Synthesis of Bisoxazole and Bromo-substituted Aryloxazoles
Round 1
Reviewer 1 Report
(See attached file)
Comments for author File: 
Comments.pdf
Author Response
We sincerely thank the editor/reviewers for their valuable comments and suggestions. All the points raised by them are valuable for the improvement of the manuscript. We have addressed all the comments/suggestions/questions of the reviewers/editor and revised the manuscript as well as supporting information accordingly. All the changes are highlighted in track change mode in the revised manuscript and supporting information. Herein, we write the point-by-point responses for all the comments (the comments are in blue and the responses are in black text).
Referee 1
This manuscript describes the synthesis and characterization of several 1,4-dimethoxybenzene derivatives substituted with one or two oxazole rings and their brominated analogues.
We thank the reviewer for summerizing our work. The following comments have been addressed in the revised version.
Comment 1:
The presence of numerous grammatical and typographical errors (too many to specify individually) is distracting, and such errors such be corrected in the final version.
Response:
We thank the reviewer for the comment, as per your comment we addressed these minor mistakes in the revised version to the best of our ability.
Comment 2:
The introductory paragraph makes the same statement twice (compare the first sentence with the one that begins on line 36. In that same paragraph, the authors note how heterocycles induce physicochemical properties, but this is not specific to heterocycles and is true of any structural feature. Also in that same paragraph, van der Waals is misspelled, though the authors probably mean London dispersion forces anyway.
Response:
We thank the reviewer for valuable comments, as per suggestion, we rephrase it in the revised version.
Comment 3:
In general, the discussion of the importance of oxazoles is too long and detailed. Figure 1 shows six different compounds containing the oxazole ring, but only two of them are identified and described. Literature references are cited which presumably pertain to the other compounds, but there’s no indication of which reference goes with which compound
Response:
Thank you very much for your comment, we included references for particular compounds and also their applications in the revised article based on the other reviewer comment.
Comment 4:
There is one curious thing in the experimental section, though it may be simply a case of roundoff error. Based on the yields reported for compounds 12-14, the products obtained account for 3.756 mmol of Br atoms, yet only 3.65 mmol of NBS was used as a reactant in the reaction described.
Response:
Thank you for your comments. We addressed this error in the revised draft.
Comment 5:
A few other specific questions/comments are as follows:
- Line 80: The text states that 9 is formed in “moderate” yield. What is the numerical value for the percent yield?
- Line 97: The text refers to “olefinic” protons, whereas the protons indicated would be considered aromatic.
- Line 120: The text refers to “10 x 5 glass plates.” Are they 10 x 5 cm?
Response:
Thank you for your question/comments. We addressed all those minor errors in the revised manuscript.
Reviewer 2 Report
The present paper describes synthesis of 1,4-bis(oxazolyl)-2,5-dimethoxybenzene and bromination of 1-oxazolyl-2,5-dimethoxybenzene leading to the formation of three types of brominated products. The protocol of the reactions described in the paper is the established ones, but the oxazoles obtained have unprecedented structural units and are adequately characterized. X-ray structure analyses are appropriately solved. Bromination of 11 gave three types of the products. The author should carry out the optimization of the reaction giving one or two of them. What about the results with lesser amounts of NBS? The reaction temperature and solvents may also affect the ratio of the products. As a fundamental question, which carbon atom is firstly brominated?
After addressing these issues and correcting grammatically incorrect English usages and awkward English expression, some of which are shown below, the paper may be publishable.
In line 19, leads should read lead.
In line 22, a useful should read useful.
Sentence from 24 to 25 is grammatically incorrect.
In line 34, oxazole’s should read oxazoles.
In line 49, 3 should be bold.
In line 61, a new should read new.
In line 100, shown should read showed.
In line 101, system represents should read system, which represents.
In line 104, shown should read showed.
In line 137, added to a should read added a
In line 195, compounds synthesized should read compounds were synthesized.
Author Response
Response letter to reviewer comments
We sincerely thank the editor/reviewers for their valuable comments and suggestions. All the points raised by them are valuable for the improvement of the manuscript. We have addressed all the comments/suggestions/questions of the reviewers/editor and revised the manuscript as well as supporting information accordingly. All the changes are highlighted in track change mode in the revised manuscript and supporting information. Herein, we write the point-by-point responses for all the comments (the comments are in blue and the responses are in black text).
Referee 2
The present paper describes synthesis of 1,4-bis(oxazolyl)-2,5-dimethoxybenzene and bromination of 1-oxazolyl-2,5-dimethoxybenzene leading to the formation of three types of brominated products. The protocol of the reactions described in the paper is the established ones, but the oxazoles obtained have unprecedented structural units and are adequately characterized. X-ray structure analyses are appropriately solved. Bromination of 11 gave three types of the products.
We thank the reviewer for summerizing our work. The following comments have been addressed in the revised version.
Comment 1:
The author should carry out the optimization of the reaction giving one or two of them. What about the results with lesser amounts of NBS? The reaction temperature and solvents may also affect the ratio of the products. As a fundamental question, which carbon atom is firstly brominated?
Response:
Thank you for your comment/suggestions. Based on your opinion, when we used lesser amount of NBS we got 13 and 14 in THF/CCl4 solvent within 1 h with less yields. But in case of rt-60 ÌŠC there is a difference in the product formation (observed by TLC in every 15 min) and we got some other unidentified products difficult to identified by spectroscopic techniques at high temperature in both solvents. At rt in THF solvent 2-4 h we got these results and CCl4 case did not observe. Meta-position of the aryl system might be the first choice for the bromination.
Comment 2:
After addressing these issues and correcting grammatically incorrect English usages and awkward English expression, some of which are shown below, the paper may be publishable.
In line 19, leads should read lead.
In line 22, a useful should read useful.
Sentence from 24 to 25 is grammatically incorrect.
In line 34, oxazole’s should read oxazoles.
In line 49, 3 should be bold.
In line 61, a new should read new.
In line 100, shown should read showed.
In line 101, system represents should read system, which represents.
In line 104, shown should read showed.
In line 137, added to a should read added a
In line 195, compounds synthesized should read compounds were synthesized.
Response:
Thank you for your comment/suggestions to improve the quality of our manuscript. We addressed all in the revised manuscript.
Reviewer 3 Report
The article entitled 'Synthesis of bis-oxazole and bromosubstituted aryloxazoles' describes the synthesis of the novel derivative of phenyl-bis-oxazole 10 and three polybrominated derivatives of phenyl-oxazole (12-14). All described compounds have not been reported in the literature before, although isomers of compounds 12-14 with different locations of functional groups (Br and MeO) are already known. Compound 10 was accessed in four-step synthesis starting from commercially available hydroquinone, while compounds 12-14 were prepared in a single step from compound 11 prepared according to the previously reported procedure (How many steps are necessary to prepare 11 from a commercial source?) All new compounds are fully characterized by 1H, 13C, DEPT 135 NMR, IR spectroscopy, and melting point measurement. The HRMS data are available for compounds 10, 13 and 14, but compound 12 was somehow omitted in this analysis, probably due to the X-ray analysis performed only for this derivative. I recommend also adding the HRMS analysis for compound 12. Comprehensive analysis of NMR data allows the Authors to precise determination of substituent – bromine location in molecule skeletons for compounds 12, 13 and 14.
The data provided in the SI part are in agreement with the experimental part of the main part, except for one piece of information. According to the main text, the crystals of 12 for X-rays were obtained from DCM / hexane solution, while in the SI mixture of ethyl acetate and hexane was mentioned.
The language of the manuscript is acceptable; however, several editorial errors listed below are founded:
- Lines 20, 21 - the word “also” is repeated in the same sentence.
- Lines 29 and 42 - The word “Nature” refers to the name of the journal, and “nature” to the natural environment. I guess both should be written in small letters.
- Line 49 – number ‘3’ should be bolded.
- Figure 9 – I recommend providing some information on the bioactivity of all listed compounds such as – 4 (VEGFR2 kinase inhibitor) – Otherwise, the Authors should mention the bioactivity of compounds 1, 2, 5 and 6 also in the text, not only for 3 and 4.
- Line 66 – some word is missed in the sentence “the most building block in organic synthesis” should be “the most common/useful building block in organic”
- Lines 63, 93, 187 - The word “via” should be in italics
- Scheme 1 - Please add yields below all synthesized compounds for clarity
- Line 80 - What does it mean “moderate yield”? – precise information is needed.
- Line 89 – sentence “to deliver the different substituted Bromo-oxazoles 12-14 in 19-24% yields, respectively” should be rewritten to “deliver the different substituted Bromo-oxazoles 14, 12, 13 in 19, 22, 24% yields, respectively”
- Line 90 – change to “The structures of Bromo-substituted oxazoles 12-14 were established”.
- Line 108 – change “we strongly established” to “confirm with certainty”
- Experimental part – why are the data related to Rf and eluent compositions marked with yellow?
- Reference part – please check the style of all references carefully, volumes are provided in different styles and references 12, 13, 14, 20, 23, 29, and 32 should be re-edited to a proper citation style of the journal.
In summary, the manuscript may be published in the Molbank Journal after minor revisions.
Author Response
Response letter to reviewer comments
We sincerely thank the editor/reviewers for their valuable comments and suggestions. All the points raised by them are valuable for the improvement of the manuscript. We have addressed all the comments/suggestions/questions of the reviewers/editor and revised the manuscript as well as supporting information accordingly. All the changes are highlighted in track change mode in the revised manuscript and supporting information. Herein, we write the point-by-point responses for all the comments (the comments are in blue and the responses are in black text).
Referee 3
Comments:
The article entitled 'Synthesis of bis-oxazole and bromosubstituted aryloxazoles' describes the synthesis of the novel derivative of phenyl-bis-oxazole 10 and three polybrominated derivatives of phenyl-oxazole (12-14). All described compounds have not been reported in the literature before, although isomers of compounds 12-14 with different locations of functional groups (Br and MeO) are already known. Compound 10 was accessed in four-step synthesis starting from commercially available hydroquinone, while compounds 12-14 were prepared in a single step from compound 11 prepared according to the previously reported procedure (How many steps are necessary to prepare 11 from a commercial source?) All new compounds are fully characterized by 1H, 13C, DEPT 135 NMR, IR spectroscopy, and melting point measurement. The HRMS data are available for compounds 10, 13 and 14, but compound 12 was somehow omitted in this analysis, probably due to the X-ray analysis performed only for this derivative. I recommend also adding the HRMS analysis for compound 12. Comprehensive analysis of NMR data allows the Authors to precise determination of substituent – bromine location in molecule skeletons for compounds 12, 13 and 14.
The data provided in the SI part are in agreement with the experimental part of the main part, except for one piece of information. According to the main text, the crystals of 12 for X-rays were obtained from DCM / hexane solution, while in the SI mixture of ethyl acetate and hexane was mentioned.
We thank the reviewer for summerizing our work. The following comments have been addressed in the revised version.
Response:
Thank you for your comment/suggestions to improve the quality of our manuscript. We addressed all in the revised manuscript. HRMS we included as well as compound 11 was prepared in one step from commercially available dimethoxy benzaldehyde.
Comments:
The language of the manuscript is acceptable; however, several editorial errors listed below are founded:
- Lines 20, 21 - the word “also” is repeated in the same sentence.
- Lines 29 and 42 - The word “Nature” refers to the name of the journal, and “nature” to the natural environment. I guess both should be written in small letters.
- Line 49 – number ‘3’ should be bolded.
- Figure 9 – I recommend providing some information on the bioactivity of all listed compounds such as – 4 (VEGFR2 kinase inhibitor) – Otherwise, the Authors should mention the bioactivity of compounds 1, 2, 5 and 6 also in the text, not only for 3 and 4.
- Line 66 – some word is missed in the sentence “the most building block in organic synthesis” should be “the most common/useful building block in organic”
- Lines 63, 93, 187 - The word “via” should be in italics
- Scheme 1 - Please add yields below all synthesized compounds for clarity
- Line 80 - What does it mean “moderate yield”? – precise information is needed.
- Line 89 – sentence “to deliver the different substituted Bromo-oxazoles 12-14 in 19-24% yields, respectively” should be rewritten to “deliver the different substituted Bromo-oxazoles 14, 12, 13 in 19, 22, 24% yields, respectively”
- Line 90 – change to “The structures of Bromo-substituted oxazoles 12-14 were established”.
- Line 108 – change “we strongly established” to “confirm with certainty”
- Experimental part – why are the data related to Rf and eluent compositions marked with yellow?
- Reference part – please check the style of all references carefully, volumes are provided in different styles and references 12, 13, 14, 20, 23, 29, and 32 should be re-edited to a proper citation style of the journal.
Response:
Thank you for your comment/suggestions to improve the quality of our manuscript. We addressed all those errors in the revised manuscript.
Comment:
Experimental part – why are the data related to Rf and eluent compositions marked with yellow?
Response:
Thank you for your question. We addressed that issue as per academic editor suggestions.
Comments from academic editor
We thank the EDITOR for the comment. The following comments have been addressed in the revised version.
The authors have made some of the requested modifications and are unable to do the remainder as they no longer have access to the compounds. I note that they have not reported the Rf values as requested to 2 dp but rather at 1 dp. This should be corrected. Furthermore, it makes no sense to report ratios of solvents used for the Rf values where the ratio is 1:0! This means that either one solvent was used or that the level or reporting to 0 dp is inaccurate. This should be fixed.
Response:
Thank you for your comment/suggestions to improve the quality of our manuscript. We fixed it all those errors in the revised manuscript.
