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Synlett 2016; 27(07): 1121-1127
DOI: 10.1055/s-0035-1561201
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© Georg Thieme Verlag Stuttgart · New York

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

Sirilak Wangngae
Department of Chemistry and Center of Excellence for Innovation in Chemistry, Faculty of Science, Chiang Mai University, Chiang Mai 50200, Thailand   Email: wongp2577@gmail.com
,
Mookda Pattarawarapan
Department of Chemistry and Center of Excellence for Innovation in Chemistry, Faculty of Science, Chiang Mai University, Chiang Mai 50200, Thailand   Email: wongp2577@gmail.com
,
Wong Phakhodee*
Department of Chemistry and Center of Excellence for Innovation in Chemistry, Faculty of Science, Chiang Mai University, Chiang Mai 50200, Thailand   Email: wongp2577@gmail.com
› Author Affiliations
Further Information

Publication History

Received: 05 November 2015

Accepted after revision: 06 December 2015

Publication Date:
05 January 2016 (online)

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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

Supporting Information

    Supporting information for this article is available online at http://dx.doi.org/10.1055/s-0035-1561201.
  • Supporting Information
 

  • 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; Rf = 0.38 (EtOAc). FTIR (neat): νmax = 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%). Rf = 0.36 (30% EtOAc–hexane). FTIR (neat): νmax = 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. Rf = 0.33 (30% EtOAc–hexane). FTIR (neat): νmax = 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%). Rf = 0.30 (30% EtOAc–hexanes). FTIR (neat): νmax = 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). Rf = 0.25 (40% EtOAc–hexanes). FTIR (neat): νmax = 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.