Bromination of substituted 5H-imidazo[1,2-b]-1,2,4-triazepin-4-ones and -thiones

Article abstract of DOI:10.1023/A:1017664207584

The reactions of substituted 5H-imidazo[1,2-b]-1,2,4-triazepin-4-ones and -thiones with bromine and N-bromosuccinimide have been studied. Derivatives of 3- and 8-bromo-, 3,8-dibromoimidazo[1,2-b]-1,2,4-triazepine and 5H-2-bromomethyl-3-methyl-7,8-diphenyl

Full text of DOI:10.1023/A:1017664207584

Chemistry of Heterocyclic Compounds, Vol. 37, No. 4, 2001
BROMINATION OF SUBSTITUTED
b
5H-IMIDAZO[1,2- ]-1,2,4-TRIAZEPIN-
4-ONES AND -THIONES
V. P. Kruglenko
The reactions of substituted 5H-imidazo[1,2-b]-1,2,4-triazepin-4-ones and -thiones with bromine and
N-bromosuccinimide have been studied. Derivatives of 3- and 8-bromo-, 3,8-dibromoimidazo[1,2-b]-
1,2,4-triazepine and 5H-2-bromomethyl-3-methyl-7,8-diphenylimidazo[1,2-b]-1,2,4-triazepin-4-one are
formed, depending on the degree of substitution, the nature of the brominating agent, and the reaction
conditions.
Keywords: 5H-imidazo[1,2-b]-1,2,4-triazepineone and -thione, bromination.
In a continuation of the reactivity studies of derivatives of imidazo[1,2-b]-1,2,4-triazepines [1-3], the
reactions of di-, tri- and tetra-substituted 5H-imidazo[1,2-b]-1,2,4-triazepine-4-one(thione) 1-4 with bromine and
N-bromosuccinimide (NBS) have been studied. The direction of the bromination of monophenyl-substituted
compound 1 was found to depend on the nature of the brominating agent, the solvent, the ratio of the reagents,
and temperature. Only 8-bromoimidazotriazepine 5 (Table 1) was isolated when equimolar amounts of
compound 1 and NBS were heated in carbon tetrachloride to 60°C. The signal of the 8-H proton is absent from
1
the H NMR spectrum of compound 5 but the signals of the imine, methylene, methyl, and phenyl protons
appear as in the spectrum of starting material 1 at 11.62 (1H, s, NH), 3.64 (2H, s, CH2), 2.28 (3H, s, CH3) and
7.73 (5H, m, H arom.) respectively.
Me
X
CH2Br
Me
Me
O
N
N
N
R
Ph
Ph
Br
Ph
N
N
N
R1
Ph
N
N
N
N
H
N
H
N
H
O
1–4
9
5
Me
Me
N
N
Br
Ph
Ph
Ph
N
N
Br
Br
N
N
N
H
N
H
O
X
6
7, 8
1 R = R1 = H; 2, 3 R = Ph, R1 = H; 4 R = Ph, R1 = Me; 1, 2, 4, 7 X = O; 3, 8 X = S
__________________________________________________________________________________________
Kherson State Technical University, Kherson 325008, Ukraine; e-mail: lvi@tic.kherson.ua Translated
from Khimiya Geterotsiklicheskikh Soedinenii, No. 4, 548-551, April 2001. Original article submitted
March 18, 1999.
500
0009-3122/01/3704-0500$25.00©2001 Plenum Publishing Corporation

The mass spectrum of compound 5 contains two molecular ion peaks of equal intensity which indicates
the presence of a single bromine atom in the molecule. Fragmentation of M+ is typical of imidazotriazepinones
– Φ and [Φ - CHCO]+ – Φ
[2-4] and includes the processes [M - CH3CN]+
the ions Φ – Φ2
2. The absence of the bromine atom in
[PhC===CBr]+
together with the formation of the charged fragments
and [PhC C-Br]+ with
≡
NH
m/z 196, 194 and 182, 180 confirms the presence of the bromine atom at C(8).
The selectivity of the process decreased when the reaction temperature was raised to 80°C, both
8-bromo- and 3,8-dibromo-substituted compounds 5 and 6 being formed, with the yield of 8-bromo derivative
predominating (Table 1). Doubling the quantity of NBS changed the proportions of the products in favor of
3,8-dibromo-substituted compound 6, while replacing of CCl4 by benzene completely excluded the formation of
8-bromoimidazotriazepine 5.
Reaction of compound 1 with bromine in acetic acid at room temperature led to predominant formation
of 3,8-dibromo derivative 6, while bromination in DMF at heating gave only 8-bromoimidazotriazepine 5
(Table 1).
1
The H NMR spectrum of 3,8-dibromoimidazotriazepine 6, like that of its monosubstituted analog 5,
contained signals for protons of the imino, methyl, and phenyl groups at 12.02, 2.43, and 7.60 ppm respectively,
but in place of the signals of the protons of the methylene group a singlet for the proton of the methyne group
appeared at 5.74 ppm. This shows that the second bromine atom is at C(3) in the bicyclic molecule 6. The
direction of bromination of compound 2, in which there is phenyl substituent at C(8), does not depend on the
nature of the brominating agent, the solvent, or the reaction temperature, but proceeds with formation of the
3-bromoimidazotriazepineone 7 [1].
Reaction of thione 3 with bromine in acetic acid at 20-25°C or with NBS in boiling CCl4 gave
5H-3-bromo-2-methyl-7,8-diphenylimidazo[1,2-b]-1,2,4-triazepin-4-thione (8). The same compound was
obtained from the reaction of bromoimidazotriazepine 7 with P2S5 in boiling pyridine.
The following signals appeared in the 1H NMR spectrum of compound 8: 11.78 (1H, s, NH); 5.63 (1H,
s, CH); 2.34 (3H, s, CH3); 7.81 ppm (10H, m, H arom.).
The bromination of the bicyclic compound 4, in which the reactive positions 3 and 8 are blocked by
methyl and phenyl substituents, occurs quite differently. When compound 4 was boiled with NBS in CCl4
5H-2-bromomethyl-3-methyl-7,8-diphenylimidazo[1,2-b]-1,2,4-triazepin-4-one (9) was obtained.
TABLE 1. Conditions and Results of Bromination of Compound 1
Brominating agent
(proportions of starting
materials, mol)
Reaction
temperature,
°C
Yield of products, %
Reaction
time, h
Method
Solvent
5
6
A
B
C
D
E
F
G
H
I
NBS (1 : 1)
NBS (1 : 1)
NBS (1 : 1)
NBS (1 : 2)
NBS (1 : 2)
Br2 (1 : 2)
Br2 (1 : 1)
Br2 (1 : 2)
Br2 (1 : 3)
CCl4
CCl4
Benzene
CCl4
Benzene
CH3COOH
DMF
55-60
80
4
3
3
4
4
5
4
4
4
63*
35*
42*
8
—
12
—
—
—
—
10
8
41
55
42
32*
52
58
80
80
80
20-25
65-70
65-70
65-70
DMF
DMF
_______
* Starting material 1 was also isolated from the reaction mixture: 20 (A),
15 (B), 8 (C), and 10% (G).
501

TABLE 2. Characteristics of the Compounds Synthesized
Found, %
——————
Com-
Empirical
Yield, %
(method)
mp, °C
Rf
Calculated, %
pound formula
C
H
Br
N
5*
6
C13H11BrN4O
48.69
48.64
4.12
4.04
25.10
24.89
17.70
17.45
194-195
178-180
0.62
0.69
0.63
63 (A)
58 (I)
C13H10Br2N4O
C19H15BrN4O
38.96
2.41
40.25
14.21
39.23
57.83
57.74
2.53
4.02
3.83
40.15
20.39
20.22
14.07
13.95
14.17
221-222*2
88 (A)
79 (B)
7
C19H15BrN4O
55.78
3.72
19.56
13.89
236-237
0.53
60 (A)
48 (B)
50 (C)
8
55.48
3.68
19.43
13.62
C20H17BrN4O
58.81
58.69
4.33
4.19
19.72
19.52
13.79
13.69
207-208
0.66
42
9
_______
* Compound 5 was crystallized from methanol, 6 from propanol-2, 7 and 8
from acetic acid, and 9 from 2-methylpropanol-1.
*2 Lit. m.p. 220-222°C [1].
The mass spectrum of compound 9 contains M+ peaks with m/z 410 and 408 (1:1 intensity ratio) which,
along with peaks for the ions [M - Br]+, [Br]+, and [HBr]+ with m/z 329, 81 and 79, 82 and 80, indicates the
presence of a single bromine atom in the molecule. The presence of a signal for the ion [M - BrCH2CN]+ with
m/z 289 in the mass spectrum of compound 9, and the absence of a peak for the ion [M - CH3CN]+ in the case of
compounds with unsubstituted methyl group at C(2) [2, 3], is direct confirmation of its structure as
2-bromomethyl-substituted imidazotriazepineone 9.
EXPERIMENTAL
1H NMR spectra of DMSO-d6 solutions with TMS as internal standard were recorded with a Bruker
WH-90 apparatus. Mass spectra were recorded with a Varian MAT 311A instrument under standard conditions.
Purity of the compounds prepared was monitored by TLC on Silufol strips with solvent system of 2:1
toluene–propanol-2. Column chromatography was carried out with column (40 × 2.5 cm) filled with L 100/160
silica gel and using 2:1 toluene–propanol-2 as eluent. Results of bromination of compound 1 are given in
Table 1 and the characteristics of compounds 5-9 – in Table 2.
b
NBS
Bromination of 5H-2-Methyl-7-phenylimidazo[1,2- ]-1,2,4-triazepin-4-one (1). Methods A-E.
(2 or 4 mmol) was added to solution of triazepine 1 (0.48 g, 2 mmol) in an organic solvent (10-15 ml) and the
mixture was heated. After cooling the precipitate of compound 5 was filtered off, washed with ether, and dried.
In reactions using methods B-D the precipitate was chromatographed on a column. Bromoimidazotriazepine 5
was obtained from the first colorless fraction with Rf 0.62 after removal of the solvent, recrystallization and
drying. Dibromide 6 was obtained from the second yellow fraction after removal of the solvent, recrystallization
and drying. From the synthesis by method E the precipitate of compound 6 obtained after cooling the mixture
was filtered off, washed with ether and dried.
Methods F-I. Mixture of compound 1 (1.2 g, 5 mmol) and bromine (5, 10, or 15 mmol) was heated in
an organic solvent (10 ml) or kept in acetic acid (10 ml) at room temperature. Treatment was as in method E. In
the case of method F, the reaction mixture was poured into water (50 ml), neutralized with sodium acetate, the
precipitate of compounds 5 and 6 was filtered off, washed with water, dried, and chromatographed as described
for methods B-D. Mass spectrum of compound 5, m/z (Irel, %): M+
320 (26), 318 (27); Φ – 279 (16), 277 (15);
502

Φ – 251 (12), 249 (12); 240 (17), 239 (14); Φ2
– 238 (4), 236 (13), 196 (11), 194 (12), 182 (10), 180 (9),
161 (20), 149 (14), 144 (10), 136 (15), 129 (30), 117 (14), 104 (50), 103 (16), 102 (12), 89 (13), 88 (99),
87 (13), 77 (27), 58 (100).
b
Bromine (0.48 g,
5H-3-Bromo-2-methyl-7,8-diphenylimidazo[1,2- ]-1,2,4-triazepin-4-one (7). A.
3 mmol) was added in three portions to solution of compound 2 (0.64 g, 2 mmol) in acetic acid (5 ml) at 25°C.
The solution was stirred for 1 h at 40°C, then poured into water (100 ml). The yellow precipitate was filtered
off, washed with water and dried.
B. Solution of compound 2 (0.64 g, 2 mmol) and NBS (0.36 g, 2 mmol) in carbon tetrachloride (10 ml)
was boiled for 10 h. After cooling, the precipitate of compound 7 was filtered off, washed with ether, and dried.
b
Solution of
5H-3-Bromo-2-methyl-7,8-diphenylimidazo[1,2- ]-1,2,4-triazepin-4-thione (8). A.
bromine (0.4 g, 2.5 mmol) in acetic acid (5 ml) was added dropwise to solution of thione 3 [2] (0.66 g, 2 mmol)
in acetic acid (10 ml) and the mixture was stirred for 1 h at 20-22°C. The precipitate which formed was filtered
off, washed with acetone, and dried.
B. Mixture of compound 3 (0.33 g 1 mmol), NBS (0.36 g, 2 mmol), and CCl4 (10 ml) was boiled for 4 h.
After cooling the precipitate was filtered off, washed with ether, and dried.
C. Mixture of compound 7 (0.4 g, 1 mmol), P2S5 (0.34 g, 1.5 mmol) and anhydrous pyridine (10 ml) was
boiled for 3 h. The reaction mixture was cooled, the precipitate was filtered off, washed with ethanol, and dried.
b
NBS (0.36 g,
5H-2-Bromomethyl-3-methyl-7,8-diphenylimidazo[1,2- ]-1,2,4-triazepin-4-one (9).
2 mmol) was added to solution of imidazotriazepineone 4 (0.66 g, 2 mmol) in CCl4 (15 ml) and the mixture was
boiled for 8 h. The reaction mixture was cooled, the precipitate was filtered off, washed with ether, and dried.
Mass spectrum, m/z (Irel, %): M+ 410 (4), 408 (13); 329 (27), 289 (25), 261 (10), 260 (12), 234 (37), 219 (7),
218 (6), 193 (53), 178 (14), 136 (48), 82 (96), 81 (34), 80 (100), 79 (36), 77 (33).
REFERENCES
1.
2.
3.
V. P. Kruglenko, N. S. Patalakha, P. V. Kurapov, N. A. Klyuev, V. A. Idzikovskii, I. I. Grandberg, and
M. V. Povstyanoi, Khim. Geterotsikl. Soedin., 694 (1985).
V. P. Kruglenko, V. A. Idzikovskii, N. A. Klyuev, and M. V. Povstyanoi, Khim. Geterotsikl. Soedin.,
386 (1988).
V. P. Kruglenko, V. A. Idzikovskii, N. N. Kobets, and M. V. Povstyanoi, Khim. Geterotsikl. Soedin.,
234 (1990).
503