Enantioselective (3+2)-Annulation of β-Keto Esters with Azoalkenes towards Bicyclic Dihydropyrroles via Cooperative Palladium and Brønsted Acid Catalysis

Abstract

A cooperative catalytic process through palladium and Brønsted acid activation is developed for the conjugate addition of cyclic β-keto esters to azoalkenes directly followed by hemiaminal formation upon cyclization. This transformation is enabled by utilizing chiral Pd-aqua complexes as combined Brønsted acid–base catalysts. Thus, bicyclic and highly functionalized dihydropyrroles with two contiguous quaternary stereogenic centers are formed in excellent yields as single diastereomers and with exceptional enantioselectivity.

Key words

asymmetric catalysis - azoalkenes - (3+2) cycloaddition - cooperative catalysis - heterocycles - Pd-aqua complexes - Pd-enolates

Publication History

Received: 05 October 2023

Accepted after revision: 13 November 2023

Accepted Manuscript online:
13 November 2023

Article published online:
14 December 2023

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• 13 Annulation; General Procedure Azoalkene 5 (0.20 mmol), β-keto ester 3 (0.30 mmol, 1.50 equiv), and [(R)-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl]-diaquo-palladium(II) bis(triflate) (1e) (0.01 mmol, 5 mol%) were added to a screw-cap vial and dissolved in dry ethyl acetate (2.0 mL) and then stirred until complete consumption of the starting material (monitored by TLC). Purification by flash column chromatography over SiO₂ resulted in the corresponding products 8. 3a-(tert-Butyl) 3-Ethyl 6a-Hydroxy-2-methyl-1-(phenylamino)-4,5,6,6a-tetrahydrocyclopenta[b]pyrrole-3,3a(1H)-dicarboxylate (8a) Yield: 79.7 mg (99%); beige solid; [α]_D ²³ –46 (c 1.00, CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ = 7.24–7.18 (m, 2 H), 6.92–6.78 (m, 3 H), 6.15 (s, 1 H), 4.22 (dq, J = 10.8, 7.1 Hz, 1 H), 4.06 (dq, J = 10.8, 7.1 Hz, 1 H), 3.79 (s, 1 H), 2.75 (s, 1 H), 2.28 (s, 3 H), 2.04–1.87 (m, 2 H), 1.80–1.61 (m, 3 H), 1.49 (s, 9 H), 1.26 (t, J = 7.1 Hz, 3 H). ¹³C NMR (100.6 MHz, CDCl₃): δ = 165.9, 162.0, 148.9, 129.5, 120.6, 112.6, 104.8, 82.1, 64.3, 59.2, 35.6, 28.2, 23.1, 14.6, 12.4. IR (KBr): 3421, 3327, 2977, 5930, 1721, 1667, 1602, 1497, 1454, 1377, 1369, 1326, 1317, 1289, 1245, 1186, 1165, 1100, 1065, 993, 921, 886, 846, 753, 695, 666, 506 cm^–1. HRMS (ESI): m/z [M + H]⁺ calcd for C₂₂H₃₁N₂O₅: 403.223; found: 403.226. HPLC: Chiralpak IA (n-hexane/2-propanol = 90:10, flow rate = 1.0 mL min^–1, λ = 280 nm); t _R = 10.05 min (major), t _R = 28.73 (minor); e.r. 99:1.
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