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Studies on the Base-Induced Rearrangement of 5-methyl-3-nitrosoindolizine Derivatives.

Byline: Peng Wang, Jin Cai, Junqing Chen and Min Ji

Summary: Here we have studied the rearrangement of 5-methyl-3-nitrosoindolizine derivatives in the presence of K2CO3. 5-Methyl-3-nitrosoindolizine derivatives can be converted to ring-opening, rearrangement and denitrosylation products respectively. Methyl at 5-position and substituent groups at 2-position of 3-nitrosoindolizine derivatives are critical for the rearrangement reaction and have slight effect on the denitrosylation under standard conditions.

Keywords: Indolizine; Rearrangement; Ring-opening; Denitrosylation

Introduction

Indolizine derivatives are one of the most studied nitrogen-fused heterocycles. As known for their intriguing molecular structures, it has been frequently employed as a key scaffold in the biologically active compounds [1-3]. For example, rosabulin possesses potent antitumor activity both in vitro and in vivo through its binding to a novel binding site in the microtubules[4]. Moreover, indolizine have been used in the dye chemistry[5], fluorescent sensors[6-8], organic semiconducting materials[9], and luminescent materials[10]. Consequently, the characteristics of indolizine derivatives have been disclosed. However, few literature reported the research on 3-nitrosoindolizine especially the 5-methyl-3-nitrosoindolizine derivatives [11-12], which are an import class of indolizine derivatives[13-14]. Herein, we have studied on the rearrangement of 5-methyl-3-nitrosoindolizine derivatives under alkaline conditions.

Experimental

General Methods

Commercial reagents were used as received. Analytical-grade solvents were used without further purification. Thin-layer chromatography (TLC) was carried out on silica gel plates with a fluorescence indicator of F254 (0.2 mm, Qingdao Haiyang Chemical Co., Qingdao, China). 1H NMR and 13C NMR spectra were recorded on a Bruker-300 MHz spectrometer and chemical shifts are reported relative to TMS; Multiplicity was indicated as follows: s (singlet); d (doublet); m (multiplet); dd (doublet of doublets). Coupling constants J is given in Hertz (Hz). Electrospray mass spectra were obtained on a Finnigan MAT-95 Spectrometer. Melting points were measured on a WRS-2A meltingpoint apparatus and are uncorrected.

General Procedure for the Synthesis of 3-nitrosoindolizine Derivatives

Indolizine derivative (5 mmol) was dissolved in 10 mL acetone under nitrogen in the dark. NaNO2 (10 mmol) was added to the mixture and cooled to 0 oC. Then 1 mL acetic acid was dropped into the solution and stirred for 0.5 h. The solution was poured into 20 mL water, and adjusted to pH 7 with saturated sodium bicarbonate solution. The mixture was filtered, and the solid washed with 2 mL ethanol and 2 mL water, and dried under vacuum to afford 5-methyl-3-nitrosoindolizine derivatives.

(5-Methyl-3-nitroso-2-phenylindolizin-1-yl)(phenyl)methanone (1a). m.p.: 98-99 oC. IR (KBr): 1643, 1496, 1333, 1199, 1165, 1156, 1053 cm-1. 1HNMR (CDCl3) d 3.17 (s, 3H), 7.28~8.28 (m, 13H). Anal. Calc.(%) for C22H16N2O2 : C 77.63, H 4.74, N 8.23; Found: C 77.85, H 4.83, N 8.33%. MS m/z: 341.1[M+H]+, 363.1[M+Na]+.

(4-Chlorophenyl)(5-methyl-3-nitroso-2-phen ylindolizin-1-yl)methanone (1b). m.p.: 150-152 oC. IR (KBr): 1639, 1582, 1496, 1333, 1197, 1050, 1010, 946, 905, 795 cm-1. 1HNMR (CDCl3) d 3.29 (s, 3H) , 7.08~7.15 (m, 5H) , 7.35~7.66 (m, 4H) , 7.66 (m, 2H) , 8.01 (d, 1H, J = 8.1 Hz). Anal. Calc.(%) for C22H15N2O2Cl : C 70.50, H 4.03, N 7.47; Found: C 70.77, H 4.36, N 7.69. MS m/z: 375.0 [M+H]+.

(E)-1-(5-Methyl-3-nitroso-2-phenylindolizin -1-yl)-3-phenylprop-2-en-1-one (1c). m.p.: 151-152.5 oC. IR (KBr): 3053, 1647, 1624, 1591, 1574, 1498, 1448, 1432, 1325, 1219, 1164, 1152, 1040, 743 cm-1. 1HNMR (CDCl3): d 3.28 (s, 3H), 6.30 (d, 1H, J = 15.6 Hz) , 7.06~7.10 (m, 3H), 7.19~7.63 (m, 6H), 7.75~7.78 (m, 2H), 8.13 (d, 2H, J = 6.0 Hz), 8.68 (d, 1H, J = 8.7 Hz). Anal. Calc.(%) for C24H18N2O2 : C 78.67, H 4.53, N 7.65; Found: C 78.78, H 4. 35, N 7.83. MS m/z: 367.1 [M+H]+, 389.1 [M+Na]+.

(5-Methyl-3-nitroso-2-phenylindolizin-1-yl)(3,4,5-trimethoxyphenyl)methanone (1d): m.p.: 147-148 oC. IR (KBr): 3448, 1611, 1580, 1499, 1456, 1415, 1327, 1229, 1129, 1003, 780 cm-1. 1HNMR (CDCl3) d 3.31 (s, 3H), 3.64~3.80 (m, 9H), 6.85 (m, 2H), 7.12~7.34 (m, 6H), 7.58 (s, 1H), 8.04 (d, 1H, J = 9.0 Hz). Anal. Calc.(%) for C25H22N2O5 : C 69.76, H 5.15, N 6.51; Found: C 69.69, H 5.32, N 6.65. MS m/z: 431.1 [M+H]+.

(2-(4-Bromophenyl)-5-methyl-3-nitrosoindol izin-1-yl)(phenyl)methanone (1e): m.p.: 103-105 oC. IR (KBr): 1641, 1595, 1494, 1449, 1383, 1330, 1225, 1208, 1175, 1158, 1010 cm-1. 1HNMR [CO(CD3)2]: d 3.23 (s, 3H), 7.07~8.00 (m, 12H). Anal. Calc.(%) for C22H15N2O2Br : C 63.02, H 3.61, N 6.70; Found: C 62.85, H 3.51, N 6.89. MS m/z: 419.2 [M+H]+, 441.0 [M+Na]+.

1-Methyl-3-nitroso-2-phenylindolizine (5): m.p.: 208-209.5 oC. IR (KBr): 1612, 1478, 1364, 1280, 1194, 1141, 1082, 1058, 871 cm-1. 1HNMR (CDCl3): d 2.35 (s, 3H), 7.37~7.46 (m, 4H), 7.65~7.71 (m, 4H), 10.52 (d, 1H, J = 6.6 Hz). Anal. Calc.(%) for C15H12N2O : C 76.25, H 5.12, N 11.86; Found: C 76.57, H 5.38, N 11.99. MS m/z: 237.1 [M+H]+.

3-Nitroso-2-phenylindolizine (8): m.p.: 88-90 oC. IR (KBr): 1620, 1477, 1465, 1411, 1335, 1215, 1206, 1124, 1101, 1078, 763 cm-1. 1HNMR (CDCl3): d 7.01 (s, 1H), 7.20~7.23 (m, 1H), 7.47~7.52 (m, 3H), 7.69 (d, 2H, J = 6.8 Hz), 8.11 (dd, 2H, J = 6.8, 2.1Hz), 10.50 (d, 1H, J = 6.8 Hz). Anal. Calc.(%) for C14H10N2O : C 75.71, H 4.54, N 12.61; Found: C 75.96, H 4.49, N 12.52. MS m/z: 223.1 [M+H]+.

General Procedure for the Rearrangement of 5-methyl-3-nitrosoindolizine Derivatives

5-methyl-3-nitrosoindolizine derivatives (3 mmol) and K2CO3 (7 mmol) were added to 10 mL DMF and warmed to 75 oC for 1 h under nitrogen in the dark. The reaction mixture was poured into 30 mL ice water. Then the solid was obtained by filter and purified by silica gel column chromatography, eluting with ethyl acetate and n-hexane (1:2) to afford 2a-e and 4a-e respectively. The filtrate was adjusted to pH 7 with 1N HCl and extracted with ethyl acetate (3A-20 mL). The combined organic phase was distilled under reduced pressure and purified by gel column chromatography with ethyl acetate and n-hexane (1:1) to give 3a-e respectively.

(E)-3-(6-(Hydroxymethyl)pyridin-2-yl)-4-ox o-2,4-diphenylbut-2-enenitrile (2a): m.p.: 110-111 oC. IR (KBr): 3468, 3064, 2201, 1671, 1593, 1452, 1234, 1168, 1058, 771, 692 cm-1. 1HNMR (CDCl3) d 4.88 (s, 2H), 7.24~7.53 (m, 9H), 7.57 (d, 1H, J = 7.8 Hz), 7.80 (t, 1H, J = 7.8 Hz), 7.86 (m, 2H). Anal. Calc.(%) for C22H16N2O2 : C 77.63, H 4.74, N 8.23; Found: C 77.84, H 4.91, N 8.42. MS m/z: 341.2 [M+H]+, 363.2 [M+Na]+.

5-Hydroxy-4-(6-(hydroxymethyl)pyridin-2-yl)-3,5-diphenyl-1H-pyrrol-2(5H)-one (3a): m.p.:185-186 oC. IR (KBr): 3426, 3211, 3081, 2920, 1706, 1591, 1447, 1093, 783, 698 cm-1. 1HNMR [CO(CD3)2]: d 4.59 (s, 1H), 7.03 (d, 1H, J = 7.8 Hz), 7.20~7.39 (m, 9H), 7.43~7.46 (m, 2H), 7.55~7.62 (m, 3H). Anal. Calc.(%) for C22H18N2O3 : C 73.73, H 5.06, N 7.82; Found: C 73.81, H 5.01, N 7.52. MS m/z: 359.3 [M+H]+, 381.3 [M+Na]+.

(5-Methyl-2-phenylindolizin-1-yl)(phenyl)m ethanone (4a): m.p.: 126-127 oC. IR (KBr): 1634, 1606, 1504, 1479, 1413, 1288, 1148, 1017, 904, 772, 738, 697 cm-1. 1HNMR (CDCl3): d 2.67 (s, 3H), 6.76 (d, 1H, J = 4.8Hz), 7.11~7.23 (m, 10H), 7.57 (d, 2H, J = 7.8Hz), 8.14 (d, 1H, J = 9.0 Hz). Anal. Calc.(%) for C22H17NO : C 84.86, H 5.50, N 4.50; Found C 84.67, H 5.58, N 4.45. MS m/z: 312.2 [M+H]+, 334.1 [M+Na]+.

(E)-4-(4-Chlorophenyl)-3-(6-(hydroxymethyl)pyridin-2-yl)-4-oxo-2-phenylbut-2-enenitrile (2b): m.p.:148-150 oC. IR (KBr): 3213, 3061, 2944, 2870, 2215, 1677, 1585, 1570, 1452, 1399, 1219, 1093, 1034, 1007, 833, 799, 769, 695 cm-1. 1HNMR (CDCl3) d 4.86 (s, 2H), 7.28~7.36 (m, 6H), 7.44~7.47 (m, 2H), 7.60 (d, 1H, J = 7.5 Hz), 7.78~7.82 (m, 3H). Anal. Calc.(%) for C22H15N2O2Cl : C 70.50, H 4.03, N 7.47; Found: C 70.77, H 4.32, N 7.65. MS m/z: 375.7 [M+H]+.

5-(4-Chlorophenyl)-5-hydroxy-4-(6-(hydrox ymethyl)pyridin-2-yl)-3-phenyl-1H-pyrrol-2(5H)-one (3b): m.p.: 239-241.5 oC. IR (KBr): 3479, 3200, 3079, 2936, 2872, 1705, 1658, 1489, 1445, 1093, 1016, 787, 696 cm-1. 1HNMR [CO(CD3)2]: d 4.69 (s, 2H), 6.95 (d, 1H, J = 7.5 Hz), 7.17 (d, 2H, J = 7.6 Hz), 7.24 (d, 1H, J = 7.5 Hz), 7.38~7.47 (m, 8H). Anal Calc.(%) for C22H17N2O3Cl : C 67.26, H 4.36, N 7.13; Found: C 67.01, H 4.51, N 7.34. MS m/z: 393.1 [M+H]+, 415 [M+Na]+.

(4-Chlorophenyl)(5-methyl-2-phenylindolizi n-1-yl)methanone (4b): m.p.: 122-124 oC. IR (KBr): 3131, 1611, 1505, 1477, 1412, 1290, 1011, 906, 785 cm-1. 1HNMR (CDCl3): d 2.63 (s, 3H), 6.70 (d, 1H, J = 6.6 Hz), 7.04~7.28 (m, 9H), 7.46 (d, 2H, J = 6.6 Hz), 8.14 (d, 1H, J = 6.6 Hz). Anal. Calc.(%) for C22H16NOCl : C 76.41, H 4.66, N 4.05; Found C 76.33, H 4.46, N 4.18. MS m/z: 346.1 [M+H]+, 368.1 [M+Na]+.

(E)-5-Hydroxy-4-(6-(hydroxymethyl)pyridin-2-yl)-3-phenyl-5-styryl-1H-pyrrol-2(5H)-one (3c): mp:194-196 oC; IR (KBr): 3438, 3191, 3083, 2859, 1704, 1572, 1444, 1426, 1364, 1043, 969, 790, 762, 704, 694 cm-1. 1HNMR [CO(CD3)2]: d 4.69 (s, 2H), 6.53 (d, 1H, J = 9.9 Hz), 6.95 (d, 1H, J = 9.9 Hz), 7.22~7.46 (m, 11H), 7.70 (t, 1H, J = 7.8 Hz). Anal. Calc.(%) for C24H20N2O3 H2O : C 71.63, H 5.51, N 6.96; Found: C 71.63, H 5.31, N 6.69. MS m/z: 385.4 [M+H]+, 407.4 [M+Na]+.

(E)-1-(5-Methyl-2-phenylindolizin-1-yl)-3-p henylprop-2-en-1-one (4c): m.p.: 148-150 oC. IR (KBr): 1642, 1580, 1500, 1474, 1412, 1148, 1044, 705 cm-1. 1HNMR (CDCl3): d 2.63 (s, 3H), 6.74 (d, 1H, J = 6.6 Hz), 6.83 (d, 1H, J = 15.6 Hz), 7.09~7.13 (m, 2H), 7.19~7.30 (m, 5H), 7.47~7.50 (m, 3H), 7.55~7.58 (m, 2H), 7.64 (d, 1H, J = 15.6 Hz), 8.59 (d, 1H, J = 9.0 Hz). Anal. Calc.(%) for C22H19NO : C 85.43, H 5.68, N 4.15; Found C 85.64, H 5.45, N 4.45. MS m/z: 338.1 [M+H]+, 360.2 [M+Na]+.

(E)-3-(6-(Hydroxymethyl)pyridin-2-yl)-4-ox o-2-phenyl-4-(3,4,5-trimethoxyphenyl)but-2-enenitril e (2d): m.p.: 113-115 oC. IR (KBr): 3501, 3500, 2942, 2837, 2221, 1660, 1582, 1503, 1461, 1415, 1334, 1234, 1128, 1063, 996, 866, 761 cm-1. 1HNMR (CDCl3): d 3.92 (s, 6H), 3.97 (s, 3H), 4.64 (s, 2H), 7.24 (d, 1H, J = 7.7 Hz), 7.31~7.32 (m, 1H), 7.35~7.43 (m, 7H), 7.71 (t, 1H, J = 7.5 Hz). Anal. Calcld. (%) For C25H22 N2O5 : C 69.76, H 5.15, N 6.51; Found: C 69.51, H 5.35, N 6.32. MS m/z: 431.3 [M+H]+, 453.3 [M+Na]+.

5-Hydroxy-4-(6-(hydroxymethyl)pyridin-2-yl)-3-phenyl-5-(3,4,5-trimethoxyphenyl)-1H-pyrrol-2(5 H)-one (3d): m.p.:159.5-161.5 oC. IR (KBr): 3585, 3473, 3292, 2945, 2833, 1712, 1700, 1594, 1415, 1329, 1238, 1127, 993, 648 cm-1. 1HNMR (CDCl3): d 3.79~3.80 (m, 9H), 4.72 (s, 2H), 6.77 (s, 2H), 7.03 (d, 1H, J = 9.0 Hz), 7.27 (d, 1H, J = 9.0 Hz), 7.41~7.47 (m, 5H), 7.52 (t, 1H, J = 9.0 Hz). Anal. Calc.(%) for C25H24N2O6 H2O : C 67.11, H 5.37, N 6.26; Found: C 66.92, H 5.49, N 6.01. MS m/z: 449 [M+H]+, 471 [M+Na]+.

(5-Methyl-2-phenylindolizin-1-yl)(3,4,5-trim ethoxyphenyl)methanone (4d): m.p.: 156-157 oC. IR (KBr): 3139, 2934, 1611, 1580, 1499, 1478, 1417, 1326, 1227, 1128, 1004, 780 cm-1. 1HNMR (CDCl3): d 2.65 (s, 3H), 3.71 (s, 6H), 3.78 (s, 3H), 6.70 (d, 1H, J = 6.7 Hz), 7.11~7.20 (m, 5H), 6.89 (s, 2H), 7.24~7.28 (m, 2H), 8.15 (d, 1H, J = 9.0 Hz). Anal. Calc.(%) for C25H23NO4 : C 74.80, H 5.77, N 3.49; Found C 74.69, H 5.64, N 3.58. MS m/z: 402.2 [M+H]+, 424.1 [M+Na]+.

(E)-2-(4-Bromophenyl)-3-(6-(hydroxymethyl)pyridin-2-yl)-4-oxo-4-phenylbut-2-enenitrile (2e): m.p.: 148.5-149.5 oC. IR (KBr): 3493, 2206, 1658, 1585, 1575, 1485, 1450, 1397, 1316, 1235, 1171, 1057, 1009, 836, 820, 794, 717 cm-1. 1HNMR (CDCl3): d 4.86 (s, 2H), 7.29~7.43 (m, 7H), 7.51 (d, 1H, J = 7.5 Hz), 7.56 (d, 1H, J = 7.5 Hz), 7.77 (t, 1H, J = 7.8 Hz), 7.83~7.86 (m, 2H). Anal. Calc.(%) for C22H15N2O2Br : C 63.02, H 3.61, N 6.68; Found: C 63.22, H 3.90, N 6.70. MS m/z: 419.0 [M+H]+, 441.0 [M+Na]+.

(2-(4-Bromophenyl)-5-methylindolizin-1-yl)(phenyl)methanone (4e): m.p.: 136-137 oC. IR (KBr): 3133, 1607, 1504, 1475, 1420, 1386, 1287, 1168, 1010, 905, 827, 785, 745, 697, 660 cm-1. 1HNMR (CDCl3): d 2.65 (s, 3H), 6.70 (d, 1H, J = 6.7 Hz), 7.08~7.36 (m, 9H), 7.57 (d, 2H, J = 8.3 Hz), 8.01 (d, 1H, J = 9.0 Hz). Anal. Calc.(%) for C22H16NOBr : C 67.71, H 4.13, N 3.59; Found C 67.52, H 4.33, N 3.73. MS m/z: 390.0 [M+H]+, 412.0 [M+Na]+.

Synthesis of 1-methyl-2-phenylindolizine (6): Compound 5 (3 mmol) and K2CO3 (7 mmol) were added to 10 mL DMF under nitrogen in the dark, and warmed to 75 oC for 2 h. The reaction mixture was poured into 30 mL ice water. Then the solid was filtered and purified by silica gel column chromatography with ethyl acetate and n-hexane (1:2) to afford 1-methyl-2-phenylindolizine in 10% yield. m.p.: 79-80 oC. IR (KBr): 3065, 2863, 1601, 1455, 1366, 1300, 1211, 735 cm-1. 1HNMR (CDCl3): d 2.49 (s, 3H), 6.48 (t, 1H, J = 6.6 Hz), 6.63 (t, 1H, J = 6.6 Hz), 7.34~7.51 (m, 6H), 7.87 (d, 1H, J = 6.6 Hz). Anal. Calc.(%) for C15H13N : C 86.92, H 6.32, N 6.76; Found: C 87.07, H 6.53, N 6.762. MS m/z: 208 [M+H]+.

Synthesis of (E)-3-cyano-3-phenyl-2-(pyridin-2-yl)allyl acetate (7): 2 mL acetic anhydride and 2 mL acetic acid was added to the solution of compound 5 (3 mmol) in 20 mL dry toluene under nitrogen in the dark. Then the solution was stirred at 70 oC for 1 h, and poured into 30 mL ice water. The mixture was adjusted to pH 7 with saturated sodium bicarbonate solution and then extracted with 30 mL ethyl acetate three times. The combined organic phase was dried over MgSO4, distilled under reduced pressure and purified by silica gel column chromatography with ethyl acetate and n-hexane (1:2) to afford compound 7 in 70% yield. m.p.: 124-126 oC. IR (KBr): 2212, 1736, 1583, 1569, 1461, 1433, 1379, 1238, 1225, 1027, 766, 707 cm-1. 1HNMR (CDCl3): d 1.91 (s, 3H), 5.18 (s, 2H), 7.39 (t, 1H, J = 6.0 Hz), 7.50 (s, 5H), 7.78 (d, 1H, J = 6.0 Hz), 7.86 (t, 1H, J = 6.0 Hz), 8.75 (d, 1H, J = 6.0 Hz).

Anal. Calc.(%) for C17H14N2O2 : C 73.37, H 5.07, N 10.07; Found: C 73.59, H 5.21, N 9.89. MS m/z: 279.3 [M+H]+, 301.3 [M+Na]+.

Synthesis of (E)-2-cyano-2-phenyl-1-(pyridin-2-yl)vinyl acetate (9): 2 mL acetic anhydride and 2 mL acetic acid was added to the mixture of compound 8 (3 mmol) in dry toluene (20 mL) under nitrogen in the dark. Then the solution was stirred at 70 oC for 1 h and poured into 30 mL ice water. The mixture was adjusted to pH 7 with saturated sodium bicarbonate solution, and then extracted three times with 30 mL ethyl acetate. The combined organic phase was dried over MgSO4, distilled under reduced pressure and purified by silica gel column chromatography with ethyl acetate and n-hexane (1:2) to afford compound 9 in 65% yield. m.p.: 109-110 oC. IR (KBr): 3067, 2930, 2212, 1765, 1576, 1428, 1375, 1206, 1120, 1087, 800, 767, 700 cm-1. 1HNMR (CDCl3): d 2.21 (s, 3H), 7.40~7.50 (m, 4H), 7.62 (m, 2H), 7.87 (t, 1H, J = 7.8 Hz), 7.97 (d, 1H, J = 7.8 Hz), 8.76 (d, 1H, J = 4.7 Hz). Anal. Calc.(%) for C16H12N2O2 : C 72.72, H 4.58, N 10.60; Found: C 72.98, H 4.82, N 10.89. MS m/z: 265.0 [M+H]+, 287.1 [M+Na]+.

Results and Discussions

Previously literatures reported that intramolecular condensation of 3-acyl-5-methylindolizine can be converted to pyrrolo-[2,1,5-cd]indolizine when it was treated with potassium hydroxide or potassium carbonate in DMF[15]. Inspired by this transformation, we hypothesized that whether 5-methyl-3-nitrosoindolizine derivatives can be converted to imidazo[2,1,5-cd]indolizines via intramolecular condensation under similar conditions. Initially, we have designed a model reaction. (5-Methyl-3-nitroso-2-phenylindolizin-1-yl)(phenyl) methanone (1a) was treated with K2CO3 in DMF at 75 oC for several hours. Unfortunately, no imidazo[2,1,5-cd]indolizine derivatives was observed even under higher reaction temperature. During the course of this experiment, we discovered that the starting material 1a was disappeared speedily in one hour and three more new products were generated.

As shown in Scheme-1, the new products were isolated and respectively determined as ring-opening product 2a, rearrangement product 3a and denitrosylation product 4a. Moreover, the yield of main product, compound 2a, was over 50%. Denitrosylation product 4a was only 5% in yield.

Scheme-1: K2CO3-induced rearrangement of (5-methyl-3-nitroso-2-phenylindolizin-1-yl)(phenyl) methanone.

Table-1: Substrate scope for the rearrangement of various 5-methyl-3-nitrosoindolizines.

###Product yield (%)

Entry###R1###R2

###2###3###4

1###Ph###Ph###51###22###5

2###4-Cl-Ph###Ph###21###27###12

3###PhCH=CH###Ph###-###38###21

4###3,4,5-(OCH3)3Ph###Ph###36###33###26

5###Ph###4-Br-Ph###48###-###8

Encouraged by the results, we investigated the influence of different substituents at 1,2-positions of 5-methyl-3-nitrosoindolizine. When the 4-chlorobenzoyl was instead of benzoyl at 1-position of 5-methyl-3-nitroso-2-phenylindolizine, the transformation proceeded smoothly to produce three products (Table-1, Entry2). Similarly, the 3,4,5-trimethoxybenzoyl substituent can give the ring-opening product, rearrangement product and denitrosylation product in the yield of 36%, 33% and 26% respectively (Table-1, Entry 4). However, when cinnamoyl group was applied to the 1-position of 5-methyl-3-nitroso-2-phenylindolizine, no ring-opening product was obtained. This result suggested that the ring-opening product 2c might be unstable in alkaline environment and converted to rearrangement product 3c. The instability of 2c in alkaline media might be caused by the extra double bond which promoted the stabilization of the intermediates.

Substituent at 2-position of 5-methyl-3-nitrosoindolizine was also investigated. When the phenyl group was replaced by 4-bromophenyl group, ring-opening product 2e was achieved in moderate yield. While there is no rearrangement product determined, because of steric or charge effect. These results indicated that substituents at 2-position are critical for this rearrangement reaction. And the various groups at 1,2-positions had slight effect on the denitrosylation.

Further experiments were conducted to elucidate the mechanism of the transformations of 5-methyl-3-nitrosoindolizine derivatives. As shown in Scheme-2, the compound 2a can be converted to rearrangement product 3a in good yield. The result stated that the rearrangement products in transformations of 5-methyl-3-nitrosoindolizine derivatives might be from ring-opening products. Then 1-methyl-3-nitroso-2-phenylindolizine (5) and 3-nitroso-2-phenylindolizine (8) were also investigated under standard conditions. Interestingly, 1-methyl-3-nitroso-2-phenylindolizine cannot carry out ring-opening and rearrangement reactions in the presence of K2CO3, and only denitrosylation product 1-methyl-2-phenylindolizine (6) was obtained in 10% yield. Compound 8 showed more stable than compound 5 under alkaline condition. None of transformation products was observed.

These results demonstrated that the methyl at 5-position of 3-nitrosoindolizine derivatives is very critical and important for the ring-opening and rearrangement reaction. Furthermore, the reactivity of compound 5 and 8 in acetic anhydride and acetic acid was tested. They can turn to ring-opening-esterification products 7 and 9 respectively.

Scheme-2: Mechanistic Insights and Experiments.

Scheme-3: Proposed mechanisms of rearrangement of 5-methyl-3-nitrosoindolizine derivatives.

On the basis of the above results and mechanism reported in the literature[16-17], a plausible reaction mechanism is shown in Scheme-3. Initially, the methyl at 5-position of compound 1 is turned to methylene carbanion A under alkaline condition and produces a H2O molecule. Then the intermediate A carries out ring-opening reaction through B to afford the intermediate C, which can convert to product 2 via reacting with H2O. Compound 2 can be transformed to intermediate G through several resonating structures. Then nitrogen anion could react with carbonyl group to form five-member ring H. Finally, intermediate H is converted to product 3 in the presence of H2O.

Conclusion

In summary, we have studied the rearrangement of 5-methyl-3-nitrosoindolizine derivatives in the presence of K2CO3. 5-Methyl-3-nitrosoindolizine derivatives can be converted to ring-opening, rearrangement and denitrosylation products respectively. Substituent groups at 2-position of 5-methyl-3-nitrosoindolizine derivatives are critical for the rearrangement reaction and have slight effect on the denitrosylation. The application of this transformation is still under research in our laboratory.

Acknowledgements

This study is supported by the National Nature Science Foundation of China (No. 81501529), Fundamental Research Funds for the Central Universities (2015PY001), National Basic Research Program of China (No. 2011CB933503) and Technology Supporting Program of Jiangsu province (BE2009639, BE2012657).

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