Synthesis of Symmetrical N-Aryl-C-phosphonoacetamidines

Abstract

An efficient synthesis of a series of novel symmetrical N-aryl-C-phosphonoacetamidines through reaction of diisopropyl (chloroethynyl)phosphonate with primary aryl amines was developed. This procedure tolerates a wide range of functional groups and has a good atom economy. The (E)-isomer was the major product that crystallized preferentially over the (Z)-isomer.

Key words

aryl amidines - carbamimidoylphosphonoacetic acid - aryl amines - phosphonoacetamidines

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• 26 N-Aryl-C-phosphonoacetamidines 3a–s; General Procedure The appropriate aniline 2a–s (2 mmol) was added to a mixture of diisopropyl (chloroethynyl)phosphonate (1; 1 mmol) and K₂CO₃ (1 mmol) in anhyd acetonitrile (10 mL) at r.t., and the mixture was stirred vigorously under reflux for 5–25 h. When the reaction was complete, the mixture was filtered and concentrated, and the residue was crystallized from hexane. Diisopropyl {(2E)-2-[(4-Fluorophenyl)amino]-2-[(4-fluorophenyl)imino]ethyl}phosphonate (3e) White needle crystals; yield: 332 mg (81%); mp 104–106 °C. IR (KBr): 995.27 (P–O–C), 1226.73 (P=O), 1500.62 (C=N) cm^–1. ¹H NMR (400.13 MHz, DMSO-d ₆): δ = 1.16 (d, ³ J _HH = 6.1 Hz, 6 H, CH₃), 1.21 (d, ³ J _HH = 6.2 Hz, 6 H, CH₃), 2.92 (d, ² J _HP = 21.8 Hz, 2 H, CH₂P), 4.53 (m, ³ J _HH = 6.1 Hz, ³ J _HP = 12.4 Hz, 1 H, CHOP), 4.54 (m, ³ J _HH = 6.1 Hz, ³ J _HP = 14.0 Hz, 1 H, CHOP), 6.82 [m, ³ J _HH = 8.8 Hz, 1 H, o-CH, Ar(NH)], 6.83 [m, ³ J _HH = 8.8 Hz, 1 H, o-CH, Ar(NH)], 7.09 (m, ³ J _HH = 9.1 Hz, 4 H, m-CH, Ar), 7.73 [m, ³ J _HH = 9.2 Hz, 1 H, o-CH, Ar(N=)], 7.75 [m, ³ J _HH = 9.2 Hz, 1 H, o-CH, Ar(N=)], 8.66 (s, 1 H, NH). ¹³C NMR (100.61 MHz, DMSO-d ₆): δ = 23.97 (d, ³ J _CP = 4.4 Hz, CH₃), 24.11 (d, ³ J _CP = 4.4 Hz, CH₃), 30.25 (d, ¹ J _CP = 133.5 Hz, CH₂P), 70.98 [d, ² J _CP = 6.6 Hz, (OCH)₂P], 115.38 [d, ² J _CF = 21.3 Hz, m-CH, Ar(NH)], 115.59 [d, ² J _CF = 22.0 Hz, m-CH, Ar(N=)], 121.02 [d, ³ J _CF = 7.3 Hz, o-CH, Ar(NH)], 123.50 [d, ³ J _CF = 8.0 Hz, o-CH, Ar(N=)], 137.57 (d, ⁴ J _CF = 1.5 Hz, C-ipso-N=), 146.67 (d, ⁴ J _CF = 1.5 Hz, C-ipso-NH), 148.09 (d, CH₂ C, ² J _CP = 7.3 Hz), 157.62 [d, ¹ J _CF = 239.1 Hz, CF, Ar(NH)], 158.40 [d, ¹ J _CF = 237.6 Hz, CF, Ar(N=)]. ³¹P NMR (161.98 MHz, DMSO-d ₆): δ = 20.63. ¹⁹F NMR (376.50 MHz, DMSO-d ₆): δ = –122.72 [F, Ar(NH)], –121.19 [F, Ar(N=)]. ESI-HRMS: m/z [M + H]⁺ calcd for C₂₀H₂₆F₂N₂O₃P: 411.1660; found: 411.1644.
• 27 CCDC 1505945 and CCDC 1518068 contain the supplementary crystallographic data for compounds 3k and 3l, respectively. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/getstructures.