Asymmetric Friedel–Crafts Alkylation of Indoles Catalyzed by Chiral Aziridine-Phosphines

Round 1

Reviewer 1 Report

Manuscript Title:

Asymmetric Friedel-Crafts alkylation of indoles catalyzed by chiral aziridine-phosphines

 

Manuscript ID : catalysts-907698

 

Recommendation: Reconsider Publication in Catalysts after minor revisions

 

Comments:

 

The authors presented the synthesis of a series of chiral aziridine-phosphine ligands, as well as their applications in asymmetric Friedel-Crafts alkylation of indoles. The ligand effect, catalyst effect, and substrate effect were investigated in this manuscript. With the aziridine-phosphine ligand 6 and Cu catalyst, the reasonable yield and ee values were observed for different indoles. I believe these chiral aziridine-phosphine ligands could be potentially used in other type of asymmetric reactions.

 

Thus, I may suggest its acceptance after some minor modifications.

 

Major concerns:

 

1. Typos in Scheme2: It should be "1-8 (10 mol%)" instead of "1-9 (10 mol%)"

 

2. It is not clear that in Scheme 3 and Table2 whether there are any metal used in the experimental system in presence of ligand 10 (triflimide) and 11 (chiral phosphoric acid)? since for other ligands, either Cu or Zn was used to enable the asymmetrical catalysis. It would be great if some reference are cited here regarding the use of 10 and 11 in asymmetric synthesis.

 

3. The authors proposed a tentative transition state model regarding the origin of the enantioselectivity in indole attack. From Figure 2, it is hard to see why this configuration is sterically favorable.

 

Also, could the authors add some discussions about why ligand 5 & 6 yield better yield and ee values than other six ligands in Table 1 based on the tentative transition state model?

 

 

Author Response

Dear Reviewer,

Thank you for the valuable comments. Below please find my response:

1) Typos in Scheme 2 have been corrected.

2) The reactions performed in the presence of triflimide and chiral phosphoric acid were performed in the presence of (CuOTf)₂∙C₆H₆ complex. Scheme 3, Table 2 and the text above Table 2 have been corrected (marked in yellow). Following your suggestion, the references regarding the use of 10 and 11 in asymmetric synthesis have been added (in yellow).

3) Concerning a tentative transition state, I am not able to present it any other way, but for your better understanding, an attack from the Re-site leading to the opposite enantiomer would require a 180 degree rotation around the C=N bond of nitrostyrene. Such a rotation would be followed by a steric interaction of the aromatic nitrostyrene ring with aromatic ring of indole.

Generally, ligands 1-4 containing a methylene linker between phenyl ring and aziridinyl nitrogen atom worked worse in the title reaction, because a methylene group may reduce rigidity of transition state leading to the lowering of stereoselectivity. Ligands 5 and 6 bearing an isopropyl aziridine subunit worked better than isobutyl analog, because thanks to the presence of the CH₂ group in the latter ligand, more conformers generating steric hindrance may be formed.

Author Response File: Author Response.pdf

Reviewer 2 Report

This manuscript describes the full details of the asymmetric Friedel-Crafts reaction of indoles as a part of the authors research project for the development of new asymmetric reaction using chiral aziridine-phosphine catalysts. The level of the yield and enantioselectivities shown in the current work are reasonable and acceptable.

Chemistries described in this paper would be a nice piece of work and of interest for a number of researchers in this field.

I recommend this manuscript for publication in Catalyst.

 

Author Response

Dear Reviewer, 

Thank you very much for your very positive revision.

Author Response File: Author Response.pdf