Synthesis of 1H-1,5,7-triazacyclopenta[c,d]phenalenes by the electrophilic amination of perimidines using sodium azide in PPA

Article abstract of DOI:10.1007/s10593-011-0662-y

A method was developed for the synthesis of 1H-1,5,7-triazacyclopenta[c,d] phenalenes by the electrophilic amination of perimidines using the new sodium azide/PPA reagent system and a subsequent one-pot reaction with 1,3,5-triazines. A multicomponent variant of this reaction is possible in the case of 2,4,6-trimethyl- and 2,4,6-triphenyl-1,3,5-triazines.

Full text of DOI:10.1007/s10593-011-0662-y

Chemistry of Heterocyclic Compounds, Vol. 46, No. 10, 2011
SYNTHESIS OF 1H-1,5,7-TRIAZACYCLOPENTA[c,d]PHENALENES
BY THE ELECTROPHILIC AMINATION OF PERIMIDINES USING
SODIUM AZIDE IN PPA
A. V. Aksenov1*, A. S. Lyakhovnenko1, and A. V. Andrienko1
A method was developed for the synthesis of 1H-1,5,7-triazacyclopenta[c,d]phenalenes by the
electrophilic amination of perimidines using the new sodium azide/PPA reagent system and a
subsequent one-pot reaction with 1,3,5-triazines. A multicomponent variant of this reaction is possible
in the case of 2,4,6-trimethyl- and 2,4,6-triphenyl-1,3,5-triazines.
Keywords: sodium azide, perimidines, PPA, 1H-1,5,7-triazacyclopenta[c,d]phenalenes, 1,3,5-triazines,
amination.
It is difficult to overstate the importance of indole derivatives among biologically active compounds.
Benzo[c,d]indoles occupy a special position and include efficient thymidylate synthase inhibitors [1].
The standard methods for the synthesis of such compounds involve annelation of a benzene [2] or
pyrrole ring [3] starting from 1-naphthylamines containing a carbonyl [3] or cyano group [1, 3] in the
neighboring peri position. When there is an electron-donor group at position 5, the carbonyl group may be
introduced in reaction [3, 4].
Prior to our work benzo[c,d]indole derivatives of perimidine had not been reported. This was primarily a
consequence of the lack of availability of perimidines containing an amino group in the peri position due to the
low yield of the corresponding nitro derivatives [5]. We have recently proposed a method for the preparation of
such compounds based on the Schmidt reaction and thermal cyclization of the intermediate amide [6]. However,
this method does not yield 1H-1,5,7-triazacyclopenta[c,d]phenalenes 3 lacking substituents in the pyrrole ring.
In the present work, we propose a method of synthesis for such compounds involving electrophilic
amination [7, 8] by means of the sodium azide/PPA reagent system recently discovered in our laboratory and
subsequent reaction with 1,3,5-triazines. The PPA sample used containing 87% P2O5 was obtained according to
Uhlig [9].
As noted in our previous work [7, 8], the reaction of perimidines 1a-c with a threefold excess of sodium
azide in PPA at 80-90°C leads to the corresponding 6(7)-aminoperimidines 3a-c in high yield. The mechanism
proposed in our previous work [7, 8] involves formation of intermediates 2, which subsequently undergo
hydrolysis.
_______
* To whom correspondence should be addressed, e-mail: biochem-org@stavsu.ru.
1 Stavropol State University, Stavropol 355009, Russia.
__________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 10, pp. 1563-1568, October, 2010.
Original article submitted February 2, 2010.
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0009-3122/11/4610-1266©2011 Springer Science+Business Media, Inc.

R
R
N
NH
N
NH
N
O
H+
R
H2O/
–N2,
NaN3
PPA
N
H
...O
P
N
N
N
–H3PO4
H
OH
NH2
1a–c
2a–c
3a–c
1–3 a R = H, b R = Me, с R = Ph
We proposed that intermediates 2a-c may not only undergo protonation but also react with two
electrophilic reagents such as 1,3,5-triazines. In this case, the reaction should proceed as in the following
scheme.
R
H
N
HN
N
R 1
O
R
H
N
–N2
N
N
+
...O
P
N
N
N
2a–c
+
–PPA
R1
N
R1
R1
OH
NH
HN
N
R1
4a–c
N
R1
R1
HN
N
R1
N
R1
5a–i
4 a R1 = H, b R1 = Me, c R1 = Ph; 5 a R = R1 = H, b R = Me, R1 = H, c R = Ph, R1 = H, d R = H,
R1 = Me, e R = R1 = Me, f R = Ph, R1 = Me, g R = H, R1 = Ph, h R = Me, R1 = Ph, i R = R1 = Ph
The subsequent fate of compounds 5a-i depends on the reaction conditions. If, after addition of
triazines 4, the reaction mixture is maintained for 2 h at 70-80°C and treated with water, the reaction product
will be the corresponding amide 6a-c.
H
N
H2O
R
5d–f
H
N
N
O
Me
6a–c
6 a R = H, b R = Me, c R = Ph
R
HN
N
R
N
NH
H
R
N
R1
R1
–
R1
N
NH2
H
N
R1
H+
N
N
NH
H
5a–i
N
N
R1
N
R1
–R1CN
H
N
+
H
N
H
2N
7a–i
R1
R1
7 a R = R1 = H, b R = Me, R1 = H, c R = Ph, R1 = H, d R = H, R1 = Me, e R = R1 = Me, f R = Ph, R1 = Me,
g R = H, R1 = Ph, h R = Me, R1 = Ph, i R = R1 = Ph
1267

The five-membered ring is closed if the reaction temperature is raised to 100-110°C and the reaction
time extended to 5 h to give 1H-1,5,7-triazacyclopenta[c,d]phenalenes 7a-i.
A multicomponent reaction may occur in the case of triazines 4b,c, while yield decreases insignificantly.
NaN3
4b,c
7d–i
1a–c
PPA
Thus, the feasibility of the peri-annelation of the pyrrole ring to give perimidines by means of
electrophilic amination using sodium azide in PPA was demonstrated in this work.
EXPERIMENTAL
1
1
The H NMR spectra were taken for 7b,e,g,i on a Bruker WP-200 spectrometer at 200 MHz, while H
and 13C NMR spectra were taken for 7a,f on a JNM-ECX 400 spectrometer at 400 and 100 MHz, respectively,
in DMSO-d6 with TMS as the internal standard. The reaction course and purity of the products were monitored
by thin-layer chromatography on Silufol UV-254 plates with ethyl acetate or 3:1 ethyl acetate–ethanol as the
eluent.
Commercial samples of 1,3,5-triazine (4a) and 2,4,6-triphenyl-1,3,5-triazine (4c) were obtained from
Aldrich. 2,4,6-Trimethyl-1,3,5-triazine (4b) was prepared according to Schaefer and Peters [10].
Synthesis of Amides 6a-c (General Method). A mixture of corresponding perimidine 1a-c (1 mmol)
and sodium azide (0.195 g, 3 mmol) in PPA (2-3 g) was heated for 5 h at 80-90°C with stirring. Then, the
temperature was lowered to 70-80°C and 2,4,6-trimethyl-1,3,5-triazine (4b) (0.135 g, 1.1 mmol) was added. The
reaction mixture was stirred at this temperature for 2 h, then treated with 50 ml water, and neutralized by adding
ammonium hydroxide. The precipitate formed was filtered off and purified by recrystallization from ethyl
acetate.
6(7)-Acetaminoperimidine (6a) was obtained in 72% yield (0.162 g); mp 225-226°C (ethyl acetate)
(mp 225-226°C [8]). The 1H NMR spectrum was identical to the spectrum given in our previous work [8].
6(7)-Acetamino-2-methylperimidine (6b) was obtained in 77% yield (0.184 g); mp 247-248°C (ethyl
acetate) (mp 247-248°C [8]). The 1H NMR spectrum was identical to the spectrum given in our previous work [8].
6(7)-Acetamino-2-phenylperimidine (6c) was obtained in 79% yield (0.238 g); mp 302-303°C (ethyl
acetate) (mp 302-303°C [8]). The 1H NMR spectrum was identical to the spectrum given in our previous work [8].
Synthesis of 1H-1,5,7-triazacyclopenta[c,d]phenalenes 7a-i (General Method). A. A mixture of
corresponding perimidine 1a-c (1 mmol) and sodium azide (0.195 g, 3 mmol) in PPA (2-3 g) was heated with
stirring for 5 h at 80-90°C. Then, corresponding 1,3,5-triazine 4a-c (1.1 mmol) was added, the temperature was
raised to 100-110°C, and the mixture was stirred at this temperature for 5 h. The reaction mixture was then
poured into water (30 ml) and neutralized by adding ammonium hydroxide. The precipitate formed was filtered
off. The solution was extracted with six 30-ml toluene portions. The precipitate was extracted with 100 ml
toluene in a Soxhlet apparatus for 5 h. The toluene solutions were combined and the solvent was evaporated off.
The residue was purified by recrystallization.
B. The reaction was carried out analogously to method A but with the simultaneous mixing of all the
components: corresponding perimidine 1a-c (1 mmol), sodium azide (0.195 g, 3 mmol), and corresponding
1,3,5-triazine 4b or 4c (1.1 mmol) in PPA (2-3 g). The reaction mixture was treated similarly to the previous
procedure.
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1H-1,5,7-Triazacyclopenta[c,d]phenalene (7a) was obtained in 38% yield (0.073 g); mp 207-209°C
(benzene). 1H NMR spectrum, , ppm (J, Hz): 7.70 (1H, d, J = 9.0, H-3); 7.91 (1H, d, J = 8.7, H-9); 8.45 (1H, d,
13
J = 8.7, H-8); 8.46 (1H, s, H-2); 8.51 (1H, d, J = 9.0, H-4); 9.48 (1H, s, H-6); 13.20 (1H, br. s, NH). C NMR
spectrum, , ppm: 111.87, 112.86, 116.34, 120.09, 120.42, 120.56, 124.88, 131.06, 136.44, 147.82, 154.91,
163.04. Found, %: C 74.71; H 3.58; N 21.64. C12H7N3. Calculated, %: C 74.60; H 3.65; N 21.75.
6-Methyl-1H-1,5,7-triazacyclopenta[c,d]phenalene (7b) was obtained in 41% yield (0.085 g) (method
A); mp 237-238°C (benzene). 1H NMR spectrum, , ppm (J, Hz): 2.93 (3H, s, CH3); 7.65 (1H, d, J = 9.0, H-3);
7.82 (1H, d, J = 8.7, H-9); 8.42 (1H, d, J = 8.7, H-8); 8.46 (1H, s, H-2); 8.50 (1H, d, J = 9.0, H-4); 13.10 (1H,
br. s, NH). Found, %: C 75.51; H 4.33; N 20.16. C13H9N3. Calculated, %: C 75.35; H 4.38; N 20.28.
6-Phenyl-1H-1,5,7-triazacyclopenta[c,d]phenalene (7c) was obtained in 47% yield (0.085 g)
1
(method A); mp 201-203°C (benzene). H NMR spectrum, , ppm (J, Hz): 7.57-7.63 (3H, m, H-3,4,5 Ph); 7.78
(1H, d, J = 8.4, H-3); 7.96 (1H, d, J = 8.5, H-9); 8.39 (1H, s, H-2); 8.43 (1H, d, J = 8.5, H-8); 8.51 (1H, d,
J = 8.4, H-4); 8.73 (2H, d, J = 7.3, H-2,6 Ph); 13.10 (1H, br. s, NH). Found, %: C 80.43; H 4.03; N 15.54.
C18H11N3. Calculated, %: C 80.28; H 4.12; N 15.60.
2-Methyl-1H-1,5,7-triazacyclopenta[c,d]phenalene (7d) was obtained in 44% yield (0.091 g)
1
(method A) and 43% yield (0.089 g) (method B); mp 259-260°C (benzene), (mp 259-260°C [6]). The H NMR
spectrum was identical to the spectrum given in our previous work [6].
2,6-Dimethyl-1H-1,5,7-triazacyclopenta[c,d]phenalene (7e) was obtained in 47% yield (0.104 g)
1
(method A) and 44% yield (0.097 g) (method B); mp 271-272°C (benzene), (mp 271-272°C [6]). The H NMR
spectrum was identical to the spectrum given in our previous work [6].
2-Methyl-6-phenyl-1H-1,5,7-triazacyclopenta[c,d]phenalene (7f) was obtained in 45% yield
1
(0.127 g) (method A) and 41% yield (0.116 g) (method B); mp 245-246°C (benzene–hexane). H NMR
spectrum, , ppm (J, Hz): 2.93 (3H, s, 6-CH3); 7.48-7.58 (3H, m, H-3,4,5 Ph); 7.62 (1H, d, J = 9.0, H-3); 7.82
(1H, d, J = 8.7, H-9); 8.29 (1H, d, J = 8.7, H-8); 8.43 (1H, d, J = 9.0, H-4); 8.71 (2H, d, J = 8.4, H-2, H-6 Ph);
13.10 (1H, br. s, NH). 13C NMR spectrum, , ppm: 12.38, 112.66, 112.94, 117.12, 120.54, 120.61, 120.65,
124.85, 128.05 (2C), 128.22 (2C), 129.36, 130.88, 136.20, 140.09, 147.88, 155.12, 159.64. Found, %: C 80.66;
H 4.56; N 14.78. C19H13N3. Calculated, %: C 80.55; H 4.62; N 14.83.
2-Phenyl-1H-1,5,7-triazacyclopenta[c,d]phenalene (7g) was obtained in 41% yield (0.110 g)
(method A) and 38% yield (0.102 g) (method B); mp 263-265°C (benzene). 1H NMR spectrum, , ppm (J, Hz):
7.54 (3H, m, H-3,4,5 Ph); 7.66 (1H, d, J = 9.0, H-3); 7.79 (1H, d, J = 8.7, H-9); 8.18 (2H, d, J = 7.7, H-2,6 Ph);
8.33 (1H, d, J = 8.7, H-8); 8.69 (1H, d, J = 9.0, H-4); 9.33 (1H, s, H-6); 13.3 (1H, br. s, NH). Found, %:
C 80.39; H 4.04; N 15.57. C18H11N3. Calculated, %: C 80.28; H 4.12; N 15.60.
6-Methyl-2-phenyl-1H-1,5,7-triazacyclopenta[c,d]phenalene (7h) was obtained in 42% yield
(0.119 g) (method A) and 39% yield (0.110 g) (method B); mp 291-202°C (benzene) (mp 291-292°C [6]). The
1H NMR spectrum was identical to the spectrum given in our previous work [6].
2,6-Diphenyl-1H-1,5,7-triazacyclopenta[c,d]phenalene (7i) was obtained in 37% yield (0.128 g)
(method A) and 34% yield (0.117 g) (method B); mp 169-171°C (benzene–hexane). 1H NMR spectrum, , ppm
(J, Hz): 7.57-7.63 (3H, m, H-3,4,5 Ph); 7.78 (1H, d, J = 8.4, H-3); 7.96 (1H, d, J = 8.5, H-9); 8.39 (1H, s, H-2);
8.43 (1H, d, J = 8.5, H-8); 8.51 (1H, d, J = 8.4, H-4); 8.73 (2H, d, J = 7.3, H-2,6 Ph); 13.1 (1H, br. s, NH).
Found, %: C 83.62; H 4.29; N 12.09. C24H15N3. Calculated, %: C 83.46; H 4.38; N 12.17.
This work was carried out with the financial support of the Russian Basic Research Fund (Grant 10-03-00193a).
REFERENCES
1.
M. D. Varney, C. L. Palmer, J. G. Deal, S. Webber, K. M. Welsh, C. A. Bartlett, C. A. Morse,
W. W. Smith, and C. A. Janson, J. Med. Chem., 38, 1892 (1995).
1269

2.
3.
4.
5.
L. I. Kruse and M. D. Meyer, J. Org. Chem., 49, 4761 (1984).
V. V. Mezheritskii and V. V. Tkachenko, Adv. Heterocycl. Chem., 51, 1 (1990).
R. Neidlein and F. Moller, Liebigs Ann. Chem., 971 (1980).
A. F. Pozharskii, V. N. Koroleva, I. V. Komissarov, and I. T. Filippov, Khim.-farm. Zh., 10, No. 12, 34
(1976).
6.
7.
8.
A. V. Aksenov, A. S. Lyakhovnenko, and N. Ts. Karaivanov, Khim. Geterotsikl. Soedin., 146 (2010).
[Chem. Heterocycl. Comp., 46, 127 (2010)].
A. V. Aksenov, A. S. Lyakhovnenko, and N. Ts. Karaivanov, Khim. Geterotsikl. Soedin., 1091 (2009).
[Chem. Heterocycl. Comp., 45, 871 (2009)].
A. V. Aksenov, A. S. Lyakhovnenko, N. Ts. Karaivanov, and I. I. Levina, Khim. Geterotsikl. Soedin.,
591 (2010). [Chem. Heterocycl. Comp., 46, 468 (2010)].
9.
F. Uhlig, Angew. Comp., 66, 435 (1954).
10.
F. C. Schaefer and G. A. Peters, J. Org. Chem., 26, 2778 (1961).
1270