Highly Efficient Asymmetric Morita–Baylis–Hillman Reaction Promoted by Chiral Aziridine-Phosphines
Round 1
Reviewer 1 Report
In this manuscript, the authors applied the previously developed catalytic system to an important asymmetric Morita-Baylis-Hillman reaction. The presented chiral aziridine-phosphines catalyzed the formation of corresponding allylic alcohols from methyl vinyl ketone and/or methyl acrylate and various aromatic aldehydes. Although a high enantioselective control was achieved in the reaction, this reviewer can recommend the publication of the manuscript after revisions made according my comments and suggestions:
- In my opinion, the authors should make more clearer what the really new aspect of this study are in comparison to related previous catalytic systems for this reaction.
- I'm surprised, why the enantiomers (R)-5 and (S)-6 (Table 1, compare entries 5 and 6) operated differently in the reaction, providing the target product with different yields and enantioselectivity? Is it possible that the compound 5 was not pure?
- What does mean phrase “for major product” in Footnote A under Table 1?
- I’m surprising why the reaction doesn’t work with p-methoxybenzaldehyde? Can the authors explain the phenomenon?
- I would rewrite the sentence “As anticipated, no reaction product was observed which may indicate that the phosphine group is a very important factor for the asymmetric Morita-Baylis-Hillman reaction” (page 4, lines 122-123). Indeed, the phosphine group is a catalytic center.
- What is the role of aziridine fragment in the reaction? Does it have any catalytic role?
- I would not recommend to compare the stereochemical outcome for the reaction with previous work (ref. 25), because there the aziridine-phosphine used as a chiral ligand in combination with copper salt.
- In the supporting information, unfortunately, I don’t see the HPLC traces for the racemic samples 12-17. The authors should provide it.
- For the target products, the authors should provide at least 1H NMR data and include the spectra in SI to show the purity of the products.
- The numbering of the compounds should be bold on page 4 (lines 108-110, 114, 120).
Author Response
Dear Reviewer,
Thank you for the valuable comments. Below please find my response (in bold):
1) In my opinion, the authors should make more clearer what the really new aspect of this study are in comparison to related previous catalytic systems for this reaction.
The corresponding phrase ‘Although there are reports in the literature describing the use of chiral phosphine catalysts in an asymmetric MBH reaction, there are no known instances of the use of phosphino-aziridines in this conversion. We also wanted to show that the chiral catalytic systems containing the aziridine ring, which have been studied for many years in our group, are universal in nature and are capable of efficiently catalyzing a wider and wider range of asymmetric reactions’ has been added in text (in yellow).
2) I'm surprised, why the enantiomers (R)-5 and (S)-6 (Table 1, compare entries 5 and 6) operated differently in the reaction, providing the target product with different yields and enantioselectivity? Is it possible that the compound 5 was not pure?
It was very valuable of your attention. Catalyst (R)-5 had impurities visible in the 31P NMR spectrum. We performed its purification again and repeated the MBH model reaction. The results have been improved (Table 1, entry 5).
3) What does mean phrase “for major product” in Footnote A under Table 1?
This is obviously a mistake. Such a remark applies to the situation when we have diastereomers and the enantiomeric excess is determined for the main one. The sentence you indicated has been deleted.
4) I’m surprising why the reaction doesn’t work with p-methoxybenzaldehyde? Can the authors explain the phenomenon?
Electron donating groups (EDGs) make carbon centers (carbonyl aldehyde group) weaker electrophiles and less reactive to nucleophiles. Probably for this reason we did not obtain the desired reaction product using p-methoxybenzaldehyde. The appropriate phrase has been added in text (in yellow). Additionally, the phrase ‘As completely unexpected’ has been removed.
5) I would rewrite the sentence “As anticipated, no reaction product was observed which may indicate that the phosphine group is a very important factor for the asymmetric Morita-Baylis-Hillman reaction” (page 4, lines 122-123). Indeed, the phosphine group is a catalytic center.
That is true. Indeed, this reaction only takes place in the presence of phosphine. Phosphine oxide is a nucleophile and therefore does not catalyze the title reaction.
6) What is the role of aziridine fragment in the reaction? Does it have any catalytic role?
The role of aziridine is crucial. The catalysts described by us are of bidentate nature. The chiral aziridine fragment is responsible for introducing chirality in the asymmetric reaction, while the non-chiral phosphine fragment makes the transition state rigid, thanks to which, for example, invertomers or rotamers are not formed. The corresponding proposed transition state model with discussion has been included.
7) I would not recommend to compare the stereochemical outcome for the reaction with previous work (ref. 25), because there the aziridine-phosphine used as a chiral ligand in combination with copper salt.
Of course, you are right. The fragment of the sentence has been changed: ‘is similar to those described by us earlier’, reference [25] has been removed from the end of the sentence, and moreover, a proposed transition state model with discussion has been added (in yellow).
8) In the supporting information, unfortunately, I don’t see the HPLC traces for the racemic samples 12-17. The authors should provide it.
Sorry for the obvious oversight. The corresponding chromatograms have been added.
9) For the target products, the authors should provide at least 1H NMR data and include the spectra in SI to show the purity of the products.
According to your suggestion, 1H NMR data of MBH products have been added in text and copies of 1H NMR spectra have also been included in SI.
10) The numbering of the compounds should be bold on page 4 (lines 108-110, 114, 120).
The numbering of the compounds on page 4 has been corrected in bold.
Thanks again for your valuable comments.
Sincerely
Michal Rachwalski
Author Response File: 
Author Response.pdf
Reviewer 2 Report
This manuscript reports the chiral aziridine-phosphines catalyzed asymmetric Morita-Baylis-Hillman reaction. The authors have developed and optimized another catalytic system to synthesize enantiopure allylic alcohols with excellent yields and enantiomeric excess. However, This manuscript can be recommended for publication after major revision. To improve the quality of the manuscript, the authors need to address the bellow comments.
1). During optimization, authors achieved both isomers (Table 1, entries 1,2, and 5,6). The authors could have focused on another isomer's optimization and substrate scope. It would have significantly improved the value of the manuscript.
2). The substrate scope is limited, and there are no new compounds in the substrate scope. Therefore, the optimized conditions failed to give the desired compound for the electron donation group. The authors could have slightly modified the optimized conditions to get the desired compounds.
3). No discussion about the mechanism, how the chiral aziridine-phosphines are helping for the success of the reaction.
4) Authors should give NMRS for all the compounds.
5). In supporting information, compounds 11, 12, and 17 only have the HPLC profiles. Therefore, authors must provide the complete HPLC profile for all compounds.
Author Response
Dear Reviewer,
Thank you very much for your very positive revision. Below please find my response (in bold):
1) During optimization, authors achieved both isomers (Table 1, entries 1,2, and 5,6). The authors could have focused on another isomer's optimization and substrate scope. It would have significantly improved the value of the manuscript.
Thank you for this suggestion. Certainly, research on the second enantiomer of the catalyst with the use of other aldehydes would strengthen our publication, but routinely during screening we usually select only the most effective catalyst and test its catalytic activity in reactions with other substrates. As we only present preliminary research results in this paper, we intend to refer to your remark in the future and extend the applicability of the second isomer of the catalyst.
2) The substrate scope is limited, and there are no new compounds in the substrate scope. Therefore, the optimized conditions failed to give the desired compound for the electron donation group. The authors could have slightly modified the optimized conditions to get the desired compounds.
The substrate scope is limited to aldehydes bearing electron withdrawing groups (EWGs) due to the fact that electron donating groups (EDGs) make carbon centers (carbonyl aldehyde group) weaker electrophiles and less reactive to nucleophiles. Probably for this reason we did not obtain the desired reaction product using p-methoxybenzaldehyde. The appropriate phrase has been added in text (in yellow). Modifying the conditions did not help us in obtaining products with EDG-containing aldehyde. Moreover, the substrate scope is limited and there are no new compounds in the substrate scope because our aim was to present the preliminary research results in the current contribution. We plan to further investigate this asymmetric transformation, including extending the scope of substrates.
3) No discussion about the mechanism, how the chiral aziridine-phosphines are helping for the success of the reaction.
The role of aziridine is crucial. The catalysts described by us are of bidentate nature. The chiral aziridine fragment is responsible for introducing chirality in the asymmetric reaction, while the non-chiral phosphine fragment makes the transition state rigid, thanks to which, for example, invertomers or rotamers are not formed. The corresponding proposed transition state model with mechanistic discussion has been included following your suggestion.
4) Authors should give NMRS for all the compounds.
According to your suggestion, 1H NMR data of MBH products have been added in text and copies of 1H NMR spectra have also been included in SI.
5) In supporting information, compounds 11, 12, and 17 only have the HPLC profiles. Therefore, authors must provide the complete HPLC profile for all compounds.
The corresponding chromatograms have been added.
Thanks again for your valuable comments.
Sincerely
Michal Rachwalski
Author Response File: Author Response.pdf
Reviewer 3 Report
The research article ‘Highly Efficient Asymmetric Morita-Baylis-Hillman Reaction 2 Promoted by Chiral Aziridine-Phosphines’ is interesting but seems incomplete. May need to do some additional research to provide adequate data for publication. Needs major revision
- Authors were stated about opposite enantioselectivity in lines 88-90, which is not clear to understand
- Started with 20 mol % catalyst which is very high, run some more studies with lower catalyst loadings and compare the results at slightly elevated temp if needed
- At elevated temp data may give information about catalyst activity, need to provide mechanistic data
- If choosing MeCN as the solvent was finalized in previous studies, at least mention the reasons behind using MeCN
- Seems the system is working only/effectively for an electron-withdrawing (EWG) at para position, and not for EDG, table 2. Need to address the reasons for this effect
- Also, ketones are less reactive than aldehydes, entry 6, Table 2. Compare this data with other studies
- Need to do some more research with additional starting materials to make clear conclusions
- What are the reasons for no reaction or nd in table 2. References and supporting information is necessary for all the points listed in the paper
- NMR data is not presented in SI
Author Response
Dear Reviewer,
Thank you for the valuable comments. Below please find my response (in bold):
1) Authors were stated about opposite enantioselectivity in lines 88-90, which is not clear to understand.
I apologize for the mental shortcut. I meant, of course, the formation of enantiomers of products having opposite absolute configurations. The corresponding phrase has been corrected in text (in yellow).
2) Started with 20 mol % catalyst which is very high, run some more studies with lower catalyst loadings and compare the results at slightly elevated temp if needed.
Following your suggestion, additional experiments with lower catalyst loading have been conducted. While we did not observe significant changes in enantioselectivity, the decrease in chemical yield was quite noticeable with the reduction of the amount of catalyst used. The corresponding Table with short discussion has been added in text (in yellow).
3) At elevated temp data may give information about catalyst activity, need to provide mechanistic data.
All the attempts at increasing the reaction temperature were associated with a drastic decrease in enantioselectivity. The corresponding phrase has been added in text (in yellow). The corresponding proposed transition state model with mechanistic discussion has been included.
4) If choosing MeCN as the solvent was finalized in previous studies, at least mention the reasons behind using MeCN.
When choosing acetonitrile as the solvent for the title reaction, we were guided by the results of optimization of the conditions carried out by other authors (Reference No. 5). The authors found that the use of nonpolar solvents such as toluene led to products with low yield and enantioselectivity values. Moreover, reactions carried out in polar solvents such as dioxane or ethanol gave moderate results. The best results were associated with the use of acetonitrile.
5) Seems the system is working only/effectively for an electron-withdrawing (EWG) at para position, and not for EDG, table 2. Need to address the reasons for this effect. Also, ketones are less reactive than aldehydes, entry 6, Table 2. Compare this data with other studies.
Electron donating groups (EDGs) make carbon centers (carbonyl aldehyde group) weaker electrophiles and less reactive to nucleophiles. Probably for this reason we did not obtain the desired reaction product using p-methoxybenzaldehyde. Table 3 has been corrected (in previous version, R = H; it should be obviously: R = Me). For the same reason, the reaction with methyl acrylate resulted in a product with lower yield values.
6) Need to do some more research with additional starting materials to make clear conclusions.
I am fully aware of and agree with you that the substrate scope is limited and there are no new compounds in the substrate scope because our aim was to present the preliminary research results in the current contribution. We plan to further investigate this asymmetric transformation, including extending the scope of substrates.
7) What are the reasons for no reaction or nd in table 2. References and supporting information is necessary for all the points listed in the paper.
As we found only traces of the desired product in the post-reaction mixture (less than 5% based on the 1H NMR spectrum analysis), we did not attempt to isolate this product, and therefore no attempt was made to determine the value of the enantiomeric excess. Hence, we have included the entries you mentioned in Table 3. Supporting information has been enriched with additional HPLC chromatograms and copies of 1H NMR spectra.
8) NMR data is not presented in SI.
According to your suggestion, 1H NMR data of MBH products have been added in text and copies of 1H NMR spectra have also been included in SI.
Thanks again for your valuable comments.
Sincerely
Michal Rachwalski
Author Response File: Author Response.pdf
Round 2
Reviewer 1 Report
The authors have carefully revised the manuscript taking into consideration the comments of the reviewers. The article can be published in Catalysts after minor changes made:
- Delete the configuration of the product in Table 3 for entry 5.
- Also, I recommend to provide the data at different temperatures (with yields and ee), instead of giving just one sentence in the main text “All the attempts at increasing the reaction temperature were associated with a drastic decrease in enantioselectivity”. Indeed, the obtained results are interesting and the readers want to see the real data to understand the work.
Author Response
Dear Reviewer,
Thank you for the valuable comments. Below please find my response (in bold):
1) Delete the configuration of the product in Table 3 for entry 5.
The configuration of the product in Table 3 for entry 5 has been deleted. It has been replaced with nd (not determined) (marked in green in the text).
2) Also, I recommend to provide the data at different temperatures (with yields and ee), instead of giving just one sentence in the main text “All the attempts at increasing the reaction temperature were associated with a drastic decrease in enantioselectivity”. Indeed, the obtained results are interesting and the readers want to see the real data to understand the work.
The corresponding Table including data you mentioned has been inserted in the text (marked in green).
Thanks again for your valuable comments.
Sincerely
Michal Rachwalski
Author Response File: Author Response.pdf
Reviewer 2 Report
The authors addressed all the comments with proper justification and clearly explained the reaction mechanism. Therefore, this manuscript can be published in catalysis.
There are several HLPC graphs for compound 11 in supporting information. However, the authors could only provide the racemic and R and S isomers HPLCS graphs while resuming the manuscript.
Author Response
Dear Reviewer,
Thank you very much for your very positive revision. Below please find my response (in bold):
1) There are several HLPC graphs for compound 11 in supporting information. However, the authors could only provide the racemic and R and S isomers HPLCS graphs while resuming the manuscript.
Following your suggestions, HPLC chromatograms of racemic 11, (S)-11 and (R)-11 has been provided in supporting information. Remaining chromatograms for compound 11 have been removed.
Thanks again for your valuable comments.
Sincerely
Michal Rachwalski
Author Response File: Author Response.pdf
Reviewer 3 Report
accept
Author Response
Dear Reviewer,
Thank you for the very positive revision. Below please find my response (in bold):
1) accept
Thanks again for your positive comment.
Sincerely
Michal Rachwalski
Author Response File: Author Response.pdf
