Efficient Syntheses of 1,2,3-Triazoloamide Derivatives Using Solid- and Solution-Phase Synthetic Approaches

Efficient synthetic routes for the preparation of secondary and tertiary 1,2,3-triazoloamide derivatives were developed. A secondary α-1,2,3-triazoloamide library was constructed and expanded by a previously developed solid-phase synthetic route and a tertiary 1,2,3-triazoloamide library was constructed by a parallel solution-phase synthetic route. The synthetic routes rely on amide formation with secondary amines and chloro-acid chlorides; SN2 reaction with sodium azide; and the selective [3 + 2] Hüisgen cycloaddition with appropriate terminal alkynes. The target secondary and tertiary 1,2,3-triazoloamide derivatives were obtained with three-diversity points in excellent overall yields and purities using the reported solid- and solution-phase synthetic routes, respectively.


Introduction
Combinatorial chemistry has emerged as a powerful technique for the synthesis of biologically active small molecules for the purpose of medicinal chemistry programs within the pharmaceutical industry [1][2][3][4][5]. Recently, the 1,2,3-triazole moiety, produced by Cu(I)-catalyzed [3 + 2] cycloaddition reactions, has been used as a scaffold for generating combinatorial libraries [6][7][8][9][10]. 1,2,3-Triazoles can mimic the topological and electronic features of an amide bond, and this be used as bioisosteres of the amide moiety. They are particularly stable to reduction, oxidation, and hydrolysis conditions.

Results and Discussion
The synthetic sequence for secondary α-1,2,3-triazoloamides 1 (R 2 = H) is shown in Scheme 1 [20]. According to the solid-phase synthetic approach with the polymer-bound amines 3, which were prepared by reductive amination reaction from Acid sensitive Methoxy Benzaldehyde (AMEBA) [20,21] resin 4 and primary amines 5 (the first diversity element R 1 ; Figure 2), polymer-bound chloroamides 7 can be easily prepared by the reaction of amine resin 3 with chloro-acid chloride 6 (the second diversity element A; Figure 3) and triethylamine in CH 2 Cl 2 at room temperature. Treatment of solid supported chloroamides 7 (R = Cl, A = CH 2 or CHCH 3 ) with sodium azide in DMF at room temperature, provides the α-azidoamide resin 8 (R = N 3 ).
The reaction progress on solid-phase was monitored by ATR-FTIR ( Figure 5). The progress of reductive amination of AMEBA resin 4 and amine 5a (R 1 = Ph) was checked by the appearance of the weak NH stretching band at 3424 cm −1 and the disappearance of the aldehyde stretching band at 1678 cm −1 . The progression of amide formation for 7aa (R 1 = Ph, A = CH2) was monitored by ATR-FTIR which displayed the disappearance of the characteristic NH band at 3424 cm −1 and appearance of the amide carbonyl stretching band at 1666 cm −1 . The SN2 reaction of 7aa (R 1 = Ph, A = CH2) with sodium azide was monitored by the appearance of the azide stretching band at 2101 cm −1 . The completion of selective [3 + 2] Hüisgen cycloaddition of 7aa and 9a was confirmed by the disappearance of the azide stretching band.  Finally, the α-1,2,3-triazoloamide resin 10aaa was cleaved from the solid support under 30% TFA in CH 2 Cl 2 at 45˝C to provide the desired α-1,2,3-triazoloamide 1aaa [24,27,30] (93% over six steps, from Merrifield resin) without formation of by-product 13.
The reaction progress on solid-phase was monitored by ATR-FTIR ( Figure 5). The progress of reductive amination of AMEBA resin 4 and amine 5a (R 1 = Ph) was checked by the appearance of the weak NH stretching band at 3424 cm´1 and the disappearance of the aldehyde stretching band at 1678 cm´1. The progression of amide formation for 7aa (R 1 = Ph, A = CH 2 ) was monitored by ATR-FTIR which displayed the disappearance of the characteristic NH band at 3424 cm´1 and appearance of the amide carbonyl stretching band at 1666 cm´1. The S N 2 reaction of 7aa (R 1 = Ph, A = CH 2 ) with sodium azide was monitored by the appearance of the azide stretching band at 2101 cm´1. The completion of selective [3 + 2] Hüisgen cycloaddition of 7aa and 9a was confirmed by the disappearance of the azide stretching band. Finally, the α-1,2,3-triazoloamide resin 10aaa was cleaved from the solid support under 30% TFA in CH2Cl2 at 45 °C to provide the desired α-1,2,3-triazoloamide 1aaa [24,27,30] (93% over six steps, from Merrifield resin) without formation of by-product 13.

Preparation of Azidoamide 16
To a solution of α-chloroamide 15aa (1.41 g, 8.62 mmol) in acetonitrile (20 mL) and H 2 O (1 mL) was added sodium azide (700 mg, 10.77 mmol). The reaction mixture was stirred at room temperature for 1 day, and then diluted with EtOAc, washed with brine, dried over MgSO 4 and filtered. The solvent was removed, and the residue was passed through a short plug of silica to give α-azidoamide 16aa (1.40 g, 99%) as a colorless oil: 1