2,2^′-[2,4-Bis(4-chlorophenyl)cyclobutane-1,3-diyl]bis(8-bromo-6-chloro-3-nitroimidazo[1,2-a]pyridine)

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

 

This manuscript by Jacquet et al. reports formation of a tetrasubstituted cyclobutane via [2+2] cycloaddition of a 1,2-disubstituted alkene. While the compound is not the product intended by the authors, it is new to the existing literature and clearly characterized by NMR, MS, and single-crystal XRD. The manuscript is well organized, and thus this reviewer recommends its publication on Molbank after just several minor corrections and clarifications as listed below.

1.      Compound name: 2,2’- (single quotation) should be 2,2′- (prime).

2.      Line 40: The meaning of the acronym “TDAE” should be defined where it first appears.

3.      Scheme 2, caption: Suzuki-Miyaura (hyphen) should be Suzuki–Miyaura (en-dash).

4.      Scheme 2, caption: “Pd(dppf)Cl2” should be PdCl2(dppf). (Anionic ligands followed by neutral ligands.)

5.      Line 74-79: The need for the E à Z isomerization in advance of the [2+2] cycloaddition is not apparent at least from the information provided in the current version of manuscript. I believe that this hypothesis on the reaction mechanism is premature for publication and would be better proposed with additional supporting data in the future.

 

 

Author Response

Please see the attachment.

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

The authors presented their motivation for conducting this research in the introduction: the development of drugs targeting Neglected Tropical Diseases (NTDs), with a particular focus on leishmaniasis, which is an escalating issue in recent times. The publication characterizes a compound obtained unexpectedly as a byproduct.

The authors discussed their ongoing research on synthesizing compounds with antileishmanial activity through modifications of substituents in the 3-nitroimidazo[1,2-a]pyridine. Based on previous findings, they aimed to obtain a compound with a substituent positioned to optimize pharmacokinetic and physicochemical properties. The reaction was performed using the Suzuki-Miyaura cross-coupling reaction. However, the obtained product differed from the intended target. The publication provides a detailed characterization of this unexpected compound. The justification for the study, as presented, is coherent and serves as a solid foundation; the decision to report on the unexpectedly obtained compound is, in my opinion, justified, as it sheds light on such compounds, which are not extensively covered in the available literature.

In the Results section, the authors described the synthetic route to the compound in question (4). It was a three-step synthesis leading to the intermediate (3). They also provided the conditions for the Suzuki-Miyaura cross-coupling reaction and the expected product. The authors confirmed the source of compound (4) by conducting an analogous reaction, demonstrating that the use only K₂CO₃ leads to the formation of compound (4).

In the Discussion section, the authors proposed a hypothesis for the formation mechanism of the compound, suggesting the formation of an alkene intermediate, followed by E → Z isomerization of this alkene, and a subsequent [2+2] cycloaddition reaction. This hypothesis is supported by literature examples. In my opinion, conducting quantum-chemical calculations for this reaction would further substantiate the proposed hypothesis, though I acknowledge this may exceed the scope of the current article.

Compound (4) was isolated and characterized by spectroscopic analysis (¹H and ¹³C NMR, HRMS, and X-ray crystallography), which are thoroughly detailed in the Materials and Methods section, where preparative procedures are also provided.

In the General Information section, TLC is mentioned; however, there is no explicit reference to the use of this technique in the experimental descriptions.

In Materials and Methods, the full name of the compound "tetrakis(dimethylamino)ethylene" is used without abbreviation, while in the Results section, only the abbreviation "TDAE" is provided. For consistency, it would be preferable to introduce the full name with the abbreviation at first mention and then use only the abbreviation.

In the Supplementary Information, files with spectral characterization are provided in various formats (.jpg, .pdf), labeled with provisional sample names. I recommend consolidating all spectra in a single file and labeling them clearly, which would enhance functionality and clarity. Additionally, X-ray crystallography files should be included in the SI.

Despite these minor adjustments, I recommend the article for publication.

Author Response

Please see the attachment.

Author Response File: Author Response.pdf