Triflic Acid Catalyzed Intermolecular α-Amination of Pterolactams To Give 5-Arylaminopyrrolidinones via N-Acyliminium Species

Abstract

A mild and efficient α-aza-amidoalkylation for the synthesis of 5-arylaminopyrrolidinones is presented. The key step of this reaction is the intermolecular interception of an N-acyliminium species, generated under the acidic conditions, with nitrogen nucleophiles such as N-silylamines.

Key words

triflic acid - N-acyliminium cation - alkylation - N-silylamine - pterolactam

• References and Notes

• 1 This compound [CAS No. 40759-90-8] is commercially available in different salt forms.
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Starting from pyroglutamic acids, the Hofmann transposition can furnish carbamoyl-5-pyrrolidinone, see:
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• 33 General Procedure for the Synthesis of 1-Alkyl-5-Arylaminopyrrolidinones Method A: Under an inert atmosphere, aniline 19a–d (1.2 equiv) was added to hydroxylactam 18a–e in anhydrous CH₂Cl₂. TfOH (10–15% vol.) was slowly added by using a syringe, and the resulting brown, homogeneous solution was stirred at 50 °C for 24–48 h. H₂O (50 mL) and CH₂Cl₂ (50 mL) were added, and the mixture was shaken in an extraction funnel, whereupon the organic phase lost most of its brown color. The organic phase was washed with H₂O (3 × 50 mL), dried over MgSO₄, and filtered. The residue obtained after evaporation was purified by flash chromatography. Method B: Under an inert atmosphere, silylated aniline 20a–d (1.2 equiv) was added to hydroxylactam 18a–e. TfOH (1–2% vol.) was slowly added by using a syringe, and the now brown, homogeneous solution was stirred at room temperature for 1 min to 24 h. H₂O (50 mL) and CH₂Cl₂ (50 mL) were added slowly to the reaction mixture, which was then shaken in an extraction funnel, whereupon the organic phase lost most of its brown color. The organic phase was washed with H₂O (3 × 50 mL), dried over MgSO₄, and filtered. The residue obtained after evaporation was purified by flash chromatography.
• 34 The cyclic N,N-aminal product 21i (45% yield) was isolated by flash chromatography (gradient: EtOAc/n-heptane) as a white solid; mp 137–138 °C (EtOH); R_f = 0.27 (EtOAc/n-heptane, 4:1). IR: 3310, 3085, 1666, 1594, 1508, 1452, 1267, 1229, 1157, 1092 cm^–1. ¹H NMR (400 MHz, CDCl₃): δ = 1.91–2.01 (m, 1 H, CH₂CH ₂CH), 2.34–2.63 (m, 3 H, CH₂ CH ₂CH), 3.53 (s, 1 H, NH), 3.75 (s, 3 H, OCH₃ ), 4.38 (d, J = 15.3 Hz, 1 H, NCH ₂Ar), 4.81 (d, J = 15.3 Hz, 1 H, NCH ₂Ar), 5.00 (m, 1 H, CH₂CH₂CH), 6.46 (d, J = 8.7 Hz, 2 H, ArH), 6.72 (d, J = 8.7 Hz, 2 H, ArH), 7.15 (d, J = 8.5 Hz, 1 H, ArH), 7.20 (dd, J = 8.5, 1.9 Hz, 1 H, ArH), 7.34 (d, J = 1.9 Hz, 1 H, ArH). ¹³C NMR (100 MHz, CDCl₃): δ = 26.4 (CH₂), 29.3 (CH₂), 41.0 (CH₂), 57.7 (CH₃), 70.3 (CH), 115.0 (2CH), 116.3 (2CH), 127.2 (CH), 129.4 (CH), 130.3 (CH), 132.9 (C), 133.8 (C), 134.2 (C), 138.6 (C), 153.5 (C), 174.2 (C). Anal. Calcd for C₁₈H₁₈Cl₂N₂O₂: C, 59.19; H, 4.97; N, 7.67. Found: C, 59.43; H, 5.12; N, 7.81.
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• 38 The predicted pK _a value of 3,4,5-trimethoxyaniline (19e) was calculated by using Advanced Chemistry Development (ACD/Labs) Software V11.02 (1994-2015 ACD/Labs).
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