Molecules 2020, 25, 1682
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(CDCl3): 7.92 (2H, m, Ar); 7.78 (2H, m, Ar); 6.94 (1H, s, 3-H); 5.74 (2H, s, CH2); 2.30 (3H, s, 6(4)-CH3);
2.25 (3H, s, 4(6)-CH3).
Phenacylation of methoxypyridine 3d: synthesis optimization without use of a solvent.
(1) The reaction of 3d with p-chlorophenacyl bromides was carried out in a sealed glass ampoule,
the reaction mass was heated in an oven for 25 h at temperature of 120–150 ◦C. TLC analysis in pure
chloroform showed the presence of the desired products. After chromatography, 0.378 g of a pure
yellow substance, identical in TLC and m.p. with the N-isomer 4a. Yield ~10%.
(2) The substances were placed in a 50 mL flask equipped with a reflux condenser. The mixture
was kept at 120 ◦C for 7 h in a Wood alloy. After 5 h of boiling, the yellow liquid began to accumulate
on the walls of the flask and flowed down. TLC analysis showed that it is phenacyl bromide. Then,
after the cessation of gas formation, the temperature was raised to 200 ◦C (continued gas formation),
and the mixture was kept at this temperature for another 3 h. The reaction mixture was applied to silica
gel and chromatographed with CHCl3, then CHCl3—EtOH. Recrystallized from acetone. The yield of
N-isomer 4a was 15%.
(3) 4 g of methoxypyridine 3d and a twofold excess of phenacyl bromide were taken. The substances
are placed in a 50 mL flask equipped with a reflux condenser. The mixture was heated in a Wood alloy
at 125 ◦C for 20 h. After this, the mixture was poured into a large amount of boiling petroleum ether
and the precipitate was filtered off. A petroleum extract containing pure starting materials was reacted
back. The precipitate was purified from the crude oil by chromatography, eluting with chloroform.
The yield of the target product 4a was 35%.
Synthesis of 5-hydroxy-8-nitroindolizines 5a,b (General methodology). A total of 0.6 g of
phenacylpyridone 4a (1.6 mmol) was dissolved in 100 mL of MeOH. The calculated amount of
Na (38 mg) was dissolved in 50 mL of MeOH. A solution of MeONa was added with stirring to
a solution of phenacylpyridone. The solution turned raspberry colored. In 30 min after the start
of the reaction the calculated amount of HOAc was added to neutralize MeONa. The reaction
mixture was diluted with diethyl ether, and the product and NaOAc precipitated. The solvent
was distilled off on a rotary evaporator, the mixture was dissolved in a minimum amount of
acetone and filtered from NaOAc. The solution was evaporated giving a brick-red substance,
2-p-chlorophenyl-5-hydroxy-7-methyl-8-nitroindolizine (5a). Yield 92%. m.p. > 250 ◦C (decomp.).
1H-NMR Spectrum (CD3OD): 7.80 (1H, m, 3-H); 7.72 (2H, m, Ar); 7.47 (2H, m, Ar); 7.29 (1H, m, 1-H);
5.37 (1H, s, 6-H); 3.40 (1H, br s, OH); 2.57 (3H, s, CH3).
2-p-Bromophenyl-7-methyl-8-nitro-5-hydroxyindolizine (5b). Yield 90%, m.p. > 250 ◦C (decomp.).
1H-NMR Spectrum (CDCl3): 7.34 (1H, m, 3-H); 7.17 (2H, m, Ar); 7.08 (2H, m, Ar); 6.82 (1H, m, 1-H);
4.37 (1H, s, 6-H); 3.10 (1H, br s, OH); 2.13 (3H, s, CH3).
2-(p-Chlorophenyl)-5,7-dimethyl-6-nitrooxazolo [3,2-a]pyridinium perchlorate (6). A mixture of 0.1 g
(0.3 mmol) of phenacylpyridone 5a and 1 mL of concentrated sulfuric acid was maintained at 22 ◦C for
18 h. Then, 0.2 mL of 70% HCiO4 was added to the mixture, incubated for 1 h, poured into 100 mL
of absolute ether and the precipitate formed was filtered off. The yield of perchlorate is 92%; m.p.
1
295–297 ◦C (decomp.). H-NMR Spectrum (DMSO-d6): 9.72 (1H, s, 3-H); 8.60 (1H, s, 8-H); 8.07 (2H, m,
Ar); 7.82 (2H, m, Ar); 2.89 (3H, s, 5-CH3); 2.67 (3H, s, 7-CH3). 13C-NMR (DMSO-d6): 15.4; 18.5; 110.6;
112.1; 122.6; 127.5; 130.1; 137.1; 137.8; 144.8; 145.8; 152.2; 152.4. X-Ray data see Figure 2a. The molecular
structure is seen in Figure 2a (perchlorate anion is omitted for clarity) [29].
2-(p-Chlorophenyl)-5-methoxy-7-methyl-8-nitroindolizine (
oxazolopyridinium salt was added to a solution of 10 mg of sodium in 10 mL of methanol.
The mixture was kept for 1 day at 22 ◦C and the precipitate formed was filtered off. Product
(110 mg)
7). A total of 200 mg (0.49 mmol) of
6
7
was obtained. Yield 73%, m.p. 175–176 ◦C. 1H-NMR Spectrum: 7.50 (6H, m, Ar); 5.73 (1H, s, 6-H); 4.22
(3H, s, O-CH3); 2.69 (3H, s, CH3). The molecular structure see Figure 2b (solvate acetone molecule is
omitted for clarity) [30].