Identification of imine in the reaction mixture

5.22 Conclusion:

In summary, a new synthetic route for the synthesis of nitrone and its [4+2] and [3+2]

annulation reaction with olefins to provide quinolines and oxazolidine has been developed.

Differently substituted nitrones and di-substituted quinolines were prepared from the reaction of nitrosoarenes, imines and styrene derivatives. Moreover, 2-arylquinolines was achieved from cycloaddition reaction with ethylvinyl ether. Mechanistic investigation suggested that the reaction proceeds via nitroso-ene pathway (using azomethine as ene-component) rather than classical [3+2] cycloaddition reaction. Additionally, single isomer of oxazolidine and its derivatives were prepared using this methodology.

Nitroso-azomethine ene reaction enabled three component annulations of nitrosoarene, azomethine and alkene to arylquinolines

5.23 Experimental Section:

General: All reactions involving air- or moisture-sensitive reagents or intermediates were carried out in oven-dried glassware under an argon atmosphere. Dichloromethane (CH2Cl2) was freshly distilled from phosphorus(V)oxide (P2O5). Commercial grade xylene, benzene and toluene were distilled over CaH2 before use. All other solvents and reagents were purified according to standard procedures or were used as received from Aldrich, Acros, Merck and Spectrochem. ¹H, ¹³C NMR spectroscopy, Bruker 400, 500, 600 MHz (at 298 K). Chemical shifts, δ (in ppm), are reported relative to TMS δ (¹H) 0.0 ppm, δ (¹³C) 0.0 ppm) which was used as the inner reference. Otherwise, the solvents residual proton resonance and carbon resonance (CHCl3, δ (¹H) 7.26 ppm, δ (¹³C) 77.2 ppm) were used for calibration. Column chromatography: Merck or Spectrochem silica gel 60-120 under gravity. Flash chromatography: Merck or Spectrochem silica gel 230-400. IR: spectra were recorded on Perkin Elmer Instrument at normal temperature. MS (ESI-HRMS): Mass spectra were recorded on an Agilent Accurate-Mass Q-TOF LC/MS 6520, and peaks are given in m/z (%

of basis peak). Nitrosoarenes were prepared by following literature procedures.

General procedure for the synthesis of nitrones (I):

Nitrosoarene (1 eq.) was added to a solution of imine derivative (1.5 eq.) in xylene (3mL).

The mixture was heated at 120-130 ^oC for 12 h under argon atmosphere. Then the solvent was evaporated under reduced pressure. The crude mixture was subjected to flash chromatography (silica-gel) to afford analytically pure products.

(Z)-N-(benzylidene)aniline oxide (5.11):¹⁸ According to GP I: Nitrosobenzene (30 mg, 0.28 mmol), (E)-N-benzyl-1-phenylmethanimine (82 mg, 0.42 mmol) were reacted for 12 h, and flash chromatography of crude product (silica gel 230-400; EtOAc : hexane, 1:5) gave 5.11 as white solid (40 mg, 73%).

1H NMR (600 MHz, CDCl3) δ = 8.41 – 8.39 (m, 2H), 7.93 (s, 1H), 7.78 – 7.77 (m, 2H), 7.50 – 7.46 (m, 6H) ppm. HRMS: Exact mass calculated for C13H12NO ([M+H]⁺): 198.0913, Found: 198.0906.

Chapter 5

(Z)-N-(2-chlorobenzylidene)aniline oxide (5.42a):¹⁹ According to GP I: Nitrosobenzene (30 mg, 0.28 mmol), (E)-N-(2-chlorobenzyl)-1-(2- chlorophenyl)methanimine (0.11 g, 0.42 mmol) were reacted for 12 h, and flash chromatography of crude product (silica gel 230-400; EtOAc : hexane, 1:5) gave 5.42a as colorless gum (34 mg, 53%). ¹H NMR (600 MHz, CDCl3) δ = 9.52 (d, J = 6.6 Hz, 1H), 8.43 (s, 1H), 7.80 – 7.78 (m, 2H), 7.52 – 7.47 (m, 4H), 7.43 – 7.38 (m, 2H) ppm. HRMS: Exact mass calculated for C13H11NClO ([M+H]⁺): 232.0524, Found:

232.0519.

(Z)-N-(2-chlorobenzylidene)(4-isopropyl-butyl)aniline oxide (5.42b): According to GP I:

1-isopropyl-4-nitrosobenzene (42 mg, 0.28 mmol), (E)-N-(2- chlorobenzyl)-1-(2-chlorophenyl)methanimine (0.11 g, 0.42 mmol) were reacted for 12 h, and flash chromatography of crude product (silica gel 230-400; EtOAc : hexane, 1:5) gave 5.42b as colorless gum (41 mg, 54%).FT-IR ( ) = 2960, 2927, 2857, 1667, 1602, 1496, 1326, 1285, 1096, 1014, 837, 750, 557 cm^-1. ¹H NMR (500 MHz, CDCl3) δ = 9.52 (d, J = 8.0 Hz, 1H), 8.41 (s, 1H), 7.70 (d, J = 8.5 Hz, 2H), 7.47 – 7.45 (m, 1H), 7.41 – 7.33 (m, 4H), 3.02 – 2.96 (m, 1H), 1.29 (d, J = 7.0 Hz, 6H) ppm. ¹³C NMR (151 MHz, CDCl3) δ = 151.6, 147.6, 133.8, 131.6, 130.4, 129.7, 129.4, 128.6, 127.4, 121.9, 34.1, 24.0 ppm. Total count of 13C is less than expected due to the merging of signals in the aromatic region. HRMS: Exact mass calculated for C16H17NClO ([M+H]⁺): 274.0993, Found: 274.0991.

(Z)-N-(4-chlorobenzylidene)(4-tert-butyl)aniline oxide (5.42c): According to GP I: 1- tertbutyl-4-nitrosobenzene (46 mg, 0.28 mmol), (E)-N-(4- chlorobenzyl)-1-(4-chlorophenyl)methanimine (0.11 g, 0.42 mmol) were reacted for 12 h, and flash chromatography of crude product (silica gel 230-400; EtOAc: hexane, 1:5) gave 5.42c as colorless gum (39 mg, 49%). FT-IR ( ) = 2963, 2936, 2870, 1593, 1543, 1419, 1262, 1179, 1089, 1013, 834 cm^-1. ¹H NMR (400 MHz, CDCl3) δ = 8.35 (d, J = 8.4 Hz, 2H), 7.89 (s, 1H), 7.68 (d, J = 8.4 Hz, 2H), 7.50 – 7.43 (m, 4H), 1.35 (s, 9H) ppm. ¹³C NMR (101 MHz, CDCl3) δ = 153.8, 146.6, 136.5, 133.4, 130.4, 129.4, 129.1, 126.3, 121.5, 35.1, 31.4 ppm. HRMS: Exact mass calculated for C17H19NClO ([M+H]⁺): 288.1150, Found: 288.1150.

^~

^~

Nitroso-azomethine ene reaction enabled three component annulations of nitrosoarene, azomethine and alkene to arylquinolines (Z)-N-(4-cyanobenzylidene)aniline oxide (5.42d):¹⁹ According to GP I: Nitrosobenzene (30 mg, 0.28 mmol), (E)-4-((benzylimino)methyl)benzonitrile (92 mg, 0.42 mmol) were reacted for 12 h, and flash chromatography of crude product (silica gel 230-400; EtOAc : hexane, 1:4) gave 5.42d as white solid (28 mg, 45%). ¹H NMR (600 MHz, CDCl3) δ = 8.48 (d, J = 8.4 Hz, 2H), 8.00 (s, 1H), 7.78 – 7.74 (m, 4H), 7.52 – 7.51 (m, 3H) ppm. HRMS: Exact mass calculated for C14H11N2O ([M+H]⁺): 223.0866, Found: 223.0871.

(Z)-N-(4-bromobenzylidene)aniline oxide (5.42e):¹⁸ According to GP I: Nitrosobenzene (30 mg, 0.28 mmol), (E)-N-benzyl-1-(4-bromophenyl)methanimine ( 0.12 g, 0.42 mmol) were reacted for 12 h, and flash chromatography of crude product (silica gel 230-400; EtOAc : hexane, 1:5) gave 5.42e as white solid (37 mg, 48%). ¹H NMR (600 MHz, CDCl3) δ = 8.28 (d, J = 8.4 Hz, 2H), 7.89 (s, 1H), 7.76 – 7.75 (m, 2H), 7.60 (d, J = 8.4 Hz, 2H), 7.50 - 7.48 (m, 3H) ppm. HRMS: Exact mass calculated for C13H11NBrO ([M+H]⁺): 276.0019, Found:

276.0010.

(Z)-N-(4-nitrosobenzylidene)aniline oxide (5.42f):¹⁸ According to GP I: Nitrosobenzene (30 mg, 0.28 mmol), (E)-N-benzyl-1-(4-nitrophenyl)methanimine (0.10 g, 0.42 mmol) were reacted for 12 h, and flash chromatography of crude product (silica gel 230-400; EtOAc : hexane, 1:2) gave 5.42f as white solid (34 mg, 50%). ¹H NMR (400 MHz, CDCl3) δ = 8.54 (d, J = 9.2 Hz, 2H), 8.30 (d, J = 9.2 Hz, 2H), 8.07 (s, 1H), 7.78 – 7.76 (m, 2H), 7.52 – 7.51 (m, 3H) ppm. HRMS: Exact mass calculated for C13H11N2O3 ([M+H]⁺): 243.0764, Found:

243.0774.

(Z)-N-(4-pyridinebenzylidene)aniline oxide (5.42g):²⁰ According to GP I: Nitrosobenzene (43 mg, 0.40 mmol), (E)-N-benzyl-1-(pyridin-4-yl)methanimine (0.12 g, 0.60 mmol) were reacted for 12 h, and flash chromatography of crude product (silica gel 230-400; EtOAc : hexane, 1:1) gave 5.42g as white solid (26 mg, 33%). ¹H NMR (600 MHz, CDCl3) δ = 8.76 (d, J = 6.0 Hz, 2H), 8.28 (d, J = 6.0 Hz, 2H), 8.03 (s, 1H), 7.78 – 7.77 (m, 2H), 7.54 – 7.52 (m, 3H) ppm. HRMS: Exact mass calculated for C12H11N2O ([M+H]⁺): 199.0866, Found: 199.0862.

Chapter 5

(Z)-N-(9-flurenylbenzylidene)aniline oxide (5.42h):²¹ According to GP I: Nitrosobenzene (43 mg, 0.40 mmol), N-benzyl-9H-fluoren-9-imine (0.16 g, 0.60 mmol) were reacted for 12 h, and flash chromatography of crude product (silica gel 230-400; EtOAc : hexane, 1:7) gave 5.42h as white solid (29 mg, 27%). ¹H NMR (500 MHz, CDCl3) δ = 8.85 (d, J = 7.5 Hz, 1H), 7.63 (d, J = 7.0 Hz, 1H), 7.57 (d, J = 7.5 Hz, 1H), 7.54 – 7.53 (m, 3H), 7.46 – 7.41 (m, 3H), 7.37 – 7.34 (m, 1H), 7.18 – 7.16 (m, 1H), 6.82 (t, J = 7.5 Hz, 1H), 5.83 (d, J = 8.0 Hz, 1H) ppm. HRMS: Exact mass calculated for C19H14NO ([M+H]⁺): 272.1070, Found: 272.1064.

General procedure for the synthesis of quinolines (II):

Nitrosoarene (1 eq.) was added to a solution of azomethine (1.5 eq.) in xylene (3mL). The mixture was heated at 120 – 130 ^oC for 12 h under argon atmosphere. After that, the reaction mixture was cooled down to room temperature. Styrene derivatives (2 eq.) and Yb(OTf)3 (15 mol%) were added to the reaction mixture. Then the reaction mixture was heated at 120 – 130 ^oC for another 24 under argon atmosphere. After the completion of reaction, the solvent was evaporated under reduced pressure. The reaction mixture was diluted with water (1x20 mL) and extracted with DCM (3x20 mL). The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The crude mixture was subjected to column chromatography (neutral alumina) to afford analytically pure products.

2-phenyl-4-(p-tolyl)quinoline (5.43a):²²According to GP II: Nitrosobenzene (30 mg, 0.28 mmol), (E)-N-benzyl-1-phenylmethanimine (82 mg, 0.42 mmol) were reacted for 12 h, 4-methylstyrene (66 mg, 0.56 mmol), Yb(OTf)3 (26 mg, 0.042 mmol) were added and reacted further for 24 h and column chromatography of crude product (neutral alumina; EtOAc : hexane, 1:40) gave 5.43a as yellow gum (53 mg, 64%). ¹H NMR (500 MHz, CDCl3) δ = 8.33 (d, J = 7.5 Hz, 1H), 8.21 (d, J = 8.0 Hz, 2H), 7.95 (d, J

= 8.5 Hz, 1H), 7.82 (s, 1H), 7.74 (t, J = 7.5 Hz, 1H), 7.55 – 7.47 (m, 6H), 7.37 (d, J = 8.0 Hz, 2H), 2.49 (s, 3H) ppm. HRMS: Exact mass calculated for C22H18N ([M+H]⁺): 296.1434, Found: 296.1441.