Synthesis of pyrimido[4,5-b]indolizines by reaction of 2-amino-3-aroyl-1-R- indolizines with formamide

Full text of DOI:10.1007/s10593-011-0749-5

Chemistry of Heterocyclic Compounds, Vol. 47, No. 2, May, 2011 (Russian Original Vol. 47, No. 2, February, 2011)
SYNTHESIS OF PYRIMIDO[4,5-b]INDOLIZINES BY REACTION
OF 2-AMINO-3-AROYL-1-R-INDOLIZINES WITH FORMAMIDE
G. E. Khoroshilov1, I. V. Demchak1*, and T. A. Saraeva1
Keywords: 2-amino-3-aroyl-1-R-indolizines, pyrimido[4,5-b]indolizines, formamide, regioselectivity.
Continuing our studies of the chemical properties of 2-amino-3-aroyl-1-R-indolizines [1] we have
examined the reaction of the indolizines 1a,b and 3a,b when refluxed for a short time with formamide to give
the corresponding pyrimido[4,5-b]indolizines 2a,b and 4a,b.
R
O
R
O
N
H2N CHO
N
N
MeO
H
N
MeO

N
H
N
NH2
O
2a,b
1a,b
a R = Me, b R = СF3
N
N
H2N CHO
N
N
N
N
R1
R1
N
H

H
N
NH2
O
4a,b
3a,b
a R1 = Н, b R1 = ОMe
Only one of the two possible reaction routes is realized and this involves the amino and carbonyl groups.
Hence, in the IR spectra of compounds 2 and 4, signals for the amino and carbonyl groups are lost and signals
appear which are typical of a secondary amide group and an imidazole NH group [2]. The mass spectrum of
compound 2a shows a signal of relative intensity 3.1% which corresponds to the molecular weight.
_______
* To whom correspondence should be addressed, e-mail: demchak@mail.ru.
1Taras Shevchenko National University, 2 Oboronnaya St., Lugansk 91011, Ukraine.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 2, pp. 306-308, February, 2011. Original
article submitted October 7, 2010.
0009-3122/11/4702-0247©2011 Springer Science+Business Media, Inc.
247

The base peak (intensity 100%, m/z 302) is due to the loss of m-toluidine from compound 2a and is typical of
similar systems [2, 3]. On this basis we conclude that compounds 2a,b are formed regioselectively.
1
IR spectra were taken on an IRS-40 spectrophotometer using vaseline oil and H NMR spectra on a
Varian VRX-200 instrument (200 MHz) using DMSO-d6 with TMS as internal standard. Mass spectra (EI,
70 eV) were obtained on a Varian 1200L instrument.
The indolizines 1a,b and 3a,b were prepared by a known method [4, 5].
4-Phenyl-10-R-pyrimido[4,5-b]indolizines 2a,b and 4a,b (General Method). The corresponding
indolizine 1 or 3 (2.5 mmol) was refluxed in formamide (15 ml) for 1 h. The solution became homogeneous and
green-brown in color. After 4 h the precipitate formed was filtered off, washed with the mother liquor, then with
water (1 ml) and formamide (5 ml), and recrystallized from ethanol.
4-(4-Methoxyphenyl)-N-(m-tolyl)pyrimido[4,5-b]indolizine-10-carboxamide (2a). Yield 46%; mp
208-209ºC, IR spectrum, , cm-1: 3418, 1652, 1559. 1H NMR spectrum, , ppm (J, Hz): 11.04 (1H, s, NH); 9.21
(1H, s, H-2); 8.69 (1H, d, J = 9.1, H-9); 8.21 (1H, d, J = 7.1, H-6); 7.85-7.52 (5H, m, H arom); 7.35-7.13 (3H,
m, H arom); 7.01 (1H, t, J = 6.9, H-7); 6.90 (1H, d, J = 7.1, H arom); 3.89 (3H, s, OCH3); 2.33 (3H, s, CH3).
Mass spectrum, m/z (Irel, %): 408 [M]+ (3.1), 304 (3.0), 303 (17.4), 302 (100), 287 (8.2), 259 (6.0), 258 (29.4),
257 (5.4), 233 (2.4), 232 (2.6), 231 (8.4), 230 (7.0), 205 (2.1), 204 (3.8), 203 (4.3), 202 (2.1), 107 (10.3), 106
(4.4), 104 (3.2), 91 (3.5), 80 (2.1). Found, %: C 73.58; H 4.88; N 13.67. C25H20N4O2. Calculated, %: C 73.51;
H 4.94; N 13.72.
4-(4-Methoxyphenyl)-N-[3-(trifluoromethyl)phenyl]pyrimido[4,5-b]indolizine-10-carboxamide
(2b). Yield 59%; mp 206-207.5ºC. IR spectrum, , cm-1: 3436, 1653, 1559. 1H NMR spectrum, , ppm (J, Hz):
11.25 (1H, s, NH); 9.14 (1H, s, H-2); 8.78 (1H, d, J = 9.0, H-9); 8.44 (1H, d, J = 7.1, H-6); 8.29 (1H, s, H arom);
7.91 (1H, d, J = 9.0, H arom); 7.74-7.60 (3H, m, H arom); 7.54 (1H, t, J = 7.6, H-8); 7.34 (1H, d, J = 8.1,
H arom); 7.17 (2H, d, J = 8.7, H arom); 6.94 (1H, t, J = 6.4, H-7); 3.94 (3H, s, OCH3). Found, %: C 64.87;
H 3.76; N 12.17. C25H17N4F3O2. Calculated, %: C 64.93; H 3.71; N 12.12.
10-(1H-Benzimidazol-2-yl)-4-phenylpyrimido[4,5-b]indolizine (4a). Yield 68%; mp 224ºC. IR
1
spectrum, , cm-1: 3488. H NMR spectrum, , ppm (J, Hz): 12.30 (1H, s, NH); 9.23 (1H, s, H-2); 9.13 (1H, d,
J = 9.2, H-9); 8.21 (1H, d, J = 6.9, H-6); 7.77-7.58 (8H, m, H arom); 7.16-7.12 (2H, m, H arom); 6.82 (1H, t,
J = 6.9, H-7). Found, %: C 76.51; H 4.09; N 19.43. C23H15N5. Calculated, %: C 76.44; H 4.18; N 19.38.
10-(1H-Benzimidazol-2-yl)-4-(4-methoxyphenyl)pyrimido[4,5-b]indolizine (4b). Yield 83%; mp
258-260ºC. IR spectrum, , cm-1: 3466. 1H NMR spectrum, , ppm (J, Hz): 12.32 (1H, s, NH); 9.26 (1H, s, H-2);
9.04 (1H, d, J = 10.0, H-9); 8.36 (1H, d, J = 8.0, H-6); 7.97-7.52 (7H, m, H arom); 7.20-7.14 (2H, m, H arom);
7.03 (1H, t, J = 8.0, H-7); 3.90 (3H, s, OCH3). Found, %: C 73.70; H 4.31; N 17.95. C24H17N5O. Calculated, %:
C 73.64; H 4.38; N 17.89.
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