Taming Silylium Ions for Synthesis: N-Heterocycle Synthesis via Stereoselective C–C Bond Formation

Published as part of the Cluster Silicon in Synthesis and Catalysis

Abstract

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 words

silylium ion - silylium catalysis - Lewis acid - Prins cyclization - Hosomi–Sakurai allylation - Si–X reagent - N-heterocycle - polycyclic scaffold

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• 13 The choice of arylsulfonyl protecting group was based on yield and general ease of substrate synthesis. Other N-protecting groups (e.g., Boc, Ac, Bz, TFA, and p-Ns) were found to be difficult to install in satisfactory yields and so were not investigated for compatibility in the Prins cyclization.
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• 16 The substrate is consumed; in the absence of a suitable trapping nucleophile, catalytic [Et₃Si][B(C₆F₅)₄] leads to a 54% NMR yield of eliminated products 22 and 23 in 78:22 cis/trans d.r.
• 17 Analysis of crude pre- and post-annulation ¹³C NMR suggests the reason for exclusively high d.r. but low yield is most likely due to double diastereo-differentiation during annulation of intermediate I; diastereomers with a trans-configuration of the C–O and C–Nu bonds decompose and/or are easily separated away from the cis-bridged products. We have not attempted to isolate or characterize the intermediate ketone diastereomers I.
• 18 Reaction with the corresponding acyclic acetophenone-derived silyl enol ether yielded only trace cyclized product (see Supporting Information).
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• 21 CCDC 1548662 contains the supplementary crystallographic data for this structure. The data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/getstructures.
• 22 DFT calculations (ωB97X-D//6-311+G**//CPCM:CH₂Cl₂) on 2-methyl-1-(phenylsulfonyl)piperidine show the lowest energy axial conformer to be 3.3 kcal/mol more stable than the lowest energy equatorial conformer. We speculate that this is paralleled in TS and TS′.
• 23 Interestingly, 10 mol% HBArF₂₄ ([H(OEt₂)₂][B(C₆H₃(CF₃)₂)₄], Brookhart’s acid) as catalyst provided hydride-trapped 6 in an inferior 47% NMR yield but 45:36:19 d.r. favoring the same dia­stereomers as those resulting from the putative silylium ion catalysis (cf. Table 1, entry 2; see Supporting Information). This suggests that the reaction can be catalyzed by Brønsted acid and that co-catalysis could be operative via adventitious water. See: Schmidt RK. Muether K. Mueck-Lichtenfeld C. Grimme S. Oestreich M. J. Am. Chem. Soc. 2012; 134: 4421
• 24 The relative stereochemistry of cis- and trans-tetrahydropyridine products was determined via X-ray crystallography and comparison of ¹H NMR and ¹³C NMR data (see S19 in the Supporting Information).
• 25a Attempts to intercept the carbocation with R₃Si–Nu using BCF have been unsuccessful; Et₃Si–H hydrosilylates the aldehyde in 32% NMR yield, along with 44% of 23, and 7% and 12%, respectively, of minor isomers B and C of 6.
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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 (R_f = 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).