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Synlett 2011(3): 405-409  
DOI: 10.1055/s-0030-1259329
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Facile Synthesis of Hydroxyformamidines by the N-Oxidation of Their Corresponding Formamidines

Mihaela Cibian, Sophie Langis-Barsetti, Garry S. Hanan*
Department of Chemistry, Université de Montréal, Montréal, QC, H3T 1J4, Canada
Fax: +1(514)3432468; e-Mail: garry.hanan@umontreal.ca;
Further Information

Publication History

Received 27 September 2010
Publication Date:
19 January 2011 (online)

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Abstract

The N-oxidation of N,N′-disubstituted amidines with MCPBA (m-chloroperoxibenzoic acid) affords a mild, rapid, and efficient route to the corresponding hydroxyamidines This novel synthetic route for the preparation of N,N′-disubstituted hydroxyamidines provides an attractive alternative to the classical one. It was found that the efficiency of the N-oxidation reaction, and the stability of the hydroxyformamidines are influenced by the substitution on the N,N′-diaryl rings, for example, higher yields (up to 92%) and more stable products are obtained for the compounds bearing substituents in the 2,6-positions of the phenyl rings. ¹H NMR and ¹³C NMR, HRMS and/or elemental analysis were used to characterize the products.

Key words

formamidines - hydroxyformamidines - peroxides - MCPBA - N-oxidation - substituent effects

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General Procedure ¹4 - Method A The EtOH was distilled from a mixture of aniline, triethylorthoformate (2:1), and a catalytic amount of glacial AcOH at 120-160 ˚C. The reactions times ranges from 1 h for compound 2h to overnight. Solids were formed which were further purified as described in ref. 7.

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General Procedure ¹5 - Method B
A mixture of aniline, triethylorthoformate (2:1), and a catalytic amount of glacial AcOH (MS 4 Å were also added) was microwave activated at 130 ˚C for 10 min. At the end of the reactions, oily solids were obtained, which were taken in CH2Cl2 (2a-e and 2g-i) or hexane(2f). The solvents were evaporated under vacuum to afford solids or oils that were further purified by recrystallization in CH2Cl2-hexane (1:1; 2a-e,g), boiling hexane (2f,i) or by trituration/sonication with hexane(2h). Colorless solids were obtained in all cases.8

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Except for compound 2f, all of the formamidines are known compounds, and their characterization is similar to reported data.¹4
Compound 2f: Compound 1f (7.5 mL, 51 mmol, 2 equiv), triethylorthoformate (4.0 mL, 25 mmol, 1 equiv) and a catalytic amount of glacial AcOH (0.30 mL, 5.1 mmol, 0.2 equiv) were reacted following the general procedure described in ref. 7. After purification by trituration with cold pentane and recrystallization in hot hexane, colorless crystals were obtained; yield 5.56 g, 78%. ¹H NMR (300 MHz, CDCl3): δ = 8.00 (s, 1 H, NHCH=N), 7.29 (d, J = 8 Hz, 2 H, C6H4), 7.20-7.08 (m, 4 H, C6H4), 7.02 (d, J = 8 Hz, 2 H, C6H4), 3.29 [sept, J = 7 Hz, 2 H, -CH(CH3)2], 1.26 [d, J = 7 Hz, 12 H, CH(CH 3)2] ppm. ¹³C NMR (75 MHz, CDCl3): d = 148.6, 139.5, 126.7, 125.9, 124.0, 118.7, 27.73, 23.21 ppm. Anal. Calcd (%) for C19H24N2: C, 81.38; H, 8.63; N, 9.99. Found: C, 81.62; H, 9.27; N, 10.17.

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General Procedure - N-Oxidation of Amidines with MCPBA A solution of MCPBA (1 equiv) in CH2Cl2 was added dropwise by addition funnel to a solution of amidine (1 equiv) and NaHCO3 (1.0-1.5 equiv) in the same solvent, at 0 ˚C (ice bath) to r.t. The reaction mixture was stirred for other 30-60 min at r.t. and was washed with an aq solution of K2CO3 (5%; 2 × 25 mL). The combined organic fractions were dried over anhyd MgSO4 or Na2SO4 and filtered. The solvent was removed by evaporation, to afford solids or oils that were further purified by recrystallization or flash chromatography on silica gel.

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Compound 3f: Compound 2f (2.0 g, 7.1 mmol, 1 equiv) and NaHCO3 (0.61 g, 7.1 mmol, 1 equiv) in CH2Cl2 (50 mL) and MCPBA (1.6 g, 7.1 mmol, 1 equiv) in CH2Cl2 (50 mL) were reacted following the general procedure described in ref. 9, and modified as specified in Table  [¹] (footnote k). After purification by flash chromatography on silica gel [gradient of eluants: hexane-EtOAc (2:8), EtOAc-MeOH (9:1), CH2Cl2 100%] and recrystallization in hot hexane, a colorless solid was obtained; yield 0.92 g, 58%. ¹H NMR (300 MHz, CDCl3): δ = 7.93 (s, 1 H, NHCH=N), 7.45-7.39 (m, 2 H, C6H4), 7.34-7.31 (m, 2 H, C6H4), 7.28-7.08 (m, 3 H, C6H4), 6.96 (d, J = 8 Hz, 1 H, C6H4), 3.67 (br s, OH), 3.40 [sept, J = 7 Hz, 1 H, CH(CH3)2], 3.27 [sept, J = 7 Hz, 1 H, CH(CH3)2], 1.33-1.29 [m, 12 H, CH(CH 3)2] ppm. ¹³C NMR (75 MHz, CDCl3): δ = 145.0, 142.1, 137.4, 136.2, 135.4, 130.1, 127.1, 127.0, 126.7, 126.6, 125.5, 124.3, 116.2, 28.12, 27.61, 24.27 (2 C), 23.08 (2 C) ppm. MS (ESI-HRMS, CH2Cl2): m/z [M + H]+ calcd for C19H25N2O: 297.1961; found: 297.1971. Anal. calcd (%) for C19H24N2O: C, 76.99; H, 8.16; N, 9.45. Found: C, 76.80; H, 8.23; N, 9.40.

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Compound 3g: Compound 2g (1.5 g, 4.3 mmol, 1 equiv) and NaHCO3 (0.38 g, 4.3 mmol, 1 equiv) in CH2Cl2 (50 mL) and MCPBA (0.96 g, 4.3 mmol, 1 equiv) in CH2Cl2 (50 mL) were reacted following the general procedure described in ref. 9, and modified as specified in Table  [¹] (footnote k). After purification by flash chromatography on silica gel [gradient of eluants: hexane-EtOAc (2:8), EtOAc-MeOH (9:1), CH2Cl2 100%] and recrystallization in CH2Cl2-hexane (1:1), a colorless solid was obtained; yield 0.93 g, 59%. ¹H NMR (400 MHz, CDCl3): δ = 7.85-7.78 (m, 1 H, C6H4), 7.55-7.32 (m, 14 H, C6H5, C6H4, NHCH=N), 7.21 (dd, J = 7, 2 Hz, 1 H, C6H4), 7.11 (td, J = 8, 2 Hz, 1 H, C6H4), 7.05 (td, J = 7, 1 Hz, 1 H, C6H4), 6.17 (d, J = 8 Hz, 1 H, C6H4), 3.67 (br s, OH) ppm. ¹³C NMR (75 MHz, CDCl3): δ = 142.0, 138.2, 137.5, 136.9, 135.7, 135.2, 131.7, 131.40, 130.7, 129.4 (2 C), 129.24 (2 C), 129.19 (2 C), 129.1 (2 C), 128.8, 128.6, 128.5 (2 C), 128.3, 128.1, 126.1, 123.7, 115.4 ppm. MS (ESI-HRMS, CH2Cl2): m/z [M + H]+ C25H21N2O calcd for: 365.1648; found: 365.1655. Anal. Calcd (%) for C25H20N2O: C, 82.39; H, 5.53; N, 7.69. Found: C, 82.33; H, 5.52; N, 7.73.

12

Compound 3h: Compound 2h (1.0 g, 4.0 mmol, 1 equiv) in CH2Cl2 (20 mL) and MCPBA (0.89 g, 4.0 mmol, 1 equiv) in CH2Cl2 (20 mL) were reacted following the general procedure described in ref. 9, and modified as specified in Table  [¹] (footnote l). After recrystallization in CH2Cl2-hexane (1:1) at -10 ˚C, a colorless solid was obtained; yield 0.98 g, 92%. ¹H NMR (400 MHz, CDCl3): δ = 7.34 (s, 1 H, NHCH=N), 7.20 (t, J = 8 Hz, 1 H, C6H3), 7.15-7.06 (m, 5 H, C6H3), 3.51 (br s, OH), 2.38 (d, J = 3 Hz, 12 H, CH3). ¹³C NMR (75 MHz, CDCl3): δ = 142.1, 140.4, 135.8, 134.8 (2 C), 133.4, 129.3, 129.0 (2 C), 128.6 (2 C), 126.7, 18.81 (2 C), 17.26 (2 C) ppm. ESI-MS (CH2Cl2): m/z (%) = 269.2 (100) [M + H]+. Anal. calcd (%) for (C17H20N2O)2CH2Cl2: C, 67.62; H, 6.81; N, 9.01. Found: C, 68.19; H, 6.81; N, 9.00.

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Compound 3i: Compound 2i (1.5 g, 4.1 mmol, 1 equiv) in CH2Cl2 (10 mL) and MCPBA (0.9 g, 4.1 mmol) in CH2Cl2 (40 mL) were reacted following the general procedure described in ref. 9, and modified as specified in Table  [¹] (footnote l). The green-white solid obtained after solvent evaporation was taken in EtOH, as the formamidine 2i has low solubility in this solvent. After filtration, EtOH evaporation, and drying under vacuum, a pale-yellow solid was obtained; yield 1.4 g, 88%; mp 165-167 ˚C. ¹H NMR (300 MHz, CDCl3): δ = 7.39-7.32 (m, 1 H, C6H3), 7.32-7.26 (m, 1 H, C6H3), 7.25-7.21 (m, 2 H, C6H3 and NHCH=N), 7.20 (d, J = 2 Hz, 2 H, C6H3), 7.18 (d, J = 1 Hz, 1 H, C6H3), 3.37 [sept, J = 7 Hz, 2 H, CH(CH3)2], 3.25 [sept, J = 7 Hz, 2 H, CH(CH3)2], 1.37 [d, J = 7 Hz, 6 H, CH(CH 3)2], 1.23 [d, J = 7 Hz, 12 H, CH(CH 3)2], 1.18 [d, J = 7 Hz, 6 H, CH(CH 3)2]. ¹³C NMR (75 MHz, CDCl3): δ = 146.6 (2 C), 146.0 (2 C), 141.7, 133.2, 132.5, 130.6, 128.8 (2 C), 124.8 (2 C), 124.7 (2 C), 29.28 (2 C) 29.10 (2 C), 25.98 (2 C), 25.05 (2 C), 24.87 (4 C). ESI-MS (CH2Cl2): m/z (%) = 381.3 (100) [M + H]+. Anal. Calcd (%) for C25H36N2O: C, 78.90; H, 9.53; N, 7.36. Found: C, 78.79; H, 9.43; N, 7.21.

19

For 3a-d pure products are only obtained by recrystallization as decomposition occurs on silica gel chromatography column. Attempts to maximize the yield by repeated evaporation-recrystallization were unsuccessful as the decomposition product (amide) is observed after 1-2 cycles.

20

Also observed by ¹H NMR, as the shielding of formamidine H decreases in the series 3i, 3h, 3g, 3f, 3e, 3c, 3d, 3b, 3a (see Supporting Information - Figure  [¹] ).