Synthesis and characterization of new quinazolinylmethylsulfanylpyridines, quinazolinylthieno[2,3-b ]pyridines and pyrido[3’’,2’’:4’,5’] thieno[3’,2’:4,5]pyrimido[6,1-b ]quinazolines

Reaction of 2-chloromethylquinazoline-4(3 H )-one with some 3-cyanopyridine-2(1 H )-thiones gave the corresponding thioethers which upon treatment with appropriate base, underwent intramolecular Thorpe-Zeigler reaction affording the isomeric 3-amino-2-(3,4-dihydro-4-oxo-2-quinazolinyl)thieno[2,3-b ]pyridines. In contrast, the reaction of 2-chloromethylquinazoline-4(3 H )-one with 3-cyanoquinoline-(1 H )-thione gave 3- amino-2-(3,4-dihydro-4-oxo-2-quinazolinyl)thieno[2,3-b ]quinoline directly. Reaction of the resulting aminothienopyridines/quinoline with some reagents namely; acetic anhydride, triethyl orthoformate and/ or nitrous acid were carried out and their products were identified


Results and Discussion
Although versatile compound, 2-chloromethylquinazoline-4(3H)-one (1) was prepared early by many chemists, its reactions with any compound of the type 2a-e, 3-cyanopyridine-2(1H)-thiones has not been reported till now.Therefore, we began this investigation from the reaction 2-chloromethylquinazoline-4(3H)-one (1) with 3-cyanopyridine-2(1H)-thiones 2a-d by refluxing in ethanol containing sodium acetate trihydrate as a basic catalyst.The products which isolated were identified as quinazolinylmethylsulfanylpyridine derivatives 3a-d (Scheme 1).Their IR spectra showed characteristic absorption bands around 3250 cm -1 for (NH), 2220 for (C≡N), 1720 for (C=O, ester) and 1670 for (C=O, quinazolinone).Their 1 H NMR spectra showed the presence of a singlet signal at δ 4.36-4.61corresponds to SCH 2 group in addition to the other signals which are in accordance with their proposed structures.
Upon heating compounds 3a-d in ethanol containing sodium ethoxide at boiling temperature or in DMF containing anhydrous K 2 CO  The IR spectra of 4a-d revealed the disappearance of C≡N band and the presence of two absorption bands around 3460, 3200 cm -1 characteristic for (NH 2 ) beside the other bands.The 1 H NMR spectra of 4a-d showed the presence of a singlet signal (exchangeable with D 2 O) around δ 6.50 instead of the signal of SCH 2 group which exists in the spectra of compounds 3a-d.
The mechanism of the latter cyclization is depicted in Scheme 2. In contrast, reaction of 1 with 3-cyanoquinoline-2(1H)-thione (2e) by refluxing in ethanol containing sodium acetate trihydrate, 3-aminothieno[2,3-b]quinoline 4e was separated directly without isolation of the intermediate 3e.The ease of spontaneous cyclization of this intermediate may be due to the absence of any steric effects since there is no any substituent at 4-position of 3e.The pathway of this reaction is given in Scheme 3. The elemental and spectral analyses of compound 4e are in accordance with its proposed structure (see Experimental part).

AUTHORS
The compounds 4a-d and 4e having the γ-aminoimine structure, were utilized as new precursors for synthesizing novel fused heterocyclic compounds containing pyridothienopyrimidoquinazolinone, quinolinothienopyrimidoquinazolinone and pyridothienotriazinoquinazolinone moiety.

Scheme 4. Synthesis of compounds 5a-e.
In a creative experiment, an attempt to react compounds 3a-d with acetic anhydride under neat conditions at reflux temperature has been succeeded and the products were identified as 6methylpyridothienopyrimidoquinazolinones 5a-d (Scheme 4).The pathway of the latter reaction may be involve: (i) initial cyclization of 3a-d into thienopyridines 4a-d by action of the last traces of acetic acid which often associated with acetic anhydride and (ii) usual acetylation of compounds 4a-d followed by cyclodehydration affording 5a-d.To prove the former step (i), an attempt to cyclize 3a-d into 4a-d by heating in acetic acid was succeeded.
The elemental and spectral analyses of compounds 5a-e are in accordance with their proposed structures (Exp.part).Their IR spectra showed the disappearance of characteristic absorption bands which corresponds to the amino and imino groups.Their 1 H NMR spectra exhibited an additional singlet signal at 2.80-3.10ppm equivalent to a new methyl group attached to the pyrimidine moiety.

Conclusions
In this paper, we have successfully synthesized novel series of quinazolinylmethylsulfanylpyridines, quinazolinylthieno [

Experimental Section
General.Melting points were determined on a Gallan-Kamp apparatus and are uncorrected.IR spectra were recorded on a Shimadzu 470 IR-spectrophotometer (KBr; ν max in cm -1 ).The 1 H NMR spectra were taken on a JEOL JNM-ECS 400 (400 MHz) or a Varian EM-390, 90 MHz spectrometer.The 13 C NMR spectra were recorded on a JEOL JNM-ECS 400 (100 MHz) spectrometer.Chemical shifts are given in , ppm and coupling constants (J) is given in Hz.Electron impact (EI) MS spectra were carried out on a JEOL JMS-600 spectrometer.Elemental analyses (C, H, N and S) were performed on an Elemental Analyses system GmbH VARIOEL V2.3 1998 CHNS Mode.The purity of the obtained compounds were checked by TLC.

Cyclization of compounds 3a-d; synthesis of quinazolinylthieno[2,3-b]pyridine derivatives 4a-d Method A)
To a hot solution of compound 3a-d (10 mmol) in absolute ethanol (30 mL), a few drops of sodium ethoxide solution (0.12 g of sodium in 30 mL absolute ethanol) was added.The reaction mixture was heated under reflux for 5 minutes.The product that formed after cooling was filtered off and recrystallized from ethanol to give canary yellow needles of compounds 4a-d.

Method B)
To a solution of compound 3a-d (0.01 mol) in DMF (30 ml), anhydrous K 2 CO 3 (3.0g) was added.The resulting mixture was heated on a steam bath for 4 h and then K 2 CO 3 was filtered off while hot.The product that formed after dilution with water was collected and recrystallized from an ethanol-chloroform mixture to give compounds 4a-d (yield: 87-90 %).

AUTHORS Method C)
Compound 3a-d (0.01 mol) in glacial acetic acid (20 ml) was heated under reflux for one hour and the allowed to cool.The product that formed upon recrystallization gave compounds 4a-d (yield: 78-83 %).