Hydroxylamine-mediated C–C amination via an aza-hock rearrangement

Despite the widespread use of anilines, synthetic challenges to these targets still exist. Selectivity is often an issue, when using the traditional nitration-reduction sequence or more modern approaches, including arene C–H aminations catalyzed by transition metals, photosensitizers, or electrodes. Accordingly, there is still a need for general methods to rapidly, directly access specific isomers of substituted anilines. Here, we report a simple route towards the synthesis of such motifs starting from benzyl alcohols, which are converted to anilines by the use of arylsulfonyl hydroxylamines, via an aza-Hock rearrangement. Good to excellent yields are observed. The method is applicable to various benzyl alcohol surrogates (such as ethers, esters, and halides) as well as simple alkylarenes. Functionalizations of pharmaceutically relevant structures are feasible under the reaction conditions. Over ten amination reagents can be used, which facilitates the rapid assembly of a vast set of compounds.

Hashmi and coworkers reported here a method for the preparation of arylamines via C-C bond cleavage from benzyl alcohols. The mild conditions, good compatibility and good yields make this method very practical for synthesis. However, some questions and limitations are obvious in this manuscript, essential improvements should be conducted. 1) TFE and HFIP are very important for the transformation. However, they are too expensive for large-scale application, is it possible to use equivalences or catalytic amount of acids in frequently-used solvents such as DCM and others.
2) Poor tolerance to strong electron-withdrawing groups were shown in Table 2 and Table 5, substrates substituted by other groups such as NO2 or amide or F were not shown, they are tolerated in previous method with sodium azide as the nitrogen source. Could this limitation be solved by trying more different amination reagents that possess similar reactivity with sodium azide, which is important and meaningful to improve this work.
Overall, This referee recommend it publication in Nature communication after addressing these questions.
Reviewer #2 (Remarks to the Author): In the submitted manuscript, Hashmi and coworkers disclose an aza-variant of the widely utilized Hock rearrangement to generate anilines from benzylic alcohols via C-C bond cleavage. While the disclosed aza-Hock rearrangment transformation is mechanistically interesting, it's unclear how useful the reaction would be to the practicing synthetic organic chemist. In the majority of cases, both the amination reagent and the benzylic alcohol starting materials take 1-2 steps to prepare from commercially available reagents. Considering that most of the products prepared in the manuscript can be made directly from commercially available aryl halides and amines using a Buchwald-Hartwig animation, the starting materials for the disclosed aza-Hock rearrangement are often more difficult to make than the products and would likely prevent the widespread adoption of this methodology. Additionally, the substrate scope excludes functionalities that those in the pharmaceutical industry would find relevant, such as heteroarenes (e.g., pyridines, pyrimidines, various azoles) and amides. Due to the perceived lack of applicability of this transformation, I recommend against publishing this manuscript in Nature Communications.
However, I do believe that disclosed transformation is mechanistically interesting. I would encourage the author to pursue additional mechanistic studies to provide more insight into their proposed mechanism and submit a fuller account elsewhere (e.g., Are the reaction kinetics consistent with one of the steps in the proposed mechanism? Would a Hammet plot be able to provide further insight into the nature of the rate determining step? Can the authors gather evidence for the proposed benzylic carbocation and/or iminium ion intermediates through intramolecular carbocationic rearrangements?). They should also remove the "Mechanistically we could prove that an aza-Hock rearrangement operates" line from the conclusion since one cannot prove a mechanism and can instead only gather evidence that supports a proposed mechanism.
Reviewer #3 (Remarks to the Author): Overall, the novel methodology demonstrated in the manuscript is sound and appropriately referenced and the introduction is useful for bringing a general audience up to speed. The transformation is novel, albeit a logical extension of known methods. This reviewer feels that the substrate Tables 2 and 5 are a bit overwhelming and substrates were not judiciously chosen. These tables could be shortened which would allow for more interesting substrates to be added (see below for comments). The mechanistic studies are scientifically sound.
[Please see the attached document for additional, specific comments.] Overall, the novel methodology demonstrated in the manuscript is sound and appropriately referenced and the introduction is useful for bringing a general audience up to speed. The transformation is novel, albeit a logical extension of known methods. This reviewer feels that the substrate Tables 2 and 5 are a bit overwhelming and substrates were not judiciously chosen. These tables could be shortened which would allow for more interesting substrates to be added (see below for comments). The mechanistic studies are scientifically sound. P1, Introduction, first sentence: no comma after "Anilines" Scheme 1c: this part of scheme 1 is confusing. The methodology studied is shown in the first arrow (left to right), but the second arrow (right to left) seems to show something else. Is TFA a typo for TFE? I don't actually know what the Ar-R 3 is at all, since this paper seems to only show transformations of benzylic alcohols (as depicted in the first left to right arrow) P3, please introduce alternate reagent MsONHMe before its appearance in the table   Table 2: although it's hinted at, some explicit negative controls would make obvious some of the challenges to this methodology, e.g. 1-(4-nitrophenyl)-ethanol. Table 2: 1k  3k (22%) and 1x  3x (30%): the text suggests that bromides and alkynes are tolerated, but this isn't obvious without explaining the mass balance of these two reactions. Is there remaining starting material or are there byproducts? Table 2: the yield difference between 1r and 3v is noteworthy but not discussed. Table 2: to be of broader interest, a more judicious choice of substrates would be useful. There are some substrates that aren't particularly interesting, such as: 1e and 1q (redundant with 1d), similarly 1o, 1s, and 1u don't provide much in terms of scope. Instead, the authors could add more variety to the heterocycle section (specifically 5-and 6-membered rings with multiple heteroatoms are of pharmaceutical interest). The natural products, drugs, and bio-renewable section is a nice addition. Table 2 / SI: moving 4-methyoxybenzyl alcohol (no reaction) to the table would be useful, removing some of the redundant substrates and adding substrates from the SI would also be a better use of space (e.g. styrenes and C-H aminated reaction with 1-(4-methoxyphenyl)propan-2-ol)  I would accept this manuscript for publication to Nature Communications after substantial revisions.

REVIEWER COMMENTS
Reviewer #1 (Remarks to the Author): Hashmi and coworkers reported here a method for the preparation of arylamines via C-C bond cleavage from benzyl alcohols. The mild conditions, good compatibility and good yields make this method very practical for synthesis. However, some questions and limitations are obvious in this manuscript, essential improvements should be conducted. 1) TFE and HFIP are very important for the transformation. However, they are too expensive for large-scale application, is it possible to use equivalences or catalytic amount of acids in frequently-used solvents such as DCM and others. OUR ACTION: Indeed, TFE and HFIP are expensive than normal solvents, but they can be recycled by simple distillation (Nat. Rev. Chem. 2017, 1, 0088). As you said, 3 equivalents of TFA as acid with DCM as solvent also finish the reaction. But for electron-deficient substrates, HFIP as solvent performed better than DCM with TFA as the acid.
2) Poor tolerance to strong electron-withdrawing groups were shown in Table 2 and Table 5, substrates substituted by other groups such as NO2 or amide or F were not shown, they are tolerated in previous method with sodium azide as the nitrogen source. Could this limitation be solved by trying more different amination reagents that possess similar reactivity with sodium azide, which is important and meaningful to improve this work. OUR ACTION: Done, we added example 1l (NO 2 ) in table 2 and example 1aj (F), 1ak (AcNH) in table 5 in the new revised manuscript.
3) Some relevant work should be cited in the manuscript including Schmidttype reaction with MeNO2 as the amination reagent, which generated AcONH2TfOH as the active species (Science 367, 281-285 (2020)) and C-H amination using hydroxylamine reagents developed by Overall, This referee recommend it publication in Nature communication after addressing these questions.

Reviewer #2 (Remarks to the Author):
In the submitted manuscript, Hashmi and coworkers disclose an aza-variant of the widely utilized Hock rearrangement to generate anilines from benzylic alcohols via C-C bond cleavage. While the disclosed aza-Hock rearrangment transformation is mechanistically interesting, it's unclear how useful the reaction would be to the practicing synthetic organic chemist. In the majority of cases, both the amination reagent and the benzylic alcohol starting materials take 1-2 steps to prepare from commercially available reagents. Considering that most of the products prepared in the manuscript can be made directly from commercially available aryl halides and amines using a Buchwald-Hartwig animation, the starting materials for the disclosed aza-Hock rearrangement are often more difficult to make than the products and would likely prevent the widespread adoption of this methodology. Additionally, the substrate scope excludes functionalities that those in the pharmaceutical industry would find relevant, such as heteroarenes (e.g., pyridines, pyrimidines, various azoles) and amides. Due to the perceived lack of applicability of this transformation, I recommend against publishing this manuscript in Nature Communications. Table 5 in the new revised manuscript.

OUR ACTION:The aza-Hock rearrangement we address here is totally different chemistry from Buchwald-Hartwig amination, which can not simply be compared from the synthetic view; besides, Buchwald-Hartwig reaction needs expensive transition-metals, while our protocol does not. For heteroarenes, we added 1am, 1an in
However, I do believe that disclosed transformation is mechanistically interesting. I would encourage the author to pursue additional mechanistic studies to provide more insight into their proposed mechanism and submit a fuller account elsewhere (e.g., Are the reaction kinetics consistent with one of the steps in the proposed mechanism? Would a Hammet plot be able to provide further insight into the nature of the rate determining step? OUR ACTION: Three kinetical plots are shown below: electron-rich substrate reacts faster than electron-neutral and electron-poor substrates. the yields are consistent with isolated yields.

As you can see in the below spectra, benzyl alcohol was decomposed very quickly after adding TFA in the reaction (measure in the d 2 -DCM with TFA as acid, method shown for the first review). The GC-kinetics with HFIP as the solvent showed the same result as NMR-kinetics: benzyl alcohols was decomposed very fast (No signal of benzyl alcohol around 3 min on GC-MS). This is why it is useless to do Hammet plot (substrates are consumed so quickly). As least, the formation of benzyl cation is not the determined step.
Can the authors gather evidence for the proposed benzylic carbocation and/or iminium ion intermediates through intramolecular carbocationic rearrangements?). OUR ACTION: two intramolecular benzylic alcohols are tested (shown in the scheme down), but none worked (no intramolecular C-C amination detected), which might be attributed to competitive intermolecular C-C amination. They should also remove the "Mechanistically we could prove that an aza-Hock rearrangement operates" line from the conclusion since one cannot prove a mechanism and can instead only gather evidence that supports a proposed mechanism. OUR ACTION: we "Mechanistically we could prove that an aza-Hock rearrangement operates" was instead of "Mechanistically we could prove that an aza-Hock rearrangement operates." Reviewer #3 (Remarks to the Author): Overall, the novel methodology demonstrated in the manuscript is sound and appropriately referenced and the introduction is useful for bringing a general audience up to speed. The transformation is novel, albeit a logical extension of known methods. This reviewer feels that the substrate Tables 2 and 5 are a bit overwhelming and substrates were not judiciously chosen. These tables could be shortened which would allow for more interesting substrates to be added (see below for comments). The mechanistic studies are scientifically sound.
[Please see the attached document for additional, specific comments.] ************************************************** Text from attached document: Overall, the novel methodology demonstrated in the manuscript is sound and appropriately referenced and the introduction is useful for bringing a general audience up to speed. The transformation is novel, albeit a logical extension of known methods. This reviewer feels that the substrate Tables 2 and 5 are a bit overwhelming and substrates were not judiciously chosen. These tables could be shortened which would allow for more interesting substrates to be added (see below for comments). The mechanistic studies are scientifically sound.   appearance in the  table  Table 2: although it's hinted at, some explicit negative controls would make obvious some of the challenges to this methodology, e.g. 1-(4-nitrophenyl)ethanol. Table 2: 1k 3k (22%) and 1x 3x (30%): the text suggests that bromides and alkynes are tolerated, but this isn't obvious without explaining the mass balance of these two reactions. Is there remaining starting material or are there byproducts? OUR ACTION: we added ", which was first used in C-H amination by our group" after MsONHMe. We added example 1l (NO 2 ) in the new revised manuscript No other basic side-products were detected with GC-MS and TLC for substrate 1j and 1v in the new revised manuscript. Maybe some acidic side-products were formed from those two substrates (reaction workup with NaHCO 3 aq.) Table 2: the yield difference between 1r and 3v is noteworthy but not discussed. OUR ACTION: Done, we added "Noteworthy, in contrast to diphenyl ether 1q, the fused benzene ring 1t delivered a better yield, which is attributed to the participation of lone pair in the aromaticity of the five-member ring." Table 2: to be of broader interest, a more judicious choice of substrates would be useful. There are some substrates that aren't particularly interesting, such as: 1e and 1q (redundant with 1d), similarly 1o, 1s, and 1u don't provide much in terms of scope. Instead, the authors could add more variety to the heterocycle section (specifically 5-and 6-membered rings with multiple heteroatoms are of pharmaceutical interest). The natural products, drugs, and bio-renewable section is a nice addition. OUR ACTION: Done, some redundant examples were removed (eg. 1e and 3e, 1o and 3o, 1u and 3u from table 2; 1u and 6u from table 5) in the old manucript. Also we added heterocycles 1am, 1an in Table 5 in the new revised manuscript. Table 2 / SI: moving 4-methyoxybenzyl alcohol (no reaction) to the table would be useful, removing some of the redundant substrates and adding substrates from the SI would also be a better use of space (e.g. styrenes and C-H aminated reaction with 1-(4-methoxyphenyl)propan-2-ol) OUR ACTION: Done. As answered in the above question, redundant substrates were removed and styrene 1af and C-H amination 1ag were added in the new revised manuscript in the old manucript, was used for arene C-H amination. Without iron as a additive, the reaction only gave around 20% NMR yield; FeSO 4 could increase the yield a little bit (for the iron role, we could not give a better explaination). And this is the first time of iron used in aza-Hock rearrangement. Now in the revised manuscript, we deleted 1aj in the old manuscript and added 1an (with COOMe) in table 5 in the new manuscript.