A new method for [c,d]pyridine peri-annelation: synthesis of azapyrenes from phenalenes and their dihydro derivatives

Article abstract of DOI:10.1016/j.tetlet.2007.11.132

An effective synthesis of various azapyrenes from phenalenes and their dihydro derivatives has been developed using 1,3,5-triazines in polyphosphoric acid (PPA).

Full text of DOI:10.1016/j.tetlet.2007.11.132

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Tetrahedron Letters 49 (2008) 707–709
A new method for [c,d ]pyridine peri-annelation: synthesis of
azapyrenes from phenalenes and their dihydro derivatives
Alexander V. Aksenov *, Ivan V. Borovlev, Inna V. Aksenova, Sergey V. Pisarenko,
Dmitry A. Kovalev
Stavropol State University, Pushkina St. 1, Stavropol 355009, Russian Federation
Received 31 July 2007; revised 13 November 2007; accepted 21 November 2007
Abstract
An effective synthesis of various azapyrenes from phenalenes and their dihydro derivatives has been developed using 1,3,5-triazines in
polyphosphoric acid (PPA).
Ó 2007 Elsevier Ltd. All rights reserved.
Keywords: Phenalenes; 1,3,5-Triazines; Polyphosphoric acid; Azapyrenes; Peri-Annelation
It is well known that 1,3,5-triazine can undergo ring
cleavage upon treatment with nucleophilic reagents and
serve as a formyl group precursor. This property has been
extensively used in organic synthesis. Thus formamidines,1a
perimidines,1b benzoimidazoles,1b benzothiazoles,1b benz-
oxazoles,1b purines,1b pyridines,1c,d pyrimidines,1c,e,f and
[1,6]naphthyridines1g–i have been obtained utilizing differ-
ent nucleophiles in reactions with 1,3,5-triazine (1a).
In the case of 1,3-binucleophiles, two aza-formyl groups
of 1,3,5-triazine (1a) are involved in the reaction (Scheme
1). As a result of cyclization, a new six-membered ring is
formed.
HX
N
YH
YH
HX
N
XH2
YH
N
N
N
NH
NH
N
N
1a
H
X
Y
X
Y
H2N
NH
+
N
NH
N
HN
Currently, there exist four examples of 1,3,5-triazine
reactions with 1,3-binucleophiles: syntheses of substituted
triazines,2a 4-aminopyridines,2b 4-hydroxypyridines,2c and
pyrimidines1c (Scheme 2). The common drawback of these
methods is that they are limited to 1,3,5-triazine (1a) itself.
On the basis of the mechanism shown in Scheme 1, we
presumed that 1,3,5-triazine would be a suitable reagent
for peri-annelation of the [c,d]pyridine nucleus of aza-
phenalenes (X = Y = phenalenes peri-positions).
Scheme 1. Mechanism of the reaction of 1,3,5-triazine (1a) with 1,3-
binucleophiles.
We chose the transformation of perimidines 2 to 1,3,7-
triazapyrenes 3 as a test reaction. However, the reaction
did not occur utilizing the conditions (HCl/MeCN or
EtONa/EtOH) described in the above mentioned reports.2
Therefore, we used PPA as a non-nucleophilic acid cata-
lyst. Pleasingly, heating perimidines 2 with a 1.5-M excess
of 1,3,5-triazines 1a–c in the medium of PPA3 (ꢀ3 g)
yielded the previously unknown 1,3,7-triazapyrenes 3a–f
(Scheme 3, Table 1).4
*
Corresponding author. Tel.: +7 865 235 9134; fax: +7 865 235 7023.
E-mail address: k-biochem-org@stavsu.ru (A.V. Aksenov).
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.11.132

708
A. V. Aksenov et al. / Tetrahedron Letters 49 (2008) 707–709
R
N
N
N
N
N
H2N
O
NH
Scheme 1
X=Y=N
N
NH
1a
1a
N
N
R
PPA
R'
NH
N
O
N
4
R'
HCl
5
1a
1a
R
NH
O
N
R
MeCN
R'=H
MeCN
R'=Alk
Scheme 4. 1,2,3,7-Tetraazapyrene (5) synthesis.
R
N
Scheme 1
Scheme 1
X=N,Y=CCOR
X=CH,Y=CCOR
H
X
R=Alk,OEt,NMe2
H
X
X
N
OH
O
O
O
O
O
1a
1a
O
O
O
O
EtONa
EtOH
PPA
N
Scheme 1
N
X=Y=CCOOMe
6,7
10,11
8,9
Scheme 2. Known reactions of 1,3,5-triazine (1a) with 1,3-binucleophiles.
6,8,10: X=CH, 7,9,11: X=N
Scheme 5. Synthesis of 2-azapyrene (10) and 2,7-diazapyrene (11).
R
R
R'
N
N
H
N
N
Table 2
Conditions for azapyrene syntheses
PPA
N
N
+
R'
Product
Temperature (°C)
Reaction time (h)
N
R'
1a-c
3a
3b
3c
3d
3e
3f
5
100
100
100
140
140
180
60 and then
100
100 and then
140
1.5
1.5
1.5
1.5
1.5
1.5
1
3
2
3
2
2a-c
R'
N
3a-f
R'
Scheme 3. Synthesis of 1,3,7-triazapyrenes (3).
Table 1
Synthesis of 1,3,7-triazapyrenes
10
11
Entry
R
R0
Product
Yield (%)
100 and then
140
1
2
3
4
5
6
H (2a)
Me (2b)
Ph (2c)
H (2a)
Me (2b)
H (2a)
H (1a)
H (1a)
H (1a)
Me (1b)
Me (1b)
Ph (1c)
3a
3b
3c
3d
3e
3f
63
55
56
71
52
78
3
In conclusion, the advantages of the method described
for [c,d]pyridine cycle peri-annelation include reagent avail-
ability, experimental simplicity and its applicability to the
synthesis of a broad range of substituted triazapyrenes.
In a similar way the reaction proceeded with 1H-naph-
tho[1,8-de][1,2,3]triazine (1,2,3-triazaphenalene, 4) (Scheme
4). The yield of the previously unknown product 1,2,3,7-
tetraazapyrene (5) was 68%.
Using the mechanism in Scheme 1, we further hypothe-
sized that the reaction should be applicable to dihydroph-
enalenes and dihydroazaphenalenes. For the formation of
azapyrenes an additional dehydrogenation step would be
required. Indeed, heating dihydrophenalenes 6 and 7 in
PPA gave rise to the corresponding 2-azapyrene (10)4
and 2,7-diazapyrene (11)4 in 74% and 55% yields, respec-
tively. Presumably, intermediates 8 and 9 undergo sponta-
neous dehydrogenation during the reaction (Scheme 5).
Acknowledgment
The authors are thankful to Professor A. Kornienko for
his assistance with editing this manuscript.
References and notes
1. (a) Hinkel, L. E.; Ayling, E. E.; Beynon, J. H. J. Org. Chem. 1935, 678;
(b) Grundmann, E. J.; Kreutzberger, A. J. J. Am. Chem. Soc. 1955, 77,
6559; (c) Gromov, S. P.; Yashunskii, D. V.; Sagitullin, R. S.; Bundel,
Yu. G. Chem. Heterocycl. Compd. (Engl. Transl.) 1992, 9, 1054; (d)
Bilbao, E. R.; Alvarado, M.; Masaguer, C. F.; Ravina, E. Tetrahedron
Lett. 2002, 43, 3551; (e) Moehrle, H.; Pycior, M. Arch. Pharm. 1994,

A. V. Aksenov et al. / Tetrahedron Letters 49 (2008) 707–709
709
327, 533; (f) Schaper, W. Synthesis 1985, 9, 861; (g) Balogh, M.;
Hermecz, I.; Naray-Szabo, G.; Simon, K.; Meszaros, Z. J. Chem. Soc.,
Perkin Trans. 1 1986, 753; (h) Balogh, M.; Hermecz, I.; Simon, K.;
Pusztay, L. J. Heterocycl. Chem. 1989, 26, 1755; (i) Kleinschroth, J.;
Mannhardt, K.; Hartenstein, J.; Satzinger, G. Synthesis 1986, 10,
859.
Calcd for C19H11N3: C, 81.12; H, 3.94; N, 14.94. Found: C, 80.92; H,
3.77; N, 15.17.
Data for 6,8-dimethyl-1,3,7-triazapyrene (3d): yellow crystals; mp 225–
226 °C (octane). 1H NMR (500 MHz, CDCl3): d 3.25 (6H, s, 6/8-CH3);
8.19 (2H, d, J = 9.14 Hz, 4/10-H); 8.72 (2H, d, J = 9.14 Hz, 5/9-H);
9.80 (1H, s, 2-H). 13C NMR (75 MHz, CDCl3): d 20.64, 111.27, 118.48,
124.48, 124.63, 131.14, 152.96, 153.78, 165.46. Anal. Calcd for
C15H11N3: C, 77.23; H, 4.75; N, 18.01. Found: C, 77.02; H, 4.65; N,
18.11.
Data for 2,6,8-trimethyl-1,3,7-triazapyrene (3e): orange crystals; mp
206–208 °C (octane). 1H NMR (500 MHz, DMSO-d6): d 2.98 (3H, s,
2-CH3); 3.08 (6H, s, 6/8-CH3); 7.92 (2H, d, J = 9.4 Hz, 4/10-H); 8.67
(2H, d, J = 9.4 Hz, 5/9-H). 13C NMR (75 MHz, CDCl3): d 20.64,
25.80, 111.27, 118.48, 124.41, 124.63, 131.14, 152.96, 153.78, 165.46.
Anal. Calcd for C16H13N3: C, 77.71; H, 5.30; N, 16.99. Found: C,
77.87; H, 5.18; N, 16.72.
Data for 6,8-diphenyl-1,3,7-triazapyrene (3f): yellow crystals; mp 257–
259 °C (ethyl acetate). 1H NMR (500 MHz, DMSO-d6): d 7.69 (6H, m,
m- and p-H C6H5); 7.95 (4H, br d, J = 7.4 Hz, o-H C6H5); 8.31 (2H, d,
J = 9.50 Hz, 4/10-H); 8.79 (2H, d, J = 9.50 Hz, 5/9-H); 9.86 (1H, s,
2-H). 13C NMR (75 MHz, CDCl3): d 118.48, 124.63, 127.42, 128.41,
128.69, 130.02, 132.10, 133.12, 133.38, 152.94, 153.67, 167.89. Anal.
Calcd for C25H15N3: C, 84.01; H, 4.23; N, 11.76. Found: C, 84.16; H,
4.18; N, 11.66.
Data for 1,2,3,7-tetraazapyrene (5): yellow crystals; mp 212–214 °C
(ethyl acetate; with dec.). 1H NMR (500 MHz, DMSO-d6): d 8.35 (2H,
d, J = 9.50 Hz, 4/10-H); 8.92 (2H, d, J = 9.50 Hz, 5/9-H); 9.83 (2H, s,
6/8-H). 13C NMR (75 MHz, CDCl3): d 116.54, 122.37, 125.03, 128.88,
133.69, 149.24, 157.17. Anal. Calcd for C12H6N4: C, 69.90; H, 2.93; N,
27.17. Found: C, 70.06; H, 2.86; N, 27.08.
2. (a) Schaefer, F. C. J. Org. Chem. 1962, 27, 3608; (b) Gromov, S. P.;
Yashunskii, D. V.; Sagitullin, R. S.; Bundel, Yu. G. Dokl. Chem.
(Engl. Transl.) 1987, 12, 292; (c) Liang, X.; Lohse, A.; Bols, M. J. Org.
Chem. 2000, 65, 7432.
3. PPA containing 86% P2O5 was used; preparation according to: Uhlig,
F. Angew. Chem. 1954, 66, 435.
4. General procedure: a mixture of compounds 2, 4, 6, or 7 (1 mmol),
corresponding 1,3,5-triazine (1a–c) (1.5 mmol), and PPA (2–3 g) was
stirred under conditions according to Table 2. After cooling to 80–
85 °C, the reaction mixture was poured into cold water (25 ml) with
vigorous stirring and ammonia was added to pH ꢀ 8. The precipitate
was filtered off, washed with water, and dried. Compounds 3, 10, and
11 were purified by recrystallization. Compound 5 was purified by flash
chromatography on silica gel, eluting with ethyl acetate.
Data for 1,3,7-triazapyrene (3a): yellow crystals; mp 240–242 °C
(octane; with sublimation). 1H NMR (500 MHz, CDCl3): d 8.32 (2H,
d, J = 9.24 Hz, 4/10-H); 8.63 (2H, d, J = 9.24 Hz, 5/9-H); 9.70 (2H, s,
6/8-H); 9.91 (1H, s, 2-H). 1H NMR (500 MHz, DMSO-d6): d 8.26 (2H,
d, J = 9.22 Hz, 4/10-H); 8.80 (2H, d, J = 9.22 Hz, 5/9-H); 9.72 (2H, s,
6/8-H); 9.76 (1H, s, 2-H). 13C NMR (75 MHz, CDCl3): d 112.81,
122.94, 125.00, 127.95, 133.29, 147.29, 153.90, 157.28. Anal. Calcd for
C13H7N3: C, 76.09; H, 3.44; N, 20.48. Found: C, 76.22; H, 3.01; N,
20.28.
Data for 2-methyl-1,3,7-triazapyrene (3b): yellow crystals; mp 230–
232 °C (octane; with sublimation). 1H NMR (500 MHz, CDCl3): d 3.20
(3H, s, CH3); 8.24 (2H, d, J = 9.16 Hz, 4/10-H); 8.62 (2H, d,
J = 9.16 Hz, 5/9-H); 9.64 (2H, s, 6/8-H). 13C NMR (75 MHz, CDCl3):
d 26.49, 111.95, 122.72, 125.17, 127.62, 133.22, 147.13, 154.22, 167.14.
Anal. Calcd for C14H9N3: C, 76.70; H, 4.14; N, 19.17. Found: C, 76.47;
H, 3.96; N, 19.41.
Data for 2-azapyrene (10): yellow crystals; mp 163–165 °C (ethanol/
water; with sublimation). Lit.5 mp 162–165 °C. 1H NMR (500 MHz,
CDCl3): d 7.52 (1H, t, J = 7.96 Hz, 7-H); 7.62 (2H, d, J = 9.14 Hz,
5/9-H); 7.82 (2H, d, J = 7.96 Hz, 6/8-H); 7.96 (2H, d, J = 9.14 Hz,
4/10-H); 9.12 (2H, s,1/3-H). Anal. Calcd for C15H9N: C, 88.65; H,
4.46; N, 6.89. Found: C, 88.79; H, 4.41; N, 6.80.
Data for 2-phenyl-1,3,7-triazapyrene (3c): white crystals; mp 260–
261 °C (octane; with sublimation). 1H NMR (500 MHz, CDCl3): d 7.63
(3H, m, m- and p-H C6H5); 8.40 (2H, d, J = 9.25 Hz, 4/10-H); 8.64
(2H, br d, o-H C6H5); 8.86 (2H, d, J = 9.25 Hz, 5/9-H); 9.68 (2H, s, 6/
8-H). 13C NMR (75 MHz, CDCl3): d 117.20, 123.76, 126.48, 128.77,
129.12, 129.20, 130.53, 130.99, 133.85, 147.90, 155.30, 167.48. Anal.
Data for 2,7-diazapyrene (11): yellow crystals; mp 283–285 °C (octane).
Lit.6 mp 282–284 °C. 1H NMR (500 MHz, CDCl3): d 8.05 (4H, s, 4/5/
9/10-H); 9.38 (4H, s, 1/3/6/8-H). Anal. Calcd for C14H8N2: C, 82.34;
H, 3.95; N, 13.72. Found: C, 82.51; H, 3.86; N, 13.63.
5. Kirchlechner, R.; Jutz, C. Angew. Chem. 1968, 80, 367.
6. Sotiriou-Leventis, C.; Mao, Z. J. Heterocycl. Chem. 2000, 37, 1665.