Recent Advancement of Ullmann Condensation Coupling Reaction in the Formation of Aryl-Oxygen (C-O) Bonding by Copper-Mediated Catalyst

Round 1

Reviewer 1 Report

In this manuscript, Rahman et al present an overview of the recent advances in Ullmann C-O coupling mediated by Cu-based catalysts. There is no doubt that Cu-catalyzed Ullmann cross-coupling is a topic of major importance in organic synthesis and catalysis. I know this area quite well, but still the authors provided several examples that I was unfamiliar with. The review is fairly comprehensive and focuses on both homogeneous and heterogeneous catalysis. The examples are well selected. I believe that the review will be of interest to the chemists involved in C-O bond formation and Cu catalysis. The following minor changes should be made prior to publication:

1. Please, add a table of contents for clarity.
2. In many examples of heterogeneous catalysis the authors present TEM, XRD, UV images, etc (e.g figures 1-3). This is not necessary for a review of this type, and all images should be at least significantly reduced in number or removed completely.
3. The same is true for optimizations, eg Figure 13. This and related figures should be removed or at least significantly reduced in number.
4. All schemes should be double checked for minor typos. For example, Scheme 40. Spaces are missing in several places. This and related errors should be checked throughout the manuscript.

Author Response

Please see attached PDF file.

Author Response File: Author Response.pdf

Reviewer 2 Report

This manuscript is an extensive and well-organized review of the recent advances for the copper-catalyzed Ullmann reaction for the creation of C-O bonds and the formation of diarylethers. The authors present and analyze the most recent results obtained with all types of copper catalysts such as nanoparticles, supported catalysts (on magnetic particles, carbon structures, MOF, zeolites...) or copper complexes with various ligands (for homogeneous catalysis). Recent applications of this catalytic reaction are also presented in the fields of medicinal chemistry and the total synthesis of complex natural molecules.

A lot of references were analyzed and compiled and this review will be very helpful for all the organic chemists interested in the synthesis of diarylethers or working on the Ullmann coupling reaction. However, some elements need to be addressed:

• The English language must be improved. Some mistakes make the text difficult to read and some sentences quite confusing. For example, the passive form is almost always used instead of the preterite: like in line 52, "Ullmann and Goldberg were also reported..."
• In the schemes representing Ullmann coupling reactions, it would be better if possible to add the catalyst loading (in % of the quantity of the substrate) in all of them. It has already been done in some (like schemes 2 or 5), but not in others (like schemes 3 or 4 for examples). It would be easier for the reader to compare the efficiency of the different catalysts described in the review, just by looking at the quantity of catalysts used in comparison to the quantity of reagents.
• In all the schemes, the indication of reaction time should be harmonized to the correct scientific unit "h". Sometimes "hour" is written "H", sometimes "hr".
• Scheme 1 is neither mentioned nor described or commented in the text.
• The use of other metals for the Ullmann coupling reaction is mentioned in line 74 but without any references. Some references must be added for the interested reader.
• I don't understand in this context the term "electrophilic" employed in line 103. Do the authors mean "electronic effect"?
• Line 105: "2,2-disubstituent"? Do the authors mean 2,2' or 2,6 ? The bicyclic phenols mentioned are not represented in scheme 2. Could you add an example?
• Line 128: it should be "DLS"
• Line 170: it should be "ICP"
• Scheme 5: there is no ketone represented in the scheme but it is mentioned in line 176. Could you add the ketones in the scheme?
• Figure 4a, the unit doesn't appear in the table. Could you add the unit in the figure or the legend?
• Scheme 5: the results obtained with eco-cu (1) or (2) are exactly the same in the scheme, is this a mistake? 
• Resolution of Figure 5 should be improved: it is impossible to read the words written in the round-bottomed flasks.
• Line 203: maybe write (hetero)aromatic because only some of the examples are heterocycles and add a mention to the benzyl substrates represented in scheme 6.
• Scheme 10: I would add a legend to indicate to the reader that the "grey balls" represent the copper-oxide nanoparticles.
• Scheme 12: for R2 and R3, I found the notation -OCH for some of the substituents confusing. If it is aldehyde functions, please correct it to -CHO.
• Scheme 13: for a, the phenol should be written OPh not Oph. Moreover, it is not easy to see the number 4 written in the particles for Fe3O4.
• Figure 8: legends for the parts g and h are missing.
• Scheme 16: where does the second H+ necessary to form H2O come from?
• Figure 13: if possible, the resolution should be improved because it is really difficult to read the text written on the different graphs (particularly for e). 
• Scheme 20: chloroform should be written CHCl3 not CHCL3.
• Table 2, entry 1: the double bond of the imine function should be present in the copper complex. Same table entry 3: there is a mistake in the first molecule, it should be -NH2 or -NH3+. Same table entry 6: there is a mistake in the representation of the functionalized particles. The organic molecule binds to the silica through hydrogen bonds, not covalent bonds (the CH2 between the particles and the SiO doesn't exist).
• Line 456: the sentence is confusing. I don't understand if the use of TOP was for the earlier results or for the ones described in the review.
• Lines 466-467 and scheme 24: there is no explanation for the utility and the role of the three-phase test. Could you add a comment to clarify this part?
• Scheme 25: in the last structure (the copper complex), each nitrogen should keep the hydrogen they have before the complexation.
• Scheme 26: resolution should be improved if possible. It is difficult to read the interatomic distance.
• Lines 499-500, 575 and elsewhere: for me, Anna and Samira are feminine names. So I'm not sure it is appropriate to use "he" or "his". I encourage the authors to use gender-neutral terms and sentences to resolve this problem (like researcher X et al. or researcher X's team and then they).
• Scheme 27: resolution for the written parts should be improved and this scheme lacks some commentary and legends to help the reader understand all the represented elements.
• Table 6: yields as low as 0 or 4% are obtained in some cases. Could you add a comment in the text to explain for which kind of substrates and to give some hypotheses for these modest results?
• Scheme 30: the yield (74%) is for just the last step or it is the global yield for the three steps of the synthesis? 
• Figure 17: resolution should be improved. It is impossible to read the written parts on the graph.
• Scheme 35: for R2, it should be 4-Cl, I suppose.
• Scheme 36: this scheme doesn't really represent a mechanism because the only molecules that appear are the reagents and the product. This scheme should be improved by adding some intermediates or it could be removed as it does not bring valuable information.
• Line 645: PPh3 and not Pph3.
• Scheme 37: the solvent toluene should be corrected (not toulene). For the first reaction, it should be 4-CF3 and for the last one, O=PPh3.
• Table 8: Is the comparison of all the catalysts done on the same reaction with the same halide and phenol? If yes, a scheme of the reaction should be added or the reagents should be given in the legend of the table. In this table, it is very important to add the catalyst loading in each case. Indeed, a good yield with a low amount of catalyst is better than a comparable yield with more catalysts.
• Scheme 43: the halogen atom is X in the reagent then it becomes I in the rest of the reaction. It should be harmonized.
• Figure 20 and scheme 46: figure 20 and the squared part in scheme 46 (representing B6) are exactly the same. One of the two could be removed.
• Figure 21: some bonds are missing in the first molecule. 
• Scheme 50: for R1, it should be 4-Ac.
• Line 808: it should be Pd-catalyzed.
• Scheme 51: toluene in the two reactions.
• Scheme 53: the second reaction is a reductive amination and should work only with X= C=O.
• Scheme 56: it should be "aldol".

Author Response

Please see attached PDF file.

Author Response File: Author Response.pdf

Round 2

Reviewer 2 Report

This review represents a considerable effort to regroup and analyze all the articles concerning the copper-catalyzed Ullmann reaction and I think it would be of great interest to readers working on catalysis.

All my previous concerns have been correctly addressed. I think that this manuscript could be accepted in the present form.