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Synlett 2008(19): 2945-2950  
DOI: 10.1055/s-0028-1087353
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Aerial Oxidation of 2,2-Dibromo-1-Aryl and Heteroaryl Ethanones: A Facile Synthesis of Aryl and Heteroaryl α-Keto Amides

D. Shanmugapriyaa, R. Shankara, G. Satyanarayanaa, Vilas H. Dahanukara, U. K. Syam Kumar*a, N. Vembub
a Technology Development Centre, Custom Pharmaceutical Services, Dr. Reddy’s Laboratories Ltd, Miyapur, Hyderabad 500049, India
Fax: +91(40)23045439; e-Mail: syam_kmr@yahoo.com;
b Urumu Dhanalakshmi College, Tiruchirappalli 620019, India
Further Information

Publication History

Received 25 March 2008
Publication Date:
12 November 2008 (online)

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Abstract

The aerial oxidation of various 2,2-dibromo-1-aryl and heteroaryl ethanones to α-keto amides in the presence of air or oxygen and secondary amines are described. The reaction provides α-keto amides in moderate to good yields. The versatility of the reaction was established by synthesizing a series of α-keto amides by the reaction of dibromoethanones derived from aryl and heteroaryl ketones with cyclic and acyclic aliphatic secondary amines.

Key words

aerial oxidation - 2,2-dibromo-1-aryl and heteroaryl ethanone - α-keto amide - oxygen - secondary amine

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Representative Procedure for the Synthesis of 1-Phenyl-2-morpholin-1-yl-ethane-1,2-dione
To a solution of 2,2-dibromo-1-phenylethanone (1a, 1 g, 0.0035 mol, 1 equiv) in THF (10 mL) was added morpholine (0.99 g, 0.014 mol, 4 equiv) dropwise over a period of 30 min at 20-30 ˚C. The temperature of the reaction mixture was slowly raised to 40-50 ˚C under an oxygen atmosphere and maintained for 18-26 h (monitored by TLC). After the completion of the reaction, THF was distilled off up to 80% of its volume. The reaction mass was then diluted with CH2Cl2 (25 mL), washed with dil. HCl (10 mL, 4×), followed by brine. The organic layer was then dried over Na2SO4, and the product 2a was obtained after column chromatographic purification in 54% of yield as off-white solid; yield 57%.
IR (KBr): 1428, 1517, 1578, 1604, 1683, 1677, 2843 cm-¹. ¹H NMR (200 MHz, CDCl3): δ = 3.40 (m, 2 H), 3.70 (m,
2 H), 3.80 (m, 4 H), 7.50 (m, 2 H), 7.70 (m, 1 H), 7.95 (m,
2 H). ¹³C NMR (50 MHz, CDCl3): δ = 41.6, 46.2, 66.6, 66.7, 129.0, 129.6, 133.0, 134.8, 165.4, 191.1. MS: m/z (%) = 220.2 [M + 1], 192,159, 105. Anal. Calcd for C12H13NO3 (219.9): C, 65.74; H, 5.98; N, 6.39. Found: C, 65.71; H, 5.95; N, 6.32.
1-Phenyl-2-piperidin-1-yl-ethane-1,2-dione (2b) Yield 52%. IR: (KBr): 1447, 1579, 1638, 1671, 2938 cm-¹. ¹H NMR (200 MHz, CDCl3): δ = 1.60 (m, 2 H), 1.71 (m,
4 H), 3.30 (m, 2 H), 3.71 (m, 2 H), 7.50 (m, 2 H), 7.64 (m,
1 H), 7.95 (m, 2 H). ¹³C NMR (50 MHz, CDCl3): δ = 24.3, 25.4, 26.1, 42.1, 47.0, 128.9, 129.5, 133.2, 134.6, 165.4, 191.9. MS: m/z (%) = 218.1 [M + 1], 190.2, 149.0, 126.0. Anal. Calcd for C13H15NO2 (203.4): C, 71.81; H, 6.96; N, 6.45. Found: C, 71.79; H, 6.91; N, 6.41.
1-Phenyl-2-pyrolidin-1-yl-ethane-1,2-dione (2c)
Yield 54%. IR (KBr): 1446, 1597, 1638, 1677, 2882, 2977 cm-¹. ¹H NMR (200 MHz, CDCl3): δ = 1.95 (m, 4 H), 3.38 (m, 2 H), 3.65 (m, 2 H), 7.49 (m, 2 H), 7.63 (m, 1 H), 7.95 (m, 2 H). ¹³C NMR (50 MHz, CDCl3): δ = 23.8, 25.7, 45.0, 46.5, 128.7, 129.6, 132.7, 134.4, 165.8, 191.4. MS: m/z (%) = 204.1 [M + 1], 176.3, 105. Anal. Calcd for C12H13NO2 (203.4): C, 70.92; H, 6.45; N, 6.89. Found: C, 70.89; H, 6.45; N, 6.89.
1-phenyl-2-dimethylamino-ethane-1,2-dione (2d) Yield 48%. ¹H NMR (200 MHz, CDCl3): δ = 2.95 (s, 3 H), 3.11 (s, 3 H), 7.50 (m, 2 H), 7.63 (m, 1 H), 7.92 (m, 2 H). ¹³C NMR (50 MHz, CDCl3): δ = 33.8, 36.9, 128.9, 129.5, 132.9, 134.6, 166.9, 191.7. MS: m/z (%) = 178.2 [M + 1], 150.2, 105.0. Anal. Calcd for C12H13NO3 (177.2): C, 67.78; H, 6.26; N, 7.90. Found: C, 67.70; H, 6.24; N, 7.89.
1-phenyl-2-diethylamino-ethane-1,2-dione (2e) IR (KBr): 720, 855, 1146, 1233, 1383, 1448, 1642, 1681, 1720, 2934, 2977 cm-¹. ¹H NMR (200 MHz, CDCl3):
δ = 1.29 (m, 3 H), 1.31 (m, 3 H), 3.2 (m, 2 H), 3.59 (m, 2 H), 7.50 (m, 2 H), 7.63 (m, 1 H), 7.93 (m, 2 H). ¹³C NMR (50 MHz, CDCl3): δ = 12.8, 14.0, 38.8, 42.1, 128.8, 129.5, 130.0, 133.0, 133.2, 134, 166.6, 191.4. MS: m/z (%) = 206.1 [M + 1], 178.1, 130. Anal.Calcd for C12H15NO2 (205.1): C, 70.22; H, 7.37; N, 6.82. Found: C, 70.19; H, 7.31; N, 6.80.
N -Benzyl- N -methyl-2-oxo-2-phenylacetamide (2f) IR (KBr): 723, 881, 1003, 1210, 1449, 1643, 1680, 2926, 3030, 3063 cm-¹. ¹H NMR (200 MHz, CDCl3): δ = 2.84-2.99 (d, 3 H), 4.39 (s, 1 H), 4.74 (s, 1 H), 7.20-7.61 (m, 8 H), 8.02-8.11 (m, 2 H), ¹³C NMR (50 MHz, CDCl3): δ = 34.4, 49.8, 128.2, 128.7, 128.8, 128.9, 129.5, 130, 133, 133.2, 133.5, 134.6, 134.8, 135.7, 167, 191.3 MS: m/z (%) = 254.1 [M + 1], 211, 198. Anal. Calcd for C15H15NO2 (253.1): C, 75.87; H, 5.97; N, 5.53. Found: C, 75.79; H, 5.96; N, 5.50.
1-(3-Bromo-4-methoxy-phenyl)-2-piperidin-1-yl-ethane-1,2-dione (2g) Yield 56%. IR (KBr): 1202, 1278, 1405, 1589, 1637, 1671, 2927 cm-¹. ¹H NMR (200 MHz, CDCl3): δ = 1.28 (m, 4 H), 1.69 (m, 2 H), 3.30 (m, 2 H), 3.70 (m, 2 H), 3.98 (s, 3 H), 6.95 (d, 1 H, J = 8.6 Hz), 7.98 (dd, 1 H, J = 2.2, 8.6 Hz), 8.15 (d, 1 H, J = 2.2 Hz). ¹³C NMR (50 MHz, CDCl3): δ = 24.2, 25.3, 26.1, 42.1, 47.0, 56.5, 111.4, 112.4, 127.3, 131.0, 134.5, 160.7, 164.9, 189.3. MS: m/z (%) = 326.10 [M + 1], 300.0, 212.8, 148.7, 112.1. Anal. Calcd for C15H20BrNO3 (326.19): C, 51.55; H, 4.94; N, 4.29. Found: C, 51.53; H, 4.28; N, 4.83.
1-(3-Bromo-4-methoxy-phenyl)-2-pyrolidin-1-yl-ethane-1,2-dione (2h) Yield 57%. IR (KBr): 1264, 1499, 1589, 1629, 1642, 1665, 2980 cm-¹. ¹H NMR (200 MHz, CDCl3): δ = 1.95 (m, 4 H), 3.40 (m, 2 H), 3.70 (m, 2 H), 3.98 (s, 3 H), 6.95 (d, 1 H, J = 8.8 Hz), 7.98 (dd, 1 H, J = 2.2, 8.8 Hz), 8.2 (d, 1 H, J = 2.2 Hz). ¹³C NMR (50 MHz, CDCl3): δ = 23.9, 25.8, 45.2, 46.7, 56.5, 111.3, 112.3, 127.0, 131.4, 135.0, 160.7, 164.3, 188.9. MS: m/z (%) = 313.90 [M + 1], 312.0 [M+], 212.9, 134.8. Anal. Calcd for C13H14BrNO3 (312.36): C, 50.02; H, 4.52; N, 4.49. Found: C, 50.0; H, 4.51; N, 4.43.
1-Naphthalen-1-yl-2-morpholin-1-yl-ethane-1,2-dione (2l)
IR (KBr):1115.7, 1226, 1252, 1273, 1628, 1669, 2923 cm-¹. ¹H NMR (200 MHz, CDCl3): δ = 3.43 (m, 2 H), 3.65 (m,
2 H), 3.83 (m, 4 H), 7.60 (m, 3 H), 8.01 (m, 3 H), 9.20 (d,
2 H, J = 8.6 Hz). ¹³C NMR (50 MHz, CDCl3): δ = 41.5, 46.2, 66.4, 124.3, 125.5, 126.9, 128.2, 128.6, 129.3, 130.7, 133.9, 134.3, 136.0, 165.9, 193.4 MS: m/z (%) = 270.1 [M + 1], 249, 177.4, 155.2. Anal. Calcd for C16H15NO3 (269.11): C, 71.36; H, 5.61; N, 5.20. Found: C, 71.30; H, 5.93; N, 5.52.