Variations on the Blaise Reaction: Synthesis of 3,5-Dioxopentanoates and 3-Amino-5-oxopent-3-enoates

Abstract

We have achieved a facile and convenient synthesis of a variety of 3,5-dioxopentanoates (3,5-diketo esters) and 3-amino-5-oxopent-3-enoates by a zinc-mediated condensation of readily available 3-oxopropanenitriles (α-cyano ketones) with ethyl bromoacetate. The reaction is a variation on the classical Blaise reaction, tuned to the synthesis of trifunctional compounds having 3,5-diketo ester or 3-enamino 5-keto ester functional groups. Our studies revealed that the Blaise reaction on the nitrile occurs in preference to the Reformatsky reaction on the neighboring ketone when the two functional groups are in a geminal relationship, as found in α-cyano ketones, possibly due to zinc complexation leading to increased electrophilicity of the nitrile.

Key words

Blaise reaction - diketo esters - aminooxopentenoates - cyano ketones - ethyl bromoacetate

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• 11 3,5-Dioxopentanoates 9a–m and 3-Amino-5-oxopent-3-enoates 10a–f; General Procedure A solution of TMSCl (10 mol%) in THF (1 mL) was added to a suspension of Zn powder (1.2 mmol, 3 equiv) in THF (8 mL), and the mixture was refluxed with vigorous stirring for 25 min. A solution of the appropriate α-cyano ketone 8 (0.4 mmol, 1 equiv) in THF (2 mL) and a solution of the α-bromo ester (0.8 mmol) in THF (2 mL) were simultaneously added dropwise over 30 min by using two syringes. After the addition, the pale-green mixture was refluxed until all the α-cyano ketone was consumed (TLC; 3–6 h), by which time the color had changed to brown. The mixture was then cooled to r.t. and centrifuged at 700 rpm. The upper solution was collected, and the residual solid was washed with THF (2 × 2 mL) and the solvent was collected after centrifugation. Method A: 3,5-Diketo Esters 9a–m The pH of the combined THF solutions was adjusted to 2 with 3 M HCl (~2 mL) and the mixture was stirred for 30 min at r.t. The THF was removed on a rotary evaporator under reduced pressure, and the residue was diluted with CH₂Cl₂ (20 mL) and H₂O (20 mL). The organic layer was separated, washed sequentially with H₂O (2 × 20 mL) and brine (10 mL), dried (Na₂SO₄), filtered, and concentrated under reduced pressure to give the crude 3,5-diketo ester, which was purified by column chromatography [silica gel (100–200 mesh), 10% EtOAc–hexane]. Method B: (3Z)-3-Amino-5-oxo-5-pent-3-enoates 10a–f The solvent was removed from the combined THF solutions under reduced pressure, the residue was diluted with CH₂Cl₂ (20 mL), and the resulting solution was stirred with 50% aq K₂CO₃ (5 mL) for 15 min. The organic layer was separated, washed sequentially with H₂O (2 × 20 mL) and brine (10 mL), dried (Na₂SO₄), filtered, and concentrated under reduced pressure to give the crude (3Z)-3-amino-5-oxo-5-pent-3-enoate, which was purified by column chromatography [silica gel (100–200 mesh), 15% EtOAc–hexane]. Ethyl 5-(4-Chlorophenyl)-3,5-dioxopentanoate (9c) Prepared by the general procedure (Method A) from 3-(4-chlorophenyl)-3-oxopropanenitrile (8c; 503 mg, 2.79 mmol) and ethyl bromoacetate (2; 932 mg, 5.58 mmol) in the presence of Zn powder (544 mg, 8.38 mmol) and TMSCl (30 mg, 10 mol %) in THF (10 mL) for 4 h followed by hydrolysis with 3 N HCl (2 mL) as a pale-yellow liquid; yield: 553 mg (74%); R_f = 0.5 (10% EtOAc). IR: 2983, 2934, 1741, 1719, 1607, 1318, 1267, 1038, 817 cm^–1. ¹H NMR (400 MHz, CDCl₃ + CCl₄, 1:1): δ = 15.73 (s, 1 H), 7.82 (d, J = 8.6 Hz, 2 H), 7.42 (d, J = 8.6 Hz, 2 H), 6.24 (s, 1 H), 4.22 (q, J = 7.2, 2 H), 3.47 (s, 2 H), 1.30 (t, J = 7.1 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃ + CCl₄, 1:1): δ = 189.3, 181.4, 167.3, 139.1, 132.8, 129.1, 128.6, 96.6, 61.6, 45.9, 14.3. HRMS (ESI): m/z [M + H] calcd for C₁₃H₁₄ClO₄: 269.0581; found: 269.0580. Ethyl (3Z)-3-Amino-5-oxo-5-phenylpent-3-enoate (10a) Prepared by the general procedure (Method B) from 3-oxo-3-phenylpropanenitrile (8a; 502 mg, 3.44 mmol) and ethyl bromoacetate (2; 1.15 g, 6.89 mmol) in the presence of Zn powder (672 mg, 10.34 mmol) and TMSCl (38 mg, 10 mol %) in THF (10 mL) for 4 h followed by hydrolysis with 50% aq K₂CO₃ (5 mL) as a pale-yellow liquid; yield: 627 mg (77%); R_f = 0.3 (10% EtOAc–hexane). IR: 3413, 3186, 2982, 2927, 1734, 1616, 1527, 1282, 1175, 1060, 737 cm^–1. ¹H NMR (400 MHz, CDCl₃ + CCl₄, 1:1): δ = 10.14 (br s, 1 H), 7.85–7.82 (m, 2 H), 7.42–7.36 (m, 3 H), 6.17 (br s, 1 H), 5.71 (s, 1 H), 4.21 (q, J = 7.1 Hz, 2 H), 3.26 (s, 2 H), 1.29 (t, J = 7.1 Hz, 3 H). ¹³C NMR (100 MHz, CDCl₃ + CCl₄, 1:1): δ = 189.9, 169.0, 157.7, 140.0, 131.1, 128.3, 127.3, 93.0, 61.7, 41.0, 14.3. HRMS (ESI): m/z [M + H] calcd for C₁₃H₁₆NO₃: 234.1130; found: 234.1128.