Enantioselective Copper-Catalyzed Reductive Coupling of Vinylazaarenes with N-Boc Aldimines

Abstract

The diastereo- and enantioselective reductive coupling of vinylazaarenes with N-Boc aldimines is described. The reactions proceed using chiral copper–bisphosphine complexes in the presence of TMDS as a hydride source to give reductive coupling products in moderate to high enantioselectivities.

Key words

asymmetric catalysis - copper - enantioselectivity - imines - vinylazaarenes

• References and Notes

• 1 For an overview of C=N-containing azaarenes as activating groups in enantioselective catalysis, see: Best D, Lam HW. J. Org. Chem. 2014; 79: 831

For reactions from our group describing the use of C=N-containing azaarenes as activating groups in enantioselective catalysis, see:
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• 9 General Procedure for the Reductive Coupling of Vinylazaarenes with Imine 2a Using Ligand L1A solution of the appropriate vinylazaarene (0.30 mmol), Cu(OAc)₂·H₂O (3.0 mg, 0.01 mmol), (S)-DTBM-SEGPHOS (L1, 17.7 mg, 0.015 mmol), and imine 2a (68 mg, 0.33 mmol) in THF (1.5 mL) was stirred at 0 °C for 15 min. TMDS (64 μL, 0.36 mmol) was then added dropwise over 1 min. The mixture was stirred at 0 °C for 1 h, then at r.t. for 15 h. The reaction was quenched carefully with SiO₂, and the resulting suspension was stirred for 15 min before being filtered through a short plug of SiO₂ using EtOAc as eluent and concentrated in vacuo. Purification of the residue by flash column chromatography gave the reductive coupling product.Data for 3a R_f = 0.31 (20% EtOAc–PE); mp 128–131 °C (EtOAc–PE); [α]_D ²⁴ +98.6 (c 1.10, CHCl₃). IR (film): 2970, 2934, 1709 (C=O), 1503, 1390, 1289, 827, 756, 700 cm^–1. ¹H NMR [500 MHz, (CD₃)₂CO]: δ = 8.14 (d, J = 8.4 Hz, 1 H), 8.05 (d, J = 8.3 Hz, 1 H), 7.88 (d, J = 8.0 Hz, 1 H), 7.75 (ddd, J = 8.4, 6.9, 1.4 Hz, 1 H), 7.57–7.51 (m, 1 H), 7.33 (d, J = 7.3 Hz, 2 H), 7.24 (t, J = 8.0 Hz, 3 H), 7.16 (t, J = 7.0 Hz, 2 H), 5.09 (t, J = 7.7 Hz, 1 H), 3.63–3.54 (m, 1 H), 1.35 (d, J = 6.9 Hz, 3 H), 1.27 (s, 9 H). ¹³C NMR [125.8 MHz, (CD₃)₂CO]: δ = 165.1, 156.0, 148.5, 144.1, 137.0, 130.2, 129.7, 128.9, 128.6, 128.0, 127.7, 127.5, 126.8, 122.8, 78.5, 60.2, 48.1, 28.5, 19.6. ESI-HRMS: m/z calcd for C₂₃H₂₇N₂O₂ [M + H]⁺: 363.2067; found: 363.2067. HPLC: Chiralcel OD-H column (i-hexane–i-PrOH, 90:10; 1.0 mL/min, 254 nm, 25 °C); t _R (major) = 4.6 min, t _R (minor) = 5.9 min; 85% ee.Data for 3f R_f = 0.32 (20% EtOAc–PE); mp 142–145 °C (EtOAc–PE); [α]_D ²⁴ +55.0 (c 1.00, CHCl₃). IR (film): 2979, 2928, 1713 (C=O), 1498, 1390, 1365, 1170, 1022, 759, 700 cm^–1. ¹H NMR [400 MHz, (CD₃)₂CO]: δ = 7.98 (t, J = 8.9 Hz, 2 H), 7.54–7.45 (m, 1 H), 7.45–7.35 (m, 3 H), 7.30 (t, J = 7.4 Hz, 2 H), 7.23 (t, J = 7.5 Hz, 1 H), 6.80 (d, J = 7.5 Hz, 1 H), 5.15–4.90 (m, 1 H), 3.88–3.65 (m, 1 H), 1.37 (d, J = 6.8 Hz, 3 H), 1.28 (s, 9 H). ¹³C NMR [125.8 MHz, (CD₃)₂CO]: δ = 174.7, 155.9, 154.1, 142.9, 135.6, 129.1, 128.0, 127.8, 126.8, 125.7, 123.4, 122.6, 78.9, 60.3, 45.1, 28.5, 19.5. ESI-HRMS: m/z calcd for C₂₁H₂₅N₂O₂S [M + H]⁺: 369.1631; found: 369.1634. HPLC: Chiralpak IC column (hexane–i-PrOH, 98:2; 0.8 mL/min, 280 nm, 25 °C); t _R (major) = 18.9 min, t _R (minor) = 27.9 min; 88% ee.
• 10 Where indicated, the relative and absolute stereochemistries of the products were assigned by analogy with those of products 3f,g, 4d,k,q,t, which were determined by X-ray crystallography (see Supporting Information for details). CCDC 1019731–1019736 contain the supplementary crystallographic data for this paper. These data can be obtained free of charge from the Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif or by writing to the ­Cambridge Crystallographic Data Centre, 12, Union Road, ­Cambridge CB2 1EZ, UK; fax: [phone]; e-mail: [e-mail].