3-Isobutyl-5,5,7-tris(3-methylbut-2-en-1-yl)-1-phenyl-1,7-dihydro-4H-indazole-4,6(5H)-dione

Round 1

Reviewer 1 Report

In their manuscript Raquel Guimaraes Jacob, Marcio Santos Silva and coworkers reported the formation of indazole product by the reaction of natural compound lupulone and phenyl hydrazine. They used ¹H, ¹³C and 2D NMR to determine the product structure. However, the Reviewer is sceptical about correctness of structure “Lupulone-H-indazole 2”. There are some issues (mainly in NMR). The Authors are asked to check the product structure and NMR assignment again.

Major issues:

• “Lupulone derivative 2” and “Lupulone-H-indazole 2” are just tautomeric forms. Why do the Authors consider these two structures as different (possible) products? Moreover, there can be one more tautomer with CH at C7 and double bonds between C6=O and C8=C9. Tautomers usually exists in rather quick equilibrium and can not be separated. Therefore Authors should modify the discussion.
• Regarding structure elucidation by NMR: couplings H9-H14 and H9-H14’ has J = 5.0 and 6.3 Hz. Considering the distance between coupling nuclei (5 bonds!) such large values of J looks improbable. In Table 2 the Authors claimed HMBC-correlations between H14,H14’ and C4, C7, C9, C15, C16. Both two bonds correlations (C7 and C15) are visible. Among three-bond correlations only one (with C16) is visible, while with C6 and C8 – not. C4 is 5 bonds away from H14, C9 is 4 bonds away from H14. Why correlation between H14 and C5, C6, C8 are not visible if they are also within 4-5 bonds? Is C4 correctly assigned? Why H10 has correlation to C3, C4 and C7? C3 is indeed within 2 bonds, but C7 is within 5 bonds. How to explain the absence of correlations to C5, C8 and C9? The Reviewer afraids that mentioned questions are enough to consider the assignment as incorrect.
• Regarding HRMS: It is written: “m/z [M + H]⁺ calcd for C₃₂H₄₂N₂O₂: 486.32463; found: 487.32438.” Is the error indeed nearly 1 mass unit or is it a mistake? Also, when Reviewer calculate M+H⁺ he got the result 487.3319. Even in this case error between calculated and found values is 15 ppm. It is more than acceptable 5 ppm. Please, check the HRMS data.

HMBC-correlations are better to be described not only by listing them (as Authors do in Table 2), but also by arrows drawn on the structure. This would allow the reader to see correlation easier.

Minor issues:

• Reference J. Chem. Soc., 1938, 1193-1195 could be cited. There are also example for interaction of 2-acyl-cyclohexa-1,3,5-trione with phenylhydrazine. Indazole structure is proposed as a product.
• Couling constants are usually rounded to decimal (e.g., 7.4 Hz, not 7.36 Hz). Similar about IR: 3225 instead of 3224.8.
• lines 46, 54 and SI, “hexane/acetate”. What is hexane? n-hexane, hexanes or petroleum ether? Should “acetate” be “ethyl acetate”?
• lines 52-53 and Experimental, “the purification was directly carried out, without extraction step.” Please, clarify the steps between heating and chromatography. Was the reaction mixture directly transferred onto chromatography column? Or was catalyst filtered before applying to column? Or was mixture diluted with some solvent, filtered and then evaporated?
• When mentioning “Lupulone derivative 3” – please, provide some reference that lupulone is able of ring contraction.
• SI, page S2, “relative intensity” is preferable instead of “relative abundance”.
• SI, check for non-English terms, e.g. RMN, intensidade relativa.
• 17, Why some surnames are written in capital letters?

Author Response

Please see the attachment,

Sincerely,

Márcio S. Silva

Author Response File: Author Response.pdf

Reviewer 2 Report

XXXXCCV

Authors describe and interesting and novel conversion of lupulone aimed at the synthesis of an annulated pyrazole (indazole derivative) after heterocyclization reaction performed with phenylhydrazine. Structure of the obtained polycyclic heterocycle was determined based on spectroscopic (NMR) data.

Potentially, this work can be of interest for circle of readers working in the chemistry of heterocycles and/or  organic synthesis with exploration of natural compounds. However, the manuscript in the current form cannot be recommended for publication and it requires revision.

Following problems are addressed to Authors in the course of preparation of the revised version:

1) Did Authors try to confirm analytical purity of the obtained product by elemental analysis ? 

2) All structures presented in schemes and discussed in the main text should be numbered. Without these numbers reading and understanding of the publication text is extremely difficult.

3) On the ‘reference list’, period of pages for all cited publications should be given in all cases (and not only in ref. [16] and [17]).

4) Instead of ’lepulone-H-indazole’ more general name, e.g. ‘lepulone derived indazole’, is recommended for the usage through the entire text.

5) An alternative proposal for the title is following: ‘Synthesis and structural studies on 3-isobutyl……-dihydro-4H-indazole-4,6(5H)-dione’

In summary: after revision this publication can be considered for possible publication in Molbank. 

Author Response

Please see the attachment

Sincerely

Márcio S. Silva

Author Response File: Author Response.pdf

Round 2

Reviewer 1 Report

After the revision manuscript is better. Structure and assignment look much more reasonable. Only one minor question left: was derivative 3 indeed among the possible products? Why the reduction was expected?

Author Response

Please see the attachment.

Sincerely

M. S. S.

Author Response File: Author Response.pdf