Substituted 2-formylbenzoic acids in the synthesis of 11H-isoindolo[2,1-a] benzimidazol-11-ones, 5H-isoindolo[2,1-a][3,1]benzoxazine-5,11(6aH)-diones, and 6,6a-dihydroisoindolo-[2,1-a]quinazoline-5,11-diones

Article abstract of DOI:10.1007/s10593-013-1382-2

Optimal conditions were developed for the synthesis of 11H-isoindolo[2,1-a] benzimidazol-11-one, 5H-isoindolo[2,1-a][3,1]benzoxazine-5,11(6aH)-dione, and 6,6a-dihydroisoindolo[2,1-a]quinazoline-5,11-dione derivatives in the reaction of substituted 2-formylbenzoic acids with o-phenylenediamine, anthranilic acid, and anthranilamide, respectively. The bifolded structure of 6,6a- dihydroisoindolo-[1,2-a]quinazoline-5,11-dione was verified and investigated.

Full text of DOI:10.1007/s10593-013-1382-2

Chemistry of Heterocyclic Compounds, Vol. 49, No. 9, December, 2013 (Russian Original Vol. 49, No. 9, September, 2013)
SUBSTITUTED 2-FORMYLBENZOIC ACIDS IN THE
SYNTHESIS OF 11H-ISOINDOLO[2,1-a]BENZIMIDAZOL-
11-ONES, 5H-ISOINDOLO[2,1-a][3,1]BENZOXAZINE-
5,11(6aH)-DIONES, AND 6,6a-DIHYDROISOINDOLO-
[2,1-a]QUINAZOLINE-5,11-DIONES
E. V. Gromachevskaya1*, A. V. Fin'ko1, A. V. Butin1,2, K. S. Pushkareva1,
V. D. Strelkov1, L. I. Isakova1, and G. D. Krapivin1
Optimal conditions were developed for the synthesis of 11H-isoindolo[2,1-a]benzimidazol-11-one,
5H-isoindolo[2,1-a][3,1]benzoxazine-5,11(6aH)-dione, and 6,6a-dihydroisoindolo[2,1-a]quinazoline-
5,11-dione derivatives in the reaction of substituted 2-formylbenzoic acids with o-phenylenediamine,
anthranilic acid, and anthranilamide, respectively. The bifolded structure of 6,6a-dihydroisoindolo-
[1,2-a]quinazoline-5,11-dione was verified and investigated.
Keywords: anthranilamide, anthranilic acid, 2-formylbenzoic acid, isoindolone, o-phenylenediamine,
heterocyclization domino reaction, N,N-bis-nucleophiles, N,O-bis-nucleophiles.
In the previous communication we described the domino reactions of substituted 2-formylbenzoic acids
(FBAs) with 2-(1-aminoalkyl)phenols and 2-aminophenyl(diethyl, diphenyl)carbinols, which lead to the formation
of 10H-isoindolo[2,1-b][1,3]benzoxazin-12(4bH)-ones and 5H-isoindolo[2,1-a][3,1]benzoxazin-11(6aH)-ones,
respectively [1]. The derivatives of the latter compound were found to have a pesticidal activity [2].
These results served as prerequisite for the reaction of FBAs with o-phenylenediamine (PDA),
anthranilic acid, and anthranilamide aimed for the synthesis of new derivatives of tetracyclic heterosystems
containing an isoindolone fragment: 11H-isoindolo[2,1-a]benzimidazol-11-one, 5H-isoindolo[2,1-a][3,1]benz-
oxazine-5,1(6aH)-dione, and 6,6a-dihydroisoindolo[2,1-a]quinazoline-5,11-dione. The isoindolone fragment is
present in the composition of natural compounds (alkaloids [3, 4]) and apparently makes a definite contribution
to the display of one or other type of biological activity [5-8].
Various products from the reaction of FBA with PDA have been described in the literature. Thus,
2-(1H-benzimidazol-2-yl)benzoic acid was obtained by refluxing equimolar amounts of the reagents in
methanol under acid catalysis [9], 4b,5-dihydro-11H-isoindolo[2,1-a]benzimidazol-11-one was obtained by
_______
*To whom correspondence should be addressed, e-mail: organics@kubstu.ru.
1Kuban State Technological University, 2 Moskovskaya St., Krasnodar 350072, Russia.
2Perm State University, 15 Bukireva St., 15, Perm 614990, Russia; e-mail: alexander_butin@mail.ru.
_________________________________________________________________________________________
Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 9, pp. 1428-1442, September, 2013.
Original article submitted June 26, 2013.
0009-3122/13/4909-1331©2013 Springer Science+Business Media New York
1331

H
N
N
N
N
O
O
4b,5-Dihydro-11H-isoindolo-
[2,1-a]benzimidazol-11-one
11H-Isoindolo-
[2,1-a]benzimidazol-11-one
O
N
O
N
O
NH
O
O
6,6a-Dihydroisoindolo-
[2,1-a]quinazoline-5,11-dione
5H-Isoindolo-
[2,1-a][3,1]benzoxazine-5,11(6aH)-dione
refluxing in the presence of TsOH with azeotropic distillation of the water [6]. A. Cul et al. [10] obtained
11H-isoindolo[2,1-a]benzimidazol-11-one by refluxing the starting materials (12 h) in toluene in the presence of
TsOH.
Various versions of the reaction of PDA with phthalic anhydride have been also used for the preparation
of 11H-isoindolo[2,1-a]benzimidazol-11-ones: refluxing equimolar amounts of the reagents in n-amyl alcohol
[5]; fusion without a solvent [11]; with microwave irradiation in solution [12].
In the present work, we used 2-(1H-benzimidazol-2-yl)benzoic acids 2a-d to produce 11H-iso-
indolo[2,1-a]benzimidazol-11-one derivatives. We found that compounds 2a-d are formed readily in the
reaction of equimolar amounts of the corresponding FBAs 1a-d and PDA at room temperature in acetic acid,
which apparently serves as both solvent and a catalyst. Although the process occurs as a sequence of cyclization
and dehydrogenation (oxidation) reactions [13] it is impossible to isolate the intermediates under the given
conditions. The reaction is complete in 1.5-2.0 h, following the filtration of colorless crystals of the products 2a-
d from the reaction mixture.
AcOH
0°C, 0.5 h
room temp., 1.5 h
NH2
NH2
R1
R
OHC
+
–H2O, –H2
HOOC
1a–d
R1
R1
4'
4
7
3
H
N
3'
N
5
6
2
+
R
R
1
5'
6'
N
H
N
H
COO–
COOH
2a–d
a R = R1 = H; b R = Cl, R1 = H; c R = NO2, R1 = H; d R = R1 = OMe
1332

The composition and structure of the synthesized compounds were established by elemental analysis, 1H
and 13C NMR spectroscopy, and mass spectrometry (Tables 1-3). The IR spectra of compounds 2a-d do not
contain bands for the stretching vibrations of the C=O bond of the carboxyl group in the region of 1720-1680 cm-1
characteristic of the starting acids 1a-d, but there are strong absorption bands at 1605-1580 and 1390-1360 cm-1
TABLE 1. Physicochemical Characteristics of the Synthesized Compounds
Found, %
Calculated, %
——————
Com-
pound
Empirical
formula
Mp, °С
Rf
Yield, %
72
С
Н
N
Hal
C14H10N2O2
70.21
70.58
4.42
4.23
11.58
11.76
―
243-245
0.11
2a
(245 [33])
C14H9ClN2O2
C14H9N3O4
C16H14N2O4
C14H8N2O
61.73
61.66
59.45
59.37
64.22
64.42
76.52
76.35
66.36
66.03
63.75
63.40
68.71
68.56
59.28
59.32
3.26
3.33
3.09
3.20
4.85
4.73
3.45
3.66
2.50
2.77
2.31
2.66
4.05
4.32
3.51
3.32
10.18 13.07
10.27 13.00
228-290
290-293
230-233
0.05
0.07
0.10
74
65
77
70
72
80
75
70
75
77
2b
2c
2d
3a
3b
3c
3d
4b
4c
5a
14.71
14.84
9.21
9.39
12.52
12.72
―
―
―
>290 (decomp.) 0.60
(>290 [5])
C14H7ClN2O
C14H7N3O3
C16H12N2O3
C15H10ClNO4
C15H10N2O6
C15H9NO3
11.35 14.20
11.00 13.92
190-192
242-245
230-233
211-213
207-209
0.71
0.80
0.37
0.53
0.71
0.45
15.48
15.84
―
10.21
9.99
―
4.36
4.61
11.82
11.67
57.10
57.33
71.52
71.71
3.35
3.21
3.83
3.61
8.64
8.91
―
5.37
5.58
―
210-212
(219 [19])
C15H8ClNO3
63.26
63.06
2.65
2.82
4.78
4.90
12.32 >250 (decomp.) 0.52
12.41
60
5b
C15H8N2O5
C17H13NO5
C15H10N2O2
C15H9ClN2O2
60.65
60.82
65.32
65.59
72.39
71.99
63.10
63.28
2.92
2.72
4.05
4.21
3.90
4.03
3.25
3.19
9.58
9.46
4.71
4.50
11.56
11.19
9.75
9.84
―
―
―
261-263
0.80
0.68
0.54
0.53
65
52
80
78
5c
5d
6a
6b
232-235
255-258
(250-253 [25])
12.31
12.45
―
292-295
C15H9N3O4
C17H14N2O4
C15H9BrN2O2
C15H9IN2O2
61.41
61.02
65.45
65.80
54.75
54.74
47.55
47.90
3.27
3.07
4.71
4.55
2.35
2.76
2.23
2.41
14.15
14.23
8.85
9.03
8.63
8.51
7.30
7.45
212-215
298-300
265-267
282-284
0.10
0.15
0.56
0.60
72
52
80
73
6c
6d
6e
6f
―
24.07
24.28
33.52
33.74
―
C16H12N2O3
68.57
68.56
4.28
4.32
10.00
9.99
286-289
0.20
80
6g
belonging to the asymmetric and symmetric stretching vibrations of the carboxylate anion. In the region of
2250-1800 cm-1 there are broad absorption bands belonging to the protonated amino groups [14, 15]. In the
1
crystalline state the compounds 2a-d are present in the zwitterionic form. In the H NMR spectra recorded in
DMSO-d6 the signals of the protons of the carboxyl and amine groups are not recorded due to fairly fast
exchange on the NMR time scale. The spectra contain signals for the aromatic protons in the region of 7.22-8.54
ppm, while the spectrum of compound 2d also contains signals for the two methoxy groups (Table 2).
1333

1334

1335

TABLE 3. Mass spectra of the Synthesized Compounds
Com-
pound
m/z (Irel, %)
2a
2b
238 [M]+ (10), 220 (15), 194 (100), 193 (20), 165 (8), 130 (12), 104 (20), 102 (25),
97 (12), 90 (40), 76 (42), 63 (67)
274 [M (37Cl)]+ (4), 272 [M (35Cl)]+ (12), 256 (16), 254 (50), 230 (35), 228 (100),
211 (10), 193 (8), 191 (15), 167 (10), 149 (11), 137 (10), 124 (15), 104 (17), 101 (18),
92 (18), 77 (20)
2c
2d
3a
3b
3c
3d
4b
4c
5a
5b
5c
5d
6a
6b
6c
6d
6e
283 [M]+ (26), 265 (7), 239 (96), 219 (17), 193 (100), 192 (35), 164 (16), 90 (20),
77 (16), 63 (48)
298 [M]+ (40), 280 (82), 265 (20), 254 (100), 252 (55), 239 (29), 237 (30), 211 (32),
195 (22), 168 (45), 140 (36), 92 (67), 77 (25)
220 [M]+ (4), 207 (10), 206 (100), 194 (12), 179 (20), 177 (18), 152 (11), 151 (20),
104 (7), 103 (22), 89 (20), 76 (33)
256 [M (37Cl)]+ (37), 254 [M (35Cl)]+ (100), 239 (3), 191 (12), 165 (5), 136 (7), 127 (6),
90 (8), 76 (5), 63 (9)
265 [M]+ (100), 235 (53), 219 (62), 191 (22), 165 (12), 164 (19), 140 (7), 90 (7), 76 (8),
75 (10)
280 [M]+ (100), 265 (27), 237 (40), 235 (15), 207 (12), 194 (38), 179 (10), 166 (12),
152 (8), 140 (15), 104 (5), 91 (8), 77 (8)
305 [M (37Cl)]+ (7), 303 [M (35Cl)]+ (22), 285 (5), 259 (7), 257 (8), 230 (10), 214 (13),
180 (10), 169 (30), 167 (100), 139 (35), 119 (22), 75 (35)
314 [M]+ (100), 296 (60), 268 (18), 251 (15), 241 (19), 225 (24), 205 (10), 178 (80),
132 (39), 119 (23), 104 (12), 76 (22)
251 [M]+ (47), 250 (17), 223 (22), 207 (100), 179 (30), 178 (32), 151 (13), 140 (6),
105 (8), 95 (8), 77 (15)
287 [M (37Cl)]+ (11), 285 [M (35Cl)]+ (30), 259 (3), 257 (10), 243 (36), 241 (100), 213 (27),
206 (7), 178 (27), 164 (12), 151 (18), 139 (10), 123 (15), 110 (20), 90 (45), 77 (35), 75 (76)
296 [M]+ (35), 268 (5), 252 (55), 206 (100), 194 (17), 177 (18), 164 (10), 151 (23),
103 (12), 90 (50), 77 (25), 75 (73)
311 [M]+ (40), 283 (20), 267 (46), 252 (41), 251 (72), 250 (38), 224 (30), 223 (60),
208 (20), 207 (100), 179 (20), 178 (40), 165 (20), 151 (20), 101 (11), 77 (17)
250 [M]+ (41), 249 (100), 222 (28), 220 (15), 192 (6), 179 (5), 146 (6), 132 (11), 130 (45),
119 (23), 102 (13), 90 (19), 77 (37)
286 [M (37Cl)]+ (35), 285 (27), 284 [M (35Cl)]+ (100), 283 (85), 258 (7), 256 (20), 249 (9),
248 (7), 239 (8), 192 (27), 187 (20), 119 (45), 105 (28), 75 (12)
295 [M]+ (25), 294 (70), 293 (51), 265 (44), 263 (50), 249 (40), 247 (57), 236 (43),
219 (55), 191 (33), 164 (55), 146 (70), 119 (35), 101 (98), 90 (100), 77 (45)
310 [M]+ (10), 309 (100), 308 (25), 294 (10), 293 (13), 265 (32), 249 (29), 222 (10),
173 (25), 119 (12), 101 (18), 95 (13), 77 (12)
331 [M (81Br)]+ (12), 330 (98), 329 [M (79Br)]+ (13), 328 (100), 303 (10), 301 (12),
249 (25), 248 (31), 210 (58), 208 (53), 192 (13), 182 (18), 155 (21), 119 (37), 103 (20),
90 (18), 77 (9)
6f
376 [M]+ (100), 375 (45), 374 (20), 295 (25), 287 (19), 249 (25), 248 (40), 222 (10),
206 (12), 191 (12), 175 (10), 119 (13), 102 (20), 90 (29), 77 (50)
280 [M]+ (100), 279 (72), 278 (7), 252 (15), 248 (5), 236 (17), 195 (6), 191 (5), 181 (9),
119 (10), 107 (8), 76 (31)
6g
A characteristic feature of the mass spectra (EI ionization) of the acids 2a-d is the successive removal
from their molecular ion [M]+ of the water and acetylene molecules, which leads to the radical-cations Φ1 and
Φ2 (Table 3).
N
N
N
N
+ ·
+ ·
R1
R
R1
R
[M]+
– HC CH
–H2O
2a–d
O
O
Ф1
[M – 18]+
Ф2
[M – 44]+
1336

As mentioned earlier [16], closure of the lactam ring in acids 2a-d takes place under harsher conditions:
the isoindolobenzimidazolones 3a,c and 3b,d, were obtained by refluxing compounds 2a,c in acetic anhydride
(method A) or by refluxing compounds 2b,d in thionyl chloride (method B), respectively.
Ac2O
6
9
5
N
, 2–3 min
Method A
Method B
2a,c
4
1
7
8
R1
R
–H2O
1N0
3
SOCl2
70–75°C, 5–10 min
11
2
2b,d
O
3a–d
–H2O
a R = R1 = H; b R = Cl, R1 = H; c R = NO2, R1 = H; d R = R1 = OMe
The structure of the isoindolobenzimidazolones 3a-d was confirmed by the presence of a strong band at
1750-1730 cm-1, characteristic of the stretching vibrations of the carbonyl group in condensed cyclic γ-lactams
[14], in their IR spectra. Another important indication confirming the structure of compounds 3a-d is the fact
that their molecular ions correspond to the radical-cations Φ1 formed at the first stage of fragmentation of the
molecular ions of the acids 2a-d (Table 3).
Researchers have use various methods, based on cyclization of N-(2-dibromomethylbenzoyl)anthranilic
acid [17], oxidation of 1H-isoindolo[2,1-a]indole-11-carboxaldehyde [18], and pyrolysis of N-benzylbenz-
isoxazolone derivatives [19], for the formation of 5H-isoindolo[2,1-a][3,1]benzoxazine-5,11(6aH)-diones.
During the reaction of substituted FBAs 1b,c with anthranilic acid in acetic acid at room temperature
1
with the reagents in an equimolar ratio we isolated the acids 4b,c (Tables 1-3). The H NMR spectra of these
compounds contain a characteristic pair of doublets (signals of the 2-CH and 1-NH protons with identical
vicinal constants) (Table 2) and a broadened singlet for the proton of the carboxyl group.
O
O
(from 1b,c)
AcOH
room temp.
2 h
5
4
4
5
PPA
70–75°С
2.5–3 h
3
O
2
6
7
O6
3
2
3'
6'
4' R1
6a
7
N 1
H
N
1
8
R1
8
–H2O
5'
–H2O
H
.
.
11
.
HOOC
4b,c
R
9
O
5a–d
COOH
10
R
(from 1a–d)
PPA, 70–75°С, 3 h
NH2
–2H2O
O
1a–g
5
6
3
4
1
O
NH
6a
2
NH2
7
12N
O
R1
8
O
NH2
11
9
AcOH, room temp.
1.5–2 h
NH
10
C
R
R1
R
6a–g
–2H2O
N
H
O
O
HOOC
N
A
N
H
R
R1
B
1337

Intramolecular dehydration of the acids 4b,c in polyphosphoric acid (PPA) leads to the 5H-iso-
indolo[2,1-a][3,1]benzoxazine-5,11(6aH)-diones 5b,c. The tetracyclic compounds 5a-d are also formed in a
single stage when formylbenzoic acids 1a-d are heated with anthranilic acid in PPA. Compounds 4b,c and 5a-d
are colorless crystals that are readily soluble in most organic solvents.
The IR spectra of isoindolobenzoxazinediones 5a-d contain characteristic bands for the stretching
vibrations of the ester and lactam carbonyl groups in the regions of 1735-1750 and 1700-1720 cm-1. In the
1H NMR spectra there are singlet signals for the methine (6a-CH) and aromatic protons at 6.66-7.25 and 7.32-
8.65 ppm, respectively (Table 2).
1
In the H NMR spectra of compounds 5b,c we observe a downfield shift (by 0.81 and 1.33 ppm,
respectively) of the signal of the aromatic proton H-1 compared with the signal of the analogous proton H-8 in
the spectra of compounds 4b,c (Table 2). This effect is clearly the result of a change in the electronegativity of
the nitrogen atom after its acylation and the appearance of an intramolecular contact between the H-1 proton and
the oxygen atom of the amide group in the structures of the isoindolobenzoxazinediones 5b,c. The same
1
relationship is observed during comparison of the H NMR spectra of the isoindolobenzimidazolones 3a-d and
benzimidazoles 2a-d with respect to the signals of the aromatic protons in the benzimidazole rings H-9 and H-7
(Table 2).
The mass spectra of compounds 4b,c and 5a-d contain molecular-ion peaks with fairly high intensity
(Table 3). The fragmentation of the molecular ions of the acids 4b,c begins with the elimination of a water
molecule; the radical-cations Φ1 [M-H2O]+ are actually the molecular ions of the corresponding molecules 5a-d.
The first step in the fragmentation of the molecular ions of compounds 5a-d affects the ester fragment of the
molecules (concurrent ejection of CO and CO2), indicating that the charge and spin in the molecular ion are
located at the carbonyl oxygen of the ester group (Table 3).
+ ·
O
O
[M]+
N
–H2O
R1
4b,c
O
R
Ф1
[M – 18]+
The domino reaction of the anthranilic acid amides and o-aminocarboxamides with o-formyl(acyl)-
benzoic acids, during which two rings (pyrimidine and isoindolone) are formed in sequence, is typically used
for the formation of the isoindoloquinazoline structure 6. The authors of the papers [20-29] consider a priori
that both primary and secondary aminocarboxamides in reaction with o-formyl(acyl)benzoic acids form
tetracyclic structures with the same angular skeleton C, although in our opinion none of the cited papers present
convincing evidence for an angular and not linear structure of the skeleton of the products from the reaction of
primary amides of anthranilic acid with the FBA.
In a recent work [8], the isoindoloquinazolinedione structures 6 were obtained by a new three-
component reaction of isatoic anhydride with unsubstituted FBA and ammonium carbonate or primary amines.
In the case of 6-(4-chlorophenyl)methyl-6,6a-dihydroisoindolo[2,1-a]quinazoline-5,11-dione an angular
structure of the heterocyclic skeleton was confirmed by X-ray structural analysis for the obtained compounds,
which in fact being the products from reaction of the secondary anthranilic acid amide with FBA must have a
skeleton with an angular structure. The 6-unsubstituted derivative of isoindoloquinazolidinedione obtained with
ammonium carbonate was assigned as an angular structure evidently by analogy with the previously reported
data, but this was not proved.
1338

TABLE 4. Results from Homonuclear (NOESY) and Heteronuclear
(HMBC) Correlation Experiments for Compound 6b
Position
of atom
1Н NMR spectrum,
δ, ppm
HSQC (13С)
HMBC
67.4; 120.5
NOESY
NН
1
9.22
8.05
7.97
7.89
7.86
7.83
7.68
7.33
6.47
―
7.89; 6.47
7.68
120.0
128.7
133.8
123.9
126.5
133.9
125.4
67.4
125.4; 120.5
163.9; 137.4; 133.9
135.6; 133.5
135.6; 163.5
139.8
4
7.33
7
6.47
10
8
―
7.89
2
137.4; 128.7; 120.0
120.5
8.05; 7.33
7.97; 7.68
9.22; 7.89
3
6a
163.5; 139.8; 133.8
Our experiments showed that the reaction of equimolar amounts of the series of FBAs 1a-g with
anthranilamide in acetic acid leads to the formation of the corresponding 6,6a-dihydroisoindolo[2,1-a]-
quinazoline-5,11-diones 6a-g without isolation of the intermediate acids A. The synthesis of 9-nitroiso-
indoloquinazolinedione 6c is proceeded at room temperature, while compounds 6a,b,d-g are only formed if the
temperature is increased to 70-75°C. We significantly simplified the procedure for the formation of compounds
6a-g compared to the methods described in the literature [8, 25] by using acetic acid as solvent and catalyst. The
obtained compounds 6a-g are colorless crystals, poorly soluble in most organic solvents.
1
The H NMR spectra of the tetracyclic compounds 6a-g contain characteristic singlet signals for the
methyne protons 6a-CH in the region of 6.25-6.92 ppm and singlet signals for the NH protons at 8.92-9.39 ppm,
which is more characteristic of amide than of amine protons [30]. In the IR spectra of these products there are
strong bands for the stretching vibrations of the lactam and amide carbonyl groups at 1710-1750 cm-1 and 1670-
1680 cm-1, respectively (Table 2).
O
H
9.22
H
H
H
5
– HMBC
4
1
6N
3
2
120.5
4a
7.89
H
– NOESY
6a
67.4
H
6.47
N
7
11
H
8
H
9
10
O
Cl
H
Fig. 1. The structurally significant HMBC and NOESY correlation spectra for compound 6b.
Analysis of the mass spectra of the isoindoloquinazolinediones 6a-g indicates that all the samples give
molecular-ion peaks in which hydrogen atom abstraction is a characteristic feature of primary dissociation
(Table 3).
The HSQC, HMBC, and NOESY correlation experiments for isoindoloquinazolinedione 6b (Table 4,
Fig. 1) do not provide a conclusive choice between structures B and C, although the absence of cross peaks
corresponding to interaction of the NH and H-1 protons, which should be characteristic of structure B, thus
indirectly favoring structure C. Similar evidence in favor of structure C may also be supported by the absence
of long-range spin-spin couplings between the NH proton and the C-1 and C-13 carbon atoms, which must be
characteristic of structure B.
1339

To make an unambiguous choice between the linear B and angular C structures of the heterocyclic
skeleton in isoindoloquinazolinediones 6, we used X-ray structural analysis of one of the representatives of this
series, 8-bromo-6,6a-dihydroisoindolo[2,1-a]quinazoline-5,11-dione (6e). A general view of this molecule is
presented in Figure 2, from which it is seen that compound 6e is actually the angular isomer C.
Fig. 2. Molecular structure of compound 6e according to X-ray structural analysis.
In the heterocyclic skeleton of the molecule there is a single sp3-hybridized atom (the C(8) carbon), and
in the end it is this that determines the bifolded structure of the molecule core as a whole. The molecule of
compound 6e is not planar and can be described by a set of three intersecting planes. The benzene ring
C(10)···C(15) and the C(9), N(1), and N(2) atoms adjacent to it form plane 1 (mean deviation of the atoms from
the plane 0.0323 Å). The C(8) atom deviates from this plane by 0.4223 Å and together with the N(1) and N(2)
atoms forms plane 2. The angle between planes 1 and 2 is 143.7°. The isoindolone fragment of the molecule
(the C(1)···C(8) and N(1) atoms) is planar (plane 3, mean deviation of the atoms from the plane 0.382 Å). The
angle between planes 2 and 3 is 127.4°. Such geometry of the heterocycle ensures the absence of angular strains
at the tetrahedral carbon atom C(8) and a planar trigonal environment at both nitrogen atoms.
Some of the compounds that we obtained were tested under laboratory and field conditions for
pesticidal activity at the All-Russian Research Institute of Biological Plant Protection (Krasnodar).
Compounds 2c, 5b, 6a,d,f exhibited antidotal activity in relation to the hormonal herbicide
2,4-dichlorophenoxyacetic acid (2,4-D) on seedlings and vegetative plants of the Master sunflower variety.
Laboratory trials of the isoindoloquinazolinediones 6a,d,f showed that after treatment of sunflower seedlings
with aqueous solutions of the herbicide (at a concentration of 10-3 %) and the antidote (at concentrations of 10-2,
10-3, 10-4, and 10-5 %, Table 5) the length of the hypocotyl increases from 116 to 131% and the length of the root
from 116 to 154% in relation to the standard. From the results of the field trials of compounds 2c, 5b it follows
that the increase in the crop yield of sunflowers in relation to the standard amounts to 14% with benzimidazole
2c as antidote and 12% with isoindolobenzoxazinedione 5b (Table 6). The results of the trials demonstrate the
prospects of using the products in the cultivation of sunflowers and in the search for new antidotes in this series
of heterocycles.
Thus, we have demonstrated the possibility of producing the tetracyclic condensed heterosystems
11H-isoindolo[2,1-a]benzimidazol-11-one, 5H-isoindolo[2,1-a][3,1]benzoxazine-5,11(6aH)-dione, and 6,6a-di-
hydroisoindolo[2,1-a]quinazoline-5,11-dione and also 2-substituted benzimidazolones by choosing optimal
conditions for the reactions of substituted FBAs with bifunctional compounds and have determined some of
their useful properties.
1340

1341

TABLE 6. Effect of the Antidotal Activity of Compounds 2c and 5b on
the Crop Yield (C/ha) of the Sunflower Master Variety during Field Trials
2,4-D
(standard)
Increase in relation
to the standard
Antidote
Control (untreated plants)
2,4-D + antidote
2с
43.4
41.8
15.3
16.4
17.5
18.4
2.2 (14%)
2.0 (12%)
5b
EXPERIMENTAL
The IR spectra were recorded on a Specord-71 instrument as suspensions in vaseline oil (compounds 2,
1
13
3a-d, 4b,c) and a Spectrum Two instrument with a DTIR attachment (compounds 5a-d, 6a-g). The H and C
NMR spectra of compounds 6a-g and also the HSQC, HMBC, and NOESY hetero- and homonuclear
correlation spectra of compound 6b were recorded on an Agilent 400/54 spectrometer (400 MHz for 1H nuclei,
1
100 MHz for 13C nuclei). The H NMR spectra of the remaining compounds were recorded on a Bruker
DRX-500 instrument (500 MHz, compounds 4b,c and 5b,c) and a Bruker AM-300 instrument (300 MHz,
compounds 2a-d, 3a-d, and 5a,d). Solvents: CDCl3 (compounds 5a, 6c) and DMSO-d6 (the other compounds)
with TMS as internal standard. The mixing time in the NOESY experiment was 200 msec. The mass spectra
were recorded on a Varian CH-6 instrument with direct injection of the sample into the ion source at 50-180°C
with electron ionization energy 70 eV. Elemental analysis was performed on a Hewlett-Packard HP-185B
C,H,N analyzer. The melting points were determined on a Stuart SNP 30 heating apparatus and were not
corrected. The reactions were monitored by TLC on Silufol UV-254 plates in the PhH–Me2CO, 4:1 (compounds
3a-d, 4b,c, 5a-d, 6a-g) and PhH–EtOH, 4:1 (compounds 2a-d) systems with iodine vapor for visualization.
The laboratory and field trials of compounds 2c, 5b, 6a,d,f were conducted by the described procedure
[31].
2-(1H-Benzimidazol-2-yl)benzoic Acids 2a-d (General Method). A mixture of the acid 1a-d
(4 mmol) and PDA (0.43 g, 4 mmol) in glacial acetic acid (5 ml) was stirred with cooling on an ice bath for
30 min and then at room temperature for 1.5 h. When the starting compounds had disappeared from the reaction
mixture the colorless precipitate was filtered off, recrystallized from a 1:1 mixture of Me2CO and DMF, washed
with water, and dried.
Synthesis of 11H-isoindolo[2,1-a]benzimidazol-11-ones 3a-d. A. A mixture of the acid 2a,c (1 mmol)
and Ac2O (2 ml) was heated until dissolved, refluxed for 2-3 min, and then cooled. The precipitate was filtered
off, washed with petroleum ether, recrystallized from EtOH, and dried. Compounds 3a,c were obtained.
B. SOCl2 (1.0-1.5 ml) was added to the acid 2b,d (1 mmol). The mixture was heated, and when the
release of gas had stopped and a uniform mass had formed it was poured onto ice. The yellow precipitate that
separated was filtered off and recrystallized from EtOH.
5-Nitro-2-(4-oxo-1,4-dihydro-2H-3,1-benzoxazin-2-yl)benzoic Acid (4c). A mixture of 2-formyl-
5-nitrobenzoic acid (1c) (0.78 g, 4 mmol) and anthranilic acid (0.55 g, 4 mmol) in glacial acetic acid (10 ml)
was stirred at room temperature for 2 h. The sediment of the starting substances was seen to disappear, and a
new one separated. The colorless precipitate was filtered off, washed with a 3:1 mixture of EtOH and H2O,
dried, and recrystallized from EtOH. Yield 0.94 g (75%).
Compound 4b was obtained similarly.
9-Nitro-5H-isoindolo[2,1-a][3,1]benzoxazine-5,11(6aH)-dione (5c). A. The acid 4c (1.25 g, 4 mmol) was
added with stirring to FBA (10 ml). The mixture was heated on a water bath at 70-75°C for 2.5-3 h, and H2O
(15-20 ml) was then added in small portions to the mixture while it was cooled on an ice bath. The precipitate that
separated was extracted with CH2Cl2. The organic layer was separated and dried, the solvent was distilled, and the
colorless residue was recrystallized from a 4:1 mixture of EtOH and PhH. Yield 0.77 g (65%).
Compound 5b was obtained similarly.
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B. The acid 1c (0.78 g, 4 mmol) and anthranilic acid (0.55 g, 4 mmol) were added with stirring to PPA
(10 ml). The mixture was heated on a water bath at 70-75°C for 2.5-3 h. The product was isolated and purified
by method A. Yield 0.91 g (77%).
Compounds 5a,b,d (colorless substances) were obtained similarly.
6,6a-Dihydroisoindolo[2,1-a]quinazoline-5,11-diones 6a-g (General Method). A mixture of the acid
1a-g (4 mmol) and anthranilamide (0.54 g, 4 mmol) in glacial acetic acid (10 ml) was stirred at 70-75°C (at
room temperature in the case of the nitro derivative 1c) for 1.5-2 h. At the end of the reaction, the precipitate
was filtered off and recrystallized from EtOH, dried. Yield 0.85 g (72%).
X-ray Structural Investigation of Compound 6e. The colorless monoclinic crystals of compound 6e
(C15H9BrN2O2) were grown by crystallization from glacial acetic acid. Crystal parameters: 0.55×0.23×0.15 mm.
At 20°C: a 13.6774(12), b 7.4891(6), c 24.544(2) Ǻ; α 90, β 103.258(2), γ 90°; V 2450.0(4) Ǻ3; M 329.15; Z 8;
d
calc.1.785 g/cm3. Space group P21/n. X-ray structural analysis was performed on a CAD4 automatic four-circle
diffractometer (graphite monochromator, MoKα radiation, ω-scan, 2θmax 24.98°); 16959 reflections, of which
7136 were unique, were obtained. The structure was solved by the direct method with SHELXTL program set
[32] and was refined in anisotropic approximation (isotropic for the hydrogen atoms) to probability factors
R1 0.0389 and wR2 0.0925. The complete set of atomic coordinates was deposited at the Cambridge
Crystallographic Data Center (deposit CCDC 934695).
The authors thank the Ministry of Education and Science of the Russian Federation for financial support
of the investigation.
REFERENCES
1.
2.
3.
4.
5.
6.
7.
8.
E. V. Gromachevskaya, A. S. Pilipenko, A. V. Butin, V. E. Zavodnik, and G. D. Krapivin, Khim.
Geterotsikl. Soedin., 125 (2010). [Chem. Heterocycl. Compd., 46, 106 (2010).]
E. V. Gromachevskaya, A. V. Butin, A. S. Pilipenko, G. D. Krapivin, A. A. Borodavko, L. I. Isaeva,
and V. D. Strelkov, RF Pat. 2345083; Byul. Izobret., No. 3, 1222 (2009).
E. V. Boltukhina, F. I. Zubkov, and V. A. Varlamov, Khim. Geterotsikl. Soedin., 963 (2006). [Chem.
Heterocycl. Compd., 42, 831 (2006).]
E. V. Boltukhina, F. I. Zubkov, and V. A. Varlamov, Khim. Geterotsikl. Soedin., 1123 (2006). [Chem.
Heterocycl. Compd., 42, 971 (2006).]
S. K. Meegalla, G. J. Stevens, C. A. McQueen, A. Y. Chen, C. Yu, L. F. Liu, L. R. Barrows, and
E. J. LaVoie, J. Med. Chem., 37, 3434 (1994).
S. N. Khattab, S. Y. Hassan, A. El-Faham, A. M. M. El Massry, and A. Amer, J. Heterocycl. Chem., 44,
617 (2007).
V. V. Lyaskovskii, Z. V. Voitenko, and V. A. Kovtunenko, Khim. Geterotsikl. Soedin., 323 (2007).
[Chem. Heterocycl. Compd., 43, 253 (2007).]
K. S. Kumar, P. M. Kumar, K. A. Kumar, M. Sreenivasulu, A. A. Jafar, D. Rambabu, G. R. Krishna,
C. M. Reddy, R. Kapavarapu, K. Shivakumar, K. K. Priya, K. V. L. Parsa, and M. Pal, Chem. Commun.,
5010 (2011).
9.
L. Yu. Ukhin, L. G. Kuz'mina, L. V. Belousova, and E. N. Shepelenko, Second International Scientific
Conference. New Directions in the Chemistry of Heterocyclic Compounds [in Russian], Zheleznovodsk,
Russia (2011), p. 241.
10.
11.
12.
A. Cul, A. Daïch, B. Decroix, G. Sanz, and L. Van Hijfte, Tetrahedron, 60, 11029 (2004).
A. Bistrzycki and A. Lecco, Helv. Chim. Acta, 4, 425 (1921).
P. V. L. Boddupally, Y. Tallapally, S. R. Pamulaparthy, and N. Banda, Heterocycles, 65, 2329 (2005).
1343

13.
14.
15.
K. N. Zelenin, I. V. Ukraintsev, and V. V. Alekseev, Khim. Geterotsikl. Soedin., 363 (1998). [Chem.
Heterocycl. Compd., 34, 329 (1998).]
A. D. Cross, Introduction to Practical Infrared Spectroscopy [Russian translation], Izd. Inostr. Lit.,
Moscow (1961), p. 93.
L. A. Kazitsyna and N. B. Kupletskaya, Application of UV, IR, NMR, and Mass Spectrometry in
Organic Chemistry [in Russian], Izd. MGU, Moscow (1979), p. 74.
J. Arient, Usp. Khim., 34, 1908 (1965).
H. Diesbach, A. Schürch, and G. Cavin, Helv. Chim. Acta, 31, 716 (1948).
E. Desarbre and J.-Y. Mérour, Heterocycles, 41, 1987 (1995).
J. Khalafy and R. H. Prager, Aust. J. Chem., 51, 925 (1998).
16.
17.
18.
19.
20.
21.
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32.
E. F. M. Stephenson, J. Chem. Soc., 2354 (1954).
J. Honzl, Chem. Listy, 49, 1671 (1955).
J. Honzl, Collect. Czech. Chem. Commun., 21, 725 (1956).
M. Lamchen, J. Chem. Soc. C, 573, (1966).
I. Butula and W. Otting, Monatsh. Chem., 99, 1320 (1968).
M. Chelardoni and V. Pestellini, Ann. Chim., 64, 421 (1974).
V. Pestellini, M. Ghelardoni, C. Bianchini, and A. Liquori, Boll. Chim. Farm., 117, 54 (1978).
V. Balasubramaniyan and N. P. Argade, Tetrahedron, 45, 835 (1989).
P. Pigeon, J. Sikoraiova, S. Marchalin, and B. Decroix, Heterocycles, 56, 129 (2002).
P. Aeberli and W. J. Houlihan, J. Org. Chem., 33, 2402 (1968).
A. Gordon and R. Ford, The Chemist’s Companion [Russian translation], Mir, Moscow (1976), p. 293.
V. D. Strelkov, L. V. Dyadyuchenko, L. I. Isakova, and I. G. Dmitrieva, Agrokhimiya, 28 (2010).
G. M. Sheldrick, SHELXL-97: Program for the Solution of Crystal Structures, University of Göttingen,
Germany (1997).
33.
C. J. Perry, J. Chem. Soc., Perkin Trans. 2, 977 (1997).
1344