1-Phenyl-3-tosyl-1H-pyrrole

Round 1

Reviewer 1 Report

Authors describe their work on direct sulfonation of pyrroles. Work is well described. Yields are still somehow low.

Author Response

Thank you very much for your valuable comments. We do agree that the yields are rather low and we plan to try to optimize the conditions by varying the reaction’s time/temperature and/or by using a combination of the zinc catalysts. An appropriate paragraph was added in the revised manuscript.  

Reviewer 2 Report

The authors reported synthesis and characterization of new sulfone derivatives with pyrrole. In the reaction of 1 with TsCl, Zn and ZnO were found to be good regents for improve the product yield. In contrast, assignment of pyrrole protons in the 1H NMR spectrum could be insufficient. This is important to determine the substitution potion of the sulfur atom on the pyrrole ring. In the supporting information, two signals at 8.08 and 6.61 seemed to be singlet peaks, but they were assigned to be multiplet peaks. I recommend publication after consideration mentioned above.

Author Response

Please see the attachment.

Author Response File: Author Response.pdf

Reviewer 3 Report

several matters posed in the paper need to be addressed:

1)   Introduction (Pg 1, line 16-17): ‘f…sulfone is one the forty most frequent function groups in bioactive molecules’…. This phrase needs to be rephrased and clarified.

2)   Discussion: some discussion on the difference/comparison of compound 2 and 3’s characterisation (IR, NMR, etc) might be helpful especially since compound 3 is a known compound. Which is the preferable route of synthesis?

 3)    There is no conclusion to the manuscript. Conclusion could be added to address future direction/improvement/modification to synthesis attempt.

Author Response

Thank you very much for your valuable comments.

1) In the revised manuscript the phrase was appropriately rephrased and clarified. Specifically it was changed to: “Also, it is known that a carbonyl and a sulfonyl group are bioisosters and, that, sulfone is one of the forty most frequent functional groups in a number of bioactive molecules [4]. Thus, we replaced the carbonyl group with a sulfone in the above bioactive scaffold, and designed 3-arylsulfonyl-1-phenyl-1H-pyrrole (Scheme 1) as a putative pharmacophore structure [5]. This pharmacophore could possibly lead to a compound with improved pharmacodynamic/pharmacokinetic properties.”

2) The assignment of the structure of the two isomers (2 and 3) was based on the difference of the position of the signals of the hydrogen at the 4-position of the pyrrole ring in the ¹H NMR spectrum. Specifically, in the 3-isomer 2 its signal was downfield/deshielded (6.69-6.52) compared to the 2-isomer 3 (6.38). An appropriate paragraph was added in the revised manuscript. Also, the preferable route for compound 3 is the reported photocatalytic sulfonylation. An appropriate phrase was added in the revised manuscript.

3) In the revised manuscript the following paragraph was added: “Overall, the yields of 2 are rather low and we plan to try to optimize the conditions by varying the reaction’s time/temperature and/or by using a combination of the zinc catalysts. On the other hand, the preferable route for compound 3 is the reported [14] photocatalytic sulfonylation.”