Quinoline Hydroxyalkylations from Iron-Catalyzed, Visible-Light-Driven Decarboxylations
Round 1
Reviewer 1 Report
Comments and Suggestions for AuthorsThe manuscript entitled “Quinoline Hydroxyalkylations from Iron-Catalyzed, Visible-Light Driven Decarboxylations” reports an unusual Minisci-type functionalization of quinoline by carboxylic acids, in which alpha-hydroxyalkylated products are produced instead of typical alkylated products. Despite the demonstrated scope of transformation is narrow (only quinoline as electron-deficient arene and only 3 carboxylic acids) the novelty of the reported reaction is sufficient for publication. Following features should emphasized:
1) Unexpected hydroxyalkylation is observed instead of typical decarboxylative alkylation for Minisci-type reactions.
2) Usually, benzylic alcohols are oxidized to the corresponding carbonyl compounds more easily than corresponding alkylarenes: hydroxy group lowers the C-H BDE in the benzylic position. However, alcohols are the final products in the reported transformation despite the high conversion.
3) Only position 4 of quinoline is selectively functionalized, whereas typically the mixture of 2-, 4- and 2,4-disubstituted products can be expected (for example, see https://doi.org/10.1021/ol201774b).
However, I noticed that very similar paper was recently published by the Authors (https://doi.org/10.1080/00958972.2023.2274799), and this paper is not cited in the manuscript. The novelty of the present manuscript in the context of this previous publication should be specified. Some additional comments are given below.
1) The introduction comprehensively covers the state of the art in the field of iron-mediated photocatalysis, but state of the art in Minisci-type reaction chemistry is not discussed. Many works are devoted photoredox-catalyzed Minisci-type reactions based on metal-free catalysts or abundant transition metals. In particular, cross-dehydrogenative C–C coupling of N-Heterocycles with ethers affords similar structural fragment to one reported in the present paper (except for OAlkyl group instead of OH). These results should be mentioned in the introduction.
2) Are products 3 and 4 new? In this case, HR-MS or elemental analysis may be necessary. Moreover, addition of all 1H and 13C NMR spectra to SI for publication is highly recommended.
3) How high 4-regioselectivity can be explained? Was substitution at 2-position of quinoline observed at any of the studied conditions? According to the mechanism, reaction includes ethyl radical attack on protonated quinoline, but this reaction is expected to be not so selective [for example, https://doi.org/10.1246/cl.1986.409, https://doi.org/10.1246/bcsj.59.3911]
4) According to the mechanism, 4-ethylquinoline is an intermediate of the discovered process. Was it detected at low conversions of the starting material?
5) Additional mechanistic experiments are highly recommended taking into account novelty and interesting nature of the discovered process. Plausible intermediate, 4-ethylquinoline, can be treated by standard reaction conditions to confirm its participation in the process. Moreover, it can be treated by some reagents separately to reveal species responsible for its oxidation to the final hydroxy product. For example, hypervalent iodine compounds can oxidize alkylquinolines to hydroxy derivatives [see scheme 3, products 3 in https://doi.org/10.1002/asia.202100704]. Can KIO3 be responsible for the similar reaction in the case of the present paper?
Author Response
1) The authors The manuscript entitled “Quinoline Hydroxyalkylations from Iron-Catalyzed, Visible-Light Driven Decarboxylations” reports an unusual Minisci-type functionalization of quinoline by carboxylic acids, in which alpha-hydroxyalkylated products are produced instead of typical alkylated products. Despite the demonstrated scope of transformation is narrow (only quinoline as electron-deficient arene and only 3 carboxylic acids) the novelty of the reported reaction is sufficient for publication. Following features should emphasized:
1) Unexpected hydroxyalkylation is observed instead of typical decarboxylative alkylation for Minisci-type reactions.
2) Usually, benzylic alcohols are oxidized to the corresponding carbonyl compounds more easily than corresponding alkylarenes: hydroxy group lowers the C-H BDE in the benzylic position. However, alcohols are the final products in the reported transformation despite the high conversion.
3) Only position 4 of quinoline is selectively functionalized, whereas typically the mixture of 2-, 4- and 2,4-disubstituted products can be expected (for example, see https://doi.org/10.1021/ol201774b).
Response: We appreciate these comments reference which were incorporated to manuscript.
However, I noticed that very similar paper was recently published by the Authors (https://doi.org/10.1080/00958972.2023.2274799), and this paper is not cited in the manuscript. The novelty of the present manuscript in the context of this previous publication should be specified. Some additional comments are given below.
Response: The suggested reference was incorporated to manuscript (reference 40). In addition, the second paragraph was also extended as follows:
1) The introduction comprehensively covers the state of the art in the field of iron-mediated photocatalysis, but state of the art in Minisci-type reaction chemistry is not discussed. Many works are devoted photoredox-catalyzed Minisci-type reactions based on metal-free catalysts or abundant transition metals. In particular, cross-dehydrogenative C–C coupling of N-Heterocycles with ethers affords similar structural fragment to one reported in the present paper (except for OAlkyl group instead of OH). These results should be mentioned in the introduction.
Response: The suggested modification was made. An extension in third paragraph in page 1 was added as follows:
“These conditions allow a new approach to the Minisci reaction which enables the alkylation of heterocyclic compounds by nucleophilic radical substitution, in particular the cross-dehydrogenative C-C coupling of N-heterocycles with ethers under mild conditions [28].”
In addition, reference 28 was incorporated to manuscript.
2) Are products 3 and 4 new? In this case, HR-MS or elemental analysis may be necessary. Moreover, addition of all 1H and 13C NMR spectra to SI for publication is highly recommended
Response: Elemental analysis for compounds 3 and 4 was added, and a supplementary information file with 1H and 13C NMR spectra was incorporated.
3) How high 4-regioselectivity can be explained? Was substitution at 2-position of quinoline observed at any of the studied conditions? According to the mechanism, reaction includes ethyl radical attack on protonated quinoline, but this reaction is expected to be not so selective [for example, https://doi.org/10.1246/cl.1986.409, https://doi.org/10.1246/bcsj.59.3911].
Response: As the reviewer rightly pointed out, the ethyl radical is not as selective, which is why 4-methylquinoline was used as the starting material in the referred publications. In this regard, Hadrys and Phipps (Synlett 2021, 179) observed that regioselectivity of Minisci-type addition to quinolines can be modulated by the solvent polarity, as polar solvents drive to 4-substituted quinolines. An extended explanation was placed in order to indicate this situation as follows:
“An outstanding fact that is noticed in this process is the relatively high degree of re-gioselectivity. In this respect, only the 4-substituted product was isolated, while substitution at the 2-position of quinoline was not detected under any of the conditions studied. A plausible explanation may be related to the findings on the solvent effect on radical substitution made by Hadrys and Phipps who found that regioselectivity of Minisci-type addition to quinolines can be modulated by the solvent polarity, as polar solvents drive to 4-substituted quinolines [38].”
In addition, reference 38 was incorporated to manuscript.
4) According to the mechanism, 4-ethylquinoline is an intermediate of the discovered process. Was it detected at low conversions of the starting material?
Response: 4-Ethyl quinoline was not detected in the process, as it can be assumed that this compound is subject to rapid oxidation.
5) Additional mechanistic experiments are highly recommended taking into account novelty and interesting nature of the discovered process. Plausible intermediate, 4-ethylquinoline, can be treated by standard reaction conditions to confirm its participation in the process. Moreover, it can be treated by some reagents separately to reveal species responsible for its oxidation to the final hydroxy product. For example, hypervalent iodine compounds can oxidize alkylquinolines to hydroxy derivatives [see scheme 3, products 3 in https://doi.org/10.1002/asia.202100704]. Can KIO3 be responsible for the similar reaction in the case of the present paper?
Response: That is a nice idea that we will further pursue, thank you very much for bring this to our attention.
Reviewer 2 Report
Comments and Suggestions for AuthorsThe authors report on quinoline hydroxyalkylation reactions involving C–C bond formation and subsequent oxidation. In the introduction, they address the important topic of photocatalysis, specifically with ruthenium and iridium catalysts, and also note the potential utility of iron-based catalysts. However, there is a notable lack of information about the synthesized compounds, specifically quinolines, which are central to the study. The description omits details on the practical applications of these compounds, which would further support the relevance of their synthesis. Currently, compounds of this type, including chiral variants, are commercially available. Moreover, the synthesis of such compounds is relatively simple and does not require light or a photocatalyst (as in the case of Grignard reactions from simple and affordable substrates). In the Results and Discussion section, some information on process optimization is provided, but a complete description is missing. There is no information regarding the specific amounts of each reagent used, including the photocatalyst, or the wavelength of visible light employed. The results presented are limited to just three examples, which does not sufficiently demonstrate the scope of applicability. Did the authors test other carboxylic acids, such as those containing a chiral element? Were other heterocyclic systems examined?
Author Response
1) The authors report on quinoline hydroxyalkylation reactions involving C–C bond formation and subsequent oxidation. In the introduction, they address the important topic of photocatalysis, specifically with ruthenium and iridium catalysts, and also note the potential utility of iron-based catalysts. However, there is a notable lack of information about the synthesized compounds, specifically quinolines, which are central to the study. The description omits details on the practical applications of these compounds, which would further support the relevance of their synthesis. Currently, compounds of this type, including chiral variants, are commercially available. Moreover, the synthesis of such compounds is relatively simple and does not require light or a photocatalyst (as in the case of Grignard reactions from simple and affordable substrates). In the Results and Discussion section, some information on process optimization is provided, but a complete description is missing. There is no information regarding the specific amounts of each reagent used, including the photocatalyst, or the wavelength of visible light employed. The results presented are limited to just three examples, which does not sufficiently demonstrate the scope of applicability. Did the authors test other carboxylic acids, such as those containing a chiral element? Were other heterocyclic systems examined?
Response: As the reviewer rightly pointed out, there are other synthetic methods to prepare titled compounds. However, these available methods have some other additional requirements. For example, the use of Grignard / organometallic reagents (as mentioned by the reviewer) would require 4-haloquinolines under specific temperatures, inert atmospheres, solvents, and additional steps starting from quinoline. On the other side, given the highly aromatic nature of quinoline core, a hydroxyalkylation based on an electrophilic substitution results difficult. This report highlights the direct, selective generation of a C-C bond at an "inactivated" 4-position as an alternative synthetic protocol. On the other hand, in experimental part, reader can find the general procedure of synthesis of 4-hydroxyalkyl quinolines with specific amounts of reactants: carboxylic acid (5 mL), quinoline (0.129 g, 1 mmol), H2SO4 (0.1 mL) in H2O (25 mL), Fe(phen)Cl3.H2O (0.036 g, 0.1 mmol) and a 0.1 M aqueous solution of KIO3 (10 mL). Regarding the information about quinolines, in final part of discussion, a brief paragraph was placed in order with this information as follows:
“The process described in this communication has some features worthy of consideration that make it an alternative method to the existing ones for the preparation of 4-substituted hydroxyalkyl quinolines, since it does not require organometallic reagents, specific temperatures, inert atmospheres, solvents, and additional steps. On the other side, the highly aromatic nature of the quinoline core makes hydroxyalkylation based on an electrophilic substitution results difficult. This report highlights the direct, selective gener-ation of a C-C bond at an "inactivated" 4-position as an alternative synthetic protocol, which is also important due to the presence of 4-substituted quinolines as a wide group of drugs and natural products [41-43].”
In addition, references 41-43 were incorporated to manuscript.
Reviewer 3 Report
Comments and Suggestions for AuthorsThe manuscript is a concise communication presenting a novel approach for preparing heterocyclic compounds. It´s well-written and organized. I recommend minor revisions to be completed after publication:
- In the introduction, include a paragraph with appropriate references discussing the synthetic methods reported for synthesizing (hydroxy)alkylated quinolines.
- Include copies of all 1H and 13C NMR spectra in a supplementary information archive.
Author Response
1) The manuscript is a concise communication presenting a novel approach for preparing heterocyclic compounds. It´s well-written and organized. I recommend minor revisions to be completed after publication:
- In the introduction, include a paragraph with appropriate references discussing the synthetic methods reported for synthesizing (hydroxy)alkylated quinolines.
Response: The suggested modification was made. We also appreciate this suggestion. An additional paragraph in page 1 was added as follows:
“Moreover, within the Minisci-type reactions, hydroxyalkylations on aromatic rings represent a kind of transformations that has been less studied, which represents an inter-esting synthetic approach compared to electrophilic acid-mediated hydroxyalkylations, considered the most important synthetic method to obtain hydroxyalkyl arenes [29-32].”
In addition, references 29-32 were incorporated to manuscript.
- Include copies of all 1H and 13C NMR spectra in a supplementary information archive.
Response: This point is also settled with response to the previous question. A supplementary information file with 1H and 13C NMR spectra was incorporated.
