Isocyanide Reactions Toward the Synthesis of 3-(Oxazol-5-yl)Quinoline-2-Carboxamides and 5-(2-Tosylquinolin-3-yl)Oxazole

A palladium-catalyzed three-component reaction between 5-(2-chloroquinolin-3-yl) oxazoles, isocyanides, and water to yield 3-(oxazol-5-yl)quinoline-2-carboxamides is described. Interestingly, sulfonylation occurred when the same reaction was performed with toluenesulfonylmethyl isocyanide (TosMIC) as an isocyanide source. The reaction with 5-(2-chloroquinolin-3-yl)oxazoles and TosMIC in the presence of Cs2CO3 in DMSO afforded 5-(2-Tosylquinolin-3-yl)oxazoles. In basic media, TosMIC probably decomposed to generate Ts− species, which were replaced with Cl−. Tandem oxazole formation with subsequent sulfonylation of 2-chloroquinoline-3-carbaldehydes to form directly 5-(2-tosylquinolin-3-yl)oxazoles was also investigated.

However, isocyanides play an important role in synthesizing N-containing heterocycles and are particularly widely applied in Ugi and Passirini reactions (Domling and Ugi, 2000;Domling, 2006). Amides are especially valuable as precursors in synthesizing of bioactive and natural structures, in medicinal chemistry as well as protein synthesis (Bode, 2006;Rönn et al., 2008).
Many natural products such as urukthapelstatin A have been isolated from marine sources, these contains, several aminocarbonyl and oxazole functional groups with cytotoxic activity against human lung cancer (Yu et al., 2009). Similarly, venturamides A and B showed in vitro antimalarial activity (Linington et al., 2007;Davyt and Serra, 2010). Additionally, aerucyclamid C, a hexameric cyclopeptide, extremely active against T. brucei rhodesiense, which causes sleeping sickness, and exhibits lower activity against P. falciparum, the deadliest species of Plasmodium, which causes malaria (Davyt and Serra, 2010). Microcyclamide A is a cyclic hexapeptide with three fivemembered heterocycles. It is isolated from cyanobacterium M. aeruginosa, and it has exhibited cytotoxic effects against P388 murine leukemia (Ishida et al., 2000;Davyt and Serra, 2010;Raveh et al., 2010) (Figure 1). Classical procedures for amide bond formation include reactions between carboxylic acids and amines (Linington et al., 2007;Davyt and Serra, 2010). Another route involves reactions of acyl halides, acyl azides, acyl imidazoles, anhydrides, or esters (activated carboxylic acid species) with amines (Ulijn et al., 2002;Montalbetti and Falque, 2005). As well as classical routes for amides synthesis which have own merits and demerits, direct aminocarbonylation from aryl halides in metal-catalyzed reactions has attracted attention from chemists due to its significant advantages benzamide preparation (Åkerbladh et al., 2017). In this regard, many synthetic methods have been introduced, including copper-catalyzed reactions of aryl halides and isocyanides in DMSO (Yavari et al., 2014). A palladiumcatalyzed reaction was developed for amidation of aryl halides (Jiang et al., 2011), as well as the synthesis of 4aminophthalazin-1(2H)-ones in a palladium-catalyzed reaction with isocyanide insertion in a multi-component reaction, which is difficult to achieve via a classical route (Vlaar et al., 2011). Palladium-catalyzed isocyanide insertion was applied to a carboxamidation/hydroamidation reaction to synthesize isoindolin-1-one derivatives (Pathare et al., 2016). Another example is the synthesis of isoquinolin-1(2H)-one derivatives via a palladium-catalyzed cascade reaction from isocyanide and amides (Wang et al., 2002;Tyagi et al., 2012;Chaudhary et al., 2013). Very recently, Guan et al reported an efficient method for the synthesis of multisubstituted 1H-imidazo-[4,5-c]quinoline derivatives via sequential van Leusen/Staudinger/aza-Wittig/carbodiimide-mediated cyclization (Guan et al., 2018).

General
The solvents and chemicals purchased from Merck and Aldrich chemical companies. Unless otherwise mentioned they used without further purification. Melting points are taken on an Electrothermal 9100 apparatus and are uncorrected. IR spectras recorded on a Shimadzu Infra-Red Spectroscopy IR-435. Nuclear magnetic resonance (NMR) spectra recorded on a Bruker AVANCE Spectrometer (400 MHz for 1 H, 100 MHz for 13 C) in DMSO-d 6 and CDCl 3 as solvent, TMS used as internal standard. The elemental analysis carried out with a Leco CHNS model 932. Mass spectra recorded on Agilent Technology (HP) 5973 Network Mass Selective Detector operating at an ionization potential of 70 eV.
The above cascade oxazole formation and sulfonylation strategy could be extended to other 2-chloroquinoline-3-carbaldehyde derivatives (Figure 2). A methyl group was tolerated on positions 6 and 8 of 2 to afford 6b and 6c, respectively, in 82 and 62% yields. Furthermore, quinoline 2d reacted with TosMIC, affording 6d in good yield. Product 6e, existing an alternative decoration of the quinoline ring, was obtained in 85% yield.
Our proposed mechanism for the tosylation of quinoline involved in situ Ts − generation by decomposition of ptoluenesulfonylmethyl-isocyanide 1 in the presence of base with subsequent aromatic nucleophilic substitution to form 2-sulfonyl quinoline 6. Although application of TosMIC as a sulfonyl source was reported by Liu et al. for synthesizing sulfonyl benzoheteroles, the sulfonation mechanism involved aliphatic nucleophilic substitution (Liu et al., 2014).

AUTHOR CONTRIBUTIONS
ZM, ZT, and SF synthesized all of the compounds with the help of ZY. MS supervised this work and wrote the paper with the help of ZY.