TRIAZOLE INTERMEDIATES USEFUL IN THE SYNTHESIS OF PROTECTED N-ALKYLTRIAZOLECARBALDEHYDES
Described herein are compounds and methods of making such compounds useful in the synthesis of protected N-alkyl-triazolecarbaldehydes.
1 . A compound of Formula I:
wherein HAr is N-alkyl-1,2,4-triazolyl, N-alkyl-1,3,4-triazolyl, or N-alkyl-1,2,3-triazolyl.
2 . The compound of claim 1 , wherein the alkyl is C 1-6 alkyl.
3 . The compound of claim 1 , wherein the HAr is N-alkyl-1,2,4-triazolyl.
4 . The compound of claim 1 , wherein the HAr is N-alkyl-1,3,4-triazolyl.
5 . The compound of claim 1 , wherein the HAr is N-alkyl-1,2,3-triazolyl.
6 . The compound of any of claims 1 - 5 , wherein the alkyl is methyl, ethyl, or propyl.
7 . The compound of any of claims 1 - 6 , wherein the alkyl is methyl.
8 . A method of making a compound of Formula I according to any of claims 1 - 7 , comprising treating a compound of formula HAr-H, or a salt thereof, with N,N-dimethylformamide in a first solvent followed by a lithium base; wherein HAr-H is N-alkyl-1,2,4-triazole, N-alkyl-1,3,4-triazole, or N-alkyl-1,2,3-triazole, and the lithium base is lithium diisopropylamide, lithium amide, lithium hydride, or lithium bis(trimethylsilyl)amide.
9 . The method of claim 8 , wherein the lithium base is lithium bis(trimethylsilyl)amide.
10 . The method of claim 8 , wherein the first solvent is tetrahydrofuran, 2-methyl-tetrahydrofuran, a furan substituted with 1 or 2 C 1-4 alkyl groups, tert-butylmethylether, cyclopentylmethylether, or dioxane.
11 . The method of claim 8 , wherein the first solvent is tetrahydrofuran or 2-methyl-tetrahydrofuran.
12 . The method of claim 8 , wherein the lithium base is lithium bis(trimethylsilyl)amide and the first solvent is 2-methyl-tetrahydrofuran.
13 . The method of claim 12 , wherein the compound of Formula I precipitates as a 2-methyl-tetrahydrofuran solvate.
14 . The method of any of claims 8 - 13 , wherein the alkyl is C 1-6 alkyl.
15 . The method of any of claims 8 - 13 , the HAr is N-alkyl-1,2,4-triazolyl.
16 . The method of any of claims 8 - 13 , wherein the HAr is N-alkyl-1,3,4-triazolyl.
17 . The method of any of claims 8 - 13 , wherein the HAr is N-alkyl-1,2,3-triazolyl.
18 . The method of any of claims 8 - 13 , wherein the alkyl is methyl, ethyl, or propyl.
19 . The method of any of claims 8 - 13 , wherein the alkyl is methyl.
20 . The method of any of claims 8 - 19 , further comprising treating the compound of Formula I and 6-fluoro-4-nitroisobenzofuran-1(3H)-one with acetic acid or acetic anhydride in the presence of water and a base to yield a compound of Formula II:
wherein HAr is N-alkyl-1,2,4-triazolyl, N-alkyl-1,3,4-triazolyl, or N-alkyl-1,2,3-triazolyl.
21 . The method of claim 20 , wherein the HAr is N-methyl-1,2,4-triazolyl.