Synthesis of N-Substituted Phthalimidoalkyl 1 H-1 , 2 , 3-Triazoles : a Molecular Diversity Combining Click Chemistry and Ultrasound Irradiation

A series of 1,2,3-triazole derivatives was synthesized from N-phthalimidoalkyl-azides (A1 -A4) and alkynes (a-e) under ultrasound irradiation in the presence of CuI, Et3N and DMF as solvent. The present protocol afforded 18 new 1,2,3-triazoles (1-4) in good-to-excellent yields (67-98%).


Introduction
The discovery of new drugs has one of the largest beneficial effects on human health. 1 Everyday, a variety of molecules are synthesized with this purpose, employing a myriad of protocols to attach structural part or functional groups into old or new chemical entities.
Phthalimide is a functional group of growing interests in the field of organic synthesis. 23][4] The conjugation of phthalimide with 1,2,3-triazole has recently emerged in the literature. 3Herein, we consider these molecular hybrids as good candidates for pharmaceutical application.
In the last decade, 1,2,3-triazoles have become attractive as target compounds for drug discovery, 5 among other applications. 6After the discovery by Meldal and co-workers 7 and Sharpless and co-workers 8 of the Cu-AAC (Cu-catalyzed azide alkyne cycloadditon) reaction, 9 a number of molecules were synthesized through this method to afford the 1,4-disubstituted 1,2,3-triazoles.Due to recent application of the products resultant from Cu-AAC protocols, 5,6,9 this reaction has encouraged many more researchers around the world.Usually, the most common methodology uses CuSO 4 as Cu(II) source and sodium ascorbate in tert-BuOH-H 2 O at ambient temperature. 8owever, this procedure was altered during the last decade mainly to overcome difficulties related to low reactivity in the presence of specific functional groups. 9or example, our group recently reported that the catalytic system CuSO 4 /sodium ascorbate acted as an undesirable copper(II)-ascorbate redox system that resulted in reduction of the electron-deficient azide group to an amine group. 10nother recent protocol used acidic conditions to promote the synthesis of 1,2,3-triazoles. 113][14][15] The effect of ultrasound on the "click chemistry" of 1,2,3-triazole synthesis has been poorly described, and only very recently few examples using this procedure have arised. 16,17erein, in the course of a project involving synthesis 3,10 and biological activity 18 of a series of 1,2,3-triazoles, we have expanded our investigation to obtain new N-substituted phthalimidoalkyl 1H-1,2,3-triazole derivatives.To achieve this goal, we employed a methodology based on click chemistry under ultrasound irradiation, which was more efficient in promoting faster reaction in good yields.
When we changed to phthalimidoethyl-azide (A 2 ), we observed lower yields of 33% after 24 h of reaction to afford compound 2a (Table 1, entry 1).Then, the reaction was performed under ultrasound irradiation and the reaction time decreased to 3 h, but no increased yields were observed (entry 1).Furthermore, we broadened our options using phthalimidopropyl-azide (A 3 ) or phthalimidobutyl-azide (A 4 ) as substrates, and yet non-homogeneous results were found (Table 1, entries 2-5).Now, in order to improve our results (yields and reaction time), we focused our endeavor on using a polar solvent, namely acetonitrile.Albeit our effort, we observed a wide yield range between 15-92% in 14-24 h at stirring conditions and room temperature (30 oC) (Table 1, entries 7-10, silent condition).On the other hand, when ultrasound irradiation was applied at short times (1-1.5 h), some results were improved (entries 8 and 9), but the reactions showed a wide yield range (40 to 90%, Table 1, entries 6-10, ultrasound condition).The literature describes that CH3CN has a high affinity for copper-(I) and therefore can inhibit the reaction, requiring the addition of an amine as ligand.9Thus, when we carried out an experiment using CH3CN, CuI, Ultrasound and Et3N (Method C) over 2 h to prepare 3b, we observed only 36 % of 3b after column chromatography.
Our methodologies (Method A, B and C), so far, showed variable results even after ultrasound irradiation.As an attempt to reach more consistent results, we replaced MeCN by DMF, as a solvent with high dielectric constant.We studied the reaction between (A3) and (b) to afford compound 3b and the results are summarized in Table 2.We found that using only DMF, compound 3b was obtained in 70% yield after 20 h of reaction, with some variation in our template reaction (Table 2, entry 1).In order to accelerate the reaction, we applied ultrasound irradiation and the reactions proceed in 2 h to yield 35% of 3b and the starting material was recovered in 28% (entry 2).When we used DMF and added 10 mol% of Et 3 N, the reaction occurred after 25 min in a moderate yield of 58% (entry 3).
As a step forward to improving our methodology, we evaluated the reaction under ultrasound conditions in 30 min to afford 3b in 67% yield (entry 4).With these experiments, we concluded that the independent use of DMF and ultrasound (entry 2) or DMF and Et 3 N (entry 3) has not sufficiently improved the results.To rationalize this fact, we believe in a synergistic effect between basic catalyst Et 3 N and ultrasound energy, contributed to more optimized conditions (Table 2, entry 4).
Based on these preliminary studies, we adopted the best condition, combining good yields and shorter reaction time.At first, our interests were focused on alkynes bearing the reactive functional groups ethyl propyolate (b), alcohol (c) and ethyl-bromide (d).The reaction proceeded in only 30 min showing more homogeneous results between 67 and 98% yields (Scheme 1 and Table 3, entries 2-4).
We started employing our previous conditions used for the synthesis of 2-(1H-1,2,3-triazole)-1,4-naphthoquinone derivatives. 10The use of CH 3 CN and CuI at room  temperature (method B/silent condition), furnished 1e in excellent yield of 96%.However, for the synthesis of compounds 2e, 3e and 4e, moderate yields (54-60%) were obtained in approximately 20 h of reaction.With those results in hands, we used the protocol developed in this work (method D: DMF/Et 3 N/CuI/ultrasound/30 min), to obtain (2e-4e) in good to excellent yields of 79-92% (Table 3, entry 5).2-Amino-1,4-naphthoquinone derivatives are a versatile class of molecules. 19In this work, we described for the first time the heterocyclic N-substituted phthalimidoalkyl-1,2,3triazole appending 2-aminomethyl-1,4-naphthoquinone; we named this new class of compounds as ANTP (aminonaphthoquinone-triazole-phthalimide) and they will be the object of studies in the future.
The structures of compounds (1-4, a-e) were assigned on the basis of their 1 H and 13 C NMR, and elemental analysis. 1H NMR spectra of compounds (1-4) confirm click condensation reaction by the presence of a singlet, generally between 7.5 and 8.6 ppm, corresponding to the hydrogen of the triazole ring.The results are also consistent with the conjugation of a phthalimide-alkyl moiety with substituted terminal alkynes.The phthalimide group was well characterized in the aromatic region in d 7.6-7.9ppm as second-order multiplets.The homologous series (CH 2 ) n showed the side chain as one singlet (when n = 1); two triplets with respect to NCH 2 (n = 2); two triplets and one quintet when n = 3; and two triplets (NCH 2 ) and two quintets for n = 4.The 13 C NMR spectra of the compounds (1-4) confirmed the presence of conjugated products and aliphatic carbons were noticed at a region down to d 67 ppm corresponding to methylene groups.Aromatic and other aliphatic groups were also characterized.

Table 1 .
Experiments using methods A and B at silent and ultrasound conditions