Taming Silylium Ions for Synthesis: N-Heterocycle Synthesis via Stereoselective C–C Bond FormationThis work was financially supported by the DOE (Basic Energy Sciences, DE-FG02-05ER15630)
Received: 08 May 2017
Accepted after revision: 28 June 2017
16 August 2017 (eFirst)
Published as part of the Cluster Silicon in Synthesis and Catalysis
Silylium ions (formally [R3Si]+) have long been the subject of investigations and significant debate in both theoretical and experimental chemistry, but few catalytic, synthetic applications have been reported due to the exceptionally high reactivity and Lewis acidity of these elusive species. Results to be discussed include the application of easily accessible silylium ion catalysts to the stereoselective synthesis of various N-heterocyclic pyrrolidine and piperidine scaffolds. The tested substrates are derived from the chiral pool and can be obtained in three high-yielding steps from amino alcohols; subsequent stereoselective silylium ion catalyzed Prins cyclization and trapping with R3Si–Nu nucleophiles (e.g., Nu = H, allyl, azide, and enol ethers) results in novel nitrogen-containing polycyclic scaffolds with potential medicinal chemistry applications.
Key wordssilylium ion - silylium catalysis - Lewis acid - Prins cyclization - Hosomi–Sakurai allylation - Si–X reagent - N-heterocycle - polycyclic scaffold
References and Notes
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- 26 Representative Procedure for the Synthesis of Piperidine 20 In a dry, N2-filled glove box, aldehyde S16 (0.150 mmol, 68.3 mg, 1.00 equiv) and trityl BArF20 (0.0150 mmol, 13.8 mg, 0.10 equiv) were weighed into a screw-cap 1 dram vial equipped with a stir bar and sealed with a septum cap. In a separate vial, Et3SiH (0.0180 mmol, 2.9 μL, 0.12 equiv) and cyclohexanone-derived silyl enol ether (0.375 mmol, 72 μL, 2.50 equiv) were dissolved in 3.00 mL of CH2Cl2 and the vial sealed with a septum cap. Both vials were removed from the glove box, and the vial containing the aldehyde and trityl BArF20 was cooled to –78 °C in an acetone/CO(s) bath. The room-temperature solution in CH2Cl2 was syringed dropwise and slowly down the side of the vial into the vigorously stirring solution over 5–10 min. The reaction was stirred for an additional 2 h at –78 °C, quenched with 50 μL Et3N, and warmed to r.t. The solution was repeatedly washed with CH2Cl2 (3×; to remove excess base) and dried in vacuo. The resulting residue was taken up in 2 mL of 1:1 CH2Cl2/MeOH, approximately 10–20 beads of Dowex resin (50W-X8) were added, and the reaction was stirred at 22 °C for 3 h. The mixture was then filtered through a cotton/sand plug, rinsed with 1 mL CH2Cl2 (2×), and concentrated in vacuo. The crude residue was purified by silica gel chromatography (Rf = 0.5, n-pentane/EtOAc = 5:1), providing heterocycle 20 as a crystalline white solid in 55% yield (44.3 mg). 1H NMR (600 MHz, CDCl3): δ = 8.50 (d, 1 H J = 1.9 Hz), 8.01 (d, 1 H, J = 8.7 Hz), 7.99 (d, 1 H, J = 8.2 Hz), 7.95 (d, 1 H, J = 8.0 Hz), 7.90 (dd, 1 H, J = 8.7, 1.9 Hz), 7.67 (ddd, 1 H, J = 8.2, 6.9, 1.4 Hz), 7.63 (ddd, 1 H, J = 8.2, 6.8, 1.4 Hz), 7.37 (t, 2 H, J = 7.7 Hz), 7.29 (dd, 2 H, J = 8.2, 1.3 Hz), 7.27–7.22 (m, 3 H), 7.18 (d, 1 H, J = 7.4 Hz), 7.16 (dd, 2 H, J = 7.1, 1.6 Hz), 4.69 (dd, 1 H, J = 11.4, 2.7 Hz), 3.89 (dt, 1 H, J = 4.0, 1.9 Hz), 3.57 (dd, 1 H, J = 12.7, 3.5 Hz), 3.40 (d, 1 H, J = 11.5 Hz), 3.30 (ddd, 1 H, J = 11.6, 3.6, 1.8 Hz), 2.85 (t, 1 H, J = 12.8, 11.6 Hz), 2.39–2.32 (m, 2 H), 2.24–2.19 (m, 1 H), 1.94–1.90 (m, 1 H), 1.72–1.53 (m, 6 H). 13C NMR (151 MHz, CDCl3): δ = 150.1, 143.5, 139.6, 138.2, 134.8, 132.4, 129.8, 129.4, 129.3, 128.9, 128.6, 128.6, 128.1, 127.8, 127.7, 126.7, 126.6, 126.4, 122.5, 106.3, 67.4, 65.5, 54.1, 39.1, 39.0, 35.8, 27.8, 24.8, 23.4, 23.1. HRMS (ESI+): m/z calcd for C34H34NO3S+ [M + H]+: 536.2260; found: 536.2259. [α]D 26 +11.7 (c 1.70, CH2Cl2, l = 100 mm).
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See (a) and (b) for Kira–Piers mechanism:
For an ACS Catalysis Perspective, see:
For a recent review, see:
For selected examples, see:
For a review, see:
For selected modern asymmetric examples, see: