(E)-1-(5-(Hydroxymethyl) furan-2-yl)-4,4-dimethylpent-1-en-3-one

Round 1

Reviewer 1 Report

The manuscript submitted by He and Qin describes the transformation of a chitin derivative, N-acetylglucosamine, into N-(3-chlorophenethyl)-4-nitrobenzamide via 5-hydroxymethylfurfural.　The product was newly synthesized by a modified catalytic process using formic acid and subsequent condensation of furfural with ketone. The selective and straightforward access to 5-hydroxymethylfurfural is very attractive, while the formation of 3-(acetamido)furan derivatives from N-acetylglucosamine has been widely reported. To emphasize the smooth C–N bond cleavage by formic acid, it would be beneficial for the readers to disclose whether such N-containing byproducts were produced or not, and to cite the recent papers of ChemistrySelect 2022, 7, e202104574 (6 pages; https://doi.org/10.1002/slct.202104574) and J. Mol. Liq. 2021, 330, 115667 (https://doi.org/10.1016/j.molliq.2021115667). In whole, this paper is valuable to the synthetic community, and merits publication in Molbank after the following issues are addressed.

1) As a reference for the catalytic conversion of N-acetylglucosamine, the following paper should be included in the reference section: H. Kobayashi, T. Sagawa, A. Fukuoka, Chem. Commun. 2023, 59, 6301-6313. 

2) For the equation in Scheme 1, a typo in H₂O should be corrected. 

3) In Figure 2 (a) and (b), revise the vertical scale values on the graphs as appropriate (i.e., 10, 20, 30…).

4) L. 101; the choice of base should be mentioned in detail. I also recommend to cite a related paper on Knoevenagel condensation of 5-hydroxymethylfurfural using aqueous NaOH: For example, K. I. Galkin, V. P. Anannikov, ChemSusChem 2019, 12, 185-189.

5) L. 165-170; the resonance frequencies of ¹H and ¹³C nuclei are inconsistent with those of the NMR spectrometer, JNM-ECP600. 

6) Regarding Fig. S2 in the Supporting Information, the assignments for the signals at 6.98 and 6.57 ppm are incorrect. It would also be better to provide HMQC data to identify the ¹³C NMR results. 

7) To confirm the purity of the new compound, elemental analysis needs to be performed. 

8) Add the information about the HPLC apparatus. Analytical procedures for HPLC should also be described. 

Some sentences (including L. 163-164) need to be revised for easy understanding.

Author Response

Thank you for your letter and the reviewers’ comments concerning our manuscript entitled “Synthesis of (E)-1-(5-(hydroxymethyl) furan-2-yl)-4,4-dimethylpent-1-en-3-one from N-acetylglucosamine”. We appreciate your approval and generous suggestions! We made changes based on the suggestions and answered the questions point by point. Questions and responses are distinguished by color. as follows：

Author Responses:

Question 1: As a reference for the catalytic conversion of N-acetylglucosamine, the following paper should be included in the reference section: H. Kobayashi, T. Sagawa, A. Fukuoka, Chem. Commun. 2023, 59, 6301-6313.

Response: We thank the reviewers for their valuable comments. We have introduced relevant references in the main text. Insert H. Kobayashi, T. Sagawa, A. Fukuoka, Chem. Commun. 2023, 59, 6301-6313 literature at line 78, number 13.

Question 2: For the equation in Scheme 1, a typo in H₂O should be corrected.

Response: We thank the reviewers for their valuable comments. We have corrected the H₂O in Scheme 1.

Question 3: In Figure 2 (a) and (b), revise the vertical scale values on the graphs as appropriate (i.e., 10, 20, 30…).

Response: We thank the reviewers for their valuable comments. We have modified the vertical scale in Figures 2 (a) and (b) to (10, 20, 30...).

Question 4: L. 101; the choice of base should be mentioned in detail. I also recommend to cite a related paper on Knoevenagel condensation of 5-hydroxymethylfurfural using aqueous NaOH: For example, K. I. Galkin, V. P. Anannikov, ChemSusChem 2019, 12, 185-189.

Response: We appreciate the valuable comments from the reviewer. We have added the relevant basis in the main text (On page 4). The detailed response is as follows:

Sodium hydroxide (NaOH), serving as a potent base, plays a crucial role in providing the necessary alkaline conditions for the reaction[18]. Under these conditions, active methylene compounds undergo deprotonation to form methylene anions, which increases their nucleophilicity and facilitates subsequent attacks on the carbonyl carbon atoms. The use of a water-methanol mixture is strategically chosen to optimize the solvent properties, balancing both polarity and non-polarity to enhance the solubility of the reactants. This balance is essential for maintaining a homogeneous reaction mixture and for accelerating the reaction kinetics. Specifically, water as a polar solvent efficiently dissolves NaOH and ensures the required hydration environment, whereas methanol enhances the solubility of organic components, notably the active methylene compounds.

The reasons for substrate selection have been explained in detail in lines 147-157, and reference K. I. Galkin, V. P. Anannikov, ChemSusChem 2019, 12, 185-189 has been cited in line 148, article 18.

Question 5: L. 165-170; the resonance frequencies of ¹H and ¹³C nuclei are inconsistent with those of the NMR spectrometer, JNM-ECP600. 

Response: We thank the reviewers for their valuable comments. We have corrected the Agilent DD2 500 spectrometer on the 190 line.

Question 6: Regarding Fig. S2 in the Supporting Information, the assignments for the signals at 6.98 and 6.57 ppm are incorrect. It would also be better to provide HMQC data to identify the ¹³C NMR results. 

Response: We thank the reviewers for their valuable comments. Through HMQC comparison, we found that there is indeed an issue with the H attribution at 6.98 and 6.57 ppm. Our signal attribution at 6.98 and 6.57 ppm is shown in Fig Changes have been made in S2 and HMQC data has been attached in Fig.S4.

Question 7: To confirm the purity of the new compound, elemental analysis needs to be performed. 

Response: We thank the reviewers for their valuable comments. We have conducted elemental analysis to confirm the purity of the new compound and added the data on line 189.

Question 8: Add the information about the HPLC apparatus. Analytical procedures for HPLC should also be described. 

Response: We thank the reviewers for their valuable comments. We added HPLC equipment information on line 193 and added analytical procedures before Figure S1.