Brucine Diol-Catalyzed Enantioselective Morita-Baylis-Hillman Reaction in the Presence of Brucine N-Oxide

Round 1

Reviewer 1 Report

The manuscript by V. Agamuthu et al. reports on the application of brucine diol (BD) and brucine N-oxide (BNO) as catalysts for Morita-Baylis-Hillman reaction by using p-nitrobenzaldehyde and methyl vinyl ketone as model substrates. The results are supplemented with three other substrates. The paper is written clearly and the introduction provide solid support to the topic, particularly to mechanisms of the MBH reaction discussed in the literature. Although the authors presented that both BD and BNO (poorly, in the latter case) can catalyze the title reaction, the observed outcomes are moderate with respect to the yield and ee.

Most importantly, the postulated cooperative catalysis is not evidenced by the presented results. The decisive experiments presented in table 1 (entry 7) and table 2 (entries 1 and 7) indicate that the addition of equimolar amounts of BNO (with respect to BD) has essentially no effect, while using 5-fold excess BNO slightly accelerates the reaction and enhances the ee by 4% only (which in fact is within the measurement error limit). The latter result is quite obvious as BNO itself also catalyzes the studied transformation to some extent. Finally, the lack of positive results by using pyridine and morpholine N-oxides as potential co-catalyst cannot be considered crucial.

For this reason I do not recommend publication of the paper in the present form.

Further issues to be clarified before resubmission:

• The mechanism presented in scheme 4 suggest that brucine N-oxide (BNO) activates the Michael acceptor while brucine diol (BD) coordinates benzaldehyde. This statement needs thorough discussion as the opposite role of BD is conceivable (and actually substantiated by the initial experiments). Furthermore the structure of brucine N-oxide (left bottom) is not correct (there should be double C=C bond instead the diol system)
• Supporting Information, Figure 7: according to caption, there should be racemic 7a presented, while the chromatogram is clearly of non-racemic product.Also, it is not clear which of the result is depicted in Figure 8 (ee. 70%). It should be linked with the appropriate experiment mentioned in the main body (e.g. table, entry, etc).

Author Response

Dear Reviewer,

We are thankful for the valuable comments and suggestions. Your comments helped us a lot to improve our work in view of conception. We have corrected according to suggestion. 

Please find an attachment 

Author Response File: Author Response.docx

Reviewer 2 Report

The authors employ brucine diol (BD) and brucine N-oxide (BNO) to cooperatively promote an asymmetric Morita-Baylis-Hillman reaction. Using the optimized reaction conditions, the BD is employed substoichiometrically, whereas BNO must be stoichiometrically employed. Although the obtained yields and ee’s are moderate (up to 78% ee), this is the first time that BD, also showing a cooperative effect with an N-oxide, are used for this transformation. Therefore, the present study deserves publication.  However, some additions/corrections should be carried out prior to publication, as follows:

1) The title should be modified to make it more illustrative. Something like “Cooperative brucine diol-catalyzed enantioselective Morita-Baylis-Hillman reaction in the presence of brucine N-oxide”, perhaps would be more clarifying.

2) The abstract mentions that in the reaction with 4-nitrobenzaldehyde (should be written like this all through the manuscript), the ee is 74%. This ee value is not in any table and should be corrected.

3) Although describing the use of brucine diol metal complexes as catalysts, the review/account by Oh should be included in the introduction (Synlett 2025, 26, 2067). In addition, a more recent review  on asymmetric organocatalytic Morita-Baylis-Hillman reaction should also be included (Tetrahedron 2017, 73, 2831).

4) In Scheme 1, R2 should be R1 in compound 9.

5) The title in Table 1 should mention “MBH”.

6) In Table 1 all the optimization is carried out with methyl vinyl ketone, therefore the column with R1 is unnecessary and should be removed. R1 should then be changed by Me in the Scheme (and “R1 = CH3” removed in 7a). In this Table “iPr” should be written as iPrOH or IPA (entry 3). 

7) In Table 2, the same corrections should be made.

8) In Scheme 4, “Ar” should be in the MBH adduct, instead of “Ph”.

Author Response

Dear Reviewer,

We are thankful for the valuable comments and suggestions. Your comments helped us a lot to improve our work in view of conception. We have corrected according to suggestion. 

Please find an attachment

Author Response File: Author Response.docx

Round 2

Reviewer 1 Report

The resubmitted manuscript by V. Agamuthu et al. dealing with the application of brucine diol (BD) as a catalyst with Morita-Baylis-Hilmann reaction: As to the fact that authors addressed all the points raised by the referee and the changes to the manuscript can be found satisfactory, herewith I recommend publication.