1-(Pyrrolidin-1-yl)naphtho[1,2-d]isoxazole

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

In this manuscript, the authors reported the 2-step synthesis of a naphtho[1,2-d]isoxazole (4) and two naphtho[1,2-e]pyrrolo-17 [2,1-b][1,3]oxazin-12-on derivatives (3 and 5) with low yields from 2-hydroxy-1-naphthaldehyde. Two end products (3 and 4) are not known in the literature. The structures of the newly synthesized compounds have been convincingly characterized by ¹H and ¹³C NMR spectroscopy, HRMS, IR, and UV-VIS. The authors proposed a mechanism for the reactions leading to the three products.  In summary, I think that this manuscript contains valuable results and may be suitable for publication in Molbank after addressing the comments below and some corrections.

 

General remarks:

1) L63: N,N-dibenzyl-2-hydroxy-3,5-dinitrobenzamide is not the solvent of the reaction but a reactant, so "with" should be used instead of "in". Moreover, in reference [17], the 3,5-dinitrobenzamide derivative is incorrectly mentioned in the preparation of the relevant 2o compound since it leads to the formation of 2n. The correct starting material should be N,N-dibenzyl-2-hydroxy-1-naphthamide.

2) In “2. Results”, the sentences about the workup of the reaction mixtures are unnecessary since they are already included in the experimental part. Therefore, the second half of L68 and lines 74-76 can be omitted. Furthermore, the sentence starting in L105 can be omitted, as the previous sentence already provides enough information.

3) L127: It is not described that product 4 is formed from intermediate 9 by eliminating water.

4) Scheme 2: I recommend to modify Scheme 2 as follows. During the 10 -->11 transformation, AcOH leaves from compound 10. Since 11 contains a negative charge on one of the carbon atoms of the pyrrolidine ring, the lead atom must be positively charged to maintain the neutrality of intermediate 11, so it is a zwitterionic compound. When intermediate 12 forms, no OAc leaves, so two OAc groups are still connected to the lead atom. Finally, during the 12 --> 13 transformation, Pb(OAc)₂ forms as a byproduct, while the oxazine ring forms. Thus, the oxidation numbers are also correct in this redox reaction since the lead atom is reduced by 2 (+4 --> +2), while the carbon atom of the pyrrolidine ring is oxidized by 2 (-1 --> +1). Accordingly, the following should be corrected in L131: " by eliminating acetate ion", since presumably no acetate ion leaves the molecule.

5) The sentence in L133-134 is not entirely true, as 3 only partially hydrolyzes to 5, not completely (15% vs 10%). Furthermore, „hydrolyzed” instead of „hydrolized”.

6) In Scheme 3, compound 18 is already the previous compound 7, isn't it? Furthermore, it is not clear how compounds 18, 22, and 8, 19, 20, and 21 in the bottom row relate to the other compounds. While the text helps with interpretation, it would be nice if Scheme 3 itself were transparent.

7) Apparently, the UV-VIS spectra of compound 3 do not correlate with the given wavelength data (284 and 339 nm). In the supplementary material the absorptions are at approximately 275 and 295 nm. Could it be that the measurements performed at different concentrations are causing the anomaly?

8) Line 306 has the IR data of compound 3 instead of 5.

 

The manuscript needs minor changes:

L31: „antithrombotic, and acetylcholinesterase” instead of „antithrombotic and, acetylcholinesterase”

Fig. 1.: Risperidone and paliperidone differ from each other only in one OH group, so it would be more space-saving to have only one common structural formula and indicate the difference below it.

L61: „using SnCl2·2H2O [16]. Six” instead of „using SnCl2·2H2O [16]Six”

L62: „copper-catalyzed” instead of „copper catalyzed”

L107:  „slightly” instead of „slighly”

L142: „oxazide 15 [19].” instead of „oxazide. 15 [19].”

L169: „formula” instead of „formulae”

L249-250: Concentration data lacks spaces between values ​​and units.

The R_f values in lines 292 and 303 should be given uniformly with two decimal places (0.20 and 0.30), as in line 281.

Author Response

Please see the attachment.

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

Varvounis et al. 's communication describes the oxidation (E)-2-hydroxy-1-naphthaldehyde-oxime using various oxidants. Unfortunately, the oxidation is neither selective nor productive, and the title compound was isolated in a maximum yield of 18 %. Another two co-products were isolated in similar (and very low) yields, making the reaction almost useless from the synthetic point of view. On the other hand, for better understanding to the structure-reactivity relationships more experiments e.g. with different secondary amines (cyclic  = piperidine; non-cyclic = diethylamine, N-methylaniline) would be carried out. The 1H NMR spectra of individual main products would be assigned using some advanced NMR technique(s) and the 13C-APT experiment would be better to distinguish between carbons carrying odd or even numbers of hydrogens. Now, only simple list of signals and their integral are commented.

Minor points: 13C NMR shifts should be rounded to only one decimal place

Finally, the communication can be published in Molbank only after major revision.

Author Response

Molbank-3493185 Comments from Referee 2 and author responses

Comments and Suggestions for Authors

Varvounis et al. 's communication describes the oxidation (E)-2-hydroxy-1-naphthaldehyde-oxime using various oxidants. Unfortunately, the oxidation is neither selective nor productive, and the title compound was isolated in a maximum yield of 18 %. Another two co-products were isolated in similar (and very low) yields, making the reaction almost useless from the synthetic point of view.

Referee Comments 1: On the other hand, for better understanding to the structure-reactivity relationships more experiments e.g. with different secondary amines (cyclic = piperidine; non-cyclic = diethylamine, N-methylaniline) would be carried out.

Author response: We appreciate the reviewer’s insightful suggestion. While we agree that such studies would enhance understanding of structure–reactivity relationships, they fall outside the scope of Molbank. However, we recognize the merit of this idea and believe it could form the basis of a more comprehensive study.

Referee Comments 2: The ¹H NMR spectra of individual main products would be assigned using some advanced NMR technique(s) and the ¹³C-APT experiment would be better to distinguish between carbons carrying odd or even numbers of hydrogens. Now, only simple list of signals and their integral are commented.

Author response: We used, among other techniques, a combination of 1D and 2D NMR spectroscopy that enabled the full characterisation of ¹H and ¹³C NMR chemical shift assignments of new compounds (E)-3 and 4. We used DEPT-135 ¹³C NMR spectra and for 2D NMR, ¹H-¹H COSY, ¹H-¹³C HSQC and ¹H-¹³C HMBC spectra. These spectra are to be found in the Suppl. Mat. where comprehensive ¹H and ¹³C NMR chemical shift assignments of compounds (E)-3 and 4 are given with the aid of arrows around their chemical structures.

Further to the above, we have re-written in the Discussion section the NMR analysis of compound (E)-3 found in lines 187-199 and of compound 4 found in lines 221-235. We also added chemical shift assignments to the ¹H and ¹³C NMR data of compounds (E)-3 and 4, in the Experimental section.

Referee Comments 3: Minor points: ¹³C NMR shifts should be rounded to only one decimal place.

Author response: We have rounded up all ¹³C NMR chemical shifts (in ppm) of compounds (E)-3, 4 and 5 to one decimal place.

Finally, the communication can be published in Molbank only after major revision.

 

Round 2

Reviewer 2 Report

Comments and Suggestions for Authors

The manuscript was improved according to some of my suggestions. Although I have some doubts concerning the synthetic utility of this procedure, I consider it publishable in Molbank in its present form.