Modified 7-Chloro-11H-indeno[1,2-b]quinoxaline Heterocyclic System for Biological Activities

Round 1

Reviewer 1 Report

Please include a mechanism (azomethine ylid intermediate) which will strengthen your paper. Is this one new??? I think so, so you should draw it because it is new. I am familiar with some early work here. Prof Ron Grigg at Leeds University and a Thailand co-worker patented 1,8-diazafluorenleneone as a reagent for the enhancement off latent fingerprints. It is the common method today replacing ninhydrin.  They also made the o-phenylenediamine  derivatives similar to yours (without the chlorine). The fingerprints required a quasar to view the fluorescence in a dark room. Please prove the position of the chlorine atom in the starting material. It should be done by an X-Ray single crystal structure determination. Why is only one isomer formed? Which one forms and why as the data for each will be similar. I think it should be a mixture which is a problem for you. In summary I thought this is a very nice paper but a few points above must be clarified. Please dont just say others did it. Maybe you could publish the proton and carbon data of the starting material a bit larger and expanded? To prove it is one compound, but which isomer? Dont calculate it either. One of my colleagues in a company has just sacked someone for doing this. Nice paper so finish it off properly. 

Author Response

Answer: We are highly thankful to the reviewer for these fundamental observations and suggestions. As per the reviewer’s comments, the corrections are made and inserted into the main text in the manuscript. A mechanism for azomethine ylid intermediate (Scheme 4 (a)) has been given in scheme 4 for the more clearance of intermediate. However, the formation of the product was confirmed by using the ¹HNMR technique by justifying the position of Cl atoms which affects to the values of surrounded H atoms (confirmed by ¹HNMR spectra). We are extremely sorry that the single XRD analysis is not possible as we are not getting any positive response for the slots/analysis due to the covid pandemic.

Scheme 4. Proposed schematic mechanism of the synthesis of Spiro derivatives. (a) A mechanism for Azomethine formation, (b) Scheme for spiro indenoquinoxaline.

Author Response File: Author Response.docx

Reviewer 2 Report

The authors report the synthesis of Spirocyclic compounds using 1, 3-dipolar cycloaddition by a multi-component reaction of L-proline, Indenoquinoxaline, and the dipolarophile of malononitrile. The functionalize Spiro pyrrolizidines were found effective towards biological uses by considering their in-vitro screening and antimicrobial impacts and showed 50% inhibition efficiency. The work can be of utility to researchers interested in the organic chemistry and medicinal chemistry. This reviewer recommends publication of this manuscript in catalysis after following majored modification is made.

1. In the abstract: Line 10, replace ‘The functionalize Spiro pyrrolizidines’ by ‘The functionalized spiro-pyrrolizidines’; Line 13 ‘bacteria due---- to’ by ‘bacteria due to’; Line 16-17 replace ‘The biological studies showed 50% inhibition efficiency for the derived Spiro heterocyclic systems’ by ‘The biological studies showed that the derived spiro heterocyclic systems have an inhibitory effect of 50%. Please polish the English language of this abstract.
2. In the introduction:

• Please remove the brackets from these references. For example correct this (Liu, Dou, and Shi, 2010) and the group, (Rahmannejadi, Yavari, and Khabnadideh, 2020) were also synthesized, (Liu, Dou, and Shi, 2010; Barkov et al., 2017) studied regio- and etc.
• To cite the references in the text, please follow the journal template.
• Please rewrite Line 3: ‘Spiro pyrrolizidines are been strongly applied towards; page 2 line 4 replace ‘synthsize’ by synthesize’; page 2 line 10; ‘These various approaches were been addressed’ by ‘These various approaches were considered’; on line 12 correct this ‘the single-step method were been explored’ and so on.
• Correct this too. Line 14, electron-rich hetero-compounds-by ‘electron-rich heterocyclic compounds’

3. In the experimental set up

• You wrote ‘The C-H, C spectral analysis’ was done by Bruker AVANCE III HD 500 MHz spectrometer’ what does it mean? Is it ¹HNMR and ¹³CNMR? If so, you did not report any ¹³CNMR data for each compound. Otherwise modify the statement.
• In Scheme 1. The product of the reaction for the p-methoxybenzaldehyde is not correct. Add methoxy (-OMe) group on the product too.
• In Scheme 2. rewrite CH3COOH as CH₃COOH (number subscript)
• Please include the amount in milligrams of each new compound.

4. In result and discussion

• Modify the proposed mechanism on Scheme 4. Because it may not be clear for the reader.
• ¹HNMR spectrum of Figure 2(a) and 8(a) are too small. Please modify.
• Page 18, line 4: please correct ‘spritopyrrolizine’.

5. Generally, a plenty of grammatical errors are found in the whole text, please polish it.
6. The references on the list are not properly written according to the journal template.
7. What’s the dr of the products? Please confirm the configuration of typical product by single crystal X-ray crystallographic analysis.

Author Response

Please see the attachment. 

Author Response File: Author Response.docx

Round 2

Reviewer 1 Report

You said you included proton and carbon data for your starting material chloro quinoxaline. I could not find it. You must characterise your starting material like this. Its your work. You can't publish this without it. It proves the rest of your data is OK and not mixtures.

Author Response

You said you included proton and carbon data for your starting material chloro quinoxaline. I could not find it. You must characterise your starting material like this. Its your work. You can't publish this without it. It proves the rest of your data is OK and not mixtures.

Response:

We are again thankful to the reviewer for this keen observation and suggestions. We have added ¹H NMR spectra for the chloro quinoxaline starting material with their recorded values. We also added ¹H NMR spectra into the main text as per reviewer suggestions (scheme 2 (b)). Now, we hope that the required data are well fitted for the asked queries.

Scheme 2 (b). ¹H Spectra for 7-Chloro-11H-indeno[1,2-b]quinoxalin-11-one.

Pale yellow powder yield: 95%, ¹H NMR 500 MHz (CDCl₃) δ: Aromatic protons 9.13 (s, 1H), 8.61 (d, 1H, J=9.46 Hz), 8.29 (d, 1H, J=9.00 Hz), 8.20 (d, 1H, J=7.50 Hz), 8.02 (d, 1H, J=7.41 Hz), 7.87 (t, 1H, J=7.28 Hz), 7.73 (t, 1H, J=7.41 Hz).

Author Response File: Author Response.docx

Reviewer 2 Report

This reviewer recommends publication of this manuscript in catalysis 

Author Response

Thank you for accepting the manuscript for publication.

Round 3

Reviewer 1 Report

This is much better although a shame you dont have an X-Ray single crystal structure determination of your starting material to prove the position of the chlorine atom. Never mind.  It looks poorly soluble from the intensity of the chloroform peak so minor impurities are showing up on the right hand side. Im sending this back to give you an opportunity to present this as an expansion from say 2.00 pm down to another lower value so you enlarge the aromatic protons and miss out the minor impurities on the right hand side.  If you like leave it as it is. You decide. This paper is now so much better. This is your key starting material for all your cycloadditions. 

Author Response

Response: Authors are highly thankful to the reviewer for this technical fundamental observations and suggestions. We want publish this original graph for the starting materials as we got the original results from instruments. So, our humble requests to the reviewer kindly please consider the same data and interpretation for the final acceptance. Again, thank you very much for the keen observations and suggestions.

Best Regards

Dr. Gajendra Kumar Inwati