Transformation of Linear Alkenyl N-Alkoxy Carbamates into Cyclic Bromo Carbonates

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

Cyclic carbonates are versatile compounds with diverse biological activities and broad applications in drug synthesis. Sathyamoorthi et al. present a protocol for the facile conversion of linear alkenyl N-alkoxy carbamates into cyclic bromo carbonates. This reaction is operationally simple, employs readily available and inexpensive reagents, and does not require rigorous exclusion of air or moisture. The manuscript demonstrates a solid foundation in research design and experimental methodology. However, the authors are encouraged to address the following points in their revision:

1) Are N-iodosuccinimide (NIS) and N-chlorosuccinimide (NCS) suitable alternatives for this reaction? A brief discussion on their compatibility would strengthen the study.

2) Formatting Corrections:

    The title should be revised to ensure proper formatting (e.g., "N-Alkoxy" instead of "N-Alkoxy").

    Chemical terms (e.g., CH₂Cl₂, CH₃CN, H₂O) should be consistently subscripted.

    Hyphenation errors (e.g., "carbamates," not "carba-mates"; "inexpensive," not "inexpen-sive"; "scalable," not "scal-able"; "transformed," not "trans-formed") must be corrected throughout the manuscript.

3) All references should be carefully reviewed. Journal titles should adhere to standard abbreviations or full names as per the required citation style.

Author Response

Cyclic carbonates are versatile compounds with diverse biological activities and broad applications in drug synthesis. Sathyamoorthi et al. present a protocol for the facile conversion of linear alkenyl N-alkoxy carbamates into cyclic bromo carbonates. This reaction is operationally simple, employs readily available and inexpensive reagents, and does not require rigorous exclusion of air or moisture. The manuscript demonstrates a solid foundation in research design and experimental methodology. However, the authors are encouraged to address the following points in their revision:

1) Are N-iodosuccinimide (NIS) and N-chlorosuccinimide (NCS) suitable alternatives for this reaction? A brief discussion on their compatibility would strengthen the study.

This is an excellent question, and we plan to study these reagents in a follow-up article.

2) Formatting Corrections:

    The title should be revised to ensure proper formatting (e.g., "N-Alkoxy" instead of "N-Alkoxy").

    Chemical terms (e.g., CH₂Cl₂, CH₃CN, H₂O) should be consistently subscripted.

    Hyphenation errors (e.g., "carbamates," not "carba-mates"; "inexpensive," not "inexpen-sive"; "scalable," not "scal-able"; "transformed," not "trans-formed") must be corrected throughout the manuscript.

We have now corrected all formatting issues. Thanks!

3) All references should be carefully reviewed. Journal titles should adhere to standard abbreviations or full names as per the required citation style.

We have now checked all references carefully. Thanks!

Reviewer 2 Report

Comments and Suggestions for Authors

Regarding the manuscript entitled 'Transformation of Linear Alkenyl N-Alkoxy Carbamates into 2 Cyclic Bromo Carbonates', submitted to Chemistry by Shyam Sathyamoorthi and Steven P. Kelly (manuscript number Chemistry-3667735). The authors present a protocol for the conversion of N-alkoxy carbamates into functionalised cyclic carbonates. The authors assumed the functionalisation of the double bond through fluorination, and were surprised to obtain a bromo derivative. The manuscript is well organised and written in a classic style. The unexpected discovery provides access to the interesting functionalisation of non-activated double bonds and produces cyclic products with good or excellent diastereoselectivity. This method is highly tolerable for a broad range of N-hydroxylamines and a variety of substituted alkens. The authors obtained products with good or very good yields. Branched alkenes (Scheme 3, Entry 7) and Z-configured alkenes (Scheme 3, Entries 1, 3 and 8) provided moderate yields.

 

Minor issues have been identified:

1. The plausible mechanism presented by the authors looks very reasonable. Could you explain examples 1–5 from Table 1? Does this reaction occur in a dry solvent, for example freshly distilled ACN?
2. Schemes 2 and 3 should be presented as tables.
3. Scheme 4 be renamed as a figure
4. While I understand that almost all of the substrates used in this paper are well known and have been published, at least one ¹H NMR should be attached.
5. The melting points of the solid products are missing.

Author Response

Regarding the manuscript entitled 'Transformation of Linear Alkenyl N-Alkoxy Carbamates into 2 Cyclic Bromo Carbonates', submitted to Chemistry by Shyam Sathyamoorthi and Steven P. Kelly (manuscript number Chemistry-3667735). The authors present a protocol for the conversion of N-alkoxy carbamates into functionalised cyclic carbonates. The authors assumed the functionalisation of the double bond through fluorination, and were surprised to obtain a bromo derivative. The manuscript is well organised and written in a classic style. The unexpected discovery provides access to the interesting functionalisation of non-activated double bonds and produces cyclic products with good or excellent diastereoselectivity. This method is highly tolerable for a broad range of N-hydroxylamines and a variety of substituted alkens. The authors obtained products with good or very good yields. Branched alkenes (Scheme 3, Entry 7) and Z-configured alkenes (Scheme 3, Entries 1, 3 and 8) provided moderate yields.

 

Minor issues have been identified:

1. The plausible mechanism presented by the authors looks very reasonable. Could you explain examples 1–5 from Table 1? Does this reaction occur in a dry solvent, for example freshly distilled ACN?

         We have seen marked reduction in yields with dry solvent, and we have discussed this in the revised manuscript. Thanks!

2. Schemes 2 and 3 should be presented as tables.

Yes, we agree that these schemes are "tabular" in nature, but we believe that they can still be called "schemes". 

3. Scheme 4 be renamed as a figure

Yes, we have kept the "schemes" nomenclature for the sake of consistency.

4. While I understand that almost all of the substrates used in this paper are well known and have been published, at least one ¹H NMR should be attached.

We have included the references for the NMR data in the supporting information. 

5. The melting points of the solid products are missing.

We apologize, but we do not have access to a melting point apparatus. 

Reviewer 3 Report

Comments and Suggestions for Authors

The manuscript presents a protocol for the transformation of linear alkenyl N-alkoxy carbamates into cyclic bromo carbonates. The reaction proceeds under mild, ambient conditions (CH₃CN, H₂O, room temperature, 3–24 h), using N-bromosuccinimide (NBS) as the bromine source and affording the target compounds in moderate to good yields (46–83%). The resulting bromo carbonates are shown to undergo nucleophilic substitution with azide, demonstrating their potential as synthetic intermediates. The reaction was performed on a 0.3–0.5 g scale, and several products—some of which may be novel—were characterized by ¹H and ¹³C{¹H} NMR, IR, and HRMS.

The transformation resembles an alkene functionalization strategy previously reported by the authors (J. Org. Chem. 2024, 89, 15352–15357). The current method appears straightforward and may offer an alternative approach to accessing cyclic carbonates of the type described. As such, the paper may be publishable, albeit it remains to be seen whether “work to be well-received by chemists engaged in the stereoselective construction of interesting heterocycles”. Some points should be addressed prior to publication.

First, the scale of the reaction (0.3–0.5 g) is modest and does not constitute a true “scale-up.” Typically, this term implies at least multigram quantities. The authors should adjust their wording in the manuscript accordingly.

The authors state that the protocol tolerates “a broad range of functional groups”, which is not sufficiently substantiated. Beyond ethers and Boc-protected amines, no evidence is presented for compatibility with other common functional groups such as nitro, aldehyde, carboxylic acid, alcohol, or halide moieties. The authors should either expand the scope or tone down the “broad range of functional groups” claim accordingly.

The authors suggest that the N–C bond of the methoxycarbamate hydrolyzes after cyclization to form the carbonate. However, could the carbamate first hydrolyze to a carbonate prior to cyclization? Could the reaction proceed directly from the carbonate form? The authors should comment on this possibility.

Some technical points.

References throughout the manuscript are not superscript.

In chemical formulas such as CH2Cl2, CH3CN, and H2O the numbers should be subscript (e.g., in lines 45 and 49). Line 100, “39” bold?.

The manuscript should be self-contained. Statements in the Supporting Information referring to procedures and characterization data on ChemRxiv (a free online preprint server) are inappropriate. The ChemRxiv document cited is unrelated to this manuscript, and any relevant material should be incorporated directly into the Supporting Information of the submitted version of this article.

Author Response

The manuscript presents a protocol for the transformation of linear alkenyl N-alkoxy carbamates into cyclic bromo carbonates. The reaction proceeds under mild, ambient conditions (CH₃CN, H₂O, room temperature, 3–24 h), using N-bromosuccinimide (NBS) as the bromine source and affording the target compounds in moderate to good yields (46–83%). The resulting bromo carbonates are shown to undergo nucleophilic substitution with azide, demonstrating their potential as synthetic intermediates. The reaction was performed on a 0.3–0.5 g scale, and several products—some of which may be novel—were characterized by ¹H and ¹³C{¹H} NMR, IR, and HRMS.

The transformation resembles an alkene functionalization strategy previously reported by the authors (J. Org. Chem. 2024, 89, 15352–15357). The current method appears straightforward and may offer an alternative approach to accessing cyclic carbonates of the type described. As such, the paper may be publishable, albeit it remains to be seen whether “work to be well-received by chemists engaged in the stereoselective construction of interesting heterocycles”. Some points should be addressed prior to publication.

1. First, the scale of the reaction (0.3–0.5 g) is modest and does not constitute a true “scale-up.” Typically, this term implies at least multigram quantities. The authors should adjust their wording in the manuscript accordingly.

         We only meant that the mmol scale was increased in a multi-fold way, thanks!

2. The authors state that the protocol tolerates “a broad range of functional groups”, which is not sufficiently substantiated. Beyond ethers and Boc-protected amines, no evidence is presented for compatibility with other common functional groups such as nitro, aldehyde, carboxylic acid, alcohol, or halide moieties. The authors should either expand the scope or tone down the “broad range of functional groups” claim accordingly.

We agree with Reviewer 3, but we have showcased a variety of groups in the article. 

3. The authors suggest that the N–C bond of the methoxycarbamate hydrolyzes after cyclization to form the carbonate. However, could the carbamate first hydrolyze to a carbonate prior to cyclization? Could the reaction proceed directly from the carbonate form? The authors should comment on this possibility.

We think that this is unlikely due to rapid decarboxylation as a competing pathway. 

We have carefully reviewed all formatting issues in the manuscript. We have given references only for known compounds, so that manuscript is self-contained. Thanks!