Copper-Catalyzed N-Arylation of Pyranoquinolinones with Boronic Acids at Room Temperature without Ligand
Round 1
Reviewer 1 Report (Previous Reviewer 1)
See the attached file.
Comments for author File: 
Comments.pdf
Author Response
Point: The authors have done minimum effort to revise the manuscript, which does not deserve to be published. Although I suggested that the authors should examine the reaction conditions with Cu(OAc)2, Et3N, pyridine, and DCM, the conditions described in Entry 8, Table 2 is different from those reported by Mederski et al. (ref. 14). The authors should also apply ortho-substituted arylboronic acids to the reaction. After major revision, the paper can be accepted as Article in Catalysts.
Response: The conditions reported by Mederski et al. (ref. 14) required 2.0 equivalent copper catalyst, and the amount of Phenylboronic acid was large. In our reaction conditions, the amounts of Pyranoquinolinone and phenylboronic acid were almost equal. This week, we have been using different amounts of copper catalysts to promote the reaction. We found a strange reaction phenomenon during the experiment, which was that when the amount of Cu(OAc)2 exceeded 1 equivalent, the reaction did not occur. Similarly, increasing the CuI loading to 50 mol% resulted in a lower 19% yield (entry 24, Table 1). And, further increasing of the Cu-catalyst loading to 100 mol% had a negative effect on the yield of the product, forming 3a only in a 9% yield (entry 25, Table 1). And, we have added this experiment to the text.
On the other hand, this week we chose o-tolylboronic acid and (2-fluorophenyl)boronic acid to test the applicability of the reaction. However, the reaction result was not good. During TCL analysis, the raw material disappeared, but the product did not appear. The results are shown in the following figure. Except steric hindrance, I don't know how to explain this reaction phenomenon.
Furthermore,
I have some points shown below that I think needs to be revised.
- 500 μg/ml (IC50) → 500 μg/mL (IC50) (Page 1, Line 22)
Response: We have made modifications according to the comments.
- Does EtOA stand for ethyl acetate? If so, EtOA should be substituted by EtOAc
(Page 2, Line 72 and Table 1, Entry 14)
Response: We have made modifications according to the comments.
Author Response File: Author Response.pdf
Reviewer 2 Report (New Reviewer)
In the present manuscript Huang and co-workers report on catalytic N-arylation of pyranoquinolinone which was obtained from citral. Inexpensive CuI salt was used as the catalyst, importantly without any ligands. The reaction proceeded well at room temperature with various arylboronic acids, mostly substituted at the para position. The authors developed a simple protocol which afforded the arylated products in yields up to 82%. In addition, the synthesized compounds exhibit activity against tumor cells. The synthesized products were adequately characterized (1H and 13C NMR, mass spectrometry) and are pure compounds. In my opinion, the manuscript can be accepted after minor revision.
Minor remarks:
1. I recommend checking by an English expert.
2. The capitals in compound names must be italic. For ex. in 4-hydroxy-1H-quinolin-2-ones. Check carefully throughout the text.
3. Lines 39 and 54: omit ‘’mother’’ in …quinoline mother ring…
4. line 109 (and below): instead of ‘’the substrates’’ use ‘’arylboronic acids’’. In my opinion the quinolinone is the substrate and aryl boronic acid is the reagent.
5. line 113-114: Of course, the steric hindrance at the para position was negligible. Usually we do not emphasize this. Optionally you could mention that the steric hindrance at the meta position was negligible.
6. Line 122: What is meant by ‘’rich electronic effect’’ ?
7. Scheme 2: In my opinion it is not necessary to include both intermediates II and III, as they are the same. Omit intermediate II.
8. A capital letter ‘’H’’ in the compound names must be italic
checking by an English expert recommended
Author Response
In the present manuscript Huang and co-workers report on catalytic N-arylation of pyranoquinolinone which was obtained from citral. Inexpensive CuI salt was used as the catalyst, importantly without any ligands. The reaction proceeded well at room temperature with various arylboronic acids, mostly substituted at the para position. The authors developed a simple protocol which afforded the arylated products in yields up to 82%. In addition, the synthesized compounds exhibit activity against tumor cells. The synthesized products were adequately characterized (1H and 13C NMR, mass spectrometry) and are pure compounds. In my opinion, the manuscript can be accepted after minor revision.
Minor remarks:
- I recommend checking by an English expert.
Response: We have made modifications according to the English expert.
- The capitals in compound names must be italic. For ex. in 4-hydroxy-1H-quinolin-2-ones. Check carefully throughout the text.
Response: We have made modifications according to the comments.
- Lines 39 and 54: omit ‘’mother’’ in …quinoline mother ring…
Response: We have made modifications according to the comments.
- line 109 (and below): instead of ‘’the substrates’’ use ‘’arylboronic acids’’. In my opinion the quinolinone is the substrate and aryl boronic acid is the reagent.
Response: We have made modifications according to the comments.
- line 113-114: Of course, the steric hindrance at the para position was negligible. Usually we do not emphasize this. Optionally you could mention that the steric hindrance at the meta position was negligible.
Response: We have made modifications according to the comments.
- Line 122: What is meant by ‘’rich electronic effect’’ ?
Response: We have deleted this sentence.
- Scheme 2: In my opinion it is not necessary to include both intermediates II and III, as they are the same. Omit intermediate II.
Response: We have made modifications according to the comments.
- A capital letter ‘’H’’ in the compound names must be italic
Response: We have made modifications according to the comments.
Author Response File: Author Response.pdf
Reviewer 3 Report (New Reviewer)
This paper describes synthesis of pyranoquinolinone derivatives by Cu-catalyzed N-arylation. It would be nice to proceed the catalytic reactions at room temperature, and various pyranoquinolinone alkaloids have been obtained in moderate to good yields. The IC50 values of the compounds on cervical cancer cell Hela has also been examined. The synthetic work and characterization of the compounds would be properly conducted. On the other hand, the catalytic reaction would be closely related to the previous reports (ref. 13), and proposed reaction mechanism (Scheme 2) would be the same as that of ref. 13. Therefore, from the view point of catalytic reaction, the reviewer did not find the novelty and originality. Alternatively, the obtained pyranoquinolinone derivatives might be important for biological science. Therefore, this paper would be appropriate for the other field of journals.
Other point:
The reviewer is curious about the description of “without ligand” in the title. Et3N would serve as not only a base but also a ligand because coordination of Et3N to Cu could stabilize intermediate species in the catalytic cycle.
no comment
Author Response
This paper describes synthesis of pyranoquinolinone derivatives by Cu-catalyzed N-arylation. It would be nice to proceed the catalytic reactions at room temperature, and various pyranoquinolinone alkaloids have been obtained in moderate to good yields. The IC50 values of the compounds on cervical cancer cell Hela has also been examined. The synthetic work and characterization of the compounds would be properly conducted. On the other hand, the catalytic reaction would be closely related to the previous reports (ref. 13), and proposed reaction mechanism (Scheme 2) would be the same as that of ref. 13. Therefore, from the view point of catalytic reaction, the reviewer did not find the novelty and originality. Alternatively, the obtained pyranoquinolinone derivatives might be important for biological science. Therefore, this paper would be appropriate for the other field of journals.
Other point:
The reviewer is curious about the description of “without ligand” in the title. Et3N would serve as not only a base but also a ligand because coordination of Et3N to Cu could stabilize intermediate species in the catalytic cycle.
Response: Although the catalytic reaction would be closely related to the previous reports (ref. 13), applying the reaction conditions described in reference 13 (Cu(OTf)2, 1, 10-Phen, DMSO), our investigation started with the reactions of 2-methyl-2-(4-methylpent-3-en-1-yl)-2H-pyrano[3, 2-c]quinolin-5(6H)-one (1) and phenylboronic acid (2a), and the desired product (3a) could only be afforded in trace (entry 1, Table 1). Now, we report on catalytic N-arylation of pyranoquinolinone which was obtained from citral, and inexpensive CuI salt was used as the catalyst, importantly without any ligands. The reaction proceeded well at room temperature with various arylboronic acids, and a simple protocol which afforded the arylated products in yields up to 82% has been developed. This is the novelty and originality. The synthesized compounds exhibit activity against tumor cells, however, the main research content of this article still focuses on synthesis methodology. We believe that this review will be of interest to general readers of Catalysts.
On the other hand, We originally thought 1, 10-Phen was acting as a ligand. Increasing the amount of 1, 10-Phen to 200 mol% had a positive impact on the isolated yield, giving desired product (3a) in 10% yield (entry 3, Table 1). Thus, we considered that 1, 10-Phen acted as a base rather than a ligand to promote the reaction. When we shifted to use pyridine indstead of 1, 10-Phen, better change was observed in the product yield with 16% (entry 4, Table 1). Encouraged by this results, we performed the transformation with K2CO3 or Et3N (2.0 equiv) as the bases with catalytic amount of Cu(OAc)2 (20 mol%) in DMSO, the desired product yields were respectively 19% and 25% (entries 5-6, Table 1). So we took Et3N as the best base. Actually, K2CO3 can also promote reaction occurrence, but as a ligand, 1, 10-Phen has a poor effect. So we believe that Et3N is a base rather than a ligand.
Author Response File: Author Response.pdf
Round 2
Reviewer 1 Report (Previous Reviewer 1)
Do the authors really believe it has been revised? They don't correct "EtOA" in the text (Page 2, Line 73) again. In addition, I think they don't read reference 14. The reaction condition shown in Entry 8, Table 1 is inconsistent with that described in the reference. The experimental section of the reference describes that a mixture of the substrate (7.6 mmol), phenylboronic acid (15.2 mmol), anhydrous cupric acetate (15.2 mmol), activated 4Å molecular sieves (2.0 g), pyridine (15.2 mmol) and triethylamine (15.2 mmol), in dichloromethane (50 mL) was treated at room temperature for 48 h. It is not interesting that the steric hindrance effect of the para-substituents of the arylboronic acids was negligible for this reaction (Page 5, Line 117). I don't understand why they would not apply ortho-substituted arylboronic acids to the reaction, the authors should add the comments on the results with ortho-substituted arylboronic acids to the text. I decline to review the manuscript anymore.
Author Response
Please see the attachment
Author Response File: Author Response.pdf
Reviewer 2 Report (New Reviewer)
line 104-105: the efficiency of the reaction was sensitive to arylboronic acids on the aromatic rings (3a-3k, Table 2). Rewrite this sentence.
How the efficiency could be sensitive to arylboronic acids on the aromatic rings???
Author Response
Please see the attachment.
Author Response File: Author Response.pdf
Reviewer 3 Report (New Reviewer)
While I respect the authors’ research results, synthesis of inhibitory active pyranoquinolinone derivatives on cervical cancer cell Hela, from the view point of catalytic reaction, I am afraid that the novelty and originality of this work would be limited. Therefore, I recommend this paper to submit to other appropriate journals.
no
Author Response
Please see the attachment.
Author Response File: Author Response.pdf
This manuscript is a resubmission of an earlier submission. The following is a list of the peer review reports and author responses from that submission.
Round 1
Reviewer 1 Report
See the attached file.
Comments for author File: Comments.pdf
Extensive editing of English language is required.
Author Response
Point: This manuscript is the report on a copper-catalyzed Chan-Lam coupling between pyranoquinolinone and arylboronic acids leading to N-aryl pyranoquinolinones. First of all, English must be corrected. If it is true that the reaction worked more efficiently with Cu+ rather than Cu2+, the authors need to demonstrate whether the reaction proceed under inert nitrogen or argon atmosphere instead of oxygen or not. In addition, I don't understand why the authors evaluated the cytotoxicity of the obtained compounds against tumor cells. I strongly suggest that they should modify the introduction part, in which cytotoxicity of either monoterpenoid or pyranoquinoline alkaloids should be mentioned. At this moment, the paper should be rejected as Article in Catalysts.
Furthermore, I have some points shown below that I think needs to be revised.
Response: “We discovered that the reaction worked more efficiently when Cu+ was used as a catalyst than Cu2+”have been modified to “We discovered that the reaction worked more efficiently under this open air condition when Cu+ was used as a catalyst than Cu2+”.
To illustrate the anti-tumor cell activity of citral and to align with the subsequent HeLa cells, this sentence of “It is particularly noteworthy that citral treatment (24 h incubation) could signifcantly decrease percentage of cell viability in HeLa, and 500 μg/ml (IC50) concentration 22 of citral was required for good inhibition of HeLa [1d].”has been added to the text。The literature “Ghosh, K. Anticancer effect of lemograss oil and citral on cervical cancer cell lines. Pharmacognosy Communications, 2013, 3(4): 41-48.” has also been added.
- Y?erbium(III) catalyzed transformations of 4-hydroxy-1H-quinolin-2-ones to enals for the preparation of pyranoquinolinones was reported by the Lee and coworkers previously → Y?erbium(III)-catalyzed transformations of 4-hydroxy-1Hquinolin-2-ones and enals into pyranoquinolinones was previously reported by Lee and coworkers (Page 1, Line 28–30)
Response: We have made modifications according to the comments.
- "EDDA(20 mol%)," → "EDDA (20 mol%)" (Scheme 1)
Response: We have made modifications according to the comments.
- 2-methyl-2-(4-methylpent-3-en-1-yl)-2H-pyrano[3, 2-c]quinolin-5(6H)-one 1 and phenylboronic acid 2a → 2-methyl-2-(4-methylpent-3-en-1-yl)-2H-pyrano[3,2-c]quinolin-5(6H)-one (1) and phenylboronic acid (2a) (Page 2, Line 57–58)
Response: We have made modifications according to the comments.
- promot → promote (Page 2, Line 62)
Response: We have made modifications according to the comments.
- Does EA stand for ethyl acetate? If so, EA should be substituted by EtOAc (Page 2, Line 68 and Table 1, Entry 12)
Response: We have made modifications according to the comments.
- What does "regio-selectivity" (Page 3, Line 95) mean? Does it mean "N-arylation, not O-arylation, occurred selectively"?
Response: The sentence of “with high efficiency and regio-selectivity” have been modified to “with high efficiency and regio-selectivity (N-arylation not O-arylation)” in the text.
- "DMSO, air, rt, 12h" → "DMSO, air, rt, 12 h" (Table 2)
Response: We have made modifications according to the comments.
- Although the authors said "interestingly, the steric hindrance effect of the substituents of the arylboronic acids was negligible for this reaction", it is common that the steric hindrance of substituents at the para-position does not affect the reactivity. They should apply ortho-substituted arylboronic acids to the reaction.
Response: “Interestingly, the steric hindrance effect of the substituents of the arylboronic acids was negligible for this reaction.” have been modified to”Interestingly, the steric hindrance effect of the para-substituents of the arylboronic acids was negligible for this reaction.”
- The authors should apply the standard reaction conditions for coupling reactions between 1H-quinolin-2-ones and arylboronic acids (Cu(OAc)2, Et3N, pyridine, DCM) to that between 1 and 2a and add the result to Table 1. Cite the following paper, Mederski, W. W. K. R.; Lefort, M.; Germann, M.; Kux, D. Tetrahedron 1999, 55, 12757–12770, which describes the reaction conditions.
Response: We apply the standard reaction conditions for coupling reactions between 1H-quinolin-2-ones and arylboronic acids (Cu(OAc)2, Et3N, pyridine, DCM) to that between 1 and 2a and add the result to Table 1. Cite the paper, Mederski, W. W. K. R.; Lefort, M.; Germann, M.; Kux, D. Tetrahedron 1999, 55, 12757–12770.
- The authors should also apply the reaction conditions described in reference 13 (Cu(OTf)2, 1,10-Phen, DMSO) and add the result to Table 1.
Response: We apply the reaction conditions described in reference 13 (Cu(OTf)2, 1,10-Phen, DMSO) and add the result to Table 1.
- Move "6-(4-fluorophenyl)-2-methyl-2-(4-methylpent-3-en-1-yl)-2,6-dihydro-5Hpyrano[
3,2-c]quinolin-5-one (3f)" to right (Page 7, Line 201)
Response: We have made modifications according to the comments.
Reviewer 2 Report
The manuscript may be published after careful correction and clarification of language and semantic inaccuracies.
It is necessary to:
1. In Scheme 1, it is necessary to indicate the structural formulas of all participants in the reaction, decipher the abbreviations. In Table 1., «Reaction temperature at…..» should be replaced by the «Reaction temperature is…».
2. In the Supporting information: indicate the abbreviation for each compound, number the spectra and sign the spectrum type, solvent in figure caption.
3. Specify in Conclusions: «This chemistry was general and the reaction conditions were mild compared to Ullmann cross-coupling and Buchwald-Hartwig…..? (reaction or coupling?)…….»
No
Author Response
Point: The manuscript may be published after careful correction and clarification of language and semantic inaccuracies.
It is necessary to:
- In Scheme 1, it is necessary to indicate the structural formulas of all participants in the reaction, decipher the abbreviations. In Table 1., «Reaction temperature at…..» should be replaced by the «Reaction temperature is…».
Response: We have made modifications according to the comments.
- In the Supporting information: indicate the abbreviation for each compound, number the spectra and sign the spectrum type, solvent in figure caption.
Response: We have made modifications according to the comments.
- Specify in Conclusions: «This chemistry was general and the reaction conditions were mild compared to Ullmann cross-coupling and Buchwald-Hartwig…..? (reaction or coupling?)…….»
Response: We have made modifications according to the comments. “Buchwald-Hartwig “ have been modified to “Buchwald-Hartwig cross coupling reaction”.
