Indium-Mediated Blaise-Type Reaction of Bromomalonates with Nitriles and Isocyanates

Abstract

The indium-mediated Blaise-type reaction of bromomalonates with nitriles and isocyanates is described. The choice of the solvent is crucial for the successful reaction; the dependency on dichloromethane proved to be nonplussed. The reaction with nitriles led to the corresponding β-enamino diesters in moderate to good yields. The conversion with isocyanates generated carbamoyl malonates in good to excellent yields. Both reactions tolerated various functional groups regarding the electronic nature. Also, steric hindrance in the starting materials, as caused by mesityl isocyanate or diisopropyphenyl isocyanate, was well tolerated. In addition, a sequential three-component one-pot reaction sequence is described for the formation of 2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylates enabling future investigations in this field.

Key words

Blaise reaction - bromomalonates - indium - isocyanates - nitriles - pyrimidines

• References

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• 8 Synthesis of Diethyl 2-[Amino(furan-2-yl)methylene]malonate (1g) The reactions were carried out in sealed tubes under argon atmosphere. Metallic indium pellets (2.00 mmol, 2.00 equiv) were sliced to smaller pieces and evacuated in a sealed tube for 15 min, then suspended with dry CH₂Cl₂ (1.0 mL). To the suspension was added diethyl bromomalonate (263 mg, 1.00 mmol, 1.00 equiv; 92% purity) and 2-furonitrile (140 mg, 1.50 mmol). The clear reaction mixture was heated to 40 °C for 24 h. The reddish-brown suspension was cooled to room temperature, poured into water (30 mL), and extracted with CH₂Cl₂ (3 × 15 mL). The combined organic layers were dried over Mg₂SO₄ and filtered off. The solvent was removed under reduced pressure, and the crude product was purified by flash chromatography on silica gel (eluent: pentane–EtOAc = 5:1 → 3:1) to afford the enamino diester 1g (239 mg, 0.94 mmol, 94%); yellowish solid, mp 33–34 °C; R_f = 0.32 (pentane–EtOAc = 3:1). IR (neat): 3414, 3301, 3134, 2981, 2904, 1697, 1663, 1604, 1580, 1516, 1474 cm^–1. ¹H NMR (300 MHz, CDCl₃-d ₁): δ = 7.40 (dd, J =1.7, 0.5 Hz, 1 H), 9.04–5.40 (m, 2 H), 6.69 (dd, J =3.6, 0.5 Hz, 1 H), 6.37 (dd, J =3.6, 1.8 Hz, 1 H), 4.09 (q, ³ J =7.1 Hz, 4 H), 1.17 (t, ³ J =7.4 Hz, 3 H), 1.12 (t, ³ J =7.4 Hz, 3 H). ¹³C NMR (75 MHz, CDCl₃-d ₁): δ = 168.2, 167.8, 149.3, 147.3, 144.1, 112.9, 111.9, 92.3, 60.9, 59.8, 14.2, 13.8. HRMS (APCI⁺–TOF): m/z [M + H]⁺ calcd for C₁₂H₁₆NO₅: 254.1023; found: 254.1022.
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• 10 Synthesis of Diethyl 2-[(4-Acetylphenyl)carbamoyl]malonate (2d) The reactions were carried out in sealed tubes under argon atmosphere. Metallic indium pellets (2.00 mmol, 2.00 equiv) were sliced to smaller pieces and evacuated in a sealed tube for 15 min, then suspended with dry CH₂Cl₂ (1.0 mL). To the suspension was added diethyl bromomalonate (263 mg, 1.00 mmol, 1.00 equiv; 92% purity,) and 4-acetylphenyl isocyanate (242 mg, 1.50 mmol). The clear reaction mixture was heated to 40 °C for 24 h. The reddish-brown suspension was cooled to room temperature, poured into water (30 mL) and extracted with CH₂Cl₂ (3 × 15 mL). The combined organic layers were dried over Mg₂SO₄ and filtered off. The solvent was removed under reduced pressure, and the crude product was purified by flash chromatography on silica gel (eluent: pentane–EtOAc = 5:1 → 3:1) to afford the malonyl amide 2d (203 mg, 0.63 mmol; 63%); yellow solid, mp 85–86 °C; R_f = 0.13 (pentane–EtOAc = 3:1). IR (neat): 3306, 3195, 3117, 2990, 2942, 2907, 1740, 1670, 1596, 1525 cm^–1. ¹H NMR (300 MHz, CDCl₃-d ₁): δ = 9.56 (s, 1 H), 7.84 (d, ³ J =8.8 Hz, 2 H), 7.59 (d, ³ J =8.8 Hz, 2 H), 4.44 (s, 1 H), 4.20 (q, ³ J =7.1 Hz, 4 H), 2.48 (s, 3 H), 1.21 (t, ³ J =7.1 Hz, 6 H). ¹³C NMR (75 MHz, CDCl₃-d ₁): δ = 197.0, 165.4, 160.6, 141.6, 133.3, 129.6, 119.4, 62.9, 59.7, 26.3, 13.8. HRMS (APCI⁺–TOF): m/z [M + H]⁺ calcd for C₁₆H₂₀NO₆: 322.1285; found: 322.1286.
• 11 Synthesis of Ethyl 6-(Furan-2-yl)-3-(2-methoxyphenyl)-2,4-dioxo-1,2,3,4-tetrahydropyrimidine-5-carboxylate (4b) The reactions were carried out in sealed tubes under argon atmosphere. Metallic indium pellets (2.00 mmol, 2.00 equiv) were sliced to smaller pieces and evacuated in a sealed tube for 15 min, then suspended with dry CH₂Cl₂ (1 mL). To the suspension was added diethyl bromomalonate (263 mg, 1.00 mmol, 1.00 equiv; 92% purity) and 2-furonitrile (140 mg, 1.50 mmol, 1.50 equiv). The clear reaction mixture was heated to 40 °C for 24 h. To the reddish-brown suspension was added 4-acetylphenyl isocyanate (350 mg, 3.00 mmol, 3.00 equiv) and heated to 40 °C for 24 h. The reddish suspension was cooled to room temperature, diluted with EtOAc, poured into water (30 mL), and extracted with EtOAc (3 × 15 mL). The combined organic layers were dried over Mg₂SO₄ and filtered off. The solvent was removed under reduced pressure, and the crude product was purified by flash chromatography on silica gel (eluent: pentane–EtOAc = 1:1 → 0:1) and recrystallized (pentane–EtOAc = 5:1) to afford the pyrimidinone 4b (259 mg, 0.73 mmol; 73%); yellowish solid, mp 215–216 °C; R_f = 0.29 (pentane–EtOAc = 1:1). IR (neat): 3127, 2957, 2838, 1738, 1697, 1650, 1602, 1550, 1499, 1459, 1434 cm^–1. ¹H NMR (300 MHz, CDCl₃-d ₁): δ = 10.01 (s, 1 H), 7.44 (d, J =1.6 Hz, 1 H), 7.40–7.30 (m, 1 H), 7.23–7.10 (m, 1 H), 7.01 (m, 1 H), 7.05–6.90 (m, 2 H), 6.39 (dd, J =3.7, 1.8 Hz, 1 H), 4.31 (q, ³ J =7.1 Hz, 2 H), 3.70 (s, 3 H), 1.27 (t, ³ J =7.1 Hz, 3 H). ¹³C NMR (75 MHz, CDCl₃-d ₁): δ = 164.4, 160.6, 155.1, 151.2, 146.2, 143.1, 137.7, 130.7, 129.9, 122.7, 121.0, 116.2, 113.1, 112.0, 104.6, 62.3, 55.9, 14.2. HRMS data could not be obtained. The identity of the product was confirmed by X-ray analysis; see Supporting Information.
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• 13 The in situ generated iodine was complexed with starch and titrated with Na₂S₂O₃ solution, see: Strähle J, Schweda E. Jander/Blasius: Lehrbuch der Analytischen und Präparativen Anorganischen Chemie. 14th ed. Hirzel; Stuttgart: 1995: 283