Synthesis of naphtho[1,2-e]-pyrazolo[5,1-b][1,3]oxazines

Article abstract of DOI:10.1007/s10593-011-0830-0

The previously unknown heterocyclic system naphtho[1,2-e]pyrazolo[5,1-b][1, 3]oxazine was synthesized by the condensation of 1-dimethylaminomethyl-2- naphthols with bromopyrazoles. It is proposed that the highly reactive o-methylenequinone of the naphthal

Full text of DOI:10.1007/s10593-011-0830-0

Chemistry of Heterocyclic Compounds, Vol. 47, No. 6, September 2011 (Russian original Vol. 47, No. 6, June, 2011)
SYNTHESIS OF NAPHTHO[1,2-e]-
PYRAZOLO[5,1-b][1,3]OXAZINES
V. A. Osyanin1*, V. Y. Nakushnov1,
and Y. N. Klimochkin1
The previously unknown heterocyclic system naphtho[1,2-e]pyrazolo[5,1-b][1,3]oxazine was synthe-
sized by the condensation of 1-dimethylaminomethyl-2-naphthols with bromopyrazoles. It is proposed
that the highly reactive o-methylenequinone of the naphthalene series is formed as an intermediate.
Keywords: 2-bromopyrazoles, o-methylenequinones, naphtho[1,2-e]pyrazolo[5,1-b][1,3]oxazines,
Mannich bases, cascade reactions.
1,3-Benzoxazines, annelated with nitrogen-containing heterocycles, are of interest as intercalating and
antibacterial agents [1–3] and also as photochromic materials [4, 5]. However, the choice of suitable methods for
preparing them is limited and includes thermolysis of imidoylketenes [6], condensation of thiophosgene with
2'-aminosalicylanilides [7], interaction of 2-azidomethylphenols with cyanogen bromide [8], and the reaction of
tetrahydrocarbazoles with 2-chloromethylphenols [9].
R2
R2
Br
Br
2
R
Br
R1
NMe2
OH
R1
O
N
N
Br
N
N
N
OH
Br
N
H
O
DMF
R1
R1
–HBr
– Me2NH
R
R
1a–c
R
R
2a–e
1a, 2a,d R = R1 = H, 1b, 2b R = 1-Ad, R1 = H, 1c, 2c,e R = H, R1 = 4-MeOC6H4; 2 a–c R2 = Br, d,e R2 = NO2
We have shown that the new heterocyclic system of naphtho[1,2-e]pyrazolo[5,1-b][1,3]oxazines 2a–e
are formed on the interaction of Mannich bases of the naphthalene series 1a–c with 3,4,5-tribromopyrazole or
3,5-dibromo-4-nitropyrazole in boiling DMF.
_______________
*To whom correspondence should be addressed, e-mail: vosyanin@mail.ru.
1Samara State Technical University, 244 Molodogvardeyskaya St., Samara 443100, Russia.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 6, 913–916, June, 2011. Original article
submitted December 29, 2010.
0009-3122/11/4706-0755©2011 Springer Science+Business Media, Inc.
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In the case of 3,4,5-tribromopyrazole the condensation was carried out in the presence of K2CO3 to ac-
celerate the conversion of the intermediate 1-(3,4,5-tribromo-1H-pyrazol-1-ylmethyl)-2-naphthols into naphtho-
[1,2-e]pyrazolo[5,1-b][1,3]oxazines 2a–c. The substituents in the starting materials do not appear to have a
substantial effect on the yields of the final products.
The reaction is cascade and include several stages: deamination of the Mannich base – formation of the
corresponding o-methylenequinone; addition of the bromopyrazole to the o-methylenequinone, and intramolecu-
lar nucleophilic substitution of the bromine atom in the pyrazole unit [10].
The absorptions corresponding to the vibrations of the OH bond are absent in IR spectra of compounds
2a–e which confirms the cyclic structure of these compounds. In the 1H NMR spectra of compounds 2a,b,d the
methylene protons resonate in the 5.53–5.62 ppm region. The signals of aliphatic methyne protons in com-
pounds 2c,e are strongly shifted to weak field and appear in the 6.86–7.30 ppm region.
Thus we have proposed an effective method for the synthesis of naphtho[1,2-e]pyrazolo[5,1-b]-
[1,3]oxazines, the advantage of which is the use of available starting materials, the absence of oligomerization
products of the corresponding o-methylenequinones, and the high yields of the final products.
EXPERIMENTAL
IR spectra of KBr tablets were recorded with a Shimadzu FTIR-8400S spectrometer. 1H, 13C, and DEPT
NMR spectra were taken with a JEOL JNM-ECX400 spectrometer (400 and 100 MHz respectively) in CDCl3
(compounds 2a–d) and DMSO-d6 solutions (compound 2e) with TMS as internal standard. Elemental analysis
was carried out on an Euro Vector EA-3000 automatic CHNS-analyzer.
The starting Mannich bases 1a–c were obtained from 2-naphthols by known methods [11, 12].
8,9-Dibromo-12H-naphtho[1,2-e]pyrazolo[5,1-b][1,3]oxazine (2a). A mixture of 1-(dimethylamino-
methyl)-2-naphthol (1a) (1 g, 5 mmol), 3,4,5-tribromopyrazole (1.51 g, 5 mmol), and K2CO3 (1.38 g, 10 mmol)
in DMF (15 ml) was boiled with stirring for 5 h, then cooled and poured into cold water (50 ml). The precipitate
was filtered off, washed with water, purified by column chromatography (toluene as eluent), and recrystallized
from a methanol–DMF mixture, to give compound 2a (1.29 g, yield 68%) as colorless crystals; mp 229–230°C.
IR spectrum, ꢀ, cm–1: 3047 (CH Ar), 2920, 2870 (CH2), 1628, 1605, 1570, 1516, 1462, 1389, 1377, 1354, 1246,
1
1211, 1014, 972, 810. H NMR spectrum, ꢁ, ppm (J, Hz): 5.56 (2H, s, CH2); 7.40 (1H, d, J = 8.7,
H Ar); 7.50–7.60 (1H, m, H Ar); 7.60–7.70 (2H, m, H Ar); 7.85–7.95 (2H, m, H Ar). 13C NMR spectrum, ꢁ,
ppm: 45.20 (CH2); 107.28 (C); 117.08 (CH); 121.57 (CH); 125.92 (CH); 128.12 (CH); 128.46 (C); 128.97 (CH);
129.83 (C); 130.42 (CH); 130.61 (C); 145.10 (C). Found, %: C 44.20; H 2.09; N 7.41. C14H8Br2N2O. Calcula-
ted, %: C 44.25; H 2.12; N 7.37.
3-(1-Adamantyl)-8,9-dibromo-12H-naphtho[1,2-e]pyrazolo[5,1-b][1,3]-oxazine (2b) was made ana-
logously to compound 2a from 6-(adamantyl)-1-dimethylaminomethyl-2-naphthol (1b) (0.5 g, 1.5 mmol),
3,4,5-tribromopyrazole (0.45 g, 1.5 mmol), and K2CO3 (0.41 g, 3 mmol) in DMF (5 ml). Yield 0.42 g (55%),
colorless crystals; mp 210–211°C (a methanol–DMF mixture). IR spectrum, ꢀ, cm–1: 3090, 3040
(CH Ar), 2901, 2847 (CH Ad), 1612, 1562, 1551, 1528, 1508, 1474, 1450, 1404, 1292, 1207, 987, 968, 879,
810. 1H NMR spectrum, ꢁ, ppm (J, Hz): 1.77–1.85 (6H, m, CH2 Ad); 2.01 (6H, br. s, CH2 Ad); 2.15 (3H, br. s,
CH Ad); 5.53 (2H, s, CH2); 7.35 (1H, d, J = 8.7, H Ar); 7.61 (1H, d, J = 8.7, H Ar); 7.74 (1H, dd, J = 8.7,
J = 1.8, H Ar); 7.77 (1H, s, H-4); 7.83 (1H, d, J = 8.7, H Ar). 13C NMR spectrum, ꢁ, ppm: 28.95 (CH); 36.42
(C); 36.81 (CH2); 43.15 (CH2); 45.19 (CH2); 106.95 (C); 116.78 (CH); 121.33 (CH); 124.09 (CH); 126.34 (CH);
127.95 (C); 128.37 (C); 130.40 (CH); 130.73 (C); 144.62 (C); 145.19 (C); 149.07 (C). Found, %: C 56.09;
H 4.26; N 5.50. C24H22Br2N2O. Calculated, %: C 56.05; H 4.31; N 5.45.
8,9-Dibromo-12-(4methoxyphenyl)-12H-naphtho[1,2-e]pyrazolo[5,1-b][1,3]oxazine (2c) was obtai-
ned analogously to compound 2a from 1-dimethylamino-1-(4-methoxyphenyl)methyl-2-naphthol (1c) (1.54 g,
5 mmol), 3,4,5-tribromopyrazole (1.53 g, 5 mmol), and K2CO3 (1.38 g, 10 mmol) in DMF (15 ml). Yield 1.71 g
(70%), colorless crystals; mp 234–235°C (a methanol–DMF mixture). IR spectrum, ꢀ, cm–1: 3040
(CH Ar), 2924, 2843 (CH), 1624, 1605, 1566, 1512, 1462, 1439, 1373, 1354, 1254, 1242, 1180, 1022, 968, 833,
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1
810. H NMR spectrum, ꢁ, ppm (J, Hz): 3.72 (3H, s, OCH3); 6.77 (2H, d, J = 8.3, H-3',5'); 6.86 (1H, s, CH);
7.24 (2H, d, J = 8.3, H-2',6'); 7.40–7.45 (2H, m, H Ar); 7.49 (1H, d, J = 9.2, H Ar); 7.60–7.65 and 85–7.90 (2H,
m, H-2,3); 7.91 (1H, d, J = 8.7, H Ar). 13C NMR spectrum, ꢁ, ppm: 55.32 (CH3); 59.19 (CH); 111.88 (C);
114.40 (CH); 116.99 (CH); 123.19 (CH); 125.59 (CH); 127.86 (CH); 128.37 (C); 128.92 (CH); 129.36 (CH);
129.81 (C); 131.00 (CH); 131.20 (C); 144.49 (C); 146.05 (C); 159.91 (C). Found, %: C 51.94; H 2.87; N 5.81.
C21H14Br2N2O2. Calculated, %: C 51.88; H 2.90; N 5.76.
9-Bromo-8-nitro-12H-naphtho[1,2-e]pyrazolo[5,1-b][1,3]oxazine (2d) was prepared analogously to
compound 2a from 1-dimethylaminomethyl-2-naphthol (1a) (1 g, 5 mmol) and 3,5-dibromo-4-nitropyrazole
(1.35 g, 5 mmol) in DMF (10 ml). After purification by column chromatography (eluent chloroform) and
recrystallization from a methanol–DMF mixture, compound 2d was obtained as colorless crystals (1.12 g, 65%);
mp 271–273°C. IR spectrum, ꢀ, cm–1: 2923, 2851 (CH2), 1597, 1570, 1539, 1512 (NO2), 1497, 1420, 1346
(NO2), 1246, 1211, 1157, 976, 806. 1H NMR spectrum, ꢁ, ppm (J, Hz): 5.62 (2H, s, CH2); 7.53 (1H, d, J = 9.2,
H Ar); 7.61 (1H, ddd, J = 8.0, J = 6.0, J = 2.0, H Ar); 7.65–7.75 (2H, m, H Ar); 7.95 ( 2H, d, J = 8.7, H Ar). 13C
NMR spectrum, ꢁ, ppm: 45.01 (CH2); 106.91 (C); 116.98 (CH); 121.54 (CH); 123.94 (C); 126.61 (CH); 128.50
(CH); 129.15 (CH); 129.46 (C); 131.08 (CH); 131.20 (C); 144.38 (C). Found, %: C 48.63; H 2.30 N 12.19.
C14H8BrN3O3. Calculated, %: C 48.58; H 2.33; N 12.14.
9-Bromo-12-(4-methoxyphenyl)-8-nitro-12H-naphtho[1,2-e]-pyrazolo[5,1-b][1,3]oxazine (2e) was
obtained analogously to compound 2d from 1-dimethylamino-1-(4-methoxyphenyl)methyl-2-naphthol (1c)
(1.54 g, 5 mmol) and 3,5-dibromo-4-nitropyrazole (1.36 g, 5 mmol) in DMF (10 ml). Yield 1.2 g (53%) of
colorless crystals; mp 266–268°C (chloroform). IR spectrum, ꢀ, cm–1: 3047 (CH Ar), 2966, 2935, 2839
(CH aliph.),1601, 1570, 1508 (NO2), 1462, 1439, 1404, 1342 (NO2), 1254, 1242, 1184, 1026, 976, 837, 806,
1
756. H NMR spectrum, ꢁ, ppm (J, Hz): 3.64 (3H, s, OCH3); 6.82 (2H, d, J = 8.2, H-3',5'); 7.30 (1H, s, CH);
7.34 (2H, d, J = 8.2, H-2',6'); 7.45–7.50 (2H, m, H Ar); 7.68 (1H, d, J = 8.7, H Ar); 7.80–7.90 and 8.00–8.05
(2H, m, H-2,3); 8.12 (1H, d, J = 8.7, H Ar). 13C NMR spectrum, ꢁ, ppm: 55.48 (CH3); 58.47 (CH); 112.36 (C);
114.68 (CH); 116.35 (C); 116.96 (CH); 123.44 (C); 124.07 (CH); 126.36 (CH); 128.16 (CH); 129.15 (CH);
129.39 (C); 129.81 (C); 129.96 (CH); 131.0 (C); 131.76 (CH); 143.82 (C); 144.92 (C); 160.06 (C). Found, %:
C 55.81; H 3.16; N 9.32. C21H14Br,N3O4. Calculated, %: C 55.77; H 3.12; N 9.29.
This work was carried out with a financial subvention from the Grants Committee of the Presidium of The
Russian Federation (program of support of young Russian scientists, grant MK-3368.2011.3), with use of
equipment of collective use center “Investigation of the physicochemical properties of substances and materials”.
REFERENCES
1.
L. Huang, E. L. Ellsworth, S. Randhawa, M. A. Stier, Y. Huang, P. Bird, M. Lebedev, K. Wu,
R. G. Micetich, J. M. Domagala, R. Singh, and N. L. Colby, Tetrahedron Lett., 41, 4061 (2000).
J. Breinholt, H. Gürtler, A. Kjær, S. E. Nielsen, and C. E. Olsen, Acta Chem. Scand., 52, 1040 (1998).
E. S. Charles, K. V. B. Rao, R. Sharma, and R. N. Iyer, Arch. Pharm., 315, 97 (1982).
M. Tomasulo, S. Sortino, and F. M. Raymo, J. Org. Chem., 73, 118 (2008).
M. Tomasulo, S. Sortino, A. J. P. White, and F. M. Raymo, J. Org. Chem., 71, 744 (2006).
N. A. Lisowskaya, M. Alajarin, and P. Sanchez-Andrada, Eur. J. Org. Chem., 1468 (2006).
H. Singh, S. Sharma, and R. N. Iyer, Synthesis, 325 (1975).
2.
3.
4.
5.
6.
7.
8.
9.
Z. P. Demko and K. B. Sharpless, Org. Lett., 3, 4091 (2001).
A. Shachkus, S. Krikshtolaitite, and V. Martinaitis, Khim. Geterotsikl. Soed., 818 (1999). [Chem.
Heterocycl. Comp., 35, 729 (1999)].
10.
N. E. Sidorina and V. A. Osyanin, Khim. Geterotsikl. Soed., 1256 (2007). [Chem. Heterocycl. Comp.,
43, 1065 (2007)].
11
12.
W. R. Brode and J. B. Littman, J. Am. Chem. Soc., 53, 1531 (1931).
S. A. Monti and G. D. Castillo, Jr., J. Org. Chem., 35, 3764 (1970).
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