Synthesis of dibenzo[b,g][1,5]diazoninedione and isoindolo[2,1-α] quinazoline derivatives

Article abstract of DOI:10.1070/MC2006v016n01ABEH002177

Starting from 2-aminobenzonitrile 1 and 2-chloromethylbenzoyl chloride 2, a new synthetic pathway to tetracyclic compound 6 is described. Reaction of 2-aminobenzamide 7 with compound 2 leads to the tricyclic ring system 9 which was easily converted to com

Full text of DOI:10.1070/MC2006v016n01ABEH002177

Mendeleev
Communications
Mendeleev Commun., 2006, 16(1), 29–30
Synthesis of dibenzo[b,g][1,5]diazoninedione and isoindolo[2,1-a]quinazoline
derivatives
Mehdi Bakavoli,*a,b Abolghasem Davoodnia,b Mohammad Rahimizadeha and Majid M. Heravia,c
a Department of Chemistry, School of Sciences, Ferdowsi University, 91779 Mashhad, Iran.
Fax: +98 511 843 8032; e-mail: mbakavoli@yahoo.com
b Department of Chemistry, School of Sciences, Islamic Azad University, Mashhad, Iran
c Department of Chemistry, School of Sciences, Azzahra University, Tehran, Iran
DOI: 10.1070/MC2006v016n01ABEH002177
Starting from 2-aminobenzonitrile 1 and 2-chloromethylbenzoyl chloride 2, a new synthetic pathway to tetracyclic compound 6 is
described. Reaction of 2-aminobenzamide 7 with compound 2 leads to the tricyclic ring system 9 which was easily converted to
compound 6 in the presence of KOH in refluxing H2O–EtOH.
Our interest in polycyclic N-heterocyclic compounds1,2 led us
to the synthesis of isoindolo[2,1-a]quinazoline 6 and dibenzo-
[b,g][1,5]diazoninedione 9. Isoindoloquinazolines are usually
prepared by the cyclocondensation of anthranyl amide with
either phthalic anhydride3–5 or 2-ketobenzoic acid.6 Other proce-
dures involve the heterocyclisation of 2-aminobenzylamine with
phthalaldehyde7,8 or anthranilic acid with 2-chloromethylbenzo-
nitrile.9
The synthesis of tricyclic compound 9 was described pre-
viously.10 Inspired by this fact and due to few reports on the
biological activities of these polycyclic N-heterocycles,11,12 we
deemed it interesting to look for specific routes to new deriva-
tives of dibenzodiazoninediones and isoindoloquinazolinones.
Our approach is based on the use of 2-chloromethylbenzoyl
chloride 2 as a starting material. Reaction of this compound
with benzonitriles 1 in boiling dichloromethane involves a
nucleophilic attack of the NH2 group on the acyl carbonyl
group13–15 to give corresponding 2-(chloromethyl)-N-(2-cyano-
phenyl)benzamides 3 (Scheme 1).† These products were cyclised
to the corresponding tetracyclic compounds, isoindolo[2,1-a]-
quinazolinones 6, by two methods.‡
Method A involves transformation of compounds 3 into iso-
indolylbenzonitriles 4§ and cyclisation of these latter compounds
through a cyclocondensation reaction. The process was carried
out by refluxing compounds 3 in the presence of potassium
tert-butoxide in tert-butanol with subsequent treatment of products
4 in a boiling aqueous ethanolic potassium hydroxide solution.
Method B consists of a direct intramolecular heterocyclisa-
tion of compounds 3 by ethanolic potassium hydroxide. The
reaction was carried out by refluxing a mixture of potassium
‡
Typical procedure for the preparation of 6a.
Method A. Compound 3a (1.17 g, 5 mmol) in a mixture of ethanol
(20 ml), water (10 ml) and potassium hydroxide (0.34 g, 6 mmol) was
heated under reflux for 5 h. After cooling the reaction mixture, the
precipitate was filtered off, washed with chloroform and recrystallised
from ethanol to yield 0.79 g of 6a as a white powder (68%).
11H-Isoindolo[2,1-a]quinazolin-5-one 6a: mp 280–282 °C (lit.,16
1
mp 274–277 °C). H NMR (CDCl3, TMS) d: 7.4–8.2 (m, 8H, aromatic
rings), 5.43 (s, 2H, CH2). FT-IR (KBr, n/cm–1): 1651 (CO). MS, m/z:
234 [M]+. Found (%): C, 76.95; H, 4.35; N, 11.90. Calc. for C15H10N2O
(234) (%): C, 76.91; H, 4.30; N, 11.96.
†
The melting points were measured on an Electrothermal type 9100
melting point apparatus. The IR spectra were obtained on a 4300 Shimadzu
spectrometer. The 1H NMR (100 MHz) spectra were recorded on a
Bruker AC l00 spectrometer. The mass spetra were scanned on a Varian
Mat CH-7 instrument at 70 eV. Elemental analysis was performed on a
Thermofinnigan Flash EA microanalyzer.
Typical procedure for the preparation of 3a. 2-Chloromethylbenzoyl
chloride 2 (4.54 g, 24 mmol) was gradually added to a boiling solution
of 2-aminobenzonitrile 1a (2.36 g, 20 mmol) in dichloromethane (25 ml).
Heating was continued for 3 h. After completion of the reaction, as
monitored by TLC, the mixture was filtered. The solvent was evaporated
to dryness, and the residue was crystallised from ethanol to yield 4.33 g
of 3a as a white solid (80%).
2-(Chloromethyl)-N-(2-cyanophenyl)benzamide 3a: mp 169–171 °C.
1H NMR (CDCl3, TMS) d: 8.47 (d, 1H, aromatic ring), 8.13 (br. s, 1H,
NH), 7.25–7.75 (m, 7H, aromatic rings), 4.91 (s, 2H, CH2Cl). FT-IR
(KBr, n/cm–1): 3209 (NH), 2230 (CN), 1651 (CO). MS, m/z: 270 [M]+.
Found (%): C, 66.59; H, 4.07; N, 10.31. Calc. for C15H11ClN2O (270.5)
(%): C, 66.55; H, 4.10; N, 10.35.
3-Chloro-11H-isoindolo[2,1-a]quinazolin-5-one 6b: white solid (0.88 g,
1
66%), mp 272–274 °C. H NMR ([2H6]DMSO, TMS) d: 7.45–8.15 (m,
7H, aromatic rings), 5.426 (s, 2H, CH2). FT-IR (KBr, n/cm–1): 1645
(CO). MS, m/z: 268 [M]+. Found (%): C, 67.10; H, 3.32; N, 10.40. Calc.
for C15H9ClN2O (268.5) (%): C, 67.05; H, 3.38; N, 10.43.
Method B. Compounds 4a and 4b were treated as in Method A to yield
desired 6a and 6b, respectively.
§
Typical procedure for the preparation of 4a. Compounds 3a (1.35 g,
5 mmol) in tert-butanol (30 ml) and potassium tert-butoxide (0.56 g, 5 mmol)
were heated under reflux for 4 h. After the reaction was ceased, water
was added, the precipitate was filtered off and recrystallised from benzene–
petroleum ether to yield 0.84 g of 4a as a white solid (72%).
2-(1-Oxo-1,3-dihydro-2H-isoindol-2-yl)benzonitrile 4a: mp 177–179 °C.
1H NMR (CDCl3, TMS) d: 7.2–8.05 (m, 8H, aromatic rings), 5.0 (s,
2H, CH2). FT-IR (KBr, n/cm–1): 2235 (CN), 1690 (CO). MS, m/z: 234
[M]+. Found (%): C, 76.97; H, 4.28; N, 11.91. Calc. for C15H10N2O
(234) (%): C, 76.91; H, 4.30; N, 11.96.
N-(4-Chloro-2-cyanophenyl)-2-(chloromethyl)benzamide 3b: white
solid (4.6 g, 75%), mp 131–133 °C. 1H NMR (CDCl3, TMS) d: 8.47 (d,
1H, aromatic ring), 8.11 (br. s, 1H, NH), 7.3–7.8 (m, 6H, aromatic
rings), 4.89 (s, 2H, CH2Cl). FT-IR (KBr, n/cm–1): 3239 (NH), 2230
(CN), 1646 (CO). MS, m/z: 304 [M]+. Found (%): C, 59.01; H, 3.25;
N, 9.22. Calc. for C15H10Cl2N2O (305) (%): C, 59.04; H, 3.30; N, 9.18.
5-Chloro-2-(1-oxo-1,3-dihydro-2H-isoindol-2-yl)benzonitrile
4b:
white solid (0.85 g, 63%), mp 252–254 °C. 1H NMR ([2H6]DMSO, TMS)
d: 7.5–8.2 (m, 7H, aromatic rings), 5.06 (s, 2H, CH2). FT-IR (KBr,
n/cm–1): 2236 (CN), 1691 (CO). MS, m/z: 268 [M]+. Found (%): C,
67.01; H, 3.35; N, 10.48. Calc. for C15H9ClN2O (268.5) (%): C, 67.05;
H, 3.38; N, 10.43.
Mendeleev Commun. 2006 29

Mendeleev Commun., 2006, 16(1), 29–30
An unequivocal decision between structures 9 and 10 was
R
CN
possible with the help of spectroscopic analysis and their ring
transformation to tetracyclic compounds 6 and 11, respectively.
The 1H NMR spectrum of the products exhibit two broad peaks
at d 8.33 to 8.38 ppm and 12.20 to 12.38 ppm, which are con-
sistent with structure 9a,b. In addition, the 13C NMR spectrum
of these compounds shows two characteristic signals due to two
different carbonyl groups. For example, in case of 9a, these
signals appear at d 166.2 and 170.8 ppm, which indicates the
formation of this product. Furthermore, when these compounds
were heated under reflux in the presence of potassium hydroxide
in aqueous ethanol the products isolated had identical physical
and spectral characteristics as compounds 6a,b,†† which were
prepared by another procedure shown in Scheme 1.
O
O
R
CN
N
H
Cl
Cl
CH2Cl2
NH2
1
2
Cl
3
ButOK
KOH
EtOH/H2O
ButOH
O
R
CN
R
N
O
KOH
In conclusion, we developed a method for preparing new
tricyclic dibenzo[b,g][1,5]diazoninediones and tetracyclic iso-
indolo[2,1-a]quinazoline derivatives in good yields.
EtOH/H2O
N
N
4
6
References
1
2
3
M. Bakavoli, A. Davoodnia, M. Rahimizadeh, M. M. Heravi and
M. Ghassemzadeh, J. Chem. Res. (S), 2002, 178.
M. Bakavoli, A. Davoodnia, M. Rahimizadeh and M. M. Heravi,
Phosphorus Sulfur Silicon Relat. Elem., 2002, 177, 2303.
G. Rabilloud, B. Sillion and G. de Gaudemaris, Makromol. Chem.,
1967, 108, 18 (Chem. Abstr., 1967, 67, 117374z).
R
CONH2
O
N
4
5
M. Kurihara, J. Org. Chem., 1969, 34, 2123.
Suh Myung Eun, Yakhak Hoechi, 1990, 34, 133 (Chem. Abstr., 1990,
114, 81755x).
P. Aeberli and W. J. Houlihan, J. Org. Chem., 1968, 33, 2402.
E. F. M. Stephenson, J. Chem. Soc., 1954, 2354.
J. Troschuetz, A. Kirfel and G. Will, Arch. Pharm. (Weinheim, Ger.),
1985, 318, 690 (Chem. Abstr., 1985, 103, 178227n).
F. S. Babichev, F. P. Trinus, L. A. Gromov, V. A. Kovtunenko, V. A.
Portnyagina, T. F. Troyan and A. K. Tyltin, Otkrytiya, Izobreteniya,
Prom. Obraztsy, Tovarnye Znaki, 1976, 53 (3), 72 (Chem. Abstr., 1977,
86, P5491w).
a R = H
b R = Cl
5
Scheme 1
6
7
8
hydroxide and 2-(chloromethyl)-N-(2-cyanophenyl)benzamides
3 in aqueous ethanol (Scheme 1). In both methods, the tetra-
cyclic compounds (isoindoloquinazolinones) were obtained in
good yields and their structures were confirmed by spectral and
microanalytical data.
Note that, in this multi-step synthesis, likely key intermediate
5 was not isolated. It seems likely that hydrolysis of the nitrile
group into amide and ring closure occur simultaneously. A study
to isolate this intermediate was carried out to monitor the for-
mation of tetracyclic compounds 6. As shown in Scheme 2,
2-aminobenzamides 7 were used as starting materials. The
reaction of 2-chloromethylbenzoyl chloride 2 with 7 in dichloro-
methane at room temperature did not give intermediate 5 or 8
but instead gave a product which may have had structure 9¶ or 10.
9
10 P. Aeberli and W. J. Houlihan, J. Heterocycl. Chem., 1978, 15, 1141.
11 W. J. Houlihan, US Patent, 3,509,147 (Cl. 260–251; C07d) (Chem.
Abstr., 1970, 73, P25510m).
12 W. J. Houlihan, US Patent, 3,609,139 (Cl. 260/239 DD; A61k) (Chem.
Abstr., 1971, 75, P151851c).
13 J. A. Tyrell and W. E. McEwen, J. Org. Chem., 1981, 46, 2476.
14 J. Kant, F. D. Popp and B. C. Uff, J. Heterocycl. Chem., 1985, 22, 1313.
15 W. Lertwanawatana, S. Thianpatanagul, J. L. Cashaw and V. E. Davis,
Tetrahedron Lett., 1984, 25, 3485.
16 F. S. Babichev and A. K. Tyltin, Ukr. Khim. Zh., 1970, 36 (2), 175 (in
Russian).
O
R
NH2
O
O
O
Received: 27th April 2005; Com. 05/2502
R
¶
N
H
Typical procedure for the preparation of 9a. To a magnetically stirred
NH2 Cl
Cl
mixture of 2-aminobenzamide 7 (1.36 g, 10 mmol) in dichloromethane
(30 ml), 2-chloromethylbenzoyl chloride (2.27 g, 12 mmol) was slowly
added. Stirring was continued for 30 min at room temperature. The
precipitate was filtered off and recrystallised from ethanol to yield
1.92 g of 9a as a white powder (76%).
NH2
7
2
Cl
8
CH2Cl2
O
5H-Dibenzo[b,g][1,5]diazonine-11,13(6H,12H)-dione 9a: white solid
(1.92 g, 76%), mp 203–205 °C. H NMR ([2H6]DMSO, TMS) d: 12.38
1
H
N
H
O
O
(br. s, 1H, NH), 8.62 (d, 1H, aromatic rings), 8.35 (br. s, 1H, NH),
7.1–8.1 (m, 7H, aromatic rings), 5.04 (s, 2H, CH2). 13C NMR (DMSO) d:
43.4, 119.8, 120.3, 122.9, 127.3, 128.7, 129.0, 130.8, 131.1, 132.4, 136.0,
136.3, 139.7, 166.2, 170.8. FT-IR (KBr, n/cm–1): 3349, 3167 (NH), 1662
(CO). MS, m/z: 252 [M]+. Found (%): C, 71.37; H, 4.83; N, 11.08. Calc.
for C15H12N2O2 (252) (%): C, 71.42; H, 4.79; N, 11.10.
2-Chloro-5H-dibenzo[b,g][1,5]diazonine-11,13(6H,12H)-dione 9b:
white solid (2.04 g, 71%), mp 235–237 °C. 1H NMR ([2H6]DMSO, TMS)
d: 12.20 (br. s, 1H, NH), 8.62 (d, 1H, aromatic rings), 8.35 (br. s, 1H,
NH), 7.4–8.1 (m, 6H, aromatic rings), 5.02 (s, 2H, CH2). 13C NMR
(DMSO) d: 43.3, 122.0, 126.8, 127.3, 127.9, 128.3, 129.0, 131.0, 131.1,
132.0, 135.7, 136.3, 138.4, 166.2, 169.4. FT-IR (KBr, n/cm–1): 3362,
3176 (NH), 1662 (CO). MS, m/z: 286 [M]+. Found (%): C, 62.90; H, 3.85;
N, 9.72. Calc. for C15H11ClN2O2 (286.5) (%): C, 62.84; H, 3.87; N, 9.77.
†† Typical procedure for the conversion of 9a to 6a. Compound 9a
(1.26 g, 5 mmol) in a mixture of ethanol (20 ml), water (10 ml) and
potassium hydroxide (0.34 g, 6 mmol) was heated under reflux for 2 h.
After cooling the reaction mixture, the precipitate was filtered off,
washed with chloroform and recrystallised from ethanol to yield 0.8 g
of 6a as a white powder (68%).
N
R
R
N
H
N
H
O
9
10
– H2O
– H2O
O
O
R
R
N
N
N
N
6
11
a R = H
b R = Cl
Scheme 2
30 Mendeleev Commun. 2006