Uses
2-Hydroxy-6-methyl-5-nitropyridine is a versatile building block that can be used to create a range of compounds, such as 5-Bromo-2-methylbenzaldehyde, 1-(5-Bromo-2-methylphenyl)ethanone, etc.
Reactions
5-Bromo-2-methylbenzonitrile is a substrate for the enzyme benzoate kinase and is used as an intermediate in the synthesis of cyclen. It can be activated by addition of acid, which leads to a rapid increase in the rate of reaction. The kinetic data for this reaction have been analyzed and show that it obeys first order kinetics with respect to both 5-bromo-2-methylbenzonitrile and benzoic acid. This reaction is also catalyzed by an analog of cyclen, which binds to the enzyme more tightly than 5-bromo-2-methylbenzonitrile, resulting in a higher activation energy. It is possible to analyze the kinetics of this reaction using agarose gel electrophoresis or supercoiled DNA analysis.
Synthesis
General procedure for the synthesis of 5-bromo-2-methylbenzonitrile from 2-methyl-5-aminobenzonitrile:
Example 22: To a flask was added water (13.5 mL), HBr (74%, 14.4 mL), and 5-amino-2-methylbenzonitrile (2.0 g, 15.1 mmol) dissolved in water (24 mL). The mixture was heated to 50 °C and kept for 20 min. Subsequently, the mixture was cooled to 0-5 °C and an aqueous solution of NaNO2 (1.2 g, 17.4 mmol) was added. The reaction mixture was stirred at 0-5 °C for 10 min and then warmed up to 40 °C. Next, a solution of CuBr (6.5 g, 45.1 mmol) in water (36 mL) and HBr (7.2 mL) was added. The mixture was refluxed for 2 hours. After completion of the reaction, the mixture was extracted with ethyl acetate (AcOEt) and the organic layer was washed sequentially with saturated NaHCO3 solution and brine and dried with Na2SO4. The crude product was purified by column chromatography (petroleum ether:ethyl acetate = 50:1) to give 2.3 g of 5-bromo-2-methylbenzonitrile as a white solid (yield: 77%).
1H NMR (400 MHz, CDCl3) δ 7.72 (s, 1H), 7.59 (d, J = 8.0 Hz, 1H), 7.19 (d, J = 8.0 Hz, 1H), 2.51 (s, 3H).
References
[1] Patent: US2009/203657, 2009, A1. Location in patent: Page/Page column 48
[2] Patent: US2009/203677, 2009, A1. Location in patent: Page/Page column 51
[3] Patent: US2009/197871, 2009, A1. Location in patent: Page/Page column 50-51
[4] Patent: WO2005/97750, 2005, A1. Location in patent: Page/Page column 69
[5] Patent: WO2009/100169, 2009, A1. Location in patent: Page/Page column 127
