4-methylquinoline oxidation really works

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Review:

This article/communication described the preapration of 2 and 4-quinolinecarboxaldehyde using 2 and 4-methylquinoline in the presence of selenous acid in refluxing dioxane. While the procedure explicitly stated the use of selenous acid, selenium dioxide can also be used in lieu of selenous acid since the author reported that both oxidants gave similar high-yield results of quinoline aldehydes. For my synthetic work, I used selenium dioxide.

I find the paper outstanding in the merits of innovation, clarity, and reproducibility. The paper is innovative because it described the direct conversion of 4-methylquinoline to 4-quinoline aldehyde (which I need in my research) in high yields. To substantiate this claim, I started small scale reactions (300-750 mg starting material) and I would obtain yields within the range of what the paper reported for 4-quinoline aldehyde. In larger scale, the reaction procedure described is reproducible. I frequently prepared 10-20 gram reaction (4-methylquinoline) on several occasions, and remarkably, I would get reproducible yields (70-73%) for each reaction.

There were some interesting notes I would like to address, and all of these were related in terms of using 4-methylquinoline as reactant. I have not used the reported procedure in the synthesis of 2-quinoline aldehyde. First, an excess oxidant was necessary to achieve product conversion. This was shown from my small and large-scale up syntheses. Second, in terms of refluxing time, a low yield of product can be obtained within 2-3-hours of reflux (33-40%) while optimal product yields are obtained when refluxed overnight. Third, I did not see any formation of 4-quinoline carboxylic acid in the reaction (based in TLC), but rather two distinct spots (product and starting material). Fourth, neutralization was not performed since no carboxylic acids were observed, and so after filtering off Se and rotovaping dioxane, the crude oil was directly purified by column chromatography (7:3, EtOAc/hexanes). Lastly, it was very interesting that this procedure only worked for 4-methylquinolines. Since I worked with quinolines, I also explored this procedure with 3, 6, and 7-methylquinolines. In all cases, no reaction was observed under the reported conditions. To utilize selenium oxidation for these compounds, modification of the procedure was done. For 3 and 7-methylquinolines (500 mg - 1g), a microwave (220-240 degrees) was needed to obtain modest yields of 3 and 7-quinoline aldehydes (39-60%) where 3-methylquinoline was more unreactive. For 6-methylquinoline (2-5 grams), the use of dioxane was not needed to geenrate the desired product (80-92%) but it required higher temperature (160-165 degrees).

In conclusion, I strongly believe the accuracy of the paper in terms of the preparation of 4-quinolinecarboxaldehyde from 4-methylquinoline using selenium dioxde in refluxing dioxane.



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