Synthesis and Crystal Structure of Ethyl 5-(4-Bromophenyl)-7-methyl-3-oxo-2,3-dihidro-5H-thiazolo[3,2-a]pyrimidine-6-carboxylate

Round 1

Reviewer 1 Report

In this manuscript, synthesis and crystal structure of ethyl 7-methyl-3-oxo-2,3-dihidro-5H-thiazolo[3,2-a]pyrimidine-6-carboxylate containing 4-bromophenyl fragment at C5 was reported. The manuscript is well written, but the authors must address some concerns before it is considered for publication.

1. In Figure 1 (c), there are two types of intermolecular interactions: green ones are Br-π halogen bonds as mentioned in Line 58. How about the light blue ones? What are they and what are their distances?

2. Line 53, you mentioned “ESI mass spectrometry (see Figures S3)”. However, I do not see Figure S3 in your Supplementary Materials.

Author Response

We are grateful to the reviewers for their constructive remarks, comments and suggestions. We've revised our manuscript according to their recommendations. The changes are highlighted in yellow in the revised version of the manuscript. Below is also our detailed point-by-point response.

Comments and Suggestions from Reviewer 1.

In this manuscript, synthesis and crystal structure of ethyl 7-methyl-3-oxo-2,3-dihidro-5H-thiazolo[3,2-a]pyrimidine-6-carboxylate containing 4-bromophenyl fragment at C5 was reported. The manuscript is well written, but the authors must address some concerns before it is considered for publication.

1. In Figure 1 (c), there are two types of intermolecular interactions: green ones are Br-π halogen bonds as mentioned in Line 58. How about the light blue ones? What are they and what are their distances?

Figure 1 (c) has been corrected. Green lines denote Br-π bonds between the heterocyclic molecules of 7 in the crystalline phase. The value of the corresponding bond distance and angle between the Br1-atom and С13-atom is added in the main the of the manuscript.

2. Line 53, you mentioned “ESI mass spectrometry (see Figures S3)”. However, I do not see Figure S3 in your Supplementary Materials.

Figure S3 showing the mass spectrum of studied compound 7 has been added in the revised version of SI file.

Reviewer 2 Report

This manuscript by Artem Agarkov, Anna Nefedova, Alexander Ovsyannikov, Igor Litvinov, Svetlana Solovieva and Igor Antipin reports the synthesis and Crystal Structure of Ethyl 5-(4-Bromophenyl)-7-methyl-3-oxo-2,3-dihidro-5H-thiazolo[3,2- a]pyrimidine-6-car-boxylate. This class of chemicals is attractive from a scientific point of view and has numerous potentials uses in medicinal chemistry and therapeutics.

In general, the communication is well written and structured, the experimental design appears to be very relevant, and the methodology is appropriate. Furthermore, from the crystallographic point of view the article is very complete and the formation of weak Br-π interactions in the crystal phase is very well observed, which leaded to the assembly of homochiral chains. The article's weakest point is related to the complete characterization, as well the graphic content. The characterization should be completed for both compounds (6 and 7) and the conclusions should be further elaborated.

I cannot suggest this work for acceptance unless such following points are improved and clarified:

1. Products 6 and 7's characterizations don't seem to be sufficient. Both products can be characterized and classified by FTIR due to their distinct functional groups. FTIR study may help to complete the characterization by describing the spectroscopic differences.

2. Regarding the products' grade of purity, the writers made no mention. Any impurity below 10% may not be detected by NMR. The spectra presented are very clean, but little amplified, especially in ¹³C. Something unusual occurs with the proton integrations in the SI file. All chemical shifts have integer values.

3. To complete the characterization, the authors can do several analyses, which will greatly enhance the article. Among these analyses, some basic ones, such as elemental analysis and Powder-RX.

4. The SI file lacks the characterization of compound 6.

5. In characterization by NMR, authors may try to attribute the observed chemical shifts to the corresponding atoms.

6. It is also common practice to ascertain their melting point as they are novel organic products.

7. Line 79: missing the temperature unities.

8. Despite detailing or summarizing the research covered in the study, the conclusions do not provide sufficient justification for the novelty of the present study. In this part, the authors could highlight how they improved upon the current state of the art. What is the key takeaway from their study?

Minor points:

1. Line 29 and throughout the text: Typographically, (R) and (S) are placed in uppercase and italic.

2. Line 47, scheme 2 and throughout the text, the °C units should be apart from 120. The same thing occurs at line 81, 84, and so on.

3. Line 77: 7 should appear in bold.

4. Graphic content can be improved, for example figure 1 is not clear and has low resolution.

Author Response

We are grateful to the reviewers for their constructive remarks, comments and suggestions. We've revised our manuscript according to their recommendations. The changes are highlighted in yellow in the revised version of the manuscript. Below is also our detailed point-by-point response.

Comments and Suggestions from Reviewer 2

This manuscript by Artem Agarkov, Anna Nefedova, Alexander Ovsyannikov, Igor Litvinov, Svetlana Solovieva and Igor Antipin reports the synthesis and Crystal Structure of Ethyl 5-(4-Bromophenyl)-7-methyl-3-oxo-2,3-dihidro-5H-thiazolo[3,2- a]pyrimidine-6-car-boxylate. This class of chemicals is attractive from a scientific point of view and has numerous potentials uses in medicinal chemistry and therapeutics.

In general, the communication is well written and structured, the experimental design appears to be very relevant, and the methodology is appropriate. Furthermore, from the crystallographic point of view the article is very complete and the formation of weak Br-π interactions in the crystal phase is very well observed, which leaded to the assembly of homochiral chains. The article's weakest point is related to the complete characterization, as well the graphic content. The characterization should be completed for both compounds (6 and 7) and the conclusions should be further elaborated.

I cannot suggest this work for acceptance unless such following points are improved and clarified:

1. 
   Products 6 and 7's characterizations don't seem to be sufficient. Both products can be characterized and classified by FTIR due to their distinct functional groups. FTIR study may help to complete the characterization by describing the spectroscopic differences.

The synthesis of compound 6 was slightly modified compared to this one reported earlier, The appropriate reference was added in the main text of the revised manuscript (see line 72-78). [Shaibuna, M., Kuniyil, M. J. K., & Sreekumar, K. (2021). Deep eutectic solvent assisted synthesis of dihydropyrimidi-nones/thiones via Biginelli reaction: theoretical investigations on their electronic and global reactivity descriptors. New Journal of Chemistry, 45(44), 20765-20775.] For this purpose, the spectroscopic characteristics of compound 6 are not discussed in this article.

Both the IR spectrum of compound 7 and the assignment of the signals were added to SI (see Figure S4) and in the experimental part of the revised version of the manuscript.

2. Regarding the products' grade of purity, the writers made no mention. Any impurity below 10% may not be detected by NMR. The spectra presented are very clean, but little amplified, especially in ¹³C. Something unusual occurs with the proton integrations in the SI file. All chemical shifts have integer values.

All presented spectral characteristics unambiguously indicate a high purity of obtained compound. Moreover, the purity of 7 was confirmed using TLC (only one spot with R_f=0,4 was observed) that was added to the main text of the revised manuscript (see line 88-89). ESI MS spectrum of compound 7 was also added to SI (see figure S3)

The low intensity signals in ¹³C NMR spectrum are related with poor solubility of 7 in d6-DMSO solvent. All presented signals in ¹H NMR spectrum are well defined and assigned to the protons of compound 7. The chemical shifts and integral intensities of the signals are in accordance with the structure of 7.

3. To complete the characterization, the authors can do several analyses, which will greatly enhance the article. Among these analyses, some basic ones, such as elemental analysis and Powder-RX.

The results of elemental analysis have been added to the revised version of the manuscript demonstrating good accordance with the structure of compound 7 (see line 96-97). The powder X-ray diffraction was not performed. We believe that the structure and the purity of compound 7 are well established using other methods which data are presented in the manuscript.

4. The SI file lacks the characterization of compound 6.

The synthesis of compound 6 was earlier reported. The appropriate reference was added in the main text of the revised manuscript (see line 72-78). [Shaibuna, M., Kuniyil, M. J. K., & Sreekumar, K. (2021). Deep eutectic solvent assisted synthesis of dihydropyrimidi-nones/thiones via Biginelli reaction: theoretical investigations on their electronic and global reactivity descriptors. New Journal of Chemistry, 45(44), 20765-20775.] For this purpose, the spectroscopic characteristics of compound 6 are not discussed in this article.

5. In characterization by NMR, authors may try to attribute the observed chemical shifts to the corresponding atoms.

For the ¹H and ¹³C NMR spectra, all signals of the corresponding protons and carbons were assigned (see figure S1 and S2)

6. It is also common practice to ascertain their melting point as they are novel organic products.

Compound 6 is known in the literature, and compound 7 is an oil at room temperature which information was added in the revised version of the manuscript.

7. Line 79: missing the temperature unities.

The appropriate correction was made in the revised version of the manuscript.

8. Despite detailing or summarizing the research covered in the study, the conclusions do not provide sufficient justification for the novelty of the present study. In this part, the authors could highlight how they improved upon the current state of the art. What is the key takeaway from their study?

Since this work is a short communication, a concise conclusion were initially made. In the revised version of the manuscript, we have expanded the conclusion.

Minor points:

1. Line 29 and throughout the text: Typographically, (R) and (S) are placed in uppercase and italic.

2. Line 47, scheme 2 and throughout the text, the °C units should be apart from 120. The same thing occurs at line 81, 84, and so on.
3. Line 77: 7 should appear in bold.
4. Graphic content can be improved, for example figure 1 is not clear and has low resolution.

We did our best to improve the text according to the referee remarks. The appropriate corrections were made all along the manuscript.

 

Round 2

Reviewer 2 Report

This manuscript by Artem Agarkov, Anna Nefedova, Alexander Ovsyannikov, Igor Litvinov, Svetlana Solovieva and Igor Antipin reports the synthesis and Crystal Structure of Ethyl 5-(4-Bromophenyl)-7-methyl-3-oxo-2,3-dihidro-5H-thiazolo[3,2- a]pyrimidine-6-car-boxylate. This study is a continuation of the research published in Molecules 2022 , 27(22), 7747; https://doi.org/10.3390/molecules27227747.

I would like to thank the authors for answering to all of my questions and concerns. I believe it was time and work well spent. The paper is much easier to read and raises significantly less questions about its accuracy and feasibility to be reproduced.

I recommend this work for acceptance, but I think that some relevant minor points should be clarified and completed before the acceptance:

1.     To SI 1H figure authors should add the real proton integrations values. As it stands it looks like the spectrum is a representation of a simulation.

2.     For the NMR characterization, the authors assigned their chemical shifts to the corresponding atoms, but neglected to include the 2D experiments, such as HSQC and HMBC.

3.     For checkCIF report the authors should supply structure factors. The checkCIF still has an Alert level C.

4.     Lines 127, 128, scheme 2, and throughout the text: The °C units should be apart from the number.

Author Response

We do thank the referee for her/his remarks. Here below we provide our detailed point-by-point responses.

1. To SI 1H figure authors should add the real proton integrations values. As it stands it looks like the spectrum is a representation of a simulation.

We uploaded the fid-file containing the 1H NMR spectroscopy data of compound 7 in order to the referee could justify by him/herself that this spectrum is not simulated.

2. For the NMR characterization, the authors assigned their chemical shifts to the corresponding atoms, but neglected to include the 2D experiments, such as HSQC and HMBC.

In our opinion, HSQC and HMBC experiments are not mandatory for this study because the structure and the purity of compound 7 were unambiguously proved by other methods described in the manuscript including the monocrystal X-ray diffraction. The given assignment of the signals in 1H and 13C NMR spectra matches well with the established structure of compound 7.

2. For checkCIF report the authors should supply structure factors. The checkCIF still has an Alert level C.

We kindly recommend referee to look carefully at the updated checkcif2 file where all necessary structure factors are provided. The Alert C level are still present because 8 reflections close to the beamstop were eliminated. In this regard, we believe that the refined structure of 7 with R-factor of 3% doesn’t contain serious issues and can be published in MolBank journal.

4. Lines 127, 128, scheme 2, and throughout the text:The °C units should be apart from the number.

This typo was corrected in the revised version of the manuscript.