Quinoline amination, regioselectivity

Related alkyne couplings yield tricyclic quinolines via a regioselective amination/C-H functionalization pathway (Equations (104) and (105)).98... 

Reactions of benzodiazines show no exceptional features compared with the simple diazines. Reactivity towards electrophiles is less than in quinoline and isoquinoline. If S Ar reactions take place, they lead to substitution of the benzene ring. As a rule, nucleophilic substitution of benzodiazines occur in the diazine ring, particularly if substituted by halogen. The quinazoline system displays C-4 regioselectivity, e.g. in the reactions of 2,4-dichloroquinazoline with amines or alcohols ... 

This reaction was first reported by Combes in 1888. It is the synthesis of quinolines by the condensation of primary aromatic amines with acetoacetone or other -diketones followed by cyclization in the presence of sulfuric acid. This method provides a rapid access to the 2,4-substituted quinoline skeleton but, it suffers from low regioselectivity, such as in the case of meto-substituted anilines with two different ortho positions for ring closure. It was found that polyphosphoric acid is a better catalyst than sulfuric acid for the cyclization," and the factors that affect this reaction have been reviewed by Roberts and Turner. ... 

In the series of azaaromatics pyridine appears to possess the least electron deficiency and cannot be aminated under these conditirms. In contrast, diazines, triazines, tetrazines, quinolines, quinoxalines, quinazolines, naphthiridines, polyazaaromatic compounds, and their nitro derivatives are able to undergo oxidative amination. Moreover, amination of highly Jt-deficient triazines, tetrazines, 3-nitropyridine, 3-nitroquinoline, etc. is possible to perform without KNH2, since ammonia itself serves as nucleophile in such cases (Scheme 6). However, the more electron deficiency of an azine substrate, the less regioselectivity of the reaction. Oxidative amination of 3-nitrop3ridine in Uquid ammonia with potassium permanganate affords a mixture of 2-amino-3-nitro- (33%), 4-amino-3-nitro- (24%), and... 

It has recently been demonstrated that bromo-tns-pyrrolidino-phosphonium hexafluorophosphate (PyBroP) can be functiOTiing as a mild activator of azine N-oxide providing regioselective addition of Ai-nucleophiles (amines, sulfonamides, and NH-heterocycUc compounds) to pyridine, quinoline, and isoquinoline N-oxides (Scheme 53) [112,113]. A strong regiochemical preference for the orf/io-substitution pattern in aU these cases is likely caused by specific electrostatic attraction of nucleophilic species and the intermediate phosphonium salt 76. This synthetic procedure was successfully extended for other types of nucleophilic reagents (phenols, thiols, malonates). 

Wang et al. [49] developed a highly regioselective Povarov reaction of an aromatic aldehyde, l//-indazol-5-amine, and methyl 3-oxobutanoate catalyzed by iodine. This novel reaction selectively gave 3/f-pyrazolo[4,3-y]quinolin-9-yl acetates 20, rather than 3//-pyrazolo[4,3-/jquinoline-8-carboxylate derivatives. Further, they [50] also extended the reaction using tetrahydropy ran-4-one instead of methyl-3 -oxobutanoate for the synthesis of 7-aiylpyrano[3,4-c]pyrazolo[3,4-/]quinoline derivatives 21 (Scheme 10.16). 

Amination of 5,7-difluoro- and 5,7,8-trifluoroquinoline, 5,7-difluoro-8-chloro-quinoline and 6-trifluoromethyl-5,7,8-trifluoroquinoline leads to the formation of rather complicated mixtures of monoaminoquinolines [101]. The reaction of hepta-fluoroquinoline with S-nncleophiles (HS , PhS , MeS , PrS h BuS) is very indicative, since it demonstrates a high regioselectivity, resulting in displac ent of halogen at the position 4 [102]. 

In 2005, Yi and coworkers reported a catalytic C-H bond activation and cyclization protocol by using the catalyst Ru3(CO)j 2/NH4PFg. This catalytic system offers an efficient method for the synthesis of tricyclic quinoline derivatives from regioselective coupling of benzocyclic amines with 2 equiv. of alkynes (Eq. (7.21)) [27]. Later, the catalytic coupling reactions of acyclic arylamines with terminal... 

---