Efficient Biginelli Synthesis of 2-Aminodihydropyrimidines under Microwave Irradiation

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.

Key words

Biginelli reaction - microwave heating - guanidine - ­dicarbonyl compounds - aminodihydropyrimidines - multicomponent ­reactions

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• 39 2-Amino-3,4-dihydropyrimidines (Table [2], Entries 1–26); 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.