Synthesis and reactions of 1,6-dibenzoyl-5H,10H-diimidazo-[1,5-a;1′,5′-d]-pyrazine-5,10- dione

Article abstract of DOI:10.1023/A:1023784811891

5,10-Dioxo-5H,10H-diimidazo[1,5-a;1′,5′-d]pyrazine-5,10- dicarboxylic acid dichloride in Friedel-Crafts reaction conditions formed with benzene the corresponding 1,6-dibenzoyl derivative 2, which reacted with alcohols and amines to give the keto esters and keto amides of 4(5)-benzoylimidazol-5(4)-carboxylic acids. The reaction of compound 2 with hydrazine gave substituted imidazo[4,5-f]pyridazine, and with o-phenylenediamine gave a derivative of imidazo[4,5-f]-1,4-benzodiazocine - a new heterocyclic system.

Full text of DOI:10.1023/A:1023784811891

Chemistry of Heterocyclic Compounds, Vol. 39, No. 2, 2003
SYNTHESIS AND REACTIONS OF
1,6-DIBENZOYL-5H,10H-DIIMIDAZO-
a
d
[1,5- ;1',5'- ]-PYRAZINE-5,10-DIONE
Yu. E. Ivanov, A. A. Yavolovsky, A. V. Mazepa, and S. P. Krasnoshchekaya
5,10-Dioxo-5H,10H-diimidazo[1,5-a;1',5'-d]pyrazine-5,10-dicarboxylic acid dichloride in Friedel–
2
Crafts reaction conditions formed with benzene the corresponding 1,6-dibenzoyl derivative , which
reacted with alcohols and amines to give the keto esters and keto amides of 4(5)-benzoylimidazol-5(4)-
2
carboxylic acids. The reaction of compound with hydrazine gave substituted imidazo[4,5-f]pyridazine,
and with o-phenylenediamine gave a derivative of imidazo[4,5-f]-1,4-benzodiazocine – a new
heterocyclic system.
Keywords: imidazo[4,5-f]-1,4-benzodiazocine, imidazo[4,5-d]pyridazine, keto amides, keto esters,
acylation.
5,10-Dioxo-5H-10H-diimidazo[1,5-a;1', 5'-d]pyrazinedicarbonyl-1,6-dichloride (1) has found a wide use
in organic synthesis for the preparation of mono- and diesters, mono- and diamides, mixed esters and diamides
of imidazole-4,5-dicarboxylic acids [1-4].
The possibility of using the acid dichloride 1 in the Friedel–Krafts acylation has not been studied
previously.
Compound 1 interacted with benzene in AlCl3–PhNO2 to give diketone 2 and keto acid 3 after steam
distillation of the organic solvent. In all likelihood compound 3 is formed by hydrolysis of diketone 2 under the
isolation conditions.
Compound 3 is readily converted to compound 2 by boiling in SOCl2–DMF.
O
O
N
Ph
O
N
Cl
O
Ph
N
O
N
O
+
PhH
O
OH
H2O, H
N
N
N
O
Ph
O
Cl
AlCl3, PhNO2
N
H
N
N
O
SOCl2
DMF
2
1
3
__________________________________________________________________________________________
A. V. Bogatsky Physico-Chemical Institute, National Academy of Sciences of Ukraine, Odessa 65080,
Ukraine; e-mail: ivanov.u@raso.net. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No.2, 281-286,
February, 2003. Original article submitted December 20, 2000.
250
0009-3122/03/3902-0250$25.00©2003 Plenum Publishing Corporation

The increased susceptibility of compounds of type 2, compared with trivial amides, to nucleophiles has
been discussed previously [5, 6].
Like other compounds of this class compound 2 is smoothly split by sodium methoxide or methanol in
the presence of Et3N, ammonia, or amines to give the corresponding keto esters 4 and keto amides 5-9 and 11.
The previously undescribed imidazo[4,5-d]pyridazine 10 was obtained by treatment of compound 2 with
hydrazine hydrate in methanol. The independent synthesis of compound 10 was carried out by the reaction of
keto ester 4 with hydrazine hydrate in boiling methanol.
Ph
Ph
o-C6H4(NH2)2
N
O
NH
N
O
OMe
CHCl3
2
NH2
N
H
N
H
O
O
11
o-C6H4(NH2)2
DMF, t, oC
4
N2H4
RNH2
p-C6H4Me2
N2H4
p-TsOH, t, oC
Ph
Ph
Ph
O
N
N
N
NH
N
O
NHR
N
N
H
N
H
N
H
H
O
O
10
12
5–9
N
5 R = H, 6 R = Me, 7 R = Ph, 8 R = Bn, 9 R =
Reaction of diketone 2 with o-phenylenediamine in chloroform gave keto amide 11, which on heating in
p-xylene in the presence of a catalytic amount of p-toluenesulfonic acid was converted into 11-phenyl-4,5-
dihydro-1H-benzo[b]imidazo[4,5-f][1,4]diazocin-4-one 12, which was also obtained by independent synthesis
by boiling a mixture of compound 2 with o-phenylenediamine in anhydrous DMF. It should be noted that there
is only one paper reporting the direct conversion of structure of type 2 into annelated cyclic systems [7].
As can be seen from Table 2, the mass spectra of compounds 4-12 contain intense molecular ion peaks.
The primary fragmentation processes for compounds 4-6 begin with the loss of amide or ester groups, which
leads to a series of even-electron fragment ions [M-R]+, [M-XR]+ (m/z 199), and [M-COXR]+ (m/z = 171). Apart
from the noted general directions of fragmentation, the mass spectrum of each compound has its own
characteristics. Comparison of the mass spectra of ester 4 and amides 5 and 6 shows that the last two are more
stable to the electron impact, which is characteristic of amides. Thus the molecular ion peak for compound 4 is
6.8% of the total ion current, whereas for compounds 5 and 6 this value is 16.2 and 15.4% respectively. In the
mass spectrum of methylamide 6, along with formation of the [M-XR]+ ions, the elimination of the fragment
NH=CH2 was observed, leading to the formation of ions with m/z 200.
For compounds 8 and 9 two basic directions of fragmentation are observed:
+
.
O
O
+
N
N
+
Ph
XR
Ph
<
A
HXR
O
N
H
N
H
C
O
m/z 199
X = NH, O
251

TABLE 1. Physicochemical Characteristics for Compounds 2-12
Found, %
——————
Com-
Empirical
dormula
Yield, %
(method)
Calculated, %
mp, °С
IR spectrum, , cm-1
ν
pound
C
H
N
C22H12N4O4
66.67
66.80
3.05
3.12
14.14
14.19
>300
205-206
200
2950, 2870, 1720, 1615, 1570, 1450, 1380 (vaseline oil)
68 (A)
92 (B)
2
C11H8N2O3
C12H10N2O3
C11H9N3O2
C12H11N3O2
C17H13N3O2
C18H15N3O2
C16H12N4O2
C11H8N4O
61.11
3.73
12.96
3050, 2850, 1710, 1660, 1415, 1190, 1160, 1070, 920
(vaseline oil)
3
80
82
87
78
72
74
43
94
62
60.70
3.59
13.3
62.61
62.70
4.38
4.31
12.17
12.07
2985, 2785, 1705, 1657, 1470, 1430, 1340, 1186, 1157, 1070, 900
4
(vaseline oil)
61.39
4.22
19.52
>300
2985, 1665, 1625, 1600, 1565, 1465, 1450, 1410, 1360, 1335,
1300, 1125, 925 (CHCl3)
5
61.27
4.16
19.60
62.87
62.95
4.84
4.91
18.33
18.23
137-138
232
2990, 1660, 1630, 1605, 1565, 1470, 1455, 1415, 1360, 1340,
6
1300, 1130, 925 (CHCl3)
70.09
4.50
14.42
2990, 2980, 2910, 1660, 1625, 1590, 1560, 1480, 1345, 1325,
1300, 1110, 910 (CHCl3)
7
70.20
4.61
14.36
70.81
70.67
4.95
5.02
13.76
13.98
142-143
232-233
>300
3050, 2980, 2910, 1640, 1565, 1480, 1360, 1350, 1310, 1300,
8
1140, 1110, 895 (CHCl3)
65.75
4.14
19.17
2950, 2880, 1780, 1640, 1440, 1365, 1270, 1125, 765
(vaseline oil)
9
65.79
4.27
19.07
62.26
62.37
3.80
3.91
26.40
26.29
3300, 3100, 2825, 2330, 1690, 1580, 1525, 1400, 1120, 1080,
10
11
12
800, 680 (vaseline oil)
C17H14N4O2
C17H12N4O
66.66
4.61
18.29
201-202
206-208
3010, 3000, 1650, 1600, 1560, 1480, 1350, 1320, 1300, 910
(CHCl3)
66.54
4.69
18.14
70.82
70.73
4.20
4.32
19.43
19.58
3050, 2985, 1625, 1590, 1560, 1490, 1465, 1400, 1300, 1275,
72 (A)
23 (B)
1165, 910, 900, (CHCl3)

TABLE 1. Mass-spectral Characteristics of Compounds 4-12
Compound
M+
m/z (I, %)
230
230 (50), 216 (23), 199 (37), 171 (71), 153 (33), 144 (26), 121 (38),
105 (56), 77 (100)
4
215
229
291
305
292
212
306
288
215 (100), 199 (22),186 (38), 171 (47), 120 (30), 105 (31), 77 (54)
229 (100), 200 (93), 171 (30), 144 (30), 105 (33), 77 (48)
291 (50), 200 (29), 105 (6), 93 (100), 77 (10)
305 (35), 199 (24), 171 (7), 145 (19), 106 (100), 91 (22), 77 (29)
292 (7), 199 (15), 187 (100), 159 (6) 105 (17), 94 (38), 77 (22)
212 (100), 195 (6), 128 (13), 69 (8)
5
6
7
8
9
10
11
12
306 (32), 289 (31), 259 (100), 199 (12), 122 (20), 105 (76), 77 (65)
288 (53), 259 (100), 144 (10), 91 (7), 77 (13)
According to the scheme, both directions occur via breakage of the amide bond, but in direction A the
charge is localized in the imidazole part of the molecule, giving rise to ions with m/z 199. Direction B is
probably due to migration of the imidazole fragment hydrogen atom, as a result of which stable aromatic amide
ions are formed, the peaks of which are maximal in the mass spectra of these compounds.
In the case of compound 7 directions A and B are accompanied by migration of hydrogen atom to the
imidazole fragment, analogous to that observed with compound 6, which leads to the formation of ions with
m/z 200 and 106. The structure of the latter probably corresponds to that of the benzylimine ion, which explains
its high stability.
Imidazo[4,5-d]pyridazine 10 is highly stable in the electron beam. The first decomposition process,
which occurs to a negligible extent, is probably explained by lactam-lactim tautomerism and is assigned to
formation of the [M-OH]+ ions:
+
+
.
Ph
Ph
Ph
.
N
N
N
N
NH
N
N
N
N
+
N
H
N
H
N
H
O
OH
m/z 195
Fragmentation of compound 12 occurs via opening of the eight-membered ring and elimination of
formyl radical.
Physicochemical characteristics of the compounds synthesised are given in Tables 1 and 2. The
composition and purity of compounds 2-12 were confirmed by elemental analysis and TLC.
EXPERIMENTAL
Purity of substances was monitored by TLC on Silufol UV-254 strips. IR spectra were recorded on a
Specord-80 instrument. Mass spectra were recorded with an MX 1321 apparatus with direct inlet of the sample
into the ion source. Ionizing radiation was 70 eV, temperature of the ionizing chamber 220°C.
1,6-Dibenzoyl-5H,10H-diimidazo[1,5-a;1',5'-d]pyrazine-5,10-dione (2). A. Acid dichloride 1 (31.3 g,
0.1 mol) was added with stirring to solution of anhydrous aluminium chloride (37.4 g, 0.28 mol) in mixture of
anhydrous benzene (150 ml) and nitrobenzene (150 ml), and the mixture was boiled while stirring for 3 h.
253

Nitrobenzene and benzene were steam distilled off. The residue was filtered off to give diketone 2 (26.9 g).
Keto acid 3 (7.3 g) was isolated from the aqueous solution by evaporation.
B. Keto acid 3 (21.6 g, 0.1 mol) was boiled in mixture of anhydrous chloroform (150 ml) and thionyl
chloride (60 ml) with a catalytic amount of DMF for 4 h. The residue was separated, washed with chloroform,
and dried in a vacuum desiccator: yield of diketone 2 18.2 g, (2%).
4(5)-Benzoylimidazole-5(4)-carboxylic Acid (3). Diketone 2 (19.8 g, 0.05 mol) was boiled in 10%
sodium hydroxide solution (100 ml) until solution was complete. The solution was treated with activated
charcoal, filtered, and acidified to pH 6. The precipitate was filtered off to give keto acid 3 (17.3 g, 80%).
4(5)-Benzoyl-5(4)methoxycarbonylimidazole (4). Diketone 2 (3.96 g, 0.01 mol) was boiled in
anhydrous methanol (100 ml) in the presence of a catalytic amount of triethylamine for 40 min. The solution
was evaporated in vacuum and the residue was recrystallized from DMF–water mixture to give compound 4
(3.77 g, 82%).
4(5)-Benzoyl-5(4)-aminocarbonylimidazole (5). Suspension of diketone 2 (3.96 g, 0.01 mol) in
anhydrous methanol (100 ml) saturated with ammonia was kept at room temperature for 48 h. The solvent was
distilled off and the residue was recrystallized from ethanol to give compound 5 (3.74 g, 87%).
4(5)-Benzoyl-5(4)-methylaminocarbonylimidazole (6) was made analogously to give keto amide 6
(3.57 g, 78%).
4(5)-Benzoyl-5(4)-phenylaminocarbonylimidazole (7). Diketone 2 (3.96 g, 0.01 mol) and aniline
(1.86 g, 0.02 mol) were boiled for 40 min in anhydrous chloroform (100 ml) in the presence of a catalytic
amount of triethylamine. The solution was evaporated to dryness on a rotary evaporator. The residue was
recrystallized from ethanol to give keto amide 7 (4.2 g, 72%).
Compounds 8, 9, and 11 were obtained analogously in yields of 4.51 g (74%), 2.5 g (43%), and 3.8 g
(62%) respectively.
7-Phenyl-4,5-dihydroimidazo[4,5-d]pyridazin-4-one (10). Hydrazine hydrate (2 ml, 80%) in
methanol (10 ml) was added to boiling solution of keto ester 4 (2.3 g, 0.01 mol) in methanol (50 ml). The
solution was boiled for 30 min. The precipitate which appeared on cooling was filtered off to give compound 10
(1.99 g, 94%).
11-Phenyl-4,5-dihydro-1H-benz[b]imidazo[4,5-f][1,4]diazocin-4-one (12). A. Solution of keto amide
11 (3.06 g, 0.01 mol) in p-xylene (100 ml) was boiled in the presence of a catalytic amount of p-toluenesulfonic
acid for 36 h. Xylene was evaporated in vacuum. The residue was extracted with boiling hexane to give
compound 12 (4.2 g, 72%).
B. Mixture of diketone 2 (3.96 g, 0.01 mol) and o-phenylenediamine (2.16 g, 0.02 mol) was boiled for
12 h in anhydrous DMF (50 ml). The solution was poured into water (200 ml), and the precipitate was filtered
off. Purification was carried out by reprecipitation with hexane from acetone solution to give compound 12
(1.32 g, 23%).
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