Reaction #1153159

Reaction equation

hexamethylenetetramine

4-(5-trifluoromethyl-tetrazol-1-yl)-phenol

trifluoroacetic acid

hexamethylenetetramine

H2SO4

→

title compound

Yield 66.4%

2-Hydroxy-5-(5-trifluoromethyl-tetrazol-1-yl)-benzaldehyde

Yield 66.4%

Solvents

water

Conditions

Workup

1. 1
   OtherTo a 2 L nitrogen purged round bottom flask fitted with a condenser
2. 2
   TemperatureThe solution was heated
3. 3
   Temperatureto reflux
4. 4
   Temperaturerefluxed for 4 h
5. 5
   Temperaturethe solution refluxed overnight
6. 6
   TemperatureThe reaction was cooled
7. 7
   FiltrationThe yellow suspension was filtered
8. 8
   Washthe cake washed with water until the filtrate
9. 9
   workup.DISSOLUTIONThe cake was dissolved in methylene chloride
10. 10
    Filtrationfiltered through 300 g of Silica Gel 60 (70-230 mesh)
11. 11
    Otherflushed with 6 L of methylene chloride
12. 12
    OtherThe solvent was removed in vacuo
13. 13
    Otherthe residue flushed with hexanes
14. 14
    Filtrationfiltered
15. 15
    OtherThe white crystalline product that was obtained
16. 16
    Otherwas dried

Procedure

To a 2 L nitrogen purged round bottom flask fitted with a condenser was charged 67.7 g (0.29 mol) of 4-(5-trifluoromethyl-tetrazol-1-yl)-phenol, 540 mL trifluoroacetic acid, and 86.3 g (0.62 mol, 2.1 eq) of hexamethylenetetramine. The solution was heated to reflux and refluxed for 4 h. An additional 10 g (0.07 mol, 0.24 equiv) of hexamethylenetetramine was added and the solution refluxed overnight. The reaction was cooled and poured slowly into 3 L of 1N H2SO4. The suspension was diluted with an additional 500 mL of water and aged at room temperature for 30 min and at 0° C. and for additional 30 min. The yellow suspension was filtered and the cake washed with water until the filtrate was neutral. The cake was dissolved in methylene chloride and filtered through 300 g of Silica Gel 60 (70-230 mesh) and flushed with 6 L of methylene chloride. The solvent was removed in vacuo and the residue flushed with hexanes. The resulting slurry was cooled to room temperature and filtered. The white crystalline product that was obtained was dried yielding 50.4 g (66.4% yield) of the title compound. An additional 6.9 g (9.1%, for a combined yield of 57.3 g, 75.5% yield) was obtained by extracting the aqueous filtrate with ether and chromatographing (Silica Gel 60, methylene chloride): 1H NMR (CDCI3) δ 7.23 (d, J=9 Hz, 1H), 7.62 (dd, J=9, 2 Hz, 1H), 7.73 (d, J=2.5 Hz, 1H), 9.96 (s, 1H). MS (EI) m/z 258. Anal. Calcd for C9H5F3N4O2: C, 41.87; H, 1.95; F, 22.08; N, 21.70. Found: C, 41.87; H, 1.98; F, 22.61; N, 21.74.

Source