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Adding a certain compound to certain chemical reactions, such as: 19847-12-2, name is Pyrazinecarbonitrile, belongs to Pyrazines compound, can increase the reaction rate and produce products with better performance than those obtained under traditional synthetic methods. Here is a downstream synthesis route of the compound 19847-12-2, Formula: C5H3N3
In order to expand the scope of this flow method, a variety of nitriles were subjected to the optimized conditions in the entry 6 (Table 1), and the results are summarized in Tables 3 and 4 {Method A). For substrates 2 and 3, where no electron- donating or electron- withdrawing group was present on the aromatic ring, or substrate 4 where the nitrile was rendered electron poor by the presence of electron- withdrawing group at the para position, the reactions proceeded to 100% conversions without the formation of any side product. Similarly, meta tolunitrile (5) and the hetero aromatic substrates (6-8) also showed excellent conversions. Electron rich nitriles 10 and 10 reacted to give moderate but clean conversions to the corresponding tetrazoles. The biphenyl nitriles 9, 13 and 14 also proved to be good substrates for this reaction regardless of position of the phenolic hydroxy group on the second aromatic ring.Notably, chiral nitrile 15 provided 15a, a derivative of which (no CBZ group) has found utility as an organocatalyst, in > 99% ee and 92% yield based on conversion. To test if an increase in the ? can drive the reaction of moderately yielding substrates to completion, the model substrate 1 was reacted at a ? of 30 min (Table 4). There was no significant change in the conversion observed; instead a small amount of hydrolysis product la was formed. However, significant improvement in the reaction rate was observed by doubling the concentration of the reaction (0.4 M). For nitrile 1, the conversion increased from 65% to 81% (? = 30 min), while similar improvement in conversions were observed for substrates 11 and 13-15 when the reaction concentration was doubled.As this continuous flow method has the advantage of using high temperatures in a safe manner, it was determined that the presence of a catalyst (e.g., ZnBr2) was not essential for all reactions carried out at these temperatures. To test this, the flow process was repeated with selected substrates without the use of ZnBr2 (Tables 3 and 4, Method B). The non- substituted benzo- and napthonitrile substrates (2 and 3), electron poor nitrile (4), and the heterocyclic substrates (6, 7 and 8), all showed excellent conversions to corresponding tetrazoles in the absence of ZnBr2. The conversions were found to decrease moderately in case of biphenyl substrates 9, 13 and 14 indicating decrease in the reaction rate of these substrates in the absence of ZnBr2. Similar decrease in conversion was observed for the electron rich substrates (1 and 12), but it was noted that there was no side product observed in the absence of ZnBr2 even at 30 min of residence time. This shows that ZnBr2 may be promoting the competing side reaction. Thus, the use of ZnBr2 may be useful for enhancing the conversion of the electron-rich nitriles, but can also lead to formation of side product. In many, if not all instances, reactions without ZnBr2 can give clean conversions. To demonstrate the scale-up capabilities of this, the synthesis of 3a was carried out using aUniqsis FlowSyn continuous flow reactor. FlowSyn is an integrated continuous flow reactor system that uses a pair of high pressure pumps to deliver reagent solutions through a ‘T’-mixer into the electrically heated flow coil or column reactors. The homogenous solution of reagents ([3] = 1M; [NaN3] = 1.05 M) in NMP:H20 (7:3) was pumped using a single pump through a coiled PFA tubing reactor (volume of heated zone ~ 6.9 mL) with a flow rate of 0.35 mL/min (tr = 20 min) at 190 C (see Example 2). The flow process was run continuously for 2.5 h to obtain 9.7 g of 3a in 96 % yield. This corresponds to a product output of 4.85 g/h or 116 g/day for the tetrazole 3a.Overall, the method performed is a safer alternative for currently used methods to synthesize 5-substituted tetrazoles as the hazards due to accumulation and condensation of HN3 are greatly minimized. Only uses a slight excess of NaN3 (1.05 equiv) was used, and hence the production of azide waste is minimal. The method is highly efficient and clean, and works for a wide range of substrates. In case of substrates where the reaction does not go to completion, the remaining NaN3 in the reaction can be quenched by introducing streams of sodium nitrite and sulfuric acid after the reaction is complete. The incorporation of this quenching procedure increases the overall safety of the process. Therefore, given the widespread applications of tetrazoles in chemical andpharmaceutical industry, this method can serve as a safe and highly efficient alternative for synthesis of tetrazoles.EXAMPLE 2This example provides additional experimental details and data in connection with Example 1.General protocol for continuous flow synthesis of tetrazoles (Method A):Sodium azide (68 mg, 1.05 mmol) was added to a solution of zinc bromide (111 mg, 0.5 mmol) in 0.5 mL water. To this solution was added the nitrile substrate (1 mmol) dissolved in 4.5 mL of N-methylpyrrolidone (NMP) and the result…
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Reference:
Patent; MASSACHUSETTS INSTITUTE OF TECHNOLOGY; JAMISON, Timothy, F.; PALDE, Prakash, B.; WO2012/24495; (2012); A1;,
Pyrazine – Wikipedia,
Pyrazine | C4H4N2 – PubChem