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

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.

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

1

On leave from Rostov State University, Russia.

For reviews, see:

2a Quirke JME. 1,3,5-Triazines In Comprehensive Heterocyclic Chemistry I   Vol. 3:  Katritzky AR. Rees CW. Pergamon; Oxford: 1984.  Part B. p.457-530  

2b Bartholomew D. 1,3,5-Triazines In Comprehensive Heterocyclic Chemistry II   Vol. 6:  Katritzky AR. Rees CW. Scriven EFV. Pergamon; Oxford: 1996.  Chap. 6.12. p.575-636  

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3f Schaefer FC, and Peters GA. inventors; US Patent,  2845422.  ; Chem. Abstr., 1958, 52, P20217h

4 Van der Plas HC. Adv. Heterocycl. Chem.  2004,  86:  1 

5 Hiroshi H. Van der Plas H. J. Heterocycl. Chem.  1982,  19:  1285 

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7 Gulevskaya AV. Maes BUW. Meyers C. Herrebout WA. Van der Veken BJ. Eur. J. Org. Chem.  2006,  5305 

8a

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.

8b Firouzabadi H. Vessal B. Naderi M. Tetrahedron Lett.  1982,  23:  1847 

9

Earlier several research groups reported that ¹H NMR spectroscopy is an effective diagnostic tool for the detection of covalent σ^H 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 σ^H adduct (see ref. 4).

10 When NH₃ is used as the nucleophile, the reaction can also occur via an alternative ANRORC-mechanism: ring-closure of 6 can give 5 in which the exocyclic nitrogen (originating from the ammonia nucleophile) has been incorporated in the ring and the original ring nitrogen is transformed into the exocyclic amino group. For a review on this topic, see: Van der Plas HC. Tetrahedron  1985,  41:  237 

11 For the calculation method of the activation barrier, see: Aganov AV. Klochkov VV. Samitov Y. Russ. Chem. Rev.  1985,  54:  931 

12 Willner I. Rosengaus J. Eichen Y. J. Phys. Org. Chem.  1993,  6:  29