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Synlett 2007(1): 0071-0074  
DOI: 10.1055/s-2006-958448
LETTER
© Georg Thieme Verlag Stuttgart · New York

A Novel Synthetic Route to 2-Amino and 2-Alkylamino-1,3,5-Triazines Based on Nucleophilic Aromatic Substitution of Hydrogen: The First Reactions of 1,3,5-Triazine with Nucleophiles without Ring Decomposition

Anna V. Gulevskaya, Bert U. W. Maes*, Caroline Meyers
Organic Synthesis, Department of Chemistry, University of Antwerp, Groenenborgerlaan 171, 2020 Antwerp, Belgium
Fax: +32(3)2653233; e-Mail: bert.maes@ua.ac.be;
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Publication History

Received 16 October 2006
Publication Date:
20 December 2006 (online)

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Abstract

2-Amino- and 2-alkylamino-1,3,5-triazines were smoothly obtained by oxidative (alkyl)amination of 1,3,5-triazine in ammonia-ethanol or alkylamine-ethanol with bis(pyridine)silver(I)permanganate (AgPy2MnO4) as the oxidant. These transformations are the first reactions of 1,3,5-triazine with nucleophiles without ring decomposition and the first examples of nucleophilic substitution of hydrogen on this substrate.

Key words

nucleophilic aromatic substitution of hydrogen - 1,3,5-triazine - oxidative (alkyl)amination - 2-amino-1,3,5-triazine - 2-alkylamino-1,3,5-triazines - rotational isomerism

    References and Notes

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    All melting points were determined on a Büchi apparatus and are uncorrected. The 1H and 13C NMR spectra were recorded on a Bruker Avance 400 spectrometer in the solvent indicated with TMS as an internal standard. All coupling constants are given in Hz and chemical shifts are given in ppm. 1,3,5-Triazine (Fluka) and the alkylamines (Acros and Aldrich) were obtained from commercial sources and were used as such. AgPy2MnO4 can be easily prepared from relatively cheap AgNO3 [Aldrich catalogue: AgNO3 (³99%) (25 g, 58.5 Euro)], pyridine and KMnO4. [8b] Flash column chromatography was performed on Kieselgel 60 (ROCC, 0.040-0.063 mm).
    2-Amino and 2-Alkylamino-1,3,5-triazines 4; General Procedure: To a stirred mixture of alkylamine (5 mL) and ethanol (5 mL) at -11 °C to -5 °C 1,3,5-triazine (1; 0.081 g, 1 mmol) was added. After dissolving of 1, AgPy2MnO4 (0.578 g, 1.5 mmol) was added in small portions over 40 min. Subsequently, alkylamine and ethanol were removed under reduced pressure. The residue was grinded with silica gel (3-4 g), brought onto a column with silica gel (3.5 × 25 cm) and chromatographed using CH2Cl2-MeOH (50:1) as the eluent, yielding 2-alkylamino-1,3,5-triazines 4. For the amination and methylamination a 7 N NH3 solution in MeOH (or 2 N NH3 in EtOH; 10 mL) and a 2 N methylamine solution in MeOH (15 mL) were used, respectively.
    2-Amino-1,3,5-triazine ( 4a): white solid; mp >206 °C (sublimation) (Lit. [3a] 226 °C). 1H NMR (400 MHz, CDCl3): δ = 8.60 (s, 2 H, H-4, H-6), 5.34 (br s, 2 H, NH2). 1H NMR (400 MHz, DMSO-d 6): δ = 8.45 (s, 2 H, H-4, H-6), 7.52 (br s, 2 H, NH2). 13C NMR (100 MHz, CDCl3): δ = 165.9, 165.7. HRMS (ESI): m/z [M + H]+ calcd for C3H5N4: 97.0514; found: 97.0511.
    2-Methylamino-1,3,5-triazine ( 4b): white solid; mp 109-110 °C (Lit. [3a] 109-110 °C). 1H NMR (400 MHz, CDCl3): δ = 8.61 (s, 1 H, H-4 or H-6), 8.48 (s, 1 H, H-6 or H-4), 5.65 (br s, 1 H, NH2), 3.04 (d, J = 5.1 Hz, 3 H, CH3). 13C NMR (100 MHz, CDCl3): δ = 166.3, 165.5, 165.1. HRMS (ESI): m/z [M + H]+ calcd for C4H7N4: 111.0671; found: 111.0667.
    2-Isopropylamino-1,3,5-triazine ( 4c): white solid; mp 73-74 °C. 1H NMR (400 MHz, CDCl3): δ = 8.57 (s, 1 H, H-4 or H-6), 8.47 (s, 1 H, H-6 or H-4), 5.51 (br s, 1 H, NH), 4.20 [m, 1 H, CH(CH3)2], 1.26 [d, J = 6.5 Hz, 6 H, CH(CH 3)2]. 13C NMR (100 MHz, CDCl3): δ = 166.3, 165.6, 163.8, 42.8, 22.5. HRMS (ESI): m/z [M + H]+ calcd for C6H11N4: 139.0984; found: 139.0990.
    2-Butylamino-1,3,5-triazine ( 4d): white solid; mp 61-63 °C (Lit. [3a] 61-62 °C). 1H NMR (400 MHz, CDCl3): δ = 8.58 (s, 1 H, H-4 or H-6), 8.46 (s, 1 H, H-6 orH-4), 6.29 (br s, 1 H, NH), 3.44 (dt, J = 5.9, 7.1 Hz, 2 H, CH 2CH2CH2CH3), 1.60 (m, 2 H, CH2CH 2CH2CH3), 1.41 (m, 2 H, CH2CH2CH 2CH3), 0.95 (t, J = 7.3 Hz, 3 H, CH2CH2CH2CH 3). 1H NMR (400 MHz, DMSO-d 6): δ = 8.56 (d, J = 1.3 Hz, 1 H, H-4 or H-6), 8.47 (d, J = 1.3 Hz, 1 H, H-6 or H-4), 8.11 (br s, 1 H, NH), 3.33 (dt, J = 6.0, 7.1 Hz, 2 H, CH 2CH2CH2CH3), 1.55 (m, 2 H, CH2CH 2CH2CH3), 1.36 (m, 2 H, CH2CH2CH 2CH3), 0.94 (t, J = 7.3 Hz, 3 H, CH2CH2CH2CH 3). 13C NMR (100 MHz, CDCl3): δ = 166.3, 165.5, 164.6, 40.7, 31.3, 20.0, 13.7. HRMS (ESI): m/z [M + H]+ calcd for C7H13N4: 153.1140; found: 153.1140.
    2-Amylamino-1,3,5-triazine ( 4e): white solid; mp 47-49 °C. 1H NMR (400 MHz, CDCl3): δ = 8.58 (s, 1 H, H-4 or H-6), 8.48 (s, 1 H, H-6 or H-4), 6.25 (br s, 1 H, NH), 3.44 (dt, J = 5.9, 7.1 Hz, 2 H, CH 2CH2CH2CH2CH3), 1.62 (m, 2 H, CH2CH 2CH2CH2CH3), 1.36 (m, 4 H, CH2CH2CH 2CH 2CH3), 0.91 (t, J = 7.1 Hz, 3 H, CH2CH2CH2CH2CH 3). 13C NMR (100 MHz, CDCl3): δ = 166.3, 165.5, 164.6, 41.0, 29.0, 28.9, 22.4, 14.0. HRMS (ESI): m/z [M + H]+ calcd for C8H15N4: 167.1297; found: 167.1303.
    2-(Piperidin-1-yl)-1,3,5-triazine ( 4f): white solid; mp 43-44 °C (Lit. [3a] 43-44 °C). 1H NMR (400 MHz, CDCl3): δ = 8.49 (s, 2 H, H-4, H-6), 3.81 (m, 4 H, α-CH2 of piperidinyl), 1.70 (m, 6 H, β-CH2 and γ-CH2 of piperidinyl). 13C NMR (100 MHz, CDCl3): δ = 165.6, 162.7, 44.3, 25.7, 24.6. HRMS (ESI): m/z [M + H]+ calcd for C8H13N4: 165.1140; found: 165.1134.
    2-(Morpholin-1-yl)-1,3,5-triazine ( 4g): white solid; mp 108-110 °C (Lit. [3c] 106-108 °C). 1H NMR (400 MHz, CDCl3): δ = 8.54 (s, 2 H, H-4, H-6), 3.87 [m, 4 H, O(CH2)2], 3.75 [m, 4 H, N(CH2)2]. 13C NMR (100 MHz, CDCl3): δ = 165.7, 163.2, 66.6, 43.5. HRMS (ESI): m/z [M + H]+ calcd for C7H11N4O: 167.0933; found: 167.0931.
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1

On leave from Rostov State University, Russia.

9

Earlier several research groups reported that 1H NMR spectroscopy is an effective diagnostic tool for the detection of covalent σH adducts because their formation is characterized by an upfield shift of all proton signals in comparison with the same signals in the substrate. The signal of the proton bound to carbon which undergoes nucleophilic attack is shifted the most (Δδ = 3.5-4.0 ppm), due to the rehybridization of this carbon atom from sp2 in the substrate to sp3 in the σH adduct (see ref. 4).