Many chemists naturally choose polar solvents to dissolve polar heterocyclic compounds for N-alkylations, especially when the ratio of nitrogen and oxygen atoms is high relative to the number of carbon atoms in the molecule. Such is the case in the N-alkylation of pyridazinone shown in the reaction diagram.
In this publication, the inventors performed N-alkylation of N-2(H) pyridazinone with a variety of alkylating agents including 3-chloromtheyl thiophene, 1-chloro-1-phenylethane and 4-chloromethyl-1,2-diphenylethane. The inventors chose acetonitrile as the solvent in all of these N-alkylations. The workup for these reactions started with evaporating the acetonitrile, then treating the residue with water and methylene chloride. These reactions were performed on a scale of 50-100 mg.
The inventors were obviously familiar with phase-transfer catalysis because they used 5 mole% TBAB to catalyze these reactions. Chemists who are aware enough of PTC to use TBAB should be also be aware that solid-liquid PTC conditions are often used for N-alkylation of heterocycles, including many PTC N-alkylations that use potassium carbonate as base, just like the inventors used.
When solid-liquid PTC is used for N-alkylations, especially when using potassium carbonate a base, the choice of solvent is most often a non-polar solvent that forms two phases with water and is inert in the presence of the N-anion that is formed. The advantage of choosing a non-polar solvent is that during workup, you can dissolve the byproduct salt(s) in water and maintain the organic product in the organic phase.
When using a solvent like acetonitrile that is miscible in water, there are extra unit operations in order to avoid entrainment of the product in a water-acetonitrile matrix. In this case, the inventors evaporated the solvent and had to treat the residue. Such unit operations, that often result in handling losses, would be unnecessary if a nonpolar solvent was used in the reaction.
Some chemists may fear that the N-anion (deprotonated heterocycle) will not be soluble in a nonpolar solvent and therefore would not be available to react with the alkylating agent. The purpose of highlighting this reaction here is to remind chemists that the quaternary ammonium cation, such as tetrabutylammonium, contains many carbons and imparts organophilicity to the ion pair consisting of the quat cation and the N-anion. In other words the quat-N-anion ion pair will be transferred into the reaction phase where it should successfully react with the alkylating agent.
The fact that the product dissolves in methylene chloride (that is immiscible with water) should be enough of a clue to know that a suitable nonpolar water-immiscible solvent can be chosen that will facilitate both the reaction and the workup.
I have been performing PTC N-alkylations for more than 40 years and it is sometimes frustrating to see chemists choose solvents that make workup harder than it should be. Then again, if everyone knew how to choose PTC process conditions, my company, PTC Organics Inc., would have less business.
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