Maybe it’s because I just finished Jobs…”the Iconic and Mysterious Steve Jobs” or perhaps I spent many years using different techniques and transformations to construct and substitute quinoline analog after analog. Yes, tis’ true I am an Apple devotee…from my days with the classic and Macintosh to my trusty MacBook Pro….and I also like to know the history of the heterocycle that I am going to bond with, call it the art in synthesis…I don’t know.

Attributed to Czech chemist, Zdenko Skraup, the formation of the quinoline ring system is a unique example of atom economy and also as an extremely aggressive or violent reaction…..love it. A number of variations of the scheme below have been used to place substitution patterns on the fused system.

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Skraup Reaction

As affectionate as I am with the original scheme, the use of copious quantities of sulfuric acid generally makes most chemist frown….I too want to protect that new pair of jeans, ha! But seriously, metal catalysts and Lewis acids have replaced the traditional reaction conditions for all practical purposes. Although not terribly new, two improvements suggest we have gotten better at finding better ways to make this system and here’s the recipe: substituted anilines, vinyl ketone, SiO2-impregnated with InCl3 and some microwave irradition (no solvent and no H2SO4).

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Skraup, mw 150C, no solvent

Since this is atypical to what people normally do, I wanted to add some of the notes from the paper (Tetrahedron 2003). The InCl3 is adsorbed in THF on SiO2 with heating for 3 hrs at 150C followed by stipping off the solvent. The remaining solid is mixed with the aniline and vinyl ketone and subjected to microwave heating at 600W for 2 intervals of 10 mins in a domestic oven (high yields across the board). Part of the table in the publication is shown below as well as a second scheme modifying starting materials to obtain dihydroquinolines. Certainly the concept would be useful in other ring constructions, eh?

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Skraup Reaction under solvent-free mw conditions

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dihydroquinolines under mw conditions

Although the process does help innovate I don’t suggest open flask domestic oven reactions. Many of these papers are difficult to repeat without more control. This particular publication may not suffer from this process, but many adsorbed catalysts of this nature don’t measure up to what we would want to do, partly because there is not reflection of the material absorbing the microwave power and if you don’t control the mixing, often hot-spots can be uncontrolled and provide a mess, or worse an unsafe environment. There are several reactors that address mixing issues with solids –of course, I would have probably done something modified after reading this because it begs to be looked at.

 

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