3.2. Synthesis
4-(2-Phenylindolizin-5-yl)-4-oxobutanoic acid (2a). The solution of 0.5 g (2.6 mmol) 2-phenylindolizine (1a) and 0.36 mL (4.0 mmol) tetramethylethylenediamine (TMEDA) in 150 mL THF was degassed, filled with argon and cooled to −80 °C. Thereto, the solution of 1.8 mL (4 mmol) of 2.24 M n-BuLi in hexane was added dropwise. The mixture was allowed to spontaneously warm up to −10 °C and stirred at this temperature for 2 h. Then solution of 0.4 g (4.0 mmol) of succinic anhydrid in 10 mL THF was added quickly at −90 ° C. The reaction mixture was allowed to warm to room temperature and stand for several hours, and then it was poured into a stirred mixture of 100 mL CH2Cl2 and 100 mL of saturated aqueous NH4Cl solution. The organic layer was separated, washed with water and dried over Na2SO4. The solvent was removed in vacuo. The crude product was placed on silica gel and purified by preparative chromatography (eluent–CHCl3:MeOH = 10:1). Yield: 0.4 g (53%); yellow powder; m.p. 204–205 °C, 1H-NMR (DMSO-d6): 12.25 (1H, bs, OH), 9.27 (1H, s, H-3), 7.89–7.86 (2H, m, H-6, H-8), 7.76–7.74 (2H, m, Ph), 7.43–7.39 (2H, m, Ph), 7.29–7.25 (1H, m, Ph), 7.12 (1H, s, H-1), 6.90 (1H, d, J = 7.5 Hz, H-7), 3.38 (2H, m, CH2), 2.67–2.64 (2H, m, CH2); 13C-NMR (DMSO-d6) 188.06 (CO), 173.82 (CO2H), 141.56 (C-2), 137.44 (C-5), 134.34 (Ph), 129.86 (C-9),128.86 (C-Ph), 126.79 (C-Ph), 125.75 (C-Ph), 120.72 (C-8), 120.68 (C-7), 115.41 (C-3), 112.99 (C-6), 99.48 (C-1), 32.99 (CH2), 28.19 (CH2); C18H15NO3·0.5H2O, calcd., %: C 71.51; H 5.33; N 4.63; found, %: C 71.23; H, 5.55; N 4.46.
4-(2-tert-Butylindolizin-5-yl)-4-oxobutanoic acid (
2b). The solution of 0.45 g (2.6 mmol) 2-
tert-butylindolizine (
1b) and 0.36 mL (4.0 mmol) TMEDA in 70 mL THF was degassed, filled with argon and cooled to −80 °C. Thereto, the solution of 1.8 mL (4 mmol) of 2.24 M
n-BuLi in hexane was added dropwise. The mixture was allowed to spontaneously warm up to −10 °C and stirred at this temperature for 2 h. Then, the solution of 0.4 g (4.0 mmol) of succinic anhydrid in 10 mL THF was added quickly at −90 °C. The reaction mixture was allowed to warm to room temperature and stand for several hours, and then was poured into a stirred mixture of 100 mL CH
2Cl
2 and 100 mL of saturated aqueous NH
4Cl solution. The organic layer was separated, washed with water and dried over Na
2SO
4. The solvent was removed in vacuo. The crude product was placed on silica gel and purified by preparative chromatography (eluent–CHCl
3: MeOH = 10:1). Yield: 0.52 g (73%); yellow crystals; m.p. = 161–164 °C;
1H-NMR (DMSO-
d6): 8.79 (1H, s, H-3), 7.83–7.78 (2H, m, H-6, H-8), 6.85–6.81 (1H, m, H-7), 6.67 (1H, s, H-1), 3.36–3.32 (2H, m, CH
2), 2.65-2.62 (2H, m, CH
2), 1.33 (9H, s,
t-Bu);
13C-NMR (DMSO-
d6) 190.73 (CO), 170.80 (CO
2H), 141.82 (C-2), 134.16 (C-5), 128.83(C-9), 124.78 (C-8), 120.11 (C-7), 114.33 (C-3), 112.51 (C-6), 99.91 (C-1), 32.89 (CH
2), 28.15 (CH
2), 31.66 (
t-Bu), 30.80 (
t-Bu); MS (
m/
z): 273 (M
+, 100), 259 (30), 172 (55); X-ray data, see
Figure 1,
Table 1.
2-[(2-Phenylindolizin-5-yl)carbonyl]benzoic acid (3a). Synthesized according to the general procedure with phtalic anhydride. Yield: 0.443 g (50%); red powder; m.p. = 129–131 °C; 1H-NMR (DMSO-d6): 9.28 (1H, s, H-3), 8.02 (1H, d, J = 7.0 Hz, H-6), 7.83–7.79 (3H, m, Ar), 7.77–7.73 (1H, m, Ar), 7.70–7.66 (2H, m, Ar), 7.60 (1H, d, J = 7.0 Hz, H-8), 7.47–7.43 (2H, m, Ar), 7.30 (2H, m, H-7), 7.16 (1H, s, H-1), 3.36 (1H, s, CO2H); 13C-NMR (DMSO-d6) 191.58 (CO), 170.20 (CO2H), 140.81 (C-2), 135.00 (C-5), 134.43 (Ph), 129.84 (C-9), 129.00 (C-Ph), 126.90 (C-Ph), 125.82 (C-Ph), 124.37 (C-8), 121.82 (C-7), 115.65 (C-3), 112.93 (C-6), 99.33 (C-1), 141.49 (Ar), 128.53 (Ar), 129.93 (Ar), 129.77 (Ar), 130.17 (Ar), 131.16 (Ar); MS (m/z): 341 (M+, 60), 312 (30), 296 (85), 268 (100); C22H15NO3·2H2O, calcd., %: C 70.02; H 5.07; N 3.71; found, %: C 69.75; H 4.79; N 3.70.
2-[(2-tert-Butylindolizin-5-yl)carbonyl]benzoic acid (3b). Prepared similarly. Yield: 0.47 g (56%); red powder; m.p. = 113–115 °C; 1H-NMR (DMSO-d6): 8.94 (1H, s H-3), 7.96–7.93 (1H, m, H-6), 7.56–7.54 (1H, m, Ar), 7.50–7.48 (2H, m, Ar), 7.36–7.35 (1H, m, Ar), 6.70–6.68 (1H, m, H-8), 6.61 (1H, s H-1), 6.43–6.40 (1H, m, H-7), 1.39 (9H, s t-Bu); 13C-NMR (DMSO-d6) 191.17 (CO), 170.26 (CO2H), 143.11 (C-2), 134.53 (C-5), 129.54 (C-9), 124.74 (C-8), 120.23 (C-7), 114.16 (C-3), 113.62 (C-6), 100.33 (C-1), 142.29 (Ar), 128.21 (Ar), 132.85 (Ar), 128.23 (Ar), 130.31 (Ar), 131.03 (Ar), 31.91 (t-Bu), 31.29 (t-Bu); 3C20H19NO3·4H2O, calcd., %: C 69.55, H 6.32, N 4.06, found, %: C 69.22, H 6.05, N 4.00.
Oxo(2-phenylindolizin-5-yl)acetyl chloride (4a). Prepared using 5-fold excess of oxallyl chloride. The resulting precipitate was filtered off and dried in vacuo. The product was used without further purification. Yield: 0.8 g; red powder; mixture of oxo(2-phenylindolizin-5-yl)acetyl chloride with an unknown amount of inorganic lithium salts; 1H-NMR (DMSO-d6): 8.10 (1H, m, H-3), 7.95 (1H, m, H-6), 7.86 (1H, m, Ph), 7.76 (2H, m, Ph), 7.43 (5H, m, Ph, Ar),7.06 (1H, m, Ar); MS (m/z): 440 (30), 283 (40).
1,2-di(2-tert-Butylindolizin-5-yl)ethane-1,2-dione (
5b). Synthesized according to the general procedure with the ratio indolizine–oxallyl chloride 2:1. Yield: 0.2 g (50%); red needles; m.p. = 207–210 °C;
1H-NMR (DMSO-
d6): 8.96 (1H, s, H-3), 7.98 (1H, d,
J = 8.4 Hz, H-6), 7.58 (1H, d,
J = 7.2 Hz, H-8), 6.90 (1H, s, H-1), 6.83 (1H, dd,
J = 7.2 Hz,
J = 8.4 Hz, H-7), 1.39 (9H, c,
t-Bu);
13C-NMR (DMSO-
d6): 187.75 (CO), 143.28 (C-2), 134.40 (C-5), 127.15(C-9), 127.22 (C-8), 125.65 (C-7), 114.76 (C-3), 113.84 (C-6), 102.04 (C-1), 31.91 (
t-Bu), 31.29 (
t-Bu). X-ray data, see
Figure 2,
Table 1.
Methyl (2-tert-butylindolizin-5-yl)(oxo)acetate (6b). Synthesized from 1b using reverse order in mixing of reactants. Indolizyl lithium B was added to oxallyl chloride, the reaction mixture was allowed to warm to room temperature and 20 mL 0.2 M solution of MeONa in MeOH was added dropwise. The mixture was then evaporated to dryness, extracted with CHCl3, and evaporated again. The resulting solid was purified by preparative chromatography (silica gel, eluent–hexane, then –CHCl3:MeOH = 10:1) followed by recrystallization (hexane–acetone). Yield: 0.2 g (30%); red needles; m.p. = 225−228 °C; 1H-NMR (DMSO-d6): 8.94 (1H, s, H-3), 7.96 (1H, d, J = 8.3 Hz, H-6), 7.56 (1H, d, J = 7.2 Hz, H-8), 6.87 (1H, m, H-1), 6.82 (1H, dd, J = 7.2 Hz, J = 8.3 Hz, H-7), 2.07 (3H, s, OMe), 1.38 (9H, s, t-Bu). C15H17NO3, calcd., %: C 69.48, H 6.61, N 5.40, found, %: C 68.99, H 6.64, N 5.36.
Ethyl 2-(2-tert-butylindolizin-5-yl)-2-hydroxypropanoate (7). Synthesized according to the general procedure with ethyl 2-oxopropanoate. Yield: 0.56 g (75%); clear oil; 1H-NMR (DMSO-d6): 7.85 (1H, s, H-3), 7.63 (2H, m, Ph), 7.47–7.39 (3H, m, Ph), 7.27–7.23 (1H, m, H-8), 6.86 (1H, s, H-1), 6.78–6.77 (2H, m, H-6, H-7), 6.45 (1H, s, OH), 4.16–4.03 (2H, m, CH2), 1.86 (3H, c, CH3), 1.04 (3H, m, CH2CH3); 13C-NMR (DMSO-d6): 175.71 (CO2Et), 141.36 (C-2), 134.30 (C-5), 133.89 (C-9), 108.68 (C-8), 118.96 (C-7), 115.41 (C-3), 108.56 (C-6), 97.34 (C-1), 31.84 (t-Bu), 30.95 (t-Bu), 74.82 (COH), 62.74 (OEt) 25.30 (CH3), 13.87 (OEt); 2C19H19NO3·H2O, calcd.,%: C 71.68, H 6.33, N 4.40; found,%: C 71.90, H, 6.43, N 4.22.
5-Bromo-2-phenylindolizine (
8a). Synthesis with phenacyl bromide. Yield: 0.42 g (60%); yellow crystals; m.p. = 85–87 °C;
1H-NMR (CDCl
3): 7.86 (1H, s, H-3), 7.71–7.69 (2H, m, Ph), 7.43–7.37 (3H, m, Ph), 7.29 (1H, d,
J = 7.7 Hz, H-6), 6.89 (1H, s, H-1), 6.78 (1H, d,
J = 7.9 Hz, H-7), 6.60–6.56 (1H, m, H-8). Identical to the sample obtained by using (BrCF
2)
2 [
12].
5-Bromo-2-tert-butylindolizine (
8b). Prepared similarly. Yield: 0.47 g (72%); pale yellow oil; (CDCl
3): 7.41 (1H, s, H-3), 7.30 (1H, d,
J = 8.7 Hz, H-6), 6.71 (1H, d,
J = 7.0 Hz, H-8), 6.54 (1H, m, H-7), 6.51 (1H, s, H-1), 1.37 (9H, c,
t-Bu). Identical to the sample obtained by using (BrCF
2)
2 [
12].
5-Bromo-2-tert-butylindolizine (8b). From the reaction with ethyl bromoacetate. Yield: 0.46 g (72%). Identical to the previous sample.
2-Chloro-1-(2-phenilindolizin-5-yl)ethanone (9). Synthesized according to the general procedure with chloroacetic ester. Yield: 0.21 g (30%); red powder; m.p. = 105–107 °C; 1H-NMR (CDCl3): 9.44 (1H, s, H-3), 7.79–7,75 (3H, m, Ph), 7.57 (1H, d, J = 6 Hz, H-6), 7.46–7.43 (2H, m, Ph), 7.32 (1H, d, J = 6 Hz, 8-H), 7.05 (1H, s, H-1), 6.80 (1H, m, H-7), 4.77 (2H, s, CH2); C16H12ClNO, calcd., %: C 71.25; H 4.48; N 5.19; found, %: C 71.45, H 4.59; N 5.20.