Synthesis and Reactivity of a Stable Prototropic Isomer of 2-Acetyl-3-methylpyrrole

Dedicated to Professor Masahiro Murakami on the occasion of his retirement

Abstract

4-Isocyanobut-1-ene reacted rapidly with acetyl bromide to afford an unstable imidoyl bromide adduct. Subsequent in situ cyclization under Heck conditions generated a stable prototropic isomer of 2-acetyl-3-methylpyrrole. The reactivity of this molecule toward ­acids, bases, and oxidants was explored, and its conversion into an α-methylidene γ-lactam was demonstrated. In protonated form, the molecule functioned as a reactive dienophile in Diels–Alder reactions.

Key words

isocyanides - imidoyl bromides - Heck cyclization - ­methylpyrrolylethanone - Diels–Alder reaction

• References and Notes

• 1 Current address: L. Li, Chinese Academy of Sciences, 52 Sanlihe Rd., Xicheng District, Beijing 100864, P. R. of China; [e-mail].
• 2a Selwood AI, Wilkins AL, Munday R, Shi F, Rhodes LL, Holland PT. Tetrahedron Lett. 2013; 54: 4705
• 2b Li L, El Khoury A, O’Neil Clement B, Wu C, Harran PG. Org. Lett. 2022; 24: 2607
• 3a Sonnet PE, Moser JC. J. Agric. Food Chem. 1972; 20: 1191
• 3b Baltes W, Bochmann G. Z. Lebensm.-Unters. -Forsch. A 1987; 184: 478
• 4 Snider BB, Zhou J. J. Org. Chem. 2005; 70: 1087
• 5a Nef JU. Justus Liebigs Ann. Chem. 1892; 270: 267
• 5b Westling M, Smith R, Livinghouse T. J. Org. Chem. 1986; 51: 1159
• 5c Wang J, Tang S, Zhu Q. Org. Lett. 2016; 18: 3074
• 6 Ricardo MG, Marrrero JF, Valdés O, Rivera DG, Wessjohann LA. Chem. Eur. J. 2019; 25: 769
• 7 CAUTION: This volatile substance has a strong unpleasant odor. Proper handling in a well-ventilated fume hood is essential. See SerlinkI.
• 8 The pyrroline is volatile, so some yield is lost on concentrating. Care needs to be taken to lose as little material as possible. See SI.
• 9 Various alkyl alkanoyl pyrrolines were synthesized by using this procedure. Bromoacetyl and trichloroacetyl congeners of 10 formed efficiently when 9 was treated with the corresponding acid halides, but these products failed to cyclize effectively under Heck conditions.
• 10 Marcoux D, Bindschädler P, Speed AW. H, Chiu A, Pero JE, Borg GA, Evans DA. Org. Lett. 2011; 13: 3758
• 11a Erbay TG, Dempe DP, Godugu B, Liu P, Brummond KM. J. Org. Chem. 2021; 86: 11926
• 11b Fotiadu F, Pardigon O, Buono G, Le Corre M, Hercouët A. Tetrahedron Lett. 1999; 40: 867
• 12 1-(4-Methylene-3,4-dihydro-2H-pyrrol-5-yl)ethan-1-one (2); Typical Procedure A solution of 4-isocyanobut-1-ene (9; 1.09 g, 13.27 mmol) in DCM (13.3 mL, 1.0 M) was treated by dropwise addition of acetyl bromide (1.03 mL, 1.1 equiv) at 23 °C. The resulting mixture was stirred for 1 h and then concentrated under vacuum. The crude crimson oily product 10 was used immediately in the next step. A separate flame-dried flask was charged with Pd(PPh₃)₄ (1.53 g, 1.33 mmol) and Ag₂CO₃ (5.49 g, 19.9 mmol), then purged with argon (×3). The catalyst mixture was suspended in toluene (110 mL) and heated to 95 °C. The crude imidoyl bromide 10 was dissolved in toluene (20 mL), and the solution was added to the catalyst mixture over 20 min. The mixture was stirred for 10 min and then removed from the heating bath. The toluene mixture was purified by column chromatography [silica gel, Et₂O–pentane (0% Et2O → 10% → 20%)]. The fractions were collected and concentrated under vacuum (250 mbar) at rt until 10 mL of solution remained. This was transferred to a vial and the solvent was further evaporated by using an argon line to avoid evaporating the product; this gave a volatile yellow oil with a pleasant, corn-like smell; yield: 920 mg (56%). ¹H NMR (500 MHz, CDCl₃): δ = 6.07 (td, J = 2.9, 0.5 Hz, 1 H), 5.45 (td, J = 2.7, 0.7 Hz, 1 H), 4.08 (m, 2 H), 2.71–2.67 (m, 2 H), 2.52 (s, 3 H). ¹³C NMR (125 MHz, CDCl₃): δ = 198.1, 168.2, 145.3, 114.1, 58.3, 30.6, 27.8. HRMS (ESI): m/z [M + H]⁺ calcd for C₇H₁₀NO: 124.0762; found: 124.0766.