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A Highly Efficient, Metal-Free, Heterogeneous Catalyst For Article OSU-6: A Highly Efficient, Metal-Free, Heterogeneous Catalyst for the Click Synthesis of 5-Benzyl and 5-Aryl-1H-tetrazoles Baskar Nammalwar, Nagendra Prasad Muddala, Rajasekar Pitchimani and Richard A. Bunce * Received: 18 November 2015; Accepted: 11 December 2015; Published: 19 December 2015 Academic Editor: Derek J. McPhee Department of Chemistry, Oklahoma State University, Stillwater, OK 74078-3071, USA; [email protected] (B.N.); [email protected] (N.P.M.); [email protected] (R.P.) * Correspondence: [email protected]; Tel.: +1-405-744-5952; Fax: +1-405-744-6007 Abstract: OSU-6, an MCM-41 type hexagonal mesoporous silica with mild Brönsted acid properties, has been used as an efficient, metal-free, heterogeneous catalyst for the click synthesis of 5-benzyl and 5-aryl-1H-tetrazoles from nitriles in DMF at 90 ˝C. This catalyst offers advantages including ease of operation, milder conditions, high yields, and reusability. Studies are presented that demonstrate the robust nature of the catalyst under the optimized reaction conditions. OSU-6 promotes the 1,3-dipolar addition of azides to nitriles without significant degradation or clogging of the nanoporous structure. The catalyst can be reused up to five times without a significant reduction in yield, and it does not require treatment with acid between reactions. Keywords: 5-benzyl and 5-aryl-1H-tetrazoles; carboxylic acid bioisosteres; click 1,3-dipolar addition; heterogeneous catalysis; recyclable catalyst 1. Introduction Tetrazoles are versatile heterocyclic systems, which have attracted considerable interest in diverse applications ranging from pharmaceuticals [1–3] and agrochemicals [4] to photographic compounds [5], explosives [6], new materials [7–9], and ligands in coordination compounds [10,11]. In biological studies, tetrazoles play a critical role as pharmacophores and also as metabolic surrogates for carboxylic acids in various therapeutic agents to treat cancer, AIDS, bacterial infections, hypertension, convulsions, and allergies [12,13]. Currently, the commercial antihypertensives Losartan and Valsartan [14] as well as an experimental 2-arylcarbapenem antibiotic [15] all incorporate a tetrazole ring within their structures. Tetrazoles have been synthesized primarily by the reaction of azides with nitriles in polar aprotic media. This process has been promoted by various metal-based agents, including aluminum chloride, aluminum bisulfate, cadmium chloride, copper-, zinc- and iron-based salts, copper delafossite nanoparticles, palladium complexes, silver benzoate, metal-based triflates, tungstates, zinc-copper alloys, and zinc sulfate nanospheres [16,17]. Additionally, other heterogeneous catalysts, including CoY zeolites [18,19], SiO2–H2SO4 [20], Amberlyst-15 [21], and cuttlebone [22], as well as soluble additives NH4OAc and NH4Cl [23,24] have also been used to facilitate this reaction. We therefore wish to report a new catalyst which performs this conversion under metal-free conditions, at moderate temperatures, and with superior conversion rates, stability toward traces of water, and recyclability. 2. Results and Discussion OSU-6, an MCM-41 type hexagonal mesoporous silica [25], has recently proven useful as a mildly acidic, reusable catalyst for several transformations in our laboratory, affording products in excellent yields with minimal purification requirements [26–28]. Encouraged by these results, we sought to Molecules 2015, 20, 22757–22766; doi:10.3390/molecules201219881 www.mdpi.com/journal/molecules Molecules 2015, 20, page–page Molecules 2015, 20, 22757–22766 2. Results and Discussion OSU-6, an MCM-41 type hexagonal mesoporous silica [25], has recently proven useful as a exploremildly OSU-6 acidic, as areusable catalyst catalyst for the for click several synthesis transformations of tetrazoles in our from laboratory, azide and affording nitriles [products29,30]. In in order to gaugeexcellent the yields feasibility with ofminimal this process, purification the requir reactionements of benzyl[26–28]. cyanideEncouraged (1a ,by 1 equiv.)these results, with we sodium azidesought (1.2 equiv.) to explore to OSU-6 generate as a catalyst 5-benzyl-1 for theH-tetrazole click synthesis (2a) of was tetrazoles chosen from as azide a model and nitriles reaction. [29,30]. Various solventsIn order were to gauge evaluated the feasibility using 15of this wt pr %ocess, of the the catalyst reaction (relativeof benzyl cyanide to 1a) under(1a, 1 equiv.) varying with temperature sodium azide (1.2 equiv.) to generate 5-benzyl-1H-tetrazole (2a) was chosen as a model reaction. Various conditions (Table1). Our optimization study determined that the reaction performed in DMF solvent solvents were evaluated using 15 wt % of the catalyst (relative to 1a) under varying temperature at 90 ˝C using 15 wt % of OSU-6, afforded the highest yield (94%) of the tetrazole product. More conditions (Table 1). Our optimization study determined that the reaction performed in DMF solvent or lessat 90 catalyst °C using did 15 wt not % improve of OSU-6, theafforded yields, the andhighes lowert yield temperatures (94%) of the tetrazole led to product. inefficient More conversions. or less In general,catalyst polardid not aprotic improve media the yields, gave and superior lower temperat resultsures since led they to inefficient solubilized conversions. both reacting In general, partners ˝ at temperaturespolar aprotic media¥90 C.gavePolar superior protic results and since nonpolar they solubilized media, on both the reacting other hand,partners led at totemperatures unsatisfactory outcomes.≥90 °C. SolventlessPolar protic and conditions nonpolar affordedmedia, on reasonablethe other hand, conversions led to unsatisfactory for the model outcomes. reaction, Solventless but were not practicalconditions for afforded solid nitriles, reasonable and conversions the requisite for higherthe model temperatures reaction, but led were to greaternot practical impurity for solid profiles. Earliernitriles, syntheses and the [23 requisite,31] generally higher temperatures utilized reaction led to greater temperatures impurity of profiles. 120–150 Earlier˝C forsyntheses this reaction, [23,31] and thus,generally the conditions utilized employed reaction temperatures in this work of are 120–150 somewhat °C for milder. this reaction, and thus, the conditions employed in this work are somewhat milder. Table 1. Reaction optimization. Table 1. Reaction optimization. Entry Solvent OSU-6 (wtOSU-6 %) Temperature (oC) Time (h) Isolated Yield (%) Entry Solvent Temperature (oC) Time (h) Isolated Yield (%) EtOH 15(wt %) 90 12 trace EtOH 15 90 12 trace 2 CH3CN 15 90 24 18 23 dioxaneCH3CN 1515 9590 1824 trace18 34 THFdioxane 1515 7095 1818 trace 10 45 solventlessTHF 1515 12070 618 7610 56 DMSOsolventless 1515 140120 66 8476 67 DMFDMSO 5015 120140 66 8884 78 DMFDMF 2550 120120 66 8788 9 DMF 15 120 6 90 8 DMF 25 120 6 87 10 a DMF 15 90 4 94 9 DMF 15 120 6 90 11 DMF 15 75 6 10 a 1012 DMFDMF 1015 9090 64 7394 1113 DMFDMF 015 12075 126 trace10 12 DMF 10 90 6 73 a Optimized conditions. 13 DMF 0 120 12 trace a Optimized conditions. Based on our preliminary findings, we now report our investigation of this catalyst for the synthesisBased of 5-benzyl- on our preliminary and 5-aryl-1 findings,H-tetrazoles we now report using our a investigation click approach. of this catalyst The optimized for the synthesis conditions (15 wtof %5-benzyl- OSU-6, and DMF, 5-aryl-1 90 ˝C,H 4–12-tetrazoles h) proved using generala click approach. for promoting The optimized the conversion conditions of benzyl (15 wt and % aryl nitrilesOSU-6, to tetrazoles. DMF, 90 °C, In addition4–12 h) proved to the general parent for systems, promoting substrate the conversion derivatives of benzyl bearing and methyl, aryl nitriles methoxy, fluoro,to tetrazoles. chloro, nitro, In addition and 3-butenyl to the parent moieties systems, were substrate evaluated, derivatives and the bearing results methyl, are summarized methoxy, fluoro, in Table 2. All ofchloro, these nitro, groups and survived 3-butenyl the moieties reaction were conditions evaluated, andand the gave results high are yields summarized of products, in Table regardless 2. All of theirof electronic these groups character survived or positionthe reaction on conditions the ring, thus and demonstratinggave high yields theof products, general applicabilityregardless of their of OSU-6 electronic character or position on the ring, thus demonstrating the general applicability of OSU-6 in in this transformation. Furthermore, in the conversion of 4-(3-butenyl)benzonitrile (1p) to tetrazole this transformation. Furthermore, in the conversion of 4-(3-butenyl)benzonitrile (1p) to tetrazole 2p, 2p, thethe reactionreaction showedshowed excellent excellent chemoselectivity chemoselectivity for forthe the nitrile nitrile over over the theterminal terminal alkene. alkene. Finally, Finally, attemptsattempts to react to react aliphatic aliphatic nitriles nitriles lacking lacking aromaticaromatic substitution substitution gave gave incomplete incomplete conversion conversion to the to the targettarget tetrazoles tetrazoles and and unacceptable unacceptable impurity impurity levelslevels under our our conditions. conditions. 2 22758 Molecules 2015, 20, page–page Molecules 2015, 20, 22757–22766 Table 2. Synthesis of tetrazoles. Molecules 2015, 20, page–page Table 2. Synthesis of tetrazoles. Table 2. Synthesis of tetrazoles. Substrate R Product Time (h) Isolated Yield (%) 1a C6H5CH2 2a 4 94 Substrate1b Substrate 4-CH3CR6 RH4CH2 ProductProduct2b
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