HETEROCYCLES

Paper | Regular issue | Vol. 78, No. 3, 2009, pp. 725-736
Received, 5th October, 2008, Accepted, 17th November, 2008, Published online, 18th November, 2008.
DOI: 10.3987/COM-08-11570

■ A Facile Approach to Indolizines via Tandem Reaction

Yan-Qing Ge, Jiong Jia, He Yang, Gui-Long Zhao, Fu-Xu Zhan, and Jianwu Wang*

School of Chemistry and Chemical Engineering, Shandong University, Jinan, 250100, China

Abstract

Indolizines were synthesized by a novel tandem reaction at rt. The operation was simple and convenient. Various indolizine derivatives were obtained in good yields. The reaction mechanism was also proposed.

INTRODUCTION
Indolizines have attracted considerable attention from medicinal and organic chemists because of the interesting similarities and diversions in structure to indole.1 Synthetic indolizines play important roles as calcium entry blockers,2 potential central nervous system depressants,3 5-HT3 receptor antagonist,4 histamine H3 receptor antagonists,5 cardiovascular agents,6 and PLA2 inhibitors.7 They have also drawn much attention owing to their possible usage as dyes and chemosensors.8
Several condensation reactions, 1,3-dipolar cycloadditions, and 1,5-dipolar cyclizations are known to facilitate the formation of indolizines.9 The most general method is the formation of the five-member ring moiety in the indolizine framework.1b Chichibabin-type cyclocondensation requires elevated temperatures and/or extended reaction time and, thus, may not be compatible with some functionality.10 Also, it provides low to moderate yields of the products.11 Dipolar cycloaddition of pyridinium ylides with alkynes,12 cyclopropenone13 or cyclopropenes14 is limited to the use of symmetric substrates, producing indolizines with two identical substituents at the pyrrole ring. Therefore new methods for the synthesis of indolizine that allow functional groups variation on indolizine nucleus are highly desirable.
Currently, transition metal-catalyzed C-N bond-forming reactions have become important methods for the preparation of indolizines in both academic and pharmaceutical research areas,15 most of which are realized by the formation of five-membered ring starting from six-membered pyridine derivatives. The formation of six-membered rings moiety in indolizine framework starting from five-membered ring system is less known.16 Our previous work17 prompted us to find a novel method to synthesize the indolizine derivatives. Herein an intramolecular condensation of α-carbon of α, β-unsaturated esters with aldehydes was discovered and the indolizine derivatives were conveniently synthesized by a novel tandem reaction under very mild conditions. The reaction mechanism was also proposed.

RESULTS AND DISCUSSION
Pyrrole-2-carboxaldehydes 1a-j were easily prepared as described in the literature.18 Vilsmeier-Haack reaction of pyrrole resulted in pyrrole-2-carboxaldehyde 1a. The Vilsmeier-Haack intermediate 7 formed from pyrrole may be acylated under normal Friedel-Crafts reaction conditions or brominated giving the corresponding substituted pyrrole-2-carboxaldehydes 1b-j in good yields. Pyrrole-2-carboxaldehydes 1a-j reacted with ethyl γ- bromo-α, β-unsaturated esters in DMF and suitable base at rt and the unexpected products indolizines were obtained.
The effects of solvent and base on the yields of the reaction were evaluated using 4-acetyl-2-pyrrole carboxaldehyde 1d and 2a as a model substrate, and the results were summarized in Table 1.
First, aprotic solvents of different polarities such as dichloromethane, tetrahydrofuran, acetone, acetonitrile, and DMF, and protic solvents such as MeOH and EtOH were examined. It was noted that protic and strong polar aprotic solvents were significantly preferred over weak aprotic solvents. The reaction was fastest in MeOH, but it afforded transesterified indolizine byproduct. Second, the choice of base was found to have a significant impact on the reaction. Strong bases such as sodium ethoxide and potassium hydroxide gave no products. Neither did weak bases such as magnesium oxide, potassium bicarbonate, and triethylamine. Carbonate bases, however, were found to be effective. Highest yield was obtained with potassium carbonate. Third, the yield of 3g increased when 1d was the limiting reagent and the number of equivalents of 2a was increased from one to two. However, an additional increase of 2a to three had no beneficial effect on the yield. Eventually, the desired 3g was obtained in good yield under conditions of 2 equivalents of 2a and 2.2 equivalents of potassium carbonate in DMF at rt (entry 1, Table 1). Under these conditions, a variety of differently substituted pyrrole-2-carboxaldehydes 1 with ester, acetyl, benzoyl, and bromine functionalities underwent smooth reaction with 2 to afford indolizines 3 in good yields (Table 2).
The structure of 3g was further confirmed by X-ray crystallographic analysis as shown in Figure 1.

On the basis of the above results and the literature,16 we proposed the reaction mechanism as follows: Firstly, an intermolecular SN2 reaction between pyrrole-2-carboxaldehydes 1 and ethyl γ- bromo-crotonates 2 occurs, and the intermediate 4 is formed. Subsequently, intermediate 4 is deprotonated by the existing base to form a γ-carbon anion of the ester, and in turn the electron pair transfers from the γ position to α position. Then the formed β, γ-unsaturated α-carbanion of ester cyclizes with the aldehyde group by intramolecular nucleophilic addition to afford intermediate 5 and then 6. The final products indolizines 3 can be obtained in situ from 6 by eliminating a water. The whole process is shown in Scheme 1.
In summary, we have developed a novel and general method for the synthesis of N-bridgehead indolizines with special substituent on them, especially with an ester group on the pyridine ring under very mild conditions. The operations are simple and convenient. Various indolizine derivatives were obtained using simple procedures in good yields. The reaction mechanism was also proposed.

EXPERIMENTAL
All reagents and solvents were purchased from Sinopharm Chemical Reagent Co. Ltd and used without further purification unless otherwise noted. Starting materials were prepared according to literatures. Thin-layer chromatography (TLC) was conducted on silica gel 60 F254 plates (Merck KGaA). 1H NMR spectra were recorded on a Bruker Avance 300 (300 MHz) spectrometer, using CDCl3 or DMSO-d6 as solvents and tetramethylsilane (TMS) as an internal standard. Melting points were determined on an XD-4 digital micro-melting point apparatus and are uncorrected. IR spectra were recorded with an IR spectrophotometer Avtar 370 FT-IR (Termo Nicolet). Elemental analyses were performed on a Vario EL III (Elementar Analysensysteme GmbH) spectroanalyzer. MS spectra were recorded on a Trace DSQ mass spectrometer.

General procedure for the synthesis and analytical data of 1a-j
Pyrrole-2-aldehydes 1a-j were easily prepared according to the literature.18
1H-Pyrrole-2-carbaldehyde (1a) 18
1H NMR (300 MHz, CDCl3): δ 10.36 (s, 1H), 7.18 (s, 1H), 7.01 (m, 1H), 6.36 (m, 1H). 13C NMR (75.4 Hz, CDCl3): δ 179.5, 132.9, 126.9, 121.8, 111.4.
Methyl 5-formyl-1H-pyrrole-3-carboxylate (1b) 18
1H NMR (300 MHz, CDCl3): δ 10.13 (s, 1H), 9.57 (d, 1H, J = 1.2 Hz), 7.71 (dd, 1H, J = 1.2 Hz, 3.0 Hz), 7.40 (dd, 1H, 2.4 Hz, 1.5 Hz), 3.86 (s, 3H). 13C NMR (75.4 Hz, CDCl3): δ 180.0, 164.0, 133.1, 129.7, 121.3, 118.8, 51.6.
4,5-Dibromo-1H-pyrrole-2-carbaldehyde (1c) 18
1H NMR (300 MHz, CDCl3): δ 10.28 (s, 1H), 9.35 (s, 1H), 6.97 (d, 1H, J = 2.4 Hz). 13C NMR (75.4 Hz, CDCl3): δ 177.7, 133.1, 123.0, 113.0, 101.9.
4-Acetyl-1H-pyrrole-2-carbaldehyde (1d) 18
1H NMR (300 MHz, CDCl3): δ 9.98 (s, 1H), 9.61 (s, 1H), 7.70 (s, 1H), 7.39 (t, 1H, J = 1.8 Hz), 2.48 (s, 3H). 13C NMR (75.4 MHz, CDCl3): δ 193.0, 180.2, 133.4, 129.2, 128.0, 120.2, 27.4.
4-Propionyl-1H-pyrrole-2-carbaldehyde (1e) 18
1H NMR (300 MHz, CDCl3): δ 10.02 (s, 1H), 9.60 (s, 1H), 7.72 (s, 1H), 7.39 (s, 1H), 2.84 (q, 2H, J = 7.4 Hz), 1.22 (t, 3H, J = 7.4 Hz). 13C NMR (75.4 MHz, CDCl3): δ 196.4, 180.5, 133.3, 129.6, 127.3, 120.7, 32.9, 8.3.
4-Benzoyl-1H-pyrrole-2-carbaldehyde (1f) 18
1H NMR (300 MHz, CDCl3): δ 10.78 (s, 1H), 9.62 (s, 1H), 7.87-7.48 (m, 7H). 13C NMR (75.4 MHz, CDCl3): δ 190.3, 180.6, 138.7, 133.3, 132.3, 131.6, 129.0, 128.5, 126.4, 122.6.
4-(4-Nitrobenzoyl)-1H-pyrrole-2-carbaldehyde (1g) 18
1H NMR (300 MHz, DMSO-d6): δ 12.99 (s, 1H), 9.65 (s, 1H), 8.37 (d, 2H, J = 8.4 Hz), 8.02 (d, 2H, J = 8.4 Hz), 7.82 (s, 1H), 7.49 (s, 1H). 13C NMR (75.4 MHz, DMSO-d6): δ 188.2, 181.4, 149.6, 144.4, 134.4, 132.7, 130.3, 124.9, 124.2, 121.5.
4-(4-Methoxybenzoyl)-1H-pyrrole-2-carbaldehyde (1h) 18
1H NMR (300 MHz, CDCl3): δ 10.21 (s, 1H), 9.63 (s, 1H), 7.89 (d, 2H, J = 8.7 Hz), 7.71 (d, 1H, J = 1.2 Hz), 7.45 (s, 1H), 6.99 (d, 2H, J = 8.7 Hz), 3.90 (s, 3H). 13C NMR (75.4 MHz, CDCl3): δ 188.6, 180.1, 163.1, 133.1, 131.4, 131.3, 130.4, 126.7, 121.9, 113.8, 55.5.
4-(2-Fluorobenzoyl)-1H-pyrrole-2-carbaldehyde (1i) 18
1H NMR (300 MHz, CDCl3: δ 10.38 (s, 1H), 9.60 (d, 1H, J = 0.6 Hz), 7.67-7.42 (m, 4H), 7.29-7.15 (m, 2H). 13C NMR (75.4 MHz, CDCl3): δ 186.7, 180.3, 161.3, 158.0, 133.4, 133.0, 132.9, 131.2, 130.3, 130.2, 127.8, 127.6, 127.5, 124.4, 124.3, 121.4, 116.6, 116.3.
4-(2,4-Dichlorobenzoyl)-1H-pyrrole-2-carbaldehyde (1j) 18
1H NMR (300 MHz, CDCl3): δ 10.84 (s, 1H), 9.58 (d, 1H, J = 0.6 Hz), 7.56 (t, 1H, J = 1.5 Hz), 7.49 (d, 1H, J = 0.9 Hz), 7.37-7.33 (m, 3H). 13C NMR (75.4 MHz, CDCl3): δ 188.0, 180.4, 137.4, 136.7, 133.7, 132.0, 131.7, 130.3, 129.7, 127.1, 126.8, 121.5.
General procedure for the synthesis and analytical data of 3a-3t
To a 100-mL round-bottomed flask were added 1a-j (6.0 mmol), enoate 2a-b (7.2 mmol), potassium carbonate (1.60 g, 12.5 mmol) and DMF (30 mL). The mixture was stirred at rt for 6-7 h and then filtered. The filtrate was concentrated by rotary evaporation. The crude products were purified by column chromatography.
Ethyl indolizine-7-carboxylate (3a)
Yellow oil. 1H NMR (300 MHz, CDCl3): δ 8.20 (s, 1H), 7.89 (d, 1H, J = 7.2 Hz), 7.42 (s, 1H), 7.05 (d, 1H, J = 7.2 Hz), 6.87 (s, 1H), 6.71 (s, 1H), 4.36 (q, 2H, J = 7.2 Hz), 1.40 (t, 3H, J = 7.2 Hz). 13C NMR (75.4 Hz, CDCl3): δ 166.1, 131.5, 124.3, 123.1, 118.6, 115.3, 115.1, 109.4, 104.4, 60.8, 14.4. IR (KBr) ν = 3103, 3061, 2981, 2936, 1706, 1629, 1520, 1478, 1260, 1199, 1130, 1092, 752 cm−1. HRMS (EI): m/z Calcd. for: C11H12NO2 [M+H]+: 190.2185; Found: 190.2188. Anal. Calcd for C11H11NO2: C, 69.83; H, 5.86; N, 7.40. Found: C, 69.86; H, 5.84; N, 7.41.
Ethyl 6-methylindolizine-7-carboxylate (3b)
Yellow solid: mp 44-45 °C. 1H NMR (300 MHz, CDCl3): δ 8.18 (s, 1H), 7.69 (s, 1H), 7.32 (s, 1H), 6.81 (t, 1H, J = 3.0 Hz), 6.63 (d, 1H, J = 3.6 Hz), 4.33 (q, 2H, J = 7.2 Hz), 2.46 (s, 3H), 1.40 (t, 3H, J = 7.2 Hz). 13C NMR (75.4 MHz, CDCl3): δ 166.7, 130.7, 124.0, 123.5, 119.5, 119.3, 117.1, 114.9, 114.0, 103.6, 60.5, 18.9, 14.4. IR (KBr) ν = cm−1. HRMS (EI): m/z Calcd. for: C12H14NO2 [M+H]+: 204.2451; Found: 204.2455. Anal. Calcd for C12H13NO2: C, 70.92; H, 6.45; N, 6.89. Found: C, 70.96; H, 6.46; N, 6.91.
7-Ethyl 2-methyl indolizine-2,7-dicarboxylate (3c)
Yellow solid: mp 105-107 °C. 1H NMR (300 MHz, CDCl3): δ 8.18 (s, 1H), 7.86 (t, 2H), 7.13-7.09 (m, 2H), 4.36 (q, 2H, J = 7.2 Hz), 3.89 (s, 3H), 1.39 (t, 3H, J = 7.2 Hz). 13C NMR (75.4 MHz, CDCl3): δ 165.5, 164.9, 131.4, 124.7, 124.2, 121.3, 120.4, 117.9, 111.3, 105.6, 61.1, 51.7, 14.4. IR (KBr) ν= 3137, 2954, 2896, 1711, 1701, 1635, 1495, 1266, 1215, 1165, 1085, 1011, 763, 556 cm−1. HRMS(EI): m/z Calcd. for: C13H14NO4 [M+H]+: 248.2546; Found: 248.2552. Anal. Calcd for C13H13NO4: C, 63.15; H, 5.30; N, 5.67. Found: C, 63.18; H, 5.33; N, 5.69.
7-Ethyl 2-methyl 6-methylindolizine-2,7-dicarboxylate (3d)
Yellow solid: mp 128-129 °C. 1H NMR (300 MHz, CDCl3):δ8.15 (s, 1H), 7.78 (d, 2H, J = 0.6 Hz), 7.65 (d, 2H, J = 0.9 Hz), 4.34 (q, 2H, J = 7.2 Hz), 3.89 (s, 3H), 2.45 (d, 2H, J = 0.9 Hz),1.40 (t, 3H, J = 7.2 Hz). 13C NMR (75.4 MHz, CDCl3): δ 166.1, 165.1, 130.7, 125.0, 123.6, 121.5, 120.8, 116.8, 105.0, 60.8, 51.6, 18.9, 14.3. IR (KBr) ν= 3143, 3068, 2944, 1718, 1688, 1640, 1536, 1220, 1154, 1061, 1004, 776, 751 cm−1. HRMS(EI): m/z Calcd. for: C14H16NO4 [M+H]+: 262.2811; Found: 262.2813. Anal. Calcd for C14H15NO4: C, 64.36; H, 5.79; N, 5.36. Found: C, 64.41; H, 5.77; N, 5.37.
Ethyl 2,3-dibromoindolizine-7-carboxylate (3e)
Yellow solid: mp 78-80 °C. 1H NMR (300 MHz, CDCl3):δ8.10 (s, 1H), 7.93 (d, 1H, J = 7.5 Hz), 7.23 (dd, 1H, J = 1.5, 7.5 Hz), 6.89 (s, 1H), 4.38 (q, 2H, J = 7.2 Hz), 1.41 (t, 3H, J = 7.2 Hz). 13C NMR (75.4 MHz, CDCl3): δ 165.4, 132.4, 122.7, 121.5, 120.1, 110.8, 107.6, 106.8, 97.9, 61.2, 14.3. IR (KBr) ν= 3120, 2988, 2907, 1711, 1628, 1517, 1463, 1246, 1145, 1018, 752, 744 cm−1. HRMS(EI): m/z Calcd. for: C11H10 Br2NO2 [M+H]+: 348.0106; Found: 348.0107. Anal. Calcd for C11H9Br2NO2: C, 38.07; H, 2.61; N, 4.04. Found: C, 38.11; H, 2.62; N, 4.06.
Ethyl 2,3-dibromo-6-methylindolizine-7-carboxylate (3f)
Yellow solid: mp 99-101 °C. 1H NMR (300 MHz, DMSO-d6): δ 8.12 (s, 1H), 7.94 (s, 1H), 7.08 (s, 1H), 4.28 (q, 2H, J = 7.2 Hz), 2.46 (s, 3H), 1.33 (t, 3H, J = 7.2 Hz). 13C NMR (75.4 MHz, DMSO-d6): δ 165.7, 131.6, 122.5, 121.2, 106.9, 106.7, 97.2, 61.1, 18.6, 14.6. IR (KBr) ν= 3123, 2986, 2933, 2898, 1697, 1627, 1517, 1496, 1472, 1423, 1251, 1175, 1131, 1071, 1017, 964, 916, 776, 605cm−1. HRMS(EI): m/z Calcd. for: C12H12Br2NO2 [M+H]+: 362.0372; Found: 362.0376. Anal. Calcd for C12H11Br2NO2: C, 39.92; H, 3.07; N, 3.88. Found: C, 39.95; H, 3.08; N,3.88.
Ethyl 2-acetylindolizine-7-carboxylate (3g)
Yellow solid: mp 105-106 °C. 1H NMR (300 MHz, CDCl3): δ 8.21 (s, 1H), 7.88 (t, 2H, J = 3.6 Hz), 7.15 (dd, 1H, J = 1.5 Hz, 7.5 Hz), 7.07 (s, 1H), 4.37 (q, 2H, J = 7.2 Hz), 2.58 (s, 3H), 1.40 (t, 3H, J = 7.2 Hz). 13C NMR (75.4 MHz, CDCl3): δ 194.5, 165.4, 131.7, 129.8, 124.9, 124.4, 120.6, 117.1, 111.6, 104.6, 61.2, 27.7, 14.3. IR (KBr) ν = 3129, 3110, 2996, 2977, 1711, 1666, 1629, 1488, 1454, 1219, 1175, 1093, 818, 750, 653 cm−1. HRMS(EI): m/z Calcd. for: C13H14NO3 [M+H]+: 232.2552; Found: 232.2550. Anal. Calcd for C13H13NO3: C, 67.52; H, 5.67; N, 6.06. Found: C, 67.52; H, 5.66; N, 6.07.
Ethyl 2-acetyl-6-methylindolizine-7-carboxylate (3h)
Yellow solid: mp 126 °C. 1H NMR (300 MHz, CDCl3): δ 8.17 (s, 1H), 7.77 (s, 1H), 7.66 (s, 1H), 7.00 (s, 1H), 4.35 (q, 2H, J = 7.2 Hz), 2.56 (s, 3H), 2.46 (s, 3H), 1.40 (t, 3H, J = 7.2 Hz). 13C NMR (75.4 MHz, CDCl3): δ 194.6, 166.0, 131.0, 129.5, 125.3, 123.8, 121.8, 121.7, 116.0, 104.1, 60.9, 27.7, 18.9, 14.3. IR (KBr) ν = 3115, 2980, 2923, 1704, 1667, 1636, 1467, 1282, 1229, 1183, 1069, 853, 769, 661 cm−1. HRMS(EI): m/z Calcd. for: C14H16NO3 [M+H]+: 246.2817; Found: 246.2815. Anal. Calcd for C14H15NO3: C, 68.56; H, 6.16; N, 5.71. Found: C, 68.59; H, 6.17; N, 5.71.
Ethyl 2-propionylindolizine-7-carboxylate (3i)
Yellow solid: mp 103-104 °C. 1H NMR (300 MHz, CDCl3): δ 8.20 (s, 1H), 7.87 (d, 2H, J = 6.9 Hz), 7.13 (dd, 1H, J = 1.5 Hz, 7.5 Hz), 7.08 (s, 1H), 4.38 (q, 2H, J = 7.2 Hz), 2.95 (q, 2H, J = 7.2 Hz), 1.40 (t, 3H, J = 7.2 Hz), 1.24 (t, 3H, J = 7.2 Hz). 13C NMR (75.4 MHz, CDCl3): δ 197.6, 165.5, 131.7, 129.4, 124.9, 124.5, 120.5, 116.7, 111.6, 104.4, 61.2, 33.3, 14.4, 8.3. IR (KBr) ν= 3140, 2985, 2970, 1715, 1673, 1630, 1488, 1259, 1160, 1093, 777, 758, 629 cm−1. HRMS(EI): m/z Calcd. for: C14H16NO3 [M+H]+: 246.2817; Found: 246.2817. Anal. Calcd for C14H15NO3: C, 68.56; H, 6.16; N, 5.71. Found: C, 68.59; H, 6.17; N, 5.72.
Ethyl 6-methyl-2-propionylindolizine-7-carboxylate (3j)
Yellow solid: mp 111-112 °C. 1H NMR (300 MHz, CDCl3:δ8.17 (s, 1H), 7.78 (d, 2H, J = 0.6 Hz), 7.66 (s, 1H), 7.01 (s, 1H), 4.35 (q, 2H, J = 7.2 Hz), 2.94 (q, 2H, J = 7.2 Hz), 2.46 (d, 2H, J = 0.9 Hz), 1.40 (t, 3H, J = 7.2 Hz), 1.23 (t, 3H, J = 7.2 Hz). 13C NMR (75.4 MHz, CDCl3): δ 197.7, 166.1, 131.0, 129.1, 124.9, 125.3, 123.8, 121.7, 121.6, 115.7, 103.8, 60.9, 33.2, 30.9, 18.9, 14.3, 8.4. IR (KBr) ν= 3114, 2971, 2937, 1701, 1664, 1479, 1264, 1163, 1082, 791 cm−1. HRMS(EI): m/z Calcd. for: C15H18NO3 [M+H]+: 260.3083; Found: 260.3088. Anal. Calcd for C15H17NO3: C, 69.48; H, 6.61; N, 5.40. Found: C, 69.47; H, 6.63; N, 5.42.
Ethyl 2-benzoylindolizine-7-carboxylate (3k)
Yellow solid: mp 108-109 °C. 1H NMR (300 MHz, CDCl3): δ 8.23 (s, 1H), 7.94-7.88 (m, 4H), 7.62-7.48 (m, 3H), 7.17-7.13 (m, 2H),4.38 (q, 2H, J = 7.2 Hz), 1.40 (t, 3H, J = 7.2 Hz). 13C NMR (75.4 MHz, CDCl3): δ 191.4, 165.4, 139.0, 132.2, 131.6, 129.4, 128.5, 128.4, 124.8, 124.5, 120.7, 118.8, 111.7, 106.5, 61.2, 14.4. IR (KBr) ν= 3056, 2984, 1714, 1633, 1485, 1400, 1274, 1233, 1119, 883, 748, 690 cm−1. HRMS(EI): m/z Calcd. for: C18H16NO3 [M+H]+: 294.3245; Found: 294.3249. Anal. Calcd for C18H15NO3: C, 73.71; H, 5.15; N, 4.78. Found: C, 73.75; H, 5.16; N, 4.77.
Ethyl 2-benzoyl-6-methylindolizine-7-carboxylate (3l)
Yellow solid: mp 142-143 °C. 1H NMR (300 MHz, CDCl3): δ 8.20 (s, 1H), 7.93-7.90 (t, 2H), 7.78 (s, 1H), 7.69 (s, 1H),7.62-7.48 (m, 3H), 7.06 (s, 1H),4.35 (q, 2H, J = 7.2 Hz), 2.47 (s, 3H),1.40 (t, 3H, J = 7.2 Hz). 13C NMR (75.4 MHz, CDCl3): δ 191.5, 166.0, 139.2, 132.1, 130.8, 129.4, 128.3, 128.2, 125.3, 123.8, 121.9, 121.8, 117.8, 105.9, 60.9, 18.9, 14.3. IR (KBr) ν= 3118, 2978, 1707, 1629, 1478, 1395, 1230, 1194, 1119, 1062, 884, 724 cm−1. HRMS(EI): m/z Calcd. for: C19H18NO3 [M+H]+: 308.3511; Found: 308.3514. Anal. Calcd for C19H17NO3: C, 74.25; H, 5.58; N, 4.56. Found: C, 74.29; H, 5.60; N, 4.55.
Ethyl 2-(4-nitrobenzoyl)indolizine-7-carboxylate (3m)
Yellow solid: mp 163-164 °C. 1H NMR (300 MHz, CDCl3): δ 8.38-8.35 (m, 2H), 8.24 (s, 1H), 8.07-8.04 (m, 2H), 7.93-7.88 (m, 2H), 7.22-7.19 (dd, 1H, J = 1.8, 7.2 Hz), 7.09 (s, 1H), 4.39 (q, 2H, J = 7.2 Hz), 1.41 (t, 3H, J = 7.2 Hz). 13C NMR (75.4 MHz, CDCl3): δ 189.5, 165.2, 149.8, 144.1, 132.0, 130.1, 127.6, 125.0, 124.5, 123.6, 121.4, 118.8, 112.2, 106.2, 61.3, 14.3. IR (KBr) ν= 3139, 3113, 2985, 1724, 1642, 1600, 1526, 1480, 1348, 1296, 1241, 1178, 1122, 848, 746cm−1. HRMS(EI): m/z Calcd. for: C18H15N2O5 [M+H]+: 339.3221; Found: 339.3226. Anal. Calcd for C18H14N2O5: C, 63.90; H, 4.17; N, 8.28. Found: C, 63.96; H, 4.18; N, 8.26.
Ethyl 6-methyl-2-(4-nitrobenzoyl)indolizine-7-carboxylate (3n)
Yellow solid: mp 164-165 °C. 1H NMR (300 MHz, CDCl3): δ 8.37-8.35 (d, 2H, J = 8.1 Hz), 8.20 (s, 1H), 8.06-8.03 (d, 2H, J = 8.1 Hz), 7.78 (s, 1H), 7.71 (s, 1H), 7.01 (s, 1H),4.36 (q, 2H, J = 7.2 Hz), 2.48 (s, 1H),1.41 (t, 3H, J = 7.2 Hz). 13C NMR (75.4 MHz, CDCl3): δ 189.5, 165.8, 149.7, 144.3, 131.2, 130.1, 127.2, 125.2, 123.8, 123.6, 122.6, 122.5, 117.7, 105.6, 61.0, 18.9, 14.3. IR (KBr) ν= 3141, 3109, 2981, 2939, 2849, 1709, 1639, 1599, 1524, 1476, 1384, 1349, 1277, 1252, 1128, 1069, 846, 710cm−1. HRMS(EI): m/z Calcd. for: C19H17N2O5 [M+H]+: 353.3487; Found: 353.3488. Anal. Calcd for C19H16N2O5: C, 64.77; H, 4.58; N, 7.95. Found: C, 64.79; H, 4.57; N, 7.96.
Ethyl 2-(4-methoxybenzoyl)indolizine-7-carboxylate (3o)
Yellow solid: mp 158-159 °C. 1H NMR (300 MHz, CDCl3): δ 8.23 (s, 1H), 7.99-7.94 (m, 2H), 7.91-7.87 (m, 2H), 7.17-7.14 (dd, 1H, J = 1.5, 7.2 Hz), 7.11 (s, 1H), 7.02-6.97 (m, 2H), 4.38 (q, 2H, J = 7.2 Hz), 3.90 (s, 3H), 1.40 (t, 3H, J = 7.2 Hz). 13C NMR (75.4 MHz, CDCl3): δ 190.0, 165.5, 163.0, 131.8, 131.6, 131.4, 128.9, 124.8, 124.4, 120.5, 118.4, 113.6, 111.5, 106.4, 61.2, 55.5, 14.4. IR (KBr) ν= 3135, 2984, 2937, 2839, 1712, 1627, 1602, 1575, 1490, 1278, 1248, 1233, 1175, 1120, 1028, 848, 759cm−1. HRMS(EI): m/z Calcd. for: C19H18NO4 [M+H]+: 324.3505; Found: 324.3510. Anal. Calcd for C19H17NO4: C, 70.58; H, 5.30; N, 4.33. Found: C, 70.63; H, 5.31; N, 4.32.
Ethyl 2-(4-methoxybenzoyl)-6-methylindolizine-7-carboxylate (3p)
Yellow solid: mp 132-133 °C. 1H NMR (300 MHz, CDCl3): δ 8.20 (s, 1H), 7.97-7.94 (d, 2H, J = 7.8 Hz), 7.77 (s, 1H), 7.69 (s, 1H), 7.04 (s, 1H), 7.00-6.97 (d, 2H, J = 7.8 Hz), 4.35 (q, 2H, J = 7.2 Hz), 3.90 (s, 3H), 2.47 (s, 3H), 1.40 (t, 3H, J = 7.2 Hz). 13C NMR (75.4 MHz, CDCl3): δ 190.1, 166.1, 163.0, 131.8, 130.7, 128.5, 125.2, 123.7, 121.7, 121.6, 117.4, 113.6, 105.8, 60.8, 55.5, 18.9, 14.4. IR (KBr) ν= 3124, 2978, 2936, 2837, 1710, 1629, 1602, 1574, 1474, 1394, 1277, 1228, 1172, 1118, 1072, 1028, 888, 847, 777, 751, 705cm−1. HRMS(EI): m/z Calcd. for: C20H20NO4 [M+H]+: 338.3771; Found: 338.3775. Anal. Calcd for C20H19NO4: C, 71.20; H, 5.68; N, 4.15. Found: C, 71.24; H, 5.66; N, 4.15.
Ethyl 2-(2-fluorobenzoyl)indolizine-7-carboxylate (3q)
Yellow solid: mp 102-103 °C. 1H NMR (300 MHz, CDCl3): δ 8.20 (s, 1H), 7.86-7.82(m, 2H), 7.64-7.49 (m, 2H), 7.29-7.13 (m, 3H), 7.08 (s, 1H), 4.37 (q, 2H, J = 7.2 Hz), 1.40 (t, 3H, J = 7.2 Hz). 13C NMR (75.4 MHz, CDCl3): δ 188.3, 165.3, 161.5, 158.1, 132.8, 132.7, 131.8, 130.3, 129.3, 128.3, 128.1, 124.9, 124.6, 124.2, 124.1, 120.8, 118.9, 116.5, 116.3, 111.9, 106.0, 61.2, 14.3. IR (KBr) ν= 3069, 2999, 2984, 2937, 1702, 1647, 1612, 1575, 1493, 1400, 1329, 1270, 1213, 1141, 1127, 1019, 886, 825, 754cm−1. HRMS(EI): m/z Calcd. for: C18H15FNO3 [M+H]+: 312.315; Found: 312.315. Anal. Calcd for C18H14FNO3: C, 69.45; H, 4.53; N, 4.50. Found: C, 69.46; H, 4.53; N, 4.51.
Ethyl 2-(2-fluorobenzoyl)-6-methylindolizine-7-carboxylate (3r)
Yellow solid: mp 115-117 °C. 1H NMR (300 MHz, CDCl3):δ8.16 (s, 1H), 7.71-7.47 (m, 4H), 7.28-7.15 (m, 2H), 7.00 (s, 1H), 4.34 (q, 2H, J = 7.2 Hz), 2.45 (s, 3H), 1.40 (t, 3H, J = 7.2 Hz). 13C NMR (75.4 MHz, CDCl3): δ 188.3, 165.9, 161.5, 158.1, 132.6, 132.5, 131.0, 130.3, 130.2, 128.9, 128.5, 128.2, 125.4, 124.1, 124.0, 123.7, 122.1, 122.0, 117.8, 116.5, 116.2, 105.4, 60.8, 18.8, 14.3. IR (KBr) ν= 3141, 3065, 2975, 2929, 1704, 1697, 1656, 1637, 1614, 1521, 1475, 1449, 1232, 1124, 1064, 891, 745cm−1. HRMS(EI): m/z Calcd. for: C19H17FNO3 [M+H]+: 326.3416; Found: 326.3222. Anal. Calcd for C19H16FNO3: C, 70.14; H, 4.96; N, 4.31. Found: C, 70.18; H, 4.98; N, 4.32.
Ethyl 2-(2,4-dichlorobenzoyl)indolizine-7-carboxylate (3s)
Yellow solid: mp 137-138 °C. 1H NMR (300 MHz, CDCl3): δ 8.19 (s, 1H), 7.84 (d, 1H, J = 7.2 Hz), 7.72 (s, 1H), 7.50 (s, 1H), 7.42 (d, 2H, J = 8.1 Hz), 7.35 (d, 2H, J = 8.1 Hz), 7.15 (d, 1H, J = 7.2 Hz), 7.00 (s, 1H), 4.37 (q, 2H, J = 7.2 Hz), 1.40 (t, 3H, J = 7.2 Hz). 13C NMR (75.4 MHz, CDCl3): δ 189.3, 165.2, 137.7, 136.5, 132.2, 132.1, 130.2, 129.9, 128.6, 127.6, 125.0, 124.6, 121.1, 119.0, 112.1, 105.9, 61.3, 14.3. IR (KBr) ν= 3123, 3085, 2989, 2902, 1705, 1648, 1630, 1586, 1550, 1479, 1390, 1293, 1232, 1127, 1102, 1021, 887, 834, 766, 751cm−1. HRMS(EI): m/z Calcd. for: C18H14Cl2NO3 [M+H]+: 363.2147; Found: 363.2149. Anal. Calcd for C18H13Cl2NO3: C, 59.69; H, 3.62; N, 3.87. Found: C, 59.72; H, 3.63; N, 3.88.
Ethyl 2-(2,4-dichlorobenzoyl)-6-methylindolizine-7-carboxylate (3t)
Yellow solid: mp 153-154 °C. 1H NMR (300 MHz, CDCl3) δ 8.15 (s, 1H), 7.64-7.62 (m, 2H), 7.50 (d, 1H, J = 1.8 Hz), 7.43-7.33 (m, 2H), 6.92 (s, 1H), 4.35 (q, 2H, J = 7.2 Hz), 2.45 (s, 3H), 1.40 (t, 3H, J = 7.2 Hz). 13C NMR (75.4 MHz, CDCl3): δ 189.4, 165.9, 137.9, 136.4, 132.2, 131.3, 130.1, 129.8, 128.2, 126.8, 125.4, 123.8, 122.4, 122.3, 117.8, 105.4, 60.9, 18.8, 14.3. IR (KBr) ν= 3143, 3065, 2983, 2902, 1708, 1656, 1637, 1588, 1521, 1475, 1383, 1340, 1284, 1231, 1125, 1103, 1064, 891, 857, 754cm−1. HRMS(EI): m/z Calcd. for: C19H16Cl2NO3 [M+H]+: 377.2412; Found: 377.2408. Anal. Calcd for C19H15Cl2NO3: C, 60.65; H, 4.02; N, 3.72. Found: C, 60.67; H, 4.03; N, 3.72.

ACKNOWLEDGEMENTS
The authors thank the Shandong Natural Science Foundation (No. Y2008B40) and Shandong Excellent Young and Mid-aged Scientist Promotive Foundation (No. 2008BS04024) for financial support of this work.We also thank State Key Laboratory of Crystal Materials of Shandong University for crystal data.

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