Use of Polymer-Supported 4-(N,N-Dimethylamino)pyridine in a Formal Conjugate Addition/Elimination Mediated by an N-Ylide Generated In Situ for the Construction of Highly Functionalized Itaconimides/Alkenes

Abstract

A simple, mild, and metal-free cascade reaction has been developed for the construction of highly functionalized olefins. The approach relies on the initial formation of [3+2]-cycloadducts from a pyridinium ylide generated in situ from polymer-bound DMAP (PS-DMAP) with an N-substituted maleimide or an α,β-unsaturated β-keto ester. The cycloadduct decomposes to regenerate supported DMAP and yield a functionalized itaconimide or olefin. The method has a broad substrate scope. The alkene product has been further transformed into trisubstituted furan. PS-DMAP could be reused for five cycles.

Key words

dimethylaminopyridine - heterogeneous catalysis - ylides - cycloaddition - itaconimides - alkenes

Publication History

Received: 30 May 2022

Accepted after revision: 30 August 2022

Accepted Manuscript online:
30 August 2022

Article published online:
28 September 2022

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• 10 During our initial optimization of the reaction conditions, we found that a minimum of 1.8 equivalents (based on DMAP content) of PS-DMAP (~3.0 mmol/g DMAP loading; matrix crosslinked with 2% divinylbenzene) is essential for effective formation of the pyridinium salt.
• 11 (3E)-1-Benzyl-3-(2-oxo-2-phenylethylidene)pyrrolidine-2,5-dione (4aa); Typical Procedure A mixture of α-bromoacetophenone (1a; 119.4 mg, 0.6 mmol) and PS-DMAP (240 mg, 0.72 mmol) in toluene (1 mL) was stirred at 80 °C for 8 h. After complete consumption of 1a, N-benzylmaleimide (3a;74.8 mg, 0.4 mmol) and Et₃N (55.8 μL, 0.4 mmol) were added, and the mixture was stirred for a further 8 h while the progress of the reaction was monitored by TLC. The mixture was cooled to rt then glacial AcOH (0.16 mmol) was added and stirring was continued at rt for 24 h. The mixture was filtered and the filtrate was concentrated under vacuum to give a crude product that was purified by flash column chromatography [silica gel, hexane–EtOAc (5:1)] to give a yellow solid; yield: 94.0 mg (77%); mp 164–167 °C. IR (neat): 2966, 2362, 2335, 1772, 1708, 1681, 1436, 1380, 1282 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 8.01 (d, J = 7.4 Hz, 2 H), 7.89 (d, J = 2.2 Hz, 1 H), 7.62 (s, 1 H), 7.51 (t, J = 7.7 Hz, 2 H), 7.43 (d, J = 6.9 Hz, 2 H), 7.32–7.28 (m, 3 H), 4.80 (s, 2 H), 3.79 (d, J = 2.2 Hz, 2 H). ¹³C NMR (125 MHz, CDCl₃) : δ = 189.45, 173.58, 169.31, 139.50, 137.09, 135.22, 133.88, 128.86, 128.85, 128.60, 128.40, 128.03, 123.17, 42.53, 34.66. HRMS (ES+): m/z [M + H]⁺ calcd for C₁₉H₁₆NO₃: 306.1125; found: 306.1128.
• 12 Ethyl (2E)-4-Oxo-2-(2-oxo-2-phenylethyl)-4-phenylbut-2-enoate (6aa): Typical Procedure A mixture of α-bromoacetophenone (1a; 119.4 mg, 0.6 mmol) and PS-DMAP (240 mg, 0.72 mmol) in toluene (1 mL) was stirred at 80 °C for 8 h. Keto ester 5a (81.7 mg, 0.4 mmol) and Et₃N (55.8 μL, 0.4 mmol) were then added, and the mixture was stirred at 80 °C for 8 h then cooled to rt. Glacial AcOH (0.16 mmol) was added, and the mixture was stirred at rt for 24 h. The mixture was then filtered and the filtrate was concentrated under vacuum to give the crude product that was purified by flash column chromatography [silica gel, hexane–EtOAc (5:1)] to give a yellow liquid; yield: 100.6 mg (78%). IR (neat): 3064, 2981, 2938, 2842, 1717, 1662, 1600, 1570, 1510, 1445, 1276, 1257, 1215, 1169, 1092 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 8.05 (s, 1 H), 7.98 (d, J = 7.8 Hz, 4 H), 7.59–7.53 (m, 2 H), 7.49–7.43 (m, 4 H), 4.56 (s, 2 H), 4.30 (q, J = 7.1 Hz, 2 H), 1.30 (t, J = 7.1 Hz, 3 H). ¹³C NMR (125 MHz, CDCl₃): δ = 196.06, 191.73, 166.59, 139.51, 137.45, 136.64, 133.79, 133.31, 133.21, 128.85, 128.73, 128.66, 128.25, 61.95, 38.16, 14.17. HRMS (ES+): m/z [M + H]⁺ calcd for C₂₀H₁₉O₄: 323.1278; found: 323.1274.
• 13 See the Supporting Information for details.
• 14 Ethyl 2-Benzoyl-5-phenyl-3-furoate (7aa) A vial was charged with product 6aa (128.9 mg, 0.4 mmol), K₂CO₃ (82.9 mg, 0.6 mmol), and I₂ (10.2 mg, 0.08 mmol). Anhyd DMSO (4 mL) was added, and the mixture was stirred at 80 °C for 1.5 h. After complete consumption of 6aa, the mixture was cooled to rt and extracted with EtOAc. The organic layer was dried (Na₂SO₄) and purified by flash column chromatography [silica gel, hexane–EtOAc (5:1)] to give a yellow liquid; yield: 83.3 mg (65%). IR (neat): 2366, 1724, 1652, 1579, 1531, 1479, 1243, 1083 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 7.99–7.92 (m, 2 H), 7.76 (dd, J = 5.3, 3.3 Hz, 2 H), 7.64–7.59 (m, 1 H), 7.50 (dd, J = 10.8, 4.7 Hz, 2 H), 7.46–7.42 (m, 2 H), 7.40–7.36 (m, 1 H), 7.10 (s, 1 H), 4.12 (q, J = 7.2 Hz, 2 H), 1.08 (t, J = 7.2 Hz, 3 H). ¹³C NMR (125 MHz, CDCl₃): δ = 183.83, 162.88, 156.05, 150.25, 137.48, 133.42, 129.77, 129.53, 129.12, 128.90, 128.62, 125.53, 125.03, 107.48, 61.55, 13.80. HRMS (ES+): m/z [M + H]⁺ calcd for C₂₀H₁₇O₄: 321.1121; found: 321.1109.