The Improved para-Selective C(sp2)-H Borylation of Anisole Derivatives Enabled by Bulky Lewis Acid
, Qi Pang 1,* and Hong-Liang Li 2,*Round 1
Reviewer 1 Report
In the paper entitled "The Improved para-Selective C(sp2)-H Borylation of Anisole Derivatives Enabled by Bulky Lewis Acid", Li and co-workers described their work on a novel synthetic method for aromatic para-borylation using an Ir-based catalyst. The obtained results are very interesting and worth publishing in Catalysts after minor revision. Two issues should be added:
1. There is no information about Ir catalysts except it is commercially available. Please add to the Introduction section more detailed information about this catalyst - especially the reason for choosing it.
2. Scheme 5 - Synthesis of PDE4 inhibitor - It is crucial to show the improvement of the presented synthetic method compared to previous ones. For this reason, please give the other synthetic route of obtaining PDE4 inhibitor with yields to demonstrate the advantages of your para-borylation method - it is needed to clearly show that this synthetic route is better than previous ones.
Author Response
Dear Editor-in-Chief of Catalysts:
Thank you very much for your attentive review process and sending me a revision request e-mail (catalysts-2496097).
Manuscript ID: catalysts-2496097
Title: The Improved para-Selective C(sp2)-H Borylation of Anisole Derivatives Enabled by Bulky Lewis Acid
Authors: Dai-Yu Li, Rui-Mu Yu, Jin-Ping Li, Deng-Feng Yang, Qi Pang, Hong-Liang Li
Pages: 15 pages using the Template for Review
Following the reviewers’ suggestions, we have revised our manuscript as follows:
Reviewer 1:
1. [Comment #1]
There is no information about Ir catalysts except it is commercially available. Please add to the introduction section more detailed information about this catalyst-especially the reason for choosing it.
[Response]
[Ir(OMe)(cod)]2 is the most commonly used Ir(I) catalyst in C-H borylation, which is not only commercially available but also relatively cheaper than other corresponding Ir(I) catalyst. In addition, iridium catalyst does not play a decisive role in the para-borylation. According to the suggestion, we have added the detail information in the section of “Material and Methods”.
2. [Comment #2]
Scheme 5-Synthesis of PED4 inhibitor-It is crucial to show the improvement of the presented synthetic method compared to previous ones. For this reason, please give the other synthetic route of obtaining PDE4 inhibitor with yields to demonstrate the advantages of your para-borylation method-it is needed to clearly show that this synthetic route is better than previous one.
[Response]
According the reviewer’s suggestion, we have added the original synthetic method in Scheme 5. Compared with it, the improvement of our method is to easily synthesize a series of para-borylated anisole with ortho-substituent, which is a useful way for enriching the diversity of PED4 inhibitor compounds.
Sincerely yours,
Prof. Dr. Hong-Liang Li
Gangxi Key Laboratory of Marine Natural Products and
Combinatorial Biosynthesis Chemistry
Guangxi Academic of Marine Sciences
Guangxi Academy of Sciences, Nanning 53007, China
Tel: +86-0771-2536109
e-mail: [email protected]
Reviewer 2 Report
The authors report the para-selective C-H borylation of anisole derivatives by the introduction of Lewis acid additives to increase the steric bulk of the methoxy substituent. The manuscript is interesting and potentially impactful in the synthesis of arylboronates.
Although the authors ascribe the reversal of selectivity to the increased steric congestion of the Lewis acid bound anisole compared to anisole, this conclusion seems rather unlikely. Just from the depiction at the bottom of Scheme 1, it does not make sense that the Lewis acid would cause steric congestion at both meta hydrogens simultaneously. If it were to increase congestion at one of the meta positions, one would expect the ~3:1 ratio of meta/para to decrease to 1.5:1. Instead the ratio reverses to 1:4. If the Lewis acid is sitting above the arene, on the other hand, that would leave the other side of the arene completely open for the Ir catalyst to approach the C-H bond.
My interpretation of the results is that the methoxy substituent adds electron density on the ortho and para positions. This leaves the meta position with less electron density, and therefore increased reactivity. Once the Lewis acid is coordinated, it is no longer able to donate to the ortho and para positions effectively. The result is that the para position is electron deficient (similar to an ammonium group in EAS). The result is increased reactivity at the para position.
This analysis is consistent with the decreased selectivity for substrates 3i-3o. The more electron withdrawing the group is, the worse the selectivity. This makes sense because there are now two electron deficient centers.
I believe the authors should rework the manuscript to explain these concepts in a way that makes better sense with the data and the nature of the system. With those changes, I think the results are appropriate for this journal.
A few other issues that can be addressed to improve the manuscript.
1) For product 1h, there should not be a p/m selectivity since there is no distinction between the two non-ortho positions. Just leave the selectivity off.
2) At the bottom of Table 1, the authors state that they use 1,2-dichlormethane as the standard instead of 1,2-dichloroethane. Please fix.
3) In the general conditions for C-H borylation, the description of the vessel is rather confusing. They say they use a Schlenk Flask, but then say they sealed the "vial" with a teflon-lined cap. I'm not sure what you used. The term Schlenk Flask is often used in several ways, but I am not familiar with a way that it is a vial with a screw on cap. Please provide clear descriptions of the reaction setup.
4) The authors use GPC to purify the compounds. As this is not as commonly used as other organic purification methods. The description of the instrument and method should be provided in the general experimental. Maybe I missed it, but it is not in a common location.
The English is not bad in this manuscript, but there are several places that the sentences are missing words and subject/verb disagreements make the content confusing. One example is the second sentence of the introduction. There are words missing that cause confusion.
Author Response
Guangxi Academy of Sciences
Guangxi Key Laboratory of Marine Natural Products and Combinatorial Biosynthesis Chemistry, Guangxi Academic of Marine Sciences
Nanning 53007, Guangxi, China
July 24, 2023
Dear Editor-in-Chief of Catalysts:
Thank you very much for your attentive review process and sending me a revision request e-mail (catalysts-2496097).
Manuscript ID: catalysts-2496097
Title: The Improved para-Selective C(sp2)-H Borylation of Anisole Derivatives Enabled by Bulky Lewis Acid
Authors: Dai-Yu Li, Rui-Mu Yu, Jin-Ping Li, Deng-Feng Yang, Qi Pang, Hong-Liang Li
Pages: 15 pages using the Template for Review
Following the reviewers’ suggestions, we have revised our manuscript as follows:
Reviewer 2:
1. [Comment #1]
Although the authors ascribe the reversal of selectivity to the increased steric congestion of the Lewis acid bound anisole compared to anisole, this conclusion seems rather unlikely. Just from the depiction at the bottom of Scheme 1, it does not make sense that the Lewis acid would cause steric congestion at both meta hydrogens simultaneously. If it were to increase congestion at one of the meta positions, one would expect the ~3:1 ratio of meta/para to decrease to 1.5:1. Instead the ratio reverses to 1:4. If the Lewis acid is sitting above the arene, on the other hand, that would leave the other side of the arene completely open for the Ir catalyst to approach the C-H bond.
My interpretation of the results is that the methoxy substituent adds electron density on the ortho and para positions. This leaves the meta position with less electron density, and therefore increased reactivity. Once the Lewis acid is coordinated, it is no longer able to donate to the ortho and para positions effectively. The result is that the para position is electron deficient (similar to an ammonium group in EAS). The result is increased reactivity at the para position.
This analysis is consistent with the decreased selectivity for substrates 3i-3o. The more electron withdrawing the group is, the worse the selectivity. This makes sense because there are now two electron deficient centers.
[Response]
The reviewer suggested that the change of electron density on the aromatic ring of anisole substrate before and after coordination with Lewis acid is the determinant of para-selectivity, which is more reasonable than what we proposed. Therefore, according to the reviewer’s suggestion, we have revised all interpretations about para-selectivity in our manuscript including “abstract section; condition screen section; substrates scope section; mechanism section; conclusion section”. All changes were emphasized by yellow colour.
Even if it is not like as we suggested, we believe that the steric hindrance of bipyridyl ligand (especially the bulky alkyl substituent at ortho-position, scheme 1 entry 11~16) also promoted the para-selectivity. However, we did not get definite evidence to confirm it at present. Further research is underway in our laboratory.
Other issues:
1. [Issue-1]
For product 1h, there should not be a p/m selectivity since there is no distinction between the two non-ortho positions. Just leave the selectivity off.
[Response]
According to the reviewer’s advice, we have deleted the selectivity of 1h.
2. [Issue-2]
At the bottom of Table 1, the authors state that they use 1,2-dichlormethane as the standard instead of 1,2-dichloroethane. Please fix.
[Response]
According to the reviewer’s advice, we have revised the 1,2-dichlormethane to 1,1,2,2-tetrachlorethane.
3. [Issue-3]
In the general conditions for C-H borylation, the description of the vessel is rather confusing. They say they use a Schlenk Flask, but then say they sealed the "vial" with a teflon-lined cap. I'm not sure what you used. The term Schlenk Flask is often used in several ways, but I am not familiar with a way that it is a vial with a screw on cap. Please provide clear descriptions of the reaction setup.
[Response]
According to the reviewer’s advice, we have revised the name of vessel to seal tube.
4. [Issue-4]
The authors use GPC to purify the compounds. As this is not as commonly used as other organic purification methods. The description of the instrument and method should be provided in the general experimental. Maybe I missed it, but it is not in a common location.
[Response]
According to the reviewer’s advice, we have added the detail information of GPC in the Material Section.
5. [Comments on the Quality of English Language]
The English is not bad in this manuscript, but there are several places that the sentences are missing words and subject/verb disagreements make the content confusing. One example is the second sentence of the introduction. There are words missing that cause confusion.
[Response]
According to the reviewer’s advice, we have revised some confused sentence and further refined the language of manuscript.
Sincerely yours,
Prof. Dr. Hong-Liang Li
Gangxi Key Laboratory of Marine Natural Products and
Combinatorial Biosynthesis Chemistry
Guangxi Academic of Marine Sciences
Guangxi Academy of Sciences, Nanning 53007, China
Tel: +86-0771-2536109
e-mail: [email protected]
Reviewer 3 Report
The manuscript entitled: " The Improved para-Selective C(sp2)-H Borylation of Anisole Derivatives Enabled by Bulky Lewis Acid" reports the methodology for C-H borylation of anisole derivatives. The current version of the work lacks significant novelty. However, the manuscript is well-written and adequately demonstrates its scope. It should be noted that the yields of the corresponding products are not particularly high.
Based on the following remarks, the manuscript has the potential to be accepted for publication:
1. The following review and article should be cited:
- Ajvazi, N.; Stavber, S., Arkivoc 2018, 2018, 288-329 (regarding the formation of the C-C bond, compound 5).
- “Iron-Catalysed C(sp2)-H Borylation with Expanded Functional Group Tolerance†” https://doi.org/10.1002/cjoc.202200465
2. Is catalytic species recovered unchanged, or does it react and give side products?
3. Is it possible to reuse the catalyst for more than one catalytic cycle?
4. Did the authors obtain any by-products in addition to the intended products? Furthermore, why did they not conduct reactions at higher temperatures to investigate the possibility of obtaining a greater yield of the desired product?
5. Did the authors perform a scale-up procedure?
6. The manuscript could be further improved by refining the language and correcting typos to enhance its quality.
The manuscript could be further improved by refining the language and correcting typos to enhance its quality.
Author Response
Guangxi Academy of Sciences
Guangxi Key Laboratory of Marine Natural Products and Combinatorial Biosynthesis Chemistry, Guangxi Academic of Marine Sciences
Nanning 53007, Guangxi, China
July 24, 2023
Dear Editor-in-Chief of Catalysts:
Thank you very much for your attentive review process and sending me a revision request e-mail (catalysts-2496097).
Manuscript ID: catalysts-2496097
Title: The Improved para-Selective C(sp2)-H Borylation of Anisole Derivatives Enabled by Bulky Lewis Acid
Authors: Dai-Yu Li, Rui-Mu Yu, Jin-Ping Li, Deng-Feng Yang, Qi Pang, Hong-Liang Li
Pages: 15 pages using the Template for Review
Following the reviewers’ suggestions, we have revised our manuscript as follows:
Reviewer 3:
1. [Comment #1]
The following review and article should be cited:
- Ajvazi, N.; Stavber, S., Arkivoc 2018, 2018, 288-329 (regarding the formation of the C-C bond, compound 5).
- “Iron-Catalysed C(sp2)-H Borylation with Expanded Functional Group Tolerance†” https://doi.org/10.1002/cjoc.202200465
[Response]
According to the reviewer’s suggestion, the papers have been cited in ref. 13b, and ref. 1c.
2. [Comment #2]
Is catalytic species recovered unchanged, or does it react and give side products?
[Response]
The catalytic species can’t be recovered because the catalytic species is unstable and it did not give side product.
3. [Comment #3]
Is it possible to reuse the catalyst for more than one catalytic cycle?
[Response]
As for transition-metal catalyzed C-H functionalization reaction, chemists rarely pay attention to recover and reuse of transition-metal catalyst, because the amount of catalyst is used in very little amount (usually <10 mg). Therefore, it is difficult to recover and reuse.
4. [Comment #4]
Did the authors obtain any by-products in addition to the intended products? Furthermore, why did they not conduct reactions at higher temperatures to investigate the possibility of obtaining a greater yield of the desired product?
[Response]
We did not obtain any by-products. As we proposed the mechanism, the increased steric congestion of the Lewis acid bound anisole compared to anisole is the determinant of para-regioselectivity. Once the reaction temperature increase, the non-covalent bond interaction (Lewis acid-base interaction) between anisole substrates and B(Mes)3 will be weakened, with less steric hindrance between them, so that the para-selectivity will decrease. Therefore, in order to obtain good para-selectivity, we have to perform the reaction at room temperature.
5. [Comment #5]
Did the authors perform a scale-up procedure?
[Response]
At present, we did not perform scale-up procedure, one of reasons is that the price of Lewis acid (B(Mes)3) is very expensive. Another one, we think the current para-selectivity is not very high, as it is not necessary to do scale-up reaction. However, further research is underway in our lab.
6. [Comment #6]
The manuscript could be further improved by refining the language and correcting typos to enhance its quality?
[Response]
According to the reviewer’s advice, we have revised some confused sentence and further refined the language of manuscript
Sincerely yours,
Prof. Dr. Hong-Liang Li
Gangxi Key Laboratory of Marine Natural Products and
Combinatorial Biosynthesis Chemistry
Guangxi Academic of Marine Sciences
Guangxi Academy of Sciences, Nanning 53007, China
Tel: +86-0771-2536109
e-mail: [email protected]
