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Original Research ARTICLE

Front. Chem., 14 June 2019 | https://doi.org/10.3389/fchem.2019.00433

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

Zahra Yasaei, Zeinab Mohammadpour, Morteza Shiri*, Zahra Tanbakouchian and Shima Fazelzadeh
  • Department of Chemistry, Faculty of Physics and Chemistry, Alzahra University, Tehran, Iran

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.

Introduction

Quinolines are heterocyclic compounds exhibiting diverse and well-documented bioactivity and physical properties as well as existing as scaffolds in complex structures of natural products (Michael, 2002; Hranjec et al., 2017). Accordingly, quinoline synthesis, and functionalization has attracted much attention from synthetic organic chemists (Marco-Contelles et al., 2009; Shiri et al., 2011; Prajapati et al., 2014; Sharma et al., 2018; Nainwal et al., 2019).

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 five-membered 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).

FIGURE 1
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Figure 1. Several natural products with amide and oxazole moieties.

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 palladium-catalyzed reaction was developed for amidation of aryl halides (Jiang et al., 2011), as well as the synthesis of 4-aminophthalazin-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).

Materials and Methods

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 1H, 100 MHz for 13C) in DMSO-d6 and CDCl3 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 Typical Procedure for the Synthesis of 5-(2-chloroquinolin-3-yl)oxazole 3a

A mixture of 2-chloro-quinoline-3-carbaldehyde 2a (191 mg, 1.0 mmol), p-toluenesulfonylmethyl isocyanide 1 (234 mg, 1.2 mmol) and K2CO3 (341 mg, 2.5 equiv.) was added to EtOH (5.0 ml) and stirred for 3.5 h, at room temperature. After completion of the reaction, monitored by TLC, the mixture poured into cool water and stirred for 30 min. The product 3a filtered, washed with water two times and dried on the air.

The Typical Procedure for the Synthesis of N-cyclohexyl-3-(oxazol-5-yl)quinoline-2-carboxamide 5a

A mixture of 5-(2-chloroquinolin-3-yl)oxazole 3a (230 mg, 1.0 mmol), of Pd(OAc)2 (11 mg, 5 mol%) and Cs2CO3 (325 mg, 1.0 mmol) stirred in DMSO:H2O, 9:1 (5 mL) at 80°C for 15 min. Cyclohexyl isocyanide 4a (120 mg, 1.1 mmol) was added and the reaction stirred for 4 h. After completion of the reaction (the progress of the reaction was monitored by TLC) organic layer was extracted by DCM, washed with brine, dried over Na2SO4 and its solvent evaporated on a rotary evaporator. The residue was washed with 2-propanol and recrystallized in methanol to give 5a. It is noteworthy that 5a and 5h purified by washing with 2-propanol but other derivatives were purified by a column chromatography (n-hexan: ethyl acetate 3:1) and recrystallized in EtOH.

The Typical Procedure for the Synthesis of 5-(2-tosylquinolin-3-yl)oxazole 6a-e

A mixture of 2-chloro-quinoline-3-carbaldehyde 2a (191 mg, 1.0 mmol), p-toluenesulfonylmethyl isocyanide 1 (468 mg, 2.4 mmol) and Cs2CO3 (810 mg, equiv.) was added to DMSO (5.0 ml) and stirred for 5 h at 80°C. After completion of the reaction and monitored by TLC, the mixture poured into cool water and stirred for 30 min, then extracted with DCM. The product 6a purified by a column chromatography (n-hexan: ethyl acetate 4:1).

Supplementary Material

N-Cyclohexyl-3-(oxazol-5-yl) quinolone-2-carboxamide (5a)

Copies of NMR spectra are provided as Supplementary Materials. White powder, mp.: 123–128°C. 1H-NMR (400 MHz, CDCl3): δ = 1.25–1.52 (m, 5H), 1.68–171 (m, 1H), 1.80–1.85 (m, 2H), 2.10–213 (m, 2H), 3.99–4.02 (m, 1H), 7.60 (s, 1H), 7.67 (t, J = 8.0 Hz, 2H), 7.82 (t, J = 7.8 Hz, 1H), 7.90 (d, J = 8.4 Hz, 1H), 8.03 (s, 1H), 8.14 (d, J = 8.4 Hz, 1H), 8.44 (s, 1H) ppm. 13C-NMR (100 MHz, CDCl3): δ = 25.0, 25.6, 33.0, 48.6, 120.4, 125.9, 127.9, 128.0, 128.6, 129.5 131.0, 137.9, 145.9, 148.5, 148.8, 151.0, 164.3 ppm. Mass: m/z 321 (M+) (calcd. For C19H19N3O2: 321.37). FT-IR (KBr): νmax: 1604, 3444 cm−1. Anal. calcd. for C19H19N3O2: C, 71.01; H, 5.96; N, 13.08. Found: C,71.10; H,5.81; N,13.17.

N-Cyclohexyl-8-methyl-3-(oxazol-5-yl)quinolone-2-carboxamide (5b)

White powder, mp: 181–185°C. 1H-NMR (400 MHz, DMSO-d6): δ = 1.15–1.74 (m, 10H), 2.75 (s, 3H), 3.83 (m, 1H), 7.52 (s, 1H), 7.63 (d, J = 8.0 Hz, 1H), 7.73 (d, J = 6.8 Hz, 1H), 7.97 (d, J = 8.0 Hz, 1H), 8.60 (s, 1H), 8.74 (s, 1H) ppm. 13C-NMR (100 MHz, DMSO-d6): δ = 17.8, 25.0, 25.6, 25.8, 32.5, 33.8, 48.5, 118.6, 121.8, 125.0, 126.7, 127.6, 128.3, 131.4, 135.2, 136.9, 145.0, 147.8, 153.0, 167.0 ppm. Mass: m/z 335 (M+) (calcd. for C20H21N3O2: 335.40). FT-IR (KBr): νmax: 1646, 2853, 2922, 3310, 3444 cm−1. Anal. calcd. for C20H21N3O2: C, 71.62; H, 6.31; N, 12.53%. Found: C, 71.55; H, 6.47; N, 12.42%.

N-Butyl-6-methyl-3-(oxazol-5-yl)quinoline-2-carboxamide (5c)

White powder, mp: 124–127°C. 1H-NMR (400 MHz, CDCl3): δ = 1.01 (t, J = 7.2 Hz, 3H), 1.45–1.54 (m, 2H), 1.67–1.74 (m, 2H), 2.61 (s, 3H), 3.53 (dd, J = 13.4 Hz, J = 6.8 Hz, 2H), 7.60 (s, 1H), 7.65 (s, 1H), 7.68 (s, 1H), 7.77 (s, 1H), 8.03 (t, J = 5.2 Hz, 2H), 8.37 (s, 1H) ppm. 13C-NMR (100 MHz, CDCl3): δ = 13.8, 20.2, 21.8, 31.7, 39.5, 120.4, 125.7, 125.8, 126.5, 126.6, 128.1, 129.0, 133.4, 137.2, 138.9, 142.9, 150.9, 165.2 ppm. Mass: m/z 309 (M+) (calcd for C18H19N3O2: 309.36). FT-IR (KBr): νmax: 1542, 1652, 2858, 2928, 2956, 2922, 3114, 3299 cm−1. Anal. calcd. for: C18H19N3O2, C, 69.88; H, 6.19; N, 13.58%. Found C, 67.03; H, 6.24; N, 13.65%.

N-Cyclohexyl-6-methoxy-3-(oxazol-5-yl)quinoline-2-carboxamide (5d)

White powder, mp: 157–162°C. 1H-NMR (400 MHz, DMSO-d6): δ = 1.04–1.27 (m, 5H), 1.57–1.74 (m, 5H), 3.93(s, 3H), 3.93 (m, 1H), 7.52 (dd, J = 9.2, J = 2.8 Hz, 1H), 7.61 (d, J = 2.8 Hz, 1H), 7.92 (d, J = 9.2 Hz, 1H), 7.96 (s, 1H), 8.71 (s, 1H), 8.77 (s,1H) ppm. 13C-NMR (100 MHz, DMSO-d6): δ = 24.9, 25.8, 30.8, 31.2, 33.8, 47.9, 56.2, 106.7, 115.8, 121.3, 124.6, 127.5, 128.3, 129.6, 135.9, 142.4, 143.1, 146.5, 153.4, 158.7 ppm. Mass: m/z 351 (M+) (calcd. for C20H21N3O3:351.40). FT-IR (KBr): νmax: 1666, 2927, 2966, 3286, 3423 cm−1. Anal. calcd. for C20H21N3O3: C, 68.36; H, 6.02; N, 11.96%. Found: C, 68.47; H, 6.14; N, 12.11%.

N-Cyclohexyl-3-(oxazol-5-yl)benzo[h]quinoline-2-carboxamide (5e)

White powder, mp: 224–267°C. 1H-NMR (400 MHz, CDCl3): δ = 1.28–1.58 (m, 6H), 1.85–1.88 (m, 2H), 2.16–2.19 (m, 2H), 4.07- 4.10 (m, 1H), 7.30 (s, 1H), 7.74 (d, J = 2.4 Hz, 1H), 7.79-7.85 (m, 3H), 7.93 (d, J = 8.8 Hz, 1H), 7.97 (d, J = 7.6 Hz, 1H), 8.07 (s, 1H), 8.49 (s, 1H), 9.19 (d, J = 7.6 Hz, 1H) ppm. 13C-NMR (100 MHz, CDCl3): δ = 24.9, 25.7, 29.7, 33.2, 48.5, 77.2, 121.3, 124.3, 124.7, 126.6, 126.9, 127.7, 128.2, 129.1, 130.1, 130.6, 134.1, 137.5, 144.2, 146.7, 148.5, 151.1, 164.5 ppm. Mass: m/z 371 (M+) (calcd for C23H21N3O2:371.43). FT-IR (KBr): νmax: 1646, 2852, 2936, 3119, 3294, 3448 cm−1. Anal. calcd. for: C23H21N3O2, C, 74.37; H, 5.70; N, 11.31%. Found: C, 74.29; H, 5.84; N, 11.52%.

6-Chloro-N-cyclohexyl-3-(oxazol-5-yl)quinoline-2-carboxamide (5f)

White powder, mp: 226–232°C. 1H-NMR (400 MHz, CDCl3): δ = 1.25–1.52 (m, 5H), 1.68–1.83 (m, 3H), 2.09–2.12 (m, 2H), 3.94–4.04 (m, 1H), 7.54 (d, J = 8.0 Hz, 1H), 7.63 (s, 1H), 7.71 (dd, J = 9.0 Hz, J = 2.4 Hz, 1H), 7.86 (d, J = 2.4 Hz, 1H), 8.02 (s, 1H), 8.05 (d, J = 9.2 Hz, 1H), 8.34 (s, 1H) ppm. 13C-NMR (100 MHz, CDCl3): δ = 24.9, 25.6, 33.0, 48.7, 77.3, 121.2, 126.4, 126.6, 128.5, 131.0, 131.9, 134.5, 136.3, 144.1, 147.9, 149.0, 151.2, 164.2 ppm. Mass: m/z 355 (M+) (calcd. for C19H18 ClN3O2: 355.82). FT-IR (KBr): νmax: 663, 1649, 2852, 2923, 3279, 3443 cm−1. Anal. calcd. for: C19H18ClN3O2, C, 64.13; H, 5.10; N, 11.81%. Found: C, 64.20; H, 5.16; N, 11.70%.

N-(tert-Butyl)-6-chloro-3-(oxazol-5-yl)quinoline-2-carboxamide (5g)

White powder, mp: 190–197°C. 1H-NMR (400 MHz, DMSO-d6): δ = 1.43 (s, 9H), 7.75 (s, 1H), 7.86 (dd, J = 9.2 Hz, J = 2.4 Hz, 1H), 8.14 (d, J = 8.8 Hz, 1H), 8.28 (d, J = 2.4 Hz, 1H), 8.46 (s, 1H), 8.64 (s, 1H), 8.76 (s, 1H) ppm. 13C-NMR (100 MHz, DMSO-d6): δ = 28.8, 51.5, 119.5, 125.5, 127.4, 128.3, 131.3, 131.8, 132.7, 133.8, 144.5, 147.4, 153.4, 167.1 ppm. Mass: m/z 329.78 (M+) (calcd. for C17H16N3O2: 329.09). FT-IR (KBr): νmax: 1626, 2852, 2928, 3334, 3423 cm−1. Anal. calcd. for C17H16 ClN3O2: C, 61.91; H, 4.89; N, 12.74. Found: C, 62.04; H, 4.95; N, 12.89.

N-(tert-Butyl)-3-(oxazol-5-yl)quinolone-2-carboxamide (5h)

White powder, mp: 102–106°C. 1H-NMR (400 MHz, DMSO-d6): δ = 1.43 (s, 9H), 7.56 (s, 1H), 7.72 (t, J = 7.4 Hz, 1H), 7.87 (t, J = 7.6 Hz, 1H), 8.13 (t, J = 8.8 Hz, 2H), 8.41 (s, 1H), 8.61(s, 1H), 8.77 (s, 1H) ppm. 13C-NMR (100 MHz, DMSO-d6): δ = 28.8, 51.4, 118.7, 125.1, 127.5, 128.4, 128.8, 129.1, 131.4, 134.7, 146.0, 147.8, 153.0, 153.1, 167.4 ppm. Mass: m/z 295 (M+) (calcd. for C17H17N3O2: 295.34). FT-IR (KBr): νmax: 1658, 2904, 2966, 3422 cm−1. Anal. calcd. for C17H17N3O2: C, 69.14; H, 5.80; N, 14.23%. Found: C, 69.20; H, 5.87; N, 14.35%.

5-(2-Tosylquinolin-3-yl)oxazole (6a)

White powder, mp: 149–152°C. 1H-NMR (400 MHz, DMSO-d6): δ = 2.46 (s, 3H), 7.50 (d, J = 7.2 Hz, 2H), 7.77–7.90 (m, 6H), 8.18 (d, J = 7.6 Hz, 1H), 8.69 (s, 1H), 8.92 (s, 1H) ppm. 13C-NMR (100 MHz, DMSO-d6): δ = 21.6, 118.2, 127.6, 128.2, 128.9, 129.5, 129.6, 130.1, 130.6, 132.9, 135.5, 141.1, 144.9, 145.3, 145.6, 153.4, 155.1 ppm. Mass: m/z 350 (M+) (calcd for C19H14N2O3S:350.39). FT-IR (KBr): νmax: 683, 1073, 1103, 2851, 2920 cm−1. Anal. calcd. for: C19H14N2O3S, C, 65.13; H, 4.03; N, 7.99; S, 9.15%. Found: C, 65.23; H, 4.14; N, 8.06; S, 9.21%.

5-(8-Methyl-2-tosylquinolin-3-yl)oxazole (6b)

White powder, mp: 162–167°C. 1H-NMR (400 MHz, DMSO-d6): δ = 2.18 (s, 3H), 2.50 (s, 3H), 7.55 (d, J = 8.0 Hz, 1H), 7.71 (d, J = 6.8 Hz, 2H), 7.88 (s, 1H), 7.90 (d, J = 7.6 Hz, 2H), 8.03 (dd, J = 6.8 Hz, J = 2.8 Hz, 1H), 8.73 (s, 1H), 8.95 (s, 1H) ppm. 13C-NMR (100 MHz, DMSO-d6): δ = 16.5, 21.7, 117.5, 126.6, 127.7, 128.3, 129.9, 130.1, 130.4, 132.5, 135.3, 137.4, 140.3, 143.5, 145.3, 145.5, 153.6, 153.8 ppm. Mass: m/z 364 (M+) (calcd for C20H16N2O3S:364.42). FT-IR (KBr): νmax: 1294, 1379, 2852, 2922 cm−1. Anal. calcd. for: C20H16N2O3S, C, 65.92; H, 4.43; N, 7.69; S, 8.80%. Found: C, 66.03; H, 4.49; N, 7.78; S, 8.93%.

5-(6-Methyl-2-tosylquinolin-3-yl)oxazole (6c)

White powder, mp: 124–127°C. 1H-NMR (400 MHz, CDCl3): δ = 2.51 (s, 3H), 2.59 (s, 3H), 7.30 (s, 1H), 7.38 (d, J = 6.4 Hz, 2H), 7.62 (d, J = 8.4 Hz, 1H), 7.68 (s, 1H), 7.84 (d, J = 8.0 Hz, 1H), 7.89 (d, J = 7.6 Hz, 2H), 8.10 (s, 1H), 8.44 (s, 1H) ppm. 13C-NMR (100 MHz, DMSO-d6): δ = 21.6, 21.7, 118.3, 127.3, 127.5, 128.2, 129.2, 129.5, 130.0, 135.1, 135.7, 140.2, 140.8, 142.9, 143.6, 145.2, 145.7, 153.3 ppm. Mass: m/z 364 (M+) (calcd for C20H16N2O3S:364.42). FT-IR (KBr): νmax: 823, 1375, 2853, 2923 cm−1. Anal. calcd. for: C20H16N2O3S, C, 65.92; H, 4.43; N, 7.69; S, 8.80%. Found: C, 65.98; H, 4.49; N, 7.77; S, 8.86%.

5-(6-Methoxy-2-tosylquinolin-3-yl)oxazole (6d)

White powder, mp: 187–190°C. 1H-NMR (400 MHz, CDCl3): δ = 2.51 (s, 3H), 3.99 (s, 3H), 7.16 (d, J = 8.8 Hz, 2H), 7.30 (s, 1H), 7.39 (s, 1H), 7.58 (d, J = 8.8 Hz, 2H), 7.84 (d, J = 9.2 Hz, 2H), 7.90 (d, J = 8.4 Hz, 1H), 8.10 (s, 1H), 8.42 (s, 1H) ppm. 13C-NMR (100 MHz, CDCl3): δ = 37.1, 55.8, 104.6, 119.1, 124.0, 124.4, 124.8, 129.2, 129.6, 131.6, 135.6, 137.5, 138.4, 138.5, 144.5, 147.1, 147.6, 147.7 ppm. Mass: m/z 380 (M+) (calcd for C20H16N2O4S: 380.42). FT-IR (KBr): νmax: 1037, 117, 2850, 2920 cm−1. Anal. calcd. for: C20H16N2O4S, C, 63.14; H, 4.24; N, 7.36; S, 8.43%. Found: C, 63.21; H, 4.29; N, 7.43; S, 8.55%.

5-(2-Tosylbenzo[h]quinolin-3-yl)oxazole (6e)

White powder, mp: 202–207°C. 1H-NMR (400 MHz, CDCl3): δ = 2.60 (s, 3H), 7.30 (s, 1H), 7.52 (d, J = 8.0 Hz, 2H), 7.57 (t, J = 7.2 Hz, 1H), 7.70 (t, J = 6.8 Hz, 1H), 7.73 (d, J = 8.8 Hz, 1H), 7.89 (d, J = 8.4 Hz, 1H), 7.92 (d, J = 9.2 Hz, 1H), 8.04 (d, J = 8.4 Hz, 2H), 8.16 (d, J = 5.6 Hz, 1H), 8.20 (d, J = 8.4 Hz, 1H), 8.60 (s, 1H) ppm. 13C-NMR (100 MHz, CDCl3): δ = 21.8, 119.0, 124.1, 124.4, 127.0, 127.8, 128.0, 128.7, 129.3, 129.3, 130.2, 130.5, 131.1, 134.0, 135.3, 137.5, 134.3, 144.8, 145.5, 151.6, 153.3 ppm. Mass: m/z 400 (M+) (calcd for C23H16N2O3S: 400.45). FT-IR (KBr): νmax: 1313, 1400, 2853, 2920 cm−1. Anal. calcd. for: C23H16N2O3S, C, 68.98; H, 4.03; N, 7.00; S, 8.01%. Found: 69.06; H, 4.11; N, 7.12; S, 8.14%.

Results and Discussion

In continuation of our interest in quinoline chemistry (Shiri et al., 2012, 2016a, 2017a) and isocyanide reactions (Shiri et al., 2016b, 2017b; Salehi and Shiri, 2019), we began our investigation with 2-chloroquinoline-3-carbaldehyde (1) and its two step reaction with two different isocyanides. In the presence of K2CO3, 2-chloroquinoline-3-carbaldehyde (1) and 4-toluenesulfonylmethyl isocyanide (TosMIC) (2) furnished 5-(2-chloroquinolin-3-yl)oxazole (3a). Several 5-(2-chloroquinolin-3-yl)oxazoles (3) were prepared under the same conditions. The reaction of quinoline 3a with cyclohexyl isocyanide 4a was selected as a model reaction in the presence of Pd(OAc)2, Ph3P, and Cs2CO3, in 1,4-dioxane with a few drops of H2O as solvent at 80 °C. Desired product 5a was obtained in 86% yield (Table 1). Solvent screening showed that DMSO is the best solvent (Table 1, entry 6). Other Pd sources such as Pd(PPh3)4 and PdCl2 did not improve the product yield, however, the best yield was obtained with 5 mol% of Pd(OAc)2 even without PPh3 (Table 1, entries 7–9). Without palladium, the reaction did not occur (Table 1, entry 10). Moreover, the effect of base is crucial for reaction completion. Hence, different bases were investigated, including K2CO3, NaOAc, (CH3)3OK, DABCO, and Et3N (Table 1, entries 14–18). In this survey, it was found that increasing the temperatures or the reaction time decreased the product yield.

TABLE 1
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Table 1. Optimization of the reaction condition for the synthesis of N-cyclohexyl-3-(oxazol-5-yl)quinoline-2-carboxamide 5a from 3a.

With the optimized reaction conditions in hand (Pd(OAc)2 (5 mol%), Cs2CO3 (1 equiv.), DMSO + H2O (9:1), 80°C), the generality of the reaction was explored (Table 2). A range of quinolines 3 bearing electron-donating groups, such as Me, and OMe and electron-withdrawing groups, such as Cl and benzo, reacted with cyclohexyl isocyanide and n-butylisocyanide to afford the corresponding 3-(oxazol-5-yl)quinoline-2-carboxamides 5a-f in 70%-94% yields (Table 2). Moreover, the bulky tert-butyl isocyanide smoothly participated in this reaction to furnish 5g and 5h in 67 and 76% yield, respectively. The yield with 1,1,3,3-tetramethylbutyl isocyanide was too low to allow its isolation and characterization.

TABLE 2
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Table 2. Synthesis of various derivatives of 5a-5ha.

The scope of the reaction was explored using tosylmethyl isocyanide (TosMIC) 1 as another isocyanide source. Surprisingly, the reaction of 3a with TosMIC under the optimized conditions afforded 5-(2-tosylquinolin-3-yl)oxazole (6a) (Scheme 1).

SCHEME 1
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Scheme 1. The reaction of TosMIC with 3a.

Although the reaction proceeded well without a palladium source, the presence of base is crucial. Among the bases Cs2CO3, K2CO3, NaOAc, t-BuOK, and DABCO, Cs2CO3 gave the best results.

Encouraged by the tosylation results with TosMIC, we explored extending the reaction to tandem oxazole formation as well as tosylation of 2-chloroquinoline-3-carbaldehyde. Subjecting 2-chloroquinoline-3-carbaldehyde and TosMIC to the standard reaction conditions yielded 5-(2-tosylquinolin-3-yl)oxazole (6a) in 83% yield after 8 h (Scheme 2). Notably, sulfones are present in different bioactive compounds (Metzner and Thuillier, 1994; Fang et al., 2016); however, well-known sulfonylating agents include sulfonyl halides (Tocco et al., 2013; Zhang et al., 2015), sulfonyl hydrazides (Yuan et al., 2018; Zhang et al., 2018), and sodium sulfinate (Sun et al., 2017; Smith et al., 2018). A few studies used TosMIC as a sulfonyl precursor (Liu et al., 2014; Phanindrudu et al., 2016; Kadari et al., 2017). Furthermore, Bounar et al. reacted tosylmethyl isocyanide (TosMIC) with propargylic alcohols in the presence of silver acetate to efficiently yield (E)-vinyl sulfones (Bounar et al., 2015); this is the only study in which TosMIC plays a dual role as both an amide and a sulfonyl source.

SCHEME 2
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Scheme 2. One-pot synthesis of 5-(6-methyl-2-tosylquinolin-3-yl)oxazole 6a.

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.

FIGURE 2
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Figure 2. 5-(2-Tosylquinolin-3-yl)oxazole 6.

Our proposed mechanism for the tosylation of quinoline involved in situ Ts generation by decomposition of p-toluenesulfonylmethyl-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).

Conclusion

In summary, we have developed a synthesis of 5-(2-chloroquinolin-3-yl)oxazole via a van Leusen procedure from 2-chloroquinoline-3-carbaldehydes and TosMIC, which were efficiently subjected to Pd-catalyzed amidation with isocyanides to form 3-(oxazol-5-yl)quinoline-2-carboxamides. The synthesis of 5-(2-tosylquinolin-3-yl)oxazole via a Cs2CO3-mediated domino process starting from 2-chloroquinoline-3-carbaldehydes with TosMIC was also demonstrated.

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.

Conflict of Interest Statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Acknowledgments

We are thankful to Alzahra University and the Iran National Science Foundation (INSF) for the financial support.

Supplementary Material

The Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fchem.2019.00433/full#supplementary-material

Supplementary Data Sheet 1. Isocyanide reactions toward the synthesis of 3-(Oxazol-5-yl)quinoline-2-carboxamides and 5-(2-Tosylquinolin-3-yl)oxazole.

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Keywords: palladium acetate, carboxamidation, isocynides, sulfonylation, TosMIC

Citation: Yasaei Z, Mohammadpour Z, Shiri M, Tanbakouchian Z and Fazelzadeh S (2019) Isocyanide Reactions Toward the Synthesis of 3-(Oxazol-5-yl)Quinoline-2-Carboxamides and 5-(2-Tosylquinolin-3-yl)Oxazole. Front. Chem. 7:433. doi: 10.3389/fchem.2019.00433

Received: 03 January 2019; Accepted: 28 May 2019;
Published: 14 June 2019.

Edited by:

Jonathan G. Rudick, Stony Brook University, United States

Reviewed by:

Steven Ballet, Vrije University Brussel, Belgium
Zhong-zhu Chen, Chongqing University of Arts and Sciences, China

Copyright © 2019 Yasaei, Mohammadpour, Shiri, Tanbakouchian and Fazelzadeh. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Morteza Shiri, mshiri@alzahra.ac.ir