Synthesis of 8,10-dimethyl-1,10b-dihydro[1,3,5]triazino-[2,1-a]isoindole-2, 4,6(3H)-trione by Direct arylation of 1,3,5-triazine-2,4(1H,3H)-dione

Article abstract of DOI:10.1134/S1070428014060037

Direct arylation of 1,3,5-triazine-2,4(1H,3H)-dione with mesitylene afforded a novel fused heterocyclic system, 8,10-dimethyl-1,10b-dihydro[1,3,5] triazino[2,1-a]isoindole-2,4,6(3H)-trione.

Full text of DOI:10.1134/S1070428014060037

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2014, Vol. 50, No. 6, pp. 783–785. © Pleiades Publishing, Ltd., 2014.
Original Russian Text © T.A. Tseitler, G.V. Zyryanov, D.S. Kopchuk, I.S. Kovalev, V.L. Rusinov, O.N. Chupakhin, 2014, published in Zhurnal Organicheskoi
Khimii, 2014, Vol. 50, No. 6, pp. 801–803.
Synthesis of 8,10-Dimethyl-1,10b-dihydro[1,3,5]triazino-
[2,1-a]isoindole-2,4,6(3H)-trione by Direct Arylation
of 1,3,5-Triazine-2,4(1H,3H)-dione
T. A. Tseitlera, G. V. Zyryanova, b, D. S. Kopchuka, b, I. S. Kovaleva,
V. L. Rusinova, b, and O. N. Chupakhina, b
a Ural Federal University, ul. Mira 19, Yekaterinburg, 620002 Russia
e-mail: gvzyryanov@gmail.com
b Postovskii Institute of Organic Synthesis, Ural Branch, Russian Academy of Sciences,
ul. S. Kovalevskoi/Akademicheskaya 22/20, Yekaterinburg, 620990
Received March 14, 2014
Abstract—Direct arylation of 1,3,5-triazine-2,4(1H,3H)-dione with mesitylene afforded a novel fused hetero-
cyclic system, 8,10-dimethyl-1,10b-dihydro[1,3,5]triazino[2,1-a]isoindole-2,4,6(3H)-trione.
DOI: 10.1134/S1070428014060037
Nitrogen-containing polynuclear heterocycles are
widely used as chemosensors for anions [1], liquid
crystals [2], photo- and electroluminescent materials
[3], ligands for complexation with metals [4], and
antiviral [5] and antitumor agents [6]. Taking into
account that the scope of practical application of fused
hetarenes is limited by their synthetic accessibility,
an important problem is development of new methods
for the preparation of such heterocyclic systems [7].
Among potential methods, the approach based on
direct nucleophilic substitution of hydrogen at an ac-
tivated carbon atom (SNH) seems to be the most promis-
ing from the viewpoint of the “green chemistry”
principles [8]. The SNH methodology is the most appro-
priate for π-deficient azines such as pyrimidines [9] or
1,2,4-triazines [10], and it ensures one-step direct func-
tionalization of an unsubstituted carbon atom in
an azine molecule with fragments of π-excessive or
CH-active compounds with formation of SNH products
which in some cases are capable of undergoing subse-
quent condensation to give polynuclear heteroaromatic
systems [11]. Only a few reactions of azines with un-
activated arenes have been reported; examples are re-
actions of pyrimidine and quinazoline with polynuclear
arenes [12, 13] and reaction of 5,6-diphenyl-1,2,4-
triazin-3(2H)-one(or thione) with benzene [14] in the
presence of Lewis acids.
react with various carbon-centered nucleophiles to give
SNAri [15–19] or SNH products [20, 21], only recently
we have obtained products of direct arylation of
1,3,5-triazines in reactions of 1,3,5-triazine-
2,4(1H,3H)-dione with arenes in the presence of AlCl3
as Lewis acid [22].
The arylation of 1,3,5-triazine with electron-rich
mesitylene was the most efficient. The use of
5–6 equiv of AlCl3 increased the yield of 6-(2,4,6-tri-
methylphenyl)-1,3,5-triazinane-2,4-dione (I) to 75%.
Attempted aromatization of I by standard methods, in
particular by the action of potassium permanganate in
neutral or acid medium or 2,3-dichloro-5,6-dicyano-
1,4-benzoquinone (DDQ) afforded no corresponding
oxidation products. When a milder oxidant, a mixture
of Co(NO3)2·6H2O and K2S2O8 in acetic acid [23],
was used, no aromatization of I was observed, but
a new fused heterocyclic system was formed, 8,10-di-
methyl-1,10b-dihydro[1,3,5]triazino[2,1-a]isoindole-
2,4,6(3H)-trione (II). Presumably, the reaction in-
volved oxidation of one methyl group in the mesity-
lene fragment to carboxy group [24, 25] and subse-
quent intramolecular condensation at the triazine nitro-
gen atom (Scheme 1).
The structure of II was confirmed by the NMR, IR,
1
and mass spectra. Its H NMR spectrum contained
signals from only two methyl groups at δ 2.45 and
2.68 ppm, and two carbonyl carbon signals were
observed in the 13C NMR spectrum at δC 157.6
Although 1,3,5-triazines are the most π-deficient
heterocycles among the azine series, which readily
783

TSEITLER et al.
784
Scheme 1.
O
Me
Me
O
HN
HN
AlCl3
N
NH
Me
NH
O
+
N
H
O
Me
Me
Me
Me
I
O
O
COOH
HN
O
Co(NO3)2 ·6H2O
K2S2O8, AcOH, 80°C
N
Me
NH
NH
O
N
HN
H
O
Me
Me
II
Me
Me
O
N
KMnO4 or DDQ
I
Me
NH
O
HN
and 164.8 ppm. Compound II displayed in the IR
spectrum a broadened carbonyl absorption band in the
region of 1644 cm–1. The molecular ion peak in the
mass spectrum of II had an m/z value corresponding to
the assumed structure.
precipitate was filtered off, washed with ethanol, and
recrystallized from aqueous acetic acid (1:1). Yield
75%, colorless crystals, mp 275–276°C. IR spectrum,
ν, cm–1: 3385, 3063, 2918, 1691, 1401, 1360, 1260,
1
1206, 1020, 768, 754. H NMR spectrum (400 MHz,
DMSO-d6), δ, ppm: 2.25 s (3H, CH3), 2.38 s (6H,
CH3), 6.05 s (1H, 6-H), 6.80 s (2H), 7.56 s (2H, NH),
9.14 s (1H, NH). 13C NMR spectrum (100 MHz,
DMSO-d6), δC, ppm: 20.3, 20.9, 60.4, 130.3, 131.2,
137.8, 138.0, 153.6. Found, %: C 61.95; H 6.52;
N 17.80. C12H15N3O2. Calculated, %: C 61.79; H 6.48;
N 18.01.
Thus we were the first to obtain a new polynuclear
heterocyclic system, 8,10-dimethyl-1,10b-dihydro-
[1,3,5]triazino[2,1-a]isoindole-2,4,6(3H)-trione (II) by
direct arylation of 1,3,5-triazine-2,4(1H,3H)-dione
with mesitylene.
EXPERIMENTAL
8,10-Dimethyl-1,10b-dihydro[1,3,5]triazino-
[2,1-a]isoindole-2,4,6(3H)-trione (II). Following the
procedure described in [23], compound I, 1 mmol, was
dissolved in 6 mL of acetic acid, 2 mL of an aqueous
solution of a mixture of 5 mmol (1.46 g) of Co(NO3)2·
6H2O and 2.5 mmol (0.68 g) of K2S2O8 was added,
and the mixture was stirred for 2.5 h at 80°C. The
precipitate of cobalt hydroxide was filtered off, the
filtrate was evaporated on a rotary evaporator, the
residue was treated with 5 mL of water, and the precip-
itate was filtered off, washed with water, and dried.
1
The H NMR spectra were recorded on a Bruker
DRX-400 spectrometer using tetramethylsilane as
internal reference. The melting points were measured
on a Boetius melting point apparatus. The mass
spectrum was obtained on a Bruker Daltonics
MicrOTOF-Q II instrument (Bremen, Germany). The
elemental compositions were determined on a Perkin
Elmer 2400 Series II CHN analyzer. The IR spectra
were recorded on a Bruker Alpha spectrometer with
Fourier transform.
1
6-(2,4,6-Trimethylphenyl)-1,3,5-triazinane-2,4-
dione (I) [22]. A mixture of 200 mg (1.53 mmol) of
1,3,5-triazine-2,4(1H,3H)-dione hydrate, 1000 mg
(7.50 mmol) of AlCl3, and 3 mL of 1,3,5-trimethyl-
benzene was stirred for 18 h at room temperature. The
mixture was then treated with 20 mL of water and
5 mL of 2 N aqueous HCl, the organic layer was
separated and added to 5–10 mL of ethanol, and the
Yield 57%, mp 275°C. H NMR spectrum (400 MHz,
DMSO-d6), δ, ppm: 2.45 s (3H, CH3), 2.68 s (3H,
CH3), 6.37–6.39 m (1H, 6-H), 7.20 m (1H, CH),
7.28 m (1H, CH), 7.39 s (1H, NH), 11.23 s (1H, NH).
13C NMR spectrum (100 MHz, DMSO-d6), δC, ppm:
18.6, 21.8, 82.1, 122.9, 124.1, 133.4, 138.5, 145.5,
146.3, 148.8, 157.6, 164.8. Mass spectrum: m/z 245
[M]+. Found, %: C 58.55; H 4.62; N 17.25.
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 50 No. 6 2014

SYNTHESIS OF 8,10-DIMETHYL-1,10b-DIHYDRO[1,3,5]TRIAZINO[2,1-a]ISOINDOLE-...
785
10. Kozhevnikov, V.N., Kozhevnikov, D.N., Nikitina, T.V.,
Rusinov, V.L., Chupakhin, O.N., Zabel, M., and
König, B., J. Org. Chem., 2003, vol. 68, p. 2882.
C12H11N3O3. Calculated, %: C 58.77; H 4.52; N 17.13.
M 245.24.
This study was performed under financial support
by the Ministry of Education and Science of the
Russian Federation (state contract no. 8430), by the
Council for Grants at the President of the Russian
Federation (project no. MK-1511.2013.3), and by the
Government of the Russian Federation (Program
no. 211, contract no. 02.A03.21.0006).
11. Chupakhin, O.N. and Beresnev, D.G., Russ. Chem. Rev.,
2002, vol. 71, p. no. 9, p. 707.
12. Girke, W.P.K., Chem. Ber., 1979, vol. 112, p. 1.
13. Girke, W.P.K., Chem. Ber., 1979, vol. 112, p. 1348.
14. Giacomelli, G. and Porcheddu, A., Comprehensive
Heterocyclic Chemistry III, Katritzky, A.R., Ram-
sden, C.A., Scriven, E.F.V., and Taylor, R.J.K., Eds.,
Amsterdam: Elsevier, 2008, vol. 9, p. 197.
15. Masquelin, T., Delgado, Y., and Baumle, V., Tetra-
hedron Lett., 1998, vol. 39, p. 5725.
16. Kunishima, M., Hioki, K., Wada, A., Kobayashi, H., and
Tani, S., Tetrahedron Lett., 2002, vol. 43, p. 3323.
17. Samaritani, S. and Menicagli, R., Tetrahedron, 2002,
vol. 58, p. 1381.
18. Bork, J.T., Lee, J.W., Khersonsky, S.M., Moon, H.-S.,
REFERENCES
1. Blázquez, M.T., Muñiz, F.M., Sáez, S., Simón, L.M.,
Alonso, Á., Raposo, C., Lithgow, A., Alcázar, V., and
Morán, J.R., Heterocycles, 2006, vol. 69, p. 73.
2. Binnemans, K., Chem. Rev., 2005, vol. 105, p. 4148.
3. Borsenberger, P.M. and Weiss, D.S., Organic Photo-
receptors for Xerography, New York: Marcel Dekker,
1998, pp. 562, 584, 632.
and Chang, Y.-T., Org. Lett., 2003, vol. 5, p. 117.
19. Samaritani, S., Signore, J., Malanga, C., and Meni-
4. Kopchuk, D.S., Prokhorov, A.M., Slepukhin, P.A., and
Kozhevnikov, D.N., Tetrahedron Lett., 2012, vol. 53,
p. 6265.
cagli, R., Tetrahedron, 2005, vol. 61, p. 4475.
20. Azev, Y.A., Shorshnev, S.V., and Gabel, D., Mendeleev
Commun., 2001, vol. 11, p. 234.
5. Schroeder, A.C. and Bardos, T.J., J. Med. Chem., 1981,
21. Azev, Y.A., Shorshnev, S.V., and Gabel, D., Pharm.
Chem. J., 2002, vol. 36, p. 146.
22. Egorov, I.N., Rusinov, V.L., and Chupakhin, O.N.,
vol. 24, p. 109.
6. Moody, D.L., Dyba, M., Kosakowska-Cholody, T.,
Tarasova, N.I., and Michejda, C.J., Bioorg. Med. Chem.
Lett., 2007, vol. 17, p. 2380.
Tetrahedron Lett., 2010, vol. 51, p. 1717.
23. Shanmugam, P., Boobalan, P., and Perumal, P.T., Tetra-
hedron, 2007, vol. 63, p. 12215.
7. Chernyak, D. and Gevorgyan, V., Org. Lett., 2010,
vol. 12, no. 23, p. 5558.
24. Nikalje, M. and Sudalai, A., Tetrahedron, 1999, vol. 55,
8. Baron, M., Waste Biomass Valoriz., 2012, vol. 3, p. 395.
p. 5903.
9. Egorov, I.N., Tseitler, T.A., Zyryanov, G.V., Rusi-
nov, V.L., and Chupakhin, O.N., Arkivoc, 2011, part (x),
p. 312.
25. Huisgen, R., Morikawa, M., Herbig, K., and Brunn, E.,
Chem. Ber., 1967, vol. 100, p. 1094.
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