Methyl 8- and 5-Bromo-1,4-Benzodioxane-2-carboxylate: Unambiguous Identification of the Two Regioisomers

Round 1

Reviewer 1 Report

In the article entitled "HMBC NMR Analysis Unambiguously Establishes the 8- or 5-Bromo Substitution at Methyl 1,4-Benzodioxane-2-carboxylate", the authors described the synthesis of Methyl 1,4-Benzodioxane-2-carboxylate derivatives substituted in position 5 or 8 by a bromide. The authors deciphered the attribution of these two isomers of position by HMBC NMR analysis. The manuscript is clear, relevant for the field and presented in a well-structured manner. The manuscript is scientifically sound and the experimental design is appropriate to test the hypothesis emitted by the authors. However, the cited 8 references are self-citations.

The introduction presents clearly the subject and the hypothesis.

In the first paragraph of the Introduction, can the authors cite a reference for each mentionned target of the 1,4-benzodioxane instead to cite their review?

The Results and Discussion part is well driven. All the experiments are clear and relevant. The figures and schemes are appropriate and well presented.

The Conclusion is consistent with the evidence and arguments presented.

 

In the main text, some typos must be corrected by the authors:

-in the title, a space between "benzodioxane" and "-2-carboxylate must be deleted

-in the abstract : "bromo-1,4 benzodioxane-2-carboxylate" must be corrected in "bromo-1,4-benzodioxane-2-carboxylate"

-in scheme 1: "rection between polysubstituted" must be corrected in "reaction between polysustituted"

-page 3 line 74 : "exceeding" must be changed by "3 equivalents"

-page 3 line 96 : "diriment" must be changed by another adjective.

-figures 5 and 6 : the authors must mention the solvent used for the nmr experiments, for example "HMBC spectrum (recorded in C6D6) ..."

-p 6 lines 145-146 : "1H NMR spectra were recorded both
DMSO-d6 and in C6D6, while 13C NMR, HSQC and HMBC spectra were recorded in C6D6." must be changed in "1H NMR spectra were recorded in C6D6, while 13C NMR, HSQC and HMBC spectra were recorded in C6D6. Spectra can be also recorded in DMSO-d6."

-p6 line 155 : "assignable in the H NMR spectra" must be changed in "assignable in the ¹H NMR spectra"

 

In the supporting information, some typos must be corrected:

- p 2 and 5 : the integrations of both compounds 1 and 2 must be correctly attributed.

- p 2, 3, 5 and 6 : Can the authors make appear the peak picking for ¹H and ¹³C spectra ?

-p 8 : can the authors add the 13C nmr for each compound ?

-p 8 : for more homogeneity, the authors could give the nmr attribution in C6D6, and not in DMSO-d6

-p 8 lines 10 and 13 : "1H NMR" must be changed in "¹H NMR"

In this current state, I can recommand this manuscript for publication in MolBank journal after minor corrections, particularly the self-citations.

Author Response

We thank the reviewer for the valuable comments, that we hope to have understood and acknowledged. Here are our responses. 

1) Now, six references, which are not self-citations have been added. One of these, the most recent one (Eur. J. Med. Chem. 2023 in press; ref. 6) is very meaningful. It also cites our review (ref. 1) to support the importance of 1,4-benzodioxane in organic and medicinal chemistry. Furthermore, it is an excellent example of the synthetic strategies A (synthesis from 3-methoxycathecol) and B (acetylation of 2-substituted 1,4-benzodioxane). Our eight self-citations are not a stretch. Three are pertinent examples of X-substituted desymmetrized catechols used to construct benzodioxanes (refrences 7-9). Three are citations dealing with the importance of benzene decoration and C2 stereochemistry in benzodioxane medicinal chemistry (references 2-4), while the reference 5 (JOC) exemplifies the different approaches to obtain 2-substituted benzodioxanes in racemic or unichiral form. So, we think that the references section is now a well-balanced list of pertinent self- and non-self citations.

2) A reference for each mentioned target of 1,4-benzodioxane. The review (reference 1) is cited because it is an updated survey of the very numerous therapeutic applications of the benzodioxane based compounds. The applications mentioned in the sentence are only some of the applications reported in the literature. Any application would require more than one citation and some of these citations would be additional self-citations, and this, we understand, is to be avoided.

3) Typos have been corrected. "exceeding" has been replaced with "3 equivalents". "diriment" has been replaced with "conclusive". C6D6 has been reported in the captions of figures 5 and 6. Lines 145-146 has been modified as required.

4) The required modifications of the supporting informations have been made.

 

Reviewer 2 Report

The paper describes the one-step synthesis and characterization of methyl 8-bromo- and 5-bromo-1,4-benzodioxane-2-carboxylates. Despite its scientific soundness, the paper should be subjected to a minor check in terms of language and suffers from a few flaws in the first part, which requires a major revision.

 

As to minor revisions:

- line 3 (title): “of” instead of “at”

- line 63: references should be added to “because of their versatility as synthetic intermediates”, and the point should be developed more

- Scheme 1: The centre figure in the top box (“regioisomers mixture”) and the second one in the bottom box (“one regioisomer”) should be different, so as not to confuse the reader. Furthermore, the scope of Z, Y and R should be indicated in the scheme (at least their electronic properties as ERG or EWG groups, which is relevant from a reactivity standpoint)

- lines 91-94 (Figure 3 caption): The signal explanation should be moved to the main text body

 

As to the major revision, the paper title and its introduction are partially out of focus.

Regarding the title: being the synthesis and characterization of the two products the main aims of the work, why does it refer to the NMR technique? HMBC is routinely used to determine the structure of compounds, as a common basic tool. There is no novelty in such an approach to justify its importance in the title, which should be rewritten according to the usual style of other papers published in the same journal.

Regarding the introduction: the part between lines 34 and 58 is additional information with no relation to the following synthesis. While it is synthetically intriguing that the preparation of the described compounds can be carried out through various strategies, the Authors intentionally rely on the most basic one, which forms two regioisomers, in order to study them. As a result, the description of the methodology based on desymmetrized catechols loses its relevance, and the same can be said about its subsequent comparison with the non-regioselective preparation. Indeed, the problem of forming two products it is not tackled from then on.

Author Response

We thank the reviewer for the valuable comments, that we hope to have understood and acknowledged. Here are our responses. 

1) line 3: the title has been changed according to the reviewer's comment (see point 5)

2) line 63 (synthetic versatility): the point has been developed and references have been added (references 6 and 10-14)

3) Scheme 1. The scope of Z, Y and R has been indicated in the caption of the scheme. Two arrows have been designed in the strategy A' to indicate that such approach requires more than one step. The regioisomer cannot be differently represented in the two boxes, we think. Anyway, we have specified that the "one regioisomer" in the second box is (5-, 6-, 7- or 8-X). The regioisomers mixture in the top box can be of two (strategy A) or more (strategy B) regioisomers. This should be comprehensible. In strategy B, four positions of benzene are reactive in theory, while the 5- and 8-substituted isomers or the 6- and 7-substituted isomers will be produced depending on the starting cathecol (3-X or 4-X substituted, respectively). 

4) Figure 3 caption - signal explanation. We have added signals explanation in the main text.

5) The title of the manuscript has been rewritten avoiding to emphasize the HMBC technique, but underlying that the challenge of the research is the analytical characterization, not the synthesis which is "obvious" if the formation of only one of the two positional isomers is not the aim, as in the adopted strategy A.

6) Information about different synthetic strategies (lines 34-58). We rely on the most basic synthetic strategy A because it is the most simple one. The analytical study is a consequent necessity. Within this context, the description of the methodology based on desymmetrized cathecols (strategy A') is not irrelevant. It is to explain that there are other methods that avoid problematic identifications of regioisomers and also separations, sometimes unfeasible (see the new reference 6), of positional isomers, but that are more laborious because requiring many synthetic steps.

 

Round 2

Reviewer 2 Report

The Authors have properly edited the text according to the revision list, as well as convincingly counter-argumented the objections related to major issues.