Microwave-Assisted Reductive Cyclization of N-Allyl 2-Nitroanilines: A New Approach to Substituted 1,2,3,4-Tetrahydroquinoxalines

Abstract

N-Allyl 2-nitrophenyl amines can be efficiently cyclized to yield alkenyl-1,2,3,4-tetrahydroquinoxalines in a single reaction step by means of a new microwave-assisted reductive domino ­process.

Key words

cyclizations - domino reactions - ene reactions - microwaves - tetrahydroquinoxalines

References and Notes

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12

Selected Data for 2a (Figure [3] ):
R _f 0.40 (PE-EtOAc, 20:1). IR (ATR): 3376 (NH), 2952, 2854 (Me, CH₂), 1691 (C=O), 1604, 1501 (C=C), 1435, 1382, 1372 (COO^-), 1232, 1211, 1146, 1061 (=COC), 900, 760, 741 cm^-1. UV-Vis (EtOH): λ_max (log ε) = 307 (2.48), 253 (2.40), 220 (2.34) nm. ¹H NMR (300 MHz, CDCl₃): δ = 1.85 (s, 3 H, 3′-Me), 3.58 (dd, ² J = 12.3 Hz, ³ J = 6.2 Hz, 1 H, 2-H), 3.81 (s, 3 H, OMe), 3.98 (dd, ³ J = 3.4, 6.2 Hz, 1 H, 3-H), 4.02 (dd, ² J = 12.3 Hz, ³ J = 3.3 Hz, 1 H, 2-H), 4.98 (br s, 1 H, 2′-H), 5.05 (br s, 1 H, 2′-H), 6.65 (dd, ³ J = 8.0 Hz, ⁴ J = 1.4 Hz, 1 H, 5-H), 6.70 (ddd, ³ J = 7.4, 8.2 Hz, ⁴ J = 1.5 Hz, 1 H, 7-H), 6.97 (ddd, ³ J = 7.4, 7.9 Hz, ⁴ J = 1.4 Hz, 1 H, 6-H), 7.48 (br s, 1 H, 8-H). ¹³C NMR (75 MHz, CDCl₃): δ = 19.57 (C-3′), 45.25 (C-2), 53.24 (OMe), 56.72 (C-3), 112.87 (C-2′), 114.4 (C-5), 116.9 (C-7), 123.9 (C-9), 124.61 (C-8), 125.4 (C-6), 137.09 (C-10), 144.3 (C-1′), 155.3 (C=O). MS (EI, 70 eV): m/z (%) = 232 (100) [M⁺], 218 (8), 199 (14), 191 (40), 173 (21), 157 (18), 131 (40), 106 (7), 77 (7). Anal. Calcd for C₁₃H₁₆N₂O₂: C, 67.22; H, 6.94; N, 12.06. Found: C, 67.43; H, 7.01; N, 11.99.

Figure 4

13

Selected Data for 3a (Figure [4] ):
R _f 0.59 (PE-EtOAc, 20:1). IR (ATR): 2980, 2958 (Me, CH₂), 1702 (C=O), 1602, 1504 (C=C), 1438, 1375, 1344 (COO^-), 1217, 1190, 1145, 1062 (=COC), 899, 733 cm^-1. UV-Vis (EtOH): λ_max (log ε) = 310 (2.49), 258 (2.41), 223 (2.35) nm. ¹H NMR (300 MHz, CDCl₃): δ = 1.17 (t, ³ J = 7.1 Hz, 3 H, 2′′-Me), 1.80 (s, 3 H, 3′-Me), 3.15-3.27 (over-lapped, 2 H, 1′′-CH₂), 3.52 (dd, ² J = 13.1 Hz, ³ J = 7.1 Hz, 1 H, 2-H), 3.76 (s, 3 H, OMe), 3.94 (t, ³ J = 7.1 Hz, 1 H, 3-H), 4.37 (dd, ² J = 12.9 Hz, ³ J = 7.1 Hz, 1 H, 2-H), 4.81 (br s, 1 H, 2′-H), 4.93 (br s, 1 H, 2′-H), 6.62 (dd, ³ J = 8.1 Hz, ⁴ J = 1.1 Hz, 1 H, 5-H), 6.75 (ddd, ³ J = 7.8, 8.1 Hz, ⁴ J = 1.2 Hz, 1 H, 7-H), 7.06 (ddd, ³ J = 7.8, 8.1 Hz, ⁴ J = 1.2 Hz, 1 H, 6-H), 7.4 (br s, 1 H, 8-H). ¹³C NMR (75 MHz, CDCl₃): δ = 11.76 (C-2′′), 19.60 (C-3′), 43.50 (C-1′′), 43.82 (C-2), 53.12 (OMe), 62.76 (C-3), 110.56 (C-2′), 113.5 (C-5), 115.1 (C-7), 124.3 (C-9), 124.7 (C-8), 125.8 (C-6), 137.9 (C-10), 143.06 (C-1′), 155.4 (C=O). MS (EI, 70 eV): m/z (%) = 260 (100) [M⁺], 245 (16), 231 (26), 219 (58), 213 (12), 190 (34), 171 (20), 159 (30), 131 (27), 119 (6), 92 (3), 77 (12), 41 (3), 28 (3). HRMS (EI): m/z [M⁺] calcd for C₁₅H₂₀N₂O₂: 260.1525; found: 260.1507.

16

Scheme [3] shows a mechanism involving a triplet nitrene. However, the occurrence of a singlet nitrene cannot be ruled out.

18

General Procedure for the Synthesis of Alkenyl-1,2,3,4-tetrahydroquinoxalines under Microwave Conditions: A solution of 1a (1 mmol), (EtO)₃P (6 mmol) and toluene (3 mL) in a 10-mL septum-sealed reaction vial was irradiated with microwaves (Discover^TM by CEM; 2450 MHz; 300 W; 200 °C). After removal of (EtO)₃P and (EtO)₃PO (10^-1 mbar) the residue was taken up in EtOAc (25 mL) and washed with brine (3 × 20 mL). The residue obtained after drying over MgSO₄ and after concentration in vacuo was purified by flash chromatography on silica gel (PE-EtOAc, 20:1).