Pyridine structures widely exist in bioactive molecules and drug molecules, so functionalization of pyridine C–H bonds is the key to expand the diversity of related molecular libraries. Among them, the regioselective C–H bond halogenation of pyridine is crucial because many subsequent bonding reactions can be achieved after the installation of a carbon–halogen (C–Hal) bond. In addition, in the research of pharmaceutical and agricultural chemistry, halogenated pyridines are key intermediates of various candidate compounds, which can be used for structure-activity relationship research and targeted synthesis. There are great limitations in the halogenation reaction of pyridine, especially the meta-substitution of pyridine is often incompatible with many biologically active substrates. Another method for the meta-halogenation of pyridines is a metallation-halogenation sequence under strong basic conditions, but most require directing groups.
Recently, through the reaction sequence of pyridine ring opening, halogenation and ring closure, the researchers realized the highly regioselective halogenation reaction of pyridine via the acyclic Zincke imine intermediate in one step (Figure 1), and successfully prepared a series of 3-halopyridines. The key to this reaction is the temporary conversion of pyridines from electron-deficient heterocycles to a series of polarized alkenes that can undergo electrophilic substitution reactions with halogen reagents.
Figure 1. Importance of pyridine halogenation and strategies based on ring-opening intermediates.
The researchers investigated a series of aliphatic amines using 2-phenylpyridine as a model substrate, and the results showed that dibenzylamine had the best reaction effect, and Zincke imine could be obtained with an isolated yield of 86%. Secondly, the reaction between Zincke imine and halogen electrophile was explored. When Zincke imine reacted with NIS at room temperature for 5 min, 92% of the product was observed in 1H NMR spectrum with 3- vs. 5-selectivity>20:1. Subsequently, the researchers studied the ring-closing conditions, and the results showed that 3-iodopyridine could be formed by reacting imine and ammonium acetate in a mixed solvent of EtOAc/EtOH at 60 °C. On the other hand, the Zincke imine obtained by ring opening of 3-phenylpyridine cannot react with NIS at room temperature, and will decompose into unknown by-products when heated to 50 °C. However, after adding TFA to it, iodopyridine can be obtained in a better yield, which may be due to the fact that TFA can promote the isomerization-cyclization process of olefins.
The researchers next used quantum chemistry to study the reaction mechanism and regioselectivity of electrophilic halogenation, and found that the most favorable route for Zincke imine halogenation is electrophilic addition (TS-I) followed by deprotonation (TS-II), and the calculation results exclude the outer electron transfer process (ΔG > 34 kcal/mol).
The researchers also investigated the range of substrates, and the results showed that 2-position aryl, alkyl and acetal, 3-position n-butyl, aryl, fluorine atom and trifluoromethyl, 4-position benzyl, 2 ,3-, 2,4- and 2,5-disubstituted pyridines and even pyrimidines are compatible with this reaction, and the desired products are obtained in moderate to good yields.
Finally, the researchers explored the halogenation reactions of complex drug-like intermediates, drug molecules, and agrochemicals, and the results showed that the five polycyclic substrates of drug-like intermediates can be efficiently halogenated and a single halogenated product is obtained. Substituted quinolines containing sulphonolactams were brominated again at the C6 position. In addition, the researchers also carried out post-halogenation of drug molecules and agrochemicals, and obtained the corresponding products in good yields.
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Reference
- Halogenation of the 3-position of pyridines through Zincke imine intermediates.
Benjamin T. Boyle, Jeffrey N. Levy, Louis de Lescure, Robert S. Paton, Andrew McNally
