A Second-Generation Palladacycle Architecture Bearing a N-Heterocyclic Carbene and Its Catalytic Behavior in Buchwald–Hartwig Amination Catalysis
, Lorenzo Palio 1, Agnieszka Czapik 2, Subhrajyoti Bhandary 1, Marcin Kwit 2, Kristof Van Hecke 1 and Steven P. Nolan 1,*Round 1
Reviewer 1 Report
Paper by S. P. Nolan et al. deals with palladacyclic coordination entities possessing N-heterocyclic carbene ligands and their use in Buchwald-Hartwig amination catalysis. A described synthetic protocol is well documented and led to Pd-based coordination entities in a mild base solvent. The resulting Pd compounds display high activity in the B-H amination using low cat. loading. Experimental data strongly support the results and discussion. I strongly recommend this paper for publication in its current form.
Author Response
Reviewer 1
Paper by S. P. Nolan et al. deals with palladacyclic coordination entities possessing N-heterocyclic carbene ligands and their use in Buchwald-Hartwig amination catalysis. A described synthetic protocol is well documented and led to Pd-based coordination entities in a mild base solvent. The resulting Pd compounds display high activity in the B-H amination using low cat. loading. Experimental data strongly support the results and discussion. I strongly recommend this paper for publication in its current form.
Answer: Thank you for this appreciation of our work
Reviewer 2 Report
The authors report the synthesis, characterization and catalytic study of two palladacycle bearing N-heterocyclic carbene ligand. The application of the synthesized palladacycle has been demonstrated in Buchwald-Hartwig amination reactions with low catalyst loading and mild reaction conditions in a green solvent such as cyclopentyl methyl ether. I recommend the acceptance of the manuscript after minor revision as follows:
1. There are many reports on palladacycle for Buchwald-Hartwig amination reactions. Therefore, a comparative table of catalytic results of previously reported catalysts should be included in the Supporting Information (SI) which will help to understand the catalytic activity of the synthesized palladacycle in this report.
2. Authors must report the elemental analysis data or HRMS data of palladacycle ‘7’.
Author Response
The authors report the synthesis, characterization and catalytic study of two palladacycle bearing N-heterocyclic carbene ligand. The application of the synthesized palladacycle has been demonstrated in Buchwald-Hartwig amination reactions with low catalyst loading and mild reaction conditions in a green solvent such as cyclopentyl methyl ether. I recommend the acceptance of the manuscript after minor revision as follows:
Answer: We have improved the manuscript according to this reviewer’s critique.
- There are many reports on palladacycle for Buchwald-Hartwig amination reactions. Therefore, a comparative table of catalytic results of previously reported catalysts should be included in the Supporting Information (SI) which will help to understand the catalytic activity of the synthesized palladacycle in this report.
Answer: We have added a comparison table in the Supporting Information (SI) and the corresponding note in the MS text.
- Authors must report the elemental analysis data or HRMS data of palladacycle ‘7’.
Answer: We have added the HRMS analysis in the SI.
Reviewer 3 Report
Nolan et al. report a second-generation NHC-ligated palladacycle precatalyst with catalytic behavior in Pd-catalyzed Buchwald-Hartwig amination reactions. Compared to previous generations of palladacyclic precatalysts, it is air stable and can be synthesized in mild condition, by mixing NHC•HCl with a palladacycle and weak base (potassium carbonate) in acetone in air at 60 °C. High catalytic behavior was shown with the new precatalysts in Buchwald-Hartwig amination with low catalyst loading and mild reaction conditions. Considering the longstanding requirement of Pd precatalysts for Buchwald-Hartwig aminations in mild conditions, the development of this NHC-ligated palladacycle with high catalytic behavior is important to the field. Therefore, I am supportive of the publication of this article, while some minor modifications are needed.
1. On Table 2, the hydrogen atom is missed on morpholine in the substrate.
2. When describing the tables, Table 2 was mistakenly referred to as Table 4, and Table 3 was referred to as Table 5, e.g., from page 186 to 204.
3. In Figure 5, when regenerating the catalyst from reductive elimination, aryl amine and -OtBu are missing.
Author Response
Nolan et al. report a second-generation NHC-ligated palladacycle precatalyst with catalytic behavior in Pd-catalyzed Buchwald-Hartwig amination reactions. Compared to previous generations of palladacyclic precatalysts, it is air stable and can be synthesized in mild condition, by mixing NHC•HCl with a palladacycle and weak base (potassium carbonate) in acetone in air at 60 °C. High catalytic behavior was shown with the new precatalysts in Buchwald-Hartwig amination with low catalyst loading and mild reaction conditions. Considering the longstanding requirement of Pd precatalysts for Buchwald-Hartwig aminations in mild conditions, the development of this NHC-ligated palladacycle with high catalytic behavior is important to the field. Therefore, I am supportive of the publication of this article, while some minor modifications are needed.
Answer: We have improved our manuscript according to this reviewer’s suggestions.
- On Table 2, the hydrogen atom is missed on morpholine in the substrate.
Answer: We have added hydrogen atom on morpholine in the substrate of Table 2.
- When describing the tables, Table 2 was mistakenly referred to as Table 4, and Table 3 was referred to as Table 5, e.g., from page 186 to 204.
Answer: We have corrected this typo in the manuscript.
- In Figure 5, when regenerating the catalyst from reductive elimination, aryl amine and -OtBu are missing.
Answer: We have corrected Figure 5 in the manuscript.
Reviewer 4 Report
The manuscript by Nolan and co-workers describe the preparation of two novel palladacyclic complexes bearing NHCs as supporting ligands and their behavior in Buchwald-Hartwig-type amination reactions. The novelty of the work is rather low since the same authors have described the behavior of analogous systems (complexes 4a,b in Figure 1) in the same process (ref. 56). However, the new synthetic route applied in the preparation of the palladacycles and the successful use of a green solvent, i.e. CPME, in the catalytic experiments may be of interest to the Catalysts readers.
It is necessary to address the following aspects to support acceptance of the manuscript:
1) The writing of the article is very poor and is full of grammatical errors (ej. tabele in line 117, omnly in line 124, moire in line 149….).
2) The last paragraph on page 3 needs to be rewritten. After a first synthesis of complex 7, the authors say that they carry out a process of optimization of the reaction parameters, but in reality they do not optimize anything since in no case the initial result is improved. In the same paragraph the numbering used contains errors (palladacycle dimer 5 instead of 7; product 7 instead of product 6). In all the reactions described in Table 1 four equivalents of base are employed. Can be the quantity of base reduced? In principle, two equivalents would be enough.
3) In Figure 3, the authors should explain why toluene, instead of acetone, is employed for the large scale synthesis of complex 7.
4) In Figure 4, the crystallographic labeling scheme of the structures should be given to be able for the readers to distinguish, for example, who is C1 and C67 in the structure of complex 7. No selected angles are included in the caption, nor selected distances for complex 8. It is indicated that they can be found in the ESI file, but I have not found them.
Author Response
The manuscript by Nolan and co-workers describe the preparation of two novel palladacyclic complexes bearing NHCs as supporting ligands and their behavior in Buchwald-Hartwig-type amination reactions. The novelty of the work is rather low since the same authors have described the behavior of analogous systems (complexes 4a,b in Figure 1) in the same process (ref. 56). However, the new synthetic route applied in the preparation of the palladacycles and the successful use of a green solvent, i.e. CPME, in the catalytic experiments may be of interest to the Catalysts readers.
Answer: We have modified the manuscript according to this reviewer’s comments:
It is necessary to address the following aspects to support acceptance of the manuscript:
- The writing of the article is very poor and is full of grammatical errors (ej. tabele in line 117, omnly in line 124, moire in line 149….).
Answer: We have corrected the language and the typos.
- The last paragraph on page 3 needs to be rewritten. After a first synthesis of complex 7, the authors say that they carry out a process of optimization of the reaction parameters, but in reality they do not optimize anything since in no case the initial result is improved. In the same paragraph the numbering used contains errors (palladacycle dimer 5 instead of 7; product 7 instead of product 6). In all the reactions described in Table 1 four equivalents of base are employed. Can be the quantity of base reduced? In principle, two equivalents would be enough.
Answer: Indeed, additional screening did not bring any improvement in performance and the use of the word "optimisation" is not appropriate here. As recommended, we reworded the last paragraph on page 3.
"Then, wanting to check the effect of changing the reaction parameters on the reaction of the synthesis of complex 7, we conducted extended research in which we used various solvents, bases and temperatures."
The amount of base we use is 3 eq. as stated in the experimental section. The value of 4 eq. was incorrectly specified in the description of Table 1 and Figure 3, this typo was corrected. The use of 2 eq. of base increased the time to reach acceptable yields , which finally led to obtaining complex 7 with a much lower yield of 56%. 3 eq of base is optimum.
- In Figure 3, the authors should explain why toluene, instead of acetone, is employed for the large-scale synthesis of complex 7.
Answer: We have added a corresponding comment in the text of MS.
"It should be noted that when carrying out the reaction to obtain the complex [Pd(IPr)(NH2)(CC)Cl] on a gram scale, acetone was used to give complete conversion after 16 h, however, the yield of the pure complex was only 46%, which resulted from the moderate solubility of both the base and the precursor of the IPr.HCl salt, and the resulting by-products that are difficult to define. Replacing the solvent with toluene allowed to improve solubility and reduce the amount of by-products, which in turn allowed to obtain a pure product in a 74% yield."
4) In Figure 4, the crystallographic labeling scheme of the structures should be given to be able for the readers to distinguish, for example, who is C1 and C67 in the structure of complex 7. No selected angles are included in the caption, nor selected distances for complex 8. It is indicated that they can be found in the ESI file, but I have not found them.
Answer: Relevant crystallographic data for complexes 7 and 8 are included in the supplementary information. In addition, in the caption of Figure 4 selected distances and angles for complex 8 have been added.
Round 2
Reviewer 4 Report
The modifications made by the authors are satisfactory. Acceptance is now recommended.
