Evidence for a Radical Mechanism in Cu(II)-Promoted SnAP Reactions

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.

Key words

SnAP reagents - N-heterocycles - morpholines - cyclization - radical clock - mechanism

• References and Notes

• 1 Present address: Michael. U. Luescher, Department of Chemistry and Chemical Biology (CCB), Harvard University, Cambridge, MA 02138, United States of America
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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, J_CF = 1.40 Hz), 130.1 (q, J_CF = 32.4 Hz), 127.7, 125.6 (q, J_CF = 3.72 Hz), 124.2 (q, J_CF = 272.2 Hz), 73.6, 67.4, 60.3, 46.5; R_f = 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; R_f = 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; R_f = 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; R_f = 0.21 (hexanes/EtOAc 2:1); mp = 70–72 °C; ESI-HRMS: m/z [M + H]⁺ calcd for C₁₄H₁₉N₄O₁: 271.1553; found: 271.1558.