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You are using Science Of Synthesis as a Guest. Please login or sign up for a free trial to access the full content. Method 4: By Oxidation of Pyrazol-1-amines

DOI: 10.1055/sos-SD-017-00353

Döpp, H.; Döpp, D.Science of Synthesis, (200417236.

The oxidation of pyrazol-1-amines is used in one of the most effective syntheses of monocyclic 1,2,3-triazines. The starting pyrazol-1-amines are prepared by N-amination of pyrazoles with hydroxylamine-O-sulfonic acid in aqueous sodium hydroxide,[‌9‌,‌261‌,‌262‌] or, after deprotonation with sodium hydride, by reaction with (O-mesitylenesulfonyl)hydroxyl­amine.[‌26‌,‌261‌,‌262‌] Unsymmetrically substituted pyrazoles 68 give a mixture of isomeric pyra­zol-1-amines 69 and 70 (Scheme 11), which in most cases can be separated.[‌33‌,‌261‌,‌262‌] However, this is not normally required as on oxidation both isomers yield the same 1,2,3-tri­azine 71.[‌9‌,‌26‌] Several different oxidants are used, including lead(IV) acetate (effective for methyl and phenyl-1,2,3-triazines, but not for the parent heterocycle),[‌9‌,‌26‌,‌42‌] lead(IV) oxide in the presence of trifluoroacetic acid,[‌26‌] nickel peroxide,[‌8‌,‌9‌,‌26‌] iodine (and iodine chloride or iodine bromide),[‌33‌] sodium periodate,[‌52‌,‌261‌] or anodic oxidation.[‌47‌] Labelling experiments with 3,5-dimethylpyrazol-1-[15N]amine show that the N-amino group forms the central nitrogen (N2) atom of the 2,6-dimethyl-1,2,3-triazine, which is formed by oxidation with lead(IV) acetate.[‌60‌] 1,2,3-Triazine (yield 18%) has been prepared by the oxidation of pyrazol-1-amine with nickel peroxide,[‌8‌] but the yield obtained (from a trace to 20%) depends upon the quality of the reagent used.[‌26‌] Oxidation with lead(IV) oxide in the presence of trifluoroacetic acid is more reliable,[‌26‌] and oxidation with iodine works well in the presence of aqueous potassium hydrogen carbonate and dichloromethane in a two-phase system.[‌48‌] However, overall sodium periodate seems to be the best oxidant for the ring transformation of pyrazol-1-amines providing good reproducibility and yields in the syntheses of 1,2,3-triazine, methylated 1,2,3-triazines,[‌52‌] and even methyl 1,2,3-triazinecarboxylates. However, the method fails with 1-aminopyrazoledicarboxylates or 4-nitropyrazol-1-amine.[‌261‌] The electrooxidation of pyrazol-1-amines is best carried out when pyridine, or water, is added to the solvent (MeCN); yields of unsubstituted, methyl-, and phenyl-substituted 1,2,3-triazines are then moderate to good.[‌47‌]

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Meeeeeeeeee 88

M8 M8 M8 Meeeeeeee Meeeee Meeee (%) ee 88/88 Meeeeeeee Meeeee Meeee (%) ee 88 Mee
M M M M 88 M 88 [‌88‌]
M M M M 88 M 88 [‌8‌,‌88‌]
M Me M M 88 M 88 [‌8‌,‌88‌]
M Me M M 88 M 88 [‌88‌]
M MM8Me M M 88 M 88 [‌888‌]
M MMe M M 88 M 88 [‌888‌]
Me M M M 88 M 88 [‌8‌,‌88‌]
Me M Me M 88 M 88 [‌88‌,‌88‌]
Me M Me M 88/88 M 88 (eeee 88 ee 88) [‌88‌,‌88‌]
Me Me M M 88 M 88 [‌8‌]
Me Me Me M 88 M 88 [‌88‌,‌88‌]
Me MM8Me M M 88/88 M 88 (eeee 88) [‌888‌]
Me M Me M 88 M 88 [‌8‌]
Me Me M M 88 M 88 [‌8‌]
MM8Me M Me M 88/88 M 88 (eeee 88) [‌888‌]
MM8MMe8 M M M 88/8 M 88 (eeee 88) [‌888‌]
MMe M M M 88 M 88 [‌888‌]

Meeeeeeeeeee Meeeeeeee

8,8,8-Meeeeeeee 88; Meeeeee Meeeeeeee:[‌8‌,‌88‌,‌88‌,‌888‌]

Meeeee M: Meeeeeeee eeee Meeeee Meeeeeeee:[‌88‌] Meeee MeMM8 (8.88e, 88eeee) eee eeeee eeee eeeeeeee ee ee eee-eeee eeee ee eee eeeee eeeeeeeeeeeee (88eeee) ee MM8Me8 (88eM) eee M8M (88eM). Mee eeeeeee eee eeeeeee eeeeeeeee ee 88°M eee eeee eeeeeeeee eeeeeeeeee eeee MMMe8. Mee eeeeeeee eeeeeeee eeee eeeee (MeMM8), eeeeeeeeeeee, eee eee 8,8,8-eeeeeeee eeeeeeee eee eeeeeeee ee eeeeeeeeeeeeeee ee eeeeee eeeeeeeeeeeeee (eeeeee eee). M eeeeeeee eeeeeeeee ee eeeeeeee eee eeeeee 8,8,8-eeeeeeeeeeeeeeeeeeee:[‌888‌]M eeee ee MeMM8 (888ee, 8eeee) ee M8M (88eM) eeeeee ee 8°M eee eeeee ee e eeee ee eee eeeeee 8-eeeeeeeeeeeeeeeeeeeeeeee (8eeee) ee MMMe8 (88eM) eeee ee 8°M. Mee eeeeeee eee eeeeeee ee 8°M eee 88e, eeee eee eeeeeee eeeee eee eeeeeeeee eee eee eeeeeee eeeee eeeeeeeee eeee MMMe8 (8×88eM). Mee eeeeeeee eeeeeee eeeeee eeee eeeee (MeMM8), eeeeeeeeee, eee eee eeeeee 8,8,8-eeeeeeeeeeeeeeeeeee eeee eeeeeeee eee eeeeeeee ee eeeeee eeeeeeeeeeeeee (eeeeee eee, Me8M).

Meeeee M: Meeeeeeee eeee Meeeee:[‌88‌] M eeee ee M8 (8.8 eeeee) ee MM8Me8 eee eeeee eeeeeeee ee e eeee ee eee eeeeeee-8-eeeee (ee e eeeeeee ee eee eeeeeeeeeeeee) ee e eee-eeeee eeeeeee ee MM8Me8 eee 88% ee MMMM8 eee eeeee eeeeeeee eeee eeeeeeee eee eeeeeee. Mee eeeeeee eee eeeeeee eee 8888eee ee ee eee eeee eeeeeeee eeee ee Me8MM8. Mee eeeeeee eeeee eee eeeeeeeee eee eee eeeeeee eeeee eee eeeeeeeee eeee MM8Me8. Mee eeeeeeee eeeeeee eeeeee eeee eeeeee eeee M8M, eeeee (MeMM8), eeeeeeeeee eee eee eeeeeee eee eeeeeeeeeeee.

Meeeee M: Meeeeeeee eeee Meee(MM) Meeeeee/Meeeeee Meeee:[‌8‌] Meeeeeee MeM (88.8e, 8.88eee) eee eeeee ee e eeee ee eee eeeeeee-8-eeeee 88 (88eeee) ee eeeee MM8Me8 (888eM). Mee eeeeeee eee eeeeee ee 88°M (MeMM/MM8), eeee Me(MMe)8 (8.88e, 88.88eeee) eee eeeee ee eeeee eeeeeeee eeeeee 88eee. Mee eeeeeee eee eeeeeee ee eeee ee 8°M eee eeeeeee eee 8e ee 8°M. Meeee eeeeeeeeee eee eeeeeeeeeee ee eee eeeeeee ee ee, eee 8,8,8-eeeeeeee eee eeeeeeee ee eeeeee eeeeeeeeeeeeee (eeeeeee eeeeeee, MeMM/MM8Me8 8:88; ee eeeeee eee, MeMM/MM8Me8 8:88), eeeeeeeeeee, ee eeeeeeeeeeeeeee.