Organozirconium-Mediated Solution- and Solid-Phase Synthesis of 3-Benzyl Pyrrolidines and Other Potentially Neuroactive Amines

Abstract

An efficient route to 3-benzylpyrrolidines using a zirconium-mediated cyclisation both in solution and on a solid support is reported. 3-Benzylidine-pyrrolidines, 3-aryl-pyrrolidines and 4-arylpiperidines were also synthesised.

zirconium - neuroactive - pyrrolidine - solid-phase - library

References and Notes

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Pyrrolidines:

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Piperidines:

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8e

Azepanes: Macfarlane, D. P. S.; Norton, D.; Whitby, R. J.; Tupper, D. Synlett, submitted.

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17

Synthesis of 1-Benzyl-3-methyl-4-(4-methyl-benzyl)pyrrolidine.
Cp₂ZrCl₂ (0.35 g, 1.2 mmol) in THF (5 mL) was cooled to -78 °C before BuLi (0.96 mL of 2.5 M solution in hexane, 2.4 mmol) was added slowly. The reaction was stirred for 20 min at -78 °C before N-allylbenzyl[(E)-3-(4-methyl-phenyl)allyl]amine (0.277 g, 1 mmol) in THF (5 mL) was added slowly. The reaction was warmed to r.t. and stirred for 24 h. MeOH (5 mL) and sat. aq NaHCO₃ solution (5 mL) were added and mixture stirred overnight. Extractive work-up and chromatography (SiO₂, 1% Et₃N, in 40:60 PE) gave the title pyrrolidine as a 5:1 mixture of trans- to cis-dia-stereoisomers as a colourless oil (226 mg, 81%). ¹H NMR (300 MHz, CDCl₃): δ = 7.25-7.10 (5 H, m), 7.00-6.94 (4 H, m), 3.57-3.50 (1 H, m), 3.48-3.39 (1 H, m), 2.94 (1 H_cis, m), 2.75-2.61 (2 H, m), 2.57-2.25 (3 H, m), 2.22 (3 H, s), 2.13-2.04 (1 H, m), 2.02-1.96 (1 H_cis, m), 1.93-1.76 (2 H_trans, m), 0.91 (3 H_cis, d, J = 7.3 Hz), 0.85 (3 H_trans, d, J = 6.5 Hz) ppm. ¹³C NMR (75 MHz, CDCl₃): δ (trans-isomer): 139.59 (C), 138.42 (C), 135.33 (C), 129.09 (CH), 128.87 (CH), 128.82 (CH), 128.31 (CH), 126.90 (CH), 62.36 (CH₂), 60.87 (CH₂), 60.30 (CH₂), 48.00 (CH), 40.49 (CH₂), 38.96 (CH), 21.16 (CH₃), 19.41 (CH₃) ppm; δ (cis-isomer): 139.70 (C), 138.65 (C), 135.26 (C), 129.14 (CH), 128.87 (CH), 128.65 (CH), 128.32 (CH), 126.90 (CH), 62.62 (CH₂), 61.12 (CH₂), 59.84 (CH₂), 41.95 (CH), 35.35 (CH₂), 34.50 (CH), 21.16 (CH₃), 15.17 (CH₃) ppm. IR: 3025 (w), 2952 (m), 2915 (m), 2782 (m), 1514 (m), 1453 (s), 1376 (m), 1028 (m) cm^-1. LRMS (EI): m/z (%) = 279 (59) [M], 187 (87), 173 (76), 158 (83). HRMS (ES⁺): m/z calcd for C₂₀H₂₆N⁺ [M + H⁺] 280.2060; found: 280.2057.

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19

A carbamate linker could not be used as Cp₂Zr(1-butene) caused cleavage of the allyl-nitrogen bond rather than cyclisation.

20 Norton D. PhD Thesis   University of Southampton; UK: 2004. 

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23

Solid-Phase Route to 14b.
Merrifield resin (18.75 g, 1.6 mmol/g, 30 mmol), allylamine (600 mmol, 45 mL) in THF (120 mL) were heated at 75 °C overnight. The resin was filtered and washed with dry distilled THF (10 × 60 mL) then dried in a vacuum oven at 40 °C for 5 d to give resin-bound N-allylamine 10 as a white solid (19.5 g). IR: 3082 (w), 3025 (w), 2919 (m), 2848 (w), 1601 (w), 1510 (m), 1493 (m), 1452 (s) cm^-1. 4-Methyl cinnamic acid (3.24 g, 20 mmol) and HOBT (2.70 g, 20 mmol) were stirred for 15 min in DMF (30 mL). The reaction flask was cooled to 0 °C before DIC (3.1 mL, 20 mmol) was added. The flask was warmed to r.t. before stirring for a further 15 min. The reaction mixture was then poured into a plastic filter vessel containing 10 (3.25 g,
5 mmol), suspended in DMF (30 mL). The reaction was agitated for 1 week, filtered and washed with hot DMF, MeOH, CH₂Cl₂ and Et₂O. The resin was dried using a vacuum oven at 40 °C for 2 d to give the pale yellow resin-bound (E)-N-allyl-3-(4-methylphenyl)acrylamide (11b, 3.38 g). IR: 3024 (w), 2924 (m), 1650 (s), 1605 (s), 1512 (m), 1452 (s), 1411 (s), 1200 (s) cm^-1. In a dry peptide tube, 11b (0.338 g, 0.5 mmol) was suspended in THF (40 mL). Then, AlH₃ (1.2 mL of a 0.55 M solution in THF, 0.65 mmol, 1.3 equiv) was added under an argon atmosphere. The reaction was shaken overnight, filtered and the resin washed under argon with dry THF and Et₂O, and dried under vacuum for 2 h to afford resin-bound N-allyl-N-[(E)-3-(4-methyl-phenyl)prop-2-enyl]amine (12b). IR: 3025 (w), 2921 (w), 1644 (w), 1602 (w), 1493 (m), 1452 (m), 1067 (m) cm^-1. Cp₂ZrCl₂ (0.438 g, 1.5 mmol, 3 equiv) in THF (10 mL) was cooled to -78 °C before BuLi (1.2 mL of 2.5 M solution, 3 mmol) was added. The reaction was stirred for 30 min at -78 °C before being added via cannular to resin 12b (0.5 mmol) suspended in THF (40 mL). The reaction was warmed to r.t. and shaken for 20 h. The resulting burgundy-coloured resin mixture was quenched with MeOH (5 mL) and sat. NaHCO₃ (5 mL), shaken overnight, filtered and washed with hot H₂O, MeOH, CH₂Cl₂ and Et₂O before drying under vacuum for 2 h to afford resin-bound 3-methyl-4-(4-methylbenzyl)pyrrolidine (13b). IR: 2923 (w), 1567 (m), 1493 (w), 1451 (w), 1367 (m), 1020 (w) cm^-1. Resin 13b (0.5 mmol) was suspended in dry CH₂Cl₂ (10 mL), ethyl chloroformate (0.15 mL, 1.5 mmol) added and the mixture boiled under reflux for 2 h. The resin was filtered, washed with CH₂Cl₂ (3 × 50 mL) and the washings were con-centrated in vacuo to give ethyl 3-methyl-4-(4-methyl-benzyl)pyrrolidine-1-carboxylate (14b) as a colourless oil (74 mg, 57% based on resin used) in >90% purity based on a comparison with the NMR spectra of the pure carbamate prepared by the solution-phase cleavage of 6b. [24]

24

Solution-Phase Route to 14b.
N-Benzyl-3-methyl-4-(4-methylbenzyl)pyrrolidine (6b, 0.14 g, 0.5 mmol) and ethylchloroformate (0.15 mL, 1.5 mmol) in CH₂Cl₂ (10 mL) were heated at 65 °C for 3 h. The CH₂Cl₂ was removed in vacuo and the resulting brown oil purified by column chromatography (SiO₂, Et₂O-PE, 1:1). Kugelrohr distillation (0.1 mmHg, 220 °C) gave 14b as a colourless oil (94 mg, 72%). ¹H NMR (400 MHz, CDCl₃): δ = 7.18-7.06 (4 H, m), 4.21-4.10 (2 H, m), 3.77-3.62 (1 H_trans, m), 3.49 (1 H, m), 3.31-2.86 (4 H + 1H_cis, m), 2.81-2.71 (2 H_cis, m), 2.58-2.41 (2 H_trans, m), 2.38 (3 H, s), 2.36-2.29 (2 H_cis, m), 2.10-1.88 (2 H_trans, m), 1.33-1.23 (3 H, m), 1.11 (3 H_trans, d, J = 7 Hz), 1.07 (3 H_cis, d, J = 7 Hz) ppm. ¹³C NMR (100 MHz, CDCl₃; where signals are separated by ‘/’ they correspond to rotomers due to the carbamate group): δ (trans-isomer) = 155.23 (C), 137.13 / 136.99 (C), 135.80 (C), 129.29 (CH), 128.74 / 128.71 (CH), 60.95 (CH₂), 53.45 / 53.21 (CH₂), 51.73 / 51.35 (CH₂), 47.70 / 46.99 (CH), 38.66 / 37.98 (CH₂), 37.71 / 37.61 (CH), 21.13 (CH₃), 16.46 (CH₃), 15.02 (CH₃) ppm; δ (cis-isomer; derived from comparison of 5:1 and 2:1 trans:cis isomer mixed from solution- and solid-phase routes, respectively) = 155.58 (C), 137.52 / 137.47 (C), 135.72 / 135.69 (C), 129.33 (CH), 128.65 (CH), 60.98 (CH₂), 53.35 (CH₂), 49.44 / 49.09 (CH₂), 43.89 / 43.24 (CH), 35.45 / 34.74 (CH), 33.88 / 33.84 (CH₂), 21.13 CH₃), 15.02 (CH₃), 13.71 / 13.64 (CH₃) ppm. IR: 2931 (w), 2870 (w), 1695 (s), 1515 (w), 1420 (s), 1349 (m) cm^-1. LRMS (EI): m/z (%) = 261 (33) [M⁺], 216 (8), 156 (79), 105 (100). Anal. Calcd (%) for C₁₆H₂₃NO₂: C, 73.53; H, 8.87; N, 5.36. Found: C, 73.29; H, 8.78; N, 5.40.

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