Synthesis and cleavage of 1,3,7-triazapyrene ethers

Article abstract of DOI:10.1007/s10593-013-1168-6

Oxidative alkoxylation of 1,3,7-triazapyrenes in the system ROH-H ₂O-KOH-K₃Fe(CN)₆ leads via a tandem S _N ^H-S _N ^H process to the formation of 6,8-dialkoxy-1,3,7-triazapyrenes. Hydrolytic cleavage of these ethers leads to products of single or double dealkylation, depending on the reaction conditions.

Full text of DOI:10.1007/s10593-013-1168-6

Chemistry of Heterocyclic Compounds, Vol. 48, No. 10, January, 2013 (Russian Original Vol. 48, No. 10, October, 2012)
SYNTHESIS AND CLEAVAGE OF
1,3,7-TRIAZAPYRENE ETHERS
O. P. Demidov1, I. V. Borovlev1*, N. A. Saigakova1,
O. A. Nemykina1, and S. V. Pisarenko1
Oxidative alkoxylation of 1,3,7-triazapyrenes in the system ROH–H2O–KOH–K3Fe(CN)6 leads via a
H
H
tandem SN –SN process to the formation of 6,8-dialkoxy-1,3,7-triazapyrenes. Hydrolytic cleavage of
these ethers leads to products of single or double dealkylation, depending on the reaction conditions.
H
Keywords: 1,3,7-triazapyrenes, cleavage of ethers, tandem SN –SNH alkoxylation.
Classical strategies for the synthesis of ethers of nitrogen-containing heterocycles are based on the
substitution of good leaving groups. Reactions proceeding by a tele-mechanism are among non-oxidative
methods for obtaining such results. For example, heteroarenes with di- and trichloromethyl substituents react
with alkoxide anions to give products of ring hydrogen substitution by an alkoxy group [1-4].
In the case of electron-deficient aza-aromatic substrates, an excellent alternative may be direct oxidative
nucleophilic substitution of hydrogen (ONSH [5]) by an alkoxy group, since it does not require a preliminary
introduction of a good nucleofuge into the molecule. Yet we have found only two literature examples of
successful heterocycle alkoxylation according to the ONSH process. Thus, the reaction of 1,3-di-
methyllumazine with N-bromosuccinamide in the corresponding primary alcohol led to 6-alkoxy- and 6,7-di-
alkoxy derivatives of 1,3-dimethyllumazine [6]. Methoxylation of 2-nitro-5,10,15,20-tetraphenylporphyrin
copper complex with sodium methoxide in DMF is reported in paper [7].
Against this background, our previous observations of the easy ONSH alkoxylation [8, 9], amination
[10], and alkylamination [11] of 1,3,7-triazapyrenes is of great interest. Thus, the oxidative alkoxylation of
1,3,7-triazapyrene (1a) and its 2-methyl derivative 1b occurs at room temperature in the corresponding aqueous
alcoholic solutions with an excess of KOH and K3Fe(CN)6 [8], whereas compounds 1a and 1b remain
unchanged in the conditions mentioned above [6]. With primary alcohols, the process results in the formation of
previously unknown 6,8-dialkoxy derivatives of this heterocycle, 2a-d.
The objective of the present work was a further investigation of this reaction, and also the possibility of
hydrolytic cleavage of the ethers obtained.
Allyl alcohol and ethylene glycol react with 1,3,7-triazapyrene (1a) under conditions used for the
synthesis of compounds 2a-d, which allowed us to obtain also the 6,8-diallyloxy- (2e) and 6,8-bis(2-hydroxy-
ethoxy)-1,3,7-triazapyrene (2f), respectively.
_______
*To whom correspondence should be addressed, e-mail: k-biochem-gcs@stavsu.ru.
1North Caucasus Federal University, 1 Pushkin St., Stavropol 355009, Russia.
________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 10, 1639-1644, October, 2012.
Original article submitted May 22, 2012.
0009-3122/13/4810-1527©2013 Springer Science+Business Media New York
1527

R
R
N
N
N
N
R1OH, H2O
KOH, K3Fe(CN)6
room temp.
OR1
N
1a,b
R1O
N
2a–f
1 a R = H, b R = Me; 2 a R = H, R1 = Me; b R = R1 = Me; c R = H, R1 = Et;
d R = H, R1 = Pr; e R = H, R1 = allyl; f R = H, R1 = CH2CH2OH
Attempts to stop the reaction at the monoalkoxylation stage were unsuccessful. Even with insufficient
quantity of the oxidant, compounds 2a-f were formed and the starting triazapyrene 1a remained. This indicates
that the second stage of alkoxylation occurred more readily than the first. The monomethoxy derivative 3a was
obtained successfully only in the case of 2-methyl-6-phenyl-1,3,7-triazapyrene (1c) in which one of the
α-positions relative to the N-7 atom is already occupied.
Me
Me
N
N
N
N
MeOH, H2O
KOH, K3Fe(CN)6
room temp.
Ph
N
Ph
N
OMe
1c
3a (67%)
When both α-positions are occupied, while the position 2 is free, as in the case of 6,8-diphenyl-1,3,7-tri-
azapyrene, this reaction does not occur.
The unusual nature of 1,3,7-triazapyrene alkoxylation includes, first of all, the high selectivity of the
substrate in relation to nucleophiles in the reaction system, and also the very possibility of a second nucleophilic
substitution. The successive exclusion of individual components of the reaction mixture showed that in the
absence of alkali or K3Fe(CN)6 the reaction did not occur, and in the absence of water the reaction was at least
very severely decelerated. It is probable that water is necessary to increase the solubility of the oxidant, since
K3Fe(CN)6 is poorly soluble in alcohols.
H
Undoubtedly, the oxidative alkoxylation of 1,3,7-triazapyrenes occurs via a tandem SN –SNH mechanism
which includes successive stages of nucleophile addition with the formation of σH-complexes 4 and 6, followed
by their oxidative aromatization.
R1O–
R1O–
[O]
[O]
R1O
OR1
–
–
OR1
N
1
N
4
N
5
OR1
N
6
H
H
R1O
N
2
OR1
From the data of paper [12], the successive elimination of an electron, a proton, and an electron from the
σH-adducts (the EPE mechanism) is the most likely route for aromatization. Considering the one-electron nature
1528

of the oxidizing agent we used, this process is entirely likely in the aromatization of the σH-complexes 4 and 6
as well. The selectivity of the reaction with respect to the nucleophiles present in the system may be explained
by the conditions of kinetic control: the more nucleophilic alkoxy anions, which are present in the system at low
equilibrium concentrations, react faster.
The greater rate of the second alkoxylation of intermediate 5 may be explained as follows. It is known
that alkoxy groups in the α-position to the pyridine nitrogen atom have an acceptor effect on the heterocycle. So
2-methoxypyridine (pKa 3.28 in aqueous solution) is a weaker base, by almost two orders, than pyridine (pKa
5.21), whereas 4-methoxypyridine is a stronger base (pKa 6.58) [13]. The nature of this phenomenon is not
completely clear, but in any case it indicates the dominance of the inductive effect, the influence of which at the
distance of one bond from the aza group is very considerable [14-16].
6-Isopropoxy-1,3,7-triazapyrene (3b) is formed along with 6,8-diisopropoxy-1,3,7-triazapyrene (2g) in
the reaction of 1,3,7-triazapyrene (1a) with a secondary alcohol (2-propanol). We did not succeed in separation
of this mixture because of their identical chromatographic mobility, but gas chromatographic and 1H NMR data
showed that the ratio of alkoxylation products 2g and 3b was ~1:1. The overall yield of these products
decreased with increasing reaction time.
N
N
N
N
i-PrOH, H2O, KOH
+
1a
K3Fe(CN)6
room temp.
N
3b
O
Pr-i
O
N
2g
O
Pr-i
i-Pr
The mass spectra of ethers 2g and 3b are characterized by low intensity of the molecular ions and the
greatest intensity of peaks of ions corresponding to the loss of one (compound 3b) or two molecules of propene
(compound 2g).
We also found that carrying out the methoxylation of triazapyrene 1a with refluxing reagents
unexpectedly gave 8-methoxy-6-oxo-6,7-dihydro-1,3,7-triazapyrene (7).
N
N
N
N
MeOH, H2O
HO– or MeO–
1a
KOH, K3Fe(CN)6

MeO
N
2a
OMe
O
N
OMe
H
7
Several formal routes for the synthesis of compound 7 may be suggested. The first – oxidative
hydroxylation with subsequent oxidative alkoxylation – is unlikely, since the product of hydroxylation in basic
medium should exist in its anion form, which is stable to nucleophiles. A second possible route – hydroxylation
of a monomethoxy intermediate – remains a possibility, since preparation of the monomethoxy derivative was
unsuccessful.
A third route for the formation of compound 7 – demethylation of the intermediate dimethoxy
derivative 2a as a result of an SN2 reaction with hydroxide or methoxide anions.
In fact, 6,8-dimethoxy-1,3,7-triazapyrene (2a) on heating with aqueous alkali or sodium methoxide in
methanol underwent monodemethylation to give compound 7.
On the other hand, it is known that ethers of azines (in contrast to alkylaryl ethers) are readily converted
by hydrolytic cleavage on heating with dilute mineral acids [17]. The reason for this is the formation of a
1529

heteroaromatic cation, which is the species attacked by a water molecule, and the reaction proceeds by ipso
substitution of alkoxy group [18]. It was shown that the dialkoxy derivatives 2a,c on heating with 60% sulfuric
acid underwent double hydrolytic cleavage, to form 6,8-dioxo-1,6,7,8-tetrahydo-1,3,7-triazapyrene (8) in
quantitative yield.
HN
N
N
NH
H2O, H+
H2O, H+
2a,c
7
O
O
N
O
N
O
H
H
8
Naturally, the product of partial demethylation, compound 7, also forms the imide 8 under acid catalysis
conditions.
The characteristic of the 1H NMR spectrum of compound 8 in DMSO-d6 is its symmetrization as a result
of the rapid proton migration between atoms N-1 and N-3.
Thus, oxidative alkoxylation of 1,3,7-triazapyrenes in the ROH–H2O–KOH–K3Fe(CN)6 system
H
proceeds via a tandem SNH–SN process, and the 6,8-dialkoxy derivatives formed in this way are capable of
undergoing hydrolytic cleavage, depending on the conditions, into products of monodealkylation or of double
dealkylation.
EXPERIMENTAL
1H and 13C NMR spectra in DMSO-d6 solution, with residual protons of the solvent as internal standard,
were recorded with a Bruker 250 instrument (250 and 63 MHz, respectively). The mass spectrum of compound
3a was recorded on an MX-1321A instrument (EI, 70 eV). Analysis of the products of triazapyrene 1a
alkoxylation with 2-propanol was carried out on an Agilent Technologies model 6890N gas chromatograph with
a 5973N mass-selective detector (EI, 70 eV). Elemental analyses were carried out with a CHN-1 apparatus.
Melting points were carried out with a PTP-1 apparatus. The course of reactions and the purity of the
compounds synthesized were monitored by TLC on Silufol UV-254 plates. The identities of compounds
prepared by different methods were determined by absence of melting point depression, when mixing with
authentic samples.
The starting 1,3,7-triazapyrenes 1a,b [19] and 1c [20], and the standards of alkoxy derivatives 2a-d [8]
were synthesized by the indicated methods.
6,8-Dialkoxy-1,3,7-triazapyrenes 2a-g and 6-Alkoxy-1,3,7-triazapyrenes 3a,b (General Method).
A mixture of compound 1a-c (0.5 mmol), KOH (0.5 g, 9 mmol), K3Fe(CN)6 (1.0 g, 3 mmol), water (5 ml), and
the corresponding alcohol (5 ml) was stirred vigorously at room temperature. The overall term of stirring to
produce compound 2a – 2 h, 2b – 3 h, 2c – 5 h, 2d – 16 h, 2e – 6 h, 2f – 20 h, 3a – 9 h, mixture of ethers 2g and 3b
– 3 h. In the middle of the process more K3Fe(CN)6 (1 g, 3 mmol) was added. At the end of the process the
reaction mixture was poured into cold water (50 ml). Compounds 2a-f and 3a separated as precipitates, were
filtered off, washed with water and dried. In the remaining cases, the reaction products were extracted with
toluene (3×30 ml), the solvent was removed in vacuum to give compound 2e or a mixture of ethers 3b and 2g.
6,8-Dimethoxy-1,3,7-triazapyrene (2a). Yield 0.130 g (98%). Yellow-green crystals; mp 260-261°C
(PhMe) (mp 260-261°C (8)].
2-Methyl-6,8-dimethoxy-1,3,7-triazapyrene (2b). Yield 0.124 g (89%). Yellow-green crystals; t. subl.
> 200°C (PhMe) (t. subl. > 200°C [8]).
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6,8-Diethoxy-1,3,7-triazapyrene (2c). Yield 0.133 g (91%). Yellow-green crystals; mp 235-236°C
(PhMe) (mp 235-236°C [8]).
6,8-Dipropoxy-1,3,7-triazapyrene (2d). Yield 0.111 g (69%). Yellow-green crystals; mp 167-168°C
(PhMe) (mp 167-168°C [8]).
The spectral characteristics of compounds 2a-d correspond to those quoted in the literature [8].
6.8-Diallyloxy-1,3,7-triazapyrene (2e). Yield 0.056 g (36%). Yellow crystals; t. subl. 119-120°C
(PhMe). 1H NMR spectrum, δ, ppm (J, Hz): 5.16-5.20 (4H, m, 2OCH2); 5.37 (2H, ddd, 2J = 1.8, 3Jcis = 10.4, 4J =
1.5) and 5.58 (2H, ddd, 2J = 1.8, 3Jtrans = 17.3, 4J = 1.5, 2CH=CH2); 6.19-6.34 (2H, m, 2CH=CH2); 7.75 (2H, d,
J = 9.3, H-4,10); 8.51 (2H, d, J = 9.3, H-5,9); 9.50 (1H, s, H-2). Found, %: C 72.07; H 4.68; N 13.33.
C19H15N3O2. Calculated, %: C 71.91; H 4.76; N 13.24.
6,8-Bis(2-hydroxyethoxy)-1,3,7-triazapyrene (2f). Yield 0.111 g (67%). Yellow-green crystals; mp
1
>300°C (EtOH). H NMR spectrum, δ, ppm (J, Hz): 3.92-3.98 (4H, m, 2OCH2CH2OH); 4.74 (4H, t, J = 5.5,
2OCH2CH2OH); 4.95 (2H, t, J = 5.9, 2OH); 7.83 (2H, d, J = 9.5, H-4,10); 8.68 (2H, d, J = 9.5, H-5,9); 9.51
(1H, s, H-2). Found, %: C 62.91; H 4.88; N 12.73. C17H15N3O4. Calculated, %: C 62.76; H 4.65; N 12.92.
6,8-Diisopropoxy-1,3,7-triazapyrene (2g). Obtained as a ~1:1 mixture with compound 3b. The
combined yield of compounds 2g and 3b 0.084 g (57%). 1H NMR spectrum, δ, ppm (J, Hz): 1.56 (12H, d, J = 6.3,
2OCH(CH3)2); 5.61-5.69 (2H, m, 2OCH(CH3)2); 7.72 (2H, d, J = 9.3, H-4,10); 8.53 (2H, d, J = 9.3, H-5,9); 9.37
(1H, s, H-2). Mass spectrum, m/z (Irel, %): 321 [M+] (18); 279 [M-C3H6]+ (4); 237 [M-2C3H6]+ (100); 219 (15);
191 (15); 164 (10).
6-Methoxy-2-methyl-8-phenyl-1,3,7-triazapyrene (3a). Yield 0.111 g (67%). Yellow-green crystals;
mp 229-230°C (PhMe). 1H NMR spectrum, δ, ppm (J, Hz): 2.98 (3H, s, 2-CH3); 4.33 (3H, s, OCH3); 7.62-7.72
(3H, m, H-3,4,5 Ph); 7.88 (1H, d, J = 9.5, H-5); 7.89-7.93 (2H, m, H-2,6 Ph); 8.13 (1H, d, J = 9.1, H-9); 8.56 (1H,
d, J = 9.5, H-4); 8.80 (1H, d, J = 9.1, H-10). Mass spectrum, m/z (Irel, %): 325 [M]+ (100), 296 [M+H-CH2O]+ (40),
280 (2), 253 (5). Found, %: C 77.69; H 4.42; N 12.77. C21H15N3O. Calculated, %: C 77.52; H 4.65; N 12.91.
1
6-Isopropoxy-1,3,7-triazapyrene (3b). Obtained in a mixture with compound 2g. H NMR spectrum,
δ, ppm (J, Hz): 1.59 (6H, d, J = 6.3, OCH(CH3)2); 5.77-5.85 (1H, m, OCH(CH3)2); 7.89 (1H, d, J = 9.3, H-5);
8.11 (1H, d, J = 9.3, H-9); 8.54 (1H, d, J = 9.3, H-4); 8.76 (1H, d, J = 9.3, H-10); 9.19 (1H, s, H-8); 9.59 (1H, s,
H-2). Mass spectrum, m/z (Irel, %): 263 [M]+ (12), 221 [M-C3H6]+ (100), 192 (5), 165 (9), 139 (9).
8-Methoxy-6-oxo-6,7-dihydro-1,3,7-triazapyrene (7). A. To a refluxing solution of compound 1a
(0.103 g, 0.5 mmol) and KOH (0.500 g, 9 mmol) in 50% aqueous MeOH (30 ml), K3Fe(CN)6 (0.691 g,
4.2 mmol) was added over 1 h in equal portions. The reaction mixture was evaporated to dryness under reduced
pressure, the product was extracted from the dry residue with boiling 1-PrOH (3×20 ml), the solvent was
evaporated to 2-3 ml and diluted with EtOAc to 10-15 ml. The precipitate was filtered off, washed with EtOAc,
1
and dried. Yield 0.115 g (92%). Brown crystals; mp 215-216°C (EtOH). H NMR spectrum, δ, ppm (J, Hz):
3.96 (3H, s, OCH3); 6.88 (1H, d, J = 8.7, H-10); 8.07 (1H, d, J = 8.7, H-9); 7.07 (1H, d, J = 8.7, H-4); 8.26 (1H,
d, J = 8.7. H-5); 8.50 (1H, br. s, NH); 8.67 (1H, s, H-2). 13C NMR spectrum, δ, ppm: 52.8; 101.4; 110.9; 113.0;
114.8; 119.4; 130.5; 132.6; 133.4; 154.8; 156.1; 157.1; 163.3; 170.1. Found, %: C 66.79; H 3.72; N 16.88.
C14H9N3O2. Calculated, %: C 66.93; H 3.61; N 16.72.
B. A mixture of 6,8-dimethoxy-1,3,7-triazapyrene (2a) (0.133 g, 0.5 mmol), KOH (0.500 g, 9.0 mmol),
H2O (5 ml) and MeOH (5 ml) was refluxed for 3 h, the reaction mixture was then evaporated to dryness under
reduced pressure. Compound 7 (0.099 g, 79%) was obtained by crystallization of the dry residue from EtOH.
C. A mixture of compound 2a (0.133 g, 0.5 mmol) and NaOMe (0.540 g, 10.0 mmol) in MeOH (15 ml)
was refluxed for 5 h, diluted with water (50 ml), and acidified with HCl to pH 7, the precipitate was filtered off,
washed with water, and dried. Yield 0.119 g (95%).
6,8-Dioxo-1,6,7,8-tetrahydro-1,3,7-triazapyrene (8). A solution of one of the compounds 2a,c or 7
(0.5 mmol) in 60% H2SO4 (10 ml) was refluxed for 24 h. After cooling, the mixture was diluted with H2O
(40 ml) and neutralized with ammonia solution to pH 7. The precipitate was filtered off, washed with water, and
1531

dried. The yields were 117 mg (99%) from compound 2a and 116 mg (98%) from compounds 2c and 7. Light-
brown crystals; mp > 300°C. 1H NMR spectrum, δ, ppm (J, Hz): 6.70 (2H, d, J = 8.5, H-4,10); 7.98 (2H, d, J =
8.5, H-5,9); 8.38 (1H, s, H-2); 10.57 (1H, br. s, NH). Found, %: C 65.70; H 3.07; N 17.76. C13H7N3O2.
Calculated, %: C 65.82; H 2.97; N 17.71.
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