Asymmetric Synthesis of 2-Arylpyrrolidines by Cationic Cyclization

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.

Key words

amines - carbocation - cyclization - enantioselectivity - heterocycles

• 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: ν_max = 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: ν_max = 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.