Di-4(3H)-quinazolinon-2-yl derivatives from the diacid chlorides of pinic and sym-homopinic acids

Article abstract of DOI:10.1023/A:1013801711372

The corresponding diamides have been synthesized by the interaction of the diacid chlorides of cis-2,2-dimethyl-3-carboxycyclobutaneacetic acid (pinic acid) and cis-2,2-dimethylcyclobutane-1,3-diacetic acid (sym-homopinic acid) with two equivalents of anthranilic acid. Treatment of the diamides with formamide gave 2,2-dimethyl-1-[4(3H)-quinazolinon-2-yl]methyl-3- [4(3H)-quinazolinon-2-yl]cyclobutane and 2,2-dimethyl-1,3-di[4(3H)-quinazolinon-2-ylmethyl]cyclobutane respectively.

Full text of DOI:10.1023/A:1013801711372

Chemistry of Heterocyclic Compounds, Vol. 37, No. 10, 2001
DI-4(3H)-QUINAZOLINON-2-YL DERIVATIVES
FROM THE DIACID CHLORIDES OF PINIC
sym
AND
-HOMOPINIC ACIDS
F. M. Avotin'sh, M. V. Petrova, and A. Ya. Strakov
The corresponding diamides have been synthesized by the interaction of the diacid chlorides of
cis-2,2-dimethyl-3-carboxycyclobutaneacetic acid (pinic acid) and cis-2,2-dimethylcyclobutane-1,3-
diacetic acid (sym-homopinic acid) with two equivalents of anthranilic acid. Treatment of the diamides
with formamide gave 2,2-dimethyl-1-[4(3H)-quinazolinon-2-yl]methyl-3-[4(3H)-quinazolinon-2-
yl]cyclobutane and 2,2-dimethyl-1,3-di[4(3H)-quinazolinon-2-ylmethyl]cyclobutane respectively.
Keywords: anthranilic acid amides, di-4(3H)-quinazolinon-2-yl derivatives on the basis of pinic and
sym-homopinic acids.
In continuation of the work [1] on the synthesis of 4(3H)-quinazolinones with a cyclobutylmethyl
substituting group in position 2, we have obtained the corresponding diamides 3a,b by reacting anthranilic acid
1 with the diacid chlorides of cis-2,2-dimethyl-3-carboxycyclobutaneacetic (pinic, 2a) and cis-2,2-dimethyl-
cyclobutane-1,3-diacetic (sym-homopinic 2b) acids. Heating the amides with formamide (molar ratio compound
3:HCONH2 1:7 to 1:9) leads to the 4(3H)-quinazolinones 4a,b with 4(3H)-quinazolinone 5 as a byproduct.
ClCO
(CH2)n
2a,b
CH2COCl
COOH
NH2
2
COOH
HOOC
CH2CNH
1
(CH2)n
NHC
O
O
3a,b
HCONH2
O
O
N
O
NH
(CH2)n
HN
NH
CH2
N
N
5
4a,b
2–4 a n = 0, b n = 1
__________________________________________________________________________________________
Riga Technical University, Riga LV-1658, Latvia; e-mail: marina@osi.lv. Translated from Khimiya
Geterotsiklicheskikh Soedinenii, No. 10, pp. 1357-1359, October, 2001. Original article submitted June 20, 2000.
0009-3122/01/3710-1241$25.00©2001 Plenum Publishing Corporation
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The structures of the compounds synthesized were confirmed by data of IR and 1H NMR spectra.
EXPERIMENTAL
The IR spectra were obtained on a Specord IR 75 spectrometer for suspensions in nujol (1500-1800 cm-1)
and in hexachlorobutadiene (2000-3600 cm-1). The frequencies of the stretching vibrations of C–H bonds in the
1
range 2800-3050 cm-1 are not indicated. The H NMR spectra were taken in DMSO-d6 on a Bruker WH 90/DS
(90 Hz) spectrometer, internal standard was TMS. A check on the purity of products was effected by TLC on
Silufol UV 254 plates in the system CHCl3–C2H5OH, 9 : 1. Visualization was in UV light or with chlorine and
subsequent treatment with KI–benzidine reagent. The initial acid chlorides 2a and 2b were obtained by the
known procedure of [2, 3]. The methods of [3, 4] were used for the synthesis of the diamides 3a and 3b.
Pinic Acid Dianthranilamide (3a). A solution of diacid chloride 2a (5.12 g, 22.9 mmol) in absolute
benzene or dioxane (30 ml) was added slowly with stirring to a solution of anthranilic acid 1 (6.29 g,
45.9 mmol) and triethylamine (6.42 ml, 45.8 mmol) in absolute benzene (dioxane) (100 ml). The reaction
mixture was stirred for a further 3 h, the solid was then filtered off, and washed with benzene or dioxane. The
filtrate was evaporated on a rotary evaporator with a water-jet pump vacuum, and the residue was recrystallized
from acetonitrile. Crystalline diamide 3a (5.38 g, 55.2%) was obtained; mp 216-217°C. IR spectrum, , cm-1:
ν
1697, 1665, 1605, 1583, 1533; 3110, 2600. 1H NMR spectrum (DMSO-d6), , ppm, J (Hz): 0.91 (3H, s, -CH3);
δ
β
1.27 (3H, s, -CH3); 1.66-2.52 (5H, m, 2CH2 and CH); 2.83 (1H, t, J = 7.0, CH); 7.06 (2H, t, J = 8.0, Harom);
α
7.52 (2H, dt, J = 8.0, J = 1.5, Harom); 7.90 (2H, dt, J = 8.0, J = 1.5, Harom); 8.46 (1H, d, J = 8.0, Harom); 8.54 (1H,
d, J = 8.0, Harom); 11.01 (2H, br s, NH); 11.20 (2H, br. s, 2OH). Found, %: C 64.89; H 5.62; N 6.54. C23H24N2O6.
Calculated, %: C 65.08; H 5.70; N 6.60.
sym
Compound
was obtained analogously to diamide
-Homopinic Acid Dianthranilamide (3b).
3b
3a
.
Yield 52.7%; mp 226-228°C (CH3CN). IR spectrum, , cm-1: 1681, 1637, 1599, 1573, 1513; 3320, 2530-2600.
ν
1H NMR spectrum (DMSO-d6), , ppm, J (Hz): 0.86 (3H, s, -CH3); 1.05 (3H, s, -CH3); 1.48-2.52 (8H, m,
δ
β
α
3CH2 and 2CH); 7.11 (2H, t, J = 7.0, Harom); 7.51 (2H, dt, J = 7.0, J = 1.5, Harom); 7.99 (2H, dd, J = 7.0, J = 1.5,
Harom); 8.49 (2H, d, J = 7.0, Harom); 8.90 (2H, br. s, NH); 10.89 (2H, br. s, 2OH). Found, %: C 65.61; H 5.89;
N 6.35. C24H26N2O6. Calculated, %: C 65.74; H 5.98; N 6.39.
2,2-Dimethyl-1-[4-(3H)-quinazolinon-2-yl]methyl-3-[4(3H)-quinazolinon-2-yl]cyclobutane (4a). A
mixture of diamide 3a (1.62 g, 3.58 mmol) and formamide (1.5 g, 33.5 mmol) in a flask fitted with a reflux
condenser was maintained for 2 h at 175±3°C. The reaction mixture was then cooled, and suspended in water
(30 ml) containing sodium bicarbonate (0.50 g, 5.95 mmol). The solid was filtered off, washed with water
(3 × 20 ml), dried in the air, and recrystallized from a DMF–H2O, 3:1 mixture. Compound 4a (0.95 g, 68.8%)
was obtained having mp 306-307°C (decomp.). IR spectrum, , cm-1: 1672, 1610, 1564, 1500; 3170, 3120.
ν
1H NMR spectrum (DMSO-d6), , ppm, J (Hz): 0.85 (3H, s, -CH3); 1.27 (3H, s, -CH3); 2.03-2.64 (5H, m,
δ
β
α
2CH2 and 1CH); 3.14 (1H, t, J = 7.0, CH); 7.41-8.16 (8H, m, Harom); 12.01 (1H, s, NH); 12.25 (1H, br. s, NH).
Found, %: C 71.59; H 5.65; N 14.39. C23H22N4O2. Calculated, %: C 71.48; H 5.74; N 14.50.
2,2-Dimethyl-1,3-di[4(3H)-quinazolinon-2-ylmethyl]cyclobutane (4b). Compound 4b was
synthesized analogously to product 4a. Yield 64.5%; mp 290-292°C (DMF–H2O, 2:1). IR spectrum, , cm-1:
ν
1
1674, 1612, 1562; 3175, 3123. H NMR spectrum (DMSO-d6), , ppm: 1.03 (3H, s, -CH3); 1.06 (3H, s,
-CH3); 1.85-2.89 (8H, m, 3CH2, 2CH); 7.38-8.14 (8H, m, Harom); 12.16 (2H, br. s, 2NH). Found, %: C 71.81;
δ
β
α
H 6.15; N 14.12. C24H24N4O2. Calculated, %: C 71.98; H 6.04; N 13.99.
4(3H)-Quinazolinone (5). The aqueous solution after isolating compound 4a was acidified to pH 5-6
with hydrochloric acid and extracted with chloroform (3 × 20 ml). The extract was dried over magnesium
sulfate. The solvent was removed in a water pump vacuum, and the residue was recrystallized from acetonitrile.
Quinazolinone 5 (0.16 g, 15.3 %) was obtained having mp 210-212°C. A mixing test of product 5 with a known
specimen of 4(3H)-quinazolinone [5] gave no depression of melting point. Quinazolinone 5 (0.20 g, 20.3%) was
obtained analogously from the aqueous solution after isolating compound 4b.
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F. M. Avotin'sh, E. Yu. Gudrinietse, L. G. Reimate, E. O. Bizdena, and L. P. Zandovska, Izv. Akad.
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