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Synlett 2004(4): 698-702  
DOI: 10.1055/s-2003-817787
LETTER
© Georg Thieme Verlag Stuttgart · New York

A New Regio- and Chemoselective Approach to β-Keto Amides and β-Enamino Carboxamides via 1,3,2-Dioxaborinanes

Bogdan Štefane*, Slovenko Polanc
Faculty of Chemistry and Chemical Technology, University of Ljubljana, Akerčeva 5, 1000 Ljubljana, Slovenia
Fax: +386(1)2419220; e-Mail: bogdan.stefane@uni-lj.si;
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Publication History

Received 26 August 2003
Publication Date:
17 February 2004 (online)

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Abstract

Surprisingly, 5,6-disubstituted 2,2-difluoro-4-alkoxy-1,3,2-dioxaborinanes, which can be easily obtained from β-keto ­esters, reacted regio- and chemoselectively with amines under mild reaction conditions to form 2,2-difluoro-4-alkylamino-1,3,2-di­oxaborinanes in almost quantitative yields. The latter compounds can be easily deprotected, yielding β-keto amides, or directly transformed into β-enamino carboxamides. This procedure was also applied to the reaction of 2,2-difluoro-4-alkoxy-1,3,2-dioxaborinanes with arylhydrazines which selectively afforded β-hydrazono esters, in some cases without further cyclization to pyrazolones.

Key words

keto amides - enamino carboxamines - dioxaborinanes - chemoselectivity.

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General Procedure for the Preparation of 2,2-Difluoro-4-alkoxy-1,3,2-dioxaborinanes (2a-e). To a solution of the corresponding 1,3-ketoester (1 mmol) in toluene (5 mL) BF3·Et2O (3 equiv) was added at r.t. After being stirred at r.t. for 16 h, the reaction mixture was concentrated to 1/3 of volume (in the case of ethyl acetoacetate, ethyl benzoylacetate, and ethyl cyclohexanone-2-carboxylate) and than cooled to -10 °C. Precipitated material was filtered off and washed with mixture of solvents petroleum ether/EtOAc = 5/1 (5 mL), yielding pure product. In the case of dimethyl 2-acetylsuccinate and 2-acetylbutyrolactone the reaction mixture was evaporated to dryness yielding yellowish oil, which was used in the next step without further purification. Compound 2a: mp 28-31 °C (from hexane). IR (NaCl-plates): ν = 2980, 1590, 1540, 1380, 1330, 1185, 1040, 790 cm-1. 1H NMR (300 MHz, CDCl3): δ = 1.42 (t, 3 H, J = 7.2 Hz), 2.18 (s, 3 H), 4.51 (q, 2 H, J = 7.2 Hz), 5.41 (s, 1 H). 13C NMR (75 MHz, CDCl3): δ = 13.8, 23.1, 66.3, 87.1, 175.0 (t, J = 2.3 Hz), 186.4 (t, J = 1.4 Hz). MS (EI, 70 eV): m/z (%) = 178 (52) [M+], 135 (42), 84 (100), 69 (97). HRMS (EI): m/z calcd for C6H9BF2O3: 178.0613; found: 178.0618. Compound 2d: yellowish oil. IR (NaCl-plates): ν = 2963, 1719, 1609, 1509, 1337, 1053 cm-1. 1H NMR (300 MHz, CDCl3): δ = 2.22 (s, 3 H), 3.35 (s, 2 H), 3.77 (s, 3 H), 4.10 (s, 3 H). 13C NMR (75 MHz, CDCl3): δ = 21.2, 29.6, 53.1, 56.6, 92.1, 172.7, 174.2, 185.4. MS (EI, 70 eV): m/z (%) = 236(16) [M+], 217(89), 177(68), 97(100), 55(75). HRMS (EI): m/z calcd for C8H11BF2O5: 236.0668; found: 236.0674.

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General Procedure for the Reaction of 2,2-Difluoro-4-alkoxy-1,3,2-dioxaborinanes (2a-e) with Amines. To a solution of the corresponding amine (1.3 mmol) in MeCN (5 mL) 2,2-difluoro-4-alkoxy-1,3,2-dioxaborinane (1 mmol) was added at r.t. The reaction mixture was stirred at r.t. for the period of time noted in Table [2] . In the case where product precipitated from the reaction mixture, it was filtered off and washed with cold MeCN (3 mL), otherwise the reaction solvent was evaporated in vacuo and the residue dissolved in CH2Cl2 or EtOAc (30 mL), washed with H2O (2 × 10 mL), dried over MgSO4 and evaporated in vacuo. In some cases products were purified by flash chromatography. Selected spectroscopic data for compound of type 3. Compound 3f: mp 151-153 °C (from MeCN). IR (KBr): ν = 3445, 3350, 1677, 1605, 1503, 1407, 1355, 1230, 911, 778, 693 cm-1. 1H NMR (300 MHz, DMSO-d 6): δ = 3.32 (s, 3 H), 5.54 (br s, 2 H), 6.78 (s, 1 H), 7.50-7.62 (m, 3 H), 7.88-7.91 (m, 2 H). 13C NMR (75 MHz, DMSO-d 6): δ = 40.0, 84.2, 127.5, 129.9, 133.2, 134.1, 169.0 (t, J = 2.6 Hz), 170.9 (t, J = 2.0 Hz). MS (EI, 70 eV): m/z (%) = 240 (41) [M+], 195(46), 105 (100), 94 (34), 77 (45). HRMS (EI): m/z calcd for C10H11BF2N2O2: 240.0882; found: 240.0891. Compound 3h: mp 135-137 °C (from Et2O-EtOAc). IR (KBr): ν = 3399, 2955, 1612, 1528, 1339, 1263, 1197, 1038, 978, 743, 698 cm-1. 1H NMR (300 MHz, DMSO-d 6): δ = 1.64-1.66 (m, 4 H), 2.19-2.26 (m, 4 H), 4.52 (s, 2 H), 7.27-7.40 (m, 5 H), 9.49 (br s, 1 H). 13C NMR (75 MHz, DMSO-d 6): δ = 21.8, 22.0, 22.3, 31.0, 44.6, 95.7, 128.3, 128.4, 129.5, 137.9, 168.0 (t, J = 2.6 Hz), 174.2 (t, J = 2.2 Hz). MS (EI, 70 eV): m/z (%) = 279 (24) [M+], 91 (100). HRMS (EI): m/z calcd for C14H16BF2NO2: 279.1242; found: 279.1249. Compound 3k: mp 108-109 °C (from light petroleum ether-EtOAc). IR (KBr): ν = 3458, 3370, 3284, 2996, 2961, 1744, 1663, 1597, 1356, 1179, 954, 784, 578 cm-1. 1H NMR (300 MHz, DMSO-d 6): δ = 2.00 (s, 3 H), 3.38 (s, 2 H), 3.59 (s, 3 H), 8.72 (br s, 1 H), 9.09 (bs, 1 H). 13C NMR (75 MHz, DMSO-d 6): δ = 20.4, 29.8, 51.8, 91.6, 169.5 (t, J = 2.3 Hz), 170.7, 176.3 (t, J = 2.3 Hz). MS (EI, 70 eV): m/z (%) = 221 (27) [M+], 162 (100), 97 (94). HRMS (EI): m/z calcd for C7H10BF2NO4: 221.0671; found: 221.0677. Compound 3p: The colorless oil obtained on work-up was subjected to flash chromatography (1:10 MeOH-CHCl3 elution). IR (NaCl-plates): ν = 3564, 3401, 2945, 1605, 1523, 1458, 1300, 1200, 1128, 1047 cm-1. 1H NMR (300 MHz, CDCl3): δ = 2.07 (s, 3 H), 2.44 (t, 2 H, J = 5.4 Hz), 3.16 (bs, 1 H), 3.37 (s, 6 H), 3.51 (t, 2 H, J = 5.4 Hz), 3.74 (dd, 2 H, J 1 = 4.8 Hz, J 2 = 5.4 Hz), 4.46 (t, 1 H, J = 5.4 Hz), 8.22 (t, 1 H J = 4.8 Hz). 13C NMR (75 MHz, CDCl3): δ = 20.4, 28.3, 42.2, 54.3, 62.5, 96.7, 101.5, 169.3 (t, J = 2.5 Hz), 174.7 (t, J = 1.7 Hz). MS (EI, 70 eV): m/z (%) = 281 (0.3) [M+], 111(81), 84(100).

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General Procedure for the Preparation of Hydrazones 4. To a stirred solution of 2,2-difluoro-4-alkoxy-1,3,2-dioxaborinane (1 mmol) in MeCN (5 mL) the corresponding arylhydrazine (1.05 mmol) was added, which promptly dissolved. The reaction mixture was stirred at r.t. for 5-12 h. The precipitated material was filtered off and washed with cold MeCN (3 mL) and then recrystallized. Compound 4c: mp 100-102 °C (from EtOH). IR (KBr): ν = 3215, 1724, 1605, 1443, 1301, 764 cm-1. 1H NMR (300 MHz, CDCl3): δ = 1.29 (t, 3 H, J = 7.2 Hz), 2.52 (s, 3 H), 3.91 (s, 2 H), 4.13 (s, 3 H), 4.28 (q, 2 H, J = 7.2 Hz), 7.43-7.46 (m, 3 H), 7.77-7.81 (m, 2 H), 10.76 (br s, 1 H). 13C NMR (75 MHz, CDCl3): δ = 14.0 (2 C), 33.6, 40.0, 61.5, 117.4, 126.2, 128.8, 129.8, 136.4, 142.6, 143.7, 147.5, 167.7. MS (EI, 70 eV): m/z (%) = 345 (100) [M+], 225 (35), 103 (91), 77 (68). HRMS (EI): m/z calcd for C16H19N5O4: 345.1437; found: 345.1449. Compound 4e: mp 102-103 °C (from light petroleum ether-EtOAc). IR (KBr): ν = 3318, 2954, 2226, 1734, 1624, 1567, 1524, 1283, 1157, 998, 918, 762 cm-1. 1H NMR (300 MHz, DMSO-d 6): δ = 2.11 (s, 3 H), 2.93 (d, 2 H, J = 6.9 Hz), 3.62 (s, 3 H), 3.69 (s, 3 H), 3.94 (t, 1 H, J = 6.9 Hz), 7.72 (d, 1 H, J = 9.0 Hz), 7.97 (dd, 1 H, J 1 = 1.8 Hz, J 2 = 9.0 Hz), 8.57 (d, 1 H, J = 1.8 Hz), 10.63 (bs, 1 H). 13C NMR (75 MHz, DMSO-d 6): δ = 15.4, 33.0, 49.4, 51.6, 52.3, 99.8, 116.1, 117.8, 130.6, 131.3, 138.1, 143.3, 152.6, 170.7, 171.4. MS (EI, 70 eV): m/z (%) = 348 (30) [M+], 317 (30), 256 (100), 210(23). HRMS (EI): m/z calcd for C15H16N4O6: 348.1070; found: 348.1081.

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General Procedure for the Preparation of β-Carboxamido Enamines 6. In a typical experiment the solution of 2,2-difluoro-4-alkylamino-1,3,2-dioxaborinane (1 mmol) and corresponding amine (5 equiv) in PrOH (5 mL) was heated with stirring in an Ace pressure tube at 130-140 °C. After heating for 5-12 h, the reaction mixture was evaporated under reduced pressure and the residue purified by flash chromatography. Spectroscopic data for compound of type 6. Compound 6a: The colorless oil obtained on work-up was subjected to flash chromatography (5:3 light petroleum ether-EtOAc elution). Mp 117-120 °C (from Et2O). IR (KBr): ν = 3213, 2963, 1624, 1593, 1428, 1303, 1212, 1171, 1124, 1035, 768, 708 cm-1. 1H NMR (300 MHz, CDCl3): δ = 1.09 (d, 6 H, J = 6.9 Hz), 3.36-3.48 (m, 1 H), 4.41 (s, 1 H), 4.48 (d, 2 H, J = 6.0 Hz), 5.45 (br s, 1 H), 7.23 (dd, 1 H, J 1 = 4.6 Hz, J 2 = 7.8 Hz), 7.34-7.39 (m, 5 H), 7.64-7.67 (m, 1 H), 8.48 (dd, 1 H, J 1 = 1.8 Hz, J 2 = 4.6 Hz), 8.54 (d, 1 H, J = 2.1 Hz), 8.86 (br s, 1 H). 13C NMR (75 MHz, CDCl3): δ = 24.2, 40.3, 45.6, 87.8, 123.4, 127.7, 128.2, 128.8, 135.0, 135.3, 137.1, 148.5, 149.0, 162.1, 170.2. MS (EI, 70 eV): m/z (%) = 295 (31) [M+], 252 (49), 188 (56), 160 (100), 146 (85), 104 (83), 92 (47). HRMS (EI): m/z calcd for C18H21N3O: 295.1685; found: 295.1690. Compound 6b: The colorless oil obtained on work-up was subjected to flash chromatography (1:1 light petroleum ether-EtOAc elution). Mp 114-116 °C (from Et2O). IR (KBr): ν = 3227, 2961, 1620, 1545, 1324, 1215, 1017, 922, 791, 768, 733, 702 cm-1. 1H NMR (300 MHz, CDCl3): δ = 1.16 (d, 6 H, J = 6.8 Hz), 4.07-4.14 (m, 1 H), 4.19 (d, 2 H, J = 6.6 Hz), 4.50 (s, 1 H), 4.98 (br s, 1 H), 7.20 (ddd, 1 H, J 1 = 0.8 Hz, J 2 = 4.7 Hz, J 3 = 7.7 Hz), 7.27-7.37 (m, 5 H), 7.56 (ddd, 1 H, J 1 = J 2 = 2.0 Hz, J 3 = 7.7 Hz), 8.32 (d, 1 H, J = 2.0 Hz), 8.45 (dd, 1 H, J 1 = 1.5 Hz, J 2 = 4.7 Hz), 9.40 (bs, 1 H). 13C NMR (75 MHz, CDCl3): δ = 23.1, 40.6, 45.7, 90.8, 123.4, 127.8, 128.4, 129.0, 134.7, 135.3, 136.3, 148.4, 148.7, 161.4, 169.4. MS (EI, 70 eV): m/z (%) = 295 (64) [M+] 237 (69), 209 (100), 92 (98). HRMS (EI): m/z calcd for C18H21N3O: 295.1685; found: 295.1694. Compound 6d: The colorless oil obtained on work-up was subjected to flash chromatography (1:10 MeOH-CHCl3 elution). Colorless oil. IR (NaCl-plates): ν = 3300, 2969, 1614, 1540, 1496, 1299, 1213, 1168, 770, 702 cm-1. 1H NMR (300 MHz, CDCl3): δ = 1.07 (d, 6 H, J = 6.6 Hz), 3.33-3.43 (m, 1 H), 3.88-3.92 (m, 2 H), 4.41 (s, 1 H), 5.07-5.22 (m, 2 H), 5.17 (br s, 1 H), 5.83-5.92 (m, 1 H), 7.33-7.38 (m, 5 H), 8.81 (bs, 1 H). 13C NMR (75 MHz, CDCl3): δ = 24.1, 41.2, 45.4, 88.4, 115.5, 127.6, 128.1, 128.6, 135.3, 137.3, 161.5, 170.1. MS (EI, 70 eV): m/z (%) = 244 (53) [M+], 188 (100), 160 (71), 146 (84), 104 (95). HRMS (EI): m/z calcd for C15H20N2O: 244.1576; found: 244.1580. Compound 6e: The colorless oil obtained on work-up was subjected to flash chromatography (10:1 light petroleum ether-EtOAc elution). Colorless oil. IR (NaCl-plates): ν = 2933, 1853, 1609, 1596, 1573, 1481, 1408, 1219, 1123, 1022, 775, 702 cm-1. 1H NMR (300 MHz, CDCl3): δ = 1.50-1.63 (m, 6 H), 3.33-3.48 (m, 4 H), 3.58-3.62 (m, 2 H), 4.77 (s, 1 H), 5.03-5.21 (m, 2 H), 5.72-5.81 (m, 1 H), 7.33-7.39 (m, 5 H), 9.52 (br s, 1 H). 13C NMR (75 MHz, CDCl3): δ = 24.7, 25.9, 46.6, 85.1, 115.3, 127.7, 128.0, 128.5, 128.6, 135.7, 137.2, 162.7, 169.1. MS (EI, 70 eV):
m/z (%) = 270 (42) [M+], 186 (100), 159 (65), 84 (66). HRMS (EI): m/z calcd for C17H22N2O: 270.1732; found: 270.1739. Compound 6f: The colorless oil obtained on work-up was subjected to flash chromatography (5:1 light petroleum ether-EtOAc elution). Mp 114-117 °C. IR (KBr): ν = 3296, 2968, 2937, 1646, 1599, 1531, 1456, 1167, 752 cm-1. 1H NMR (300 MHz, CDCl3): δ = 1.14 (d, 3 H, J = 6.6 Hz), 1.18 (d, 3 H, J = 6.6 Hz), 1.61-1.70 (m, 2 H), 1.70-1.92 (m, 3 H), 2.12-2.45 (m, 3 H), 3.21 (t, 1 H, J = 4.9 Hz), 4.05-4.16 (m, 1 H), 6.31 (br s, 1 H), 6.85-6.90 (m, 1 H), 7.04-7.07 (m, 2 H), 7.24-7.30 (m, 3 H). 13C NMR (75 MHz, CDCl3): δ = 22.7, 22.8, 23.3, 24.3, 25.0, 29.0, 41.3, 49.9, 112.9, 119.2, 145.4, 148.2, 170.6. MS (EI, 70 eV): m/z (%) = 273 (25) [M+], 214 (100), 93 (32). Anal. Calcd for C16H23N3O: C, 70.30; H, 8.48; N, 15.37. Found: C, 70.01; H, 8.32; N, 15.63.