Arylation of 1,2,4-triazines in the presence of AlCl3

Article abstract of DOI:10.5560/ZNB.2014-4103

This paper presents a method for introducing toluene and bromobenzene moieties into 1,2,4-triazines as an alternative to cross-coupling reactions. It is demonstrated that the C=N bond of a wide range of 1,2,4-triazines undergoes addition of arenes in the presence of AlCl₃.

Full text of DOI:10.5560/ZNB.2014-4103

Arylation of 1,2,4-Triazines in the Presence of AlCl3
Ilya N. Egorov
Ural Federal University, Mira St. 19, Ekaterinburg, 620 002, Russia
Reprint requests to Dr. Ilya N. Egorov. E-mail: i.n.egorov@gmail.com
Z. Naturforsch. 2014, 69b, 899 – 905 / DOI: 10.5560/ZNB.2014-4103
Received May 15, 2014
This paper presents a method for introducing toluene and bromobenzene moieties into 1,2,4-
triazines as an alternative to cross-coupling reactions. It is demonstrated that the C=N bond of a wide
range of 1,2,4-triazines undergoes addition of arenes in the presence of AlCl3.
Key words: Arylation, 1,2,4-Triazine, Aluminum Chloride
Introduction
(e. g. phenols and anilines) into 1,2,4-triazines can
be achieved by activation of the latter with acids,
The structure of 1,2,4-triazines is analogous to which leads to the formation of triazinium cations
that of nucleobases, which encourages an ongoing and subsequent oxidation of the formed dihydro in-
search of bioactive compounds among them. Re- termediates (route A, Scheme 2) [14, 19, 20]. How-
cent publications devoted to 5,6-biaryl derivatives ever, no 5,6-biaryl derivatives have been synthesized
of 1,2,4-triazines describe them as potential adeno- via this route. Increasing the reactivity of arenes by
sine A2A receptor antagonists (anti-Parkinsonism) [1] conversion to Grignard reagents allows to perform
as well as neuroprotective [2, 3] and anti-tumor reactions with non-activated 1,2,4-triazines (route B,
agents [4, 5]. These substances are also known to in- Scheme 2) [21 – 24] and even 1,2,4-triazin-4-oxides 7
hibit thrombocyte aggregation [6] and to possess anti- (route C, Scheme 2) [25]. It is also known that in
inflammatory [7 – 9], antidepressant [10], antibacte- acidic media 1,2,4-triazin-4-oxides 7 can form adducts
rial [11], herbicidal [11], fungicidal [11, 12], and pes- with arenes bearing strongly electron-donating groups
ticidal [11, 13] properties.
(R = OR) (route D, Scheme 2) [26, 27]. The third
A general synthetic pathway towards 1,2,4-triazines possible substrates for the synthesis of 3 are halo-
3 involves condensation of 1,2-dicarbonyl compounds genated triazine derivatives 8. Studies of mono- and
1 with amidrazones 2 (Path A, Scheme 1) [14]. This diazahetarenes have demonstrated that the presence of
approach is very convenient for the synthesis of 1,2,4- a halogen atom in an azine molecule (pyridine [28],
triazines bearing identical substituents at C(5) and phthalazine [29], quinazoline [30], quinolines [30]) al-
C(6). However, for 1,2,4-triazines with different sub- lows to employ ipso-substitution reactions with arenes
stituents at these positions this method is challenging bearing various electron-donating groups in the pres-
due to the formation of mixtures of isomeric 1,2,4- ence of AlCl3 (route E, Scheme 2), or to react the
triazines from unsymmetrical 1,2-dicarbonyl com- arenes with the corresponding Grignard reagents (route
pounds (R1 = R2) (Scheme 1) [15 – 18].
F, Scheme 2) [31]. Cross-coupling reactions allow to
The current paper is devoted to the synthesis of 5,6- introduce a wide range of aryl substituents into halo-
diaryl derivatives of 1,2,4-triazines 3 with R1 = R2 genated azines (route G, Scheme 2) [32, 33]. How-
(Path B, Scheme 1). For this objective there are cur- ever, successful cross-coupling arylation (Suzuki reac-
rently four possible starting triazine substrates avail- tion) has been reported only for 6-bromo derivatives
able (Scheme 2). First, it is 1,2,4-triazine (6) with an (R = Cl, CH3, OH), at C(6) [1]. Another noteworthy
unsubstituted carbon atom. It is known that introduc- substrate for the target compounds 3 are 1,2,4-triazines
tion of arenes with strong electron-donating groups 9 bearing a CCl3 group at C(3), that undergo tele-
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I. N. Egorov · Arylation of 1,2,4-Triazines in the Presence of AlCl3
Scheme 1. Two pathways to the substituted 1,2,4-triazines.
Scheme 2 (color online). The routes for the introduction of aryl substituents into azaarenes.
substitution with OH-substituted arenes, leading to the Results and Discussion
formation of triazines 3 (route H, Scheme 2) [34].
Among the described triazine precursors to aryl-
In the current study, AlCl3-mediated reactions of
triazines 3, compounds 6 attract the highest inter- arenes with a wide range of 1,2,4-triazines not bearing
est due to the easier availability of most unsubsti- any additional good leaving groups were investigated.
tuted triazines. Recently, the arylation of 1,3,5-triazin- Most valuable are triazines bearing arene moieties with
2,4(1H,2H)-dione, which is highly reactive towards substituents that allow further modification. Thus, the
nucleophiles, has been reported. It was demonstrated possibility of introducing bromobenzene and toluene
that this compound can add benzene and its derivatives fragments into 1,2,4-triazines was studied. Reactions
with various electron-donating groups (R = CH3, Cl, of arenes with 1,2,4-triazin-3(2H)-ones 10–13 and 5,6-
Br, NMe2) in the presence of AlCl3 [35].
diphenyl-1,2,4-triazin-3(2H)-thione (14) proceed with
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I. N. Egorov · Arylation of 1,2,4-Triazines in the Presence of AlCl3
901
Studies of the reactions of triazines without C=O or
C=S groups with arenes have shown that this reaction
similarly leads generally to the formation of adducts at
C(5). The only difference was observed for the reaction
of 5,6-unsubstituted triazine 20 with toluene at room
temperature. An oxidized product 26 was obtained,
presumably due to the low stability of the formed
adduct to atmospheric oxygen. The triazine 20 is very
Scheme 3.
the formation of arene adducts at C(5) position of the susceptible to nucleophiles, and after 18 hours of re-
triazine ring with 23 – 69% yields (Scheme 3, Table 1). action it was usually not possible to obtain products of
Reactions with bromobenzene are too slow at room a nucleophilic addition because of decomposition reac-
temperature, and that is why the temperature of boil- tions (Scheme 4, Table 2). Compounds 22, 23 and 24
ing bromobenzene was used. In most cases the reac- do not react with bromobenzene neither at 25 ◦C nor at
tion conditions lead to the partial destruction of the tri- 156 ◦C.
azines under formation of complex mixtures of prod-
ucts.
1,2,4-Triazines bearing an oxo group at posi-
tion C(5), such as 3-Ph-1,2,4-triazin-5(4H)-one,
Table 1. Synthesis of 5-aryl derivatives from 1,2,4-triazin-3(2H)-ones and 1,2,4-triazin-3(2H)-thiones.
Triazine
10
R1
Ph
R2
H
X
O
Ar
p-CH3Ph
p-BrPh
T (◦C)
25
Time (h)
18
1
Product
15a
Yield (%)
57
156
–
mixture of
products
11
12
p-CH3Ph
p-BrPh
H
H
O
O
p-CH3Ph
p-BrPh
25
156
18
1
16a
16b
66
44
p-CH3Ph
p-BrPh
25
156
18
1
17a
–
63
mixture of
products
13
14
Ph
Ph
Ph
Ph
O
S
p-CH3Ph
p-BrPh
25
156
18
1
18a
–
69
no reaction
p-CH3Ph
p-BrPh
25
156
18
1
19a
–
23
decomposition
Scheme 4.
Table 2. Synthesis of 5-arylderivatives of 1,2,4-triazines.
Triazine
20
R1
H
R2
H
R3
SMe
Ar
p-CH3Ph
p-BrPh
p-CH3Ph
p-BrPh
p-CH3Ph
p-CH3Ph
p-CH3Ph
p-CH3Ph
T (◦C)
Time (h)
Product
26
27
mixture
28
29
30
31
32
Yield (%)
25
25
25
25
25
25
25
25
1
23
40
18
18
18
18
18
18
18
21
H
H
Ph
47
38
51
61
73
22
23
24
25
H
Ph
Ph
Ph
Ph
Ph
H
CH3
Ph
CH3
Ph
p-CH3Ph
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902
I. N. Egorov · Arylation of 1,2,4-Triazines in the Presence of AlCl3
Scheme 5. The proposed mechanism for the arylation of 1,2,4-triazin-3(2H)-ones.
Scheme 6. The proposed mechanism for the arylation of 1,2,4-triazines.
6-Ph-1,2,4-triazin-5(4H)-one or 6-Ph-1,2,4-triazin- 1,2,4-triazines were obtained as a result of its applica-
3,5(2H,4H)-dione appeared not to be susceptible tion.
to activation with aluminum chloride at ambient
temperature and at reflux in the corresponding arene.
Deaza analogs of 6-Ph-1,2,4-triazin-3(2H)-one,
Experimental Section
6-Ar-1,2,4-triazin-3(2H)-ones (10–12) [42], 5,6-
diphenyl-1,2,4-triazin-3(2H)-one (13) [43], 5,6-diphenyl-
1,2,4-triazine-3(2H)-thione (14) [44], 3-(methylthio)-
1,2,4-triazine (20) [45], 3-phenyl-1,2,4-triazine (21) [45],
3-methyl-5-phenyl-1,2,4-triazine (22) [17], 3,5,6-triphenyl-
1,2,4-triazine (23) [46], 3-methyl-5,6-diphenyl-1,2,4-triazine
(24) [46] and 3-phenyl-6-p-tolyl-1,2,4-triazine (25) [47]
were synthesized by known methods, other starting materials
were commercially available. Column chromatography was
performed on Merck silica gel 60. 1H and 13C NMR spectra
were recorded on a Bruker DRX-400 spectrometer; tetram-
ethylsilane (TMS) was used as an internal standard. Mass
spectra were recorded on a Bruker Daltonics MicroTOF-Q
II mass spectrometer with electrospray ionization.
5-Ph-pyrimidin-2(1H)-one and 1-Me-5-Ph-pyrimidin-
2(1H)-one, were also inert under the described
conditions.
In the presence of strong acids, the studied tri-
azines usually form triazinium cations, which can add
strong nucleophiles, such as indoles, anilines and phe-
nols [14, 19, 20]. It was demonstrated that activation
with CF3COOH is not sufficient to perform reactions
with toluene and bromobenzene. The suggestion is that
aluminum chloride in the studied process acts as a su-
peracid [36] which leads to the conversion of 1,2,4-
triazine to a dication [37 – 41] which is capable of
reacting with arenes with the formation of dihydro-
products (Schemes 5, 6).
General procedure for the synthesis of compounds 15–19a,
16b and 26–32
Conclusion
Method A. A mixture of 300 mg of triazine (1 eqv.),
anhydrous aluminum chloride (4 eqv.) and 3 mL of the
corresponding arene was stirred vigorously at room tem-
perature for 18 h. Then the reaction mixture was treated
with 10 mL of cooled water, and the water layer was de-
In the current study a convenient method for the
activation of triazines with aluminum chloride is pre-
sented, which can afford 1,2,4-triazines with different
substituents at C(5) and C(6). This method is a viable
alternative to the existing ones, and a number of novel canted. The organic layer was evaporated, and the resulting
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I. N. Egorov · Arylation of 1,2,4-Triazines in the Presence of AlCl3
903
residue was crystallized or chromatographed (see below for 8.5 Hz), 7.95 (s, 1 H, NH), 10.14 ppm (s, 1 H, NH). – 13C
details). NMR (100 MHz, [D6]DMSO): δ = 21.1, 53.5, 122.9, 127.3,
Method B. A mixture of 300 mg of triazine and anhydrous 128.1, 130.0, 132.0, 133.7, 137.9, 138.0, 142.8, 151.6 ppm.
aluminum chloride (4 eqv.) was refluxed in 3 mL of the cor- – HRMS ((+)-ESI): m/z = 344.0399 (calcd. 344.0393 for
responding arene for 1 h. For further work-up see method A. C16H15BrN3O, [M+H]+).
5-(p-Tolyl)-5,6-diphenyl-4,5-dihydro-1,2,4-triazin-
3(2H)-one (18a)
6-Ph-5-(p-Tolyl)-4,5-dihydro-1,2,4-triazin-3(2H)-one (15a)
The substance was crystallized from an EtOAc-EtOH
mixture. M. p. 270 – 272 ◦C.
–
1H NMR (400 MHz,
The substance was crystallized from an EtOAc-EtOH
mixture. M. p. 261 – 262 ◦C.
–
1H NMR (400 MHz,
[D6]DMSO): δ = 2.23 (s, 3 H, CH3), 5.66 (d, 1 H, J =
3.15 Hz, C(5)H), 7.13 (d, 2 H, J = 8.1 Hz, p-Tol), 7.19 (d,
2 H, J = 8.1 Hz, p-Tol), 7.30 – 7.37 (m, 3 H, Ph), 7.69 – 7.71
(m, 2 H, Ph), 7.98 (s, 1 H, NH), 10.23 ppm (d, 1 H, J =
1.9 Hz, NH). – 13C NMR (100 MHz, [D6]DMSO): δ = 21.1,
53.6, 126.1, 127.4, 129.0, 129.5, 129.9, 134.5, 137.8, 138.1,
143.8, 151.9 ppm. – HRMS ((+)-ESI): m/z = 266.1282
(calcd. 266.1288 for C16H16N3O, [M+H]+).
[D6]DMSO): δ = 2.33 (s, 3 H, CH3), 7.01 – 7.21 (m, 9 H),
7.21 – 7.34 (m, 5 H), 8.31 (s, 1 H, NH), 10.21 ppm (s, 1
H, NH). – 13C NMR (100 MHz, [D6]DMSO): δ = 19.6,
66.1, 127.1, 127.8, 127.9, 128.2, 128.4, 128.5, 128.5, 128.6,
135.6, 137.9, 138.3, 141.5, 149.1, 154.1 ppm. – HRMS ((+)-
ESI): m/z = 342.1606 (calcd. 342.1601 for C22H20N3O,
[M+H]+).
5-(p-Tolyl)-5,6-diphenyl-4,5-dihydro-1,2,4-triazine-
3(2H)-thione (19a)
5,6-Di-(p-tolyl)-4,5-dihydro-1,2,4-triazin-3(2H)-one (16a)
The substance was crystallized from an EtOAc-EtOH
The substance was crystallized from EtOH. M. p.
239 – 240 ◦C. – 1H NMR (400 MHz, [D6]DMSO): δ = 2.33
(s, 3 H), 7.03 – 7.24 (m, 9 H), 7.24 – 7.35 (m, 5 H), 9.94
(d, 1 H, J = 1.4 Hz, NH), 11.54 ppm (d, 1 H, J = 1.5 Hz,
NH). – 13C NMR (100 MHz, [D6]DMSO): δ = 21.1, 64.6,
128.1, 128.5, 128.6, 129.0, 129.1, 129.2, 129.3, 135.5, 137.9,
138.3, 141.5, 148.5, 172.4 ppm. – HRMS ((+)-ESI): m/z =
358.1370 (calcd. 358.1372 for C22H20N3S, [M+H]+).
mixture. M. p. 260 – 261 ◦C.
–
1H NMR (400 MHz,
[D6]DMSO): δ = 2.28 (s, 3 H, CH3), 2.30 (s, 3 H, CH3),
5.50 (d, 1 H, J = 3.1 Hz, C(5)H), 7.08 – 7.10 (m, 4 H), 7.17
(d, 2 H, J = 8.0 Hz), 7.54 (d, 2 H, J = 8.1 Hz), 7.80 (s, 1
H, NH), 9.95 ppm (d, 1 H, J = 1.6 Hz, NH). – 13C NMR
(100 MHz, [D6]DMSO): δ = 21.1, 21.2, 53.6, 126.1, 127.3,
129.6, 129.9, 131.8, 137.8, 138.2, 139.2, 143.8, 152.0 ppm.
– HRMS ((+)-ESI): m/z = 280.1449 (calcd. 280.1444 for
C17H18N3O, [M+H]+).
3-(Methylthio)-5-p-tolyl-1,2,4-triazine (26)
5-(4-Bromophenyl)-6-(p-tolyl)-4,5-dihydro-1,2,4-triazin-
3(2H)-one (16b)
The substance was chromatographed with EtOAc-DCM
(1 : 1) as eluent. M. p. 146 – 148 ◦C. – Rf = 0.6. – 1H NMR
(400 MHz, CDCl3): δ = 2.44 (s, 3 H, CH3), 2.72 (s, 3 H,
SCH3), 7.34 (d, 2 H, J = 8.0 Hz, p-Tol), 8.05 (d, 2 H,
J = 8.2 Hz, p-Tol), 9.33 ppm (s, 1 H, NH). – 13C NMR
(100 MHz, [D6]DMSO): δ = 13.9, 21.7, 127.6, 130.1, 130.3,
141.8, 143.6, 154.5, 173.6 ppm. – HRMS ((+)-ESI): m/z =
218.0758 (calcd. 218.0746 for C11H12N3S, [M+H]+).
The substance was crystallized from an EtOAc-EtOH
mixture. M. p. 240 – 241 ◦C.
–
1H NMR (400 MHz,
[D6]DMSO): δ = 2.28 (s, 3 H, CH3), 5.68 (d, 1 H, J =
3.0 Hz, C(5)H), 7.16 (d, 2 H, J = 8.0 Hz), 7.22 – 7.42 (m,
4 H), 7.61 (d, 2 H, J = 8.1 Hz), 7.95 (s, 1 H, NH), 10.14 ppm
(s, 1 H, NH). – 13C NMR (100 MHz, [D6]DMSO): δ = 21.1,
54.3, 126.1, 127.4, 128.4, 129.3, 129.5, 132.0, 139.2, 141.1,
144.0, 151.9 ppm. – HRMS ((+)-ESI): m/z = 344.0389
(calcd. 344.0393 for C16H15BrN3O, [M+H]+).
5-(4-Bromophenyl)-3-(methylthio)-4,5-dihydro-
1,2,4-triazine (27)
The substance was crystallized from
a CH3CN-
(CH3)2CHOH mixture. M. p. 185 – 186 ◦C. – 1H NMR
(400 MHz, [D6]DMSO): δ = 2.76 (s, 3 H, SCH3), 5.43 (d,
1 H, J = 2.4 Hz, C(5)H), 7.36 (d, 2 H, J = 8.0 Hz), 7.56
6-(4-Bromophenyl)-5-(p-tolyl)-4,5-dihydro-1,2,4-triazin-
3(2H)-one (17a)
The substance was crystallized from an EtOAc-EtOH (d, 1 H, J = 2.4 Hz), 7.68 (d, 2 H, J = 8.0 Hz), 12.94 ppm
mixture. M. p. 261 – 262 ◦C. 1H NMR (400 MHz, (br.s, 1H). – 13C NMR (100 MHz, [D6]DMSO): δ = 13.7,
–
[D6]DMSO): δ = 2.28 (s, 3 H, CH3), 5.54 (d, 1 H, J = 50.9, 122.2, 129.1, 132.0, 136.3, 144.4, 160.4 ppm. –
2.9 Hz, C(5)H), 7.09 (d, 2 H, J = 7.8 Hz), 7.17 (d, 2 H, HRMS ((+)-ESI): m/z = 283.9846 (calcd. 283.9852 for
J = 7.9 Hz), 7.43 (d, 2 H, J = 8.5 Hz), 7.59 (d, 2 H, J = C10H11BrN3S, [M+H]+).
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I. N. Egorov · Arylation of 1,2,4-Triazines in the Presence of AlCl3
5-(4-Bromophenyl)-3-Ph-4,5-dihydro-1,2,4-triazine (28)
(100 MHz, [D6]DMSO): δ = 21.1, 64.0, 128.5, 129.1, 129.4,
129.5, 129.8, 129.9, 130.5, 130.8, 133.8, 135.2, 135.3, 139.0,
The substance was crystallized from CH3CN. M. p.
185 – 186 ◦C. – 1H NMR (400 MHz, [D6]DMSO): δ = 5.63
(d, 1 H, J = 3.0 Hz, C(5)H), 7.47 (m, 2 H), 7.65 – 7.73
(m, 4 H), 7.79 – 7.83 (m, 1 H), 7.95 – 7.99 (m, 2 H), 12.16
(br.s, 1 H), 13.54 ppm (br.s, 1 H). – 13C NMR (100 MHz,
[D6]DMSO): δ = 50.3, 123.1, 125.0, 129.5, 129.6, 130.1,
132.7, 135.2, 137.3, 145.9, 154.6 ppm. – HRMS ((+)-
ESI): m/z = 314.0293 (calcd. 314.0287 for C15H13BrN3,
[M+H]+).
153.3 ppm. – HRMS ((+)-ESI): m/z = 402.1956 (calcd.
402.1965 for C28H24N3, [M+H]+).
3-Methyl-5,6-diphenyl-5-(p-tolyl)-4,5-dihydro-1,2,4-triazine
(31)
The substance was crystallized from an EtOH-EtOAc
mixture. M. p. 236 ◦C. – 1H NMR (400 MHz, [D6]DMSO):
δ = 2.35 (s, 3 H), 2.44 (s, 3 H), 7.14 – 7.21 (m, 4 H),
7.25 – 7.29 (m, 5 H), 7.35 – 7.40 (m, 5 H), 12.42 ppm (s, 1
H). – 13C NMR (100 MHz, [D6]DMSO): δ = 16.1, 21.0,
63.5, 128.4, 129.0, 129.1, 129.2, 129.3, 129.7, 130.5, 134.1,
137.1, 138.9, 140.2, 150.6, 155.3 ppm. – HRMS ((+)-ESI):
m/z = 340.1795 (calcd. 340.1808 for C23H22N3, [M+H]+).
3-Me-5-Ph-5-(p-tolyl)-4,5-dihydro-1,2,4-triazine (29)
The substance was chromatographed with EtOAc-DCM
(1 : 1) as eluent. M. p. 130 – 131 ◦C. – Rf = 0.5. – 1H NMR
(400 MHz, [D6]DMSO): δ = 2.32 (s, 3 H, CH3), 2.44 (s,
3 H, CH3), 7.09 – 7.14 (m, 5 H), 7.23 – 7. ppm m, 5 H). –
13C NMR (100 MHz, [D6]DMSO): δ = 16.3, 21.1, 60.3,
127.3 (2C), 128.8, 129.0, 129.8, 137.7, 138.9, 140.7, 145.2,
154.8 ppm. – HRMS ((+)-ESI): m/z = 264.1495 (calcd.
264.1495 for C17H18N3, [M+H]+).
3-Phenyl-5,6-di(p-tolyl)-4,5-dihydro-1,2,4-triazine (32)
The substance was crystallized from a large amount of
1
acetone. M. p. 239 ◦C. – H NMR (400 MHz, [D6]DMSO):
δ = 2.31 (s, 3 H), 2.38 (s, 3 H), 6.19 (s, 1 H, C(5)H), 7.20
(d, 2 H, J = 7.8 Hz), 7.25 (d, 2 H, J = 8.0 Hz), 7.38 (d,
2 H, J = 7.8 Hz), 7.60 – 7.64 (m, 2 H), 7.74 – 7.78 (m, 1
H), 7.81 (d, 2 H, J = 8.0 Hz), 8.02 (d, 2 H, J = 7.8 Hz),
12.87 (br.s, 1 H, NH), 13.80 (br.s, 1 H, NH). – 13C NMR
3,5,6-Triphenyl-5-(p-tolyl)-4,5-dihydro-1,2,4-triazine (30)
The substance was crystallized from EtOH. M. p.
185 – 186 ◦C. – 1H NMR (400 MHz, [D6]DMSO): δ = 2.35 (100 MHz, [D6]DMSO): δ = 20.6, 20.9, 49.4, 124.2, 127.0,
(s, 3 H, CH3), 7.18 – 7.23 (m, 4 H), 7.28 – 7.42 (m, 9 H), 127.3, 128.8, 129.0, 129.2, 129.5, 129.9, 134.6, 134.6, 138.9,
7.59 – 7.63 (m, 2 H), 7.74 – 7.78 (m, 1 H), 8.02 – 8.04 (m, 141.9, 150.0, 152.4. – HRMS ((+)-ESI): m/z = 340.1811
2 H), 12.23 (s, 1 H), 14.50 ppm (br.s, 1 H). – 13C NMR (calcd. 340.1808 for C23H22N3, [M+H]+).
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