Synthesis of 1,5-Disubstituted Tetrazoles in Aqueous Micelles at Room Temperature

Round 1

Reviewer 1 Report

Most important of all, this type of reactions has been reported: Org. Lett. 2016, 18, 19, 4762–4765 and Chemistry - A European Journal (2016), 22(9), 3009, Asian Journal of Organic Chemistry (2017), 6(7), 798 etc. These should be included in the citations, compared and discussed to demonstrate the progress the authors made.

In addition, Table 1 does not specify which substrates they applied.

The structure-drawing is not consistent throughout the manuscript.

Introduction is fragmented.

Author Response

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Author Response File: Author Response.doc

Reviewer 2 Report

This paper describes an useful procedure for synthesis of 1,5-disubstituted tetrazoles based on multi component Ugi reaction in “green” conditions using water as a solvent and long chain ammonium salt as micellar catalyst. All the compounds have been properly characterized.

This paper may be published after minor revision (see comments below).

Comments.

1. Figure 1, structure F: It has no sense to draw a stereochemical bold bond of methyl group on the tetrazole nitrogen, since there is an inversion of stereochemical configuration of the nitrogen.
2. Page 2, 2-nd paragraph, line 1: It should be “Ivar Ugi”.
3. Pages 3-4, Table 2: It is not clear what are the reaction conditions for reactions given in Table 2. What are yield (a) and yield (b)? Please, clarify that. Put a reaction scheme in a head of the Table.
4. Page 5, section General procedures: Please, check what is procedure A and B. In the current version, there are two procedure A. Are these procedures connected with Table 1 or 2? It is not clear from the text! Apart from that, I did not find any mention of TTAB in the procedures. Where is it in A or B? Did you really use it?
5. According to description of compound characterization, all the compounds were obtained by procedure A, which is not completely “green” since methanol use used as a solvent. What about procedure B?

Author Response

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Author Response File: Author Response.doc

Reviewer 3 Report

The manuscript should be re-structured in all sections. Overall, they did not follow the recommendations of the guideline for authors. In particular, ¹H and ¹³C NMR of all tetrazoles should be properly processed including integration of each signal (¹H NMR) and chemical shifts of proton and carbon signals (¹H and ¹³C NMR) after previous calibration with TMS (d = 0 ppm) or CDCl₃ (d = 7.26 ppm for 1H NMR and d = 77.16 ppm ¹³C NMR). According to the guideline of the Molbank, I consider that tetrazoles AM02, AM03, AM05, AM07 and AM09 could be removed of the manuscript because they are dirty. Additional comments and suggestions are included to improve this manuscript:

(1) Please, the title in minuscule.

(2) See abstract. The redaction should be improved. For instance: (a) one-pot instead of one pot, (b) the range of yields (xx-xx%) should be added, (c) the catalyst loading (xx.xx mol%) of TTAB should be included, (d) the following sentence it not clear “this approach is promoting for a green chemistry reaction of tetrazole”, (e) Ugi-azide four-component reaction for the synthesis of 1,5-disubstituted tetrazole instead of one pot Ugi azide reaction of 1,5-disubstituted tetrazole, (f) HRMS, IR, and 1D NMR experiments instead of ¹H NMR, ¹³C NMR and IR analyses, (g) the word “multicomponent reaction” or four-component reaction” should be included, and (h) the role of the catalyst (TTAB) should be briefly explained. You can use the following paper as a guide: (E)-3-[3-(2-Butoxyquinolin-3-yl)acryloyl]-2-hydroxy-4H-chromen-4-one, Molbank 2018, 2018 (3), 1001; https://doi.org/10.3390/M1001.

(3) See keywords. According to protocols reported for the synthesis of tetrazole derivatives, I consider that “one-pot” is not necessary to use in this manuscript. Please, Ugi-azide multicomponent reaction instead of Ugi azide reaction.  

(4) See introduction, ¿how are you citing the references? The guideline of Molbank should be carefully revised to see ¿how should it be included?. You can use the following paper as a guide: (E)-3-[3-(2-Butoxyquinolin-3-yl)acryloyl]-2-hydroxy-4H-chromen-4-one, Molbank 2018, 2018 (3), 1001; https://doi.org/10.3390/M1001.

(5) See Figure 1. (a) Roman numerals (I to VI) instead of letters (A-F), (b) the size of all structures, type and size of the letter should be the same, (c) SO_n into structure C is not clear (it should be improved).  

(6) See introduction. The spaces between words and punctuation marks should be revised. Some paragraphs should be unified by using appropriate connectors.

(7) See Results and discussion. (a) distilled water instead of pure water, (b) ambient temperature instead of room temperature, (c) the size of all structures, type and size of the letter should be the same in Scheme 1.

(8) See results and discussion. The explanation of the optimization process (entries 1-4, Table 1) is very disorganized as well as the redaction is not good. It is important to have present the following aspects: (a) the depth of the explanation of result´s entry 3 should be improved (i.e. ¿why in methanol (25 °C) the product was obtained in 68% yield while in water (25°C) was not possible?), (b) the depth of the explanation of result´s entry 4 should be improved (i.e. It corroborates that catalyst works very well in water (25 °C); however, a short paragraph should be included to explain ¿how is it acting?. For that reason, the paragraph wrote by authors could be included there: “It is of note to point-out that after introducing (TTAB), there was formation of micelles where most of organic substrates are concentrated. Those micelles are hydrophobic reaction site, which increase in the effective concentration of organic reactants, leading to an increase of reaction rate via concentration effect. Hence, organic substrates, in micellar solution, are pushed away from water molecules towards the hydrophobic core of micelles thus inducing efficient collision between organic substrate which enhances the reaction rate”.

(9) See Results and discussion. Authors mention that “Afterwards, we used a variety of electronically and structurally different aldehyde, amines, and isocyanides to obtain 1,5-DST, with presence of TTAB as catalyst. Moreover, the reaction was also performed under classical conditions using MeOH at room temperature”. (a) This paragraph should be added after explanation of the optimization process, (b) I did not find an explanation of advantages and differences of two protocols employed (see Table 2). From an organic point of view ¿which was better? ¿why?

(10) See Scheme 1. If you are performing an optimization process, the exact structure of the amine (1a), carbonyl compound (2a), isocyanide (3a), trimethylsilyl azide (4) and tetrazole (5a) should be drawn. In addition, all starting materials should have numeration like 1a, 2a, 3a, 4 and 5a (tetrazole).

(11) See title of the Scheme 1. Ugi-azide multicomponent synthesis of 1,5-DST catalyzed by TTAB instead of Synthesis of 1,5-DST.

(12) See title of the scheme 2. Plausible mechanism for the synthesis of 1,5-DST instead of Synthesis mechanism of 1,5-DST.

(13) See Scheme 2. Some intermediates are missing. For instance: iminium ion could be added. Additionally, the numeration of structures should be included as well as the size of all structures, type and size of the letter should be the same. See the arrow “ Ugi-azide” instead of “azide”.

(14) See explanation of the scheme 2. (a) The numeration of starting materials, intermediates and product should be included, (c) analyzing the plausible mechanism, it is important to explain which is the best protocol TTAB/MeOH versus TTAB/water in terms of the yield (i.e. in particular, the role of the water in the mechanism when nitrilium ion is attacked by water to afford an amide as by-product ¿did you isolate it?), (c) some references should be include to support the proposed mechanism.

(15) See table 2. (a) The numeration of all starting materials and products should be included, (b) below table 2 should indicate the condition reactions of two protocols [authors report two yields using conditions (a) and (b)].   

(16) See table 2. The structures of all synthesized tetrazoles should be indicated instead of starting materials. A simple solution is using a different color for each fragment (amine, carbonyl compound, isocyanide and azide). You can use the following article as a guide: Efficient catalyst-free four-component synthesis of novel γ-aminoethers mediated by a mannich type reaction. ACS Comb. Sci. 2013, 15, 2–9.  https://doi.org/10.1021/co300105t.

(17) See 3.1. Generalities. You can use the following paper as a guide: (E)-3-[3-(2-Butoxyquinolin-3-yl)acryloyl]-2-hydroxy-4H-chromen-4-one, Molbank 2018, 2018 (3), 1001; https://doi.org/10.3390/M1001. It is important to check the guideline of Molbank. For instance: (a) The name and country of the supplier of equipments should be used, (b) ¹H NMR instead of 1H NMR, (c) ¹³C NMR instead of 13C NMR, (d) 2D NMR experiments including COSY, HSQC and HMBC spectra were carried out to determine the assignation of carbon and proton signals instead of (Two-dimensional NMR spectroscopy [1H -1H COSY spectra, 1H -13C COSY spectra (HSQC) and long-range 1H -13C COSY spectra (HMBC)], were carried out to determine the correlation between 1H and 13C), (e) 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. 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”.

(18) See 3.2. General procedures. Some information is missing. For instance: (a) I did not find in the procedure the presence of the catalyst (10 mol%) ¿did you use it?, (b) Which is the aims to add (55-68 % yields) or (43-58 % yields) (i.e. connectors should be added).

(19) See spectroscopic characterization. (a) The name and numeration of each tetrazole should be included by using IUPAC nomenclature (chemdraw program), (b) authors should not numerate structures as you want because it is not according to the IUPAC nomenclature (i.e. these personal assignations might be removed). Overall, the reporting data should be improved.  You can use the following paper as a guide: (E)-3-[3-(2-Butoxyquinolin-3-yl)acryloyl]-2-hydroxy-4H-chromen-4-one, Molbank 2018, 2018 (3), 1001; https://doi.org/10.3390/M1001.

(20) See Supplementary Material. ¹H and ¹³C NMR of all tetrazoles should be properly processed including integration of each signal (¹H NMR) and chemical shifts of proton and carbon signals (¹H and ¹³C NMR) after previous calibration with TMS (d = 0 ppm) or CDCl₃ (d = 7.26 ppm for ¹H NMR and d = 77.16 ppm ¹³C NMR). You can use the following paper as a guide: (E)-3-[3-(2-Butoxyquinolin-3-yl)acryloyl]-2-hydroxy-4H-chromen-4-one, Molbank 2018, 2018 (3), 1001; https://doi.org/10.3390/M1001.

(21) See references. The guideline of the Molbank should be carefully revised.       

Author Response

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Author Response File: Author Response.doc

Round 2

Reviewer 1 Report

OK!

Author Response

Dear reviewer,

I have done my best to satisfy you and respond to the comments you have asked me. (see manuscript)

Reviewer 3 Report

Authors performed major modifications suggested by reviewers. However, I consider that is mandatory that ¹H and ¹³C NMR spectra of each synthesized compound should be properly processed and included in the Supplementary Material as suggested in the first revision. Additional comments and suggestions are included: 

(1) See lines 10-11. The institutional e-mail should be included.

(2) See Figure 1, Scheme 1, Scheme 2, Scheme 3, and Table 2. The size of all structures, the font and size should be unified. Overall, some structures are larger than others.

(3) See lines 96-97. Scheme 3 instead of Scheme 2. In this sense, it is necessary to carefully review the manuscript.

(4) See entries of the table 2. Thus, 1 instead of 01, 2 instead of 02, 3 instead of 03, etc.   

(5) See experimental section. All structures drawn should be removed. It is not necessary due to them are including in the table 2 (it is redundant). To corroborate this affirmation, you can unload any article recently published in Molbank as a guide.   

(6) See Supplementary Material. ¹H and ¹³C NMR of each synthesized compound should be processed including integration of each signal (¹H NMR) and chemical shifts of proton and carbon signals (¹H and ¹³C NMR) after previous calibration using the signal of the deuterated solvent CDCl₃ (d = 7.26 ppm for ¹H NMR and d = 77.16 ppm ¹³C NMR). To corroborate this affirmation, you can unload any article recently published in Molbank as a guide.

(7) See references. According to the guideline of Molbank, the DOI of each article should be included.    

Author Response

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Author Response File: Author Response.pdf