Electromediated Alcohol-Based Passerini-Type Reaction

Abstract

An electrochemical variant of the alcohol-based oxidative Passerini reaction is reported here. It relies on an indirect anodic oxidation process followed by a three-component coupling, in which TEMPO serves as a key redox mediator. This electrochemical approach permits to operate without the need for a metal catalyst nor oxygen atmosphere and allows the use of nonactivated alcohols as reaction partners. It could be applied to the preparation of good variety of α-acyloxy-carboxamides in yields ranging from 24% to 80%.

Key words

multicomponent reaction (MCR) - Passerini-type coupling - electrosynthesis - catalytic oxidation - isocyanides - TEMPO

Publication History

Received: 02 April 2024

Accepted after revision: 27 May 2024

Accepted Manuscript online:
27 May 2024

Article published online:
12 June 2024

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See also:
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• 33 Typical Procedure for the Passerini-Type Reaction In a 5 mL IKA® ElectraSyn electrochemical cell equipped with a carbon graphite anode, a stainless-steel cathode, and a stir bar, the following were successively introduced under an argon atmosphere: TBABF₄ (247 mg, 0.75 mmol, 0.25 eqiuv), TEMPO (46 mg, 0.30 mmol, 0.10 equiv), MeCN (3.0 mL), the alcohol partner (9.0 mmol, 3.0 equiv), the carboxylic acid partner (7.5 mmol, 2.5 equiv), and the isocyanide partner (3.0 mmol, 1.0 equiv). The resulting solution was then electrolyzed at a constant current (i = 50 mA, j = 20 mA cm^–2) until the total electrical charge reached 2.7 F per mol of alcohol. After the reaction mixture was evaporated, yields were determined by ¹H NMR spectroscopy using TBABF₄ as an internal standard and/or after purification by column chromatography on silica gel. 2-(tert-Butylamino)-2-oxoethyl Acetate (4aaa) Purified with a gradient 100% cyclohexane to 50:50 cyclohexane–EtOAc. Yield: 77% (400 mg), white solid; mp 64–66 °C. ¹H NMR (300 MHz, CDCl₃): δ = 5.89 (br s, 1 H), 4.41 (s, 2 H), 2.13 (s, 3 H), 1.35 (s, 9 H). ¹³C NMR (101 MHz, CDCl₃): δ = 169.5, 166.1, 63.3, 51.5, 28.7, 20.8. HRMS (ESI): m/z [M + Na]⁺ calcd for C₈H₁₅NO₃Na: 196.0944; found: 196.0945. 1-(tert-Butylamino)-1-oxopropan-2-yl Acetate (4baa) Purified with a gradient 100% cyclohexane to 50:50 cyclohexane–EtOAc. Yield: 60% (337 mg), white solid; mp 61–62 °C. ¹H NMR (300 MHz, CDCl₃): δ = 5.87 (br s, 1 H), 5.04 (q, J = 6.8 Hz, 1 H), 2.11 (s, 3 H), 1.41 (d, J = 6.8 Hz, 3 H), 1.34 (s, 9 H). ¹³C NMR (101 MHz, CDCl₃): δ = 169.5, 71.1, 51.2, 28.8, 21.2, 17.9. HRMS (ESI): m/z [M + H]⁺ calcd for C₉H₁₈NO₃: 188.1281; found: 188.1281. 1-(tert-Butylamino)-1-oxobutan-2-yl Acetate (4caa) Purified with a gradient 100% cyclohexane to 50:50 cyclohexane–EtOAc. Yield: 80% (483 mg), white solid; mp 74–75 °C. ¹H NMR (300 MHz, CDCl₃): δ = 5.82 (br s, 1 H), 4.95 (dd, J = 6.0, 5.4 Hz, 1 H), 2.10 (s, 3 H), 1.95–1.64 (m, 2 H), 1.32 (s, 9 H), 0.87 (t, J = 7.4 Hz, 3 H). ¹³C NMR (101 MHz, CDCl₃): δ = 169.7, 168.8, 75.3, 51.3, 28.7, 25.0, 21.1, 8.9. HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₀H₁₉NO₃Na: 224.1257; found: 224.1257. 1-(tert-Butylamino)-1-oxopentan-2-yl Acetate (4daa) Purified with a gradient 100% cyclohexane to 50:50 cyclohexane–EtOAc. Yield: 69% (446 mg), beige solid; mp 108–110 °C. ¹H NMR (300 MHz, CDCl₃): δ = 5.79 (br s, 1 H), 4.99 (t, J = 6.0 Hz), 2.10 (s, 3 H), 1.93–1.61 (m, 2 H), 1.51–1.06 (m, 2 H), 1.32 (s, 9 H), 0.88 (t, J = 7.3 Hz, 3 H). ¹³C NMR (101 MHz, CDCl₃): δ = 169.7, 169.0, 74.3, 51.3, 34.0, 28.7, 21.1, 18.1, 13.8. HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₁H₂₁NO₃Na: 238.1414; found: 238.1413. 2-(tert-Butylamino)-1-cyclopropyl-2-oxoethyl Acetate (4eaa) Purified with a gradient 100% cyclohexane to 50:50 cyclohexane–EtOAc. Yield: 45% (288 mg), white solid; mp 100–101 °C. ¹H NMR (300 MHz, CDCl₃): δ = 5.78 (br s, 1 H), 4.46 (d, J = 8.5 Hz, 1 H), 2.11 (s, 3 H), 1.33 (s, 9 H), 1.31–1.08 (m, 1 H), 0.73–0.32 (m, 4 H). ¹³C NMR (101 MHz, CDCl₃): δ = 169.9, 168.3, 51.4, 28.8, 21.1, 13.2, 3.2, 3.0. HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₁H₁₉NO₃Na: 236.1257; found: 236.1257.
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