3-((λ3-Oxidanylidene)(propylamino)methyl)-2-ethoxybenzo[e]-[1,2]oxaphosphinine-2-oxide
Round 1
Reviewer 1 Report
Comments and Suggestions for AuthorsThe scientific paper titled "3-((λ3-Oxidanylidene)(propylamino)methyl)-2-ethoxybenzo[e][1,2]oxaphosphinine-2-oxide" presents an innovative approach to the synthesis of phosphorus amides using ultrasound techniques and catalytic amounts of copper iodide (CuI). The authors focus on synthesizing the compound 2-ethoxy-N-propylbenzo[e][1,2]oxaphosphinine-3-carboxamide 2-oxide and describe in detail the reaction mechanism, which includes E → Z isomerization
One of the main strengths of this article is the potential utility of the described reaction, although the universality of the reaction to coumarins containing different substituents in the benzylidene ring has not been documented. This discovered compound may have interesting biological properties, so I hope to continue research in this direction.
One aspect that may be of concern is the lack of experiments confirming the feasibility of reactions without ultrasonic energy. While the authors indicate that sonication energy promotes the reaction, there is no data to confirm whether the reaction can occur without this factor.
The following are other suggestions for the work:
It would be beneficial to include the structures of compounds 3a and 3b in Scheme 2. This would provide the reader with a clearer visual context and improve understanding of the reaction pathway.
Line 80: "on the phosphonic group" - Consider "of the phosphonic group"
Line 104: It would also be helpful to clarify the abbreviation used for para-toluenesulphonic acid by writing it as "(para-toluenesulphonic acid, p-TsOH)" when first mentioned. This would provide clarity later in the text where the abbreviation is used.
Line 122: The description of chromatographic separation using Accucore™ C18 columns and formic acid in the eluent system seems unnecessary, given that the subsequent procedure involves purification using column chromatography with n-hexane/EtOAc as an eluent.
Line 116: the paper mentions the use of 15N NMR spectroscopy with liquid ammonia as a reference, I did not notice any recorded NMR spectrum provided in the study.
Author Response
Reviewer:
We would like to thank the reviewer for the comments on our manuscript.
Comment 1: One aspect that may be of concern is the lack of experiments confirming the feasibility of reactions without ultrasonic energy. While the authors indicate that sonication energy promotes the reaction, there is no data to confirm whether the reaction can occur without this factor.
Response 1: We did try the reaction under reflux unfortunately it did not undergo the same way – the starting material did not fully convert (only small amount of it reacted for 1 day) and different products detected by chromatography were observed. However, we did not continue to investigate it further since there are a large number of articles indicating the opening of the lactone ring in the presence of nucleophiles. Therefore, we tried to continue on our investigation on the behavior of 3-phosphonocoumarin under ultrasound and to emphasize the importance of the sonication energy.
Comment 2: It would be beneficial to include the structures of compounds 3a and 3b in Scheme 2. This would provide the reader with a clearer visual context and improve understanding of the reaction pathway.
Response 2: Thank you for the recommendation, Scheme 2 was changed.
Comment 3: Line 80: "on the phosphonic group" - Consider "of the phosphonic group". Line 104: It would also be helpful to clarify the abbreviation used for para-toluenesulphonic acid by writing it as "(para-toluenesulphonic acid, p-TsOH)" when first mentioned. This would provide clarity later in the text where the abbreviation is used.
Response 3: Thank you for the recommendation, we added the abbreviation and some technical mistakes were corrected as well.
Comment 4: Line 122: The description of chromatographic separation using Accucore™ C18 columns and formic acid in the eluent system seems unnecessary, given that the subsequent procedure involves purification using column chromatography with n-hexane/EtOAc as an eluent.
Response 4: The first chromatographic conditions are related with the standard method for HRMS with liquid chromatography before the ionization chamber. The HPLC system is inseparable part from the mass-spectrometer, therefore the apparatus’s operator could not skip this part. Another reason for the additional separation is the possibility of traces of impurities even after column chromatography that could easily be detected by a high-resolution mass-spectrometer due to the high sensitivity of the analysis.
The second conditions n-hexane/EtOAc are for the laboratory applied column chromatography.
Comment 5: Line 116: the paper mentions the use of 15N NMR spectroscopy with liquid ammonia as a reference, I did not notice any recorded N NMR spectrum provided in the study.
Response 5: The NMR techniques for 15N chemical shift are two and they relied on 1D and 2D NMR spectra. During acquisition the NMR spectrum should be calibrated using internal or external standard. In our characterization a 2D technique 1H-15N HMBC was used, and it is shown in the Supplementary materials file on page S5.
