Skraup type

The Skraup-type reactions proceed by the use of acrolein or 2-bromo-acrolein in the presence of mineral acids or with glycerol and sulfuric acid [52CI(L)562 60NKZ509], The quinaldine-type products are afforded by acetaldehyde, crotonaldehyde, or paraldehyde in the presence of hydrochloric acid (54JCS286). 

All possible isomers of the phenanthrolines are known and can be prepared by Skraup-type reactions, with the exception of the 2,8- and 3,8-phenanthrolines (which are structurally related to isoquinolines). Some of these compounds are commercially available. There have been no major advances in the synthesis of these compounds since CHEC-II(1996) <1996CHEC-II(7)921>. 

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. ... 

Skraup/Doebner-von Miller-type reactions with lanthanide catalysts under microwave radiation are efficient for a variety of different anilines. For example, cyclisation of aniline 44 with acetone in the presence of scandium triflate gave the desired product 45 in excellent yield. 

General synthetic methods used to prepare various types of naphthyridines include the Skraup, Friedlander and some other name reactions. They include cyclization, cyclocondensation, dimerization reactions, etc. 

Although the Skraup/Doebner-von Miller reaction represents one of the most common reaction for the synthesis of quinoline core for more than a century, its mechanism is still dedebated. To date, both of the two more popular mechanistic explanations are involving fragmentation-recombination pathways. In the first one, initially the amine reacts with the aldehyde or ketone under acidic conditions to form an imine. Dimerization and Pictet-Spengler type cyclization forms a diazetine core. Protonation and subsequent cyclization-ring cleavage reaction assembles the isoquinoline nucleus. 

Before closing this section, a few additional remarks about quinoline 42 are in order. Most typically, heterocycles of this type are prepared by the Skraup method, which, as shown in... 

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