Practical Approach for the Preparation of α-Keto Amides by Direct Aminocarbonylation of Carboxylic Esters with a Carbamoylsilane

Abstract

A novel and practical method has been developed for the preparation of α-keto amides by a catalyst-free aminocarbonylation of carboxylic esters with N,N-dimethylcarbamoyl(trimethyl)silane under neutral conditions. A new protocol for the synthesis of vicinal tricarbonyl compounds was also developed by using this method. In the case of diesters, only one ester group reacted selectively with 1.2 equivalents of the carbamoylsilane, leading to the formation of a single α-keto amide. The reaction was suitable for aryl, hetaryl, or open-chain esters containing strongly electron-withdrawing groups.

Keywords

keto amides - esters - carbamoylsilanes - aminocarbonylation - tricarbonyl compounds

• References and Notes

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• 22 Aminocarbonylation of Carboxylic Esters with N,N-Dimethylcarbamoyl(trimethyl)silane (2); General Procedure A Schlenk tube equipped with a Teflon vacuum stopcock and micro-stirrer bar was flame-heated under vacuum and refilled with Ar. The appropriate ester (0.5 mmol) and anhyd toluene (1.5 mL) were added at ice-bath temperature. After 20 min, carbamoylsilane 2 (0.6 mmol) was added and the tube was sealed. The mixture was stirred at 110 °C until no carbamoylsilane 2 could be detected by TLC. For the reactions shown in Tables 1 and 2, CH₂Cl₂ (5 mL), H₂O (2 mL), and concd HCl (0.5 mL) were added, and the mixture was stirred for 2 h at r.t. The organic layer was then decanted and the aqueous phase was extracted with CH₂Cl₂ (2 × 5 mL). The combined organic layers were dried (MgSO₄) and concentrated to afford the crude product, which was purified by column chromatography (silica gel) to afford α-keto amides 3 or 5. For the reactions shown in Table 3, entries 1–3, the residue was directly isolated by Kugelrohr distillation to give product 7a. For the reactions shown in Table 3, entry 4 and Scheme 2, volatiles were removed under vacuum, and the residue was purified by chromatography (silica gel, PE–EtOAc) to yield products 7d and 9, respectively. N,N-Dimethyl-2-(4-nitrophenyl)-2-oxoacetamide (3a) Yellowish solid; yield: 76.8 mg (69.1%, 0.5 mmol); mp 137.0–138.0 °C. IR (KBr): 1698, 1650, 1512 cm^–1. ¹H NMR (600 MHz, CDCl₃): δ = 8.38–8.16 (m, 4 H), 3.17 (s, 3 H), 3.03 (s, 3 H). ¹³C NMR (150.8 MHz, CDCl₃): δ = 189.3, 165.6, 151.1, 137.5, 130.8, 124.1, 37.1, 34.3. Anal. Calcd for C₁₀H₁₀N₂O₄: C, 54.05; H, 4.54; N, 12.61. Found: C, 54.19; H, 4.58; N, 12.55. 2-Hydroxy-N,N,N′,N′-tetramethyl-2-(trifluoromethyl)malon­amide (7a) Purified by Kugelrohr distillation to give a colorless solid; yield: 56.9 mg (47.0%, 0.5 mmol); mp 118.0–120.0 °C. IR (KBr): 3278, 1658, 1414 cm^–1. ¹H NMR (600 MHz, CDCl₃): δ = 5.64 (s, 1 H,), 3.09 (s, 6 H), 3.01 (s, 6 H). ¹³C NMR (150.8 MHz, CDCl₃): δ = 164.4, 123.6, 121.7, 37.8, 37.2. ¹⁹F NMR (564 MHz, CDCl₃): δ = –74.4. Anal. Calcd for C₈H₁₃F₃N₂O₃: C, 39.67; H, 5.41; N, 11.57. Found: C, 39.79; H, 5.38; N, 11.36.3,3,3-Trichloro-2-ethoxy-2-hydroxy-N,N-dimethylpropanamide (7d)Directly purified by flash chromatography (silica gel) to give a slightly brown liquid; yield: 67.7 mg (51.2%, 0.5 mmol). IR (KBr): 3368, 1768, 1535 cm^–1. ¹H NMR (600 MHz, CDCl₃): δ = 4.43–4.39 (m, 2 H), 3.21 (s, 3 H), 3.07 (s, 3 H), 1.62 (s, 1 H), 1.42–1.36 (m, 3 H). ¹³C NMR (150.8 MHz, CDCl₃): δ = 163.6, 161.8, 79.7, 64.6, 38.5, 37.9, 13.7. Anal. Calcd for C₇H₁₂Cl₃NO₃: C, 31.78; H, 4.57; N, 5.29. Found: C, 31.81; H, 4.49; N, 5.56.Ethyl 3-(Dimethylamino)-2,3-dioxopropanoate (9)Colorless liquid; yield: 58.1 mg (67.1%, 0.5 mmol). IR (KBr): 1768, 1735, 1654, 1455 cm^–1. ¹H NMR (600 MHz, CDCl₃): δ = 4.40 (q, J = 7.2 Hz, 2 H), 3.07 (s, 3 H), 3.06 (s, 3 H), 1.39 (t, J = 7.2 Hz, 3 H). ¹³C NMR (150.8 MHz, CDCl₃): δ = 180.8, 164.0, 160.5, 63.3, 36.8, 34.6, 14.0. Anal. Calcd for C₇H₁₁NO₄: C, 48.55; H, 6.40; N, 8.09. Found: C, 48.68; H, 6.60; N, 7.90.