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

Mihaela Cibian; Sophie Langis-Barsetti; Garry S. Hanan

doi:10.1055/s-0030-1259329

LETTER

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;

Abstract

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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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References

References and Notes

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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.

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

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.

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.

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.

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.

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.

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.

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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.

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] ).

Supplementary Material

Supporting Information (PDF)