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.

Key words

zirconium - neuroactive - pyrrolidine - solid-phase - library

References and Notes

• 1a Kane BE. Svensson B. Ferguson DM. AAPS Journal  2006,  8:  E126 
• 1b Glennon RA. Ismaiel AM. Smith JD. Yousif M. El-Ashmawy M. Herndon JL. Fischer JB. Howie KJB. Server AC. J. Med. Chem.  1991,  34:  1855 
• 2 Horwell DC. Naylor D. Willems HMG. Bioorg. Med. Chem. Lett.  1997,  7:  31 
• 3 Thomas C. Ohnmacht U. Niger M. Gmeiner P. Bioorg. Med. Chem. Lett.  1998,  8:  2885 
• 4a Defauw JM. Murphy MM. Jagdmann GE. Hu H. Lampe JW. Hollinshead SP. Mitchell TJ. Crane HM. Heerding JM. Mendoza JS. Davis JE. Darges JW. Hubbard FR. Hall SE. J. Med. Chem.  1996,  39:  5215 
• 4b Jagdmann GE. Defauw JM. Lampe JW. Darges JW. Kalter K. Bioorg. Med. Chem. Lett.  1996,  6:  1759 
• 5a Negishi E. Holmes SJ. Tour JM. Miller JA. J. Am. Chem. Soc.  1985,  107:  2568 
• 5b Nugent WA. Taber DF. J. Am. Chem. Soc.  1989,  111:  6435 
• 6 Dixon S. Fillery SM. Kasatkin A. Norton D. Thomas E. Whitby RJ. Tetrahedron  2004,  60:  1401 ; and references therein
• Pyrrolidines:
• 7a Rousset CJ. Swanson DR. Lamaty F. Negishi E. Tetrahedron Lett.  1989,  30:  5105 
• 7b Uesaka N. Saitoh F. Mori M. Shibasaki M. Okamura K. Date T. J. Org. Chem.  1994,  59:  5633 
• 7c Saitoh F. Mori M. Okamura K. Date T. Tetrahedron  1995,  51:  4439 
• 7d Mori M. Kuroda S. Zhang CS. Sato Y. J. Org. Chem.  1997,  62:  3263 
• 7e Campbell AD. Raynham TM. Taylor RJK. J. Chem. Soc., Perkin Trans. 1  2000,  3194 
• Piperidines:
• 8a Kemp MI. Whitby RJ. Coote SJ. Synthesis  1998,  557 
• 8b Kemp MI. Whitby RJ. Coote SJ. Synthesis  1998,  552 
• 8c Mori M. Imai AE. Uesaka N. Heterocycles  1995,  40:  551 
• 8d Bird AJ. Taylor RJK. Wei X. Synlett  1995,  1237 
• 8e

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

• 9 Zhou Z.-L. Keana JFW. J. Org. Chem.  1999,  64:  3763 
• 10 Brown RCD. Fisher M. Chem. Commun.  1999,  1547 
• 11a Bolton GL. Tetrahedron Lett.  1996,  37:  3433 
• 11b Bolton GL. Hodges JC. Rubin JR. Tetrahedron  1997,  53:  6611 
• 11c Spitzer JL. Kurth MJ. Schore NE. Tetrahedron  1997,  53:  6791 
• 12 Brown RCD. Castro JL. Moriggi JD. Tetrahedron Lett.  2000,  41:  3681 
• 13 Jones G. Org. React.  1967,  15:  204 
• 14 Akamatsu H. Kusumoto S. Fukase K. Tetrahedron Lett.  2002,  43:  8867 
• 15a Yoon NM. Brown HC. J. Am. Chem. Soc.  1968,  90:  2927 
• 15b Matecka D. Rothman RB. Radesca L. de Costa BR. Dersch CM. Partilla JS. Pert A. Glowa JR. Wojnicki FHE. Rice KC. J. Med. Chem.  1996,  39:  4704 
• 15c Shah JH. Kline RH. Geter-Douglass B. Izenwasser S. Witkin JM. Newman AH. J. Med. Chem.  1996,  39:  3423 
• 16a Negishi E. Holmes SJ. Tour JM. Miller JA. Cederbaum FE. Swanson DR. Takahashi T. J. Am. Chem. Soc.  1989,  111:  3336 
• 16b Negishi E. Cederbaum FE. Takahashi T. Tetrahedron Lett.  1986,  27:  2929 
• 18a Whitesell JK. Minton MA. Stereochemical Analysis of Alicyclic Compounds by C-13 NMR Spectroscopy   Chapman and Hall; London, New York: 1987.  p.37-55  
• 18b Ando T. Kusa K. Uchiyama M. Yoshida S. Takahashi N. Agric. Biol. Chem.  1983,  47:  2849 
• 20 Norton D. PhD Thesis   University of Southampton; UK: 2004. 
• 21 Sasakura K. Adachi M. Sugasawa T. Synth. Commun.  1988,  18:  265 
• 22 Vojkovsky T. Peptide Res.  1995,  8:  236 
• 25a Bishop DC. Selway RA. Webb NE. Winder CV. Welford M. Cavalla JF. J. Med. Chem.  1965,  1:  316 
• 25b Lyles-Eggleston M. Altundas R. Xia J. Sikazwe DMN. Fan P. Yang Q. Li S. Zhang W. Zhu X. Schmidt AW. Vanase-Frawley M. Shrihkande A. Villalobos A. Borne RF. Ablordeppey SY. J. Med. Chem.  2004,  47:  497 
• 25c Sonesson C. Wikstrom H. Smith MW. Svensson K. Carlsson A. Waters N. Bioorg. Med. Chem. Lett.  1997,  7:  241 
• 26 Leander DJ. Cantrell BE. Reel JK. Snoddy J. Laurane MG. Johnson BG. Mitch CH. Zimmerman DM. J. Med. Chem.  1993,  36:  2833 

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.

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 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.