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A Convenient Synthesis of α-Keto Esters Using Ethyl 2-Pyridyl Oxalate

에틸 2-피리딜 옥살레이트를 이용한 α-케토 에스터의 간편한 합성

  • Lee, Jae-In (Department of Chemistry, Duksung Women's University)
  • 이재인 (덕성여자대학교 자연과학대학 화학과)
  • Published : 2004.02.20

Abstract

Keywords

${\alpha}$-Keto esters;Ethyl 2-pyridyl oxalate;Coupling;Chelate

EXPERIMENTAL

Preparation of ethyl 2-pyridyl oxalate (1). To a solution of ethyl chlorooxoacetate (1.5 mL, 13.4 mmol) in methylene chloride (15 mL) was slowly added a solution of 2-hydroxypyridine (1.28 g, 13.4 mmol) and triethylamine (1.9 mL, 13.6 mmol) in methylene chloride (25 mL) at 0 ℃. After stirring for 0.5 h, methylene chloride was evaporated in vacuo and the mixture was dissolved in dry tetrahydrofuran, followed by filtering off triethylamine hydrochloride. The condensed filtrate was purified by Kugelrohr vacuum distillation to afford 1 (2.52 g, 96%) as a colorless liquid. B.p. 118-123 ℃/0.3 mm Hg; 1H NMR(300 MHz, CDCl3) d 7.84 (d, J=7.4 Hz, 1H), 7.39-7.45 (m, 1H), 6.57 (d, J=9.3 Hz, 1H), 6.33-6.37 (m, 1H), 4.45 (q, J=7.5 Hz, 2H), 1.41 (t, J=7.5 Hz, 3H); FT-IR (film) 3060, 2985, 1753 (COO-2-Py), 1730 (COOEt), 1620, 1468, 1182, 764 cm-1; Ms m/z(%) 195(M+, 7), 150(5), 101(6), 96(8), 95(100), 86(21), 67(74).

Preparation of ethyl 2-oxo-2-(p-methylphenyl) acetate (4c) . To a solution of ethyl 2-pyridyl oxalate (586 mg, 3.0 mmol) in tetrahydrofuran (25 mL) cooled to -78 ℃ under argon was added dropwise a solution of p-methylphenylmagnesium bromide (15.0 mL, 0.2 M in THF, 3.0 mmol) via cannula over 45 min. After stirring for 0.5 h at -78 ℃, the reaction mixture was quenched with saturated NH4Cl (2 mL). Tetrahydrofuran was evaporated in vacuo and the reaction mixture was extracted with methylene chloride (3×20 mL) and washed with saturated NH4Cl (20 mL). The combined organic phases were dried over anhydrous MgSO4, filtered, and evaporated to dryness in vacuo. The crude product was purified by Kugelrohr vacuum distillation to give 4c (415 mg, 72%) as a colorless liquid. 1H NMR(300 MHz, CDCl3) d 7.92 (d, J=8.4 Hz, 2H), 7.31 (d, J=8.4 Hz, 2H), 4.45 (q, J=7.2 Hz, 2H), 2.44 (s, 3H), 1.43 (t, J=7.2 Hz, 3H); FT-IR (film) 3054, 2984, 1736 (COO), 1681 (CO), 1606, 1446, 1175, 1024, 827 cm-1; Ms m/z(%) 192(M+, 1), 120(12), 119(100), 91(45), 65(16). Spectral data, 4a: 1H NMR(300 MHz, CDCl3) d 8.01-8.04 (m, 2H), 7.65-7.67 (m, 1H), 7.50-7.55 (m, 2H), 4.44 (q, J=7.2 Hz, 2H), 1.44 (t, J=7.2 Hz, 3H); FT-IR (film) 3066, 2985, 1736 (COO), 1688 (CO), 1597, 1451, 1201, 1017, 741, 689 cm-1; Ms m/z(%) 178(M+, 1), 150(5), 106(10), 105(100), 77(46). 4b: 1H NMR(300 MHz, CDCl3) d 7.71 (d, J=7.8 Hz, 1H), 7.48-7.53 (m, 1H), 7.31-7.36 (m, 2H), 4.45 (q, J=7.2 Hz, 2H), 2.63 (s, 3H), 1.43 (t, J=7.2 Hz, 3H); FT-IR (film) 3064, 2983, 1736 (COO), 1682 (CO), 1601, 1457, 1195, 1017, 729 cm-1; Ms m/z(%) 192(M+, 2), 120(11), 119(100), 91(50), 65(16). 4d: 1H NMR(300 MHz, CDCl3) d 8.00 (d, J=8.7 Hz, 2H), 6.97 (d, J=8.7 Hz, 2H), 4.44 (q, J=7.2 Hz, 2H), 3.89 (s, 3H), 1.43 (t, J=7.2 Hz, 3H); FT-IR (film) 3068, 2983, 1735 (COO), 1675 (CO), 1600, 1511, 1209, 1020, 840 cm-1; Ms m/z(%) 208(M+, 3), 136(14), 135(100), 107(12), 92(16), 77(18). 4e: 1H NMR(300 MHz, CDCl3) d 7.98 (d, J=6.9 Hz, 2H), 7.49 (d, J=6.9 Hz, 2H), 4.45 (q, J=7.2 Hz, 2H), 1.42 (t, J=7.2 Hz, 3H); FT-IR (film) 3080, 2985, 1736 (COO), 1687 (CO), 1589, 1494, 1202, 1013, 830 cm-1; Ms m/z(%) 212(M+, 1), 141(35), 139(100), 113(11), 111(33), 75(17). 4f: 1H NMR(300 MHz, CDCl3) d 7.24 (d, J=9.0 Hz, 1H), 7.08 (d, J=9.0 Hz, 2H), 4.38 (q, J=7.2 Hz, 2H), 2.27 (s, 6H), 1.42 (t, J=7.2 Hz, 3H); FT-IR (film) 3063, 2983, 1732 (COO), 1675 (CO), 1595, 1465, 1195, 1020, 776 cm-1; Ms m/z(%) 206(M+, 1), 134(13), 133(100), 105(42), 77(15). 4g: 1H NMR(300 MHz, CDCl3) d 9.04 (d, J=8.1 Hz, 1H), 8.09 (d, J=8.1 Hz, 1H), 7.97 (d, J=7.2 Hz, 1H), 7.89 (d, J=7.5 Hz, 1H), 7.65-7.69 (m, 2H), 7.50-7.57 (m, 1H), 4.48 (q, J=7.2 Hz, 2H), 1.43 (t, J=7.2 Hz, 3H); FT-IR (film) 3053, 2983, 1730 (COO), 1668 (CO), 1593, 1462, 1371, 1165, 1073, 774 cm-1; Ms m/z(%) 228(M+, 11), 156(15), 155(100), 127(69), 126(14). 4h: 1H NMR(300 MHz, CDCl3) d 7.26-7.29 (m, 2H), 7.16-7.22 (m, 3H), 4.30 (q, J=7.2 Hz, 2H), 2.85 (t, J=7.2 Hz, 2H), 2.67 (t, J=7.2 Hz, 2H), 1.99 (quintet, J=7.5 Hz, 2H), 1.35 (t, J=7.2 Hz, 3H); FT-IR (film) 3063, 2986, 2939, 1728 (slightly broad, overlapped COO & CO), 1454, 1069, 749, 701 cm-1; Ms m/z(%) 220(M+, 2), 202(30), 147(87), 129(23), 104(40), 91(100). 4i: 1H NMR(300 MHz, CDCl3) d 4.31 (t, J=7.2 Hz, 2H), 2.83 (t, J=7.2 Hz, 2H), 1.57-1.63 (m, 2H), 1.27-1.39 (m, 10H), 1.37 (t, J=7.2 Hz, 3H), 0.88 (t, J=6.7 Hz, 3H); FT-IR (film) 2983, 2934, 2856, 1726 (slightly broad, overlapped COO & CO), 1450, 1274, 1068 cm-1; Ms m/z(%) 214(M+, 2), 142(11), 141(100), 71(39), 57(40). 4j: 1H NMR(300 MHz, CDCl3) d 4.30 (q, J=7.2 Hz, 2H), 3.00-3.03 (m, 1H), 1.78-1.90 (m, 6H), 1.30-1.37 (m, 4H), 1.35 (t, J=7.2 Hz, 3H); FT-IR (film) 2934, 2856, 1726 (slightly broad, overlapped COO & CO), 1450, 1273, 1067 cm-1; Ms m/z(%) 184 (M+, 3), 111(39), 84(7), 83(100), 55(43).

 

RESULTS AND DISCUSSION

Scheme 1

Ethyl 2-pyridyl oxalate (1) was prepared by the addition of a solution of 2-hydroxypyridine (3) and triethylamine to ethyl chlorooxoacetate (2) in methylene chloride at 0 ℃ (Scheme 1). After completion of the reaction, methylene chloride was evaporated under vacuum and the reaction mixture was dissolved in dry tetrahydrofuran, followed by filtering off triethylamine hydrochloride. The condensed residue was purified by vacuum distillation (Kugelrohr) to afford 1 in 96% yield as a colorless liquid. The reagent 1 could be stored in a refrigerator for several weeks without any decomposition.

The preparation of α-keto esters was conveniently carried out by the addition of Grignard reagents to an equimolar amount of 1 in a one-step. For instance, the treatment of 1 with 1 equiv of p-methoxyphenylmagnesium bromide at -78 ℃ over 45 min afforded ethyl 2-oxo-2-(p-methoxyphenyl)acetate (4d) in 69% yield. Although ethyl 2-hydroxy-2,2-di(p-methoxyphenyl)acetate was formed by the overaddition of p-methoxyphenylmagnesium bromide as a side product (7%) during the reaction, it was easily separated by vacuum distillation. The success of this reaction is presumably due to the fact that 6-membered chelate between magnesium of Grignard reagent and oxygen/ring nitrogen atom of 1 is partially formed by the preferential attack of Grignard reagent to the carbon atom of carbopyridyloxy group even in the presence of electron-withdrawing carboethoxy group.

As shown in Table 1, various α-keto esters were conveniently prepared by this method in high yields. Especially, the reaction worked well with aromatic Grignard reagents and the presence of electron-donating (4b-4d) or electron-withdrawing group (4e) in substituted phenylmagnesium bromide didn’t affect the efficiency of the reaction under the present reaction conditions. Furthermore, the reaction of 1 with sterically hindered 2,6-dimethylphenylmagnesium bromide afforded 4f in 78% yield without a significant side product. The aliphatic α-keto ester was prepared by a modified procedure, treating Grignard reagent (4h-4j) with lithium bromide/copper(I) bromide. Thus, the addition of cyclohexyl magnesium chloride to a greenish solution of lithium bromide (2 equiv) and copper (I) bromide in tetrahydrofuran provided a light brownish solution, which was slowly added to 1 at -78 ℃ to afford 4j in 68% yield.

Table 1.aThe Grignard reagents were added over 45 min at -78 ℃ and stirred for 0.5 h. bC6H5(CH2)3MgBr · CuBr · 2LiBr was used. cThe corresponding RMgCl · CuBr · 2LiBr was used.

In conclusion, the present method provides an efficient synthesis of α-keto esters using 1 in connection with high yields of aromatic α-keto esters, availability of starting material, and the convenience of one-step operation.

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