Synlett 2018; 29(08): 1047-1054
DOI: 10.1055/s-0036-1591900
letter
© Georg Thieme Verlag Stuttgart · New York

Efficient Biginelli Synthesis of 2-Aminodihydropyrimidines under Microwave Irradiation

Fulvia Felluga*
Dipartimento di Scienze Chimiche e Farmaceutiche, Università di Trieste, via L. Giorgieri 1, I-34127 Trieste, Italy   Email: ffelluga@units.it
,
Fabio Benedetti
Dipartimento di Scienze Chimiche e Farmaceutiche, Università di Trieste, via L. Giorgieri 1, I-34127 Trieste, Italy   Email: ffelluga@units.it
,
Federico Berti
Dipartimento di Scienze Chimiche e Farmaceutiche, Università di Trieste, via L. Giorgieri 1, I-34127 Trieste, Italy   Email: ffelluga@units.it
,
Sara Drioli
Dipartimento di Scienze Chimiche e Farmaceutiche, Università di Trieste, via L. Giorgieri 1, I-34127 Trieste, Italy   Email: ffelluga@units.it
,
Giorgia Regini
Dipartimento di Scienze Chimiche e Farmaceutiche, Università di Trieste, via L. Giorgieri 1, I-34127 Trieste, Italy   Email: ffelluga@units.it
› Author Affiliations
Financial support by the University of Trieste (FRA 2016: Finanziamento di Ateneo per progetti di ricerca scientifica) is gratefully ­acknowledged.
Further Information

Publication History

Received: 23.11.2017

Accepted after revision: 25 December 2017

Publication Date:
31 January 2018 (online)


Abstract

A practical and general method for the Biginelli cyclocondensation of guanidine with aldehydes and β-dicarbonyl compounds is described and illustrated with the synthesis of a set of 26 functionalized 2-amino-3,4-dihydropyrimidines. The simple protocol involves the ­microwave-mediated reaction of a twofold excess of guanidine hydrochloride with the required reaction partners in an alcohol at 120 °C. Yields are generally good, with short reaction times and a simple workup. The scope is considerably wider than that of similar reactions ­carried out under conventional heating.

Supporting Information

 
  • References and Notes

  • 1 Yamamoto Y. Kojima S. In Amidines and Imidates . Vol. 2. Patai S. Rappoport Z. Wiley; Chichester: 1991: 486
  • 2 Ishikawa T. Kumamoto T. Synthesis 2006; 737
  • 3 Superbases for Organic Synthesis: Guanidines, Amidines, Phospha­zenes and Related Organocatalysts. Ishikawa T. Wiley; Chichester: 2009
  • 4 Coles MP. Chem. Commun. 2009; 3659
  • 5 Leow D. Tan C.-H. Synlett 2010; 1589
  • 6 Taylor JE. Bull SD. Williams JM. J. Chem. Soc. Rev. 2012; 41: 2109
  • 7 Selig P. Synthesis 2013; 45: 703
  • 8 Coles MP. Dalton Trans. 2006; 985
  • 9 El-Hamruni SM. Sözerli SE. Smith JD. Coles MP. Hitchcock PB. Aust. J. Chem. 2014; 67: 1071
  • 10 Herce HD. Garcia AE. Cardoso MC. J. Am. Chem. Soc. 2014; 136: 17459
  • 11 Patil KM. Naik RJ. Vij M. Yadav AK. Kumar VA. Ganguli M. Fernandes M. Bioorg. Med. Chem. Lett. 2014; 24: 4198
  • 12 Nicolas J. Treat NJ. Smith D. Teng C. Flores JD. Abel BA. York AW. Huang F. McCormick CL. ACS Macro Lett. 2012; 1: 100
  • 13 Berlinck RG. S. Romminger S. Nat. Prod. Rep. 2016; 33: 456
  • 14 Ebada SS. Proksch P. Mini-Rev. Med. Chem. 2011; 11: 225
  • 15 Greenhill JV. Lue P. Prog. Med. Chem. 1993; 30: 203
  • 16 Berlinck RG. S. Kossuga MH. Nat. Prod. Rep. 2005; 22: 516
  • 17 Lagoja IM. Chem. Biodiversity 2005; 2: 1
  • 18 Watanabe M. Koike H. Ishiba T. Okada T. Seo S. Hirai K. Bioorg. Med. Chem. 1997; 5: 437
  • 19 Capdeville R. Buchdunger E. Zimmermann J. Matter A. Nat. Rev. Drug Discovery 2002; 1: 493
  • 20 Biginelli P. Gazz. Chim. Ital. 1893; 23: 360
  • 21 Kappe CO. Stadler A. Org. React. (Hoboken, NJ, U. S.) 2004; 63: 1
  • 22 Nagarajaiah H. Mukhopadhyay A. Narasimha Moorthy J. Tetra­hedron Lett. 2016; 57: 5135
  • 23 Kappe CO. Eur. J. Med. Chem. 2000; 35: 1043
  • 24 Cho H. Shima K. Hayashimatsu M. Ohnaka Y. Mizuno A. Takeuchi Y. J. Org. Chem. 1985; 50: 4227
  • 25 Milcent R. Malanda J.-C. Barbier GJ. Vaissermann J. J. Hetero­cycl. Chem. 1997; 34: 329
  • 26 Vanden Eynde JJ. Hecq N. Kataeva O. Kappe CO. Tetra­hedron 2001; 57: 1785
  • 27 Atwal KS. Rovnyak GC. O’Reilly BC. Schwartz J. J. Org. Chem. 1989; 54: 5898
  • 28 Matloobi M. Kappe CO. J. Comb. Chem. 2007; 9: 275
  • 29 Nilsson BL. Overman LE. J. Org. Chem. 2006; 71: 7706
  • 30 Nolasco Fidencio JJ. Ríos-Guerra H. González-Villanueva G. Penieres-Carrillo JG. Balcázar GG. Nicolás-Vázquez MI. Delgado F. Heterocycles 2016; 92: 1803
  • 31 Ahmed B. Khan RA. Habibullah Keshari M. Tetrahedron Lett. 2009; 50: 2889
  • 32 Mansoor SS. Shafi SS. Ahmed ZS. Arabian J. Chem. 2016; 9: s846
  • 33 Ahmad MJ. Hassan SF. Nisa RU. Ayub K. Nadeem MS. Nazir S. Ansar FL. Qureshi NA. Rashid U. Med. Chem. Res. 2016; 25: 1877
  • 34 Nishimura Y. Takanori K. Okamoto Y. Cho H. Tetrahedron Lett. 2017; 58: 4236
  • 35 Heravi MM. Ghavidel M. Heidari B. Curr. Org. Synth. 2016; 13: 569
  • 36 Desai B. Dallinger D. Kappe CO. Tetrahedron 2006; 62: 4651
  • 37 Chen Q. Jiang L.-L. Chen C.-N. Yang G.-F. J. Heterocycl. Chem. 2009; 46: 139
  • 38 Kefayati H. Mirfarhadi SM. Kazemi-Rad R. J. Chin. Chem. Soc. (Weinheim, Ger.) 2015; 62: 107
  • 39 2-Amino-3,4-dihydropyrimidines (Table [2], Entries 126); General Method The appropriate1,3-dicarbonyl compound (1.1 mmol), guanidine·HCl (2.0 mmol), and NaHCO3 (4 mmol) were added to a 0.5 M solution of the appropriate aldehyde (1 mmol) in EtOH. The mixture was irradiated for 10 min in a microwave oven at 120 °C (unless otherwise stated), then cooled. Cold H2O was added to dissolve the NaHCO3, and the mixture was left in a refrigerator for 30 min until the product completely precipitated. The solid that formed was collected by filtration, washed with cold water, dried in vacuo, and purified by trituration with i-Pr2O.
  • 40 Ethyl 2-Amino-4-methyl-6-(2-naphthyl)-1,6-dihydropyrimidine-5-carboxylate (Table 2, Entry 12) Prepared by reacting 2-naphthaldehyde, guanidine·HCl, and ethyl acetoacetate as a pale-brown solid; yield: 210 mg (68%); mp 165–167 °C. IR (Nujol): 3350, 3500–2700 (br), 1703, 1661, 1602 cm–1. 1H NMR (500 MHz, DMSO-d 6): δ = 1.06 (t, J = 7.4 Hz, 3 H, CH 3CH2O), 2.24 [s, 3 H, C(6)CH3], 3.92 (q, J = 7.4 Hz, 2 H, CH3CH 2O), 5.38 (s, 1 H, H-4), 6.24 (s, 2 H, NH2), 7.43–7.51 (m, 4 H, ArH), 7.64 (s, 1 H, ArH), 7.85 (m, 3 H, ArH and NH). 13C NMR (125.68 MHz, DMSO-d 6): δ = 14.77, 23.64, 53.43, 58.68, 97.76, 124.73, 125.62, 126.11, 126.58, 127.88, 128.21, 128.57, 132.72, 133.13, 144.13, 155.35, 160.26, 166.51. HRMS-ESI: m/z [M + H]+ calcd for [C18H20N3O2]+: 310.1550; found: 310.1558.
  • 41 2-Amino-4-(2-naphthyl)-4,6,7,8-tetrahydroquinazolin-5(3H)-one (Table 2, Entry 22) Prepared by reacting 2-naphthaldehyde, guanidine·HCl, and cyclohexane-1,3-dione at 140 °C for 20 min as a yellow solid; yield: 247 mg (85%); mp >240 °C. IR (Nujol): 3270, 3500–2500, 1684, 1654 (br) cm–1. 1H NMR (400 MHz, DMSO-d 6): δ = 1.76, 1.80 (2 m, 1 H each, ring CH2), 2.12 (m, 2 H, CH2C=), 2.35 (m, 2 H, CH2CO), 5.43 (s, 1 H, H-4), 6.49 (br s, 2 H, NH2), 7.36 (br s, 1 H, NH), 7.41–7.48 (m, 3 H, naphthyl), 7.63 (s, 1 H, naphthyl), 7.81–7.85 (m, 3 H, naphthyl). 13C NMR (DMSO-d 6): δ = 21.11, 29.95, 36.65, 50.57, 108.52, 124.61, 125.26, 125.97, 126.36, 127.62, 128.00, 128.39, 132.48, 132.87, 142.86, 155.30, 163.04, 192.90. HRMS-ESI: m/z [M + H]+ calcd for [C18H18N3O]+: 292.1444; found: 292.1444.