Skraup dihydroquinoline synthesis

A number of dihydroquinolines have been prepared by treating aniline derivatives with acetone or mesityl oxide in the presence of iodine. In these cases aromatization to the fully unsaturated quinoline would require the loss of methane, a process known as the Riehm quinoline synthesis. Such Skraup/Doebner-von Miller-type reactions are often low yielding due to large amounts of competing polymerization. For example, aniline 37 reacts with mesityl oxide to give dihydroquinolines 39, albeit in low yield. ... 

The initial product is a dihydroquinoline it is formed via Michael-like addition, then an electrophilic aromatic substitution that is facilitated by the electron-donating amine function. A mild oxidizing agent is required to form the aromatic quinoline. The Skraup synthesis can be used with substituted anilines, provided these substituents are not strongly electron withdrawing and are not acid sensitive. 

Bismuth triflate catalyzes the synthesis of 1,2-dihydroquinolines in an improved version of Skraup s procedure [74]. Accordingly, treatment of aniline with... 

The use of Sc(OTf)3 as the catalyst facilitated the Skraup synthesis of 1,2-dihydroquinolines from anilines and a variety of dialkyl ketones at mild conditions (room temperature). Nevertheless, an elevated temperature was necessary if acetophenone was employed in the cyclo condensation with anilines [109]. Microwave dielectric heating at 150 °C for 50 min was sufficient to bring about the formation of the desired 1,2-dihydroisoquinolines (Scheme 40). 

Scheme 40 Microwave-promoted Skraup synthesis of 1,2-dihydroquinolines...

Nitro compounds in alkaline medium are used for rather specific oxidations. 2-Nitropropane in the form of its sodium salt converts benzylic halides into aromatic aldehydes under fairly mild conditions [987. Nitrobenzene transforms isoeugenol [95S] and similar aromatic compounds with side chains that contain double bonds conjugated with the aromatic rings into aldehydes [988, 989], In the Skraup synthesis, nitrobenzene dehydrogenates the dihydroquinoline intermediate to quinoline. 

Quinolines are often prepared by the Skraup synthesis, in which an aniline reacts with an a. -unsaturated aldehyde and the dihydroquinoline product is oxidized. Suggest a mechanism. 

Theoclitou, M.-E., Robinson, L. A. Novel facile synthesis of 2,2,4-substituted-1,2-dihydroquinolines via a modified Skraup reaction. 

In the synthesis of pyridines it proved advantageous to make a dihydropyridine and oxidize it to a pyridine afterwards. The same idea works well in probably the most famous quinoline synthesis, the Skraup reaction. The diketone is replaced by an unsaturated carbonyl compound so that the quinoline is formed regiospecifically. The first step is conjugate addition of the amine. Under acid catalysis the ketone now cyclizes in the way we have just described to give a dihydroquinoline after dehydration. Oxidation to the aromatic quinoline is an easy step accomplished by many possible oxidants. 

Bose et al. were also able to successfully achieve the microwave-assisted synthesis of quinoline (72) and dihydroquinoline (73) derivative under solvent-free condition via Skraup synthesis. They demonstrated that 25 mol% of KjCoW,20 q (PDTC) was effective for one-pot reaction of aniline with alkyl vinyl ketones as shown in Scheme 6.28. This reagent was also demonstrated to be an effective catalyst for the Friedlander synthesis [67]. 

Scheme 6.28 Microwave-assisted synthesis of quinoline (72) and dihydroquinoline (73) derivative under solvent-free eondition via Skraup synthesis...

For the synthesis of quinoUnes and isoquinoUnes the classical approaches are the Skraup and the Bischler-Napieralski reactions. The reaction of substituted anilines with different carbonyl compounds in acid mediiun has been reported to be accelerated under microwave irradiation to give differently substituted quinohnes and dihydroquinolines [137]. Although the yields are much better and the conditions are milder than imder conventional heating, the acidity of the mediiun may prevent the preparation of acid-sensitive compounds. Thus, alternative approaches have been investigated. Substituted anilines and alkyl vinyl ketones reacted under microwave irradiation on the surface of sihca gel doped with InCU without solvent [137] to furnish good yields of quinohnes 213 (Scheme 77). 

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