N-(3-(tert-Butyl)-1-methyl-1H-pyrazol-5-yl)-4-methyl-N-tosylbenzenesulfonamide
Round 1
Reviewer 1 Report
Comments and Suggestions for AuthorsThis short note on the synthesis, NMR/IR spectroscopic analysis and HRMS of a sulfonamide-substituted pyrazole derivate fits well the scope of the Topical Collection: Heterocycle Reactions. Although the manuscript is a spin-off of related article on the sulfonylation of heterocycles using arylsulfonyl chlorides cited in ref 21 and 22, the content is of sufficient originality and quality deserving publication. The fact that some sulfonamide-derivatives display an important biological activity also justifies the investigation of this family of N-heterocycles.
Before acceptance, I suggest just some minor improvements:
- Scheme 1 would also benefit from some coloration.
In ref 21 and 22 the authors use DCM as solvent, why they switch to MeCN for the preparation of the title compound ?
- Say some words concerning the consistency and color of compound 3.
- Is 4-methylbenzenesulfonyl chloride 2 a commercial product or was is it synthesized (ref ?)
- A important point is the NMR-spectroscopic analysis of the final product 3. However, its difficult to follow the discussion since the NMR spectra are hidden in the Supplementary Material. The NMR spectra should be moved from the Supplementary Material into the main text, thus facilitating the discussion.
-The 1H NMR spectra are shown in a wide range from -1.5 to 10.5 ppm. Showing them in a narrower range from 0-8.5 ppm would be sufficient, allowing to spread the resonances and to better identify the pattern of some multiplets in the aromatic region. Iti s in my opinion also sufficient to show the 13C NMR spectra only in the 0-180 ppm range.
Comments on references:
I agree that 5 self-citations for just 23 references in total represents a quite high pourcentage.
However, references 8 and 9 provide useful complementary informations for the introduction concerning the biological importance of pyrazole derivatives, whereas ref 21-23 deal on synthetic protocols for attaching a sulfonamide moiety. So I’m not particularly worried about this.
Author Response
This short note on the synthesis, NMR/IR spectroscopic analysis and HRMS of a sulfonamide-substituted pyrazole derivate fits well the scope of the Topical Collection: Heterocycle Reactions. Although the manuscript is a spin-off of related article on the sulfonylation of heterocycles using arylsulfonyl chlorides cited in ref 21 and 22, the content is of sufficient originality and quality deserving publication. The fact that some sulfonamide-derivatives display an important biological activity also justifies the investigation of this family of N-heterocycles. Before acceptance, I suggest just some minor improvements:
(1) Scheme 1 would also benefit from some coloration.
R/ Thanks reviewer for valuables suggestions. It was included.
(2) In ref 21 and 22 the authors use DCM as solvent, why they switch to MeCN for the preparation of the title compound?
R/ In references 21 and 22, dichloromethane was used as the solvent. However, for the preparation of the title compound, we opted for acetonitrile due to its lower toxicity and environmental impact. As a greener alternative, MeCN is less harmful than DCM, a halogenated solvent with known carcinogenic and environmental risks.
(3) Say some words concerning the consistency and color of compound 3.
R/ It was included.
(4) Is 4-methylbenzenesulfonyl chloride 2 a commercial product or was is it synthesized (ref ?)
R/ Starting material 2 is commercially available.
(5) A important point is the NMR-spectroscopic analysis of the final product 3. However, its difficult to follow the discussion since the NMR spectra are hidden in the Supplementary Material. The NMR spectra should be moved from the Supplementary Material into the main text, thus facilitating the discussion.
R/ In accordance with the Molbank formatting guidelines, this information has been included in the Supplementary Material. The 2D NMR spectra are provided therein, and Table 1 has been added to the manuscript to present the 1D and 2D NMR signal assignments and correlations for compound 3.
(6) The 1H NMR spectra are shown in a wide range from -1.5 to 10.5 ppm. Showing them in a narrower range from 0-8.5 ppm would be sufficient, allowing to spread the resonances and to better identify the pattern of some multiplets in the aromatic region. Iti s in my opinion also sufficient to show the 13C NMR spectra only in the 0-180 ppm range.
R/ It has been revised accordingly. Moreover, the 2D NMR spectra have been included.
(7) I agree that 5 self-citations for just 23 references in total represents a quite high pourcentage. However, references 8 and 9 provide useful complementary informations for the introduction concerning the biological importance of pyrazole derivatives, whereas ref 21-23 deal on synthetic protocols for attaching a sulfonamide moiety. So I’m not particularly worried about this.
R/ Thanks reviewer for valuables suggestions. In accordance with the suggestions made by Reviewer 2, the following paragraph was removed: “Building on our previous studies on the sulfonylation of heterocyclic compounds [21,22], 3-(tert-butyl)-1-methyl-1H-pyrazol-5-amine (1) was synthesized following a previously reported procedure [23].’” Additionally, references [21] and [22] were removed from the manuscript.
Reviewer 2 Report
Comments and Suggestions for AuthorsThe authors present an efficient synthesis of N-(3-(tert-butyl)-1-methyl-1H-pyrazol-5-yl)-4-methyl-N-tosylbenzenesulfonamide by the use of 3-(tert-butyl)-1-methyl-1H-pyrazol-5-amine and 2 equivalents each of 4-methylbenzenesulfonyl chloride and triethylamine.
The introduction describes clearly and comprehensibly the use of pyrazole in chemistry as well as in biology and pharmacology. Pyrazoles have a good record in drug discovery. The provided introduction was extracted from a recent good number of research articles and reviews.
A very good structure analysis of the single product was deduced from FT-IR, 1H and 13C NMR and DEPT-135 NMR experiments whereas HRMS confirmed the molecular formula of the product.
The description of the structure of the product using 13C NMR and DEPT-135 NMR could be improved by mentioning the equivalent carbon atoms for the methyl carbon atoms and the methine carbon atoms. Thus, the total number of carbon atoms will be presented as 22. This should also be done in the Experimental section for the 13C{1H} data.
The spectra provided in the Suppl. Info. are of very good quality and in general the manuscript is written in very good English. These are however a few typographical mistakes and grammatical errors.
Two indicative errors:
Line 32: “has garnered significant” change to “has gathered significant”
Line 66: “ratio of 1:2:2.4 in acetonitrile” change to “ratio of 1:2:2 in acetonitrile”
After these minor corrections the manuscript could be resubmitted for publication in Molbank
Comments on references:
I checked references 21-23 and confirm that they do not add any significant information to the manuscript since they are very general. References 21 and 22 refer to another heterocyclic system whereas the reported procedure in 23 is difficult to find and confusing. I therefore suggest that the following sentence be removed which means that the authors should renumber references throughout the text.
"Building on our previous studies on the sulfonylation of heterocyclic compounds [21,22], 3-(tert-butyl)-1-methyl-1H-pyrazol-5-amine 1 was synthesized following a previously reported procedure [23]."
References 8 and 9 provide information which is relevant to pyrazole (biological and pharmacological properties).
Author Response
(1) The description of the structure of the product using 13C NMR and DEPT-135 NMR could be improved by mentioning the equivalent carbon atoms for the methyl carbon atoms and the methine carbon atoms. Thus, the total number of carbon atoms will be presented as 22. This should also be done in the Experimental section for the 13C{1H} data. The spectra provided in the Suppl. Info. are of very good quality and in general the manuscript is written in very good English. These are however a few typographical mistakes and grammatical errors.
R/ Thanks reviewer for valuables suggestions. It has been included in both sections. Moreover, the 2D NMR spectra are provided therein, and Table 1 has been added to the manuscript to present the 1D and 2D NMR signal assignments and correlations for compound 3.
(2) Line 32: “has garnered significant” change to “has gathered significant”
R/ It was included.
(3) Line 66: “ratio of 1:2:2.4 in acetonitrile” change to “ratio of 1:2:2 in acetonitrile”
R/ It was included.
(4) I checked references 21-23 and confirm that they do not add any significant information to the manuscript since they are very general. References 21 and 22 refer to another heterocyclic system whereas the reported procedure in 23 is difficult to find and confusing. I therefore suggest that the following sentence be removed which means that the authors should renumber references throughout the text. "Building on our previous studies on the sulfonylation of heterocyclic compounds [21,22], 3-(tert-butyl)-1-methyl-1H-pyrazol-5-amine 1 was synthesized following a previously reported procedure [23]." References 8 and 9 provide information which is relevant to pyrazole (biological and pharmacological properties).
R/ It was removed from the manuscript.
