3-(tert-Butyl)-N-(4-methoxybenzyl)-1-methyl-1H-pyrazol-5-amine

Round 1

Reviewer 1 Report

This article reported a one-pot reaction for reductive amination, which is quite efficient to conduct for synthesis of secondary amine. It is suggested to publish this paper on Molbank before some minor revisions were made.
1. Condensation between the active primary amine and the aldehyde could produce some water, which could react with the following added NaBH4.
2. How could the author avoid the decomposition of NaBH4 in water and the solvent?
3.The author has mentioned the possible antifungal activities of the target compound in the introduction portion, albeit in the conclusion, they did not mention the result.
4.It is better to provide the biological result of the compound, or at least supplement the ADMET evaluation via CADD.

Author Response

(1) Condensation between the active primary amine and the aldehyde could produce some water, which could react with the following added NaBH₄.

Thank’s reviewer. We included additional details in the experimental section related with the elimination of the water condensed on the walls of the open-topped tube under heating at 120 °C. In particular, the synthesized N-pyrazolyl imine is very stable under normal atmospheric conditions and high temperature. The following paragraph was included in the manuscript (red):      

“Then, the water vapor condensed on the walls of the open-topped tube was removed with a small piece of cotton attached to a spatula”.

(2) How could the author avoid the decomposition of NaBH₄ in water and the solvent?

Thank’s reviewer. The major amount of water vapor condensed on the walls of the test tube was removed to avoid the decomposition of the reducing agent in the next step. However, the purpose for using an excess of sodium borohydride (one molecule can transfer four hydrides) in methanol (the best choice) was performed the reduction in only 1 hour instead of several hours. According to previous reports, the sodium borohydride is very stable in methanol at room temperature.     

(3) The author has mentioned the possible antifungal activities of the target compound in the introduction portion, albeit in the conclusion, they did not mention the result.

We mentioned in the introduction that “we visualized the possibility of combine amine and pyrazole moieties within the structure of product 3, aiming to evaluate its antibacterial and antifungal activities in a future project”. Actually, we are using this protocol for the synthesis of diverse N-pyrazolyl amines to be used as secondary amines in the catalytic amidation reaction with non-activated carboxylic acids. The antibacterial and antifungal activities of these pyrazole-containing tertiary amides will be tested in a future project. To avoid any confusion, the following paragraph was included in the manuscript (red):      

“Due to the powerful physiological activities of pyrazole derivatives and secondary amines as building blocks for the synthesis of potential drug-like compound libraries and important pharmaceutical intermediates, we described the synthesis of a novel N-pyrazolyl amine 3 as a potential bioactive N-heterocycle through a simple and efficient one-pot reductive amination”.

(4) It is better to provide the biological result of the compound, or at least supplement the ADMET evaluation via CADD.

Thank´s reviewer for this kind suggestion. However, we do not have a biological result of the N-pyrazolyl amine 3 because this work is focus on the development of a simple and efficient one-pot reductive amination to prepare potential bioactive N-heterocyclic amines. Moreover, we did not have experience on ADMET evaluation because our expertise area is synthetic organic chemistry. To avoid any confusion, the following paragraph was included in the manuscript (red):

“Due to the powerful physiological activities of pyrazole derivatives and secondary amines as building blocks for the synthesis of potential drug-like compound libraries and important pharmaceutical intermediates, we described the synthesis of a novel N-pyrazolyl amine 3 as a potential bioactive N-heterocycle through a simple and efficient one-pot reductive amination”.

Reviewer 2 Report

In the submitted manuscript (ID: molbank-1136660), the compound 3-(tert-Butyl)-N-(4-methoxybenzyl)-1-methyl-1H-pyrazol-5-amine has not been reported previously. The structure of the compounds was fully characterized by 1D and 2D NMR experiments, FTIR-ATR, EIMS and elemental analysis. It is of great significance to further broaden the application of these compounds. However, there are some issues needing to clarify before the manuscript can be considered for possible publication. 1. In order to make readers more clearly understand the importance of these compounds, it is suggested that the author list the specific applications of these compounds in a certain field to enrich the background introduction. 2. In this manuscript, the attribution of peaks in some spectra is not very clear, which can be confusing for the readers. For example, in the FTIR-ATR spectra on the C-O bond attribution did not indicate the specific type. 3. In the summary, the authors proposes that the synthetic methods of the compounds in the paper are eco-compatible, but it does not reflect this in the whole reaction. Please explain.

Author Response

(1) In order to make readers more clearly understand the importance of these compounds, it is suggested that the author list the specific applications of these compounds in a certain field to enrich the background introduction.

Thank’s reviewer. To avoid any confusion, the following paragraph was included in the manuscript (red):     

“Due to the powerful physiological activities of pyrazole derivatives and secondary amines as building blocks for the synthesis of potential drug-like compound libraries and important pharmaceutical intermediates, we described the synthesis of a novel N-pyrazolyl amine 3 as a potential bioactive N-heterocycle through a simple and efficient one-pot reductive amination”.

(2) In this manuscript, the attribution of peaks in some spectra is not very clear, which can be confusing for the readers. For example, in the FTIR-ATR spectra on the C-O bond attribution did not indicate the specific type.

Thank’s reviewer for this suggestion. We specify the infrared signals of compounds 3 and 4 in the manuscript as shown below (red):

“C–O–C functionalities”

“FTIR–ATR: ν = 3243 (v N–H), 2958, 2863, 1611 (v C=N_pyrazole), 1558 (v C=C), 1506 (v C=C), 1449, 1356, (1240 and 1036 for v_a and v_s C–O–C, respectively), 832, 753, 717 cm⁻¹”

“FTIR–ATR: ν = 2955, 2862, 1619 (v C=N_pyrazole), 1596 (v C=N_imine), 1573, 1518 (v C=C), 1461, 1362, (1251 and 1025 for v_a and v_s C–O–C, respectively), 837, 760, 729 cm⁻¹”

(3) In the summary, the authors proposes that the synthetic methods of the compounds in the paper are eco-compatible, but it does not reflect this in the whole reaction. Please explain.

Thank’s reviewer for this observation. We changed the word “eco-compatible” by “efficient” in the manuscript (red). We consider that the one-pot amination reductive is eco-compatible because the “first step” does not require solvent, molecular sizes, catalyst, dehydrating agent or inert atmosphere to remove the water generates in the reaction. Moreover, the water vapor condensed on the walls of the open-topped tube is removed with a small piece of cotton attached to a spatula, which favor the displacement of the equilibrium chemical toward the formation of the aldimine.      

Reviewer 3 Report

The manuscript entitled “3-(TERT-BUTYL)-N-(4-METHOXYBENZYL)-1-METHYL-1H-PYRAZOL-5-AMINE” submitted by Becerra et al., reports on some very interesting findings and might deserve publication in Molbank. In this reviewer’s opinion, the whole study appears sound and the paper, before acceptance, should undergo only the following minor revisions:

1) the synthesis of intermediate 4 is not entirely new since it was inspired by a previous work (Castillo J.-C et al Org. Lett. 2015, 17, 3374–3377). This aspect should be specified in the discussion.

2) the authors stated, both in the main text and in the experimental part, that the crude product 3 was purified by flash chromatography on silica gel using dichloromethane (DCM) as eluent to give the target amine 3. However, in experimental part, a R_f (DCM/MeOH: 30/1) = 0.37 was reported for compound 3. 0.37 is an optimal R_f for flash column chromatography because the volume of eluant required for elution (leaving out the volume for packing) should be about three times the column volume. In the reviewer’s opinion, the authors should correct the above sentences by writing that the chromatography occurs in gradient (for example: (0-3% MeOH in DCM) or they should report the correct R_f (presumably very low!) in DCM. A similar consideration could be also argued for intermediate 4 (Rf (DCM/MeOH: 30/1) = 0.65) 
3) pag. 2 row 44: please change “structure of product 3,” into “structure of product 3 (scheme 1),”.

Author Response

(1) The synthesis of intermediate 4 is not entirely new since it was inspired by a previous work (Castillo J.-C et al Org. Lett. 2015, 17, 3374–3377). This aspect should be specified in the discussion.

The following paragraph was included in the manuscript to clarify it (red):

“Although the intermediate 4 has been described in our previous work [24], the synthesis and characterization of the target N-pyrazolyl amine 3 has not been reported on Reaxys database”.

(2) The authors stated, both in the main text and in the experimental part, that the crude product 3 was purified by flash chromatography on silica gel using dichloromethane (DCM) as eluent to give the target amine 3. However, in experimental part, a Rf (DCM/MeOH: 30/1) = 0.37 was reported for compound 3. 0.37 is an optimal Rf for flash column chromatography because the volume of eluent required for elution (leaving out the volume for packing) should be about three times the column volume. In the reviewer’s opinion, the authors should correct the above sentences by writing that the chromatography occurs in gradient (for example: (0-3% MeOH in DCM) or they should report the correct Rf (presumably very low!) in DCM. A similar consideration could be also argued for intermediate 4 (Rf (DCM/MeOH: 30/1) = 0.65)

Thank’s reviewer for this important observation. Checking our notebook, we found that the eluent was DCM/MeOH (30:1, v/v) instead of DCM. The following sentence was included in the manuscript to modify it (red):

“using a mixture of DCM/MeOH (30:1, v/v) as eluent”