Copper-catalysed enantioconvergent N-alkylation of hydrazines with racemic α-haloamides to access enantioenriched hydrazines

Domain: neuroscience
Published: 2026-01-27
Editorial outcome: minor_revision

Abstract
Chiral hydrazines are important building blocks in chiral drug molecules, N-aminopeptides, and aza-heterocycles. The catalytic enantioconvergent N-alkylation of readily available hydrazine derivatives with various racemic alkyl halides offers a highly attractive route to chiral hydrazines. However, this process remains challenging due to the lack of efficient asymmetric catalytic systems and the difficulty in achieving regioselectivity at the N1/N2 positions of hydrazine derivatives. Herein, we demonstrate a general copper-catalysed enantioconvergent N-alkylation of hydrazine derivatives with racemic α-haloamides. This strategy provides a modular approach for the synthesis of diverse enantioenriched hydrazines with excellent regio- and enantioselectivity. The key to success lies in the development of a radical-polar crossover nucleophilic substitution process and the employment of suitable hydrazine nucleophiles. Furthermore, this method provides a versatile platform to access a series of enantioenriched aza-heterocycles through facile subsequent transformations. It also enables the stereodivergent synthesis of all four possible stereoisomers of N-aminodipeptides bearing two stereocenters, with excellent stereoselectivity.

Introduction
Chiral hydrazines are not only prevalent in various natural products and drug molecules, but also serve as versatile chiral building blocks and catalysts in organic synthesis and asymmetric catalysis1–6. Specifically, the distinctive hydrazine moiety in N-aminopeptides derived from chiral hydrazines endow these peptides with unique secondary conformations and biological activities7,8. Furthermore, they are also vital precursors for synthesizing a wider range of aza-heterocycles with potential pharmacological activity9,10 (Fig. 1a). Consequently, considerable progress has been achieved in developing catalytic enantioselective approaches for their efficient preparation11–38. The most widely used methods are the asymmetric hydrogenation of hydrazones16–22 and nucleophilic addition to hydrazones23–29 (Fig. 1b, left). This is presumably due to the tunable reactivity of hydrazones and their ability to assist in the coordination of chiral catalysts. Nevertheless, the synthesis of hydrazones by condensation of hydrazine derivatives with carbonyl compounds often requires laborious separation and purification. Meanwhile, notable advances have also been made in the catalytic asymmetric electrophilic amination of carbonyl compounds with azodicarboxylates30–38 (Fig. 1b, left). Notably, azodicarboxylates, which are derived from the oxidation of hydrazine derivatives, are explosive and necessitate careful handling. Given the importance of atom- and step-economy in constructing such valuable enantioenriched hydrazines, the development of a new asymmetric catalytic system to directly access these skeletons from readily available and inexpensive hydrazine derivatives remains highly desirable.

In this context, the catalytic enantioconvergent N-alkylation of simple hydrazine derivatives with various racemic alkyl (pseudo) halides would provide a general method for accessing enantioenriched hydrazines, as these two classes of starting materials are easily available and widely applied in industry and academia (Fig. 1b, right). As a notable precedent, Carreira and co-workers pioneered an iridium-catalysed asymmetric allylic substitution of racemic allylic alcohols with hydrazine derivatives39. Subsequently, Zhou40 and Xu41 independently reported copper-catalysed asymmetric propargylic substitutions of propargylic alcohol derivatives with hydrazine derivatives. Nevertheless, these reactions are confined to allylic and propargylic electrophiles, which are well-established as versatile coupling partners in asymmetric catalysis. On the other hand, Fu42–46 and our group47–51 have respectively developed the enantioconvergent radical cross-coupling of racemic alkyl halides with nitrogen-containing nucleophiles using chiral copper catalysts. Such catalytic systems offer an alternative route to access enantioenriched hydrazines, albeit through multistep transformations. However, to the best of our knowledge, the direct cross-coupling of racemic alkyl halides with hydrazine derivatives for the synthesis of enantioenriched hydrazines remains unreported. A critical obstacle is the inherently low acidity of hydrazine derivatives (e.g., pKa = 8.07 for NH2NH2 in H2O)52, which impedes the transmetalation step required for forming the key hydrazine-sequestered Nu−MnL* complex intermediate (Fig. 1c). Clearly, the design of a conceptually distinct catalytic system is highly desirable to overcome the challenges posed by this nucleophile and enable enantioconvergent N-alkylation with a broad scope of racemic electrophiles, which, if successful, would complement the previously reported approaches39–41.

As part of our continuous interest in asymmetric radical reactions53–58, we have recently developed a general radical-polar crossover nucleophilic substitution platform: a chiral copper catalyst promotes the single-electron reduction of racemic α-haloamides to generate CuII-bonded prochiral alkyl intermediates. This intermediate then undergoes intramolecular radical rebound to form a CuIII intermediate, which subsequently undergoes polar outer-sphere nucleophilic attack by various nucleophiles59–61 (Fig. 1c). This radical-polar crossover platform offers an alternative mechanistic paradigm, in which nucleophiles can directly attack the highly reactive hypervalent transition metal complex. This provides an opportunity for the coupling of challenging nucleophiles such as aliphatic amines, bulky aromatic amines, and alcohols, thereby significantly expanding the scope of nucleophiles in this field. Inspired by these observations and aiming to address the aforementioned challenges associated with using hydrazine derivatives as nucleophiles, we sought to determine whether enantioenriched hydrazines could be accessed through the direct enantioconvergent N-alkylation of readily available and inexpensive hydrazine derivatives with racemic α-haloamides under mild conditions. However, even though the transmetalation hurdles for hydrazine derivatives in the aforementioned classic cross-coupling reactions42–51 have been overcome, several additional challenges still need to be well addressed: (1) the non-stereoselective background nucleophilic substitution between hydrazine derivatives and α-haloamides occurs via an aziridinone intermediate in the presence of an inorganic base62 due to the strong nucleophilic properties of hydrazine derivatives (e.g., nucleophilicity N = 16.45 for NH2NH2 in CH3CN)63; (2) the high Lewis basicity of hydrazine derivatives (e.g., pKa = 16.61 for NH2NH2 in CH3CN)64 would probably cause transition-metal catalyst poisoning—a problem analogous to that observed with our previously reported aliphatic amines59; and (3) most importantly, the regioselective control between the N1 and N2 positions of protected hydrazines presents an additional synthetic challenge65–68, contrasting with the reported aliphatic amine, aniline, and alcohol nucleophiles59–61. To address these challenges, we envisaged that: (1) chiral tridentate anionic ligands with strong binding affinities to copper catalysts could not only enhance the reducing capability of copper, thereby accelerating the radical process and outcompeting non-stereoselective background reactions, but also overcome catalyst poisoning; and (2) the selection of suitable hydrazine derivatives with readily removable protecting groups could not only enable regioselective alkylation but also provide access to enantioenriched unprotected hydrazines through simple deprotection (Fig. 1c).

Herein, we demonstrate a general copper/chiral anionic N,N,N-ligand-catalysed enantioconvergent N-alkylation of hydrazine derivatives with racemic α-haloamides, providing a modular approach for the synthesis of diverse enantioenriched hydrazines with excellent regio- and enantioselectivity (Fig. 1d). The key to success lies in the development of a radical-polar crossover nucleophilic substitution process and the employment of hydrazine derivatives bearing easily removable protecting groups as nucleophiles. This method can accommodate a broad range of readily accessible racemic α-haloamides, including those with (hetero)aryl or alkyl substituents at the α-carbon center, as well as aryl, alkyl, and amino acid motifs as N-substituents. The synthetic utility of this method is demonstrated by the synthesis of enantioenriched N-amino dipeptides and aza-heterocycles. Furthermore, this reaction can produce all four possible stereoisomers of N-aminodipeptides bearing two chiral centers, demonstrating high catalyst-controlled stereoselectivity that overrides the influence of substrate chirality.

Results
Reaction development
Considering the significant influence of hydrazine substituents on reactivity and selectivity, we initially investigated the enantioconvergent N-alkylation of various hydrazine derivatives with racemic α-chloroamide E1 using CuTc as the catalyst and our previously reported anionic N,N-ligand L*559 as the ligand (Fig. 2). As anticipated, the results revealed that the structure of hydrazine derivatives has a significant effect on the reaction efficiency and enantioselectivity. When N-phenyl hydrazine N1 was employed, the corresponding hydrazine 1a was obtained in 8% yield and 3% e.e., accompanied by side product 1a’ formed in 7% yield through the rapid oxidation of the freshly generated 1a67,69. Subsequently, the evaluation of N-sulfonyl hydrazine N2 and benzoyl hydrazine N3, which had previously been utilized in propargylic substitution reactions40, revealed that E1 was completely consumed without the formation of any corresponding hydrazines. Considering the widespread application of the Boc group in hydrazine protection, utilization of N-Boc hydrazine N4 as the substrate afforded the desired hydrazine 1d in 30% yield and 8% e.e. However, the byproduct 1d’ was also formed in 16% yield, likely attributed to the relatively high acidity of the N−H bond adjacent to the Boc moiety. To enhance product stability and reaction efficiency, we hypothesized that introducing an additional substituent into N-Boc hydrazine N4 would suppress side reactions and improve the stability of the resulting product. Encouragingly, the use of N-Me-N-Boc hydrazine N5 significantly improved reaction efficiency, thus affording the desired product 1e with 80% yield and 71% e.e. Similarly, other alkyl-substituted N-Boc hydrazines were evaluated, and they exhibited comparable reactivity and stereoselectivity (Supplementary Fig. 1). Furthermore, motivated by the urgent need for unprotected chiral hydrazines in versatile synthesis, the potential of N-aminophthalimide N6 was investigated. Unfortunately, this reaction afforded 1f in only 28% yield with 62% e.e. In order to balance practicability and reaction efficiency, N,N-bis-Boc hydrazine N7 was subsequently used. To our delight, this reagent provided the corresponding hydrazine 1 with a comparable yield (49%) and excellent enantioselectivity (82% e.e.), outperforming both N5 and N6 in overall synthetic utility. Consequently, N,N-bis-Boc hydrazine N7 was identified as the optimal hydrazine source for this synthetic strategy, given its unique ability to enable regioselective alkylation while serving as a viable source for synthesizing enantioenriched unprotected hydrazines.

Having identified N,N-bis-Boc hydrazine N7 as the optimal hydrazine source, we then systematically screened various ligands to improve the yield and enantioselectivity of 1. Our investigations commenced with neutral ligands, including N,N-ligand L*1, N,P-ligand L*2, DTBM-SEGPHOS L*3, and N,N,N-ligand L*4. Although these ligands could furnish the desired product 1 with 20−40% yield, negligible enantiomeric excess (<5% e.e.) was consistently observed. This strongly indicates that these neutral ligands failed to trigger the proposed radical pathway, instead undergoing non-stereoselective background nucleophilic substitution via an aziridinone intermediate61. In order to promote the proposed radical-polar crossover pathway59–61, we hypothesized that chiral tridentate anionic ligands with strong binding affinity to copper catalysts could not only enhance the reducing capability of copper to accelerate the radical process over non-stereoselective background reactions, but also stabilize the highly active CuIII intermediate by forming a coordinatively saturated intermediate, thereby suppressing side processes. Gratifyingly, the tridentate anionic ligand L*6, which incorporates an additional nitrogen-coordinating site based on L*5, significantly increased the yield to 75% and the enantioselectivity to 95%. To further clarify the role of the tridentate N,N,N-ligand, we synthesized L*7 by introducing a methyl group at the α-position of the nitrogen-coordinating moiety, observing a decrease in both yield and e.e. The importance of the tridentate anionic N,N,N-ligand was further validated by replacing the cinchona alkaloid chiral skeleton with 1,2-diphenyl-ethyl-diamine (L*8) and cyclohexyl-diamine (L*9). Notably, reactions with L*8 and L*9 afforded 1 in good yields with excellent e.e. These results highlight the importance of the chiral tridentate anionic N,N,N-ligand in forming a coordinatively saturated CuIII intermediate, which plays a crucial role in improving enantioselectivity and reactivity. After further optimization of reaction parameters, including copper catalysts, solvents, inorganic bases as well as reaction temperature (Supplementary Tables 1–3 for the results of conditions screening), we identified the optimal conditions as follows: 1.0 equiv. E1, 1.2 equiv. N7, 10 mol% Cu(OAc)2, 15 mol% L*6, and 3.0 equiv. Cs2CO3 in CH2Cl2 at 10 °C for 48h. Under the optimal conditions, the desired enantioenriched hydrazine 1 was obtained in 80% yield with 97% e.e.

Substrate scope
With the optimal reaction conditions in hand, we examined the reaction’s generality. Concerning the scope of α-aryl haloamides (Fig. 3), a panel of α-phenyl rings bearing electron-neutral, -donating or -withdrawing groups were well-tolerated under these conditions, delivering products 1–14 in 42–82% yields and 88–99% e.e. α-Phenyl rings with diverse functional groups, such as halogens (2–8), methyl (9–11), methoxyl (12), trifluoromethyl (13) were all compatible with the reaction conditions. Notably, the reaction was sensitive to the steric effect at the ortho-position of the aromatic ring. While the less sterically hindered ortho-fluoro and ortho-methyl substituents (4 and 11) were well tolerated, the bulkier ortho-phenyl substituent (15) was incompatible with the reaction conditions. Furthermore, 2-naphthyl, 1-naphthyl and thienyl-substituted substrates were also viable, yielding products 16–18 with moderate yields and good enantioselectivity. Notably, substrates bearing a complex moiety derived from the bioactive molecule isoxepac could also be used in this reaction, delivering the desired product 19 with 96% e.e., albeit in a moderate yield. In addition, α-aryl haloamides bearing various N-aryl (20–24) and N-alkyl (25) groups, as well as the bioactive molecule amlodipine (26), could be employed in the reaction with good results.

To further enhance the synthetic utility of this method, we investigated the enantioconvergent N-alkylation of α-alkyl haloamides. Unfortunately, N,N-bis-Boc hydrazine N7 showed low reactivity in the N-alkylation of α-ethyl haloamide E27, affording the desired product in only 5% yield (Supplementary Table 4). This result highlights the critical impact of hydrazine derivatives in reaction efficiency. To address this limitation, we further modified hydrazine derivatives and reoptimized the reaction conditions (Supplementary Tables 4–5 for condition optimizations). Gratifyingly, the combination of 1,1-diphenylhydrazine hydrochloride N8 with ligand L*9 afforded the optimal reactivity and enantioselectivity, delivering product 27 in 62% yield and 87% e.e. Regarding the scope of α-alkyl haloamides (Fig. 4), a wide range of substrates bearing simple unfunctionalized aliphatic chains, as well as those functionalized with phenyl, ether, thioether, trifluoromethyl, ester, alkenyl, and imidyl groups, afforded products 27−41 in 51−71% yields and 79−93% e.e. Notably, sterically hindered isobutyl or isopropyl groups did not significantly diminish the reaction efficiency or enantioselectivity, and products 31–32 were obtained with comparable results. Furthermore, for the reaction of N,N-bis-Boc hydrazine N7 with α-methyl haloamide E28, we screened different types of ligands and reoptimized the reaction conditions (see Supplementary Table 6). These efforts identified that the oxazoline-derived tridentate N,N,N-ligand L*10 afforded the best reactivity and enantioselectivity (60% yield and 86% e.e. for 42). The absolute configurations of compounds 8, 27, and 42 were determined to be S by X-ray crystallographic analysis (Supplementary Fig. 2–4), and all other compounds were assigned by analogy.

Synthetic utility
It is well known that enantioenriched N-aminopeptides play a pivotal role in the stabilization of protein secondary structures and resistance to proteolysis7,8. To demonstrate the synthetic potential of this method, we investigated the feasibility of constructing enantioenriched N-amino peptides via enantioconvergent N-alkylation of hydrazines with α-amino acid-derived α-chloroamides. To our delight, the reaction proceeded smoothly with glycine-derived α-chloroamide E42 under the standard conditions, delivering the desired enantioenriched N-amino dipeptide 43 with 57% yield and 99% e.e. (Fig. 5a). Encouraged by this success, we wondered whether our strategy could circumvent the stereoselectivity induced by the pre-existing stereocenters in α-chloroamides to achieve full catalyst control. We found that more challenging α-chloroamides, derived from chiral amino acids (e.g., Val, Leu, Phe), could successfully furnish the corresponding N-amino dipeptides 44–49 in satisfactory yields and with high diastereoselectivity (Fig. 5a). These results highlight the compatibility and potential of this method for the late-stage functionalization of complex compounds. Furthermore, stereodivergent synthesis plays a crucial role in modern synthesis, particularly in drug discovery, since each isomer of multiple stereocenter compounds often possesses distinct physical and biological properties70. Leveraging our proposed radical-polar crossover pathway, we were also interested in applying this method to synthesize all possible stereoisomers of the N-amino dipeptide 50 from readily available starting materials. Notably, by employing the L*6 and (8R,9R)-L*6 ligands, the N-alkylation of N,N-bis-Boc hydrazine N7 with L-alanine/D-alanine-derived α-chloroamides E49/E49’ readily afforded all four stereoisomers of the enantioenriched N-amino dipeptides 50 with high catalyst-controlled stereoselectivity (Fig. 5b). These results clearly demonstrate that this method provides an efficient platform for achieving stereochemical diversity in peptidomimetics, thereby showcasing potential applications for high-throughput drug screening.

To further demonstrate the synthetic utility of this method, a gram-scale reaction (3.5 mmol) was successfully performed, yielding product 1 with comparable yield and enantioselectivity. Subsequently, the enantioenriched product 1 was efficiently deprotected with HCl in 1,4-dioxane to produce the corresponding hydrazine hydrochloride salt 51 (Fig. 6a). Meanwhile, the scale-up reaction of enantioenriched hydrazine 50 also provided consistent yield and diastereoselectivity, followed by efficient deprotection to yield the corresponding hydrazine hydrochloride salt 52. Notably, the synthetic potential of this strategy is enhanced by the readily available unprotected hydrazine moiety, which can be exploited to generate valuable enantioenriched aza-heterocycles (Fig. 6b). For instance, the unprotected hydrazine moiety in 51 undergoes condensation with various carbonyl compounds to form structurally diverse enantioenriched aza-heterocycles, including phthalazin-1(2H)-one (53), 1H-pyrazoles (54–56), and 1H-pyrazolo[3,4-d]pyrimidine (57). These transformations afford 42–96% yields without apparent erosion of enantiopurity. Furthermore, the hydrochloride salt of the enantioenriched hydrazine 52 enabled the synthesis of peptide-fused enantioenriched aza-heterocycles (58 and 59), further expanding the utility of this platform for constructing complex biologically relevant architectures. These results clearly demonstrate the broad application of this method for achieving structural diversity.

Mechanistic investigations
In order to gain insight into the reaction mechanism, a series of control experiments were performed. A radical trapping experiment with butylated hydroxytoluene (BHT) afforded product 1 in reduced yield alongside the formation of BHT-trapped product 60 under the standard conditions, indicating the generation of an alkyl radical from racemic α-haloamides via a halogen atom transfer (XAT) process (Fig. 7a). Furthermore, a linear relationship was observed between the enantiopurities of the products and the enantiopurities of the corresponding chiral ligands, suggesting that a mononuclear copper species coordinated with a chiral N,N,N-ligand is likely the active catalyst in this process (Fig. 7b). Additionally, Hammett analysis was conducted by employing para-substituted phenylhydrazines with varied electronic properties in conjunction with α-haloamide E1 (Supplementary Fig. 5 for details), and a negative linear relationship was observed between the log(k Ar /k Ph ) and the substituent constants σ p of the phenylhydrazines71 (Fig. 7c). These findings are consistent with a transition state bearing partial positive charge in the rate-determining step, which presumably suggests the generation of the key electrophilic CuIII intermediate. Based on these mechanistic results and our previous reports59–61, we proposed a plausible mechanism as shown in Fig. 7d. First, CuI reacted with the chiral ligand L* and racemic α-haloamide in the presence of a base to generate a CuI intermediate I. Next, intermediate I undergoes an XAT process to form a CuII-bonded prochiral alkyl intermediate II, which undergoes an intramolecular radical rebound to form a CuIII intermediate III. Subsequently, a polar outer-sphere nucleophilic attack of intermediate III by hydrazine derivative in the presence of a base delivers intermediate IV. Finally, ligand exchange with α-haloamide E regenerates intermediate I and releases the enantioenriched hydrazine, completing the catalytic cycle. For the key enantiodetermining C(sp3)−N bond formation step, two transition states (re-TS and si-TS) are proposed, corresponding to the formation of the two product enantiomers59 (Fig. 7e). The steric clash between the ligand sulfonyl group and the relatively bulky R1 group in si-TS render this transition state energetically disfavored. In contrast, the energetically favorable re-TS favors the formation of the desired products with the S absolute configuration, consistent with the experimental results.

Methods
Representative procedure for the synthesis of 1–26, 42–50
Under an argon atmosphere, an oven-dried resealable Schlenk tube equipped with a magnetic stir bar was charged with Cu(OAc)2 (3.6 mg, 0.02 mmol, 10 mol%), L*6 (15.4 mg, 0.03 mmol, 15 mol%), Cs2CO3 (195.5 mg, 0.6 mmol, 3.0 equiv.) and anhydrous CH2Cl2 (2.0 mL). Then, the mixture was stirred at r.t. for 1 h. After that, racemic α-haloamides E (0.2 mmol, 1.0 equiv.), N,N-bis-Boc hydrazine N7 (55.7 mg, 0.24 mmol, 1.2 equiv.) and anhydrous CH2Cl2 (2.0 mL) were sequentially added into the mixture and the reaction mixture was stirred at 10 °C for 48 h. Upon completion (monitored by thin-layer chromatography), the precipitate was filtered off and washed by EtOAc. The filtrate was evaporated and the residue was purified by preparative thin-layer chromatography on silica gel to afford the desired product.

Representative procedure for the synthesis of 27–41
Under an argon atmosphere, an oven-dried resealable Schlenk tube equipped with a magnetic stir bar was charged with Cu(OAc)2 (3.6 mg, 0.02 mmol, 10 mol%), L*9 (10.0 mg, 0.03 mmol, 15 mol%), Cs2CO3 (260.7 mg, 0.8 mmol, 4.0 equiv.) and anhydrous THF (2.0 mL). Then, the mixture was stirred at r.t. for 1 h. After that, racemic α-haloamides E (0.2 mmol, 1.0 equiv.), 1,1-diphenylhydrazine hydrochloride N8 (54.0 mg, 0.24 mmol, 1.2 equiv.) and anhydrous THF (2.0 mL) were sequentially added into the mixture and the reaction mixture was stirred at r.t. for 72 h. Upon completion (monitored by thin-layer chromatography), the precipitate was filtered off and washed by EtOAc. The filtrate was evaporated and the residue was purified by preparative thin-layer chromatography on silica gel to afford the desired product.

Peer review rounds
[{"round": 1, "reviewer_comments": {"reviewer_1": "The authors developed chiral copper(I)-catalyzed enantioselective radical N-alkylation of hydrazines with racemic 2-chlorocaroxamides to give enantioriched hydrazines. The strategy is new, results are excellent, and products are highly useful. Therefore theses results may be acceptable as a paper in Nat. Commun. However the following revisions are requested before further consideration.\n(1) According to the experiments with BHT and TEMPO shown in Fig. 6a, racemic products 43 and 44 were produced together with enantioriched hydrazines 1. Therefore, enantioselective N-alkylation of hydrazines may proceed through SN2 or SN1 pathway via intermediate III. If the authors propose such a mechanism shown in Fig. 6c, “radical N-alkylation” in the title is not suitable. If this is “radical N-alkylation”, products 43 and 45 should also be enantioriched.\n(2) Please show a plausible mechanism about asymmetric induction.\n(3) If any experimental evidence of intermediate III is shown, the proposed mechanism is more reliable.\n(4) Fig. 1b: As examples of the asymmetric nucleophilic addition to hydrazones, refs. 23–29 are cited. The following paper should be added as a more recent example. K. Nishimura, Y. Ogura, K. Takeda, W. Guo, K. Ishihara Org. Lett. 2022, 24, 7685–7689.", "reviewer_2": "The manuscript by Liu, Chen, and co-workers describes an enantioconvergent radical N-alkylation of racemic α-haloamides with hydrazine derivatives. This strategy broadens the synthetic toolbox for accessing enantioenriched chiral hydrazines, with the key to success attributed to the careful choice of a suitable hydrazine nucleophile. The authors further demonstrate the synthetic utility of this method through the enantioselective synthesis of aza-heterocycles as well as the stereodivergent synthesis of N-amino dipeptides. Overall, I recommend publication of this work after the following issues are addressed:\n1) Can this strategy be extended to α-tertiary haloamides?\n2) The substrate scope appears somewhat limited. For instance, it would be informative to examine more sterically hindered substituents at the ortho position of the α-phenyl ring, such as alkyl or aryl groups. In addition, only one example (compound 18) bearing an α-alkyl substituent was investigated, and the obtained 86% ee is a promising result. It would strengthen the work to include additional examples featuring longer or bulkier alkyl groups.\n3) With respect to the scope of hydrazine derivatives, how do N-Et-N-Boc hydrazine or N-iPr-N-Boc hydrazine perform under the reaction conditions?\n4) Since the authors propose a radical–polar crossover process, a Hammett analysis would be highly desirable to support the mechanistic proposal.", "reviewer_3": "Liu and coworkers reported a Cu(I)-catalyzed enantioconvergent radical N-alkylation of N,N-bis-Boc hydrazine with racemic α-haloamides, for the modular synthesis of structurally diverse enantioenriched\nhydrazines with excellent enantioselectivity. Interestingly, this protocol allowed the highly diastereoselective synthesis of enantioenriched N-amino peptides by using α-amino acid-derived α-chloroamides. A remarkable feature of this protocol is the high synthetic value of the products, which can serve as platform molecules for the synthesis of a variety of chiral azacycles. Enough mechanism study is also provided, and the supporting information is organized well. In general, this is a nice work and should be published on Nature Communication.\nThe only issue to be addressed is the diversity of the aliphatic substituents of the product. Only one example 18 is reported by using ligand 10. Can aliphatic substituents other than methyl groups could be integrated in to this method?"}, "author_response": "Point-by-Point Responses to the Comments of the Reviewers\nReviewer 1\nComment 1: The authors developed chiral copper(I)-catalyzed enantioselective\nradical N-alkylation of hydrazines with racemic 2-chlorocaroxamides to give\nenantioriched hydrazines. The strategy is new, results are excellent, and products are\nhighly useful. Therefore theses results may be acceptable as a paper in Nat. Commun.\nHowever the following revisions are requested before further consideration.\nOur response: We greatly thank the reviewer for the positive comments on our work.\nWe also thank the reviewer for their reconsideration of its publication in Nat. Commun.\nfollowing appropriate revisions. We have made great efforts in carrying out additional\nstudies to fully address all the concerns of the reviewer. Accordingly, we have carefully\nrevised the manuscript according to the reviewer’s suggestions.\nComment 2: According to the experiments with BHT and TEMPO shown in Fig. 6a,\nracemic products 43 and 44 were produced together with enantioriched hydrazines 1.\nTherefore, enantioselective N-alkylation of hydrazines may proceed through SN2 or\nSN1 pathway via intermediate III. If the authors propose such a mechanism shown in\nFig. 6c, “radical N-alkylation” in the title is not suitable. If this is “radical N-\nalkylation”, products 43 and 45 should also be enantioriched.\nOur response: We greatly thank the reviewer for bringing this issue to our attention.\nWe agree with the reviewer that our current data does not fully support the original title\nand feel very sorry for it. Accordingly, we have rephrased the manuscript title to\n“Copper-catalysed enantioconvergent N-alkylation of hydrazines with racemic α-\nhaloamides to access enantioenriched hydrazines” to describe the strategy more\naccuracy. In addition, we have rephrased the term “radical N-alkylation” with “N-\nalkylation” in many places of the revised manuscript.\nRegarding the radical trapping experiments, we have supplemented the determination\nof enantiomeric excess (e.e.) values for the BHT-trapped product 60 (originally labeled\nas 43) and TEMPO-trapped product S10 (originally labeled as 44). Notably, these\nresults reveal that compound 60 is obtained as a racemic mixture (0% e.e), whereas\ncompound S10 exhibits a moderate e.e. value. To elucidate the origin of this\nstereochemical discrepancy, we have performed in-depth mechanistic analysis\ncombined with relevant literature precedents (e.g., Nat. Commun. 16, 4922 (2025); Nat.\nCommun. 15, 7313 (2024); Nat. Catal. 7, 1372 (2024); Nature 618, 294 (2023).). For\nproduct 60, we propose that the addition of the generated radical II to BHT proceeds\nvia a non-stereoselective radical addition pathway, which accounts for the formation of\nracemic 60 (Fig. 1 in this letter). In contrast, the moderate e.e. value observed for\nproduct S10 can be rationalized by two plausible reaction pathways: (1) a radical-\nradical coupling between the intermediate carbon-centered radical and TEMPO, which\nproceeds without chiral induction; and (2) the outer-sphere nucleophilic attack of the\nTEMPO− species on the CuIII intermediate III—analogous to the stereocontrolled\nformation of enantioenriched hydrazines—thereby further supporting our proposed\nouter-sphere nucleophilic attack mechanism (Fig. 2 in this letter). Collectively, the\ncoexistence of these two pathways explains the moderate e.e. value of product S10.\nAccordingly, we have retained the BHT trapping experiments in the revised manuscript,\nwhile the TEMPO trapping experiments (for which two plausible pathways exist) have\nbeen included in the Supporting Information with corresponding clarifications. Thanks\nagain for your valuable suggestions.\nFig. 1 | A reaction pathway for the formation of 60.\nFig. 2 | A reaction pathway for the formation of S10.\nComment 3:Please show a plausible mechanism about asymmetric induction.\nOur response: We greatly appreciate the reviewer’s constructive comment on\nclarifying the details of asymmetric induction. Building upon the mechanistic\nframework for the key enantiodetermining C(sp3)−N bond formation established in our\nprevious work (Nature 618, 294 (2023)), we propose two transition states (re-TS and\nsi-TS) that correspond to the formation of the two product enantiomers, respectively\n(Fig. 3 in this letter). We identified that the steric clash between the ligand sulfonyl\ngroup and the relatively bulky R1group in si-TS would be expected to render this\ntransition state energetically disfavored. In contrast, the energetically favorable re-TS\nthus favors the formation of the desired products with the S absolute configuration,\nwhich is consistent with the experimental results. Accordingly, this discussion has been\nincorporated into the revised manuscript.\nFig. 3 | Proposed transition states for asymmetric induction.\nComment 4: If any experimental evidence of intermediate III is shown, the proposed\nmechanism is more reliable.\nOur response: We greatly appreciate the reviewer for bringing this issue to our\nattention. The proposed direct outer-sphere attack by hydrazine avoids the\nthermodynamically unfavorable direct deprotonation of hydrazine by mild bases, which\nis likely a key factor contributing to the success of our current N-alkylation reaction.\nFurthermore, the stereocontrolled formation of product 44 provides additional support\nfor our proposed outer-sphere nucleophilic mechanism on the CuIII intermediate III (Fig.\n2 in this letter).\nAs suggested by Reviewer 2, we have also conducted Hammett analysis by using para-\nsubstituted phenylhydrazines with varied electronic properties in conjunction with α-\nhaloamide E1. We found a negative linear relationship between the log(k /k ) and the\nAr Ph\nsubstituent constants σ of the phenylhydrazines (Fig. 4 in this letter). These findings\np\nare consistent with a transition state bearing partial positive charge in the rate-\ndetermining step, which presumably suggest the generation of the key electrophilic\nCuIII intermediate. Accordingly, we have added all these results to the revised\nmanuscript.\nFig. 4 | Elucidating the polarity requirements of the radical–polar crossover\nprocess through the competition Hammett analysis.\nComment 5: Fig. 1b: As examples of the asymmetric nucleophilic addition to\nhydrazones, refs. 23–29 are cited. The following paper should be added as a more\nrecent example. K. Nishimura, Y. Ogura, K. Takeda, W. Guo, K. Ishihara Org. Lett.\n2022, 24, 7685–7689.\nOur response: We greatly appreciate the reviewer’s valuable suggestion. Accordingly,\nthe work of Nishimura and coworkers—representing a prominent precedent for the\ncatalytic asymmetric electrophilic amination of carbonyl compounds with\nazodicarboxylates—has been cited as ref. 37 in the revised manuscript to better\ncontextualize our study.\nReviewer 2\nComment 1: The manuscript by Liu, Chen, and co-workers describes an\nenantioconvergent radical N-alkylation of racemic α-haloamides with hydrazine\nderivatives. This strategy broadens the synthetic toolbox for accessing enantioenriched\nchiral hydrazines, with the key to success attributed to the careful choice of a suitable\nhydrazine nucleophile. The authors further demonstrate the synthetic utility of this\nmethod through the enantioselective synthesis of aza-heterocycles as well as the\nstereodivergent synthesis of N-amino dipeptides. Overall, I recommend publication of\nthis work after the following issues are addressed:\nOur response: We greatly thank the reviewer very much for the positive comments on\nour work and the recommendation for the publication of this work after appropriate\nrevisions. We have spared no efforts in carrying out additional studies to fully address\nall the concerns of the reviewer. Accordingly, we have carefully revised the manuscript\nas suggested by the reviewer.\nComment 2:Can this strategy be extended to α-tertiary haloamides?\nOur response: We greatly appreciate the reviewer’s valuable suggestion regarding the\nextension of this strategy to α-tertiary haloamides. Accordingly, we have first\ninvestigated the enantioconvergent N-alkylation of N,N-bis-Boc hydrazine N7 with\nracemic α-tertiary haloamide E50 using our previously reported anionic N,N,N-ligands\n(L*11–L*14) (Fig. 5 in this letter). These initial trials afforded the desired product S1\nin low to moderate yields and low enantiomeric excess (e.e.). To further optimize the\noutcome, we evaluated the enantioconvergent N-alkylation of N7 with racemic α-\ntertiary haloamide E51 under the same ligand screening conditions. For ligands L*13\nand L*14, modest improvements in both yield and e.e. were observed, though these\nresults remained unsatisfactory. In a further effort to address this challenge, we explored\nthe enantioconvergent N-alkylation of N,N-bis-Ph hydrazine N8 with racemic α-tertiary\nhaloamide E50 and E51 using ligands L*11–L*14 (Fig. 5). These reactions afforded\nmoderate yields but persistently low e.e. values, presumably arising from the strong\nnucleophilicity of N8, which promotes non-selective background reactions. We are\nactively continuing to explore this promising direction and anticipate reporting our\nprogress in due course.\nFig. 5 | Reaction optimization. Reaction conditions: racemic E (0.05 mmol), N (1.2\nequiv.), CuI (10 mol%), L* (15 mol%), and K PO (3.0 equiv.) in THF (1.0 mL) at r.t.\n3 4\nfor 72 h under argon. Yields were based on 1H NMR analysis of the crude product using\n1,3,5-trimethoxybenzene as an internal standard; e.e. values were based on chiral HPLC\nanalysis. aHydrazine hydrochloride N8 (0.05 mmol) and K PO (4.0 equiv.).\n3 4\nComment 3:The substrate scope appears somewhat limited. For instance, it would be\ninformative to examine more sterically hindered substituents at the ortho position of the\nα-phenyl ring, such as alkyl or aryl groups. In addition, only one example (compound\n18) bearing an α-alkyl substituent was investigated, and the obtained 86% ee is a\npromising result. It would strengthen the work to include additional examples featuring\nlonger or bulkier alkyl groups.\nOur response: We greatly appreciate the reviewer’s valuable and constructive\nsuggestion. As recommended, we have evaluated two new α-aryl haloamides bearing\northo-substituted aryl moieties. The less sterically hindered ortho-methyl-substituted\nα-aryl haloamide (E11) was well tolerated, affording product 11 in moderate yield and\nexcellent enantioselectivity. In contrast, the bulkier ortho-phenyl-substituted α-aryl\nhaloamide (E15) delivered the corresponding product 15 in low yield, along with\nsignificantly diminished enantioselectivity (Fig. 6 in this letter). Accordingly, we have\nadded these results in the revised manuscript. We have also incorporated the following\ncomment to address this observation: “Notably, the reaction was sensitive to the steric\neffect at the ortho-position of the aromatic ring. While the less sterically hindered ortho-\nfluoro and ortho-methyl substituents (4 and 11) were well tolerated, the bulkier ortho-\nphenyl substituent (15) was incompatible with the reaction conditions.”.\nFig. 6 | Substrate scope of α-aryl haloamides bearing ortho-substituted aryl\nmoieties. Standard reaction conditions: racemic E (0.20 mmol), N7 (1.2 equiv.),\nCu(OAc) (10 mol%), L*6 (15 mol%), and Cs CO (3.0 equiv.) in CH Cl (4.0 mL) at\n2 2 3 2 2\n10 ℃ for 48 h under argon. Isolated yields were shown; e.e. values were based on chiral\nHPLC analysis.\nRegarding the scope of α-alkyl haloamides, we try great efforts and have accomplished\nthe enantioconvergent N-alkylation of α-alkyl haloamides with 1,1-diphenylhydrazine\nN8 during the revision of the manuscript (Fig. 7, Table 1 and Fig. 8 in this letter).\nAccordingly, we have added all these results to the revised manuscript. We have also\nincorporated the following comment to address this observation: “To further enhance\nthe synthetic utility of this method, we investigated the enantioconvergent N-alkylation\nof α-alkyl haloamides. Unfortunately, N,N-bis-Boc hydrazine N7 showed low reactivity\nin the N-alkylation of α-ethyl haloamide E27, affording the desired product in only 5%\nyield (Supplementary Table 4). This result highlights the critical impact of hydrazine\nderivatives in reaction efficiency. To address this limitation, we further modified\nhydrazine derivatives and reoptimized the reaction conditions (Supplementary Tables\n4–5 for condition optimizations). Gratifyingly, the combination of 1,1-\ndiphenylhydrazine N8 with ligand L*9 afforded the optimal reactivity and\nenantioselectivity, delivering product 27 in 62% yield and 87% e.e. Regarding the scope\nof α-alkyl haloamides (Fig. 4), a wide range of substrates bearing simple\nunfunctionalized aliphatic chains, as well as those functionalized with phenyl, ether,\nthioether, trifluoromethyl, ester, alkenyl, and imidyl groups, afforded products 27−41\nin 51−71% yields and 79−93% e.e. Notably, sterically hindered isobutyl or isopropyl\ngroups did not significantly diminish the reaction efficiency or enantioselectivity, and\nproducts 31–32 were obtained with comparable results.”.\nO O\nBr NHPh + N\nNH2 Cu(OAc)2(10 mol%), L*6(15 mol%)\nN\nH\nN NHPh\nCs2CO3( 3.0 equiv.), CH2Cl2, r.t.\nEt Et\nRacemic E27 N 27a 27c, 27\nEffect of hydrazine derivatives\nBoc\nN\nNH2 Boc\nN\nNH2 Me\nN\nNH2 Ph\nN\nNH2\nBoc Ph Ph Ph\nN7 N11 N12 N8\n27a, 5%, n.d. e.e. 27b, 15%, 12% e.e. 27c, 47%, 54% e.e. 27, 70%, 81% e.e.a\nEffect of different ligands\nOMe Ph NMe2 NMe2\nN O\nPh NH N NH N O S NH O\nNH N O S O S N\nN Ph\nN O S O O\nPh\nO\nL*6,27, 70%, 81% e.e.a L*8,1,27, 85%, 79% e.e.a L*9, 27, 75%, 81% e.e.a L*10, 27, 79%, -40% e.e.a\nFig. 7 | Reaction discovery and optimization. Reaction conditions: racemic E27 (0.05\nmmol), N (1.2 equiv.), Cu(OAc) (10 mol%), L* (15 mol%), and Cs CO (3.0 equiv.)\n2 2 3\nin CH Cl (1.0 mL) at r.t. for 72 h under argon. Yields were based on 1H NMR analysis\n2 2\nof the crude product using 1,3,5-trimethoxybenzene as an internal standard; e.e. values\nwere based on chiral HPLC analysis. aHydrazine hydrochloride N8 (0.05 mmol) and\nCs CO (4.0 equiv.).\n2 3\nTable 1 | Reaction condition optimization with racemic 2-bromo-N-phenylbutanamide\nE27 and 1,1-diphenylhydrazine N8: screening of different solvents\nEntry Solvent Yield of 31 (%) E.e. of 31 (%)\n2 2\n3\n8 1,4-Dioxane 63 71\nReaction conditions: racemic E27 (0.05 mmol), hydrazine hydrochloride N8 (0.06 mmol),\nCu(OAc) (10 mol%), L*6 (15 mol%), and Cs CO (4 equiv.) in solvent (1.0 mL) at r.t. for 72\n2 2 3\nh. Yield was based on 1H NMR analysis of the crude product using 1,3,5-trimethoxybenzene as\nan internal standard; e.e. value was based on chiral HPLC analysis.\nFig. 8 | Substrate scope of α-alkyl haloamides. Standard reaction conditions: racemic\nE (0.20 mmol), hydrazine hydrochloride N8 (1.2 equiv.), Cu(OAc) (10 mol%), L*9\n2\n(15 mol%), and Cs CO (4.0 equiv.) in THF (4.0 mL) at r.t. for 72 h under argon.\n2 3\nIsolated yields were shown; e.e. values were based on chiral HPLC analysis.\nComment 4: With respect to the scope of hydrazine derivatives, how do N-Et-N-Boc\nhydrazine or N-iPr-N-Boc hydrazine perform under the reaction conditions?\nOur response: We greatly appreciate the reviewer for this valuable suggestion.\nAccordingly, we have tested the reaction of N-Et-N-Boc hydrazine N9 and N-iPr-N-Boc\nhydrazine N10 with L*5 under the standard conditions (Fig. 9 in this letter). Both\nsubstrates afforded the desired products in moderate yields and good e.e. Given the\nsimilarity of these results, we have added these results in the revised Supporting\nInformation and added the following comment to the revised manuscript: “Similarly,\nother alkyl-substituted N-Boc hydrazines were evaluated, and they exhibited\ncomparable reactivity and stereoselectivity (see Supplementary Fig. 1).”.\nFig. 9 | Substrate scope of hydrazine derivatives. Reaction conditions: racemic E1\n(0.05 mmol), N (1.2 equiv.), CuTc (10 mol%), L*5 (15 mol%), and Cs CO (3.0 equiv.)\n2 3\nin CH Cl (1.0 mL) at r.t. for 48 h under argon. Yields were based on 1H NMR analysis\n2 2\nof the crude product using 1,3,5-trimethoxybenzene as an internal standard; e.e. values\nwere based on chiral HPLC analysis.\nComment 5:Since the authors propose a radical–polar crossover process, a Hammett\nanalysis would be highly desirable to support the mechanistic proposal.\nOur response: We greatly thank the reviewer for this valuable suggestion. To examine\nthe polarity requirements in the C−N bond forming process, we have conducted\nHammett analysis by using para-substituted phenylhydrazines with varied electronic\nproperties in conjunction with α-haloamide E1. We found a negative linear relationship\nbetween the log(k /k ) and the substituent constants σ of the phenylhydrazines (Fig. 4\nAr Ph\nin this letter). These findings are consistent with a transition state bearing partial\npositive charge in the rate-determining step, which presumably suggest the generation\nof the key electrophilic CuIII intermediate. Accordingly, we have added all these results\nto the revised manuscript.\nFig. 4 | Elucidating the polarity requirements of the radical–polar crossover\nprocess through the competition Hammett analysis.\nReviewer 3\nComment 1:Liu and coworkers reported a Cu(I)-catalyzed enantioconvergent radical\nN-alkylation of N,N-bis-Boc hydrazine with racemic α-haloamides, for the modular\nsynthesis of structurally diverse enantioenriched drazines with excellent\nenantioselectivity. Interestingly, this protocol allowed the highly diastereoselective\nsynthesis of enantioenriched N-amino peptides by using α-amino acid-derived α-\nchloroamides. A remarkable feature of this protocol is the high synthetic value of the\nproducts, which can serve as platform molecules for the synthesis of a variety of chiral\nazacycles. Enough mechanism study is also provided, and the supporting information\nis organized well. In general, this is a nice work and should be published on Nature\nCommunication.\nOur response: We greatly appreciate the reviewer for the highly positive comments on\nour manuscript. We also appreciate the reviewer for supporting its publication in Nature\nCommunication after appropriate revisions and the valuable suggestions for further\nrevision. We have spared no efforts in carrying out additional studies to fully address\nall the concerns of the reviewer. Accordingly, we have carefully revised the manuscript\naccording to the reviewer’s suggestion.\nComment 2:The only issue to be addressed is the diversity of the aliphatic substituents\nof the product. Only one example 18 is reported by using ligand 10. Can aliphatic\nsubstituents other than methyl groups could be integrated in to this method?\nOur response: We greatly appreciate the reviewer’s valuable and constructive\nsuggestion. Regarding the scope of α-alkyl haloamides, we try great efforts and have\naccomplished the enantioconvergent N-alkylation of α-alkyl haloamides with 1,1-\ndiphenylhydrazine N8 during the revision of the manuscript (Fig. 7, Table 1 and Fig. 8\nin this letter). Accordingly, we have added all these results to the revised manuscript.\nWe have also incorporated the following comment to address this observation: “To\nfurther enhance the synthetic utility of this method, we investigated the\nenantioconvergent N-alkylation of α-alkyl haloamides. Unfortunately, N,N-bis-Boc\nhydrazine N7 showed low reactivity in the N-alkylation of α-ethyl haloamide E27,\naffording the desired product in only 5% yield (Supplementary Table 4). This result\nhighlights the critical impact of hydrazine derivatives in reaction efficiency. To address\nthis limitation, we further modified hydrazine derivatives and reoptimized the reaction\nconditions (Supplementary Tables 4–5 for condition optimizations). Gratifyingly, the\ncombination of 1,1-diphenylhydrazine N8 with ligand L*9 afforded the optimal\nreactivity and enantioselectivity, delivering product 27 in 62% yield and 87% e.e.\nRegarding the scope of α-alkyl haloamides (Fig. 4), a wide range of substrates bearing\nsimple unfunctionalized aliphatic chains, as well as those functionalized with phenyl,\nether, thioether, trifluoromethyl, ester, alkenyl, and imidyl groups, afforded products\n27−41 in 51−71% yields and 79−93% e.e. Notably, sterically hindered isobutyl or\nisopropyl groups did not significantly diminish the reaction efficiency or\nenantioselectivity, and products 31–32 were obtained with comparable results.”.\nFig. 7| Reaction discovery and optimization. Reaction conditions: racemic E27 (0.05\nmmol), N (1.2 equiv.), Cu(OAc) (10 mol%), L* (15 mol%), and Cs CO (3.0 equiv.)\n2 2 3\nin CH Cl (1.0 mL) at r.t. for 72 h under argon. Yields were based on 1H NMR analysis\n2 2\nof the crude product using 1,3,5-trimethoxybenzene as an internal standard; e.e. values\nwere based on chiral HPLC analysis. aHydrazine hydrochloride N8 (0.05 mmol) and\nCs CO (4.0 equiv.).\n2 3\nTable 1 | Reaction condition optimization with racemic 2-bromo-N-phenylbutanamide\nE27 and 1,1-diphenylhydrazine N8: screening of different solvents\nEntry Solvent Yield of 31 (%) E.e. of 31 (%)\n2 2\n3\n8 1,4-Dioxane 63 71\nReaction conditions: racemic E27 (0.05 mmol), hydrazine hydrochloride N8 (0.06 mmol),\nCu(OAc) (10 mol%), L*6 (15 mol%), and Cs CO (4 equiv.) in solvent (1.0 mL) at r.t. for 72\n2 2 3\nh. Yield was based on 1H NMR analysis of the crude product using 1,3,5-trimethoxybenzene as\nan internal standard; e.e. value was based on chiral HPLC analysis.\nFig. 8 | Substrate scope of α-alkyl haloamides. Standard reaction conditions: racemic\nE (0.20 mmol), hydrazine hydrochloride N8 (1.2 equiv.), Cu(OAc) (10 mol%), L*9\n2\n(15 mol%), and Cs CO (4.0 equiv.) in THF (4.0 mL) at r.t. for 72 h under argon.\n2 3\nIsolated yields were shown; e.e. values were based on chiral HPLC analysis."}, {"round": 2, "reviewer_comments": {"reviewer_1": "This revised manuscript is fine and acceptable without further revision.", "reviewer_2": "The authors have addressed my questions with the manuscript, I recommend this paper for publication.", "reviewer_3": "The authors left no stone unturned to improve the manuscript. They have carefully revised the manuscript according to the comments of all the reviewers, provided subtantial information for the mechanism, and greatly improved the substrate scope. The only concern in my previous reviewing was the scope of the aliphatic substituted alfa-haloamide, and the authors systematically optimized the condition and provided the performance of 15 examples.Therefore, I recommend the publication of this manuscript without reservation."}, "author_response": ""}]

Decision letter