Dearomatization of N-Phenyl-2,6-dialkylpiperidines: Practical Synthesis of (±)-Solenopsin A and (±)-Dihydropinidine

Abstract

The fire ant venom alkaloid (±)-solenopsin A was prepared in 4 steps (34%) starting from the N-phenyl-2-undecyl piperidine (1c). The key step in this synthesis involved the dearomatization of the phenyl group of N-phenyl-2-methyl-6-undecyl-piperidine (9c), which was carried out under Birch conditions.

alkaloids - carbanions - diastereoselectivity - lithium - piperidines

References

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General Procedure (Method B) for the Preparation of Amines 4c-f: To 20 mL of liquid NH₃ 2 mL of anhyd. EtOH and 10 mL of THF containing 350 mg (1.35 mmol) of N-phenyl-2-heptylpiperidine (1e) were successively added. Under a stream of Ar, Li (0.1 g, 10 equiv) was added in small pieces, upon which the solution became blue. The resulting solution was stirred at -40 °C for 2 h. After the blue color had disappeared, the mixture was diluted with 10 mL of EtOH. To this mixture H₂O (100 mL) was added, and the aqueous phase was extracted with Et₂O. The combined organic phases were dried and concentrated in vacuo. The residue was dissolved in 10 mL of EtOH containing 1 mL of 37% HCl and refluxed for 10 min. EtOH was distilled, and the solid residue was stirred in a 20% KOH (5 mL) solution and extracted several times with Et₂O. The ethereal layers were combined and dried over MgSO₄. The crude product was chromatographed on silica column eluting with Et₂O saturated with gaseous NH₃ to give 200 mg (81%) of 2-heptylpiperidine(4e) as a slightly yellow oil: ¹H NMR (300 MHz, CDCl₃): δ = 0.85 (t, 3 H, J = 6.4 Hz), 0.95-1.10 (m, 1 H), 1.20-1.65 (m, 17 H), 1.70-1.80 (m, 1 H), 2.23-2.42 (m, 1 H), 2.10 (td, 1 H, J = 11.70 Hz and 2.85 Hz), 3.05 (dm, 1 H, J = 10.50 Hz). ¹³C NMR (75 MHz, CDCl₃): δ = 14.06, 22.63, 24.94, 25.88, 26.69, 29.25, 29.78, 31.80, 33.04, 37.53, 47.27, 56.91. HRMS: m/z calcd for C₁₂H₂₅N [M⁺]: 183.1987; found: 183.1987.

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<A NAME="RG17304ST-20C">20c</A>

Ref. [4e]

<A NAME="RG17304ST-21">21</A>

Preparation of (±)-Solenopsin A: To 20 mL of liquid NH₃ 4 mL of anhyd EtOH and 10 mL of THF containing 250 mg (0.76 mmol) of N-phenyl-2-methyl-6-undecylpiperidine (9c, c:t, 35:65) were successively added. Under a stream of Ar, Li (60 mg, 30 equiv) was added in small pieces, upon which the solution became blue. The resulting solution was stirred at -40 °C for 2 h. Workup [13] gave an oily residue, which was chromatographed on silica (eluent: Et₂O saturated with gaseous NH₃) to afford cis-10c (48 mg, 25%) and trans-10c (90 mg, 47%). (±)-Solenopsin A: ¹H NMR (300 MHz, CDCl₃): δ = 0.85 (t, 3 H, J = 6.30 Hz), 1.04 (d, 3 H, J = 6.60 Hz), 1.16-1.66 (m, 27 H), 2.80-2.88 (m, 1 H), 2.97-3.08 (m, 1 H). ¹³C NMR (75 MHz, CDCl₃): δ = 14.07 (CH₃-), 19.56, 21.24 (CH₃-), 22.63, 26.45, 29.33, 29.62, 29.64 (2 C), 29.78, 30.80, 31.89, 33.00, 34.07, 45.78 (CH-), 50.80 (CH-). HRMS: m/z calcd for C₁₇H₃₅N [M⁺]: 253.2769; found: 253.2760. (±)-Isosolenopsin A: ¹H NMR (300 MHz, CDCl₃): δ = 0.87 (t, 3 H, J = 6.04 Hz), 0.94-1.05 (m, 1 H), 1.05 (d, 3 H, J = 6.30 Hz), 1.20-1.65 (m, 25 H), 1.70-1.80 (m, 1 H), 2.42-2.50 (m, 1 H), 2.55-2.66 (m, 1 H). ¹³C NMR (75 MHz, CDCl₃): δ = 14.09, 22.67, 23.10, 24.88, 25.99, 29.34, 29.60, 29.62, 29.66, 29.84, 31.90, 32.28, 34.44, 37.47, 52.46, 57.13. HRMS: m/z calcd for C₁₇H₃₅N [M⁺]: 253.2769; found: 253.2767.