3-Phenyl-3H-naphtho[1,2-e][1,2,3]oxadiazine

Round 1

Reviewer 1 Report

This manuscript describes the two-steps synthesis of a novel naphtooxadiazine from 2-hydroxy-1-naphthaldehyde and phenylhydrazine via an oxidative cyclisation with iodobenzene diacetate. The title compound was synthesized with an overall yield of 9%. NMR (1H and 13C) and HRMS were used to confirm the proposed structure. The introduction describes a brief and consistent history on bioactive oxadiazines. For D5281, the authors should expand -(CH2)2F to -CH2-CH2F. In the second part of the manuscript, it makes more sense to present the synthesis of compound 2 before discussing compound 5. In the oxidative cyclisation, the authors obtained a very poor yield in methanol or DCM. This weak point must be discussed (by-products? problem of reactivity of compound 2? presence of intermediates 3 or 4?) with precision on the role of time and temperature in this reaction. Finally, the discussion (third part) complete the results since a different reactivity was observed by other research groups with an oxime to give oxazine in excellent yield (around 75%). The nitrogen nucleophilicity or the steric hindrance of compound 2 (phenyl) vs oxime could explain this regioselectivity but all these points would require optimization to determine all the compounds generated in this oxidative cyclisation of 2. In relation to this discussion, please add Infrared in the supplementary material to confirm the presence of functions such as phenol, ketone or imine. Thus, I recommend this manuscript for publication in Molbank after major revisions.

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Reviewer 2 Report

The structure elucidation is not conclusive, i.e. NMR 7.24-7.18 (m, 1H). 2D-NMR is suggested

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Reviewer 3 Report

The authors describe the one step synthesis of a naphtoloxadiazine scaffold involving an oxidative cyclization of a starting phenylhydrazone in presence of iodobenzene diacetate.
The structural hypothesis of the obtained compound is convincing and also the reaction mechanism proposed is coherent.
Actually, as even recognized by the authors themselves, the major weakness of the presented work concerns the very low reaction yield.
Generally, the low yield can be ascribed to the incomplete conversion of the starting material into the product, or to the formation of undesired side compounds, or still to the instability of the starting material under reaction conditions.
Could the authors try to make some speculations which can explain the reasons of the disappointing result?

Author Response

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Reviewer 4 Report

The manuscript of the Short Note

3-Phenyl-3H-naphtho[1,2-e]oxadiazine

by

Аlia D. Aouant and George Varvounis

concerns the obtainment of the title compound, containing a rather unusual kind of polyheter-cycle , rarely, and only recently found in a natural, biologically active, compound.

Unluckily, yields are very low, but this should not be so unexpected, as an analogous system (2-hydroxy-1-naphthaldeyde oximes, under oxidation with lead tetraacetate) was studied by the Authors some years ago (Te Le 2000, Te 2001).

Hereinafter some corrections needed:

Line17: it should be: “natural oxadiazines were considered non-existent until…”

Line 41: yields of 10% and 11% are reported, while in the abstract 12% was declared

Line 45: the sentence should be corrected as: the latter undergoes 6p-electrocyclization to afford …

Line 52: the caption should be changed as: Synthesis and oxidation by PhI(OAc)2 of hydrazone 2

Line 70: please change the sentence as “the conceivable structures for the isolated compound could be in principle isomers 5, 10 and 11”. The authors could possibly add a short comment about formation of ortho fused cycle rather than peri fused.

Line 72: please correct as: in the aromatic region, multiplets at 8.02-6.93 correspond

Line 86: after “PhI(OAc)2.” Ref 13 should be cited.

Line 87: please change as: Analogously, products 10-12 could be expected for reaction of 2

Line 90: maybe the authors can indicate which other 3 derivatives have been obtained and in which yields (at least, indicated as a range)

Line 116: the spectrum described for compound 2 is said to be in CDCl3, in SI-fig 1 is still said in CDCl3, but the plot caption reports DMSO. So, could authors furnish the spectrum in CDCl3, or rather correct the text?

Line 133: authors say that at delta 7.24-7.18 ppm there is a signal that integrates one. Actually, in the spectra reported in SI, such signal is almost overlapped with the signal of CDCl3. I think that a clearer spectrum should be included, possibly changing the solvent (DMSO for instance), so to confirm definitively the presence of this proton.

I think that this manuscript, as the authors themselves declare, cannot have but a very low significance, but on the other hand, one task of MolBank is that of giving some evidence also for molecules obtained in very low yield.

So, I recommend publication, after the required corrections.

Author Response

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Round 2

Reviewer 2 Report

No more suggestions