3-(3-Hydroxypropyl)-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carboxaldehyde Methyl Hemiacetal
Round 1
Reviewer 1 Report
The author reports on the synthesis of a novel uracil derivative via a three-step route. The chemistry is the same as that reported by the author in reference 3b. The compound described herein is a one-carbon homolog of product 3f from that paper.
The manuscript meets the main novel compound requirement for publication in Molbank however my main concern is that the paper describes the synthesis, isolation and characterization of a hemiacetal derivative of the title compound. To address this issue, the authors should repeat the reaction and omit methanol from the chromatography eluent to obtain the title compound. If this is done the manuscript may be suitable for publication provided the following minor issues are addressed.
Mechanisms: The mechanisms contain a number of minor errors in the arrow pushing (e.g. addition-elimination of a carbonyl derivative) and proton transfer steps are missing.
Scheme 2: Was compound 8/9 ever detected?
Scheme 3: Was compound 11 detected/isolated? How do the authors know that it is stable. Can the authors rule out an attack of the urea nitrogen onto the ketone in compound 10?
Author Response
Response to Reviewer Comments
The author is thankful to the reviewers for the detailed analysis on the manuscript and the useful and relevant comments for improving the quality of the paper.
The reviewers' comments were analysed point by point and my responses are as follows:
Point 1: The manuscript meets the main novel compound requirement for publication in Molbank however my main concern is that the paper describes the synthesis, isolation and characterization of a hemiacetal derivative of the title compound. To address this issue, the authors should repeat the reaction and omit methanol from the chromatography eluent to obtain the title compound.
It is not possible to carry out the chromatographic separation without methanol in the eluent mixture because the aldehyde product is polar and remains anchored to silica. I believe that the hemiacetal product is an excellent compromise for obtaining a stable product, which acts as a protecting group of the aldehyde. I do not have experimental data to justify the formation of this derivative and the more detailed study requires an accurate kinetic and thermodynamic analysis. The electronic distribution in position 6 of uracil rings is unique, as already demonstrated in some articles (“Umpulong” of reactivity at the C-6 position of uridine: a simple and general method for 6-substituted. Tetrahedron, 1982, 38, 2635-2642). I thought it was more appropriate in the title to indicate the aldehyde derivative as precursor to further processing, for example for the synthesis of BODIPY, as evidenced by the first preliminary tests. The hemiacetal group can be removed in solution and chemically behaves like an aldehyde, as well known. However, I can modify and insert hemiacetal in the title if the reviewer deems appropriate.
Point 2: Mechanisms: The mechanisms contain a number of minor errors in the arrow pushing (e.g. addition-elimination of a carbonyl derivative) and proton transfer steps are missing.
I apologize, but I don't understand which addition-elimination of a carbonyl derivative should be indicated in the mechanism. I preferred to streamline the mechanism in order to highlight the aspects of the relevant transformations.
Point 3: Scheme 2: Was compound 8/9 ever detected?
Products 8 and 9 were not isolated but were indicated in Scheme 2 only to justify the low yields of 3. The formation of 8 and 9 was reported in references 14 (ex 5a) and 15 (ex 5b).
Point 4: Scheme 3: Was compound 11 detected/isolated? How do the authors know that it is stable. Can the authors rule out an attack of the urea nitrogen onto the ketone in compound 10?
The formation and the stability of open-chain derivatives analogous to 11 was demonstrated in my previous article (ref. 9 ex 3b). These are generated at lower temperatures and are isolated by crystallization from the mother liquors. Derivative 11 was not isolated because it would not have provided any useful information.
Given the quasi-quantitative yields in conversion from open-chain to cycle derivative, the possibility of other mechanisms can be reasonably excluded.
Reviewer 2 Report
In this paper, the author presents the synthesis and structural characterization of an interesting pyrimidine highly functionalized. Final product ‘3-(3-hydroxypropyl)-2,6-dioxo-1,2,3,6-tetrahydropyrimidine-4-carboxaldehyde’ was obtained by a convenient 3-step procedure. In general, the synthetic method is convenient, several of the presented results are interesting, the work is well presented (well written and analyzed), and products are conveniently characterized. However, the experiment results are not surprising given the “trivial nature” of the reactions described and some experimental data should be improved. On balance, this assessment is optimistic; I believe this paper might be appropriate for its publication in Molbank journal after some revisions and answers for the questions, suggestions, and/or corrections:
- Keywords must be in alphabetical order, and the author could include at least two others.
- Due to the high versatility of this methodology, the author could be to explore the synthesis of some other pyrimidine. Anyway, there is an acceptable experimental contribution.
- Abstract: change ‘aldehyde group’ to ‘formyl group’
- The authors must include four decimal places in the data found and calculated date for [M + H+] in the mass analysis. Likewise, the results must be corroborated. For example, the calculated m/z: [M+H]+ data for 1-propanol-6-methyluracil (4) must be 185.0921 instead of 185.18, while the calculated m/z: [M+H]+ data for 1-propanol-6-formyluracil (5) must be 199.0713 instead of 199.18. These results are not very good.
- Throughout the document, there should be 13C and 1H with the numbers in superscript.
- The + sign outside the parentheses in [M+H]+ must be superscript.
- The letter 'd' in DMSO-d6 must be italicized.
- Capital letter 'H' must be italicized.
- The letter 'J' in coupling constants must be italicized.
- Units (ppm) must be included in the NMR data.
- Page 1, line 33. Enter a comma (,) after finally.
- Improve 13C NMR analysis by including each signal's carbon type (i.e., C, CH, CH2 CH3). Likewise, DEPT 135 experiment should be included for both compounds 4 and 5.
- ETC…
Author Response
Response to Reviewer Comments
The author is thankful to the reviewers for the detailed analysis on the manuscript and the useful and relevant comments for improving the quality of the paper.
The reviewers' comments were analysed point by point and responses are as follows:
Point 1: However, the experiment results are not surprising given the “trivial nature” of the reactions described and some experimental data should be improved. On balance, this assessment is optimistic; I believe this paper might be appropriate for its publication in Molbank journal after some revisions and answers for the questions, suggestions, and/or corrections:
The aim of the reactions described would not to be trivial, considering that the reported procedures, described for the first time, could be of great interest and offer large potential, especially for scale-up production.
Point 2: Keywords must be in alphabetical order, and the author could include at least two others.
The keywords have been sorted and two items have been added as proposed by the reviewer: Aldehydes; Cyclization reaction; Low-cost procedures; Solventless reactions; Uracil derivatives.
Point 3: Due to the high versatility of this methodology, the author could be to explore the synthesis of some other pyrimidine. Anyway, there is an acceptable experimental contribution.
Thanks to the reviewer for this advice, it is planned to develop and expand this procedure to specific functionalized uracil as well as thymine derivatives.
Point 4: Abstract: change ‘aldehyde group’ to ‘formyl group’
Aldehyde with formyl was changed as suggested.
Point 5: The authors must include four decimal places in the data found and calculated date for [M + H+] in the mass analysis. Likewise, the results must be corroborated. For example, the calculated m/z: [M+H]+ data for 1-propanol-6-methyluracil (4) must be 185.0921 instead of 185.18, while the calculated m/z: [M+H]+ data for 1-propanol-6-formyluracil (5) must be 199.0713 instead of 199.18. These results are not very good.
The mass analyses were performed at University of Nijmegen before the Covid-19 pandemic and mass technician provided me only mass spectra in pdf format. Unfortunately, now I am unable to ask for further specific details. I corrected the calculated mass data by indicating only the third decimal place for uniformity to the experimental data.
Point 6: Throughout the document, there should be 13C and 1H with the numbers in superscript.
The + sign outside the parentheses in [M+H]+ must be superscript.
The letter 'd' in DMSO-d6 must be italicized.
Capital letter 'H' must be italicized.
The letter 'J' in coupling constants must be italicized.
Units (ppm) must be included in the NMR data.
Page 1, line 33. Enter a comma (,) after finally.
All typos indicated by the reviewer have been corrected.
Point 7: Improve 13C NMR analysis by including each signal's carbon type (i.e., C, CH, CH2 CH3). Likewise, DEPT 135 experiment should be included for both compounds 4 and 5.
The assignment of each carbon of molecules 4 and 5 was carried out as suggested by the reviewer, by comparison with the data of similar molecules reported in reference 9.
Reviewer 3 Report
In this manuscript, the author reported a facile synthesis of multi-site functionalized nucleic acid derivative. The introduction of hydroxyl and aldehyde groups warrant further derivatizations to fit in various applications. The synthetic route is well described and the proposed mechanism of each step is provided. All new compounds are fully characterized.
In summary, this manuscript is recommended for publication in Molbank as it's current version.
Author Response
I thank the reviewer for the positive opinion on my manuscript.
Round 2
Reviewer 1 Report
The author has provided some explanation regarding my comments however the following issues must be addressed before the manuscript is suitable for publication.
Point 1: The author should indicate that methanol is crucial for efficient purification of the compound. The authors should also describe other unsuccessful attempts to purify the aldehyde (i.e other eluent systems).
Yes the author must change the title, schemes and text references to indicate that the hemiacetal product was actually isolated. The author can include a description of the hemiacetal as a protected aldehyde suitable for further manipulation. Unfortunately, as it is written now the manuscript is misleading.
Point 2: The author has not presented a mechanism but rather a reaction sequence. The caption and reference should be updated to reflect this.
Point 3. An LCMS of the reaction mixture would be helpful.
Point 4. The author should discuss the previous studies and their relevance to the present work in the text. The text should also be revised to reflect the fact that it is a suggested reaction sequence rather that based on experimental observations from the present reaction.
Author Response
Response to Reviewer 1 Comments
The author is thankful to the reviewer for the relevant comments. The author apologizes for not having met the requirements of the previous review. The reviewers' comments were analysed point by point and my responses are as follows:
Point 1: The author should indicate that methanol is crucial for efficient purification of the compound. The authors should also describe other unsuccessful attempts to purify the aldehyde (i.e other eluent systems).
Response 1: Based on the reviewer's comment I have added more details on the purification procedure.
Yes the author must change the title, schemes and text references to indicate that the hemiacetal product was actually isolated. The author can include a description of the hemiacetal as a protected aldehyde suitable for further manipulation. Unfortunately, as it is written now the manuscript is misleading.
Based on the reviewer's comments, I modified the title, scheme 1 and text of the manuscript to focus on the preparation of the hemiacetal derivative rather than the aldehyde.
Point 2: The author has not presented a mechanism but rather a reaction sequence. The caption and reference should be updated to reflect this.
Response 2: The captions of the schemes have been adapted as proposed by the reviewer.
Point 3. An LCMS of the reaction mixture would be helpful.
Point 4. The author should discuss the previous studies and their relevance to the present work in the text. The text should also be revised to reflect the fact that it is a suggested reaction sequence rather that based on experimental observations from the present reaction.
Responses 3 and 4: This work reports the synthesis of a new compound, meeting the criteria of Molbank journal. The insights into the mechanisms and the details on the reaction course, already published (ref. 9) and reasonably used as reference, are here not reported. Thanking the reviewer, the text has been modified according to the suggestions.
