Reactions Friedlaender

Transition metal catalyzed hetero-annulation provides a useful and convenient tool for the construction of N-heterocycles [1]. Quinolines are of special interest in that they display attractive applications in pharmaceuticals and are synthetic building blocks [2, 3]. Catalytic processes employing palladium [4—6], rhodium [7-9], ruthenium [10-14], and iron [15] have been studied and developed to synthesize quinoline skeletons. There are five common methods used to prepare substituted quinolines the Skraup reaction [16], the Doebner-Von Miller reaction [17], the Conrad-Limpach reaction [18], the Friedlaender reaction [19, 20], and the Pfitz-inger reaction [21, 22]. All five of the reactions require environmentally unfriendly acids or bases, high temperatures, or harsh conditions. Quinoline yields are usually low due to numerous side reactions. Even though much work has been done to find catalytic routes to quinolines, the use of non-precious metals remains an active area of research. 

Friedlaender reaction of 64 with 65 completed the assemblage of the carbon skeleton 66 (Scheme 8) which was taken to the final molecule. 

Various synthetic approaches to 2-(trifluoromethyl)quinolines are based on use of the trifluoromethyl-containing reagents. In particular, 2-aminoaryl aldehydes (ketones) or ortho-v myl substituted anilines are appropriate starting materials to be condensed with readily available trifluoromethyl 1,3-diketones or aldehyde hydrates respectively. For instance, the regioselective Friedlaender reaction of unsymmetrical trifluoromethyl 1,3-diketones with 2-aminoaryl aldehydes appears to be an efficient way to 2-trifluoromethylquinolines 83a and 83b (Scheme 33) [54]. 

As mentioned above, amines of the thienopyridine series synthesized by the Thorpe reaction always contain an electron-withdrawing substituent (acyl, alkoxy-carbonyl, etc.) at position 2. The presence of the o-aminocarbonyl fragment in these compounds makes these compounds useful as synthons for pyridine ring construction in the Friedlaender synthesis. Generally, condensation occurs in the presence of a basic catalyst. The acid-promoted synthesis can be exemplified by the preparation of tetracyclic structure 59 from pyranothienopyridine 60 (1996RFP1417446). 

Reaction of 201 with 1,3-dicarbonyl compounds, or with aliphatic and cyclic ketones 203 in the presence of dilute sulfuric acid, gave the 3//-l,2,3-triazolo[4,5-6]pyridines 204 (79CPB2861). The mechanism of transformation involves ring fission to 202, followed by reaction with 203 to give 204, a type of Friedlaender synthesis (see Scheme 42). 

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