DIRECT ONE STEP PREPARATION FOR QUINAZOLINES DERIVATIVES Abdelhakim El Ouali Lalami,1,2 Saïd Boukhris,1Nouzha Habbadi,1 Najib Ben Larbi2
and Abdelaziz Souizi1*
1. Laboratoire de Synthèse Organique et d’Agrochimie. Département de Chimie.
Faculté des Sciences. Université Ibn Tofaïl. B.P 133- Kénitra. Maroc 2. Laboratoire de chimie Organique . Département de Chimie.
Faculté des Sciences DHM, Université Sidi Mohammed Ben Abdellah B.P 1796-Atlas, Fès. Maroc
Abstract : The double addition of anthranilamide 2 on epoxides 1 is observed when the reaction is carried out at room temperature in acetonitrile while 2-alkyl-quinazolin-4-ones 4 are obtained at higher temperature.
Résumé : La double addition de l’anthranilamide 2 sur les époxydes 1 est observée quand la réaction est réalisée à température ambiante, tandis que les 2-alkyl-quinazolin-4-ones 4 sont obtenues à reflux de l’acétonitrile.
Key words : anthranilamide , gem-diyano epoxides, quinazolinones
The quinazolin-4-ones constitute a class of compounds of very important medicinal chemists interest and has acquired commercial success as drugs for various kinds of CNS(central nervous system) disturbances [1], they are, for example, used as tranquillizers [2], antidepressive [3], analgesic [4], antithrombic [5], antifibrillatory [6], drugs for the treatment of arteriosclerosis [7], Several derivatives have also been used in the industry [8].
Indeed, the epoxides 1 are widely used as precursors in the synthesis of new heterocyclic systems [9-15]. Contrary to the reactivity of the anthranilamide with epoxydes cyano esters [16] , in this paper we will show that the reaction of epoxides 1 with anthranilamide 2 follows a different route and leads to compounds 3 and quinazolinones 4 depending on the reaction conditions (Scheme 1).
It appears that the temperature has an important effect on the outcome of the reaction.
Indeed, when the epoxide 1 was reacted with anthranilamide 2 at room temperature during 20 hours in acetonitrile, products 3 were obtained and characterized.
H2NOC
3a-c H
CONH2
Ar H
NH O
N
2
reflux, 16h CH3CN
4a-b H
NH N Ar
H O
45-52 % CH3CN,reflux, 20h
50-56 % CH3CN, r.t., 20h
CN H CN
Ar
O +
CONH2
NH2
1
Scheme 1
This reaction proceed first by the opening of the epoxide cycle by the most nucleophile site of the anthranilamide which leads to the unstable cyanhydrine 5 that evolues to a very reactive derivative cyanoformyle 6 [17], which then immediately reacts with the second molecule of anthranilamide to yield the compounds 3 (scheme 2).
H2NOC
3 H
CONH2
Ar H
NH O
N CN
H CN Ar
O
CONH2
NH2
1
N Ar CN
C O
NH2
HO CN +
N Ar CN O C O
NH2 - HCN
CONH2
NH2
5
6
H
H
Scheme 2
Compounds 4, were formed when the reaction was performed in refluxing acetonitrile.
Compounds 3 was also the early formed derivative when an excess of anthranilamide was used.
It is noted that the thermolysis of Compound 3 under the reaction conditions did not give 3- aryl-quinazolin-4-ones 4.
Good yields of 8 were obtained by reacting epoxide 1 with o-phenylenediamine 7 (Scheme 3). It was clear that 4 and 8 were isomers towing different physical characteristics.
7
8a-c H N N Ar
H O CN
H CN Ar
O +
NH2
NH2
1
CH3CN, reflux, 16h 60-82 %
H
Scheme 3
As with other nucleophilic reagents, the attack of the epoxide ring gives a cyanoformyl intermediate 9. However the relative low reactivity of the amide group toward the cyanoformyl group may allow the elimination of HCOCN molecule giving an imine intermediate 10 which leads to 3-aryl-quinazolin-4-ones 4 (Scheme 4).
4 NH N Ar
H O
+ [O=C=C=NH]
10 _ CN
H CN Ar
O
CONH2
NH2
1
N Ar
C
C O
NH2
O H
N +
H N
Ar
C O
NH2 - HCN
9
H
Scheme 4
Table 1: Reaction of epoxides 1 with anthranilamide 2 and o-phenylenediamine 7.
Physical Data of compounds 3a-c, 4a-b and 8a-c.
________________________________________________________________________________
Products Ar Solvent Temperature Reaction Yields % mp °C)a (°C) time (h)
---
3a 4-MeC6H4 MeCN 25 20 55 138
3b 4-ClC6H4 MeCN 25 20 50 142
3c C6H5 MeCN 25 20 56 136
4a 4-MeC6H4 MeCN 78 20 52 237
4b 4-ClC6H4 MeCN 78 20 45 244-6
8a 4-MeC6H4 MeCN 78 16 60 186-7
8b 4-ClC6H4 MeCN 78 16 75 183
8c C6H5 MeCN 78 16 82 207Litt.(82 , 206 )18-
19
________________________________________________________________________________
a. Yields of isolated and purified products. The solid compounds 3 and 4 are recrystallized from ethanol. The solid compounds 8 are recrystallized from 1,2-dichloroethane.
In conclusion we have shown that anthranilamide 2 react with dicyanoepoxide to give 2-aryl- quinazolin-4-ones 4. During this reaction epoxide 1 is no more acting as the synthetic equivalent of the synthon 11 but rather as a dicationic synthon 12. This reactivity may be linked to the low nucleophilic character of the nitrogen of an amide group and to the possibility of an elimination of HCOCN.
R CH C O+ +
R CH2+
11 12
Experimental section
13C NMR spectra were recorded at 75 MHz, 1H NMR spectra at 300 MHz. 1H and 13C chemical shifts () are given in ppm relative to TMS as internal standard. Multiplicities are expressed as follows : singlet = s, doublet = d, broad = br and multiplet = m. Infrared spectra were determined with a PERKIN ELMER 1600 Series FTIR Spectrometer. Mass spectra were recorded on a VARIAN MAT 311 mass Spectrometer. Elemental microanalyses were performed by CNRS (Lyon). Melting points were taken with a KOFLER hot stage apparatus and are uncorrected.
1. Double addition product 3 General procedure :
To a solution of gem-dicyano epoxides 1 (5 mmol) in acetonitrile (20 mL) was added a solution of anthranilamide 2 (5 mmol) in acetonitrile (20 mL). The mixture was stirred for 20 hours at room temperature. After evaporation of the solvent under reduced pressure, the residue is treated with ethyl ether / petroleum ether (4 : 1). The precipitated product 3 is recrystallised.
RMN 1H (DMSO-d6) : 2.26 (s, 3H, CH3); 5.10 (d, 1H, J = 5.5 Hz, CH) ; 6.51-8.50 (m, 12H, Ar);
9.20 (d, 1H, exchangeable with D2O, J = 5.5 Hz, NH); 12.4 (s, 1H, exchangeable with D2O, NHCO).
HRMS calc. for C23H23N4O3m/z : cal. : 403.1770 (M+H)+; found : 403.1776 (M+H)+.
3b: IR (Nujol) :CO = 1654, 1684, 1690 cm-
1;NH = 3250-3412 cm-
1
RMN 1H (DMSO-d6) : 5.29 (s, 1H, CH); 6.55-8.47 (m, 16H, Ar); 9.29.(s, 1H, exchangeable with D2O, NH); 12.38 (s, 1H, exchangeable with D2O, NHCO).
RMN 13C (DMSO-d6) : 61.58 (dm, 1J = 140.8 Hz, CHN); 112.5, 116.8, 122.9, 125.8, 127.4, 128.6, 129.9, 130.5, 139.8, 142.6 (Ar-ring C); 169.14 (m, CO) 170.38 (m, CO) 171.24 (m, CO).
3c: IR (Nujol) :CO = 1645, 1655, 1696 cm-
1;NH = 3200-3497 cm-
1
RMN1H (DMSO-d6) : 5.18 (s, 1H, CH); 6.59-8.65 (m, 16H, Ar); 9.28 (br, 1H, NH); 12.45 (s, 1H, NHCO).
RMN13C (DMSO-d6) : 62.72 (dm,1J = 141.3 Hz, CHN); 112.6, 116.7, 122.7, 125.6, 127.6, 128.8, 129.8, 130.6, 139.9, 147.8 (Ar-ring C); 169.72 (m, CO), 170.42 (m, CO), 171.25 (m, CO).
Quinazolin-4-ones 4 General procedure :
Gem-dicyano epoxides 1 (5 mmol) and anthranilamide 2 (5 mmol) are heated under reflux in acetonitrile (40 mL) for 20 hours. After evaporation of the solvent under reduced pressure, the residue is treated with ethyl ether / acetone (4 : 1). The precipitated product 4 is recrystallised.
1,2,3,4-tertrahydro 2-(p-tolyl) quinazolin-4-one 4a IR (Nujol) :CO = 1672, 1678 cm-
1;NH = 3280-3490 cm-
1
RMN 1H (DMSO-d6) : 2.30 (s, 3H, CH3); 3.45 (s, 1H; NH); 5.75 (s, 1H, CH); 6.67-7.67 (m, 8H, Ar); 8.28 (s, 1H, NHCO).
RMN13C (DMSO-d6) : 20.65 (CH3); 66.37 (CHN); 113.5, 116.9, 122.5, 125.6, 127.8, 128.4, 129.5, 130.2, 139.9, 142.2 (Ar-ring C); 163.66 (broad s, CO)
HRMS calc. for C15H14N2O m/z : cal : 237.1028 (M-H)+; found : 237.102 (M-H)+.
C15H14N2O : Calc. C 75.32 H 6.03 N 11.40 Found 75.05 5.91 11.38
1,2,3,4-tertrahydro 2-(4-chloro phenyl) quinazolin-4-one 4b IR (Nujol) :CO = 1683, 1688 cm-
1;NH = 3257-3460 cm-
1
RMN 1H (DMSO-d6) : 1.90 (s, 1H, NH); 4.80 (s, 1H, CH); 7.16-7.81 (m, 8H, Ar); 7.99 (s, 1H, NHCO).
RMN 13C (DMSO-d6) : 56.50 (CHN); 113.2, 115.8, 121.9, 124.8, 126.4, 128.6, 129.9, 130.5, 139.8, 146.4 (Ar-ring C) ; 164.24 (CO).
3-aryl quinoxalin-2-one 8 General procedure :
Gem-dicyano epoxides 1 (5 mmol) and o-phenylenediamine 8 (5 mmol) are heated under reflux in acetonitrile (40 mL) for 16 hours. After evaporation of the solvent under reduced pressure, the residue is treated with ethyl ether / petroleum ether (4 : 1). The precipitated product 8 is filtered by column alumina (eluent : acetone) and recrystallised.
1,2,3,4-tertrahydro 3-(p-tolyl) quinoxalin-2-one 8a IR (KBr): 2967 - 3319, 1670 cm-1.
1H NMR (CDCl3+ CF3CO2H) : 2.28 (s, 3 H,CH3); 5.11 (s, 1 H, CH); 9.78 (s, 1 H, NHCO); 6.84 - 7.22 (m, 8 H, Ar).
13C NMR (CDCl3+ CF3CO2H) : 20.98 (qt, 1J = 126.0 and2J = 4.1 Hz, CH3 ); 60.01 (dd,1J = 144.1 and 2J = 3.3 Hz, CHN ); 116.48, 116.87, 122.77, 125.04, 125.79, 127.46, 129.36, 129.90, 130.47, 139.82 (Ar-ring C); 169.05 (d,2J = 6 Hz , CO).
C15H14N2O : Calc. C 75.59 H 5.92 N 11.76 Found 75.55 6.05 11.71
1,2,3,4-tertrahydro 3-(4-chloro phenyl) quinoxalin-2-one 8b IR (KBr): 3049 - 3413, 1672 cm-1.
1H NMR (CDCl3+ CF3CO2H) : 5.19 (s,1 H, CH); 9.79 (s, 1 H, NHCO); 6.87 - 7.30 (m, 8 H, Ar).
13C NMR (CDCl3 + CF3CO2H) : 59.58 (d, 1J = 144.2 Hz, CHN); 116.68, 117.03, 123.28, 124.91, 126.08,128.81, 128.96,129.42, 133.58, 135.81(Ar-ring C); 169.11 (d,2J = 6.6 Hz, CO).
C14H11N2OCl Calc. C 65,10 H 4,29 N 10,85 Cl 13,55 Found 64,91 4,31 10,40 13,37 1,2,3,4-tertrahydro 3-phenyl quinoxalin-2-one 8c
IR (KBr): 3300 - 3460, 1666 cm-1.
1H NMR (CDCl3+ CF3CO2H) : 5.17 (s, 1 H, CH); 9.78 (s, 1 H, NHCO); 6.81-7.38 (m, 9 H, Ar).
13C NMR (CDCl3 + CF3CO2H) : 60.23 (d, 1J = 144.5 Hz, CHN ); 116.71, 120.50, 124.51, 125.91, 127.44, 128.92,129.22,130.04, 135.87, 135,87 (Ar-ring C); 169.11 (d,2J = 18.1 Hz, CO ) .
C14H12N2O Calc. C 74,96 H 5,39 N 12,49 Found 74,69 5,36 13,11
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