Novel Quinazolinone–Isoxazoline Hybrids: Synthesis, Spectroscopic Characterization, and DFT Mechanistic Study

Round 1

Reviewer 1 Report

Rhazi, Chtita, El Yazidi and co-workers submitted this paper and described the synthesis and characterization of a few quinazolinone-isoxazoline compounds. The authors also use a computational method to explain the reaction selectivity. Overall,  I think this work's synthesis and computational studies are solid and exciting. Thus, I recommend publication with minor revision.

Here are my comments and suggestions.

1) Did the author dry the chloroform before the reaction? 

2) I suggest the authors move the R group out of the aromatic ring in Scheme 1

3) In line 248, the word"perfect" seems too extreme.

4) it would be good for the authors to demonstrate one application of those compound.

Author Response

[General Comment] Rhazi, Chtita, El Yazidi and co-workers submitted this paper and described the synthesis and characterization of a few quinazolinone-isoxazoline compounds. The authors also use a computational method to explain the reaction selectivity. Overall, I think this work's synthesis and computational studies are solid and exciting. Thus, I recommend publication with minor revision.

Comments/suggestions

• Comment 1. Did the author dry the chloroform before the reaction?

Author’s response: we would like to thank the reviewer for his positive feedback. The used chloroform is of analytical grad and used as received without any treatment.

• Comment 2. I suggest the authors move the R group out of the aromatic ring in Scheme 1.

Author’s response: the R group has been moved out of the aromatic ring as suggested the reviewer.

• Comment 3. In line 248, the word "perfect" seems too extreme.

Author’s response: the comment has been taken into consideration and the perfect has been replaced by “in accordance” in the edited text

• Comment 4. it would be good for the authors to demonstrate one application of those compound.

Author’s response: In this study, we focused only on the synthesis as well as the spectroscopic and spectrometric characterization of new quinazolinone-isoxazoline hybrids. In addition, the regiochemistry studies of the synthesized cycloadducts were carried out by QM DFT calculations at the B3LYP/cc-pVDZ level. Indeed, the hybrid compounds can present improved biological activities, and the assessment of their biological properties is among our objectives, but is the subject of our future work.

Reviewer 2 Report

This manuscript described the synthesis and NMR characterization of a new synthesis quinazolinone-isoxazoline compounds, the authors also explained the DFT mechanistic study. This is a very nice writing paper; all supporting data is very clear, very beautiful. I only have few questions listed here.

1.   Page 7, 255-259. “The formation of the 3,4-disubstituted isoxazoline regioisomer is not observed in any case as evidenced by TLC and NMR of the reaction mixture.”

This could be misunderstood. This isooxazoline is certainly 3,5-disubstituted, considering the mechanism and the starting material.

2.   The last step forming the isooxazoline ring by using TEA under RT, yield is very high. Only 4f, Is comparably very low. What is the reason?

3.   I would recommend added at least one more reference,

J. Org. Chem. 1980, 45, 19, 3916–3918; doi.org/10.1021/jo01307a039.

This is the 1st publication described using the generated Nitrile oxides by elimination of HCl from hydroximinoyl chlorides in the presence of a base.

After “The intermediate 2 was subjected to a series of arylnitriloxides to synthesis the targeted compounds 4a-h. The arylnitriloxides are generated in situ from hydroxamoyl chlorides 3a-h in chloroform at room temperature 209 in the presence of triethylamine.”

4.   I would also recommend added description of BTBA, which is Bu4NBr, working as Phase transfer catalysis. This would offer a much better reading experience.

5.   The title was

 “Synthesis, Structural Elucidation and Theoretical DFT Mechanistic Study”

If the authors could spend more words describe the spin-spin coupling, that would be much more helpful for other reader to understanding the structure.

Author Response

[General Comment] This manuscript described the synthesis and NMR characterization of a new synthesis quinazolinone-isoxazoline compounds, the authors also explained the DFT mechanistic study. This is a very nice writing paper; all supporting data is very clear, very beautiful. I only have few questions listed here.

Comments/suggestions

• Comment 1. Page 7, 255-259. “The formation of the 3,4-disubstituted isoxazoline regioisomer is not observed in any case as evidenced by TLC and NMR of the reaction mixture.” This could be misunderstood. This isooxazoline is certainly 3,5-disubstituted, considering the mechanism and the starting material.

Author’s response:  we would like to thank the reviewer for his positive comment. Undoubtedly, the obtained isoxazoline in this study is 3,5-disubstituted which is checked by NMR and TLC analysis of the crude product. We are of the point of view of the reviewer regarding the above sentence it could be misunderstood. For this reason, we have removed it from the text.

• Comment 2. The last step forming the isooxazoline ring by using TEA under RT, yield is very high. Only 4f, Is comparably very low. What is the reason?

Author’s response: the low yield observed for compound 4f compared to other synthesized hybrids 4 probably is probably due to the instability of the generated dipole from the precursor 3f (liquid). Dipoles generated from other precursors of the series 3 (solids) are stabilized by electronic effects exerted by substituents on the phenyl ring.

• Comment 3. I would recommend added at least one more reference, “J. Org. Chem. 1980, 45, 19, 3916–3918; doi.org/10.1021/jo01307a039”. This is the 1st publication described using the generated Nitrile oxides by elimination of HCl from hydroximinoyl chlorides in the presence of a base. After “The intermediate 2 was subjected to a series of arylnitriloxides to synthesis the targeted compounds 4a-h. The arylnitriloxides are generated in situ from hydroxamoyl chlorides 3a-h in chloroform at room temperature 209 in the presence of triethylamine.”

Author’s response: we would like to thank the reviewer for pointing this out. The reference has been embedded to the text as suggested the reviewer.

• Comment 4. I would also recommend added description of BTBA, which is Bu4NBr, working as Phase transfer catalysis. This would offer a much better reading experience.

Author’s response: the description of BTBA (TBAB) has been incorporated to the edited text.

• Comment 5. The title was “Synthesis, Structural Elucidation and Theoretical DFT Mechanistic Study” If the authors could spend more words describe the spin-spin coupling, that would be much more helpful for other reader to understanding the structure.

Author’s response: The title has been slightly modified, and we believe it now sufficiently reflects and describes the article's content.

Author Response File: Author Response.pdf

Reviewer 3 Report

1) The authors reported the synthesis, structural elucidation, and theoretical DFT mechanistic study of novel quinazolinone-isoxazoline hybrids. I think this is a fragmentation work. Although the authors reported the synthesis, structural elucidation, and theoretical DFT mechanistic study well, they do not examine biological activities of quinazolinone-isoxazoline hybrids which is the most important part in this study. As described in the introduction part, quinazolinone-isoxazoline complex was prepared by expectations of hybridization of these two heterocyclic parts. It may possess important biological properties. In this work, they only conducted the synthesis of titled compounds and clarified the regioselectivity. They use usual reactions for the synthesis and recently the regioselectivity is easily determined by some measurements. I recommend they should submit the paper after the examination of biological activities,.

2) p. 6, Scheme 1 is partly difficult to understand. I recommend adding the next equation in Scheme 1.

2 + 3a-h → 4a-h

Minor errors:

p. 1 line 10 from the bottom, “Heterocycle” to “Heterocyclic”

p. 11 line 11 from the bottom, “farther” to “further”

Author Response

[General Comment] The authors reported the synthesis, structural elucidation, and theoretical DFT mechanistic study of novel quinazolinone-isoxazoline hybrids. I think this is a fragmentation work. Although the authors reported the synthesis, structural elucidation, and theoretical DFT mechanistic study well, they do not examine biological activities of quinazolinone-isoxazoline hybrids which is the most important part in this study. As described in the introduction part, quinazolinone-isoxazoline complex was prepared by expectations of hybridization of these two heterocyclic parts. It may possess important biological properties. In this work, they only conducted the synthesis of titled compounds and clarified the regioselectivity. They use usual reactions for the synthesis and recently the regioselectivity is easily determined by some measurements. I recommend they should submit the paper after the examination of biological activities.

Author’s response: We would like to thank the reviewer for his careful and thorough reading of this manuscript and for his comments and suggestions. We agree with the reviewer regarding the importance of biological evaluation of these kinds of molecules. However, the main objective of this work is the synthesis, structural elucidation, and DFT theoretical mechanistic study of new quinazolinone-isoxazoline hybrids. We believe that the results presented are promising and may be interest the readership of the journal.  The biological assessment of the reported compounds will be the subject of our future work.

• Comment (1). 6, Scheme 1 is partly difficult to understand. I recommend adding the next equation in Scheme 1. 2 + 3a-h → 4a-h

Author’s response: Thank you for pointing this out. the suggestion of the reviewer has been taken into consideration in the edited manuscript.

• Comment (2). 1 line 10 from the bottom, “Heterocycle” to “Heterocyclic”

Author’s response: heterocycle has been replaced by heterocyclic.

• Comment (3). 11 line 11 from the bottom, “farther” to “further”

Author’s response: farther has been replaced by further.

Author Response File: Author Response.docx

Round 2

Reviewer 3 Report

The authors corrected all points suggested by the reviewer. I think the manuscript became good compared with before.