CC BY-ND-NC 4.0 · Synlett 2019; 30(04): 464-470
DOI: 10.1055/s-0037-1611670
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Evidence for a Radical Mechanism in Cu(II)-Promoted SnAP Reactions

,
Laboratory of Organic Chemistry (LOC), Department of Chemistry and Applied Biosciences (D-CHAB), ETH Zurich, 8093 Zurich, Switzerland   eMail: bode@org.chem.ethz.ch
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This work was supported by the European Research Council (ERC Starting Grant No. 306793-CASAA).
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Publikationsverlauf

Received: 14. Dezember 2018

Accepted after revision: 10. Januar 2019

Publikationsdatum:
05. Februar 2019 (eFirst)

  

Dedicated to a great mentor and teacher – Rick L. Danheiser

Published as part of the 30 Years SYNLETT – Pearl Anniversary Issue

Abstract

Saturated nitrogen heterocycles can be found with increasing abundance in bioactive molecules despite a limited number of methods to access these scaffolds. However, the coupling of recently introduced SnAP [tin (Sn) amine protocol] reagents with a wide range of aldehydes and ketones has proven to be a reliable, practical, and versatile one-step approach to saturated N-heterocycles. While effective, the lack of mechanistic understanding limits efforts to develop new catalytic and enantioselective variants. To distinguish between a polar or radical mechanism, we assessed Lewis and Brønsted acids, radical trapping experiments, and radical clock SnAP reagents reinforcing the current understanding of the SnAP protocol as a radical cyclization.

Supporting Information

 
  • References and Notes

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  • 20 General Procedure SnAP Protocol Imine formation: To a solution of the SnAP reagent (0.50 mmol, 1.00 equiv) in CH2Cl2 or acetonitrile (3.0 mL) at r.t. was added the corresponding aldehyde (0.50 mmol, 1.00 equiv) and 3 Å or 4 Å MS powder (ca. 50 mg). The reaction mixture was stirred at r.t. for 4 h and filtered through a short layer of Celite (CH2Cl2 rinse). The filtrate was concentrated under reduced pressure to afford the pure air-stable imine that was used in the next step without further purification. SnAP cyclization: Separately, anhydrous Cu(OTf)2 (0.50 mmol, 1.00 equiv) was suspended in CH2Cl2–HFIP (3:1; 8.0 mL). 2,6-Lutidine (0.50 mmol, 1.00 equiv) was added and the resulting bluish suspension was stirred at r.t. for 1 h to afford a dark green suspension. A solution of the imine (0.50 mmol, 1.00 equiv) in CH2Cl2 (2.0 mL) was added in one portion and the resulting mixture was stirred at r.t. for 12 h. The reaction mixture was diluted with CH2Cl2 (20 mL), treated with a solution of 12% aq NH4OH and brine (1:1, 20 mL), and stirred vigorously for 20 min at r.t. The layers were separated, and the aqueous layer was extracted with CH2Cl2 (2 x 5 mL). The combined organic layers were washed with H2O (2 x 5 mL) and brine (10 mL), dried with anhydrous Na2SO4, filtered, and concentrated. Purification by flash column chromatography afforded the desired C-substituted unprotected morpholines. Spectral Data for Selected Compounds
    3-(4-(Trifluoromethyl)phenyl)morpholine (7)
    : Yield: 98.5 mg (86%); clear colorless oil; IR (thin film): 3313, 3068, 2961, 2912, 2889, 2852, 1676, 1603, 1584, 1398, 1365, 1335, 1232, 1105 cm–1; 1H NMR (400 MHz, CDCl3): δ = 7.59 (d, J = 8.2 Hz, 2 H), 7.52 (d, J = 8.2 Hz, 2 H), 3.99 (dd, J = 10.0, 3.2 Hz, 1 H), 3.93–3.85 (m, 1 H), 3.81 (dd, J = 11.1, 3.2 Hz, 1 H), 3.65 (td, J = 11.1, 2.7 Hz, 1 H), 3.35 (dd, J = 11.1, 10.0 Hz, 1 H), 3.14 (td, J = 11.6, 3.3 Hz, 1 H), 3.01 (dt, J = 11.8, 2.0 Hz, 1 H), 1.90 (br s, NH); 13C NMR (100 MHz, CDCl3): δ = 144.7 (q, JCF = 1.40 Hz), 130.1 (q, JCF = 32.4 Hz), 127.7, 125.6 (q, JCF = 3.72 Hz), 124.2 (q, JCF = 272.2 Hz), 73.6, 67.4, 60.3, 46.5; Rf = 0.18 (hexanes/EtOAc 1:1); ESI-HRMS: m/z [M + H] calcd for C11H13F3N1O1: 232.0944; found: 232.0946. (±)–cis-3-Ethyl-5-(4-methyl-3-nitrophenyl) morpholine (15): Yield: 102 mg (82%, d.r. > 20:1); colorless oil; IR (thin film): 2963, 2932, 2878, 2848, 1528, 1454, 1349, 1105cm–1; 1H NMR (400 MHz, CDCl3): δ = 8.03 (d, J = 1.8 Hz, 1 H), 7.52 (dd, J = 7.9, 1.8 Hz, 1 H), 7.29 (d, J = 7.9 Hz, 1 H), 4.01 (dd, J = 10.2, 3.2 Hz, 1 H), 3.84 (dd, J = 10.9, 3.0 Hz, 1 H), 3.78 (dd, J = 11.0, 3.2 Hz, 1 H), 3.28–3.14 (m, 2 H), 2.96–2.85 (m, 1 H), 2.56 (s, 3 H), 1.89 (br s, NH), 1.50–1.27 (m, 2 H), 0.94 (t, J = 7.5 Hz, 3 H); 13C NMR (100 MHz, CDCl3): δ = 149.5, 147.4, 140.3, 132.9, 132.7, 132.0, 123.4, 73.2, 72.0, 59.7, 56.8, 25.5, 20.2, 10.1; Rf = 0.30 (hexanes/EtOAc 1:1); ESI-HRMS: m/z [M + H]+ calcd for C13H19N2O3: 251.1390; found: 251.1394. (3S,5R)-3-(4-Methyl-3-nitrophenyl)-5-vinylmorpholine (16): Yield: 94.4 mg (76%, d.r. > 20:1); colorless oil; IR (thin film): 2988, 2849, 1738, 1528, 1275, 1261, 1102 cm–1; 1H NMR (400 MHz, CDCl3): δ = 8.06 (d, J = 1.8 Hz, 1 H), 7.55 (dd, J = 7.9, 1.8 Hz, 1 H), 7.30 (d, J = 7.9 Hz, 1 H), 5.77 (ddd, J = 17.3, 10.4, 6.8 Hz, 1 H), 5.35 (dt, J = 17.3, 1.4 Hz, 1 H), 5.23–5.12 (m, 1 H), 4.07 (dd, J = 10.2, 3.2 Hz, 1 H), 3.81 (td, J = 10.4, 3.2 Hz, 2 H), 3.65–3.50 (m, 1 H), 3.33–3.19 (m, 2 H), 2.58 (s, 3H), 1.93 (br s, NH); 13C NMR (100 MHz, CDCl3): δ = 149.5, 140.1, 136.5, 133.1, 133.0, 132.0, 123.5, 117.6, 72.9, 71.3, 59.2, 58.6, 20.3; Rf = 0.68 (hexanes/EtOAc 1:1); ESI-HRMS: m/z [M + H]+ calcd for C13H17N2O3: 249.1234; found: 249.1231. (±)-cis-3-[4-(1H-1,2,4-Triazol-1-yl)phenyl]-6-vinyl-1,4-oxazepane (25): Yield: 64.5 mg (48%, d.r. > 20:1); colorless oil; IR (thin film): 3433, 2938, 2857, 1638, 1522, 1280, 1144, 983, 836 cm–1; 1H NMR (400 MHz, CDCl3): δ = 8.53 (s, 1 H), 8.09 (s, 1 H), 7.63 (d, J = 8.5 Hz, 2 H), 7.51 (d, J = 8.5 Hz, 2 H), 5.91 (ddd, J = 17.3, 10.5, 8.1 Hz, 1 H), 5.14–5.00 (m, 2 H), 4.13–3.97 (m, 3 H), 3.56 (dd, J = 12.4, 9.6 Hz, 1 H), 3.43 (dd, J = 13.0, 10.5 Hz, 1 H), 3.24 (dd, J = 13.9, 4.9 Hz, 1 H), 3.12 (dd, J = 13.9, 3.5 Hz, 1 H), 2.77–2.66 (m, 1 H), 2.09 (br s, NH); 13C NMR (100 MHz, CDCl3): δ = 152.7, 141.6, 141.0, 138.8, 136.4, 128.6, 120.3, 115.6, 80.6, 75.5, 66.3, 51.9, 47.2; Rf = 0.21 (hexanes/EtOAc 2:1); mp = 70–72 °C; ESI-HRMS: m/z [M + H]+ calcd for C14H19N4O1: 271.1553; found: 271.1558.