New approach to the synthesis of benzo[e]pyrazolo[5,1-b][1,3]oxazines

Full text of DOI:10.1007/s10593-010-0622-y

Chemistry of Heterocyclic Compounds, Vol. 46, No. 8, 2010
NEW APPROACH TO THE SYNTHESIS OF
BENZO[e]PYRAZOLO[5,1-b][1,3]OXAZINES
V. A. Osyanin1*, V. Yu. Nakushnov1, D. V. Osipov1, and Yu. N. Klimochkin1
Keywords: o-methylenequinones, pyrazolo[5,1-b][1,3]benzoxazines, salicyl alcohols, 3,4,5-tribromo-
pyrazole.
1,3-Benzoxazines fused to nitrogen heterocycles hold interest in light of their potential physiological
activity. However, the number of available methods for the preparation of these compounds is very limited
[1-3]. We propose a one-step method for the synthesis of pyrazolo[5,1-b][1,3]benzoxazines 1a,b involving
heating 3,4,5-tribromopyrazole with salicyl alcohols in DMF at reflux in the presence of K2CO3.
Br
Br
Br
N
Br
O
N
Br
N
N
OH
R
Br
Br
R
DMF
K2CO3
DMF
OH
N
+
Br
N
HO
H
R
2a,b
a R = H, b R = Br
1a,b
Pyrazolylmethylphenols 2a,b are formed selectively in the absence of potassium carbonate. The active
alkylating agents in these reactions are probably o-methylenequinones formed upon the dehydration of the
salicyl alcohols.
1
The IR spectra were taken on a Shimadzu FTIR-8400S spectrometer for KBr pellets. The H NMR
spectra were taken on a Bruker AM-400 spectrometer at 400 MHz in CDCl3 (1a,b) and DMSO-d6 (2a,b) with
TMS as the internal standard. The mass spectra were taken on a Finnigan Trace DSQ mass spectrometer. The
ionizing electron energy was 70 eV. The elemental analysis was carried out on a Eurovector EA-3000 automatic
CHNS analyzer.
2,3-Dibromo-9H-pyrazolo[5,1-b][1,3]benzoxazine (1a). A mixture of 3,4,5-tribromopyrazole [4] (1 g,
3.3 mmol), salicyl alcohol (0.41 g, 3.3 mmol), and K2CO3 (1.38 g, 10 mmol) in DMF (10 ml) was heated at
reflux for 6 h with stirring. The mixture was cooled and poured into 50 ml water. The precipitate formed was
_______
* To whom correspondence should be addressed, e-mail: vosyanin@mail.ru.
1Samara State Technical University, Samara 443100, Russia.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 8, pp. 1266-1268, August, 2010.
Original article submitted June 15, 2010.
0009-3122/10/4608-1027©2010 Springer Science+Business Media, Inc.
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filtered off and recrystallized from ethanol–DMF to give 0.89 g (82%) compound 1a as colorless crystals;
mp 174-176°C. IR spectrum, , cm-1: 2920, 1562, 1527, 1485, 1458, 1389, 1358, 1242, 1180, 1103, 1011, 899,
752. 1H NMR spectrum, , ppm: 5.25 (2H, s, CH2); 7.10-7.45 (4H, m, H arom). Mass spectrum for 79Br isotope,
m/z (Irel, %): 328 [M]+ (64), 327 [M-H]+ (32), 248 [M-HBr]+ (28), 169 [M-Br-HBr]+ (9), 104 (35), 89 (20), 78
(50), 77 [C6H5]+ (28), 63 (12), 52 (24), 51 (32). Found, %: C 36.48; H 1.79; N 8.55. C10H6Br2N2O. Calculated,
%: C 36.40; H 1.83; N 8.49.
2,3,7-Tribromo-9H-pyrazolo[5,1-b][1,3]benzoxazine (1b) was obtained analogously to compound 1a
from 3,4,5-tribromopyrazole (1 g, 3.3 mmol), 4-bromo-2-hydroxymethylphenol (0.67 g, 3.3 mmol), and potassium
carbonate (1.38 g, 10 mmol) in DMF (10 ml) as colorless crystals with mp 189-190°C (methanol–DMF). The yield
of compound 1b was 1.14 g (85%). IR spectrum, , cm-1: 2928 (CH2), 1562, 1528, 1477, 1416, 1385, 1358,
1
1265, 1246, 1177, 1115, 1014, 903, 872, 814, 644. H NMR spectrum, , ppm (J, Hz): 5.24 (2H, s, CH2); 7.16
(1H, d, J = 8.8, H-5); 7.40 (1H, s, H-8); 7.49 (1H, d, J = 8.8, H-6). Mass spectrum for 79Br isotope, m/z (Irel, %):
406 [M]+ (56), 405 [M-H]+ (16), 326 [M-HBr]+ (16), 248 [M-2Br]+ (21), 220 [M-2Br-CO]+ (10), 182 [C2Br2]+
(11), 156 [C6H5Br]+ (21), 113 (26), 89 [C7H5]+ (29), 77 [C6H5]+ (79), 63 (41), 51 (45). Found, %: C 29.43;
H 1.26; N 6.78. C10H5Br3N2O. Calculated, %: C 29.38; H 1.23; N 6.85.
2-(3,4,5-Tribromo-1H-1-pyrazolylmethyl)phenol (2a). A mixture of 3,4,5-tribromopyrazole (1 g,
3.3 mmol) and salicyl alcohol (0.41, g (3.3 mmol) in DMF (10 ml) was heated at reflux with stirring for 2 h.
The mixture was cooled and poured into 50 ml water. The precipitate formed was filtered off and recrystallized
from ethanol to give 0.85 g (63%) compound 2a as colorless crystals with mp 145-146°C. IR spectrum, , cm-1:
3400-3000 (OH), 1601, 1504, 1454, 1423, 1366, 1285, 1254, 1177, 1099, 1011, 849, 760. 1H NMR spectrum, ,
ppm: 5.25 (2H, s, CH2); 7.13-7.50 (4H, m, H arom); 9.41 (1H, s, OH). Mass spectrum for 79Br isotope, m/z
(Irel, %): 408 [M]+ (12), 391 [M-OH]+ (1), 329 [M-Br]+ (13), 302 [C3HBr3N2]+ (2), 250 [M-2Br]+ (6), 249
[M-2Br-H]+ (7), 107 [C7H7O]+ (70), 106 [C7H6O]+ (100), 79 (26), 78 (64), 77 [C6H5]+ (67). Found, %: C 29.30;
H 1.68; N 6.85. C10H7Br3N2O. Calculated, %: C 29.23; H 1.72; N 6.82.
4-Bromo-2-(3,4,5-tribromo-1H-1-pyrazolylmethyl)phenol (2b) was obtained analogously to
compound 2a from 3,4,5-tribromopyrazole (1 g, 3.3 mmol) and 4-bromo-2-hydroxymethylphenol (0.67 g,
3.3 mmol) in DMF (10 ml) as colorless crystals with mp 197-199°C (ethanol). The yield of compound 2b was
1.19 g (74%). IR spectrum, , cm-1: 3400-3000, 1593, 1493, 1416, 1362, 1342, 1308, 1281, 1254, 1173, 1119,
1
1053, 1011, 883, 818, 779, 629. H NMR spectrum, , ppm (J, Hz): 4.43 (1H, s, H-3); 5.28 (2H, s, CH2); 7.17
(1H, d, J = 8.8, H-6); 7.50 (1H, d, J = 8.8, H-5); 9.45 (1H, s, OH). Mass spectrum for 79Br isotope, m/z (Irel, %):
486 [M]+ (8), 469 [M-OH]+ (1), 407 [M-Br]+ (9), 328 [M-2Br]+ (4), 301 [C3Br3N2]+ (3), 185 [C7H6BrO]+ (84),
184 [C7H5BrO]+ (100), 156 [C6H5Br]+ (35), 77 [C6H5]+. Found, %: C 24.48; H 1.27; N 5.67. C10H6Br4N2O.
Calculated, %: C 24.52; H 1.23; N 5.72.
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