I am doing a chlorination of Quinazolin-4-one to 4-ChloroQuinazoline. I am refluxing Quinazolin-4-one with POCl3 for 4 hrs and checking TLC of reaction mixture, it's clearly showing the product spot. Then I'm evaporating excess POCl3, and then adding icecold water and neutralizing with ammonium hydroxide (50%). Then after checking TLC, again the starting material spot showing up. Even melting point of product is similar to starting material. Do I have any problem with work out? Or reaction is not completed. I think, maybe the product is getting hydrolyzed back to starting material again. Can anyone please give me a solution for this?
Thanking you in advance.
Experimental Procedure
Step 1
Synthesis of Quinazoline Derivative (19). 4-Chloroquinazoline (23). A solution of anthranilic acid 22 (400 mg, 2.92 mmol) and formamidine acetate (380 mg, 3.65 mmol) in EtOH (15 mL) was heated in a sealed microwave tube at 130 °C for 40 min. After evaporation of the solvent under reduced pressure, the residue was partitioned between EtOAc (20 mL) and Na2CO3 5% (20 mL). The organic layer was further washed with brine (2 × 20 mL), dried (Na2SO4), and evaporated in vacuo. quinazolin-4(3H)-one, white powder, yield 89%.
Step 2
This derivative (340 mg, 2.36 mmol) was subsequently dissolved in POCl3 (8 mL) and heated at 110 °C for 2 h. After evaporation of POCl3, the crude residue was partitioned between CH2Cl2 and 5% aqueous NaHCO3 solution. The organic layer was washed with water and brine and dried over Na2SO4. The solution was concentrated under reduced pressure, which was used without any further purification.89 4-chloroquinazoline, brown solid, yield 86%.
Hi Arka Das
In case of when a thionyl chloride (SOCl2) used instead of POCl3: quinazolin-4(3H)-one (0.1 mol) was dissolved in 50 mL thionyl chloride, and then heated to reflux for 4-6 h. Next the reaction was over by TLC monitoring, the mixture was poured into ice water and stirred for about 30 min, filtered and washed the solid with anhydrous diethyl ether to get 4-chloroquinazoline as brown solid with yield of 92.7%. Using 50% of NH₄OH solution in the workup procedure is a major point herein (it should be around 5-15%, and you should add into reaction mixture slowly), follow to Jürgen Wintner suggested method, i.e. step 2.
Dear Arka Das many thanks for your interesting technical question. POCl3 has the general disadvantage that it is not that easy to remove after the reaction. Did you follow a literature procedure? Personally I would suggest to try thionyl chloride (SOCl2) for this reaction instead of POCl3. An axcess of SOCl2 is more easily removed under vacuum than phosphorylchloride. For example, please have a look at the attached Master thesis entitled
2-ARYL-6,8-DIBROMO-4-CHLOROQUINAZOLINE AS SCAFFOLD FOR THE SYNTHESIS OF NOVEL 2,6,8-TRIARYL-4-(PHENYLETHYNYL)QUINAZOLINES WITH POTENTIAL PHOTOPHYSICAL PROPERTIES
On page 29 of the thesis the conversion of quinazoline-4-one derivatives to 4-chloroquinazolines using SOCl2 / DMF is outlined. A detailed description of the synthetic procedure is given on pages 64-66. The isolated yields of the resulting 4-chloroquinazoline derivatives is in the range of 77-96%. Thus using this method you should be able to isolate your product in high yield.
Good luck with your research and please stay safe and healthy! 👍
Dear Arka Das, I have been struggling with the same issue as you in the last month. After extensive experimental work and research, I have found that 4-chloroquinazolines are very unstable toward water and bases (ammonium hydroxide solution, sodium bicarbonate solution). Therefore, prone to dechlorination (removal of Cl and recovering of starting material). Check the following publication I have recently found, which demonstrates that 4-chloroquinazolines undergo hydrolysis upon standing one week at refrigerator temperatures (https://doi.org/10.1002/jhet.5570150319).
I have confirmed through performing microextractions using Eppendorf tubes and TLC analysis that 4-chloroquinazolines are unstable toward water treatment. Try to put on your TLC a spot of your crude reaction and another from a microextraction (water/chloroform).
Right now, I am considering two options: proceeding to the next step without purification and adding the nucleophile right after the reaction completion, or performing column chromatography purification.
Good luck with your research, and I hope I have helped you!
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