Organocatalytic Asymmetric Michael Addition of Ketones to α, β-Unsaturated Nitro Compounds

Round 1

Reviewer 1 Report

This paper deals with  the efficiency of primary amine thiourea DPEN dérivatives as new organocatalysts for asymmetric Michael addition.The novalty of such catalytic system lies on in its structure which presents an alkyl substituant on the thiourea moiety.

The catalyst bearing an isopropyl group is as effective as that described by kokotos et al  (ref 28) for the same reactions in terms of yield and ee (see table 4 (ref 28))but the conditions developped by Kokotos used less than 10 equivalent of  ketones.

In the introduction  scheme 1 does not appears in the text. The results presented in scheme 1 seems to be results from the literature. If it is the case, references must be included in the table of this scheme.

line 41 references 27 and 28 must be placed respectively just after Shao and kokotos but not line 45

Moreover in the experimental part (supporting information)  if we consider HPLC, for products 4f, 5e, 5g, the resolution is not good at all. Peaks are not well separated, the resolution being less than 1.5 thus the corresponding ee's are not correct. And for compounds 7a and 7b the retention times are too different between racemic and enantioselective mixtures; are the HPLC conditions the same? The HPLC conditions of  these compounds must be improved.

line 69 enantioselectivity 

line 79 non polar

Author Response

"Please see the attachment."

Author Response File: Author Response.pdf

Reviewer 2 Report

Manuscript of Ha and co-workers reports the synthesis of new organocatalysts for the Michael reaction between ketones and alfa-beta-unsaturated nitro derivatives. The manuscript is interesting, the amount of the experimental work is huge. All compounds are well characterized, but some important points need to be addressed before the publication:

• In the abstract, “(R, R)-1,2-diphenylethylenediamine derivative” should be reported in parenthesis
• In Scheme 1, reaction is reported two times
• Line 47: nitro group is contained into the styrene
• Dimensions of Figure 1 should be increased
• Line 69: please, check “enan-tioselectivity”
• seems to be normal that the enantioselectivity of the reaction is strictly related to steric factors. However, considering structures reported in Figure 1, seems to be that the less steric hindrance leads to higher yields and ee. This point should be clarified in the manuscript.
• Table 2 is not cited in the text. In addition, what about the solubility of reagents, catalyst and product(s) in water? Furthermore, some comments about the conversion values are required.
• Table 4: X is not reported. While the text reports that the authors changed also acetophenone equivalents. Please check
• Table 5: I suggest to change "ambient temperature" with "r.t."
• Line 113: “There was no difference in the enantioselectivity according to the position of substitution in the aromatic ketones”; I am not in agreement with this point: the orto derivative leads to higher ee
• Lines 115-117: “The enantioselectivity in the presence of an electron-donor substituent (Table 6, entries 4 and 5) was lower than that in the presence of an electron-acceptor substituted (Table 6, entries 1, 2, and 3)”. An explanation of this point is required.
• Lines 121-123: “The resulting yield and enantioselectivity were high when α, β-unsaturated nitroalkene was substituted with electron acceptors (Table 7, 4-Br or 4-Cl) as well as electron donors”: so, what is the effect that increase the efficiency of the reaction? the presence of an electron acceptor or donor?
• Section 2.1.8 does not contain text. Probably the text is included in the next section. Please check.
• Lines 178 and 192: if the diamine in toluene is a suspension, the authors cannot define a concentration
• Line 196: it is not clear what is "ethyl"
• a reference is reported twice
• English style must be revised

Author Response

"Please see the attachment."

Author Response File: Author Response.pdf

Round 2

Reviewer 1 Report

I am very surprised by the  answer of the authors concerning the following §

"Moreover in the experimental part (supporting information)  if we consider HPLC, for products 4f, 5e, 5g, the resolution is not good at all. Peaks are not well separated, the resolution being less than 1.5 thus the corresponding ee's are not correct. And for compounds 7a and 7b the retention times are too different between racemic and enantioselective mixtures; are the HPLC conditions the same? The HPLC conditions of  these compounds must be improved."

if we consider for example compound 5e : Authors simply expanded the area (ie time from 7 min to 17 min instead of 5 min to 30 min)  but the resolution is aways bad and the enantioselectivity is always not correct values haven't been changed. An expansion of the area cannot change the resolution of the peaks!....HPLC for compounds 4f, 5e, 5g and 7 a and b have to be done again.

even if I have not indicated it in my precedent review ee's changes should appear in tables and also in comments.

line 119 nitroalk  instead of nitroalkenes

180 to a disolve of???   to a solution of ?

Author Response

"Please see the attachment."

Author Response File: Author Response.pdf

Reviewer 2 Report

manuscript is now suitable for the publication

Author Response

Thank you very much

Round 3

Reviewer 1 Report

In they response, authors have written : "we will exclude entry 4f, 5g and 5e from the table" but they have forgotten to remove in table 8 entry 5 which corresponds to compound 5e and the comment of table : lines 137-138 entries 3 and 6 (6 ????)  must be  removed.

Moreover the HPLC of 5e has not been removed from supplementary file, resolution been not correct ee value is then not correct.

line 119 nitroalkenes not nitroalkens!.... Always not corrected correctly!..

Author Response

Please see the attachment.

Author Response File: Author Response.pdf