DBU Catalyzed Phospho-Aldol-Brook Rearrangement for Rapid Preparation of α-Phosphates Amide in Solvent-Free Conditions
Round 1
Reviewer 1 Report
In this manuscript the authors report the Phospho-Aldol-Brook Rearrangement reaction of α-ketoamide and dialkyl phosphate catalyzed by DBU in solvent free conditions at room temperature. In my opinion the present work can be published on Catalysts after major revision. More detailed comments below:
- I suggest the authors to improve the quality of the way they present their results; I suggest first to comment the results obtained in the presence of solvent and then the solvent free conditions;
- A deeper discussion of the found results should be provided in the revised manuscript. Why, in the authors opinion, DBU is the better base?
- What is the influence of the investigated parameters on the studied reaction?
- English of the manuscript should be improved. The introduction part and the subsequent paragraph are not so clear and easily understandable.
Author Response
Comments：
In this manuscript the authors report the Phospho-Aldol-Brook Rearrangement reaction of α-ketoamide and dialkyl phosphate catalyzed by DBU in solvent free conditions at room temperature. In my opinion the present work can be published on Catalysts after major revision. More detailed comments below:
Response: Thanks for your recommendation of our manuscript. This paper have been revised acooding to your and another three reviewers' comments and suggestions.We believe that the revised version hereby is much more suitable for publication in the Catalysts than before.
Comments：
1.I suggest the authors to improve the quality of the way they present their results; I suggest first to comment the results obtained in the presence of solvent and then the solvent free conditions;
Response: Thanks for the referee’s valuable suggestion. I have rediscussed the result according to your opinion.
Comments：
2.A deeper discussion of the found results should be provided in the revised manuscript. Why, in the authors opinion, DBU is the better base?
Response: Thanks for your suggestion. We have rediscussed the corresponding result according to your suggestions. the reason for DBU is the better base were also discused in our revised manuscript. The revised content were also listed as follows.
"Several organic solvents including EtOH, CH2Cl2 and THF were firstly investigated, the yields of products were 81%, 83% and 89%, respectively (Table 1, entries 1-3). We also investigated the effect of water on this reaction, unfortunately, only trace product of the model was provided in water (Table 1, entry 4). Surprisingly, we found the reaction could be conducted smoothly (92% yield) in resent of DBU in solvent-free condition (Table 1, entry 5). In order to screen more suitable alkali, different alkalis including 4-dimethylaminopyridine (DMAP), triethylamine (TEA), K2CO3, NaOH were then investigated (Table 1, entries 6-10). Unfortunately, the inorganic alkalis (NaOH or K2CO3) shewed low catalytic capability due to low solubility in dialkyl phosphite (Table 1, entries 6, 7). Under the same condition (solvent-free, 50 ℃, 60 min), the reaction catalyzed by TEA could provide 5% yield of the product (Table 1, entry 8). Desirably, the yield could be enhanced (yield, 78%) by using 10 mol% DMAP at room temperature (rt) within 5 min (Table 1, entry 9). However, the yield (up to 92%) could be improved by DBU (Table 1, entry 10). For these three organic alkalis, both DMAP and DBU show good nucleophilicity than that of TEA. In addition, DBU shows much stronger alkalinity than DMAP and better capability for capture the proton from dialkyl phosphite than of DMAP. Hence, the catalytic capability of DBU is the best in these alkalis. Moreover, the reaction time, amount of DBU, and the reaction temperature were also investigated, more reaction time (Table 1, entries 11 and 13), higher temperature (Table 1, entries 13 and 15) and more dosage of DBU (20 mol%, entry 12) could not increase the yield of products obviously. However, the yield of product was sharply reduced by decreasing the amount of DBU (Table 1, entry 14). Hence, the optimized reaction conditions for the preparation of α-phosphates amide could be concluded as follow: solvent-free, 10 mol% DBU as catalyst and room temperature"
Comments：
3.What is the influence of the investigated parameters on the studied reaction?
Response: Thanks for your question. Actually, we just want to screen a best condition for this reaction. Just as you known, different conditions (such as reaction time, tempreture, type of catalyst, etc) could effected the yields of the products. We have revised the discussion for the influence of different conditions (see the response to last comment).
Comments：
4.English of the manuscript should be improved. The introduction part and the subsequent paragraph are not so clear and easily understandable.
Response: Thanks for your sggustion. The English of the manuscript have been improved by the authors, some of the reviewer also give us some modifications for improment of the MS. We believe that the revised version is much more better than before. The introduction part and the subsequent paragraph were also improved.
Reviewer 2 Report
In this manuscript the Authors present an extensive synthetic work on the Phospho-Aldol-Brook rearrangement involving alpha-ketoamides and dialkylphosphates and reactants. On the basis of systematic optimisation experiments they found DBU as the most efficient catalyst under solvent-free conditions. Unfortunately, the presentation and interpretation of the results of the impressive synthetic work is far from being satisfactory. The superiority of DBU over other base catalysts tested in the research would deserve at least an attempted rationalisation in the light of the proposed mechanism. On the other hand, some details in the catalytic cycle outlined in Scheme 1 needs reconsideration with special regard to the transition state presented as a simple H-bonded structure. According to the general view about the mechanism of [1,2] Brook-type rearrangements a transition state structure contains a three-membered ring. However, in the investigated transformations proceeding via the nucleophilic attack by the carbanion on the P=O center, an addition-elimination sequence should be assumed rather than a synchronous process. Moreover, in order to get more insight in the crucial proton-transfers, the research sould be extended to a few related ketoamides without N-H group serving as reference models. The structure of the rearranged product derived from the oxoesther reaction (Figure 1) should also be corrected. Finally, an extensive revision of English is indispensable for the publication of this work.
Author Response
In this manuscript the Authors present an extensive synthetic work on the Phospho-Aldol-Brook rearrangement involving alpha-ketoamides and dialkylphosphates and reactants. On the basis of systematic optimisation experiments they found DBU as the most efficient catalyst under solvent-free conditions. Unfortunately, the presentation and interpretation of the results of the impressive synthetic work is far from being satisfactory. The superiority of DBU over other base catalysts tested in the research would deserve at least an attempted rationalisation in the light of the proposed mechanism. On the other hand, some details in the catalytic cycle outlined in Scheme 1 needs reconsideration with special regard to the transition state presented as a simple H-bonded structure. According to the general view about the mechanism of [1,2] Brook-type rearrangements a transition state structure contains a three-membered ring. However, in the investigated transformations proceeding via the nucleophilic attack by the carbanion on the P=O center, an addition-elimination sequence should be assumed rather than a synchronous process. Moreover, in order to get more insight in the crucial proton-transfers, the research sould be extended to a few related ketoamides without N-H group serving as reference models. The structure of the rearranged product derived from the oxoesther reaction (Figure 1) should also be corrected. Finally, an extensive revision of English is indispensable for the publication of this work.
Response：Thanks for your comment.
Firstly, in our revised manuscript，the proposed mechanism have been improved accoding to your suggestion. Generally speaking, we agree with your opinions and suggestions, the Scheme 1 was redrawn and the corresponding text were rewritten.
Secondly, for the suggestion of "shoud be extended to a few related ketoamides without N-H group". Actually，we can not buy (or get）such a type of compounds，are they diketones or trione? however, if yes, some other paper have reported the similar work (see Phosphorus, Sulfur, and Silicon, 2010 185,1850–1857). But we thank so much for your good suggestion.
Thirdly，the structure of the rearranged product in Figure 1have been corrected，thanks for pointing this mistake out.
Finally, the English of this manuscript have been improved and polished, we believe that it was much more suitable for publication than before.
Reviewer 3 Report
This paper deals with the formation of alpha phosphate amide derivatives in high yield via a phospho-aldol brook rearrangement between an alpha ketoamide and a dialkylphosphite catalyzed by DBU. This rearrangement was performed without solvent in few minutes at room temperature and could be applied to various phospate and amide.
The originality of this paper lies in the fact that this rearrangement is performed without solvent.
English language needs to be checked by a native english speaker.
Abstract lines 13 and 15 dialkyl phosphite (cf structure B fig 1)instead of dialkyl phosphate
all references must be checked :
In the text line 46 ref 35 is cited « in the contrast the removal of solvents….[35] » and let us think that the authors of this paper (paper of your previous work) have carried out their reactions without solvent. But there is not solvent free protocols. Moreover for ref 35 there is no journal named organic chemistry, it is J. Org. Chem. (line 265). Ref 34 presents solvent free reaction conditions but not refs 35 and 36 !..
moreover for ref 36 the reaction time is at least 1 h (+ 15 min) it is not a so short reaction time as said Line 49
line 108 ref 38 is cited to explain why only traces of product are obtained (ie steric hindrance) but in ref 38 it is only reported formation of isatin derivatives and their pharmacological evaluation ???
Line 55 Fig 1 Nakamura product is no correct and ref 35 does not correspond to Nakamura’s one ?(not 2011 , 2019 !...) it is ref 25 not 35
Fig 1 It is not quiniding but quinidine and in this paper (ie ref 25) R2 is always Et : replace R2 by Et
Line 63 Triethylamine : triethylamine
Line 74 Catalyzed : catalyzed
- 111 to 123 As phospho aldol brook rearrangement of dialkylphosphite with isatins has been studied by other groups, it will be interesting to add some references
Line 125 phosphite (A) not phosphate A
Tables 2 and 3 atoms and group abbreviations (for example H instead of hydrogen, Me instead of methyl etc….) must be used and numbering of molecules must be added and write down , in the same manner, in the supporting materials .
Scheme 2 : 2.0 g and 1.3657 g and 3.85 g ? is it the same weighing machine ? The result shall not contain more significant figures than are justified by the precision of the weighing machine used.
Lines 85 and 162 A, B in bold
Supporting materials
Some number of molecules are missing (cf comment tables 2 and 3)
Line 46 Dialkylphosphites not phosphates
Line 55 structure : O atom is missing
Line 529 dz ??? what does it mean ?
Some O-C-H chemical shifts are missing :For 4-bromo-2-oxoindolin-639 3-yl diethyl phosphate. ; 5-chloro-2-oxoindolin-3-yl dimethyl phosphate.; dimethyl (5-methyl-2-oxoindolin-3-yl) phosphate ; diethyl (5-nitro-2- oxoindolin-3-yl) phosphate. ; 7-bromo-2-oxoindolin-3-yl dimethyl phosphate ; and for 5,7-dimethyl-2-oxoindolin-3-yl diethyl phosphate.
Author Response
Comments：
This paper deals with the formation of alpha phosphate amide derivatives in high yield via a phospho-aldol brook rearrangement between an alpha ketoamide and a dialkylphosphite catalyzed by DBU. This rearrangement was performed without solvent in few minutes at room temperature and could be applied to various phospate and amide.
The originality of this paper lies in the fact that this rearrangement is performed without solvent.
English language needs to be checked by a native english speaker.
Abstract lines 13 and 15 dialkyl phosphite (cf structure B fig 1)instead of dialkyl phosphate
Response: Dear reviewer, thank you for comments to our manuscript. Your recommendations of our manuscript are appreciated. This manuscript has also been improved according to the comments and suggestions that from you, the editor and other three reviewers. As well as the manuscript has been improved in English. We believe that the revised version hereby is much more suitable for publication than before. Moreover, dialkyl phosphite have been instead of dialkyl phosphate.
Comments：
all references must be checked :
In the text line 46 ref 35 is cited « in the contrast the removal of solvents….[35] » and let us think that the authors of this paper (paper of your previous work) have carried out their reactions without solvent. But there is not solvent free protocols. Moreover for ref 35 there is no journal named organic chemistry, it is J. Org. Chem. (line 265). Ref 34 presents solvent free reaction conditions but not refs 35 and 36 !..
Response: We regreted this error，ref 35 and 36 have been updated to"
35. Sarkar, A.; Santra, S.; Kundu, S.K.; Hajra, A.; Zyryanov, G.V.; Chupakhin, O.N.; Charushin, V.N.; Majee, A. A decade update on solvent and catalyst-free neat organic reactions: A step forward towards sustainability. Green Chem. 2016, 18, 4475–4525.
36. Zangade, S.; Patil, P. A. Review on Solvent-Free Methods in Organic Synthesis. Curr. Org. Chem. 2019, 23, 2295–2318. "
Comment：
moreover for ref 36 the reaction time is at least 1 h (+ 15 min) it is not a so short reaction time as said Line 49
Response: We regreted this error，ref 36 have been updated as mentioned above.
Comment：
line 108 ref 38 is cited to explain why only traces of product are obtained (ie steric hindrance) but in ref 38 it is only reported formation of isatin derivatives and their pharmacological evaluation ???
Response: We regreted this error， ref 38 have been corrected.
Comment：
Line 55 Fig 1 Nakamura product is no correct and ref 35 does not correspond to Nakamura’s one ?(not 2011 , 2019 !...) it is ref 25 not 35
Response: We regreted this low-level error，Fig 1 was corrected.
Comment：
Fig 1 It is not quiniding but quinidine and in this paper (ie ref 25) R2 is always Et : replace R2 by Et
Response: Thanks for your kind suggestion. it was corrected as suggestion.
Comment：
Line 63 Triethylamine : triethylamine
Response: Thanks for your correction.
Comment：
Line 74 Catalyzed : catalyzed
Response: Thanks for your correction.
Comment：
111 to 123 As phospho aldol brook rearrangement of dialkylphosphite with isatins has been studied by other groups, it will be interesting to add some references
Response: Thanks for your suggustion. a corresponding reference was added.
Comment：
Line 125 phosphite (A) not phosphate A
Response: Thanks for your suggustion. it was corrected.
Comment：
Tables 2 and 3 atoms and group abbreviations (for example H instead of hydrogen, Me instead of methyl etc….) must be used and numbering of molecules must be added and write down , in the same manner, in the supporting materials .
Response: Thanks for your suggustion, Tables 2 and 3 were be improved as suggestions.
Comment：
Scheme 2 : 2.0 g and 1.3657 g and 3.85 g ? is it the same weighing machine ? The result shall not contain more significant figures than are justified by the precision of the weighing machine used.
Response: We regret this mistake. This mistake have been redressed as two decimal.
Comment：
Lines 85 and 162 A, B in bold
Response: Thanks, we have corrected as suggestion.
Comment：
Supporting materials
Some number of molecules are missing (cf comment tables 2 and 3)
Response: Thanks for your kind suggestion. Corrected.
Comment：
Line 46 Dialkylphosphites not phosphates Line 55 structure : O atom is missing
Response: It was corrected in our revised manuscrit.
Comment：
Line 529 dz ??? what does it mean ?
Response: We regreted this mistake, it was corrected in our revised manuscrit.
Comment：
Some O-C-H chemical shifts are missing :For 4-bromo-2-oxoindolin-639 3-yl diethyl phosphate. ; 5-chloro-2-oxoindolin-3-yl dimethyl phosphate.; dimethyl (5-methyl-2-oxoindolin-3-yl) phosphate ; diethyl (5-nitro-2- oxoindolin-3-yl) phosphate. ; 7-bromo-2-oxoindolin-3-yl dimethyl phosphate ; and for 5,7-dimethyl-2-oxoindolin-3-yl diethyl phosphate.
Response: We regreted these mistakes. the O-C-H chemical shifts have been added in revised version.
Reviewer 4 Report
Wu et, all. Have used a cheap and popular base for synthesis of various range of α-Phosphates Amide. This method is interesting for industry and large scale synthesis. I would like to know this method is applicable for large scale batch or no. Please set a model reaction in mole scale and report its result in manuscript.
Author Response
Comments:
Wu et, all. Have used a cheap and popular base for synthesis of various range of α-Phosphates Amide. This method is interesting for industry and large scale synthesis. I would like to know this method is applicable for large scale batch or no. Please set a model reaction in mole scale and report its result in manuscript.
Response: Thanks for your recommendation of our manuscript. After getting your suggestion，a mol-scale synthesis was supplemented as suggestion，the result indicated this method is applicable for large scale batch.
Round 2
Reviewer 1 Report
I think that the authors answered to all my question and concerns, so the manuscript can be accepted for publication as it is.
Author Response
Thank you very much for your comments again. Your recommendation of our manuscript is appreciated. The English of the manuscript has been improved again. We believe that the revised manuscript was much more suitable for the publication in Catalysts than before.
Thanks Again!
Reviewer 2 Report
After a minor revision this version of maniscript can be published in Catalyst. However prior to final acceptance the pKB values should be inserted in the text about the comparision of the activity of base catalysts.
Author Response
Dear reviewer. Thanks for your suggestion again.
The pKb values of DBU (pKb=2), DMAP( pKb=4.8), TEA (pKb=4.25) have been inserted into the corresponding position in text. However, the pKb values of NaOH and K2CO3 have not been added as their pKb values are associated with concentration in water, and the reaction in our manuscript is solvent-free, we could not confirm the concentration in a organic solvent.
Reviewer 3 Report
To publish this work a revision of the English is necessary
fig 1 : quinidine instead of quiniding
line 101 phosphite instead of phosphate
Author Response
Dear reviewer.
Thanks for your comment and suggestion again.
The manuscript have revised according to your suggestions. Also the English have been improved further. We believe that the revised manuscript was much more suitable for the publication in Catalysts the last version.
The changes were also listed as follows.
- The “quiniding” has been changed to “quinidine” .
- The “phosphate” have corrected as “phosphite”.
- Changed from the authors:
- Page one line 26, the “in” has been deleted form the manuscript.
- Page one line 30, the proposed has been changed to “proposing”, and a space has been added between that and α.
- Page one line 32, the extra comma hereby has been deleted.
- Page one line 34, “catalyst” has been changed to “catalysts”.
- Page one line 36, the “proceed” has been deleted.
- Page two line 47 “recently” has been changed to “recent”.
- Page two line 76 adding a “that” between “than” and “of”.
- Page two line 77 adding a “one” between “best” and “in”.
- Page three line 90 the extra “showed” has been deleted and the “affect” has been changed to “affected”.
- Page five Line 127 the extra space has been deleted.
- Page five line 128 adding a period after reference 44.
- Page five line 129 the “to” has been deleted and “yield” has been changed to “yields”.
