(S)-N¹,N³-Dibenzyl-1-cyclohexyl-N¹,N³-bis((R)-1-phenylethyl)propane-1,3-diamine

Round 1

Reviewer 1 Report

This article “(S)-N1,N3-dibenzyl-1-cyclohexyl-N1,N3-bis((R)-1-phe- nylethyl)propane-1,3-diamine” reported the synthesis of titled compound via three-step reaction starting from commercially available chemicals. Indeed, as the authors claimed chiral amine synthesis and its application is a critical topic in chemistry society. Herein, chiral 1,3-diamine derivative was obtained with high yield and fully characterized with 1H NMR, 13C NMR, DEPT, HRMS, as well as IR. Moreover, the manuscript is well-written and well-organized. 

Therefore, this reviewer recommends it be published on Molbank. 

However, there are some concerns that need to be addressed.

First of all, please clarify how the author define the newly formed chiral center as “R” configuration.

Line 39, “n-BuLi (2.5 M in hexane)” is inconsistent with Line 78 “n-BuLi 1.6 M”. Please double check and keep them same as the original experiment.

Line 49, “carbon moiety” would be more accurate as “carbonyl moiety”.

Table 1, the description is not in accordance with the number listed in the table. For example, line 50: 38% yield which is 37% in the table. The same issue appeared at line 87. Please double check and keep them same as the original experiment.

Line 56, “The amine substituent’s high steric requirement difficult C-N bond rotation, obtaining more signals than carbon atoms in the molecule.”: This claim is very confusing. 

Line 104, compound “1” should be “4”.

Supporting information: if possible, please define the intergration of aromatic protons as 20 in 1H NMR rather than 1.

Author Response

Dear Reviewer,

Thank you so much for your guidelines in reviewing our manuscript, the following changes have been introducing accordingly to your comments:

Referee: First of all, please clarify how the author define the newly formed chiral center as “R” configuration.

Author´s answer: In our case the new created stereocenter has configuration S. Accordingly with experimental[1-3] and theoretical[4] studies, the use of a homochiral amide R-5 produces (usually in a >95% d.e.) the corresponding stereocenter at the beta position which implies the entry of the amide through the upper face of the double bond (drawn in figure 2), the configuration R or S, depends on the substituent in the new stereocenter.

1. Davies, S.G.; Smith, A.D.; Price, P.D. The conjugate addition of enantiomerically pure lithium amides as homochiral ammonia equivalents: scope, limitations and synthetic applications. Tetrahedron: Asymmetry 2005, 16, 2833-2891. [https://doi.org/10.1016/j.tetasy.2005.08.006].
2. Davies, S.G.; Fletcher, A.M.; Roberts, P.M.; Thomson, J.E. The conjugate addition of enantiomerically pure lithium amides as chiral ammonia equivalents part III: 2012–2017. Tetrahedron: Asymmetry 2017, 28, 1842-1868. [https://doi.org/10.1016/j.tetasy.2017.10.031].
3. Davies, S.G.; Fletcher, A.M.; Roberts, P.M.; Thomson, J.E. The conjugate addition of enantiomerically pure lithium amides as chiral ammonia equivalents part II: 2005−2011. Tetrahedron: Asymmetry 2012, 23, 1111-1153. [https://doi.org/10.1016/j.tetasy.2012.08.009].
4. Nieto, C.T.; Díez, D.; Garrido, N.M. To be or not to be butterfly: New mechanistic insights in the Aza-Michael asymmetric addition of lithium (R)-N-benzyl-N-(α-methylbenzyl)amide. Journal of Computational Chemistry 2014, 35, 1846-1853. [https://doi.org/10.1002/jcc.23694].

Referee: The amine substituent’s high steric requirement difficult C-N bond rotation, obtaining more signals than carbon atoms in the molecule.”: This claim is very confusing.

Author´s answer: That statements has been rewritten as follows: “The C-N bond of the amide group has no free rotation, so the amide N substituents show duplicated signals in both C NMR and H NMR”

Referee: Table 1, the description is not in accordance with the number listed in the table. For example, line 50: 38% yield which is 37% in the table. The same issue appeared at line 87. Please double check and keep them same as the original experiment.

Author’s answer: The inconsistencies found were due to misreading the original table. The text has been double checked and the mistakes has been corrected.

Referee: “Line 39, 49 and 104”

Author’s answer: All suggestions has been applied.

Referee: if possible, please define the intergration of aromatic protons as 20 in 1H NMR rather than 1

Author’s answer: Aromatic protons has been defined as 20 H.

Referee: Any compound mentioned in the article, including compounds 2, 3 and 5, must be described in the experimental part, or there must be literature data regarding these compounds.

Author’s answer: In “Supplementary Material” a new reference ([2]) containing the spectroscopic information of compound 2 has been included and new paragraph has been created containing the spectroscopic information of compound 3. According to compound 5, a new reference including his spectroscopic information has been added (24).

1. Das M, Manvar A, Fox I, Roberts DJ, O’Shea DF. Bu4N -controlled addition and olefination with ethyl 2-(trimethylsilyl) acetate via silicon activation. Synlett. 2017;28(18):2401-2406 https://doi.org/10.1002/chem.202100014
2. Koperniku A, Schafer LL. Zirconium catalyzed hydroaminoalkylation for the synthesis of α‐Arylated amines and N‐Hetero‐207 cycles. Chemistry–A European Journal. 2021;27(20):6334-6339. https://doi.org/10.1002/chem.202100014

Round 2

Reviewer 1 Report

Thanks for the author’s careful revision. The concerns have been well addressed.

This reviewer recommends its publication on Molbank.