Results and Discussion
Chlorination of 4-hydroxy-8-methylquinolin-2(1
H)-one (
1) [
7] with a mixture of phosphoryl chloride and phosphorus pentachloride afforded 2,4-dichloro-8-methylquinoline (
2) [
1]. Acid hydrolysis of dichloroquinoline
2, using dilute dichloroacetic acid, furnished 4-chloro-8-methylquinolin-2(1
H)-one (
3). Heating of compound
3 with phosphorus pentasulfide gave its thio-isomer 4-chloro-8-methylquinoline-2(1
H)-thione (
4), in a relatively low yield. The same compound
4 was prepared in fair yield when dichloroquinoline
2 was reacted with a 1:1 molar ratio of thiourea in boiling ethanol. The
1H-NMR spectrum of compound
4 in DMSO revealed the existence of a thiolactam-thiolactim equilibrium. Thus, the acidic proton (deuterium exchangeable) is fractionally present at two chemical shifts. We found that the thiolactam tautomer is predominant (thione : thiol ratio 3 : 2). This behaviour is similar to the known behaviour of most thiolactams and lactams, in particular 2-quinolinones [
8].
The mass fragmentation pattern showed the stability of the molecular ion (m/e 209.5), which appeared as the base peak (
cf. Chart 1). Increasing of the molar ratio of thiourea and using boiling DMF as the solvent led to formation of 8-methyl-4-sulfanylquinoline-2(1
H)-thione (
5). Application of these conditions to the reaction of thiourea with compound
4 also gave compound
5. Tthe mass fragmentation pattern of compound
5 also showed the molecular ion (m/e 207) as the base peak (
cf. Chart 2). The direct thiation of hydroxyquinolinone
1 with phosphorus pentasulfide was tested and the yield again is found to be much poorer. Building on the reaction yield and product purity we can conclude that direct thiation of quinolinones
1 and
3 using phosphorus pentasulfide is disfavored, when it is compared with the described thiation of chloroquinolines (
Scheme 1).
4-Chloroquinolinone
3 was used as a precursor for obtaining some new 4-substituted quinolinones. Thus, thiation of compound
3 with thiourea was carried out under fusion conditions to give 8-methyl- 4-sulfanylquinolin-2(1
H)-one (
6). It was found that compound
6 is selectively
S-alkylated, using alkyl iodides; namely ethyl iodide and butyl iodide, in the presence of a base catalyst, leading to 4-alkylthio- 8-methylquinolinones
7a and
7b, respectively. Alternatively, compounds
7a and
7b were also obtained when chloroquinolinone
3 was treated with the appropriate alkanethiol in the presence of sodium ethoxide. Similarly, 8-methyl-4-phenylthioquinolin-2(1
H)-one (
7c) was prepared from compound
3 and thiophenol. Hydrazination of each of 4-chloroquinolinone
3, 4-ethylthioquinolinone
7a and/or 4- tosyloxyquinolinone
9 resulted in the same product, which was characterized as 4-hydrazino-8- methylquinolin-2(1
H)-one (
8). The tosylate
9 was prepared from reaction of 4-hydroxyquinolinone
1 with toluene-4-sulfonyl chloride in pyridine. Although the yield of hydrazinoquinolinone
8 is apparently the lowest (53 %), we can say that use of tosylate
9, as a reagent for preparing hydrazinoquinolinone
8, is much more favorable as a synthetic approach. This is obvious if we compare this obtained yield with the overall yield starting from preparation of dichloroquinoline
2 (overall yield = 36.8 %) (
Scheme 2). In a similar fashion both chloroquinolinone
3 and tosylate
9 were subjected to azidation reaction with sodium azide in DMF, furnishing 4-azido-8-methylquinolin-2(1
H)- one (
10). The compound
10 was also obtained in a much higher yield and purity, by action of nitrous acid on the hydrazinoquinolinone
8.
Staudinger reaction [
9] was employed to reduce the azide
8 to its corresponding amine. The advantage of this method goes back to its controlled conversion of azide function to phosphazene, which subsequently could be hydrolyzed smoothly to the desired amine. Other reduction methods like catalytic hydrogenation are more expensive and could lead to several by-products especially when other sensitive functions are present in the substrate [
10]. Thus, treatment of the azide
10 with triphenylphosphine afforded the phosphazene
11, which upon hydrolysis, using dilute hydrochloric acid, gave 4-amino-8-methylquinolin-2(1
H)-one (
12) [
1] (
Scheme 2).
Chart 1.
Mass Fragmentation Pattern of Compound 4
Chart 1.
Mass Fragmentation Pattern of Compound 4
Chart 2.
Mass Fragmentation Pattern of Compound 5
Chart 2.
Mass Fragmentation Pattern of Compound 5
4-Chloroquinoline-2-thione
4 was subjected to alkylation reactions, using dimethyl sulfate and/or ethyl iodide, resulting in 2-alkylthio-4-chloro-8-methylquinolines
13a and
13b. Interestingly compound
13a (R = C
2H
5) was hydrazinated at both the 2- and 4- sites to give 2,4-dihydrazino-8-methylquinoline (
14). Hydrazination of dichloroquinoline
2 revealed the inactivity of position-2 towards this nucleophilic displacement. This shows that the presence of ethylthio group instead of chloro group at position-2 enabled the hydrazinolysis reaction i.e. the leaving group plays an important role in such substitution reactions at position-2. The structure of dihydrazinoquinoline
14 was established by its reaction with nitrous acid which led to 5-azido-8-methyltetrazolo[1,5-
a]quinoline (
15) [
1] (
Scheme 3).
Reaction of 4-chloroquinolinethione
4 with certain thiols,
viz. ethanethiol, butanethiol and thiophenol, gave the corresponding 4-alkyl(or phenyl)thio-8-methylquinolin-2(1
H)-thiones
16a-c. Hydrazination of the chloroquinolinethione
4 or the sulfide
16a (R = C
2H
5) led to the same product; 4- hydrazino-8-methylquinoline-2(1
H)-thione (
17). The structure of compound
17 was elucidated
via the mass fragmentation pattern (
Chart 3). Reaction of compound
4 with sodium azide furnished 4-azido-8- methylquinolin-2(1
H)-thione (
18), which was also prepared by reacting the hydrazinoquinolinethione with nitrous acid. 4-Amino-8-methylquinolin-2(1
H)-thione (
20) was prepared in a similar manner to obtain aminoquinolinone
12. Thus, the azide
18 was reacted with triphenylphosphine in boiling benzene to give the phosphazene
19 which was subjected to acid hydrolysis furnishing the desired 4- aminoquinoline-2-thione
20 (
Scheme 3).
Chart 3.
Mass Fragmentation Pattern of Compound 17
Chart 3.
Mass Fragmentation Pattern of Compound 17