3-(Ethoxycarbonyl)-1-(5-methyl-5-(nitrosooxy)hexyl)pyridin-1-ium cation: A green alternative to tert-butyl nitrite for synthesis of nitro-group-containing arenes and drugs at room temperature
Abstract
Due to their remarkable properties, task-specific ionic liquids have turned out to be progressively popular over the last few years in the field of green organic synthesis. Herein, for the first time, we report that a new task-specific nitrite-based ionic liquid such as 3-(ethoxycarbonyl)-1-(5-methyl-5-(nitrosooxy)hexyl)pyridin-1-ium bis(trifluoromethanesulfonyl)imides (TS-N-IL) derived from biodegradable ethyl nicotinate indeed acted as an efficient and eco-friendly reagent for the synthesis of highly valuable nitroaromatic compounds and drugs including nitroxynil, tolcapone, niclofolan, flutamide, niclosamide and nitrazepam. The bridging of an ionic liquid with nitrite group not only increases the yield and rate of direct C
N bond formation reaction but also allows easy product separation and recyclability of a byproduct. Nonvolatile nature, easy synthesis, merely stoichiometric need and mildness are a portion of the extra focal points of TS-N-IL while contrasted with tert-butyl nitrite an outstanding and highly-flammable reagent utilized largely in organic synthesis.
Introduction
Nitro compounds [1] are highly valuable and versatile building blocks used to a great extent for the preparation of dyes, explosives, fertilizers, perfumes, plastics and so on. Numerous nitro compounds are also biologically active that are used as drugs and diagnostic aids [1]. Over the quite a long while, various synthetic strategies have been portrayed for their preparation [2]. Among these, in the course of the most recent decade, a significantly utilized methodology employs tert-butyl nitrite (TBN) as a radical nitrating agent [3]. Despite works in acid- and additive-free conditions [3], TBN remains associated with many obstacles; for example, extremely flammable (flash point: −10 °C), highly volatile (bp: 59–62 °C), required large quantity (2–5 equivalence) and on inward breath show harmful impacts on the cardiovascular systems and focal nervous systems (see: hazard statements and signal word for TBN) [1], [1](a), [1](b), [1](c), [2], [2](a), [2](b), [2](c), [2](d), [2](e), [2](f), [2](g), [2](h), [2](i), [2](j), [2](k), [2](l), [2](m), [2](n), [2](o), [2](p), [2](q), [2](r), [2](s), [2](t), [2](u), [2](v), [3], [3](a), [3](b), [3](c), [3](d), [3](e), [3](f), [3](g), [3](h), [3](i), [3](j), [3](k), [3](l), [3](m), [3](n). Moreover, in large-scale reactions, one of the TBN’s byproducts, i.e., tert-butanol entangles the product separation and poses crucial ecological concerns [3]. As an outcome, the advancement of a practical and environmentally benign derivative would supplant TBN is a challenging area for investigation.
Ionic liquids are low flammable, non-volatile, possess excellent thermal- and chemical stabilities, have great solvating capability, exhibit wide liquid range and simplicity of recycling [4]. They are additionally known to have influences on the reaction rate, selectivity, etc. [4a]. After their successful use in various chemical and enzymatic reactions, Davis and coworkers [5] presented an idea of task-specific ionic liquids (TSILs) in which a functional group is covalently tethered to the cation or anion of the ionic fluid to carry not only as a solvent but also as reagent and/or catalyst in the chemical reactions [6]. Afterwards, a few TSILs were created and utilized as solvents and reagents or catalysts in Diels-Alder reactions [7], Friedel-Crafts reactions [8], transition metal-catalyzed reactions [9] and so forth. Nevertheless, to the best of our knowledge, the use of a task-specific ionic liquid in general and a task-specific nitrite-based ionic liquid [10] in particular for the synthesis of nitro-group-containing arenes and drugs has not yet been accounted.
In continuation of our ongoing works on the utilization of ionic fluids in organic synthesis [11], herein, for the first time; we report that a new task-specific nitrite-based ionic liquid such as 3-(ethoxycarbonyl)-1-(5-methyl-5-(nitrosooxy)hexyl)pyridin-1-ium bis(trifluoromethanesulfonyl)imides (TS-N-IL, Scheme 1) derived from biodegradable ethyl nicotinate in fact acted as an efficient and eco-friendly reagent for the synthesis of exceptionally important nitroaromatic compounds and drugs including nitroxynil, tolcapone, niclofolan, flutamide, niclosamide and nitrazepam (Scheme 1). Nonvolatile nature, easy synthesis, merely stoichiometric need and mildness are few advantages of TS-N-IL while contrasted with tert-butyl nitrite a well-known and a toxic reagent utilized in organic synthesis.
Section snippets
Results and discussion
The nitrite functionalized ionic liquid, i.e., TS-N-IL was prepared in three steps by i) alkylation of ethyl nicotinate with 6-bromo-2-methylhexan-2-yl acetate at reflux temperature, ii) nitrification of resultant ionic liquid (IL, Scheme 2) with aqueous NaNO2 and HCl at 0 °C and iii) anion exchange with lithium trifluoromethylsulfonimide, cf. Scheme 2. The synthesized TS-N-IL was characterized by FT-IR, NMR, TGA, DSC and elemental analysis, cf. Electronic Supporting Information (ESI). The IR
Conclusion
In contrast to TBN, a novel TS-N-IL has observed to be nonvolatile, less flammable, required only stoichiometric amount, highly efficient, good functional group tolerance, affords mono-nitration products exclusively, and stable up to 150 °C. In addition, the byproduct (IL) is reusable and immiscible with molecular solvents that disentangle the workup procedure and increase the product yield due to absence of watery workup. Moreover, nicconinate-based ionic fluids are known to degrade within
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Acknowledgements
The authors gratefully acknowledge the financial support from Council of Industrial Scientific Research (CSIR), New Delhi, India, through extra mutual research grant with a project number 02(0380)/19/EMR-II.
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