Synthesis of some novel 1-aryl-1 H -1,2,3-triazole-4-carboxamides and ethyl 1- aryl-5-(1,2,3-triazol-1-yl)-1 H -pyrazole-4-carboxylates

Starting from 5-(pyrrol-1-yl)pyrazole derivatives


Introduction
2][3] Pyrazoles and pyrroles have become privileged scaffolds in medicinal chemistry due to their demonstrated or potential applications in the pharmaceutical field.Notable contributions in the recent literature have described a large number of drugs or drug candidates (Figure 1) that have pyrazole 4 or pyrrole 5 structures.Over the years, we have extensively studied the synthesis and chemical and pharmacological properties of 3-/5-pyrrolylpyrazoles. [6][7][8][9] Recently, a non-targeted screening of an in-house library of pyrazole derivatives with the aim of revealing possible antimicrobial potential has brought to light some derivatives of the series (e.g., 1, Figure 2) that possess indirect antibacterial activity. 10This means that although they are not able to inhibit bacterial replication per se, they can lower the IC50 value of known antibiotics, especially colistin (a mixture of polymyxin E1/E2), by several log units against Gram-negative bacteria of great clinical importance. 11The significant results prompted us to investigate further structural modifications of 1.
Thanks to the development of click chemistry for the synthesis of 1,2,3-triazole, 12,13 this structure has become easily accessible synthetically and is attracting increasing interest as an isosteric replacement for trans-amide bond and, more generally, as a metabolically stable scaffold for drug development. 14,15ccordingly, we wanted to investigate the possibility of a scaffold-hopping approach in which the pyrazole or pyrrole ring can be replaced by the 1,2,3-triazole core to obtain compounds of general structure 2 and 3 (Figure 2).© AUTHOR(S) Compared to lead compound 1, this isosteric modification should not alter the three-dimensional structure and general physicochemical properties of the new molecules but should allow them to better associate with biological targets through hydrogen bonding and dipole interactions. 13

Results and Discussion
For the synthesis of the compounds of general structure 2, we aimed to use the 1,3-dipolar cycloaddition reaction between -ketoamides and aryl azides, which has been recently reported in the literature, 16 since these starting materials can be easily prepared.In particular, -ketoamides were obtained by Vandavasi et al. by the reaction of -ketoesters and anilines in the presence of AgOTf in nitromethane as solvent. 17To test this procedure, we used ethyl acetoacetate and p-toluidine as reactants.However, this reaction did not proceed as we expected, and even when we changed some experimental conditions (time and/or temperature), we always obtained a mixture of -enamino ester and -ketoamide 4a, the latter being isolated in a yield never exceeding 35% (Scheme 1, Equation a).Therefore, we decided to use an alternative procedure that allowed us to obtain -ketoamides 4a and 4b in satisfactory yields by simply refluxing p-toluidine or 3-fluoroaniline with TMD (2,2,6-trimethyl-4H-1,3-dioxin-4one) in water for 4 h (Scheme 1, Equation b).Compounds 4a and 4b were then subjected to organocatalyzed cycloaddition with azides 5a-c (namely p-tolyl azide, 3-fluorophenyl azide, and phenyl azide, respectively) to afford triazole derivatives 2a-d in 61-82% yield (Scheme 1, Equation c).
Although this approach was quite efficient, it suffered from a limitation due to the availability of starting materials such as TMD.Therefore, to increase the possibility of expanding the chemical diversity at position 5 of the triazole ring, a modification was introduced in the synthesis of compounds 2 involving cycloaddition as the first step followed by the amidation reaction.Thus, ethyl benzoylacetate and azides 5b-d (namely 3fluorophenyl azide, phenyl azide, and 4-chlorophenyl azide, respectively) were heated in chloroform with DBU as catalyst to afford the triazole derivatives 6a-c (Scheme 2).Alkaline hydrolysis of 6b,c led to the corresponding acids 7a,b, which were then converted to the final amides 2e-i by coupling reaction with EDC/HOBt, using different amines to test the possibility of accessing compounds with different structural features.As for the 5-(1,2,3-triazol-1-yl)pyrazole derivatives of general structure 3, these new compounds were synthesized starting from ethyl 5-amino-1-phenyl-1H-pyrazole-4-carboxylate (8) (Scheme 3). 18This was diazotized with sodium nitrite in TFA to give the diazonium salt, which reacted in situ with sodium azide to give the azide derivative 9 with an overall yield of 89%, compared with the 50% yield reported from a similar procedure. 19The azide 9 was subjected to cycloaddition with various alkynes to afford the desired compounds 3a-c with a yield of 20-48%.Compound 3c was then hydrolyzed with lithium hydroxide to give the corresponding carboxylic acid 3d, but subsequent attempts to convert 3d to an amido derivative with Lphenylalanine ethyl ester hydrochloride under standard condensation conditions (EDC, HOBt) were © AUTHOR(S) unsuccessful.Therefore, this procedure for obtaining 3d from 8 proved to be quite fast and easy to perform, while further work is needed to establish the use of 3d in subsequent transformations.

Conclusions
Different scaffold hopping approaches were evaluated to obtain two small families of isosteric compounds starting from the lead compound 1.The results obtained show the possibility of expanding each class of these isosteres into larger libraries in view of their possible biological evaluation.

Experimental Section
General.Merck silica gel 60 was used for flash chromatography (23-400 mesh).For thin layer chromatography (TLC), silica-coated aluminum plates (Merck Kieselgel F254) were used.Melting points were determined on a Gallenkamp apparatus and are uncorrected. 1H NMR and 13 C NMR were recorded on a Bruker Avance DPX400 or Bruker Avance 600 spectrometers operating at 400/100 MHz or 600/150 MHz, respectively.Chemical shifts (d) are in part per million (ppm) relative to TMS as internal standard and coupling constants (J) are reported in Hz.Mass spectral (MS) data were obtained using an Agilent 1100 LC/MSD VL system (G1946C) with a 0.4 mL/min flow rate using a binary solvent system of 95:5 methanol/water.UV detection was monitored at 254 nm.Elemental analyses were performed on a Perkin-Elmer PE 2400 elemental analyzer and the data for C, H, and N are within 0.4% of the theoretical values.The chemical purity of the target compounds was determined using an Acquity Waters UPLC-MS system under the following conditions: Waters BEH C18 (2.1 mm x 50 mm, 1.7 µm) reversed phase column; method: gradient elution, solvent A (0.1% formic acid in water), solvent B (0.1% formic acid in acetonitrile) 90:10 to 0:100 over 2.9 min, flow rate 0.5 mL/min, UV detector, 254 nm.For compound 3b, the following conditions were used: Symmetry® C18 column (4.6x75 mm, 3.5 μm) with methanol as the mobile phase at a flow rate of 0.5 mL/min, UV detector, 254 nm.
Heating was maintained for 4-6 h with stirring and the progress of the reaction was monitored by TLC (silica, EtOAc/hexane, 1:3).After completion of the reaction, the mixture was cooled and extracted with dichloromethane.The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated.The residue was purified by flash chromatography (silica, EtOAc/hexane, 1:4) to give products 4.

Figure 1 .
Figure 1.Structure of some representative pyrazole and pyrrole drugs.