Radical C–H 18F-Difluoromethylation of Heteroarenes with [18F]Difluoromethyl Heteroaryl-Sulfones by Visible Light Photoredox Catalysis
, Laura Trump 1,2,†, Bénédicte Lallemand 2, Patrick Pasau 2, Joël Mercier 2, Christian Lemaire 1, Jean-Christophe Monbaliu 3, Christophe Genicot 2,* and André Luxen 1,*Round 1
Reviewer 1 Report
Manuscript Number: catalysts-725857
Taking advantage of a previous work reported by the authors on the use of [18F]difluoromethyl benzothiazolyl-sulfone ([18F]1) as a 18F-difluoromethylating reagent, here in the authors describe the synthesis of six new [18F]difluoromethyl heteroaryl-sulfones [18F]5a-[18F]5f and evaluated this new compounds as 18F-difluoromethylating reagents. Mechanistic studies were also performed to demonstrate the involvement of radical species in the C-H 18F-difluoromethylation process.
Congratulations the manuscript is well written and the SI very completed. Before publication, this referee requests the authors to address the following points:
The introduction is easy to read and the literature review is described very clearly. Just a suggestion, in Figure 2, please write in the top of the figure “This Work” In the Results please: a) In line 215 please change 22 min to 23 min. b) Besides the described benefits of using the continuous-flow system for the C-H 18F-difluoromethylation of N-containing heteroarenesLine 249-251 “The use of a continuous-flow system assures an efficient irradiation of the reaction mixture during the photocatalytic processes in significantly reduced reaction times.”
Please discuss in terms of productivity.
c) In line 249 please specified the flow rate or the range of flow rate. d) Present the mechanism in the main manuscript. Figure S104 of the SI.Author Response
Taking advantage of a previous work reported by the authors on the use of [18F]difluoromethyl benzothiazolyl-sulfone ([18F]1) as a 18F-difluoromethylating reagent, here in the authors describe the synthesis of six new [18F]difluoromethyl heteroaryl-sulfones [18F]5a-[18F]5f and evaluated this new compounds as 18F-difluoromethylating reagents. Mechanistic studies were also performed to demonstrate the involvement of radical species in the C-H 18F-difluoromethylation process.
Congratulations the manuscript is well written and the SI very completed. Before publication, this referee requests the authors to address the following points:
Answer: The authors would like to thank to the reviewer’s comments.
The introduction is easy to read and the literature review is described very clearly. Just a suggestion, in Figure 2, please write in the top of the figure “This Work”.
Answer: The authors followed the reviewer’s suggestion and, in the revised manuscript version, the expression “This work” was added on top of the Figure 2.
In the Results please: a) In line 215 please change 22 min to 23 min.
Answer: The authors would like to suggest keeping the “22 min”, since the collection of the radioactive compound [18F]5a was initiated at the instant t=22 min, according to the radio-HPLC profile of the crude [18F]5a (see Figure 4B of the revised manuscript version). Please note that the retention times of the radioactive peaks [18F]5a, [18F]5c, and [18F]5f presented in Figures 4B, 4D, and 4F (submitted manuscript version), respectively, do not correspond to the instant when the collection of the radiotracers was initiated. For clarity, some modifications in the UV- and radio-HPLC chromatograms were performed: (i) the retention times presented in the chromatograms of the submitted manuscript version were eliminated; (ii) two vertical lines delimiting the radioactive peaks corresponding to the radiotracers [18F]5a, [18F]5c, and [18F]5f were included in the chromatograms to highlight the starting- and the end-point of the collection of the radiotracers.
b) Besides the described benefits of using the continuous-flow system for the C-H 18F-difluoromethylation of N-containing heteroarenes
Line 249-251 “The use of a continuous-flow system assures an efficient irradiation of the reaction mixture during the photocatalytic processes in significantly reduced reaction times.”
Please discuss in terms of productivity.
Answer: In the revised manuscript version, the authors mentioned the potential benefit of the development of a continuous-flow system in terms of productivity. Therefore, the original sentence “The use of a continuous-flow system assures an efficient irradiation of the reaction mixture during the photocatalytic processes in significantly reduced reaction times.” was replaced by “The use of a continuous-flow system assures an efficient irradiation of the reaction mixture during the photocatalytic processes and can potentially lead to an enhanced productivity in significantly reduced reaction times.”
c) In line 249 please specified the flow rate or the range of flow rate.
Answer: In the revised manuscript version, the authors mentioned the distinct flow rates used in each optimization step throughout the section 2.2.3. and in the caption of the Scheme 5. An additional row with the distinct flow rates used in each optimization step was included in Table 4.
d) Present the mechanism in the main manuscript. Figure S104 of the SI.
Answer: In the revised manuscript version, the mechanism was included in the main manuscript (Figure 7).
Reviewer 2 Report
Reviewer comments for the manuscript submitted to Catalysts
Manuscript Title: “Radiosynthesis of [18F]difluoromethyl heteroarylsulfones for radical C-H 18F-difluoromethylation of heteroarenes by visible light photoredox catalysis”
Authors: A. L. P. Lemos, L. Trump, B. Lallemand, P. Pasau, J. Mercier, C. Lemaire, C. Genicot, A. Luxen
General comments
Manuscript entitled “Radiosynthesis of [18F]difluoromethyl heteroarylsulfones for radical C-H 18F-difluoromethylation of heteroarenes by visible light photoredox catalysis” by Lemos et aldescribes an extension of application of fluorine-18 difluoromethyl sulfone 1by using differently substituted sulfones in the difluoromethylation of heteroarenes. The extension of application, details on how to prepare sulfones, and optimization process are highly useful to Synthetic/Radiosynthetic community and thus this manuscript is well placed for publication in the Catalyst. This reviewer would like to compliment the authors for the exceptionally high level of presentation of the Supplementary information and the details of experimental procedures and the quality of the data reported both in terms of chemical characterization through the NMR analyses as well as UV and radio traces for radiochemical transformations. This reviewer highly recommends the publication of this manuscript after very minor changes.
Specific comments
Although the title describes what the paper is about, this reviewer feels it requires some rephrasing as it is somewhat confusing at the first glance. Perhaps focus on the reaction difluoromethylation of heteroarenes, and only then state using various sulfones. Also it should be radiosyntheses of sulfones, as it was more than one sulfone made. For clarity please distinguish between the conversion and the yield. In several places it states page 5, lines 156-157: “By raising the amount of NaIO4 from 0.24 mmol to 0.72 mmol, the [18F]4a was fully converted into the labeled compound [18F]5a in 70.9 ± 6.1% RCY (Table 1, Entry 4).” Something can be fully converted, but then isolated in certain yield. Please correct for this throughout the manuscript. It is also good to indicate how was conversion measured (HPLC conversion, NMR conversion, etc). In this reviewer’s view it is more practically important to report molar activity at the EOS and not the EOB. Authors do an excellent job in defying how they determines RCY ndc and RCY dc, and the molar activity, but should remain consistent throughout the manuscript.
Author Response
General comments: Manuscript entitled “Radiosynthesis of [18F]difluoromethyl heteroarylsulfones for radical C-H 18F-difluoromethylation of heteroarenes by visible light photoredox catalysis” by Lemos et aldescribes an extension of application of fluorine-18 difluoromethyl sulfone 1 by using differently substituted sulfones in the difluoromethylation of heteroarenes. The extension of application, details on how to prepare sulfones, and optimization process are highly useful to Synthetic/Radiosynthetic community and thus this manuscript is well placed for publication in the Catalyst. This reviewer would like to compliment the authors for the exceptionally high level of presentation of the Supplementary information and the details of experimental procedures and the quality of the data reported both in terms of chemical characterization through the NMR analyses as well as UV and radio traces for radiochemical transformations. This reviewer highly recommends the publication of this manuscript after very minor changes.
Answer: The authors would like to thank the reviewer’s comments.
Specific comments
Although the title describes what the paper is about, this reviewer feels it requires some rephrasing as it is somewhat confusing at the first glance. Perhaps focus on the reaction difluoromethylation of heteroarenes, and only then state using various sulfones.
Answer: The authors agree with the reviewer’s comment and the title of the main manuscript was replaced by “Radical C-H 18F-difluoromethylation of heteroarenes with [18F]difluoromethyl heteroaryl-sulfones by visible light photoredox catalysis”.
Also it should be radiosyntheses of sulfones, as it was more than one sulfone made.
Answer: The authors agree with the reviewer’s comment and the expression “radiosynthesis” was appropriately replaced by “radiosyntheses” throughout the manuscript.
For clarity please distinguish between the conversion and the yield. In several places it states page 5, lines 156-157: “By raising the amount of NaIO4 from 0.24 mmol to 0.72 mmol, the [18F]4a was fully converted into the labeled compound [18F]5a in 70.9 ± 6.1% RCY (Table 1, Entry 4).” Something can be fully converted, but then isolated in certain yield. Please correct for this throughout the manuscript.
Answer: The sentence “By raising the amount of NaIO4 from 0.24 mmol to 0.72 mmol, the [18F]4a was fully converted into the labeled compound [18F]5a in 70.9 ± 6.1% RCY (Table 1, Entry 4).” was replaced by “By raising the amount of NaIO4 from 0.24 mmol to 0.72 mmol, the [18F]4a was fully consumed and the labeled compound [18F]5a was isolated in 70.9 ± 6.1% RCY, after cartridge purification (Table 1, Entry 4).”
It is also good to indicate how was conversion measured (HPLC conversion, NMR conversion, etc).
Answer: The conversion was determined by UPLC. In Tables 1 and 4, the authors included an additional row with the different percentages of UPLC conversion of the substrates.
In this reviewer’s view it is more practically important to report molar activity at the EOS and not the EOB.
Answer: The authors followed the reviewer’s suggestion and the molar activities were reported at the EOS in the revised manuscript version.
Authors do an excellent job in defying how they determines RCY ndc and RCY dc, and the molar activity, but should remain consistent throughout the manuscript.
Answer: Regarding the determination of the RCYs of the C-H 18F-difluoromethylation reactions, the authors suggested excluding the expression “ndc”. As these RCY values were calculated based only on the radio-UPLC and the radio-TLC purities of an aliquot of the reaction mixture after the C-H 18F-difluoromethylation reaction and the starting activity of the 18F-difluoromethylating reagents for each reaction was not taken into account, the authors considered that the use of the expression “ndc” was useless. According to the “International Consensus Radiochemistry Nomenclature Guidelines”[1,2], the authors could not find an alternative and suitable radiochemical terminology to define the multiplication between the radio-UPLC and the radio-TLC purities. The expression “radiochemical conversion (RCC)” has been employed in several publications in the field of radiochemistry, however the use of this terminology is not in agreement with the “International Consensus Radiochemistry Nomenclature Guidelines”[1,2]. Therefore, the authors decided to keep the expression “RCY”, based on the above-mentioned guidelines. More details about the determination of the different RCY values were mentioned in the captions of the Schemes 2,3, and 5 and of the Tables 1-4. The authors expect that these additional details may clarify the readership.
References
- Coenen, H.H.; Gee, A.D.; Adam, M.; Antoni, G.; Cutler, C.S.; Fujibayashi, Y.; Jeong, J.M.; Mach, R.H.; Mindt, T.L.; Pike, V.W.; Windhorst, A.D. Open letter to journal editors on: International Consensus Radiochemistry Nomenclature Guidelines. Nucl. Med. 2018, 32, 236–238.
- Coenen, H.H.; Gee, A.D.; Adam, M.; Antoni, G.; Cutler, C.S.; Fujibayashi, Y.; Jeong, J.M.; Mach, R.H.; Mindt, T.L.; Pike, V.W.; Windhorst, A.D. Status of the “consensos nomenclature rules in radiopharmaceutical sciences’ initiative. Med. Biol. 2019, 71, 19-22.
Reviewer 3 Report
The manuscript ‘Radiosynthesis of [18F]difluoromethyl heteroarylsulfones for radical C-H 18F-difluoromethylation of heteroarenes by visible light photoredox catalysis’ by Lemos et al. presents a detailed study of substituent effects on difluoromethyl heteroarylsulfones for use in Ir catalyzed radical difluoromethylation under continuous-flow conditions. The manuscript is well written, the findings are clearly presented and the conclusions are supported by the experimental evidence.
I have only some minor points that the authors should address before publication in Catalysts and recommend acceptance after minor revisions.
Closely related compounds have been published by Wagner et al in a patent [Ger. Offen. (1997), DE 19523447 A1 19970102]. This should, be referenced. At the end of the manuscript the authors extend the procedure towards heteroarenes of medicinal relevance. This section should be referenced. Line 308. I suggest to use inhibited instead of abolished.Somewhat more critical are the following two points:
This manuscript was submitted to Catalysts. I find the focus on catalysts a bit lacking. I would suggest to add the reaction mechanism proposal to the main manuscript. The authors find that none of the new compounds performs as good as the one previously published by the authors in Angew. Chemie. This finding is conveniently ignored in the conclusions and should not be hidden. Furthermore, I wonder if the authors could speculate why both EDGs and EWGs are having a negative effect.Author Response
The manuscript ‘Radiosynthesis of [18F]difluoromethyl heteroarylsulfones for radical C-H 18F-difluoromethylation of heteroarenes by visible light photoredox catalysis’ by Lemos et al. presents a detailed study of substituent effects on difluoromethyl heteroarylsulfones for use in Ir catalyzed radical difluoromethylation under continuous-flow conditions. The manuscript is well written, the findings are clearly presented and the conclusions are supported by the experimental evidence.
I have only some minor points that the authors should address before publication in Catalysts and recommend acceptance after minor revisions.
Answer: The authors would like to thank the reviewer’s comments.
Closely related compounds have been published by Wagner et al in a patent [Ger. Offen. (1997), DE 19523447 A1 19970102]. This should, be referenced.
Answer: The above-mentioned patent was cited in the revised manuscript version (reference 31).
At the end of the manuscript the authors extend the procedure towards heteroarenes of medicinal relevance. This section should be referenced.
Answer: The references 48, 49, and 50 were conveniently added in the section 2.2.3. These references describe the medicinal relevance of the drugs acyclovir (reference 48), moxonidine (reference 49), and pentoxifylline (reference 50).
Line 308. I suggest to use inhibited instead of abolished.
Answer: The authors agree with the reviewer’s suggestion and the expression “abolished” was replaced by “inhibited”.
Somewhat more critical are the following two points:
This manuscript was submitted to Catalysts. I find the focus on catalysts a bit lacking. I would suggest to add the reaction mechanism proposal to the main manuscript.
Answer: The authors followed the reviewer’s suggestion and the mechanism proposal was included in the main manuscript (Figure 7).
The authors find that none of the new compounds performs as good as the one previously published by the authors in Angew. Chemie. This finding is conveniently ignored in the conclusions and should not be hidden.
Answer: The authors agree with the reviewer’s comment. In the section 2.2.3., the authors included the following sentence “Regardless of the employed 18F-difluoromethylating reagent, the labeled compound [18F]8e was furnished in lower RCYs, in comparison with the sulfone [18F]1.”(lines 273-274 of the revised manuscript version). In the conclusion, the authors included the following sentence “Interestingly, these newly synthesized compounds revealed to be competent reagents for the C-H 18F-difluoromethylation of the antiherpetic drug 7e, under the reaction conditions recently reported in our laboratories [37]. Still, none of the new reagents performed as good as the original sulfone [18F]1 in the radiosynthesis of the labeled compound [18F]8e.”
Furthermore, I wonder if the authors could speculate why both EDGs and EWGs are having a negative effect.
Answer: Based on the results described throughout the manuscript, the authors were not able to find a clear explanation for the negative effect of the newly synthesized compounds in the C-H 18F-difluoromethylation reactions.
Reviewer 4 Report
The use of PET (positron emission tomography, positron emission tomography) as a new cancer diagnostic test has begun to spread. PET injects a substance incorporating atoms (fluorine, carbon, hydrogen, nitrogen) that emit positrons (positrons) into the body, detects light emitted during the process of accumulation and metabolism of the substance, and images. The most commonly used radioisotope for cancer diagnosis is 18F. In this paper, the authors described the effective synthesis of the 18F-contained organic compound ([18F]difluoromethyl heteroaryl-sulfones) and investigation of their activities of difluoromethylating of heterocyclic compounds. It is very interesting and useful for chemistry and medicinal science. Then, I think this paper must be published in your journal (Spelling check was needed).
Author Response
The use of PET (positron emission tomography, positron emission tomography) as a new cancer diagnostic test has begun to spread. PET injects a substance incorporating atoms (fluorine, carbon, hydrogen, nitrogen) that emit positrons (positrons) into the body, detects light emitted during the process of accumulation and metabolism of the substance, and images. The most commonly used radioisotope for cancer diagnosis is 18F. In this paper, the authors described the effective synthesis of the 18F-contained organic compound ([18F]difluoromethyl heteroaryl-sulfones) and investigation of their activities of difluoromethylating of heterocyclic compounds. It is very interesting and useful for chemistry and medicinal science. Then, I think this paper must be published in your journal (Spelling check was needed).
Answer: The authors would like to thank the reviewer’s comments.
