Synthesis of 1,5-Disubstituted Tetrazoles in Aqueous Micelles at Room Temperature

The ongoing study is a Ugi-azide four-component reaction for the synthesis of 1,5-disubstituted tetrazole(1,5-DST), which involves an aldehyde, different amines, isocyanides, and as azide’s source the Trimethylsilylazide (TMSN3), in water as solvent using as catalyst the tetradecyltrimethylammonium bromide (TTAB) with a load of (10% mole), which provides a hydrophobic micellar reaction site. This approach is a step toward a green chemistry reaction of 1,5 disubstituted tetrazole. A serie of 1, 5- disubstituted tetrazole was synthesized by engaging a large substrate scope, leading to yields between 43% and 56%, which are compared afterwards with those obtained with methanol as solvent. The results were confirmed by HRMS, IR, and 1D NMR experiments.


Introduction
Tetrazole derivatives attained remarkable attention as prime heterocycles due to a large utilization in numerous fields such as in medicine, in pharmacology, in photography, and as a potential explosives and rockets propellant components based on their high energy properties [1].
To date, we can review in the literature several synthesis methods of 1,5-DST, but the main routes are [2+3] intermolecular cycloaddition and Ugi-azide reaction (UA) [10].
In 1959, Ivar Ugi introduced the Ugi-4components reaction, the most important approach to aminomethyl tetrazoles using Multicomponent reaction (MCR), since it emerged as an extremely powerful tool in combinatorial chemistry and drug discovery, offering significant advantages over conventional linear stepwise syntheses. Years later, Ugi described a Passerini MCR variation leading to α-hydroxymethyl tetrazoles [21,22]. The Ugi azide MCR differs from the classical Ugi-4CR by replacing the carboxylic acid with an azide source, which traps out the intermediate nitrilium to lead finally to the formation of 1,5-DSTs [9].
In the last decades, green chemistry emerged as an alternative and sustainable solution that enables to design processes and syntheses that reduce or eliminate the use or generation of hazardous substances, which sometimes give toxic residues at the end of the reaction and are difficult to remove [23]. Hence, using water as solvent instead of MeOH would be a better solution in the synthesis of 1,5-DST, since it is safe, non-toxic, inexpensive, and represents no threat to environment.
However, the use of water is rare or even unconsidered as solvent due to the limited solubility of organic compounds in it. Therefore, the incorporation of surface-active agents (surfactants) as catalyst in aqueous media has been proven to enhance the reactivity of water via the formation of micelles or vesicular cavities [24]. Micellar catalysis refers to the acceleration of the rate of a reaction by catalytic amounts of amphiphiles that self-aggregate spontaneously to form micelles in water [24].
In our report, we have tried to describe an efficient synthesis method of 1,5-DSTsin water using micellar catalyst, tetradecyltrimethylammonium bromide (TTAB).
Molbank 2021, 2021, x FOR PEER REVIEW 2 of 11 cycloaddition of p-toluenesulfonyl cyanide (TsCN) with aromatic and aliphatic azides under solvent-free condition followed by simple isolation with good yield [18][19][20] However, a high reaction temperature was required.
In 1959, Ivar Ugi introduced the Ugi-4components reaction, the most important approach to aminomethyl tetrazoles using Multicomponent reaction (MCR), since it emerged as an extremely powerful tool in combinatorial chemistry and drug discovery offering significant advantages over conventional linear stepwise syntheses. Years later Ugi described a Passerini MCR variation leading to α-hydroxymethyl tetrazoles [21,22] The Ugi azide MCR differs from the classical Ugi-4CR by replacing the carboxylic acid with an azide source, which traps out the intermediate nitrilium to lead finally to the formation of 1,5-DSTs [9].
In the last decades, green chemistry emerged as an alternative and sustainable solution that enables to design processes and syntheses that reduce or eliminate the use or generation of hazardous substances, which sometimes give toxic residues at the end of the reaction and are difficult to remove [23]. Hence, using water as solvent instead of MeOH would be a better solution in the synthesis of 1,5-DST, since it is safe, non-toxic inexpensive, and represents no threat to environment.
However, the use of water is rare or even unconsidered as solvent due to the limited solubility of organic compounds in it. Therefore, the incorporation of surfaceactive agents (surfactants) as catalyst in aqueous media has been proven to enhance the reactivity of water via the formation of micelles or vesicular cavities [24]. Micellar catalysis refers to the acceleration of the rate of a reaction by catalytic amounts of amphiphiles that self-aggregate spontaneously to form micelles in water [24].
In our report, we have tried to describe an efficient synthesis method of 1,5-DSTsin water using micellar catalyst, tetradecyltrimethylammonium bromide (TTAB).

Results and Discussion
At first, the reaction was conducted with aniline (a1), propan-2-one (a2), ethyl-2isocyano-2-(4-methoxybenzyl) pent-4-enoate(a3), and TMSN3 (a4)in distilled water without TTAB, ambient temperature (Table 1, entry1) and with heating (Table 1, entry2) No reaction occurred in both cases, which can be explained by the fact that the substrates are either less soluble or insoluble in water, something that directly affects the reaction. Afterwards, we conducted the same reaction and used TTAB as catalyst (Table  1, entry3), which enables the formation of micelles where most of organic substrates are