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3-Selective Pyridine Halogenation via Zincke Imine Intermediates

21 July 2025

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Halogenation of pyridines is of critical importance in the development of pharmaceuticals and agrochemicals, as the introduction of halogen atoms can enable a wide range of subsequent bond-forming transformations. However, achieving selective halogenation at the 3-position of pyridine remains a significant challenge. Existing methods often suffer from harsh reaction conditions, require directing groups, or exhibit poor compatibility with functional groups.
Common strategies for halogenation at the 3-position of pyridine include:

1. Direct bromination: This typically proceeds via electrophilic substitution. However, due to the electron-deficient nature of the pyridine ring, the reaction often requires relatively harsh conditions. Although this method can offer selectivity for the 3-position, the formation of substitution products at other positions is still possible.

2. Metal–halogen exchange: This approach generally relies on the presence of a directing group within the substrate molecule to facilitate regioselectivity.

3. 3-Position activation followed by halogenation: In this strategy, the 3-position is first selectively activated through highly regioselective transformations, followed by halogenation. An example is iridium-catalyzed borylation, which enables the selective functionalization of the 3-position before halogen introduction.

Figure 1. A. Value of halogenated pyridines in pharmaceutical and agrochemical development. B. Pyridine C3-halogenation via Zincke imine intermediates. C. Zincke ring-opening study under mild reaction conditions.

In 1903, Thodor Zincke first reported that pyridinium salts, when attacked by nucleophiles such as aliphatic or aromatic amines, could undergo ring-opening to form N-aryl or N-alkyl pyridinium salts—a reaction that was later named the Zincke reaction. In 2022, Paton and McNally cleverly exploited the ring-opening intermediate of this reaction, known as a Zincke imine, to achieve site-selective halogenation at the 3-position of pyridine under mild conditions, successfully obtaining the corresponding halogenated products. Their work was published in Science.
Typically, the Zincke ring-opening reaction of pyridines requires relatively harsh conditions, and the transformation becomes particularly challenging when a substituent is present at the 2-position of the pyridine ring. However, when using the strong electrophilic reagent trifluoromethanesulfonic anhydride (Tf2O), the corresponding Zincke imine intermediates can be smoothly obtained under mild conditions, even in the presence of a 2-substituent, except in the case of 2,6-disubstituted pyridine.
Upon screening various nucleophilic amines, dibenzylamine was identified as the optimal choice, affording a stable Zincke imine intermediate (compound 2-6) in 86% isolated yield.
Halogenation reactions were subsequently explored using Zincke imine intermediates derived from either 2-phenyl- or 3-phenyl-substituted pyridines. For the 2-substituted intermediates, the addition of halogenating agents (NXC) led to the rapid formation of the corresponding halogenated products. Among these, iodinated products showed the highest selectivity (>20:1), while the selectivity of brominated products was influenced by the solvent and reaction temperature. Chlorinated products exhibited relatively lower selectivity. Following halogenation, cyclization could be efficiently achieved by heating the reaction mixture in the presence of ammonium acetate.
In contrast, for 3-substituted Zincke imine intermediates, activation with 2 equivalents of trifluoroacetic acid (TFA) was necessary for the halogenation to proceed. Under these conditions, N-iodosuccinimide (NIS) gave the highest efficiency, and both halogenation and cyclization occurred in a single step without requiring an additional cyclization step. Furthermore, a one-pot protocol combining pyridine ring-opening, Zincke imine halogenation, and cyclization was successfully developed, affording the desired product in excellent yield.

Figure 2. A/B. Halogenation of 2/3-substituted Zincke imines. C. One-pot pyridine halogenation protocols.

Then, in 2025, McNally reported a method for selective fluorination of the 3-position of pyridine through a Zincke imine intermediate. Fluorination is a common method to improve the properties of drugs containing aromatic rings, especially pyridine rings, because the C-F bond has a significant effect on the pharmacokinetic and pharmacodynamic (PKPD) properties of drugs. McNally's team used Selectfluor or NFSI as a fluorination reagent to achieve the synthesis of 3-fluoropyridine with high regioselectivity. For example, using Selectfluor as a fluorination reagent in methanol and Na2CO3 as a base, fluorination of pyridine at the 3-position was successfully achieved with a yield of 68%; using NFSI as a fluorination reagent in TFE, the yield of fluorination of pyridine at the 3-position reached 71%.

Figure 3. Optimization of reaction conditions for 3-fluorination of 2-substituted Zincke imines

Figure 4. Optimization of reaction conditions for 3-fluorination of 3-substituted Zincke imines

This study presents a novel and efficient method for halogenation at the C3 position of pyridine, overcoming the limitations of traditional approaches and offering a new pathway for the synthesis of pyridine derivatives in drug and agrochemical development. The high regioselectivity, mild reaction conditions, and compatibility with complex molecular structures endow this method with broad application potential.

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References

[1]Hart M A, Uhlenbruck B J H, Levy J N, et al. 3-Selective Pyridine Fluorination via Zincke Imine Intermediates. J. Am. Chem. Soc. 2025, 147(22), 18406-18411.

[2]Boyle B T, Levy J N, de Lescure L, et al. Halogenation of the 3-position of pyridines through Zincke imine intermediates. Science 2022, 378(6621), 773-779.

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