Functionalized 4‐Aminoquinolines by Rearrangement of Pyrazole N‐Heterocyclic Carbenes

Abstract

Thermal decarboxylation of 1‐phenylpyrazolium‐3‐carboxylates from the mesomeric betaine class of substances leads to pyrazole‐N‐heterocyclic carbenes, which immediately rearrange to multiply substituted 4‐aminoquinolines (see scheme). These species are of interest for the synthesis of heterocycles and pharmacologically active compounds.

Dimerisation, rhodium complex formation and rearrangements of N-heterocyclic carbenes of indazoles

“…Undoubtedly the N-heterocyclic carbenes of imidazole, imidazoline and the triazoles play the most important roles as ligands in metal-organic chemistry [14] or as organocatalysts [15–16]. The N-heterocyclic carbenes of indazole (and pyrazole [17–18]), however, have a chemistry of their own which set them apart from the NHCs of the aforementioned ring systems. Portions of that field have been covered in recent review articles [18–19].…”

“…It proved to be advantageous to start these rearrangements from indazolium salts which are readily available by copper-catalyzed aryl couplings or Buchwald–Hartwig reactions [22]. Pyrazol-3-ylidenes rearrange similarly to quinolines [17]. …”

Synthesis of Highly Functionalized 4‐Aminoquinolines

“…[2a,4] 4-Amino-substituted quinolines are of particular pharmaceutical interest, [4a,6] and over the years,s everal synthetic routes to these compounds have been explored. [7] Them ain drawback of al ot of the existing quinoline syntheses is the difficulty of functionalization at the C2 and C3 positions.Herein, we present the synthesis of adiverse array of new, highly substituted 4-aminoquinolines from sulfonyl ynamides and electrophilically activated amides.I nc ontrast to other methods,t his approach allows for substitution at the C2 and C3 as well as at the C5 to C8 positions.F urthermore,t he installed 4-amino group is accessible after deprotection, thus providing further points of diversity (Scheme 1).Quinolines can be made in several different ways.M ore recently developed approaches for the formation of quinolines are based on the conversion of 2-alkynyl arylazides into substituted 4-acetoxyquinolines under gold catalysis, [8] onepot InCl 3 /SiO 2 catalyzed reactions towards 4-methylquinolines, [9] and the use of ring-closing metathesis to access 4-hydroxy-or 4-methylquinolines.[10] 4-Phenylquinolines are accessible by aY b(OTf) 3 catalyzed multicomponent reaction [11] or by a" green" solvent-free one-pot process between 2-aminoaryl ketones and aryl acetylenes.[12] 4-Aminoquinolines can be prepared by the reduction of quinoline-4-phenylhydrazine, [13] by hypobromite oxidation of 2,3-dimethylquinoline-4-carboxyamides, [14] via a4 -chloroquinoline precursor, [6a] by rearrangements of pyrazolium-3-carboxylates via pyrazol-3-ylidene intermediates, [15] by reacting 2-(trifluoromethyl)-4H-3,1-benzoxazinones with ynamines, [16] or by an aerobic oxidative Pd-catalyzed imidoylative coupling with double C À Ha ctivation.[17] These approaches usually allow for some degree of functionalization on the quinoline core,and with the 4-chloro precursor strategy,4-aminoquinolines with aw ide range of functional groups at the C5 to C8 positions have been synthesized and found to be promising in antimalarial assays.[18] However,a ccessing both the C2, C3 and the C5 to C8 positions has remained achallenge thus far.Thek ey to our synthesis of 4-aminoquinolines is the activation of the amides with ac ombination of triflic anhydride [19] (Tf 2 O) and 2-chloropyridine (2-ClPy), ap rocedure used by Movassaghi and co-workers to prepare aw ide …”

Synthese hochfunktionalisierter 4‐Aminochinoline

“…[10] 4-Phenylchinoline sind aus Yb(OTf) 3 -katalysierten Mehrkomponentenreaktionen [11] oder durch eine "grüne", lçsungsmittelfreie Eintopfreaktion von 2-Aminoarylketonen mit Arylacetylenen zugänglich. [12] 4-Aminochinoline kçnnen durch Reduktion von Chinolin-4-phenylhydrazin, [13] durch Oxidation von 2,3-Dimethylchinolin-4-carboxyamid mit Hypobromit, [14] aus einer 4-Chlorchinolin-Vorstufe, [6a] durch Umlagerung von Pyrazolium-3-carboxylaten über Pyrazol-3-yliden-Zwischenstufen, [15] durch Reaktion von 2-(Trifluormethyl)-4H-3,1-benzoxazinonen mit Inaminen [16] oder durch aerobe oxidative Pd-katalysierte imidoylierende Kupplungen mit doppelter C-H-Aktivierung hergestellt werden. [17] Diese Herangehensweisen ermçglichen die Funktionalisierung des Chinolingerüstes und durch eine 4-Chlor-Vorstufen-Strategie die Herstellung von 4-Aminochinolinen mit einer Vielfalt von Funktionalisierungen an den Positionen C-5 bis C-8.…”