1-(4-Chlorophenyl)-2-methyl-2-phenyl-5-(thiophen-2-yl)-1,2-dihydro-3H-pyrrol-3-one

Round 1

Reviewer 1 Report (Previous Reviewer 1)

The authors described the synthesis of 1-(4-chlorophenyl)-2-methyl-2-phenyl-5-(thiophen-2-yl)-1,2-dihydro-3H-pyrrol-3-one. The authors performed most of the suggestions of reviewers. According to the guideline of Molbank, I consider that manuscript meets all requirements to be published after major revision. In particular, the plausible mechanism should be revised. Additional suggestions and comments are included: (1) See lines 74-76. The authors mention that “in the IR spectrum of 3H-pyrrol-3-one 2, there are no characteristic absorption bands of the C≡C and N-H bonds of the starting 4-((4-chlorophenyl)amino)-pent-2-yn-1-one 1 at 3309 and 2216 cm^–1, respectively”. However, Figure S9 shows the IR spectrum of compound 2. ¿How do you explain the presence of bands at 2242 and 3333/3446 cm^–1? This affirmation should be carefully revised in the manuscript. On the other hand, it can be removed from Supplementary Material to avoid these inconsistencies and doubts.    (2) See lines 78 and 79. The authors mention that “The cyclization of aminoacetylenic ketone 1 probably starts with the addition of a water molecule to afford enol A rearranging to 1,3-diketone B (Scheme 3)”. If you read the procedure, you mentioned that “To a solution of aminoacetylenic ketone 1 (0.365 g, 1.0 mmol) in EtOH (2 mL), KOH (0.033 g, 0.5 mmol) was added”. I have several doubts: (i) ¿who is more nucleophilic water or hydroxyl anion? I consider that hydroxyl anion should participate in the nucleophilic addition. If it is correct, the stoichiometric quantity should be 1.0 mmol instead of 0.5 mmol ¿do you use 0.5 mmol? (ii) if you are mentioning that water is adding  to the triple bond ¿How do you explain the presence of water (at least 1.0 mmol) in the medium? It can come from EtOH (azeotropic mixture) or you are using a solution of NaOH in water instead of NaOH solid (0.5 mmol). (iii) During the nucleophilic addition followed by a protonation process, the solvent EtOH should play a key role ¿do you try this reaction in an aprotic polar solvent? These aspects should be carefully explained in the plausible mechanism. It has been previously reported in the literature in similar compounds. Thus, some references should be included to support these affirmations.   (3) See lines 78 and 79. The authors mention that “The cyclization of aminoacetylenic ketone 1 probably starts with the addition of a water molecule to afford enol A rearranging to 1,3-diketone B (Scheme 3)”. The correct symbology for keto-enol equilibrium should be properly drawn in Scheme 3 (A to B).

Comments for author File: Comments.pdf

Author Response

 

Below follows our response to the reviewer’s critics and suggestions.

 

Reviewer wrote:

«The authors mention that “in the IR spectrum of 3H-pyrrol-3-one 2, there are no characteristic absorption bands of the C≡C and N-H bonds of the starting 4-((4-chlorophenyl)amino)-pent-2-yn-1-one 1 at 3309 and 2216 cm^–1 , respectively”. However, Figure S9 shows the IR spectrum of compound 2. ¿How do you explain the presence of bands at 2242 and 3333/3446 cm^–1 ? This affirmation should be carefully revised in the manuscript. On the other hand, it can be removed from Supplementary Material to avoid these inconsistencies and doubts».

 

IR spectrum of 1-(4-сhlorophenyl)-2-methyl-2-phenyl-5-(thiophen-2-yl)-1,2-dihydro-3H-pyrrol-3-one (Figure S9) was obtained in a microlayer from CDCl₃. The absorption band at 2242 cm^-1 corresponds to the vibrations of the C-D bond of chloroform. The absorption bands at 3333 and 3446 cm^-1 can be explained by the presence of residual water in the solvent. This was confirmed by the absence of these absorption bands when recording IR spectrum of compound 2 in vaseline oil (Figure S8). To “avoid inconsistencies and doubts”, Figure S9 has been removed from Supplementary Material as recommended.

 

Reviewer wrote:

“Who is more nucleophilic water or hydroxyl anion? I consider that hydroxyl anion should participate in the nucleophilic addition. If it is correct, the stoichiometric quantity should be 1.0 mmol instead of 0.5 mmol ¿do you use 0.5 mmol?”

 

Certainly, the water addition to aminoacetylenic ketone in the presence of KOH starts with addition of hydroxide anion followed by the neutralization of the carbanionic center of the intermetiade carbanion with proton. Since the water molecule is eliminated during the cyclization, it can participate further in the reaction; hence stoichiometric quantity of water here is not required. Besides, the reaction proceeds in aqueous (96%) ethanol therefore in the reaction mixture there is in fact more than stoichiometric quantity of water.

 

Reviewer wrote:

“if you are mentioning that water is adding to the triple bond ¿How do you explain the presence of water (at least 1.0 mmol) in the medium? It can come from EtOH (azeotropic mixture) or you are using a solution of NaOH in water instead of NaOH solid (0.5 mmol).”

 

As mentioned above, water molecule is eliminated during the reaction. Also, excessive amount of water is present in aqueous (96%) ethanol. NaOH was not used in our reaction, only KOH in form of KOH∙0.5H₂O.

 

Reviewer wrote:

“During the nucleophilic addition followed by a protonation process, the solvent EtOH should play a key role ¿do you try this reaction in an aprotic polar solvent?”.

 

In aprotic solvents such as dioxane, DMSO and MeCN the reaction proceeded too slow (96 h in dioxane, 50 h in MeCN) or gave much lower yield (40% in dioxane and MeCN, 62% in DMSO) than in aqueous ethanol. In ethyl acetate, the reaction did not give target product at all. These results confirm that the presence of water is required for the successful synthesis of pyrrolone 2 and that in the “anhydrous” media the reaction proceeded only with the participation of trace water always present in aforementioned solvents.

The corresponding sentences have been included in the manuscript.

 

Reviewer wrote:

“It has been previously reported in the literature in similar compounds. Thus, some references should be included to support these affirmations”.

 

The synthesized pyrrolone is a new compound and its synthesis from aminoacetylenic ketone was implemented in this work for the first time. Therefore, we failed to find any relevant references for the synthesis of similar compounds.

 

Reviewer wrote:

“The correct symbology for keto-enol equilibrium should be properly drawn in Scheme 3 (A to B)”.

 

Done as recommended.

 

 

Now, we hope that after all the above amendments the manuscript has been improved to the state suitable for publication in MolBank.

 

Best regards,

Boris Trofimov

Round 2

Reviewer 1 Report (Previous Reviewer 1)

The authors performed all modifications suggested by reviewers

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

The authors described the synthesis of 1-(4-chlorophenyl)-2-methyl-2-phenyl-5-(thiophen-2-yl)-1,2-dihydro-3H-pyrrol-3-one. Unfortunately, the explanation of the 2D NMR spectra is completely absent. I do not find the NOESY spectrum in the Supplementary Material and its corresponding analysis in the manuscript. In conclusion, the assignment of the structure is not conclusive. I recommend obtaining monocrystals to confirm the structure by X-ray diffraction analysis. According to the guideline of Molbank, I consider that manuscript does not meet all requirements to be published in this form. Additional suggestions and comments are included: (1) See line 11. 4-((4-chlorophenyl)amino)-4-phenyl-1-(thiophen-2-yl)pent-2-yn-1-one under mild reaction conditions instead of 4-((4-chlorophenyl)amino)-4-phenyl-1-(thiophen-2-yl)pent-2-yn-1-one. (2) See line 42. Performed instead of realized. (3) See lines 47-49. The IR spectrum should be explained in a better form. It is very important to explain the most important bands of compound 2 including C-Cl, C=C, and C=O stretching bands as well as symmetric and asymmetric C-N stretching bands. In addition, it is very important to include the absence of both CºC and N-H stretching bands.   (4) See lines 47-49. An explanation of the most important proton and carbons signal of compound 2 should be included. (5) See lines 47-49. An explanation of the most relevant results of bi-dimensional spectra should be included to confirm the structure of 2. Also, NOESY should be taken and carefully analyzed. (6) From an organic point of view, the plausible mechanism to form compound 2 should be included (i.e. ¿how is happening the reduction of the CºC? ¿Which is the evidence to confirm the presence of 2-thiophenyl moiety attached to the carbon C-5?   (7) See line 42. KOH instead of KOH∙0.5H2O. It should be modified in the manuscript. (8) See Figure S7. ¿How do you explain the presence of bands at 2242, 3333, and 3446 cm-1? It does not correlate with the proposed structure 2. (9)  I consider that X-ray crystallographic analysis might be included. Thus, I could be published in another journal with a higher impact factor.