Copper-Catalyzed Arylation of Alkenyl Aziridines via Three-Component Coupling Reaction involving Alkynes and Benzyne

Abstract

Alkenyl aziridines can be successfully arylated in a three-component coupling triggered by in situ generated benzyne with a simple copper catalyst (CuI–PPh₃), without the need of any palladium salts. The corresponding allylic amines can be obtained with good to high regioselectivity in mild reaction conditions with a variety of cyclic and acyclic alkenyl aziridines. A new domino reaction with ethyl propiolate to give tetrahydrophenanthridine was also found.

Key words

arylation - copper catalysis - aziridine - terminal alkyne - benzyne

• References

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• 12 The following reagents were purchased from Aldrich and used as received: CuI (99.999%); 2-(trimethylsilyl)phenyl trifluoromethanesulfonate (97%); CsF (99.9%); Ph₃P (≥99%); phenylacetylene (98%); propargyl acetate (98%); 1-octyne (97%); ethyl propiolate (99%). Typical Procedure for the Three-Component Coupling with Alkenyl Aziridines (Table 1, Entry 8): In a dried Schlenk tube flushed with argon, CuI (1.5 mg, 8.1 μmol), and Ph_3P (4.2 mg, 16.2 μmol) were placed in anhyd MeCN (1.2 mL). The solution was stirred for 10 min at r.t. and then CsF (68.4 mg, 0.45 mmol), o-trimethylsilylphenyl triflate (41.3 μL, 0.17 mmol), phenylacetylene (16.5 μL, 0.15 mmol) and aziridine 1a (0.135 mmol) were sequentially added. After stirring at 55 °C for 5 h, the suspension was filtered on Celite through a glass sintered Buchner funnel washing with CH₂Cl₂. The crude residue was purified by flash chromatography eluting with hexanes–EtOAc (8:2; R_f  0.10) to afford 46 mg (80%) of (1R*,4R*)-4-{[2-(phenylethynyl)phenyl]cyclohex-2-enyl}benzenesulfon-amide (3aa), as an oil. ¹H NMR (250 MHz, CDCl₃): δ = 1.60–2.22 (m, 4 H), 2.43 (s, 3 H), 4.00 (br, 2 H), 4.78 (br, 1 H, NHTs), 5.62 (d, 1 H, J = 10.1 Hz), 5.81 (d, 1 H, J = 10.1 Hz), 7.08–7.52 (m, 11 H), 7.81 (d, 2 H, J = 8.5 Hz). ¹³C NMR (62.5 MHz, CDCl₃): δ = 21.53, 28.9, 29.8, 39.2, 49.7, 87.5, 93.6, 122.3, 123.2, 126.3, 127.0, 128.4 (2 × C), 128.6, 129.0, 129.8, 131.4, 132.4, 133.7, 138.3, 143.4, 146.2. MS (ESI): m/z = 450 [M + Na]⁺. Anal. Calcd for C₂₇H₂₅NO₂S: C, 75.85; H, 5.89; N, 3.28. Found: C, 76.04; H, 5.68; N, 3.13. Compound 3ca (Table 2, Entry 3): Following the typical procedure, the crude residue was purified by flash chromatography eluting with hexanes–EtOAc (8:2; R_f 0.27), to afford compound 3ca (53 mg, 82%) as an oil. ¹H NMR (250 MHz, CDCl₃): δ = 2.34 (s, 3 H), 3.50 (d, 2 H, J = 6.1 Hz), 4.73 (d, 1 H, J = 7.1 Hz, NHTs), 4.92 (t, 1 H, J = 6.2 Hz), 5.52 (dd, 1 H, J = 15.3, 6.1 Hz), 5.60–5.77 (m, 1 H), 7.05–7.28 (m, 10 H), 7.30–7.39 (m, 3 H), 7.41–7.53 (m, 3 H), 7.57 (d, 2 H, J = 7.9 Hz). ¹³C NMR (62.5 MHz, CDCl₃): δ = 21.4, 37.1, 59.3, 87.8, 93.4, 122.7, 123.2, 126.2, 127.0, 127.1, 127.5, 128.3, 128.4 (2 × C), 128.5, 128.8, 129.3, 130.5, 131.2, 131.4, 132.2, 137.6, 139.9, 141.3, 143.0. MS (ESI): m/z = 500 [M + Na]⁺. Anal. Calcd for C₃₁H₂₇NO₂S: C, 77.96; H, 5.70; N, 3.28. Found: C, 78.02; H, 5.68; N, 3.14. Compound 3cb (Table 2, Entry 4): Following the typical procedure, the title compound was purified by semipreparative TLC plates eluting with hexanes–EtOAc (9:1; R_f 0.16, two runs), to afford compound 3cb (29 mg, 45%) as a yellowish oil. ¹H NMR (250 MHz, CDCl₃): δ = 0.89 (t, 3 H, J = 6.0 Hz), 1.25–1.72 (m, 10 H), 2.37 (s, 3 H), 3.41 (d, 2 H, J = 6.3 Hz), 4.67 (d, 1 H, J = 6.5 Hz, NHTs), 4.92 (app. t, 1 H, J = 6.5 Hz), 5.49 (dd, 1 H, J = 6.3, 15.5 Hz), 5.59–5.71 (m, 1 H), 6.95–7.42 (m, 11 H), 7.58 (d, 2 H, J = 7.8 Hz). ¹³C NMR (62.5 MHz, CDCl₃): δ = 14.0, 19.5, 21.5, 22.5, 28.6, 28.8, 31.3, 37.0, 59.3, 79.1, 94.6, 123.6, 126.1, 127.0, 127.2, 127.6, 127.6, 128.5, 129.3, 130.3, 131.6, 132.2, 137.7, 140.0, 141.1, 143.1. MS (ESI): m/z = 508 [M + Na]⁺. Anal. Calcd for C₃₁H₃₅NO₂S: C, 76.66; H, 7.26; N, 2.88. Found: C, 76.85; H, 7.13; N, 2.80. Compound 3dd (Table 2, Entry 5): Following the typical procedure, the crude residue was purified by flash chroma-tography eluting with hexanes–EtOAc (8:2; R_f 0.05) to afford compound 3dd (41 mg, 60%) as a brown oil. ¹H NMR (250 MHz, CDCl₃): δ = 2.11 (s, 3 H), 2.37 (s, 3 H), 3.30–3.50 (m, 2 H), 3.75 (s, 3 H), 4.80–4.90 (m, 3 H), 5.18 (d, 1 H, J = 7.1 Hz), 5.49–5.56 (m, 2 H), 6.67–6.87 (m, 2 H), 6.97–7.43 (m, 8 H), 7.57 (d, 2 H, J = 8.3 Hz). ¹³C NMR (62.5 MHz, CDCl₃): δ = 20.7, 21.4, 37.1, 52.8, 55.2, 58.7, 84.8, 86.9, 113.7, 121.6, 127.1, 128.2, 128.9, 129.0, 129.2, 130.5, 130.7, 132.2, 132.6, 137.7, 141.8, 142.8, 158.9, 170.7. MS (ESI): m/z = 530 [M + Na]⁺. Anal. Calcd for C₂₉H₂₉NO₅S: C, 69.16; H, 5.80; N, 2.78. Found: C, 70.04; H, 5.76; N, 2.65. Compound 3ac (Table 2, Entry 6): Following the typical procedure the chromatographic purification was performed with hexanes–EtOAc (9:1) containing 4% of Et₃N (R_f 0.12) to afford compound 3ac (43 mg, 74%) as a yellow oil. ¹H NMR (250 MHz, CDCl₃): δ = 1.46–1.75 (m, 7 H), 2.09–2.25 (m, 5 H), 2.43 (s, 3 H), 3.91–4.03 (m, 2 H), 4.68 (br, 1 H, NHTs), 5.57 (dt, 1 H, J = 10.1, 2.3 Hz), 5.76 (dt, 1 H, J = 10.1, 0.8 Hz), 6.13–6.20 (m, 1 H), 7.03–7.38 (m, 6 H), 7.80 (d, 2 H, J = 8.5 Hz). ¹³C NMR (62.5 MHz, CDCl₃): δ = 21.4, 21.5, 22.2, 25.7, 28.7, 29.1, 29.7, 39.0, 49.6, 84.4, 95.5, 120.7, 122.8, 126.1, 126.8, 127.0, 127.9, 128.8, 129.7, 132.1, 133.8, 135.0, 138.2, 143.3, 145.8. MS (ESI): m/z = 454 [M + Na]⁺. Anal. Calcd for C₂₇H₂₉NO₅S: C, 75.14; H, 6.77; N, 3.25. Found: C, 75.25; H, 6.60; N, 3.20. Compound 3ad (Table 2, Entry 7): Following the typical procedure, the title compound was purified by semipreparative TLC plates eluting with toluene–hexanes–Et₂O (4:2:1, 2 runs; R_f 0.18), to afford 3ad (48 mg, 84%) as a yellow oil. ¹H NMR (250 MHz, CDCl₃): δ = 1.39–1.99 (m, 3 H), 2.01–2.19 (m, 4 H), 2.44 (s, 3 H), 3.79–3.89 (m, 1 H), 3.90–4.04 (m, 1 H), 4.50 (d, 1 H, J = 8.9 Hz, NHTs), 4.89 (s, 2 H), 5.58 (dt, 1 H, J = 10.1, 2.4 Hz), 5.73 (dt, 1 H, J = 10.1, 0.8 Hz), 7.06–7.45 (m, 7 H), 7.80 (d, 2 H, J = 6.7 Hz). ¹³C NMR (62.5 MHz, CDCl₃): δ = 20.8, 21.5, 29.0, 29.8, 39.0, 49.7, 52.8, 84.6, 87.0, 121.2, 126.2, 126.9, 127.0, 129.0, 129.1, 129.7, 132.7, 133.4, 138.3, 143.3, 146.7, 170.3. MS (ESI): m/z = 446 [M + Na]⁺. Anal. Calcd for C₂₄H₂₅NO₄S: C, 68.06; H, 5.95; N, 3.31. Found: C, 68.60; H, 5.70; N, 3.30. Compound 3ec (Table 2, Entry 8): Following the typical procedure, the crude residue was purified by flash chromatography eluting with hexanes–EtOAc (9:1) containing 4% Et₃N (R_f 0.07) to afford compound 3ec (32 mg, 57%) as a yellow oil. ¹H NMR (250 MHz, CDCl₃): δ = 1.57–1.75 (m, 4 H), 1.94–2.24 (m, 6 H), 2.42 (s, 3 H), 4.41–4.65 (m, 3 H), 5.65–5.71 (m, 1 H), 5.90–5.96 (m, 1 H), 6.13–6.20 (m, 1 H), 6.94–7.21 (m, 3 H), 7.25–7.40 (m, 3 H), 7.77 (d, 2 H, J = 8.3 Hz). ¹³C NMR (62.5 MHz, CDCl₃): δ = 21.4, 21.5, 22.3, 25.7, 40.5, 46.0, 47.4, 59.7, 85.0, 97.2, 120.1, 123.0, 125.4, 126.3, 127.0, 128.1, 129.7, 131.9, 132.1, 135.1, 138.1, 143.1, 145.0, 145.5. MS (ESI): m/z = 440 [M + Na]⁺. Anal. Calcd for C₂₆H₂₇NO₂S: C, 74.79; H, 6.52; N, 3.35. Found: C, 75.10; H, 6.45; N, 3.32.Compound 3ae: Purified by flash chromatography eluting with hexanes–EtOAc (8:2; R_f 0.12); yellowish oil. ¹H NMR (250 MHz, CDCl₃): δ = 1.35 (t, 3 H, J = 7.0 Hz), 1.45–1.65 (m, 2 H), 1.85–2.00 (m, 1 H), 2.05–2.20 (m, 1 H), 2.43 (s, 3 H), 3.83–3.94 (m, 1 H), 3.93–4.05 (m, 1 H), 4.28 (q, 2 H, J = 7.0 Hz), 4.71 (d, 1 H, J = 9.0 Hz, NHTs), 5.60–5.67 (m, 2 H), 7.10–7.41 (m, 5 H), 7.53 (d, 1 H, J = 7.8 Hz), 7.80 (d, 2 H, J = 8.3 Hz). ¹³C NMR (62.5 MHz, CDCl₃): δ = 14.1, 21.5, 29.4, 29.8, 39.2, 49.6, 62.1, 84.3, 84.7, 118.7, 126.5, 127.0, 127.3, 129.6, 129.8, 130.9, 132.8, 133.9, 138.3, 143.4, 148.4, 174.9. MS (ESI): m/z = 446 [M + Na]⁺. Anal. Calcd for C₂₄H₂₅NO₄S: C, 68.06; H, 5.95; N, 3.31. Found: C, 68.22; H, 5.88; N, 3.24. Compound 4: Purified by flash chromatography eluting with hexanes–EtOAc (8:2; R_f 0.28); yellowish oil. ¹H NMR (250 MHz, CDCl₃): δ = 1.24 (t, 3 H, J = 7.0 Hz), 1.30–1.42 (m, 1 H), 1.82–2.02 (m, 1 H), 2.32 (s, 3 H), 2.28–2.38 (m, 1 H), 2.86 (br dd, 1 H, J = 2.8, 12.3 Hz), 3.14–3.32 (m, 2 H), 4.16 (q, 2 H, J = 7.0 Hz), 5.88–6.00 (m, 1 H), 6.11 (br d, 1 H, J = 11.5 Hz), 6.49 (s, 1 H), 6.81–7.42 (m, 8 H). ¹³C NMR (62.5 MHz, CDCl₃): δ = 14.3, 21.6, 25.7, 31.6, 40.6, 60.5, 60.6, 120.3, 121.2, 123.0, 124.9, 128.0, 128.7, 129.3, 129.6, 130.0, 132.7, 134.9, 137.6, 143.9, 147.0, 165.3. MS (ESI): m/z = 446 [M + Na]⁺. Anal. Calcd for C₂₄H₂₅NO₄S: C, 68.06; H, 5.95; N, 3.31. Found: C, 68.45; H, 5.78; N, 3.28.