516 Journal of Combinatorial Chemistry, 2010 Vol. 12, No. 4
Volochnyuk et al.
General Procedure for the Synthesis of Carboxylic
Acids 4. Method A. A solution of ester 5 (1 mmol) and
potassium hydroxide (2 mmol) in 2-propanol (15 mL) was
refluxed for 2-5 h, then cooled, diluted with water (15 mL),
and neutralized with acetic acid. The precipitate was collected
by filtration and dried in vacuo over phosphorus pentoxide.
Method B. The method was used for the synthesis of
library members 4{5(10,11)-6(1-30)}. A solution of ester
5 (1 mmol) and lithium hydroxide (1 mmol) in methanol
(15 mL) was stirred overnight, then diluted with water (15
mL) and neutralized with acetic acid. The precipitate was
collected by filtration, recrystallized from ethanol, and dried
in vacuo over phosphorus pentoxide.
General Procedure for the Synthesis of Amides 17.
Method A. A mixture of acid 4 (2 mmol), amine 16(1-10)
(2 mmol), diisopropylethylamine (5.8 mmol), and 1-methyl-
2-chloropyridinium iodide (2.9 mmol) in dry acetonitrile (3
mL) was stirred at reflux for 1-4 h. The reaction mixture
was diluted with water (10 mL). The precipitate was filtered
off and washed with 5% aqueous sodium bicarbonate
solution (10 mL) and ethanol (2 mL).
Method B. Carbonyldiimidazole was added to a solution
of acid 4 in dry DMF (2 mL), and the reaction mixture was
brought to 60 °C and stirred at this temperature for 2 h. Then
amine was added to the reaction mixture in one portion.
The reaction mixture was sonicated at 60 °C for 12 h. The
reaction mixture was diluted with water (10 mL). The
precipitate was filtered off and washed with 5% aqueous
sodium bicarbonate solution (10 mL) and EtOH (2 mL).
General Procedure for the Synthesis of Esters 19. A
mixture of acid 4 (2 mmol), alkylating agent (2 mmol), and
diisopropylethylamine (2 mmol) in DMF (2 mL) was heated
at 60 °C for 4 h. The reaction mixture was diluted with water
(10 mL). The precipitate was filtered and washed with
2-propanol (2 mL).
General Procedure for the Synthesis of Hydrazides
24. A solution of the corresponding ester 7 (1 mmol) and
hydrazine hydrate (5 mmol) in 2-propanol (15 mL) was
refluxed for 2-5 h. After cooling, the precipitate was filtered
and washed with 2-propanol (2 mL).
General Procedure for the Synthesis of 1,2,4-Triaz-
oles 21. A solution of hydrazide 24 (3 mmol) and compound
20 (3 mmol) in 2-propanol (20 mL) was refluxed for 2 h.
The solvent was removed in vacuo, the residue was refluxed
in acetic acid for 4 h. The solvent was removed in vacuo,
the residue was triturated with water, filtered, and recrystal-
lized from ethanol (in most cases).
General Procedure for the Synthesis of 1,2,4-Oxadia-
zoles 23. Method A. (used for the synthesis of
23{5(1)-6(27)-22(1)}). A mixture of hydrazide 24 (2
mmol) and ethyl orthoformate 22(1) (2 mmol) was stirred
at 100 °C for 12 h. The precipitate was filtered off and
washed with Et2O (2 mL).
Method B. (used for the synthesis of 23{5(1)-6(27)-
22(2)}). Carbonyldiimidazole (1 mmol) was added to a
solution of acid 4 in dry DMF (2 mL), the reaction mixture
was brought to 60 °C, and stirred at this temperature for
2 h. Then hydrazide 22(2) was added to the reaction mixture
in one portion. The reaction mixture was sonicated at 60 °C
for 12 h. The reaction mixture was diluted with water (10
mL). The precipitate was filtered, washed with 5% aqueous
sodium bicarbonate solution (10 mL) and EtOH (2 mL) to
give the corresponding acyl hydrazide. A mixture of acyl
hydrazide (2 mmol) and 5 mL of phosphorus oxychloride
was refluxed with stirring for 4 h. The reaction mixture was
poured onto ice (20 g), and the precipitate was filtered off
and washed with 2-propanol (2 mL).
Supporting Information Available. Figures and com-
pound/library member characterization. This material is
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