Hydrazine Derivatives as C-Centered Radical Precursors for C-C Bond Formation Reactions
Round 1
Reviewer 1 Report
Comments and Suggestions for AuthorsThis review summarizes the synthetic application of monosubstituted hydrazine derivatives (arylhydrazines, carbazates, acylhydrazides, hydrazine carboxamides and alkylhydrazines) in free-radical C-C bond forming reactions, such as (a) alkene difunctionalization, (b) cascade cyclization starting from acrylamides and isonitriles, and (c) CH-functionalization of (hetero)arenes. This is a very nice review paper, well organized and comprehensively described. Due to the importance of C-centered radicals in organic synthesis, this review should be scientifically sound.
Before publication, some minor issues should be considered.
- page 1, lines 23-24, the reference should be placed here.
- It is too difficult to understand the contents in Scheme 1. If possible, divide it into four subschemes, and draw more detailed structures.
- In scheme 6, 7, and 9, it better to give the structure of heterocycles, not to give the names.
- In table 1, 3, 4, 5, 6, 7, better replace HD with RNHNH2 or something more appropriate.
- In some schemes, the blank between numbers and units (M, h) are missing.
- Through the manuscript, the compounds are not numbered. It is not easy to catch which compound the text is discussing.
Author Response
Dear Reviewer,
Thank you for attentive reading of the manuscript and giving valuable comments that helped us to significantly improve the paper. The step-by-step answers to all comments are listed below. The illustrated version of answers is attached in PDF format.
Reviewer’s comment: This review summarizes the synthetic application of monosubstituted hydrazine derivatives (arylhydrazines, carbazates, acylhydrazides, hydrazine carboxamides and alkylhydrazines) in free-radical C-C bond forming reactions, such as (a) alkene difunctionalization, (b) cascade cyclization starting from acrylamides and isonitriles, and (c) CH-functionalization of (hetero)arenes. This is a very nice review paper, well organized and comprehensively described. Due to the importance of C-centered radicals in organic synthesis, this review should be scientifically sound.
Answer: Thank you for the high evaluation of the manuscript!
Reviewer’s comment: Before publication, some minor issues should be considered.
- page 1, lines 23-24, the reference should be placed here.
Answer: The reference to the pioneering work was added:
Old version: The first examples of the carbon-centered radical generation from hydrazine derivatives started emerging at the end of the 20th century.
Corrected version: The first examples of the carbon-centered radical generation from hydrazine derivatives started emerging at the end of the 20th century.[1]
Reviewer’s comment: 2. It is too difficult to understand the contents in Scheme 1. If possible, divide it into four subschemes, and draw more detailed structures.
Answer: Thank you for the note, we agree that the Scheme 1 was difficult to understand and thus we did our best to improve it. It was important to show the same general formula of the starting materials, so general structure of the scheme was retained. We have added details regarding substituents for each method (a–g) and improved the design.
Old version:
Corrected version:
Reviewer’s comment: 3. In scheme 6, 7, and 9, it better to give the structure of heterocycles, not to give the names.
Answer: The structures of the heterocycles are now shown in the selected scope sections of Schemes 6, 7, and 9.
Reviewer’s comment: 4. In table 1, 3, 4, 5, 6, 7, better replace HD with RNHNH2 or something more appropriate.
Answer: The abbreviation “HD” was introduced in the review's introduction and is also defined in the “Abbreviations” section. To avoid overloading the tables visually with various notations for different hydrazide derivatives, we used this shorter, unambiguous abbreviation.
Reviewer’s comment: 5. In some schemes, the blank between numbers and units (M, h) are missing.
Answer: Thank you for the note. The space was added where needed.
Reviewer’s comment: 6. Through the manuscript, the compounds are not numbered. It is not easy to catch which compound the text is discussing.
Answer: The compounds and intermediates referenced in the text are designated with capital letters (A, B, etc.). As you noted, this aids clarity; therefore, we have added more such designations to the schemes where mechanistic steps are discussed (for example, Schemes 9, 11).
Author Response File: 
Author Response.pdf
Reviewer 2 Report
Comments and Suggestions for AuthorsIn this review, the authors summarise recent findings in the use of hydrazine derivatives as synthetically accessible and stable carbon-centred radical precursors for C–C bond formation. Indeed, it represents an atom-economical approach. The authors highlight major developments in alkene difunctionalisation, cascade cyclisations involving acrylamides and isonitriles, and (hetero)arene C–H functionalisation. The authors also reported current limitations. Finally, authors emphasise the limited number of examples involving aliphatic radical substitution and alkyne functionalisation. Overall, this review provides a comprehensive overview of the field while pinpointing key challenges that remain to be addressed. Therefore, I will recomand this article for the publication after through revision of the current manscript.
Line 36, The authors state: 'Currently, hydrazine derivatives (HD) constitute a privileged class of C-centred radical precursors for diverse synthetic applications.' To enhance the clarity and informativeness of this statement, I suggest the authors provide a few representative examples of these applications.
A few recommendations for Figure 1
Figure 1 contains many sections. I suggest labelling them clearly as (a), (b), and (c), and ensuring the corresponding text refers to these labels. This would improve clarity and help the reader follow the discussion more easily.
The legend should be more descriptive and clearly convey the key message of each of these sections shown in the figure. A more detailed legend would improve clarity and help readers better understand the distinctions between the individual components.
In the third part of the figure, some of the reactants labelled as 1 and 2 do not clearly convey a meaningful message. Therefore, I suggest either removing these labels or providing an explanation in the text. Additionally, I recommend removing the word etc. mention at the bottom of the scheme.
While I understand that this is an introductory section, the figure presents a lot of information that has not been completely explained in the main text. To improve clarity, I suggest simplifying the scheme and ensuring that key information is included in the text. Additionally, the text should be clearly connected to the figure to help the reader follow the material more easily.
The authors state: 'The presence of a base is critical for the reaction's success; in this case, DABCO serves this essential role in both chemical and photochemical approaches (Scheme 1, d, e).' I am curious if the authors could elaborate on what they mean by the “crucial role” of the base. Specifically, what mechanistic function does DABCO serve in these chemical and photochemical contexts?
I suggest that the authors should mention what R represents in the scheme 1.
Line 140-143: I suggest that the authors provide the reaction yields for the transformations mentioned.
In Scheme 2, the authors mention 3–82%, which is somewhat confusing. Does the 3% represent the lowest yield for these reactions? It would be helpful to clarify this in the main text. Currently, the only yield mentioned is 60% for a particular reaction, but it would be valuable to address the potential limitation if the 3% yield is the result for a specific set of reactions. I suggest the authors review this section, provide a clear yield range, and ensure the text accurately references the molecular number and corresponding yields.
Same for scheme 4 and rest of the manucsript.
It is unclear to me the use of variuos colors in the scheme/figures. For example, in scheme 3, i-Pr and Bn marked as red? any reson for that? if so please highlight the facts in the manin text. same for scheme 2 and rest of the manuscript where it is apliicable.
In most of the schemes, the authors mention Ar but do not specify what it represents. Could the authors provide some representative examples of Ar in the same way they did for R, for example, in Scheme 5?
Line 188, Authors stated 'However, the yields for these substrates did not exceed 50%.' Any thoughts or plausible explanations to account for the moderate yiled of the product?
Scheme 8, the notation 4-NO₂C₆H₄ appears to represent a failed reaction. If this is the case, could the authors please mention this in the text as well?
In general, when the authors describe reaction mechanisms, such as in Scheme 8 and Scheme 9, it would be helpful if they numbered the molecules/intermediates and referred to these numbers in the text. This would make it easier for readers to follow the mechanisms and understand the steps more clearly.
Line 219, please give a refernce to support your sratemnet.
Line 228, if the authors state that the reported method is sustainable, it would be helpful to provide additional information or data to support this statement (if its reported in the original paper).
Line 234: The authors mention Scheme 11 discussed above,but Scheme 11 actually appears after this paragraph. I suggest the authors modify this statement.
In Scheme 11, the representation of deprotonation of the iminyl cation using BH with a lone pair looks a bit unusual. I suggest replacing this with a generic base representaion and providing examples of bases that are used for deprotonation in these type of the reactions.
I had some difficulty understanding Table 1. I suggest reconsidering the best way to present the information the authors wish to highlight. If the goal is to emphasise the different reaction conditions and the use of various oxidants along with their corresponding outputs, I recommend removing the green bulb and their notaions. If, on the other hand, the authors intend to show the functional groups or substituents, then it would be helpful to specify what X, R1, and R2 represent. Additionally, I suggest including the structure of the products along with their yields for better clarity. Alternatively, simply listing the different oxidation conditions along with their references should be sufficient. These are just my thoughts on how to make the table more readable.
Line 274, please provide a reference to support your statment.
Line 308, the authors mention the excellent diastereoselectivity, where the alkoxycarbonyl radical preferentially attacks the neutral vinyl moiety. Could the authors please explain why this occurs?
Scheme 18, Could the authors specify what type of (hetero)aromatic systems have been explored?
Line 348, The authors mention 'electron-withdrawing substituents.' Could the authors please specify which functional groups are being referred to here?
Line 375, The authors state, 'however, the PhCF3 solvent here was slightly more efficient than PhF.' It's helpful that the authors refer to the SI for more details, but a concise explanation of why PhCF3 is more efficient would be valuable in the main text as well.
Scheme 20, the colors used to represent X are not very clear.
Schem 21, in the proposed mechanism, the structure drawn as CH2O2Me appears to be incorrect. Could the authors please correct this?
Line 440, I suggest modifying the sentence 'two pyridine-type nitrogen atoms' to refer to the structure mentioned in Scheme 24. they can be called as quinoxaline and its derivatives.
Scheme 25, The authors represent a salt as x HCl. Could the authors please explain the rationale behind this notation? In contrast, Scheme 24 uses a dot, which I believe is the correct way to represent the salt.
Line 476, should be 'It turns out' instead of In turns out.
Line 604, Ortho should be italicised.
The representation in Scheme 33 could be improved for clarity.
Could the authors please check if R = CO2Me is correct in Scheme 37b? I believe R in the product should be OMe instead.
In Scheme 37b (mechanism part), could the authors please check the structure of the multicomponent product? It should not be in its radical form, and the final product should have a hydrogen atom at the N center. Please review.
Author Response
Dear Reviewer,
Thank you for attentive reading of the manuscript and giving valuable comments that helped us to significantly improve the paper. The step-by-step answers to all comments are listed below. The illustrated version of answers is attached in PDF format.
Reviewer’s comment: In this review, the authors summarise recent findings in the use of hydrazine derivatives as synthetically accessible and stable carbon-centred radical precursors for C–C bond formation. Indeed, it represents an atom-economical approach. The authors highlight major developments in alkene difunctionalisation, cascade cyclisations involving acrylamides and isonitriles, and (hetero)arene C–H functionalisation. The authors also reported current limitations. Finally, authors emphasise the limited number of examples involving aliphatic radical substitution and alkyne functionalisation. Overall, this review provides a comprehensive overview of the field while pinpointing key challenges that remain to be addressed. Therefore, I will recomand this article for the publication after through revision of the current manscript.
Answer: Thank you for the very thorough reading and high evaluation of the manuscript!
Reviewer’s comment: Line 36, The authors state: 'Currently, hydrazine derivatives (HD) constitute a privileged class of C-centred radical precursors for diverse synthetic applications.' To enhance the clarity and informativeness of this statement, I suggest the authors provide a few representative examples of these applications.
Answer: Since the synthetic applications of hydrazine derivatives are the focus of this review and have not been summarized in previous literature, we deemed it premature to address them in the introduction. However, to not waste the reader's attention, we provided representative examples as you suggested.
Old version: Currently, hydrazine derivatives (HD) constitute a privileged class of C-centered radical precursors for diverse synthetic applications.
Corrected version: Currently, hydrazine derivatives (HD) constitute a privileged class of C-centered radical precursors for diverse synthetic applications, for example, alkene difunctionalization, cascade cyclizations, and (hetero)arenes CH-functionalization.
Reviewer’s comment: A few recommendations for Figure 1 Figure 1 contains many sections. I suggest labelling them clearly as (a), (b), and (c), and ensuring the corresponding text refers to these labels. This would improve clarity and help the reader follow the discussion more easily.
The legend should be more descriptive and clearly convey the key message of each of these sections shown in the figure. A more detailed legend would improve clarity and help readers better understand the distinctions between the individual components.
In the third part of the figure, some of the reactants labelled as 1 and 2 do not clearly convey a meaningful message. Therefore, I suggest either removing these labels or providing an explanation in the text. Additionally, I recommend removing the word etc. mention at the bottom of the scheme.
While I understand that this is an introductory section, the figure presents a lot of information that has not been completely explained in the main text. To improve clarity, I suggest simplifying the scheme and ensuring that key information is included in the text. Additionally, the text should be clearly connected to the figure to help the reader follow the material more easily.
Answer: Thank you for the comments. We tried out best to improve the clarity and design of such a big scheme: 1) Each section was labeled, each label is mentioned now in the corresponding discussion in the main text; 2) Section titles (Figure 1, a–c) were revised to clearly convey the key message of each of these sections; 3) Labels 1 and 2 were removed from the bottom part of Figure 1 (c), a comment was added instead to the main text (“It should be noted that curved arrows in Figure 1, c for cascade cyclizations do not imply a concerted process, but show sequential mechanistic steps (one step per each curved arrow).”); 4) “etc.” was removed
Old version:
Corrected version:
Reviewer’s comment: The authors state: 'The presence of a base is critical for the reaction's success; in this case, DABCO serves this essential role in both chemical and photochemical approaches (Scheme 1, d, e).' I am curious if the authors could elaborate on what they mean by the “crucial role” of the base. Specifically, what mechanistic function does DABCO serve in these chemical and photochemical contexts?
Answer: Thank you for the important question. However, no direct elaboration on the role of DABCO is present in the articles discussed in the scheme 1. To extract some understanding from the experimental data, we add some valuable facts from the optimization tables and added corresponding text.
Added text: In fact, without DABCO arylketone is produced in 10% yield instead of 80% in optimal conditions.[49] Transition-metal catalysis with Cu and Fe salts proved effective for the further oxidation of the second benzylic position of the resultant aryl ketone, yielding the 1,2-diketone (Scheme 1, f).[48] This transformation is also dependent on base: it deprotonates the intermediate arylketone, facilitating its further oxidation to diketone.[48] It should be noted that the base catalysis is quite typical for aerobic oxidation hydrazine derivatives, especially arylhydrazines, as will be shown later in the text.
Reviewer’s comment: I suggest that the authors should mention what R represents in the scheme 1.
Answer: The Scheme 1 was redesigned according to the comments of the Reviewer 1, R values were specified. Also, limitations for the Ar in the arylhydrazine were specified both in the scheme and in the text.
Added text: There are no special limitations on the nature of aryl substituent in the arylhydrazine for all mentioned in the Scheme 1 transformations. However, successful reactions using 4-NO2C6H4NHNH2[45] and 4-CNC6H4NHNH2[46] as substrates are each limited to a single example.
Reviewer’s comment: Line 140-143: I suggest that the authors provide the reaction yields for the transformations mentioned. In Scheme 2, the authors mention 3–82%, which is somewhat confusing. Does the 3% represent the lowest yield for these reactions? It would be helpful to clarify this in the main text. Currently, the only yield mentioned is 60% for a particular reaction, but it would be valuable to address the potential limitation if the 3% yield is the result for a specific set of reactions. I suggest the authors review this section, provide a clear yield range, and ensure the text accurately references the molecular number and corresponding yields.
Same for scheme 4 and rest of the manucsript.
Answer: The yields were added for R3 = Bn and t-Bu. In fact, 3% is the lowest observed yield, and the reasons for that are presented in the following sentence:
Old version: The lowest yields were observed for R3 = Bn and t-Bu in carbazate, presumably, due to side process of decarboxylation favored by formation of stabilized Bn and t-Bu radicals.
Corrected version: The lowest yields were observed for R3 = Bn (3%) and t-Bu (7%) in carbazate, presumably, due to side process of decarboxylation favored by formation of stabilized Bn and t-Bu radicals. The reaction with other alkyl and phenyl carbazates generally proceeds in moderate to good yields (47-82%).
The same considerations are true for the scheme 4.
Added text: As in the example, presented above, the lowest yield (5%) was observed for the benzyl carbazate (R4 = Bn).
Reviewer’s comment: It is unclear to me the use of variuos colors in the scheme/figures. For example, in scheme 3, i-Pr and Bn marked as red? any reson for that? if so please highlight the facts in the manin text. same for scheme 2 and rest of the manuscript where it is apliicable.
Answer: The colors on the substituents were removed, except for the red color for substituents that did not provide any yield of the desired product. For example, Scheme 15, R ≠ t-Bu. Explanations were added to the corresponding titles:
Added text: “Red color represents substituents for which no target product was formed.”
Reviewer’s comment: In most of the schemes, the authors mention Ar but do not specify what it represents. Could the authors provide some representative examples of Ar in the same way they did for R, for example, in Scheme 5?
Answer: Ar substituents were not specified for cases of transformations without clear limitations on Ar structure to avoid overloading of schemes. To provide more information of the presented reaction, we added “Selected scope” section to the Scheme 5.
Old version:
Corrected version:
Reviewer’s comment: Line 188, Authors stated 'However, the yields for these substrates did not exceed 50%.' Any thoughts or plausible explanations to account for the moderate yiled of the product?
Answer: Authors of the original article did not elaborate on the reasons for the moderate yields for azauracil, cinnolin-4(1H)-one, isoquinoline, 2,3-diazonaphthalene, quinoxaline, phenanthridine, 2H-benzo[b][1,4]oxazin-2-one, and coumarin. However, this can be attributed to the fact that the optimization was performed specifically for quinoxalinones. To successfully apply it to such a diverse series of heterocycles, the conditions would need to be optimized for each case.
Reviewer’s comment: Scheme 8, the notation 4-NO₂C₆H₄ appears to represent a failed reaction. If this is the case, could the authors please mention this in the text as well?
Answer: We have added this fact to the main text.
Added text: Among the limitations of this process is the inability to obtain the desired product with 4-nitrophenylhydrazine.
Reviewer’s comment: In general, when the authors describe reaction mechanisms, such as in Scheme 8 and Scheme 9, it would be helpful if they numbered the molecules/intermediates and referred to these numbers in the text. This would make it easier for readers to follow the mechanisms and understand the steps more clearly.
Answer: Thank you for the valuable comment. Intermediates, which are referenced in the text, generally denoted with capital letters (e.g. A in the Scheme 37). As you noted, this aids clarity; therefore, we have added more such designations to the schemes where mechanistic steps are discussed (for example, Schemes 8, 9, 11).
Reviewer’s comment: Line 219, please give a refernce to support your sratemnet.
Answer: The relevant references, there imine tautomerization to enamine occurs, were added: Wang, Y.; Wang, Y.-J.; Liang, X.-C.; Shen, M.-H.; Xu, H.-D.; Xu, D. An Aryl Thiol–Vinyl Azide Coupling Reaction and a Thiol–Vinyl Azide Coupling/Cyclization Cascade: Efficient Synthesis of β-Ketosulfides and Arene-Fused 5-Methylene-2-Pyrrolidinone Derivatives. Org. Biomol. Chem. 2021, 19, 5169–5176, doi:10.1039/D1OB00328C. Doronin, M.M.; Klikushin, A.S.; Mulina, O.M.; Medvedev, M.G.; Vil’, V.A.; He, L.-N.; Terent’ev, A.O. α-Sulfonylated Ketazine Synthesis from Vinyl Azides and Sodium Sulfinates Using CAN: Radical C–S/N–N Coupling Cascade as a Key Reaction Pathway. Org. Chem. Front. 2025, 12, 5271–5278, doi:10.1039/D5QO00508F. Paveliev, S.A.; Segida, O.O.; Mulina, O.M.; Krylov, I.B.; Terent’ev, A.O. Decatungstate-Catalyzed Photochemical Synthesis of Enaminones from Vinyl Azides and Aldehydes. Org. Lett. 2022, 24, 8942–8947, doi:10.1021/acs.orglett.2c03364.
Reviewer’s comment: Line 228, if the authors state that the reported method is sustainable, it would be helpful to provide additional information or data to support this statement (if its reported in the original paper).
Answer: The word “sustainable” was used as a synonym of the “environmentally benign”, used in the original article. This referred to the use of water as a solvent and hydrogen peroxide as an oxidant, which produces only water as a by-product. We stated it more clearly in the text:
Old version: Taking into account the scalability and cost-efficiency of the developed procedure, as well as the use of water as a solvent and hydrogen peroxide as an oxidant, which produces only water as a by-product, it represents not only a sustainable method for the synthesis of arylketones but can be considered a promising strategy for the aryl radical addition to different substrates.
Corrected version: Taking into account its scalability, cost-efficiency, the use of water as a solvent, and hydrogen peroxide as an oxidant (which produces only water as a by-product), the developed procedure represents not only a sustainable method for synthesizing arylketones but also a promising strategy for aryl radical addition to different substrates.
Reviewer’s comment: Line 234: The authors mention Scheme 11 discussed above,but Scheme 11 actually appears after this paragraph. I suggest the authors modify this statement.
Answer: Thank you, the text was corrected. The corresponding reference was added.
Old version: N-vinylacetamides are efficient radical acceptors, which make possible realization of formal hydrogen substitution by radical instead of C=C bond difunctionalization reactions discussed above (Scheme 11).
Corrected version: N-vinylacetamides are efficient radical acceptors, which make possible realization of formal hydrogen substitution by radical (Scheme 11) instead of C=C bond difunctionalization reactions discussed above (Schemes 2-10).
Reviewer’s comment: In Scheme 11, the representation of deprotonation of the iminyl cation using BH with a lone pair looks a bit unusual. I suggest replacing this with a generic base representaion and providing examples of bases that are used for deprotonation in these type of the reactions.
Answer: Thank you for the important note. The base should be represented as B with the lone pair, the typo was removed.
Reviewer’s comment: I had some difficulty understanding Table 1. I suggest reconsidering the best way to present the information the authors wish to highlight. If the goal is to emphasise the different reaction conditions and the use of various oxidants along with their corresponding outputs, I recommend removing the green bulb and their notaions. If, on the other hand, the authors intend to show the functional groups or substituents, then it would be helpful to specify what X, R1, and R2 represent. Additionally, I suggest including the structure of the products along with their yields for better clarity. Alternatively, simply listing the different oxidation conditions along with their references should be sufficient. These are just my thoughts on how to make the table more readable.
Answer: Since the nature of R1, R2 and X in the substrate are very similar in all presented in the Table examples, their specification is depicted on the scheme above the table. The crucial are the oxidative systems applicable for the certain type of hydrazine derivatives, so that characteristics occupy the main part in the Table.
Reviewer’s comment: Line 274, please provide a reference to support your statment.
Answer: The relevant reference was added: Li, Q.; Han, L.; Zhou, H.; Hou, J.; Shi, X. Advances in Synthetic Strategies for Indolo[2,1‐ a ]Isoquinoline Derivatives. Adv. Synth. Catal. 2025, 367, e202500035, DOI:10.1002/adsc.202500035.
Reviewer’s comment: Line 308, the authors mention the excellent diastereoselectivity, where the alkoxycarbonyl radical preferentially attacks the neutral vinyl moiety. Could the authors please explain why this occurs?
Answer: Thank you for this deep question. We found that Authors of this work (Scheme 15) did not discussed reasons for the observed high diastereoselectivity. A possible reason is instability of an alternative diastereomer with trans-fused rings. Taking into account the fact that in many cases yields are around 50% or lower, this does not mean that first intramolecular radical cyclization is absolutely diastereoselective: the “incorrect” diastereoselectivity at this step can prevent successful second cyclization, which results in lower yields of target products observed as single diastereomers with cis-fused rings. So, the question of diastereoselectivity in this reaction is complicated and it is not discussed in the original paper, so we removed the sentence “One more key feature of this reaction is the excellent diastereoselectivity.”. Regarding the preferential attack of the electron-neutral vinyl moiety following comment was added in accordance with the original paper: “Authors note that according to computational data from literature alkoxycarbonyl radicals are less nucleophilic compared to acyl radicals and can generally react as ambiphilic or electrophilic radicals, which make their reactivity in the discussed case not obvious.[81]”
Reviewer’s comment: Scheme 18, Could the authors specify what type of (hetero)aromatic systems have been explored?
Answer: The heteroaromatic systems, in fact, include only 3-thiophenyl substituent, which was specified on the Scheme 18.
Reviewer’s comment: Line 348, The authors mention 'electron-withdrawing substituents.' Could the authors please specify which functional groups are being referred to here?
Answer: Thank you for the important note, the nature of substituents was specified.
Old version: Strong electron-withdrawing substituents on either the arylhydrazine or the acetylene were not tolerated in this method.
Corrected version: Strong electron-withdrawing substituents on either the arylhydrazine (p-CN, m-NO2) or the acetylene (pyridine-2-yl) were not tolerated in this method.
Reviewer’s comment: Line 375, The authors state, 'however, the PhCF3 solvent here was slightly more efficient than PhF.' It's helpful that the authors refer to the SI for more details, but a concise explanation of why PhCF3 is more efficient would be valuable in the main text as well.
Answer: Since the authors of the original paper did not provide the explanation in the main text, we limited our description of the article to the factual data. However, the main difference in the solvents PhF and PhCF3 is the boiling point: 84 and 103 °C, respectively. The use of PhCF3 allows authors to increase the reaction temperature to 100 °C, and it slightly affected the yield (70% instead of 67%). We added the above consideration to the review.
Old version: The conditions are similar to the conditions of runs 1 and 2 in the Table 3, however, the PhCF3 solvent here was slightly more efficient than PhF (see SI for the paper[87]).
Corrected version: The conditions are similar to the conditions of runs 1 and 2 in the Table 3, however, the PhCF3 solvent here was slightly more efficient than PhF (see SI for the paper[87]). These results can be attributed to the higher reaction temperature (100 °C instead of 80 °C) due to higher boiling point of PhCF3.
Reviewer’s comment: Scheme 20, the colors used to represent X are not very clear.
Answer: The colors were intended to represent good and moderate yields, but considering no proper clarification in the text, we decided to remove the colors.
Reviewer’s comment: Scheme 21, in the proposed mechanism, the structure drawn as CH2O2Me appears to be incorrect. Could the authors please correct this?
Answer: Thank you for the attentive revision of the schemes. The error was removed.
Reviewer’s comment: Line 440, I suggest modifying the sentence 'two pyridine-type nitrogen atoms' to refer to the structure mentioned in Scheme 24. they can be called as quinoxaline and its derivatives.
Answer: The text was improved:
Old version: An electrochemical method for the functionalization of quinoxalines and related condensed heterocycles containing two pyridine-type nitrogen atoms was developed.
Corrected version: An electrochemical method for the functionalization of quinoxaline and its derivatives was developed.
Reviewer’s comment: Scheme 25, The authors represent a salt as x HCl. Could the authors please explain the rationale behind this notation? In contrast, Scheme 24 uses a dot, which I believe is the correct way to represent the salt.
Answer: The “x” symbol was changed to a dot.
Reviewer’s comment: Line 476, should be 'It turns out' instead of In turns out.
Answer: The typo was corrected.
Reviewer’s comment: Line 604, Ortho should be italicised.
Answer: Ortho was italicised.
Reviewer’s comment: The representation in Scheme 33 could be improved for clarity.
Answer: The arrows were added for clarity.
Old version:
Corrected version:
Reviewer’s comment: Could the authors please check if R = CO2Me is correct in Scheme 37b? I believe R in the product should be OMe instead.
In Scheme 37b (mechanism part), could the authors please check the structure of the multicomponent product? It should not be in its radical form, and the final product should have a hydrogen atom at the N center. Please review.
Answer: Thank you for this note. The R1 and R2 were specified instead to clarify the difference in the substituents in the reactions a and b. In the mechanism part we emphasize the common mechanistic patterns in the reactions with [1.1.1]propellanes. The final stage of the mechanism with azodicarboxylates was intentionally omitted. However, as you correctly pointed out, depicting the final product is better for clarity. The scheme has been improved accordingly.
Old version:
.
Corrected version:
Author Response File: Author Response.pdf
Round 2
Reviewer 2 Report
Comments and Suggestions for AuthorsI am pleased with the revisions made to the manuscript titled ‘Hydrazine Derivatives as C-Cantered Radical Precursors for C–C Bond Formation Reactions.’ The modifications have significantly improved the manuscript, making it much clearer and more comprehensive. The work provides valuable insights into the use of hydrazine derivatives as stable and synthetically accessible C-cantered radical precursors, which are crucial for C–C bond formation reactions.
Given these improvements, I recommend the manuscript for publication. It will make a meaningful contribution to the literature and will be valuable to the synthetic chemistry community.
