Synlett 2012; 23(16): 2405-2407
DOI: 10.1055/s-0032-1317114
letter
© Georg Thieme Verlag Stuttgart · New York

Asymmetric Synthesis of 2-Arylpyrrolidines by Cationic Cyclization

Iain Coldham*
a   Department of Chemistry, University of Sheffield, Brook Hill, Sheffield S3 7HF, UK, Fax: +44(114)2229346   Email: i.coldham@sheffield.ac.uk
,
Steven P. Robinson
a   Department of Chemistry, University of Sheffield, Brook Hill, Sheffield S3 7HF, UK, Fax: +44(114)2229346   Email: i.coldham@sheffield.ac.uk
,
Carl A. Baxter
b   Global Process Chemistry, Merck Sharp and Dohme Research Laboratories, Hertford Road, Hoddesdon EN11 9BU, UK
› Author Affiliations
Further Information

Publication History

Received: 28 June 2012

Accepted after revision: 24 July 2012

Publication Date:
24 August 2012 (online)


Abstract

Homoallylic amines were prepared by asymmetric deprotonation of benzylamines using n-BuLi and (–)-sparteine to give chiral organolithiums to which were added prenyl bromide. Removal of the Boc protecting group gave anilines that were found to undergo Brønsted acid catalyzed or iodine-mediated cyclization to give aryl-substituted pyrrolidine heterocyclic products with high enantioselectivity.

 
  • References and Notes

  • 1 Leonori D, Coldham I. Adv. Synth. Catal. 2009; 351: 2619
  • 2 For a review of hydroaminations, see: Müller TE, Hultzsch KC, Yus M, Foubelo F, Tada M. Chem. Rev. 2008; 108: 3795
    • 3a Miura K, Hondo T, Nakagawa T, Takahashi T, Hosomi A. Org. Lett. 2000; 2: 385
    • 3b Schlummer B, Hartwig JF. Org. Lett. 2002; 4: 1471
    • 3c Haskins CM, Knight DW. Chem. Commun. 2002; 2724
    • 3d Yin Y, Zhao G. Heterocycles 2006; 68: 23
    • 3e Baeza A, Nájera C. Synlett 2011; 631
    • 4a For photocyclization of anilines, see: Benali O, Miranda MA, Rormos R, Gil S. J. Org. Chem. 2002; 67: 7915
    • 4b For acid-mediated cyclization of aminopyridines, see: Métro T.-X, Fayet C, Arnaud F, Rameix N, Fraisse P, Janody S, Sevrin M, George P, Vogel R. Synlett 2011; 684
  • 5 Barker G, McGrath JL, Klapars A, Stead D, Zhou G, Campos KR, O’Brien P. J. Org. Chem. 2011; 76: 5936 ; and references cited therein
    • 6a Park YS, Beak P. J. Org. Chem. 1997; 62: 1574
    • 6b Kim BJ, Park YS, Beak P. J. Org. Chem. 1999; 64: 1705
    • 6c Faibish NC, Park YS, Lee S, Beak P. J. Am. Chem. Soc. 1997; 119: 11561

      For iodine-mediated cyclizations of sulfonamides, see:
    • 7a Amjad M, Knight DW. Tetrahedron Lett. 2006; 47: 2825
    • 7b Davis FA, Song M, Augustine A. J. Org. Chem. 2006; 71: 2779
  • 8 For a preference for conjugate addition of this organolithium·(–)-sparteine complex with an enone, see: Park YS, Weisenburger GA, Beak P. J. Am. Chem. Soc. 1997; 119: 10537
  • 9 Procedure for the Acid-Mediated Cyclization TFA (0.4 mL, 5.2 mmol) was added to the carbamate 4a (200 mg, 0.52 mmol) in CH2Cl2 (0.5 mL), and the mixture was heated under reflux. After 16 h, the mixture was cooled to r.t., and H2O (5 mL) was added. The aqueous layer was extracted with CH2Cl2 (3 × 10 mL). The organic layers were combined, dried (MgSO4), and evaporated. Purification by column chromatography on silica, eluting with PE–EtOAc (9:1), gave the pyrrolidine 5a (102 mg, 69%) as an oil; [α]D 20 +16.3 (c 6.5, CHCl3). IR: νmax = 2975, 2930, 1690, 1510 cm–1. 1H NMR (400 MHz, CDCl3): δ = 7.38–7.23 (5 H, m, Ph), 6.80–6.59 (4 H, m, Ar), 4.26 (1 H, t, J = 6.5 Hz, CH), 3.72 (3 H, s, CH3), 2.06–1.87 (2 H, m, CH2), 1.77–1.59 (2 H, m, CH2), 1.52 (3 H, s, CH3), 1.51 (3 H, s, CH3). 13C NMR (100 MHz, CDCl3): δ = 156.0, 128.8, 127.7, 126.9, 115.8, 114.7, 113.9, 112.9, 88.6, 65.7, 55.6, 37.2 (2 × CH2), 25.5, 25.3. HRMS (ES): m/z calcd for C19H24NO [MH+]: 282.1858; found: 282.1854. Resolution between the enantiomers was achieved using a Beckmann HPLC system fitted with a Daicel Chiralcel OJ column (250 mm × 4.6 mm) as the stationary phase with a mixture of hexane–i-PrOH (99:1 v/v) as the mobile phase with a flow rate of 1 mL/min; ambient temperature, detection by UV absorbance at λ = 254 nm. Injection volume 25 μL of the sample prepared in a 2 g/L solution of the eluent. Under these conditions the components were eluted at t R = 35.5 min (major) and t R = 48.5 min (minor), er 94:6.
  • 10 Procedure for the Iodine-Mediated Cyclization Iodine (203 mg, 0.8 mmol) was added to the carbamate 6a (75 mg, 0.26 mmol) in MeCN (0.9 mL) at r.t. After 24 h, sat. aq Na2SO4 (5 mL) was added. After 30 min, the solvent was evaporated, and Et2O (10 mL) was added. The organic layer was washed with H2O (5 mL), dried (MgSO4), and evaporated. Purification by column chromatography on silica, eluting with PE–EtOAc (9:1), gave the pyrrolidine 7a (86 mg, 79%) as an oil; [α]D 20 +48.0 (c 1.0, CHCl3). IR: νmax = 2970, 2920, 1605, 1505 cm–1. 1H NMR (400 MHz, CDCl3): δ = 7.29–7.24 (3 H, m, Ph), 6.92 (2 H, t, J = 8.5 Hz, Ph), 6.84 (2 H, d, J = 9.0 Hz, Ar), 6.71 (2 H, d, J = 9.0 Hz, Ar), 4.81 (1 H, dd, J = 9.5, 6.0 Hz, CH), 4.25 (1 H, dd, J = 12.0, 6.0 Hz, CH), 3.72 (3 H, s, CH3), 2.84 (1 H, dt, J = 12.0, 6.0 Hz, CH), 2.35 (1 H, td, J = 12.0, 9.5 Hz, CH), 1.70 (3 H, s, CH3), 1.24 (3 H, s, CH3). 13C NMR (100 MHz, CDCl3): δ = 138.6, 127.9, 122.3, 120.5, 118.3, 115.4, 115.1, 113.7, 64.2, 63.8, 55.3, 45.9, 36.0, 31.2, 24.5. HRMS (ES): m/z calcd for C19H23INO [MH+]: 408.0819; found: 408.0817.