Divergent Reactivity of D-A Cyclopropanes under PTC Conditions, Ring-Opening vs. Decyanation Reaction
Round 1
Reviewer 1 Report
The manuscript by Bernardi, Fochi and coworkers describes divergent reactivity with donor-acceptor cyclopropanes in the presence of thioacetic acids under phase transfer conditions. Depending on the reaction conditions, the major products were either 1-acetyl-1cyano-cyclopropanes or ring-opening S-thiolate products. In general, this study is well conducted and thorough. The substrate scope is a bit narrow. It is mostly limited to phenyl cyclopropanes in which the acceptor end of the cyclopropane contains two cyano groups. The nucleophiles that work include just thioacetic acid for the decyanation product and both thioacetic acid and thiobenzoic acid for the ring opening products. Below are a couple of general suggestions I have:
-Given the variability in yields, the authors should comment on what factors lead to high yields and low yields in the scope. Are there certain substrates or substitutions on the arene that lead to higher yields? This wasn’t clear in both substrate scopes.
-The authors mention that product 4 is accessed with high diastereoselectivity. What is the relative stereochemistry in these products? This should be indicated used wedges/dashes.
-For product 4aa, the reference for literature comparison is missing in the experimental section.
Aside from these suggestions, I think the paper looks good and should be published once these things are addressed. This reaction is interesting, and the divergent reactivity is unique for this type of transformation.
Author Response
Reply:
We thank the reviewer for the positive evaluation and for the useful suggestions.
A very short sentence concerning the variability in yields with regard to the presence of EWG or EDG on phenyl ring, was present at line 125 and line 155. These comments have been enlarged.
As reported in the manuscript we could observe a single diastereoisomer in all the reactions we have performed. As far as the relative stereochemistry is concerned, as product 4aa was already reported in the literature, we have suggested the same relative position of the substituents and corroborated this assignment by some NOE experiments (added to the Supporting Information). Unfortunately, any tentative to obtain a single crystal of the only solid compound (product 4ka) for X-ray spectroscopy failed. We have also added a sentence justifying the observed relative stereochemistry in the mechanistic part (lines 224-225).
Reference 44 for product 4aa has been added in the experimental section.
Reviewer 2 Report
1. The manuscript describes the use of phase-transfer catalysis for activation of donor-acceptor (D-A) cyclopropanes. The authors discovered a very interesting change in reactivity pattern of 2-arylcyclopropane-1,1-dicarbonitriles in reaction with thioacetic acid (some examples of reaction with thiobenzoic acid are also presented) caused by a seemingly minor change in reaction conditions. The use of an aqueous solution of Cs2CO3 as a base resulted in a typical ring-opening reaction of D-A cyclopropanes with the formation of S-thiolate products. On the contrary, the use of solid Cs2CO3 led unexpectedly to formation of new D-A cyclopropane derivatives via decyanation reaction followed by diastereoselective acetylation. The authors studied the substrate scope of these reactions, screened catalysts, bases, solvents, varied concentration and eventually suggested a reasonable mechanism of the newly discovered transformation. The authors emphasize the preparative importance of their finding which allows one to prepare either cyclic or open chain products in moderate to good yields by using the “tailored reaction conditions”.
2. Unfortunately, the discussion of the reasons of the discovered bimodal reactivity of D-A cyclopropanes (observed either in the presence or in the absence of water) is limited to the statements of the importance of “the nature of the inorganic base (solid vs aqueous) as the key factor” or “typology of base used”. The Reviewer believes that the addition of any plausible hypothesis concerning the role of water in modulation of reactivity of D-A cyclopropanes will greatly benefit the manuscript.
3. RECOMMENDATION. The manuscript should definitely be published after correction of the following minor issues.
3.1. Addition of a discussion of the role of water in directing the reaction to cyclopropane ring-opening pathway or to decyanation pathway. Of course, the manuscript may be published without this discussion. But if the authors have a hypothesis explaining the role of water, then it should be added to the manuscript since the presence of the hypothesis would stimulate the readers’ response.
3.2. The text of the manuscript should be re-checked for misprints.
Author Response
Reply:
We thank the reviewer for the positive evaluation and for the useful suggestions concerning the role of the base.
A sentence regarding the role of the base and the PTC catalyst was present at line 190.
This sentence has been enlarged to better explain our hypothesis and a reference concerning the mathematical modeling of solid-liquid phase-transfer catalysis has been added (45).
The manuscript has been re-checked for misprints (see text).
