Tetramethyl 1,1′-(2-[{4,5-bis(Methoxycarbonyl)-1H-1,2,3-triazol-1-yl}methyl]-2-[(4-methylphenyl)sulfonamido]propane-1,3-diyl)bis(1H-1,2,3-triazole-4,5-dicarboxylate)
, Salaheddine Boukhssas 1, Hassane Faraj 1 and Anouar Alami 1,*Round 1
Reviewer 1 Report
A. Alami and co-workers describe the synthesis and characterization of one tris-tetrazole prepared via two-stepped linear strategy involving a SN2 coupled to a [3+2] dipolar cycloaddition, in a good overall yield. I found this paper suitable for publication in the Molbank journal practically in its present form. The introduction part shows suitably the context of the chemistry involved. After searching in databases, I found that effectively this compound has not been reported anywhere. The results, experimental part and characterization are described in detailed manner. 2D-NMR was described masterfully. Supplementary material confirms unequivocally the structure of the product. Conclusions are well supported. Nice job guys!!
Author Response
Dear reviewer
All the authors thank you for the time you took to evaluate our research work.
Best regards
Prof. Anouar Alami
Reviewer 2 Report
The present manuscript by Serigne Abdou Khadir Fall et al describes the synthesis of a new tetra-triazole derivative. It is a well-written paper and the presented methodology might be useful to researchers in the field of syntheses of tetra-triazoles. Overall, the results are interesting and merit publication after one minor revision. In page 1 and line 43 the phrase "In the same wake,” should change "In the same way,”
Author Response
Dear reviewer
All the authors thank you for the time you took to evaluate our research work.
Please find attached the revised version of our manuscript.
Bets regards
prof. Anouar Alami
Author Response File: 
Author Response.docx
Reviewer 3 Report
Tetramethyl 1,1'-(2-[{4,5-bis(methoxycarbonyl)-1H-1,2,3-triazol-1-yl}methyl]-2-[(4-methylphenyl)sulfonamido]propane-1,3-diyl)bis(1H-1,2,3-triazole-4,5-dicarboxylate). I consider that manuscript is more according to “short note” instead of “communication”; however, the final decision would correspond to the scientific editor. Overall, the manuscript should be re-structured in all sections. Although compounds 2 and 3 have not been reported in Reaxys database, the manuscript does not have a scientific rigor. Additional comments and suggestions are included to improve this manuscript:
(1) See title. The prefix “bis” should be in italic. It should be revised in all manuscript.
(2) See abstract, line 17. in two steps instead of in two stages.
(3) See abstract, line 19. copper-free Huisgen cycloaddition instead of cycloaddition reaction.
(4) See abstract, line 20. commercially available dimethyl acetylenedicarboxylate instead of commercial dimethyl acetylenedicarboxylate.
(5) See abstract, line 21. was determined by IR, 1D and 2D NMR experiments, and elemental analysis instead of was confirmed by IR, NMR 1D and 2D, and elemental analysis. It is important to mention that word “confirmed” is commonly employed by X-ray diffraction analysis.
(6) See keywords, lines 22-23. From an organic point of view, the keywords should be improved. For instance: 1,3-dipolar cycloaddition instead of dipolar-1,3 cycloaddition. You can include as keywords “copper-free Huisgen cycloaddition” and “nucleophilic substitution reaction”. The keywords substitution reaction and 2D NMR experiments should be replaced.
(7) See introduction. It should be improved. For instance: (a) I did not find a paragraph explaining the differences between copper-free Huisgen cycloaddition versus copper-catalyzed azide−alkyne cycloaddition (CuAAC) in terms of regioselectivity of the 1,2,3-triazole product, reaction rate, yield, reaction times, and mild reaction conditions. I understood that symmetric alkyne would afford only one product; however, the drawbacks of this protocol involves long reaction time (i.e. 72 hours), high temperature (i.e. approximately 110 °C) due to its low reaction rate, and toxicity of the solvent (i.e. toluene instead of water or ethanol) in compare with the CuAAC reaction, and (b) it is not clear the goal to synthesize the product 3 in the introduction; for instance, a short paragraph could be included: the tris(triazolyl)amine-bearing ligands has been widely applied to protect Cu(I) from oxidation and disproportionation; thus, these drawbacks would not be relevant. You can use the following paper as potential guide: ACS Omega 2020, 5, 30148, doi: 10.1021/acsomega.0c04592.
(8) See introduction, lines 39-40. Authors mention that “This cycloaddition reaction has been widely used in our laboratory [11-20] for the synthesis of new triazole compounds, precursors of heterocyclic amino acids”. The references [11-20] should be included at the end. Overall, authors should try the novel tris(triazolyl)amine-bearing ligand in the CuAAC reaction in a future project using mainly terminal alkynes.
(9) See introduction, line 53. was fully characterized instead of was characterized.
(10) See introduction, lines 53-54. by 1D and 2D NMR, IR, and elemental analysis (see Supplementary Materials) instead of by 1D-NMR (1H, 13C), 2D-NMR (1H1H, 1H13C), IR, and elemental analysis (Supplementary Materials).
(11) See introduction. copper-free Huisgen cycloaddition reaction instead of dipolar cycloaddition reaction.
(12) See introduction, lines 51-52. The numeration of the compounds should be included.
(13) See Scheme 1. (a) The final product did not have numeration, (b) the reaction time of each step should be included, and (c) the yield of products 2 and 3 should be included.
(14) See results and discussion, lines 56-70. From an organic point of view, the explanation should be improved.
(15) Line 82. triazole rings instead of triazole cycles.
(16) Line 87. tris-triazole derivative instead of tri-triazole derivative.
(17) Line 88. This sentence should be improved (i.e. the presence of methoxy groups in α of the carbonyl group). The concept of “alpha” position is not well used.
(18) Lines 92-98. The vibrational analysis should be improved.
(19) See table 1. The 13C NMR reporting data should include only one decimal after the point
(20) See Materials and Methods. The following paragraph could be included: “NMR spectroscopic data were recorded in CDCl3 using as internal standards the residual non-deuterated signal (d = 7.26 ppm) for 1H NMR and the deuterated solvent signal (d = 77.16 ppm) for 13C NMR spectroscopy. DEPT spectra were used for the assignment of carbon signals. Chemical shifts (d) are given in ppm and coupling constants (J) are given in Hz. The following abbreviations are used for multiplicities: s = singlet, d = doublet, t = triplet, q = quartet, dd = doublet of doublets, and m = multiplet”.
(21) See 3.1. Synthesis of N-(1,3-diazido-2-(azidomethyl)propan-2-yl)-4-methylbenzenesulfonamide (2), lines 122-133. (a) The CAS of the commercially available chemical reagents should be included, (b) the amount of each starting materials in mg should be added in parenthesis, (c) 1H NMR reporting data should have the following order: (multiplicity, coupling constant, integration, and assignation); moreover, if you are reporting a signal as a doublet, you can not report the chemical shift as a range xx-xx, (d) 3J = instead of 3JH-H = (it should be revised for compounds 2 and 3), (e) 300 MHz instead of 300.13 MHz, (f) 75 MHz instead of 75.47 MHz, (g) the 13C NMR reporting data should include only one decimal after the point.
(22) See 3.1. Synthesis of N-(1,3-diazido-2-(azidomethyl)propan-2-yl)-4-methylbenzenesulfonamide (2). The assignation of some bands of the infrared spectrum are not corrected (i.e. 1580 and 1350 cm-1). It should be carefully revised.
(23) See 3.1. Synthesis of N-(1,3-diazido-2-(azidomethyl)propan-2-yl)-4-methylbenzenesulfonamide (2). MS and elemental analysis should be included. This compound has not been reported in Reaxys database.
(24) Lines 137-153. (a) The CAS of the commercially available chemical reagents should be included, (b) the amount of each starting materials in mg should be added in parenthesis, (c) 1H NMR reporting data should have the following order: (multiplicity, coupling constant, integration, and assignation); moreover, if you are reporting a signal as a doublet, you can not report the chemical shift as a range xx-xx, (d) 3J = instead of 3JH-H = (it should be revised for compounds 2 and 3), (e) 300 MHz instead of 300.13 MHz, (f) 75 MHz instead of 75.47 MHz, (g) the 13C NMR reporting data should include only one decimal after the point.
(25) Lines 137-153. The correlation of some bands with vibration modes into infrared spectrum are not corrected (i.e. 1580 and 1300 cm-1). It should be carefully revised.
(26) Lines 137-153. MS data should be included. This compound has not been reported in Reaxys database.
(27) See supporting information of compound 1. MS spectra should be included.
(28) See supporting information of compound 2. HMBC and MS spectra should be included.
(29) See supporting information of compound 3. HMBC and MS spectra should be included.
(30) See conclusion. It should be improved including more scientific results. It is important to add a short paragraph related to potential applications of the synthesized compound 3 into medicinal chemistry, drug discovery or copper(I)-stabilizing ligand in the CuAAC reaction.
(31) See Supplementary Material. The title of the Figure S2 of each PDF file did not correspond to 13C NMR.
(32) See Supplementary Materials (SM) or Supporting Information (SI). Three PDF files for compounds 1-3 should be unified in only one PDF file (it is mandatory).
(33) See Supplementary Materials, lines 161-171. (a) I consider that names of 2D experiments should be included (i.e. HSQC, HMBC, COSY and NOESY), and (b) if you have only one PDF file for Supporting Information, the numeration of all figures should be modified.
(34) See references. The doi of each article should be included.
(35) See Figure 1. If compound 3 has symmetry ¿why did you use a different numeration for each triazole ring.
Author Response
Dear reviewer
All the Authors thank you for your efforts and comments aimed to improve the quality of our manuscript.
Please find attached the revised version of our manuscript “ Tetramethyl 1,1'-(2-[{4,5-bis(methoxycarbonyl)-1H-1,2,3-triazol-1-yl}methyl]-2-[(4-methylphenyl)sulfonamido]propane-1,3-diyl)bis(1H-1,2,3-triazole-4,5-dicarboxylate). You will find below the answers to your comments and suggestions, point by point.
Best regards
Prof. Anouar Alami
Author Response File: 
Author Response.pdf
Round 2
Reviewer 3 Report
Authors performed modifications suggested by reviewers.
