A Two-Step Synthesis of Selected 1,2,3,4-Tetrahydroquinoxaline Derivatives from N-Aryl-2-nitrosoanilines and Arylidenecyanoacetic Esters

Abstract

Reaction of N-aryl-2-nitrosoanilines with alkyl aryl­idenecyanoacetates in the presence of Et₃N in MeCN leads to substituted 1,2,3,4-tetrahydroquinoxaline derivatives in reasonable yields. The reaction comprises nucleophilic addition of the nitrosoaniline to the Michael acceptor followed by cyclization involving the nitroso group. Since the reactive nitrogen groups in N-aryl-2-­nitrosoanilines are of opposite character the reaction is regioselective and additionally it was found to be diastereoselective.

Key words

Michael addition - ring closure - condensation - heterocycles - reduction

• References and Notes

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• 10 General Procedure for the Synthesis of Compound 4 To a solution of N-aryl-2-nitrosoaniline 1 (1 mmol) and arylidenecyanoacetic ester 2 (1.2 mmol) in dry MeCN (10 mL) was added Et₃N (0.73 mL, 5 mmol). The mixture was stirred until the reaction was complete (TLC control, times shown in Table 1). The mixture was then evaporated to dryness, treated with AcOH (10 mL), then Zn dust (650 mg, 10 mmol) was added. The mixture was stirred for 30 min at r.t. and evaporated to dryness in vacuo. The residue was treated with EtOAc (30 mL) and aq NaHCO₃, filtered through a Celite pad, and extracted with EtOAc (3 × 20 mL). The extract was dried (Na₂SO₄), the solvent was evaporated, and the product was isolated by column chromatography (SiO₂, hexane–EtOAc).
• 11 Analytical Data for Representative Products Compound 3a: grey crystals; mp 132–134 °C (Et₂O–hexane). ¹H NMR (500 MHz, DMSO-d ₆): δ = 0.95 (t, J = 7.0 Hz, 3 H), 2.20 (s, 3 H), 4.00–4.06 (m, 2 H), 5.60 (s, 1 H), 6.10 (s, 1 H), 6.84 (dd, J = 8.5, 1.1 Hz, 1 H), 7.10 (s, 5 H), 7.45 (d, J = 8.5 Hz, 1 H), 7.22–7.28 (m, 3 H), 7.33–7.40 (m, 2 H), 10.52 (s, 1 H). ¹³C NMR (125 MHz, DMSO-d ₆): δ = 13.4, 20.5, 63.0, 66.2, 70.9, 113.2, 114.2, 117.6, 118.5, 126.6, 128.1, 128.8, 129.1, 129.2, 130.2, 132.9, 133.9, 136.4, 137.4, 139.6, 162.8. Anal. Calcd for C₂₅H₂₂ClN₃O₃: C, 67.04; H, 4.95; N, 9.38. Found: C, 67.08; H, 5.03; N, 9.28. Compound 4a: white crystals; mp 185–187 °C (EtOH). ¹H NMR (500 MHz, DMSO-d ₆): δ = 1.01 (t, J = 7.0 Hz, 3 H), 2.24 (s, 3 H), 4.06–4.17 (m, 2 H), 5.25 (s, 1 H), 6.27 (d, J = 2.3 Hz, 1 H), 6.74 (dd, J = 8.5, 2.3 Hz, 1 H), 6.81 (d, J = 8.5 Hz, 1 H), 6.89–6.92 (m, 2 H), 7.11–7.15 (m, 2 H), 7.32 (s, 5 H), 7.76 (s, 1 H). ¹³C NMR (125 MHz, DMSO-d ₆): δ = 14.1, 20.9, 60.2, 63.7, 64.8, 114.2, 116.2, 116.4, 119.5, 123.1, 126.3, 128.7, 128.9, 129.2, 130.6, 130.8, 133.6, 135.8, 136.9, 142.1, 165.4. MS (EI): m/z = 433 (36), 432 (29), 431 (100), 406 (13), 405 (10), 404 (35), 360 (28), 359 (23), 358 (81), 333 (21), 332 (18), 331 (58), 330 (13), 329 (30), 328 (12), 327 (54). Anal. Calcd for C₂₅H₂₂ClN₃O₂: C, 69.52; H, 5.13; N, 9.73. Found: C, 69.60; H, 5.19; N, 9.79.
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