C−H Methylation Using Sustainable Approaches

Round 1

Reviewer 1 Report

The review authors Mohamed Mokhtar and Debabrata Maiti with co-authors is devoted to the C−H methylation of sp2 and sp3 carbon centers. This review is devoted to the methylation of organic molecules due to the activation of C-H. The review describes such approaches to methylation as photo-redox, electrochemical, mechanochemical and metal free approaches. An analysis of the literature on this issue is important, since the methylation of organic molecules is of great importance in medicinal chemistry.

The review can be published in a journal. There are the following small comments:

- Page 2, line 57: In my opinion 2.1. "Methylation using peroxides" would be better called "Ir(III)-catalysed methylation using peroxides".

- Page 10, line 289: “2.5. Ru-catalyzed methylation using methyl boronic acids’’ instead of ‘2.5 Methylation using methyl boronic acids’’.

- Page 16, line 447: “5. Ru-catalyzed mechanochemical C−H methylation’’ instead of “5. Mechanochemical C−H methylation’’.

- On all diagrams instead of "eq."  need to write "equiv."

This review is very useful as it summarizes the literature on C−H methylation, which is of great biological importance for medical chemistry. Therefore, this review, after minor corrections, is worthy of publication in the Catalysts journal.

Comments for author File: Comments.pdf

Author Response

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Author Response File: Author Response.pdf

Reviewer 2 Report

Title: C−H methylation using sustainable approaches

The review written by Ishika Agrawal and co-workers summarized the synthetic approaches that are widely used in medicinal chemistry for methylation of arenes and heteroarenes. In this review, the authors have given concise introduction about the methylation and its importance. It mainly covers the green methodologies for the C−H methylation. First, the authors explained the photoredox-redox catalyzed C(sp²)−H methylation strategies including methylation using peroxides, methylation using methanol, methylation using acetic acid and derivatives, methylation using dimethyl sulfoxide, and methylation using methyl boronic acids. Later, the authors explained photo-redox catalyzed C(sp³)−H methylation strategies, which includes oxidative C(sp³)−H methylation and formation of radical via peroxides. Then, the authors focused on C−H methylation by electrochemical oxidation and mechanochemical C−H methylation. Finally, the authors explained the metal free approaches for C−H methylation. This review gives valuable information for the methylation strategies and can be adopted by researchers. Overall, this review is clearly written, providing the mechanism for all the reactions which is very important for the readers to understand the chemistry. All the references are in proper format. This review could be accepted as is in “Catalysts” after addressing the below comments.

• I suggest the authors to give percentage yield for the schemes 10,11,15,19, and 37.
• Page 10, line 290: Please change “methyl radical sources due its high efficiency” to “methyl radical sources due to its high efficiency”
• Page 11, line 293: Please replace “Chenand co-workers” with “Chen and co-workers”

Author Response

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Author Response File: Author Response.pdf

Reviewer 3 Report

This review focuses on methylation via C-H bond activation. While it is interesting and does cover an important topic, it is not well written. From a scientific standpoint, the authors need to cite their statements more appropriately - for example, when they introduce mechanochemistry they should include some reviews etc. Also, the work is not written in a particularly insightful manner. At times it reads like a list of examples rather than being a coherent flow and there should be more discussion of how things fit together and the pros and cons of the different approaches. This would greatly improve the impact of the review and it use to the catalysis community.

From a stylistic perspective, there are many idiomatic errors and some sentences are incomplete.

With some extensive editing, the work may be suitable for publication after further peer review.

Author Response

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Author Response File: Author Response.pdf

Reviewer 4 Report

Maiti and co-workers present a review connected to the topic "green methods for C-H methylation". C-H methylation chemistry has in past years emerged as a highly popular synthetic strategy, particularly in the realm of medicinal chemistry where it is used to "methyl-edit" molecules in order to tune their biological properties. The angle of presenting sustainable methods for this type of chemistry is in line with the time, and also perhaps necessary to limit the scope of the review.

Unfortunately, and it hurts me to say this as I have much respect for the work of the Maiti group, but I had very large difficulties going through this review. Mainly, because of the language that was of an extremely low standard, and to me it seems that this review was not proof-read before submission but instead submitted in a hurry. It is a shame, because the authors have done a very good job covering the literature, and in my opinion all of the key studies within this area have been surveyed.  But still, I cannot support the publication of this review in the current state, as I am afraid that also the readership of this journal will struggle to get through it. Below are some feedback that could help improve the review for the next submission, and I apologize if some are nitpicky in nature (the list is also quite extensive, apologize for that too), but I tried my best to point out as many of the elements that should be corrected, to properly guide the authors in their revision work. 

1) Below are listed some sentences that grammatically is not optimal and should be revised for improved readibility. Beware, this list is not covering all of the sentences I found but just the major ones, so I advice the authors to have a thorough read-through of the entire manuscript once again.

• C−H functionalization has become interesting tool in medicinal chemistry
• Scientific communities came up with modern advanced 36 approaches such as photo-redox strategies which have been proved to be an effective al- 37 ternative for the formation of radical than the classical thermal approach, as it eliminated 38 the need for radical initiators and harsh reaction condition
• C−H transformation using electrochemistry where 40 electrical current is used as oxidant becoming an alternative green approach
• Various methyl sources can be used for C−H methylation of arenes and het- 55 eroarenes which have been discussed below.
• Entire paragraph: Ir(III) catalyst was used to reduce t-BPA under acidic condition that helps in lower 66 the barrier to reduction. Ir(III) is then excited to decompose t-BPA through single e- 67 transfer generating an unstable a−peroxy radical which further gave tert-butoxy radical 68 that undergoes in b−scisson to generate methyl radical.Me radical then added to 69 protonated heterocycle followed by oxidation of amino radical cation by Ir(IV) to give 70 desired product (Scheme-2).
• After several strategies on 77 radical based alkylation via peroxide, an idea of MeOH to be used as methyl source 78 introduced as it is easily available, cheap and avoid energy intensive peroxides.
• Ir(ppy)2(dtbbpy)+ as photo-catalyst under 87 blue LEDs excited under irradiation by light to *Ir(III) which further oxidized to Ir(IV) by 88 protonated heteroarene
• A mechanistic principle of SCS is a leaving 96 group was eliminated that is adjacent to radical with the transferal of spin density to the 97 adjacent atom
• The radical intermediate that form after SCS further undergoes in protonation and 104 on reduction by *Ir(III) to give desired product. In 2016, DiRocco and co-workers reported 105 the hydroxymethylation protocols with methanol in the presence of peroxides by the 106 photo-redox catalysis in which besides hydroxymethylation they also observed the meth- 107 ylated product
• As per the proposed mechanism, protonated heteroarene first excited to singlet state in 154 presence of light which then quenched by methanol to generated protonated radical in- 155 termediate and hydroxymethyl radical, this radical then reacts with electrophilic proto- 156 nated heteroarene to give radical cation intermediate which further form an intermediate 157 via PCeT as shown in Scheme-6, then by eliminating H2O and after tautomerisation give 158 methylated product
• Then this MesAcr radical transfers an electron to hypervalent iodine adduct which 207 undergo in radical anion collapse and form methyl radical and then further attacks on 208 protonated heteroarene to form an intermediate that after deprotonation and single elec- 209 tron transfer gives the methylated product
• The selectivity of C−H insertion of highly reactive methyl carbenes was 365 governed by strong absorption of it on GaN surface, which makes them more selective 366 towards more substituted carbon centers while when temperature was raised, selectivity 367 for 1°C−H enhanced due to the desorption of carbenes on GaN surface, which is in consist 368 with classical carbene chemistry
• Since it avoids the use of solvents, so no solvent waste is generated after the reaction 457 unlike other processes making it cheaper and greener as compare to other traditional ap- 458 proaches
• In the proposed mechanism, PhI(OAc)2 reacts with tert-butanol 602 to form an intermediate, that reacts with the substrate and generates an intermediate 603 which undergoes homolytic C−C bond cleavage of alcohols via SET pathway, then by aro- 604 matization yields the 2-methylated product. 

2) In the introduction, the authors use the amino acids to examplify the "magic methyl effect". Unfortunately, I don't approve of this examples, as the authors are  comparing the amino acids alanine, valine, leucine and isoleucine that actually differ in size as well, and that could in many cases be the reason why they affect peptides differents.

3) The following terms should be corrected

• Should be metal-free instead of metal free,
• should be photophysical instead of photo physical,
• should be PCET instead of PCeT
• should be Lewis acid instead of lewis acid
• should be photo-redox instead of photoredox,
• NiCl2.dimethoxyethane should have the dot elevated as a multiplication sign (fix in scheme 18 too).
• should be e− donating/withdrawing instead of electron-donating/withdrawing

4) The authors are mixing methanol/MeOH and water/H₂O randomly in the text. The authors should be consistent choosing only one for each.

5) Different depiction of methyl radical in Schemes, compare for example Scheme 2 and Scheme 9.

6) Error in Scheme 10, a bond is missing between a nitrogen and an oxygen

7) & is used to abbreviated and in many places. I do not think this is proper in an academic text.

Author Response

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Author Response File: Author Response.pdf

Round 2

Reviewer 3 Report

The manuscript is somewhat improved. It still reads more like a laundry list of examples rather than an insightful review. That said, it could add value to the literature and as such can go forward for acceptance but will need significant editing for English. The authors can't even spell "mechanochemical" correctly in the keywords!

Reviewer 4 Report

Maiti and co-workers presents a very timely review that surveys the field of C-H methylation chemistry, which is an emerging field within the area of C-H functionalization. The focus of this review is on sustainable methods, which is a suitable restriction to make to limit the scope of studies to be reviewed, and it also helps directing future research along the correct path.

I previously reviewed the original version of this review, which was very comprehensive in terms of the prior art it surveyed, but at the same time it was very difficult to read through due to the poor quality of the language. Gratifyingly, the language has been significantly improved in this version, and I no longer have the same difficulties I previously had. It should be pointed out that there are still a few things left to fix in terms of language (I have attached a file, marking those that stood out to me), but I now consider it to be of a rather minor nature. I am sure this work will be further refined as a part of the final publication process between the authors and Catalysts staff.

Therefore, I will this time recommend this review for publication, as I believe it very comprehensively covers the science in the field, which should be the primary point to judge.

Comments for author File: Comments.pdf