Synlett 2012; 23(17): 2463-2468
DOI: 10.1055/s-0031-1290467
letter
© Georg Thieme Verlag Stuttgart · New York

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

Francesco Berti
Dipartimento di Scienze Farmaceutiche, Sede di Chimica Bioorganica e Biofarmacia, Università di Pisa, Via Bonanno 33, 56126 Pisa, Italy   Fax: +39(050)2219660   eMail: pineschi@farm.unipi.it
,
Paolo Crotti
Dipartimento di Scienze Farmaceutiche, Sede di Chimica Bioorganica e Biofarmacia, Università di Pisa, Via Bonanno 33, 56126 Pisa, Italy   Fax: +39(050)2219660   eMail: pineschi@farm.unipi.it
,
Giulio Cassano
Dipartimento di Scienze Farmaceutiche, Sede di Chimica Bioorganica e Biofarmacia, Università di Pisa, Via Bonanno 33, 56126 Pisa, Italy   Fax: +39(050)2219660   eMail: pineschi@farm.unipi.it
,
Mauro Pineschi*
Dipartimento di Scienze Farmaceutiche, Sede di Chimica Bioorganica e Biofarmacia, Università di Pisa, Via Bonanno 33, 56126 Pisa, Italy   Fax: +39(050)2219660   eMail: pineschi@farm.unipi.it
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Publikationsverlauf

Received: 19. Juli 2012

Accepted after revision: 27. August 2012

Publikationsdatum:
21. September 2012 (online)


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.

 
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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 Ph3P (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; Rf  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; Rf 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; Rf 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; Rf 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 (Rf 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; Rf 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 (Rf 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; Rf 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; Rf 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.