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Synlett 2006(19): 3314-3318  
DOI: 10.1055/s-2006-951553
LETTER
© Georg Thieme Verlag Stuttgart · New York

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

Rupert A. Hunter, Donald P. S. Macfarlane, Richard J. Whitby*
School of Chemistry, University of Southampton, Southampton, Hants SO17 1BJ, UK
Fax: +44(2380)593781; e-Mail: rjw1@soton.ac.uk;
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Publication History

Received 29 August 2006
Publication Date:
23 November 2006 (online)

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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.

Key words

zirconium - neuroactive - pyrrolidine - solid-phase - library

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 Hcis, 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 Hcis, m), 1.93-1.76 (2 Htrans, m), 0.91 (3 Hcis, d, J = 7.3 Hz), 0.85 (3 Htrans, 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.

19

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

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 Htrans, m), 3.49 (1 H, m), 3.31-2.86 (4 H + 1Hcis, m), 2.81-2.71 (2 Hcis, m), 2.58-2.41 (2 Htrans, m), 2.38 (3 H, s), 2.36-2.29 (2 Hcis, m), 2.10-1.88 (2 Htrans, m), 1.33-1.23 (3 H, m), 1.11 (3 Htrans, d, J = 7 Hz), 1.07 (3 Hcis, 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.