). mp 202–203 oC (Lit.9 202–204 oC). 1H NMR (CDCl3, 400 MHz) δ 8.04 (br, 1H, NH), 7.33–7.25 (m, 5H, ArH), 5.74 (br, 1H, NH), 5.05 (s, 1H, CH), 4.08 (q, J = 7.2 Hz, 2H, CH2O), 2.36 (s, 3H, CH3), 1.18 (t, J = 7.2 Hz, 3H, CH3).
Ethyl 4-(4-methoxyphenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (4b). mp 201–202 oC (Lit.9 201–203 oC). 1H NMR (DMSO-d6, 400 MHz) δ 9.14 (br, 1H, NH), 7.70 (br, 1H, NH), 7.15 (d, J = 8.6 Hz, 2H), 6.88 (d, J = 8.6 Hz, 2H), 5.10 (d, J = 3.4 Hz, 1H), 3.98 (q, J = 7.2 Hz, 2H, CH2O), 3.72 (s, 3H, CH3), 2.24 (s, 3H, CH3), 1.11 (t, J = 7.2 Hz, 3H, CH3). HR-MS(EI): calcd for C15H18N2O4: 290.1267, found: 290.1271.
Ethyl 4-(4-chlorophenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (4c). mp 214–216 oC (Lit.9 213–215 oC). 1H NMR (DMSO-d6, 400 MHz) δ 9.25 (br, 1H, NH), 7.78 (br, 1H, NH), 7.39 (d, J = 8.4 Hz, 2H), 7.24 (d, J = 8.4 Hz, 2H), 5.14 (d, J = 3.0 Hz, 1H), 3.98 (q, J = 7.1 Hz, 2H, CH2O), 2.26 (s, 3H), 1.10 (t, J = 7.1 Hz, 3H, CH3).
Ethyl 4-(4-fluorophenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (4d). mp 176–178 oC (Lit.34 175–177 oC). 1H NMR (CDCl3, 400 MHz) δ 8.13 (br, 1H, NH), 7.26 (d, J = 8.4 Hz, 2H), 7.01 (d, J = 8.4 Hz, 2H), 5.40 (d, J = 3.2 Hz, 1H), 4.08 (q, J = 7.2 Hz, 2H, CH2O), 2.33 (s, 3H), 1.18 (t, J = 7.2 Hz, 3H, CH3).
Ethyl 4-(4-nitrophenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (4e). mp 207–211 oC (Lit.9 208–211 oC). 1H NMR (DMSO-d6, 400 MHz) δ 9.38 (br, 1H, NH), 8.20 (d, J = 8.6 Hz, 2H), 7.50 (d, J = 8.6 Hz, 2H), 5.26 (d, J = 2.0 Hz, 1H), 3.97 (q, J = 7.2 Hz, 2H, CH2O), 2.26 (s, 3H), 1.10 (t, J = 7.2 Hz, 3H, CH3).
Ethyl 4-(2-furanyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (4f). mp 209–212 oC (Lit.34 207–209 oC). 1H NMR (CDCl3, 400 MHz) δ 7.86 (br, 1H, NH), 7.32 (d, J = 6.0 Hz, 1H), 6.29–6.24 (m, 2H), 6.13 (d, J = 6.2 Hz, 1H), 5.47 (s, 1H, CH), 4.15 (q, J = 7.2 Hz, 2H, CH2O), 2.35 (s, 3H), 1.20 (t, J = 7.2 Hz, 3H, CH3).
Ethyl 4,6-dimethyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (4g). mp 194–196 oC (Lit.14 194–195 oC). 1H NMR (CDCl3 , 400 MHz): δ 8.11 (br, 1H, NH), 5.70 (br, 1H, NH), 4.43–4.32 (m, 1H, CH), 4.20 (q, J = 7.2 Hz, 2H, CH2O), 2.28 (s, 3H, CH3), 1.29–1.26 (m, 6H, 2×CH3). HR-MS(EI): calcd for C9H14N2O3: 198.1004, found: 198.1003.
Ethyl 4-hexyl-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (4h). mp 208–210 oC (Lit.12 208–210 oC). 1H NMR (CDCl3, 400 MHz): δ 8.15 (br, 1H, NH), 5.87 (br, 1H, NH), 4.35–4.25 (m, 1H, CH), 4.19 (q, J = 7.2 Hz, 2H, CH2O), 2.30 (s, 3H, CH3), 1.55–1.52 (m, 2H, CH2), 1.35–1.10 (m, 11H, CH3 + 4×CH2), 0.88 (t, J = 7.2 Hz, 3H, CH3).
Methyl 6-methyl-2-oxo-4-phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxylate (4i). mp 210–212 oC (Lit.9 209–212 oC). 1H NMR (DMSO-d6, 400 MHz) δ 8.10 (br, 1H, NH), 7.33–7.28 (m, 5H, ArH), 5.38 (d, J = 2.6 Hz, 1H), 3.61 (s, 3H), 2.35 (s, 3H).
Methyl 4-(4-methoxyphenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (4j). mp 193–194 oC (Lit.9 192–194 oC). 1H NMR (DMSO-d6, 400 MHz) δ 9.16 (br, 1H, NH), 7.71 (br, 1H, NH), 7.20(d, J = 8.4 Hz, 2H), 6.83 (d, J = 8.4 Hz, 2H), 5.30 (d, J = 2.2 Hz, 1H), 3.76 (s, 3H), 3.62 (s, 3H), 2.31 (s, 3H).
Methyl 4-(4-chlorophenyl)-6-methyl-2-oxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (4k). mp 205–207 oC (Lit.12 204–207 oC). 1H NMR (DMSO-d6, 400 MHz) δ 9.21 (br, 1H, NH), 7.71 (br, 1H, NH), 7.15 (d, J = 8.4 Hz, 2H), 6.88 (d, J = 8.4 Hz, 2H), 5.10 (d, J = 2.8 Hz, 1H), 3.54 (s, 3H), 2.27 (s, 3H).
Ethyl 6-methyl-4-phenyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (4l). mp 231–234 oC (Lit.14 232–234 oC). 1H NMR (CDCl3, 400 MHz): δ 7.88 (br, 1H, NH), 7.28–7.26 (m, 5H, ArH), 5.39 (d, J = 3.4 Hz, 1H, CH), 4.05 (q, J = 7.2 Hz, 2H, CH2O), 2.35 (s, 3H, CH3), 1.16 (t, J = 7.2 Hz, 3H, CH3). HR-MS(EI): calcd for C14H16N2O2S: 276.0932, found: 276.0940.
Methyl 6-methyl-4-phenyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (4m). mp 220–222 oC (Lit.35 221–222 oC). 1H NMR (CDCl3, 400 MHz): δ 7.90 (br, 1H, NH), 7.30–7.25 (m, 5H, ArH), 5.25 (d, J = 3.4 Hz, 1H, CH), 3.60 (s, 3H, CH3), 2.27 (s, 3H, CH3).
7-Benzylidene-4-phenyl-3,4,6,7-tetrahydro-1H-cyclopenta[d]pyrimidin-2(5H)-one (6a). mp 237–239 oC (Lit.32 236–239 oC). 1H NMR (DMSO-d6, 400 MHz): δ 8.78 (s, 1H, NH), 7.41–7.23 (m, 11H, ArH, =CH), 6.64 (s, 1H, NH), 5.16 (s, 1H, CH), 2.84–2.80 (m, 2H, CH2), 2.36–2.35 (m, 1H, CH), 2.04–1.98 (m, 1H, CH). HR-MS (EI): calcd for C20H18N2O: 302.1419, found: 302.1418.
7-(4-Nitrobenzylidene)-4-(4-nitrophenyl)-3,4,6,7-tetrahydro-1H-cyclopenta[d]pyrimidin-2(5H)-one (6b). mp 280–282 oC (Lit.34 281–282 oC). 1H NMR (DMSO-d6, 400 MHz): δ 8.88 (s, 1H, NH), 8.36–8.18 (m, 4H, ArH), 7.66–7.38 (m, 4H, ArH), 6.90–6.79 (m, 2H, NH+CH), 5.40 (s, 1H, CH), 2.93–2.89 (m, 2H, CH2), 2.27–2.19 (m, 1H, CH), 2.04–2.02 (m, 1H, CH).
7-(4-Chlorobenzylidene)-4-(4-chlorophenyl)-3,4,6,7-tetrahydro-1H-cyclopenta[d]pyrimidin-2(5H)-one (6c). mp 227–228 oC (Lit.32 226–228 oC). 1H NMR (DMSO-d6, 400 MHz): δ 8.84 (s, 1H, NH), 7.47–7.28 (m, 9H, ArH, =CH), 6.63 (s, 1H, NH), 5.18 (s, 1H, CH), 2.83–2.78 (m, 2H, CH2), 2.44–2.38 (m, 1H, CH), 2.03–1.97 (m, 1H, CH).
7-(4-Methoxybenzylidene)-4-(4-methoxyphenyl)-3,4,6,7-tetrahydro-1H-cyclopenta[d]pyrimidin-2(5H)-one (6d). mp 250–252 oC (Lit.32 250–252 oC). 1H NMR (DMSO-d6, 400 MHz): δ 8.65 (s, 1H, NH), 7.27 (d, 2H, J = 8.4Hz, ArH), 7.16 (d, 2H, J = 8.4Hz, ArH), 7.05 (s, 1H, ArH), 6.94 (d, 4H, J = 7.5Hz, ArH, =CH), 6.58 (s, 1H, NH), 5.10 (s, 1H, CH), 3.76 (s, 6H, 2×OCH3), 2.79 (s, 2H, CH2), 2.40–2.36 (m, 1H, CH), 2.01–1.94 (m, 1H, CH); HR-MS (EI): calcd for C22H22N2O3: 362.1630; found: 362.1626.
7-(4-Methylbenzylidene)-4-(p-tolyl)-3,4,6,7-tetrahydro-1H-cyclopenta[d]pyrimidin-2(5H)-one (6e). mp 239–241 oC (Lit.32 238–241 oC). 1H NMR (DMSO-d6, 400 MHz): δ 8.99 (s, 1H, NH), 7.40–7.25 (m, 9H, ArH, =CH), 6.94 (s, 1H, NH), 5.20 (s, 1H, CH), 2.85–2.83 (m, 2H, CH2), 2.44–2.36 (m, 1H, CH), 2.10 (s, 7H, 2 ×CH3+CH). HR-MS (EI): calcd for C22H22N2O: 330.1732; found: 330.1729.
9-Benzylidene-4-phenyl-3,4,6,7,8,9-hexahydro-1H-cyclohepta[d]pyrimidin-2(5H)-one (6f). mp 287–288 oC (Lit.34 286–288 oC). 1H NMR (DMSO-d6, 400 MHz): δ 9.02 (s, 1H, NH), 7.43–7.22 (m, 11H, ArH, =CH), 6.93 (s, 1H, NH), 5.24 (s, 1H, CH), 2.85–2.83 (m, 2H, CH2), 2.44–2.43 (m, 1H, CH), 2.09 (s, 5H, CH, 2CH2).
4-(Naphthalen-1-yl)-7-(naphthalen-1-ylmethylene)-3,4,6,7-tetrahydro-1H-cyclopenta[d]pyrimidin-2(5H)-one (6g). mp 262–264 oC (Lit.34 260–264 oC). 1H NMR (DMSO-d6, 400 MHz): δ 9.20 (s, 1H, NH), 8.39–6.76 (m, 14H, ArH), 7.05 (s, 1H, =CH), 6.03 (s, 1H, NH), 5.29 (s, 1H, CH), 2.80–2.70 (m, 2H, CH2), 2.45–2.41 (m, 1H, CH), 1.83–1.75 (m, 1H, CH). HR-MS (EI): calcd for C28H22N2O: 402.1732; found: 402.1725.

ACKNOWLEDGEMENTS
This work is financially supported by the Anhui Provincial Natural Science Foundation (No. 1208085QB24).

References

1. Y. Huang, L. Taylor, X. Chen, and N. Ayres, J. Polym. Sci., Part A: Polym. Chem., 2013, 51, 5230. CrossRef
2. C. O. Kappe, Eur. J. Med. Chem., 2000, 35, 1043. CrossRef
3. Y.-S. Huang and G.-W. Wang, J. Mol. Struct.: THEOCHEM, 2008, 860, 24. CrossRef
4. C. O. Kappe, O. V. Shishkin, G. Uray, and P. Verdino, Tetrahedron, 2000, 56, 1859. CrossRef
5. Y. Huang and X. Chen, Nano LIFE, 2014, 4, 1441006. CrossRef
6. B. G. Krista, H.-F. Cui, and E. D. Sarah, J. Med. Chem., 2007, 50, 6. CrossRef
7. Y. Huang, J. Li, X. Chen, and X. Wang, RSC Adv., 2014, 4, 62160.
8. P. Biginelli, Gazz. Chim. Ital., 1893, 23, 360.
9. E. H. Hu, D. R. Sidler, and U. -H. Dolling, J. Org. Chem., 1998, 63, 3454. CrossRef
10. J. Lu and H. R. Ma, Synlett, 2000, 63.
11. J. Lu, Y. Bai, Z. Wang, B. Yang, and H. Ma, Tetrahedron Lett., 2000, 41, 9075. CrossRef
12. Y. Ma, C. Qian, L. Wang, and M. Yang, J. Org. Chem., 2000, 65, 3864. CrossRef
13. A. S. Paraskar, G. K. Dewkar, and A. Sudalai, Tetrahedron Lett., 2003, 44, 3305. CrossRef
14. N. Y. Fu, Y. F. Yuan, Z. Cao, S. W. Wang, J. T. Wang, and C. Peppe, Tetrahedron, 2002, 58, 4801. CrossRef
15. B. K. Banik, A. T. Reddy, A. Datta, and C. Mukhopadhyay, Tetrahedron Lett., 2007, 48, 7392. CrossRef
16. K. Ramalinga, P. Vijayalaxmi, and T. N. B. Kaimal, Synlett, 2001, 863. CrossRef
17. K. A. Kumar, M. Kasthuraiah, C. S. Reddy, and C. D. Reddy, Tetrahedron Lett., 2001, 42, 7873. CrossRef
18. J. S. Yadav, B. V. S. Reddy, R. Srinivas, C. Venugopal, and T. Ramalingam, Synthesis, 2001, 1341. CrossRef
19. K. V. N. S. Srinivas and B. Das, Synthesis, 2004, 2091.
20. C. S. Reddy and A. Nagaraj, Heterocycl. Commun., 2007, 13, 67. CrossRef
21. H. X. Lin, J. C. Ding, X. T. Chen, and Z. Y. Zhang, Molecules, 2000, 5, 1240. CrossRef
22. H. Salehi and Q. X. Guo, Synth. Commun., 2004, 34, 171. CrossRef
23. G. K. Surya Prakash, T. Mathew, and G. A. Olah, Acc. Chem. Res., 2012, 45, 565. CrossRef
24. P. Yan, P. Batamack, G. K. Surya Prakash, and G. A. Olah, Catal. Lett., 2005, 103, 165. CrossRef
25. P. Yan, P. Batamack, G. K. Surya Prakash, and G. A. Olah, Catal. Lett., 2003, 85, 1. CrossRef
26. S. Kobayashi, I. Komoto, and J. Matsuo, Adv. Synth. Catal., 2001, 343, 71. CrossRef
27. R. V. Nguyen and C.-J. Li, J. Am. Chem. Soc., 2005, 127, 17184. CrossRef
28. Y. Huang, M. A. Shaw, E. S. Mullins, T. L. Kirley, and N. Ayres, Biomacromolecules, 2014, 15, 4455. CrossRef
29. X. M. Deng, X. L. Sun, and Y. Tang, J. Org. Chem., 2005, 70, 6537. CrossRef
30. R. V. Nguyen and C. J. Li, J. Am. Chem. Soc., 2005, 127, 17184. CrossRef
31. H. J. Li, H. Y. Tian, Y. C. Wu, Y. J. Chen, L. Liu, D. Wang, and C.-J. Li, Adv. Synth. Catal., 2005, 347, 1247. CrossRef
32. Y.-L. Zhu, S.-L. Huang, and Y.-J. Pan, Eur. J. Org. Chem., 2005, 2354. CrossRef
33. R. Wang and Z.-Q. Liu, J. Org. Chem., 2012, 77, 3952. CrossRef
34. D. Li, H. Mao, L. An, Z. Huang, and J. Zou, Chin. J. Chem., 2010, 28, 2025. CrossRef
35. Z. H. Huang, J. P. Zou, and W. Q. Jiang, Tetrahedron Lett., 2006, 47, 7965. CrossRef