Metal-Free Csp³–N Bond Cleavage of Amides Using tert-Butyl Hydroperoxide as Oxidant

Abstract

A mild and efficient protocol for the metal-free C–N bond-cleavage of amides has been developed. The methodology employs iodine as a catalyst to cleave the C(Me)–N bond of dimethylformamide or dimethylacetamide, providing novel access to methylene-bridged bis-1,3-dicarbonyl compounds instead of enol carbamates in the presence of tert-butyl hydroperoxide.

Key words

metal-free - C–N bond cleavage - amides - dicarbonyl compounds - oxidation

• References and Notes

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• 14 Preparation of 2a; Typical Procedure: A mixture of ethyl 3-oxo-3-phenylpropanoate (0.5 mmol), iodine (6.4 mg, 0.025 mmol), DMA (2.0 mL), and 70% TBHP (32.0 μL) was stirred at 100 °C for 24 h under an N₂ atmosphere. The reaction was monitored by TLC. Upon completion, the reaction mixture was poured into H₂O (20 mL) and extracted with EtOAc (3 × 15 mL). The organic phase was concentrated and the resulting crude product was purified by column chromatography on silica gel (petroleum ether–EtOAc, 10:1) to provide the desired compound. The identity of the product and the diastereomer ratio were determined by 1H NMR analysis.Diethyl 2,4-dibenzoylpentanedioate (2a): Yield: 61%; two diastereomers (1.1:1). ¹H NMR (601 MHz, CDCl₃): δ = 8.06–8.05 (m, 4 H), 7.62–7.61 (m, 2 H), 7.52–7.46 (m, 4 H), 4.64 (t, J = 7.2 Hz, 1 H), 4.55 (t, J = 7.2 Hz, 1 H), 4.24–4.21 (m, 2 H), 4.11–4.09 (m, 2 H), 2.78–2.52 (m, 2 H), 1.22 (t, J = 7.2 Hz, 3 H), 1.11 (t, J = 7.2 Hz, 3 H). ¹³C NMR (151 MHz, CDCl₃): δ = 195.29, 194.92, 169.80, 169.44, 135.95, 135.46, 133.93, 133.92, 129.01, 128.92, 61.77, 61.75, 51.65, 51.39, 28.30, 27.75, 14.10, 13.97.Dimethyl 2,4-dibenzoylpentanedioate (2b): Yield: 47%; two diastereomers (6:5). ¹H NMR (601 MHz, CDCl₃): δ = 8.05 (dd, J ₁ = 7.2 Hz, J ₂ = 1.2 Hz, 4 H), 7.63–7.58 (m, 2 H), 7.52–7.47 (m, 4 H), 4.67 (t, J = 7.2 Hz, 1 H), 4.58 (t, J = 7.2 Hz, 1 H), 3.75 (s, 4 H), 3.64 (s, 2 H), 2.77–2.55 (m, 2 H). ¹³C NMR (151 MHz, CDCl₃): δ = 195.22, 194.82, 170.33, 169.93, 135.89, 135.42, 134.05, 134.03, 129.08, 129.01, 128.98, 128.87, 52.78, 51.41, 51.16, 28.47, 27.93.Diethyl 2,4-bis(4-nitrobenzoyl)pentanedioate (2c): Yield: 41%; two diastereomers (1.1:1). ¹H NMR (400 MHz, CDCl₃): δ = 8.34–8.37 (m, 4 H), 8.20–8.25 (m, 4 H), 4.66 (t, J = 8.0 Hz, 1 H), 4.55 (t, J = 8.0 Hz, 1 H), 4.21–4.25 (m, 2 H), 4.11–4.14 (m, 2 H), 2.54–2.79 (m, 2 H), 1.21 (t, J = 8.0 Hz, 3 H), 1.11 (m, 3 H).Dimethyl 2,4-bis(4-bromobenzoyl)pentanedioate (2d): Yield: 51%; two diastereomers (1.3:1). ¹H NMR (601 MHz, CDCl3): δ = 7.94–7.88 (m, 4 H), 7.67–7.60 (m, 4 H), 4.59 (t, J = 7.2 Hz, 1 H), 4.50 (t, J = 7.2 Hz, 1 H), 3.75 (s, 4 H), 3.64 (s, 2 H), 2.72–2.51 (m, 2 H). ¹³C NMR (151 MHz, CDCl₃): δ = 194.23, 193.82, 170.05, 169.61, 134.60, 134.17, 132.41, 130.55, 130.45, 129.59, 129.53, 52.92, 51.24, 51.08, 28.24, 27.64.Dimethyl 2,4-bis(4-chlorobenzoyl)pentanedioate (2e): Yield: 59%; two diastereomers (1.3:1). ¹H NMR (400 MHz, CDCl₃): δ = 8.01 (d, J = 8.4 Hz, 4 H), 7.47 (t, J = 8.8 Hz, 4 H), 4.60 (t, J = 7.2 Hz, 2 H), 3.75 (s, 6 H), 2.73–2.50 (m, 2 H). ¹³C NMR (101 MHz, CDCl₃): δ = 194.03, 170.09, 140.78, 133.72, 130.50, 129.40, 73.08, 52.98, 51.29, 28.30.Dimethyl 2,4-bis(4-fluorobenzoyl)pentanedioate (2f): Yield: 50%; two diastereomers (4:3). ¹H NMR (400 MHz, CDCl₃): δ = 8.14–8.08 (m, 4 H), 7.20–7.14 (m, 4 H), 4.63 (t, J = 8.0 Hz, 1 H), 4.53 (t, J = 8.0 Hz, 1 H), 3.76 (s, 4 H), 3.65 (s, 2 H), 2.75–2.50 (m, 2 H). ¹³C NMR (100 MHz, CDCl₃): δ = 193.70, 193.22, 170.25, 169.74, 167.67, 165.12, 131.98, 131.88, 116.35, 116.14, 52.90, 51.31, 51.08, 28.45, 27.77.Dimethyl 2,4-bis(4-methylbenzoyl)pentanedioate (2g): Yield: 51%; two diastereomers (1.2:1). ¹H NMR (400 MHz, CDCl₃): δ = 7.94 (d, J = 8.0 Hz, 4 H), 7.27 (d, J = 8.0 Hz, 4 H), 4.52–4.64 (m, 2 H), 3.74 (s, 5 H), 3.63 (s, 1 H), 2.74–2.52 (m, 2 H), 2.42 (d, J = 8.8 Hz, 6 H). ¹³C NMR (101 MHz, CDCl₃): δ = 194.82, 170.44, 145.03, 132.99, 129.68, 129.21, 52.72, 51.36, 28.59, 21.85.Dimethyl 2,4-bis(4-methoxybenzoyl)pentanedioate (2h): Yield: 57%; two diastereomers (1.1:1). ¹H NMR (400 MHz, CDCl₃): δ = 8.06 (d, J = 8.8 Hz, 4 H), 6.99–6.93 (m, 4 H), 4.60 (t, J = 7.2 Hz, 1 H), 4.52 (t, J = 7.6 Hz, 1 H), 3.89 (d, J = 7.6 Hz, 6 H), 3.75 (s, 3 H), 3.64 (s, 3 H), 2.75–2.51 (m, 2 H). 13C NMR (101 MHz, CDCl₃): δ = 193.79, 193.34, 170.63, 170.17, 164.29, 131.57, 131.47, 128.92, 128.41, 114.20, 55.70, 55.68, 52.71, 51.25, 50.96, 28.86, 28.20.Dimethyl 2,4-bis(3-methoxybenzoyl)pentanedioate (2i): Yield: 43%; two diastereomers (5:4). ¹H NMR (400 MHz, CDCl₃): δ = 7.66–7.61 (m, 2 H), 7.57 (s, 2 H), 7.39 (dt, J = 16.8, 8.0 Hz, 2 H), 7.19–7.09 (m, 2 H), 4.63 (t, J = 7.2 Hz, 1 H), 4.54 (t, J = 7.2 Hz, 1 H), 3.88 (d, J = 8.8 Hz, 6 H), 3.75 (s, 3 H), 3.64 (s, 3 H), 2.77–2.53 (m, 2 H). ¹³C NMR (101 MHz, CDCl₃): δ = 195.08, 194.64, 170.31, 169.93, 160.14, 160.11, 137.19, 136.71, 130.00, 121.70, 121.58, 120.96, 120.85, 55.65, 52.80, 52.78, 51.61, 51.34, 28.65, 28.08.Dimethyl 2,4-di(2-naphthoyl)pentanedioate (2j): Yield: 53%; two diastereomers (1.3:1). ¹H NMR (400 MHz, CDCl₃): δ = 8.63 (d, J = 12.0, 2 H), 8.12 (d, J = 20.0 Hz, 2 H), 8.05–8.02 (m, 2 H), 7.94–7.92 (d, J = 8.0 Hz, 2 H), 7.89–7.82 (m, 3 H), 7.65–7.49 (m, 4 H), 4.85 (t, J = 8.0 Hz, 1 H), 4.79 (t, J = 8.0 Hz, 1 H), 3.78 (s, 3 H), 3.64 (s, 3 H), 2.93–2.69 (m, 2 H). ¹³C NMR (101 MHz, CDCl₃): δ = 195.22, 194.74, 170.36, 170.06, 136.04, 135.97, 133.21, 132.78, 132.65, 132.56, 131.43, 131.25, 130.08, 130.04, 129.15, 129.08, 128.91, 128.85, 127.89, 127.79, 127.10, 126.98, 124.20, 124.11, 52.87, 52.81, 51.46, 51.33, 28.83, 28.24.Dimethyl 2,4-bis(4-morpholinobenzoyl)pentanedioate (2k): Yield: 50%; two diastereomers (1:1). ¹H NMR (400 MHz, CDCl₃): δ = 8.00 (d, J = 9.2 Hz, 4 H), 6.87 (dd, J = 12.8, 8.8 Hz, 4 H), 4.58 (t, J = 7.2 Hz, 1 H), 4.50 (t, J = 7.2 Hz, 1 H), 3.85 (d, J = 3.6 Hz, 8 H), 3.74 (s, 3 H), 3.63 (s, 3 H), 3.35–3.32 (m, 8 H), 2.74–2.50 (m, 2 H). ¹³C NMR (101 MHz, CDCl₃): δ = 193.27, 192.82, 170.82, 170.34, 154.68, 154.66, 131.28, 131.20, 126.28, 125.75, 113.30, 66.56, 52.53, 51.09, 50.69, 47.30, 29.01, 28.33.2,4-Dibenzoyl-1,5-dimorpholinopentane-1,5-dione (2l): Yield: 30%; two diastereomers (6:5). ¹H NMR (601 MHz, CDCl₃): δ = 8.15 (d, J = 7.8 Hz, 1 H), 8.12–8.08 (m, 3 H), 7.63 (t, J = 7.2 Hz, 1 H), 7.58 (t, J = 7.2 Hz, 1 H), 7.54 (t, J = 7.8 Hz, 1 H), 7.49 (t, J = 7.8 Hz, 3 H), 4.90–4.84 (m, 2 H), 3.74–3.56 (m, 16 H), 2.75–2.25 (m, 2 H). ¹³C NMR (151 MHz, CDCl₃): δ = 196.32, 196.25, 168.70, 168.65, 135.61, 135.41, 134.01, 129.21, 129.16, 128.68, 66.87, 66.76, 66.67, 49.56, 49.52, 46.49, 46.36, 42.67, 42.55, 29.06, 28.94