Chemistry of Substituted Quinolinones. Part VI. † Synthesis and Nucleophilic Reactions of 4-Chloro-8-methylquinolin-2(1H)-one and its Thione Analogue

Mostafa M. Ismail, Mohamed Abass* and Mohamed M. HassanDepartment of Chemistry, Faculty of Education, Ain Shams University, Roxy, 11711 Cairo, Egypt.Tel: + 202 7104060, Fax: + 202 2581243. * Author to whom correspondence should be addressed; E-mail: mohamedabass@hotmail.com† For part V see reference [1].Received: 12 October 2000; in revised form: 2 November 2000 / Accepted: 9 November 2000 /Published:18 December 2000Abstract: The synthesis of 4-chloro-8-methylquinolin-2(1H)-one and its thione analogue is described. Some nucleophilic substitution reactions of the 4-chloro group were carried out to get new 4-substituted 2-quinolinones and quinolinethiones, such as 4-sulfanyl, hydrazino, azido and amino derivatives, which are of important synthetic use. The structure of the new compounds was established by their elemental analysis, IR and

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(1H)-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).

General
Melting points were determined on a Gallenkamp apparatus and are uncorrected.IR spectra were recorded on a Perkin-Elmer FT-IR 1650 spectrophotometer using KBr disks. 1 H-NMR spectra were measured in CDCl 3 or DMSO-d 6 on Jeol FX-90 (90 MHz) and Jeol EX-270 (270 MHz) spectrometers, using TMS as an internal standard.Mass spectra were obtained on a HP MS-5988 (Electron energy 70 eV).Elemental analyses were performed at Cairo University Microanalytical Centre.Compounds 1 and 2 were prepared as previously described in the literature (References [7] and [1], respectively).

Method B
To a solution of chloroquinolinone 3 (1.94g, 10 mmol) in o-xylene (100 mL), phosphorus pentasulfide (4.44 g, 10 mmol) was added and the mixture was heated under reflux for 24 h.The solvent was removed by evaporation and the residue extracted several times with chloroform (4 x 25 mL).The extracts were washed with water and dried over anhydrous calcium chloride.The solvent was removed in vacuo and the residue was crystallized to give quinolinethione 4 (identified by its m.p., mixed m.p. and spectral data).

8-Methyl-4-sulfanylquinoline-2(1H)-thione (5)
Method A A mixture of dichloroquinoline 2 (2.12 g, 10 mmol) and thiourea (2.28 g, 30 mmol), in DMF (30 mL), was heated under reflux for 4h.Afterwards the reaction mixture was poured onto cold water and the solid so obtained was dissolved in 0.5 M sodium hydroxide solution (100 mL) and filtered off to remove insoluble materials.The alkaline solution was precipitated using 1 M hydrochloric acid (60 mL) to give yellow precipitates, which were collected by filtration and crystallized.

Method B
To a solution of hydroxyquinolinone 1 (1.75 g, 10 mmol) in o-xylene (100 mL), phosphorus pentasulfide (8.88 g, 20 mmol) was added and the reaction was processed as described for compound 4, 4, Method A.

Method C
Using the same method B that used for obtaining compound 4, compound 5 was obtained from equimolar amounts (10 mmol) of chloroquinolinethione 4 and thiourea in boiling DMF (30 mL).

Method B
A solution of potassium hydroxide (1.12 g, 20 mmol) in ethanol (50 mL) was added to a mixture of sulfanylquinolinone 6 (1.91 g, 10 mmol) and ethyl iodide or butyl iodide (15 mmol).The mixture was heated under reflux on a boiling water-bath.The precipitate that formed was filtered off and crystallized to give compounds 7a and 7b, respectively (identified by m.p., mixed m.p. and spectral data).

Method B
A mixture of 4-ethylthioquinolinone 7a (1.1 g, 5 mmol), hydrazine hydrate (2 mL, 40 mmol) and DMF (25 mL) was heated under reflux for 6h.The reaction mixture was left to cool, poured onto crushed ice to give white deposits, which were filtered off and crystallized.

8-Methyl-4-tosyloxyquinolin-2(1H)-one (9)
To a suspension of compound 1 (1.75 g, 10 mmol), in pyridine (50 mL), tosyl chloride (1.91 g, 10 mmol) was added portion-wise with continuous stirring.Then the mixture was heated under reflux on a boiling water-bath for 2h.The precipitate thus formed during the course of reaction was filtered off, washed thoroughly with acidified cold water, dried and crystallized.

Method A
To a solution of chloroquinolinone 3 (1.94g, 10 mmol), in DMF (20 mL), sodium azide (1g, 15 mmol) was added and the mixture was heated under reflux for 2h.The reaction mixture was poured onto ice-cold water and the precipitate that formed was filtered off and crystallized.

Method C
To a solution of hydrazinoquinolinone 8 (1.89 g, 10 mol), in 2 M hydrochloric acid (10 mL), sodium nitrite solution (10 mL, 11 mmol) was added drop-wise with continuous stirring, in a crushed ice bath.The precipitate that formed was collected by filtration, washed and crystallized.

2,4-Dihydrazino-8-methylquinoline (14)
A mixture of compound 13b (2.38 g, 10 mmol) and hydrazine hydrate (2 mL, 40 mmol) was heated under reflux for 8h.Then the mixture was poured onto ice-cold water to give a precipitate, which was collected by filtration washed well with cold water and crystallized.

Method B
To 10 mmol of either sulfides 16a (2.35 g) or 16b (2.63 g), hydrazine hydrate (1 mL, 2 mmol) was added and heated under reflux for 3h.On dilution of the cooled reaction mixture, a precipitate was obtained which was collected by filtration and crystallized.
Chart 2. Mass Fragmentation Pattern of Compound 5 S + H .

Table 1 .
Analytical data of the new compounds., b and c yields by Methods A, B and C, respectively. a