One-Pot Synthesis of C ₂ Symmetric and Asymmetric N,N′,N′′-Substituted Guanidines from Aryl Isothiocyanates and Amines

Abstract

Highly substituted guanidines were conveniently prepared through a one-pot reaction between aryl isothiocyanates and amines mediated by the Ph₃P–I₂/Et₃N system. The C ₂-symmetric N,N′,N′′-substituted guanidines were readily accessed using a 1:2 molar ratio of an aryl isothiocyanate and an amine; while sequential addition of two different amines in equimolar ratios gave rise to asymmetric derivatives. Both primary and secondary amines were found to react preferentially with electron-deficient aryl isothiocyanates, rapidly providing guanidines in good yields under mild conditions.

Key words

condensation - desulfurization - guanidine - isothiocyanate

• References and Notes

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• 11 General Procedure Amine (0.56 mmol) and Et₃N (1.4 mmol) were added to a solution of aryl isothiocyanate (0.28 mmol) in CH₂Cl₂ (2 mL). After stirring at r.t. for 10 min, the mixture was cooled to 0 °C, then Ph₃P (0.33 mmol) and iodine (0.33 mmol) were added in one portion. The reaction mixture was stirred at r.t. until reaction completion as indicated by TLC. The reaction mixture was washed with H₂O, and the combined organic layers were dried over anhydrous Na₂SO₄ before filtering and concentrating in vacuo. The residue was purified by flash column chromatography to give the product. All products were identified by NMR spectroscopic and mass spectrometric analysis. In the synthesis of asymmetrically substituted guanidines, the amount of the first amine added to aryl isothiocyanate was reduced to 0.28 mmol, while the second amine (0.28 mmol) was added after treatment with Ph₃P–I₂ when the formed thiourea has completely disappeared (ca. 5–10 min). N-(Dimorpholinomethylene)-4-nitroaniline (3e, Table 2 Entry 5) Yellow solid (0.0761 g, 85%); mp 158–159 °C; R_f = 0.38 (EtOAc). FTIR (neat): ν_max = 2965, 2854, 1547, 1321, 1265, 1111 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 8.10 (d, J = 8.0 Hz, 2 H), 6.76 (d, J = 8.0 Hz, 2 H), 3.66 (s, 8 H), 3.16 (s, 8 H). ¹³C NMR (100 MHz, CDCl₃): δ = 157.0, 150.9, 141.4, 125.3, 121.4, 66.3, 49.2. 1,3-Dibenzyl-2-[4-(trifluoromethyl)phenyl]guanidine (3g, Table 2, Entry 7) Colorless oil (0.0859 g, 80%). R_f = 0.36 (30% EtOAc–hexane). FTIR (neat): ν_max = 3426, 3289, 3031, 2922, 2871, 1632, 1596, 1323, 1164 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 7.52 (d, J = 8.4 Hz, 2 H), 7.35–7.26 (m, 6 H), 7.24–7.22 (m, 4 H), 7.01 (d, J = 8.4 Hz, 2 H), 4.36 (s, 4 H). ¹³C NMR (100 MHz, CDCl₃): δ = 153.3, 151.1, 138.4, 128.8, 128.6, 127.6, 127.2, 126.6 (q, J = 14.8 Hz), 123.5, 46.0. 1-Benzyl-3-cyclohexyl-2-(4-nitrophenyl)guanidine (3p, Table 3, Entry 1) Yellow solid (0.0828 g, 84%); mp 109–110 °C. R_f = 0.33 (30% EtOAc–hexane). FTIR (neat): ν_max = 3393, 3275, 2931, 2854, 1617, 1572, 1451, 1307, 1108 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 8.08 (d, J = 8.8 Hz, 2 H), 7.38–7.28 (m, 5 H), 6.95 (d, J = 8.8 Hz, 2 H), 4.39 (s, 2 H), 3.41–3.36 (m, 1 H), 1.92–1.88 (m, 2 H), 1.65–1.61 (m, 2 H), 1.57–1.53 (m, 1 H), 1.32–1.22 (m, 2 H), 1.17–1.06 (m, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 156.4, 151.6, 141.4, 138.0, 128.9, 127.8, 127.4, 125.5, 122.6, 50.7, 46.3, 33.4, 25.4, 24.6. 1-Benzyl-3-butyl-2-(4-nitrophenyl)guanidine (3q, Table 3, Entry 2) Yellow oil (0.0813 g, 89%). R_f = 0.30 (30% EtOAc–hexanes). FTIR (neat): ν_max = 3417, 3298, 2957, 2930, 2871, 1571, 1493, 1306, 1107 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 8.10 (d, J = 8.8 Hz, 2 H), 7.38–7.29 (m, 5 H), 6.97 (d, J = 8.8 Hz, 2 H), 4.42 (s, 2 H), 3.14 (t, J = 7.2 Hz, 2 H), 1.50–1.43 (m, 2 H), 1.30–1.22 (m, 2 H), 0.87 (t, J = 7.2 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 156.4, 152.1, 141.6, 138.0, 129.0, 127.9, 127.4, 125.5, 122.8, 46.2, 42.0, 31.6, 19.9, 13.7. N-Cyclohexyl-N′-phenylmorpholine-4-carboximidamide (3w, Table 3 Entry 8) Colorless oil (0.0418 g, 52% yield). R_f = 0.25 (40% EtOAc–hexanes). FTIR (neat): ν_max = 3374, 2928, 2853, 1620, 1588, 1116 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 7.26 (t, J = 7.6 Hz, 2 H), 6.99 (t, J = 7.6 Hz, 1 H), 6.83 (d, J = 7.6 Hz, 2 H), 3.71 (t, J = 4.8 Hz, 4 H), 3.22 (t, J = 4.8 Hz, 4 H), 3.11–3.04 (m, 1 H), 1.88–1.84 (m, 2 H), 1.68–1.62 (m, 2 H), 1.57–1.53 (m, 1 H), 1.27–1.16 (m, 2 H), 1.10–1.01 (m, 3 H). ¹³C NMR (100 MHz, CDCl₃): δ = 156.2, 147.2, 129.3, 122.5, 66.6, 53.8, 48.6, 33.8, 25.3, 25.2.
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