1,3-dipolar cycloaddition in a series of 7-oxoalkyl-1,3,7-triazapyrenium salts

Article abstract of DOI:10.1007/s10593-012-1100-5

A series of new 7-R-1,3,7-triazapyrenium salts has been synthesized. The 1,3-dipolar cycloaddition reaction has been investigated in the case of 7-β-oxoalkyl-1,3,7-triazapyrenium salts.

Full text of DOI:10.1007/s10593-012-1100-5

Chemistry of Heterocyclic Compounds, Vol. 48, No. 7, October, 2012 (Russian Original Vol. 48, No. 7, July, 2012)
1,3-DIPOLAR CYCLOADDITION IN A SERIES
OF 7-OXOALKYL-1,3,7-TRIAZAPYRENIUM SALTS
I. V. Borovlev1*, O. P. Demidov1, S. V. Pisarenko1,
O. A. Nemykina1, and N. A. Saigakova1
A series of new 7-R-1,3,7-triazapyrenium salts has been synthesized. The 1,3-dipolar cycloaddition
reaction has been investigated in the case of 7-β-oxoalkyl-1,3,7-triazapyrenium salts.
Keywords: 7-β-oxoalkyl-1,3,7-triazapyrenium salts, pyrrolo[2,1-h][1,3,7]triazapyrene, 1,3-dipolar cyclo-
addition, quaternization.
Against a background of known achievements in the chemistry of azines, azoles, and their condensed
analogs the properties of peri-annelated azaheteroaromatic systems remain practically unknown. The objects of
our study, 1,3,7-triazapyrene (1) and 7-alkyl-1,3,7-triazapyrenium salts (2), belong to their number.
Generalizing the investigations carried out previously it should be noted that the unusual type of carbo- and
heteroring fusion in a molecule of this heterocycle also determines its remarkable properties. The extraordinary
ease of ONSH (Oxidative Nucleophilic Substitution of Hydrogen) reactions, taking place in aqueous solution in
neutral, alkaline, and acidic media, and also the inclination towards a double nucleophilic substitution are some
of these properties [1-7].
For a more detailed study of the oxidative hydroxylation reaction, in addition to the already known
7-alkyl-1,3,7-triazapyrenium salts [1], we have synthesized a series of new salts containing an active methylene
group. It became clear that quaternization of 1,3,7-triazapyrene (1) with allyl bromide and benzyl chloride, and
also ethyl bromoacetate in acetonitrile, results in an equilibrium, in spite of the excess of halide and extended
refluxing. The best yields were obtained on refluxing the reactants in toluene. As a result, 7-allyl- (2b),
7-benzyl- (2c), and 7-ethoxycarbonylmethyl-1,3,7-triazapyrenium (2d) halides were synthesized for the first
time. The salt 2a was described previously [1].
On attempting oxidative hydroxylation of 7-phenacyl- (2a), 7-allyl- (2b), and 7-benzyl-1,3,7-triaza-
pyrenium (2c) salts in aqueous alcoholic solution in the presence of alkali and an oxidizing agent (K3Fe(CN)6) it
became clear that the reaction proceeded ambiguously with the formation of resinous products. The sole
compound isolated by us in the case of salts 2b and 2c, somewhat unexpectedly proved to be the already known
6,8-diethoxy-1,3,7-triazapyrene (3) in yields of 36 and 70%, respectively. It was simple to propose that the
formation of compound 3 is the result of a SN2 dealkylation of cations 2a,b and subsequent oxidative
_______
*To whom correspondence should be addressed, e-mail: k-biochem-gcs@stavsu.ru.
1Stavropol State University, 1 Pushkina St., Stavropol 355009, Russia.
_________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 7, pp. 1146-1152, July, 2012. Original
article submitted June 1, 2011.
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0009-3122/12/4807-1064©2012 Springer Science+Business Media New York

N
N
N
N
RX
PhMe, 
N+
R
X–
N
1
2a–d
2 a R = CH2COPh, X = Br; b R = allyl, X = Br; c R = Bn, X = Cl; d R = CH2CO2Et, X = Br
alkoxylation of the 1,3,7-triazapyrene with ethyl alcohol [6]. In the case of 7-phenacyl-1,3,7-triazapyrenium
bromide (2a), apart from the diethoxy derivative 3 (yield 11%), a new compound was isolated, which on the
basis of spectral data was assigned the structure 10-benzoyl-11-phenylpyrrolo[2,1-h][1,3,7]triazapyrene (4).
Ph
11
N
N
12
Ph
10
1
KOH, K3Fe(CN)6
2
N 9
2a–c
+
O
EtOH, H2O
room temp.
8
3 N
4
7
EtO
N
3
OEt
N
6
5
4 (from 2a)
As it became clear further, compound 4 is formed from salt 2a under the action of an aqueous dioxane
solution of KOH (yield 25%), and also in a triethylamine–tetrahydrofuran system (35% yield).
N
N
N
N
N
N
– HX
– Br–
+
N
+
Ph
OH
X
H
N
O
_
_
O
O
H
:X
N
4
H
Ph
Ph
Ph
+
– HX
5
Br–
N
N
– H2O
X
X
O
N
7
2a
Ph
– Triazapyrene
– Br–
O
HO
Ph
Ph
6
X = OH-, Et3N
We assumed that compound 4 is formed as a result of 1,3-dipolar cycloaddition, where the ylide 5
formed on deprotonation of cation 2a plays the role of 1,3-dipole, and the enol form of phenacyl derivative 6,
formed in situ as a result of SN2 reaction, plays the role of dipolarophile. Aromatization of the intermediate
adduct 7 occurs by cleavage of molecules of simple substances, i.e., oxidant is not required in this reaction.
We found further that if a compound with an activated double bond, such as chalcones 8a-e, are used as
dipolarophile, then 7-β-oxoalkyl-1,3,7-diazapyrenium salts 2a,d readily form red colored cycloaddition
products 9a-f. However, in view of their instability the reaction was carried out in the presence of an oxidizing
agent (I2), giving the previously unknown pyrrolo[2,1-h][1,3,7]triazapyrenes 10a-f (Table 1).
1065

O
O
R2
R2
R1
R1
R1
O
R
R
[O]
Et3N
THF
2a,d
N
N
+
O
O
R2
N
N
8a–e
N
N
9a–f
10a–f
TABLE 1. Yields of Pyrrolo[2,1-h][1,3,7]triazapyrenes 10a-f
Compound
R
R1
R2
Yield, %
10a
10b
10c
10d
10e
10f
Ph
Ph
Ph
Ph
Ph
Ph
Me
Ph
Ph
56
52
42
47
50
45
4-ClC6H4
4-O2NC6H4
4-Me2NC6H4
Ph
Ph
Ph
Ph
OEt
4-ClC6H4
Attempts to use other solvents and oxidizing agents did not lead to improved yields of the compounds
10a-f. It is not ruled out that the starting cation 2 partially displays oxidative properties at the aromatization
stage. The unstable dihydro derivative of 1,3,7-triazapyrene thus formed is subject to oligomerization.
On attempting to carry out a reaction of salt 2a with cyclohexene we obtained only a product of self-
assembly, compound 4. This allows us to conclude that the intermediate 6 playing the role of a dipolarophile
enters the process of cycloaddition at a greater rate than an unactivated alkene.
Compounds 4 and 10a-f are crystalline substances, their color varies from orange to red-brown. In UV
light they are characterized by an intense orange fluorescence.
1
The characteristic H NMR spectral features of these compounds are the low-field singlet signals of
protons in the positions 4 (10.5-10.7 ppm) and 8 (9.6-9.7 ppm, Table 2). In accord with the structure, there were
30 signals in the 13C NMR spectrum of compound 10b, and the lowest field signals (188.5 and 195.8 ppm)
undoubtedly belong to the carbon atoms of the two carbonyl groups.
The molecular ion of compound 4 was relatively stable (peak intensity of 83%), but the molecular ions
of compounds 10a-f were extremely unstable (peak intensity of 0-32%, Table 3). The principal direction of the
primary molecular ion fragmentation of these compounds was cleavage of the carbonyl group bonds, where
signals of the aryl and aroyl cations were characterized by having the greatest intensity.
Thus, the first representatives of a new heteroaromatic system, pyrrolo[2,1-h][1,3,7]triazapyrene, have
been obtained by 1,3-dipolar cycloaddition and subsequent mild oxidation. Formation of 10-benzoyl-11-phenyl-
pyrrolo[2,1-h][1,3,7]triazapyrene from 7-phenacyl-1,3,7-triazapyrenium bromide in alkaline medium proved to
be rather nontrivial, since it occurs in the absence of an external dipolarophile. 7-Alkyl-1,3,7-triazapyrenium
salts with labile N-substituents are readily dealkylated on oxidative hydroxylation, and the resulting 1,3,7-tri-
azapyrene enters into further transformations.
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1067

TABLE 3. Mass Spectra of Compounds 4 and 10a-f
Com-
pound
m/z (Irel, %)
4
423 [M]+ (83), 422 (11), 395 (11), 394 (31), 347 (6), 346 (19), 318 (20), 317 (53), 316 (16),
290 (9), 289 (10), 262 (7), 211 (12), 205 (32), 204 (8), 178 (10), 177 (6), 151 (6), 106 (6),
105 (71), 78 (10), 77 (100), 76 (8), 51 (25), 50 (7), 39 (7)
10a
10b
10c
10d
527 [M]+ (20), 450 (5), 422 (5), 225 (6), 106 (7), 105 (100), 78 (11), 77 (93), 51 (9)
562 [M]+ (0.3), 242 (6), 106 (7), 105 (95), 78 (8), 77 (100), 51 (12)
571 [M–H] + (0.2), 106 (6), 105 (100), 78 (7), 77 (100), 51 (12)
570 [M]+ (32), 423 (12), 394 (6), 318 (6), 317 (12), 316 (8), 285 (6), 134 (6), 106 (6),
105 (100), 78 (8), 77 (67), 51 (12)
10e
10f
465 [M]+ (13), 450 (6), 317 (5), 316 (6), 289 (7), 262 (7), 106 (9), 105 (99), 78 (10),
77 (100), 51 (28), 50 (6), 43 (69)
529 [M]+ (0.2), 106 (5), 105 (62), 78 (10), 77 (100), 76 (5), 51 (21)
EXPERIMENTAL
1
The IR spectra were recorded on a Varian 800 FT-IR instrument in a thin film. The H and 13C NMR
spectra were recorded on a Bruker-250 instrument (250 and 63 MHz, respectively), internal standard was TMS.
The mass spectra were recorded on a Finnigan MAT INCOS 50 instrument (EI 70 eV). Monitoring of the
reaction progress and purity control of the synthesized compounds were performed on Silufol UV-254 plates.
The identity of compounds obtained by various means was established by comparison of their IR spectra.
1,3,7-Triazapyrene [8] and 7-phenacyl-1,3,7-triazapyrenium bromide [1] were obtained by literature
procedures.
7-Alkyl-1,3,7-triazapyrenium Salts (2b-d) (General Method). A solution of 1,3,7-triazapyrene (1)
(0.21 g, 1 mmol) and the corresponding alkyl halide (3 mmol) in toluene (20 ml) was refluxed for 4 h. The
precipitated solid was filtered off, washed with hot toluene, then petroleum ether, dried, and used without
further purification.
7-Allyl-1,3,7-triazapyrenium Bromide (2b). Yield 0.26 g (80%). Red-brown crystals, mp 248-250oC
1
(decomp.). H NMR spectrum (DMSO-d6), δ, ppm (J, Hz): 5.53-5.63 (2H, m, N+CH2); 5.74-5.81 (2H, m,
CH=CH2); 6.30-6.46 (1H, m, CH=CH2); 8.67 (2H, d, 3J = 9.3) and 9.10 (2H, d, 3J = 9.3, H-4,5,9,10); 10.17 (1H,
s, H-2); 10.31 (2H, s, H-6,8). Found, %: C 59.03; H 4.00; N 12.58. C16H12BrN3. Calculated, %: C 58.91; H 3.71;
N 12.88.
7-Benzyl-1,3,7-triazapyrenium Chloride (2c). Yield 0.24 g (75%). Dark-brown crystals, mp
238-240oC. 1H NMR spectrum (DMSO-d6), δ, ppm (J, Hz): 6.39 (2H, s, N+CH2); 7.30-7.45 (5H, m, H Ph); 8.65
3
3
(2H, d, J = 9.4) and 9.10 (2H, d, J = 9.4, H-4,5,9 10); 10.16 (1H, s, H-2); 10.55 (2H, s, H-6,8). Found, %:
C 72.14; H 4.20; N 12.51. C20H14ClN3. Calculated, %: C 72.40; H 4.25; N 12.66.
7-Ethoxycarbonylmethyl-1,3,7-triazapyrenium Bromide (2d). Yield 0.27 g (78%). Dark-brown
1
crystals, mp 242-245oC (decomp.). H NMR spectrum (DMSO-d6), δ, ppm (J, Hz): 1.31 (3H, t, J = 7.0,
CH2CH3); 4.31 (2H, q, J = 7.0, CH2CH3); 6.22 (2H, s, N+CH2); 8.64 (2H, d, 3J = 9.3) and 9.09 (2H, d, 3J = 9.3,
H-4,5,9,10); 10.14 (1H, s, H-2); 10.32 (2H, s, H-6,8). Found, %: C 54.73; H 3.88; N 11.40. C17H14BrN3O2.
Calculated, %: C 54.86; H 3.79; N 11.29.
Interaction of 7-Phenacetyl- (2a), 7-Allyl- (2b), and 7-Benzyl-1,3,7-triazapyrenium (2c) Salts with
Aqueous Alcoholic Alkali in the Presence of an Oxidizing Agent (General Method). A mixture of salt 2a-c
(1 mmol), KOH (1 g, 18 mmol), and K3Fe(CN)6 (2 g, 6 mmol) was stirred at room temperature for 7 h in 50%
aqueous EtOH (20 ml). At the end of the reaction the mixture was poured into water (100 ml). Further isolation
was carried out by various methods (see below).
From Salt 2a. The products were extracted with toluene (330 ml), and the solvent was evaporated to
dryness in vacuum. The dry residue was ground with silica gel (0.5 g) and transferred to a column for flash
1068

chromatography [9] (adsorbent was silica gel). On eluting with EtOAc, the second (yellow) and third (orange)
fractions were collected (the first fraction, brown in color, contained a small quantity of resinous substances).
After distilling the solvent from the second fraction, compound 3 (0.032 g, 11%) was obtained, and from the
third fraction 10-benzoyl-11-phenylpyrrolo[2,1-h][1,3,7]triazapyrene (4) (0.105 g, 25%) was obtained.
From Salt 2b. Isolation and purification of the reaction product was carried out as in the previous
procedure, eluting the yellow second fraction with EtOAc. After distilling off the solvent, 6,8-diethoxy-1,3,7-tri-
azapyrene (3) (0.105 g, 36%) was obtained.
From salt 2c. The solid product precipitated on pouring into water was filtered off, washed with water,
and dried. Yield of 6,8-diethoxy-1,3,7-triazapyrene (3) was 0.204 g (70%). Yellow-green crystals, mp 235236oC
(PhMe), which corresponded to literature data [6].
10-Benzoyl-11-phenylpyrrolo[2,1-h][1,3,7]triazapyrene (4). A. An aqueous solution (10 ml)
containing KOH (0.227 g, 4 mmol) was added with vigorous stirring to a solution of 7-phenacyl-1,3,7-tri-
azapyrene bromide (2a) (0.404 g, 1 mmol) in 50% aqueous dioxane (20 ml) at ~80oC. The mixture was stirred at
the same temperature for an additional 1 h, H2O (30 ml) was added, and the mixture was extracted with n-BuOH
(320 ml). The extract was evaporated to dryness, the dry mixture was ground with silica gel (0.5 g) and
transferred to a column for flash chromatography [9] (adsorbent was silica gel). By eluting with a mixture of
EtOAc–EtOH, 1:1, the orange-red fraction was collected. After distilling off the solvent, compound 4 (0.106 g,
25%) was obtained. IR spectrum (thin film), ν, cm-1: 1662 (C=O). Found, %: C 82.33; H 4.21; N 9.75.
C29H17N3O. Calculated, %: 82.25; H 4.05; N 9.92.
B. A solution of 7-phenacyl-1,3,7-triazapyrenium bromide (2a) (0.404 g, 1 mmol) and Et3N (0.510 g,
5 mmol) in THF (10 ml) was stirred vigorously for 2 h at 75-80oC, the solvent was evaporated to dryness in
vacuum, and the product was purified by method A. Yield 0.148 g (35%).
Pyrrolo[2,1-h][1,3,7]triazapyrenes 10a-f (General Method). A mixture of 7-phenacyl- (2a) or
7-ethoxycarbonylmethyl-1,3,7-triazapyrenium bromide (2d), chalcone 8a-e (4 mmol), and Et3N (1.21 g,
12 mmol) in THF (20 ml) was refluxed for 30 min. Iodine (2.54 g, 10 mmol) was then added to the solution, and
the mixture was refluxed for a further 2 h. The reaction mixture was diluted with saturated Na2S2O3 solution
(20 ml) and extracted with benzene (350 ml). The extract was washed with water and evaporated to dryness in
vacuum. The dry residue was ground with silica gel (0.5 g) and transferred to a column for flash
chromatography, which was eluted with EtOAc, collecting the orange-colored fraction (red-brown color when
obtaining compound 10f). The residue obtained after evaporating the solvent was recrystallized from an EtOH–
C6H6 mixture.
10,12-Dibenzoyl-11-phenylpyrrolo[2,1-h][1,3,7]-triazapyrene (10a) was obtained from the salt 2a
and benzalacetophenone (8a). Orange crystals, mp 292-293oC. IR spectrum, , cm-1: 1610 (br., C=O). Found,
%: C 82.07; H 4.11; N 7.87. C36H21N3O2. Calculated, %: C 81.96; H 4.01; N 7.96.
10,12-Dibenzoyl-11-(4-chlorophenyl)pyrrolo[2,1-h][1,3,7]triazapyrene (10b) was obtained from salt
2a and 4-chlorobenzalacetophenone (8b). Orange crystals, mp 264-265oC. IR spectrum, , cm-1: 1613 (br.,
C=O). 13C NMR spectrum (CDCl3), δ, ppm: 117.0; 117.2; 119.0; 119.9; 121.4 (2C); 128.0; 128.2; 128.3; 128.5;
128.6; 128.7; 129.0; 130.0; 130.2; 131.0; 131.8; 132.3; 132.7; 134.2; 134.3; 135.5; 137.9; 138.2; 139.1; 151.3;
157.8; 157.9; 188.5; 195.8. Found, %: C 76.79; H 3.72; N 7.56. C36H20N3O2. Calculated, %: C 76.94; H 3.59;
N 7.48.
10,12-Dibenzoyl-11-(4-nitrophenyl)pyrrolo[2,1-h][1,3,7]triazapyrene (10c) was obtained from the
salt 2a and 4-nitrobenzalacetophenone (8c). Yellow-brown crystals, sublimed > 254oC. IR spectrum, , cm-1:
1618 (br., C=O). Found, %: C 75.32; H 3.61; N 9.65. C36H20N4O4. Calculated, %: C 75.52; H 3.52; N 9.78.
10,12-Dibenzoyl-11-(4-dimethylaminophenyl)pyrrolo[2,1-h][1,3,7]triazapyrene (10d) was obtained
from the salt 2a and 4-dimethylaminobenzalacetophenone (8d). Red-brown crystals, mp 145-146oC. IR
spectrum, , cm-1: 1605 (C=O). Found, %: C 80.09; H 4.73; N 9.89. C38H26N4O2. Calculated, %: C 79.98;
H 4.59; N 9.82.
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12-Acetyl-10-benzoyl-11-phenylpyrrolo[2,1-h][1,3,7]triazapyrene (10e) was obtained from the salt
2a and benzalacetone (8e). Orange crystals, mp 279-280oC. Found, %: C 80.13; H 3.98; N 9.17. C31H19N3O2.
Calculated, %: C 79.99; H 4.11; N 9.03.
12-Benzoyl-11-(4-chlorophenyl)-10-ethoxycarbonylpyrrolo[2,1-h][1,3,7]triazapyrene (10f) was
obtained from the salt 2d and 4-chlorobenzalacetophenone (8b). Red-brown crystals, mp 130-132oC. IR
spectrum, , cm-1: 1680 (br., C=O), 1598 (br., C=O). Found, %: C 72.34; H 4.01; N 7.85. C32H20ClN3O3.
Calculated, %: C 72.52; H 3.80; N 7.93.
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