
==== Front
Nat Commun
Nat Commun
Nature Communications
2041-1723
Nature Publishing Group UK London

46890
10.1038/s41467-024-46890-9
Article
Metal free cross-dehydrogenative N-N coupling of primary amides with Lewis basic amines
http://orcid.org/0000-0003-0774-2528
Kathiravan Subban suppan.kathiravan@lnu.se

12
http://orcid.org/0000-0001-7683-2928
Dhillon Prakriti 1
Zhang Tianshu 1
http://orcid.org/0000-0002-0407-6542
Nicholls Ian A. ian.nicholls@lnu.se

1
1 https://ror.org/00j9qag85 grid.8148.5 0000 0001 2174 3522 Bioorganic & Biophysical Chemistry Laboratory, Centre for Biomaterials Chemistry, Department of Chemistry & Biomedical Sciences, Linnaeus University, Kalmar, SE-39182 Sweden
2 grid.423758.f 0000 0004 0570 8737 Attana AB, Greta Arwidssons väg 21, 11419 Stockholm, Sweden
26 3 2024
26 3 2024
2024
15 264313 9 2023
14 3 2024
© The Author(s) 2024
https://creativecommons.org/licenses/by/4.0/ Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
Hydrazides, N-N containing structural motifs, are important due to their presence in a wide variety of biologically significant compounds. While the homo N-N coupling of two NH moieties to form the hydrazide N-N bond is well developed, the cross-dehydrogenative hetero N-N coupling remains very unevolved. Here we present an efficient intermolecular N-N cross-coupling of a series of primary benzamides with broad range of Lewis basic primary and secondary amines using PhI(OAc)2 as both a terminal oxidant and a cross-coupling mediator, without the need for metal catalysts, high temperatures, and inert atmospheres, and with substantial potential for use in the late-stage functionalization of drugs.

While the homo N-N coupling of two NH moieties to form the hydrazide N-N bond is well developed, the crossdehydrogenative hetero N-N coupling remains unevolved. Here the authors present an efficient, PhI(OAc)2-mediated intermolecular N-N cross-coupling of primary benzamides with primary and secondary amines.

Subject terms

Synthetic chemistry methodology
Catalyst synthesis
Synthetic chemistry methodology
https://doi.org/10.13039/501100004359 Vetenskapsrådet (Swedish Research Council) 2014-4573 2023-03406 Nicholls Ian A. issue-copyright-statement© Springer Nature Limited 2024
==== Body
pmcIntroduction

Cross-dehydrogenative coupling (CDC) is a powerful tool for organic synthesis that involves the direct coupling of two C-H/N-H/S-H etc. bonds to form a C-C/N-N/S-S bond, without the need for pre-functionalization of either substrate1–17. This reaction has emerged as an important tool in organic synthesis due to its simplicity, efficiency, and environmental sustainability derived from its high atom and step economies. CDC reactions have been exploited in the synthesis of a wide variety of biologically active heterocyclic compounds18. including complex natural products, pharmaceuticals, and agrochemicals19,20. While the direct cross coupling of two C-H bonds under oxidative conditions has been extensively researched21–27 the cross coupling of two N-H bonds has received little attention with only a limited number of examples developed to date.

Functionalized hydrazides are nitrogen-nitrogen (N-N) bond containing molecules, which are important intermediates used in the synthesis of many natural products and pharmaceuticals, and have found important applications in materials chemistry (Fig. 1)28–35. The functionalization of hydrazine or diazo compounds is currently the most prevalent approach for the synthesis of hydrazides36, though reaction selectivity is limited by competing NH-bonds. Accordingly, a method for direct cross-coupling would be most desirable, as this could simplify synthetic routes to this class of compound37–43. Moreover, the possibility for hetero-coupling is particularly attractive due to the broader scope of products that can be made accessible. Examples of direct N-N coupling are very scarce and remain challenging due to the high electronegativity of the nitrogen, thus a method for direct nucleophilic substitution of N-H functional groups would be highly valuable. While a few reports of metal-catalyzed homo-coupling have been made44,45, only one example of an intermolecular hetero cross-coupling has appeared, using nickel catalysis46. Recently electrochemical methods for the formation of N-N bond through the generation of carbazolium radical ions were presented as an attractive sustainable method, but their synthetic applicability is limited to carbazoles and β-carbolines29,47,48. The other example of hydrazide synthesis is the elegant nitrene-mediated intermolecular N-N coupling of dioxazolones and arylamines under iridium or iron catalysis, as reported by Chang and Chen (Fig. 1b)49. Transition metal-catalyzed cross-dehydrogenative coupling for homo or hetero N-N bond formation has begun to evolve over the past decade. For example, Stahl and co-workers developed a copper-catalyzed aerobic oxidative N-N coupling of carbazoles and diarylamines to yield the corresponding N-N coupled bicarbazoles and tetraarylhydrazines (Fig. 1c)44,45. Recently, the transition metal-free dehydrogenative N-N coupling of secondary amines and amides has been reported50–55. In contrast to the cross-dehydrogenative coupling of secondary amines or amides, that generally leads to homo coupling, the hetero intermolecular N-N cross-coupling of simple primary benzamides and Lewis basic primary and secondary amines is significantly more challenging, with only a single recent report of a nickel catalyzed reaction for the N-N coupling of secondary benzamides and secondary amines46. The limited number and scope of methods for hydrazine synthesis through cross dehydrogenative N-N coupling and the possibility of performing these reactions in the absence of a transition metal-based reagent, make the development of methodologies highly attractive.Fig. 1 Methods for hydrazide synthesis.

a Biologically important hydrazide molecules: b Iridium or iron catalyzed hydrazide synthesis: c Copper catalyzed N-N bond formation: d This work: Transition metal-free cross-dehydrogenative coupling (CDC) of primary amides with Lewis basic primary and secondary amines including late-stage functionalization of drugs.

Herein, we report a transition metal-free method for the efficient cross-dehydrogenative coupling of readily available benzamide derivatives with a variety of amines (Fig. 1d). The reaction exclusively produced hetero N-N bond formation, with no evidence of homo-coupling products. This straightforward method is amenable to a wide scope of substrates and can be used in the late-stage modification of drug molecules.

Results and discussion

Optimization studies

Initially, we investigated the reaction conditions for synthesizing hydrazides using p-toluamide (1) and morpholine (2) as model substrates (Table 1). By utilizing 2 equivalents of diacetoxyiodobenzene [PhI(OAc)2] as the catalyst, mediator, and terminal oxidant, 2 equivalents of sodium acetate as the base, and 1,2-dichloroethane as the solvent at 80 °C, the desired product was obtained in a yield of 55% (Table 1, entry 1). Notably, no evidence of homo-coupled products was observed under the optimized reaction conditions. Following this successful preliminary assessment of the reaction conditions, we examined the impact of using alternative bases. Using potassium and lithium acetate bases resulted in product yields of 56% and 49%, respectively (Table 1, entry 2–3). The use of other bases led to lower yields (Table 1, entries 5–7). We were pleased to observe that using K3PO4 as the base provided the desired product in a yield of 73% (Table 1, entry 4). Efforts with other solvents, acetonitrile and methanol, produced lower yields, 69% and 12%, respectively (Table 1, entries 8–9). Reaction in the absence of base still yielded the product albeit in 45% yield (Table 1, entry 10). We also evaluated the effectiveness of PhI(OCOCF3)2, another iodinium salt, though found that it failed to afford the product (Table 1, entry 11). Subsequently, we investigated the influence of the p-toluamide (1) – morpholine (2) stoichiometric ratio. A significant amine-dependent reduction in yield was observed when the amide to amine ratio was reduced from 1:2 to 1:1 (Table 1, entries 4, 12–14). While increasing the relative concentration of amine had no significant influence (Table 1, entry 15). This implies that the second equivalent of amine is necessary for neutralizing the acetic acid formed during the reaction.Table 1 Reaction optimization

	
S. No.	Amide/amine	Base	Solvent	Oxidant	Yield (%) (equiv.)	
1	1:2	NaOAc	DCE	PhI(OAc)2	55	
2	1:2	KOAc	DCE	PhI(OAc)2	56	
3	1:2	LiOAc	DCE	PhI(OAc)2	49	
4	1:2	K3PO4	DCE	PhI(OAc)2	73	
5	1:2	K2HPO4	DCE	PhI(OAc)2	46	
6	1:2	K2CO3	DCE	PhI(OAc)2	50	
7	1:2	Cs2CO3	DCE	PhI(OAc)2	70	
8	1:2	K3PO4	ACN	PhI(OAc)2	69	
9	1:2	K3PO4	Methanol	PhI(OAc)2	12	
10	1:2	–	DCE	PhI(OAc)2	45	
11	1:2	K3PO4	DCE	PhI(OCOCF3)2	NR	
12	1:1	K3PO4	DCE	PhI(OAc)2	45	
13	1:1.25	K3PO4	DCE	PhI(OAc)2	56	
14	1:1.75	K3PO4	DCE	PhI(OAc)2	62	
15	1:1.5	K3PO4	DCE	PhI(OAc)2	71	
Reaction conditions: All yields are isolated. 1a (50 mg, 0.37 mmol, 1 equiv.), 2 (0.74 mmol, 2 equiv.), PhI(OAc)2 (2 equiv.), K3PO4 (2 equiv.), in DCE (2 mL) at 80 °C for 18 h under air. (DCE = 1,2-dichloroethane), (PhI(OAc)2 = diacetoxyiodobenzene).

Survey of substrate scope

Having obtained the optimized conditions, we focused on exploring the reaction scope, initially with various benzamides (1a-1m) and morpholine (2) (Fig. 2). A series of ortho, meta and para substituted benzamides were deployed: methyl (1a-d), methoxy (1e), unsubstituted (1f), fluoro (1g-h), chloro (1i-j), and bromo (1k). Among the tested benzamides, the strongly electron withdrawing trifluoromethyl (1 l) group provided the product in 98% yield. Unfortunately, in the case of the para-nitro derivative (1m) no reaction was observed due to the benzamide’s insolubility.Fig. 2 Scope of benzamides with morpholine.

Reaction conditions: All yields are isolated. 1a (0.37 mmol, 1 equiv.), 2 (0.74 mmol, 2 equiv.), PhI(OAc)2 (2 equiv.), K3PO4 (2 equiv.), in DCE (2 mL) at 80 °C for 18 h under air.

We then investigated the use of thiomorpholine (4) in this reaction (Fig. 3), discovering that a broad scope of benzamide substituents were tolerated, with the corresponding products in most cases obtained in good to excellent yield (5a-5t). It is noteworthy that thiomorpholine (4) exhibited considerably higher reactivity than morpholine (2) in the synthesis of the corresponding hydrazides.Fig. 3 Scope of benzamides with thiomorpholine.

Reaction conditions: All yields are isolated. 1a (0.37 mmol, 1 equiv.), 4 (0.74 mmol, 2 equiv.), PhI(OAc)2 (2 equiv.), K3PO4 (2 equiv.), in DCE (2 mL) at 80 °C for 18 h under air.

Scope of aliphatic secondary amines

Subsequently, the scope of secondary amines amenable to the CDC-coupling hydrazide synthesis was explored (Fig. 4). From the results obtained, it is evident that the yields were lower than for the two morpholine derivatives described above and varied significantly depending on the nature of the secondary amine and, importantly, benzamide substituents. While the current direct CDC hydrazide synthesis protocol yielded satisfactory results in most instances, there were exceptions where the yields fell short. In these specific cases, we observed minimal reactivity between the amine and amides, leading to the presence of unreacted amides after the standard reaction time, as indicated by thin layer chromatography analysis. Initially we screened various acyclic dialkyl Lewis basic secondary amines (6a-6e) and found that they are provided the corresponding products (7a-7e) in moderate yields. Notably, product 7e was obtained with an 18% yield, accompanied by the detection of unreacted starting material in the reaction mixture. This outcome prompted us to explore the other benzamide substituents. The better yields obtained using the trifluoromethyl substituent (Figs. 1 and 2) prompted the use of a 3,5-bistrifluoromethyl substituted benzamide (1r), which resulted in a significantly improved yield (7e′, 43%), a trend consistent across reactions performed with other amine substrates employed in the study. Significantly, this approach for the efficient incorporation of trifluoromethyl-substituted amides is envisaged to find applicability in medicinal chemistry. It should be noted that gaseous dimethyl amine (6a) was used as a 40% solution in water, this highlights the suitability of water for use in this reaction system, which was easily applied on in a gram scale reaction. Dicyclohexylamine (6f) gave a higher yield (7f, 60%).Fig. 4 Scope of secondary amines.

Reaction conditions: All yields are isolated. 1a/1r (0.37 mmol, 1 equiv.), 6 (0.74 mmol, 2 equiv.), PhI(OAc)2 (2 equiv.), K3PO4 (2 equiv.), in DCE (2 mL) at 80 °C for 18 h under air.

Since pyrrolidine and piperidine moieties are abundant in bioactive compounds and due to their significant interest in medicinal chemistry, we examined various C2, C3 and C4 substituted derivatives56–58. Interestingly, while 4-methyl substituted benzamide (1a) provided the product 7g in 26% yield, 3,5-bistrifluoromethyl benzamide (1r) gave product 7g′ in 40% yield. In both the reactions we noticed the presence of unreacted starting material, though our efforts to isolate the unreacted starting material yielded only trace amounts of pure starting materials, with the remainder ultimately decomposed. Piperidine derivatives were tolerated, though demonstrated a range of yields, for example, 4-methylpiperidine (6k) was well tolerated (7k, 62%), while 2-methylpiperidine (6i) and 3-methylpiperidine (6j) gave lower yields (7i, 35% and 7j, 23%, respectively). The yields were increased to (7i′) 47% and (7j′) 74% when we used more reactive benzamide (1r). Moreover, the sterically hindered 2,6-dimethyl piperidine (6l) provided the product (7l) in 42% yield. This indicates that an interplay between steric and electronic effects influences the outcome of this CDC-reaction.

Next, we observed that polar functional group (6m-6u) substituted piperidines were generally compatible, as in the cases of fluoro (6m), chloro (6n), hydroxyl (6o & 6p), carbamate (6q), cyano (6r), ketal (6s), and ester (6t & 6u) functionalities, the latter has previously been shown to be problematic in CDC reactions59. Again, enhanced yields were achieved by employing benzamide 1r with fluoro (7m′, 73%), 3-OH (7o′, 27%), NHBoc (7q′, 66%), and 3-COOMe (7t′, 90%) substituted piperidines. Intriguingly, we observed different reactivity patterns among piperidines with similar functional group substitutions, such as 3-OH (6o) and 4-OH (6p), and 3-COOMe (6t) and 4-COOMe (6 u). The meta-substitution resulting in lower yields may suggest that steric factors or interaction with the reactive intermediate in the case of the hydroxyl 6o, can impact on the reaction mechanism. However, in the case of 3-COOMe (6t) substituted piperidine, which failed to yield the product with benzamide 1a, when using benzamide 1r, the product was obtained in a remarkable 90% isolated yield. This finding underscores the pivotal role played by the amide substituent in governing reactivity along with functional group present in piperidine. Phenyl (6v) and benzyl (6w) substituted piperidines gave the products 7v and 7w in moderate yields (46% and 52%).

The 2,6-dimethylmorpholine (6x) moiety has been of significant importance in medicinal chemistry60. This heterocyclic amine has proven a valuable building block and reagent in the synthesis of various pharmaceutical agents and in this reaction, it gave 7x in 42% yield. Other important heterocycles like azepane (6y) and 1,4-oxazepane (6z), which play pivotal roles in medicinal chemistry due to their unique structural and pharmacological properties, were also incorporated in our study61. The strategic incorporation of small heterocycles has emerged as a widely used approach in programs focused on exploring the chemical landscape surrounding lead compounds62–64. In order to explore the use of small heterocycles, we used azetidine (6aa) and 2-oxa-6-azaspiro[3.3]heptane (6bb) a spirocyclic bioisostere of morpholine. Acyclic N-methyl benzyl amine (6cc) was also suitable for this reaction affording the functionally diverse product (7cc), albeit in only 18% yield after isolation. This yield was significantly increased when we used 1r (7cc′, 44%). Finally, the use of a highly functionalized piperidine (6dd) was also successful, demonstrating the use of our hydrazide synthesis for the late-stage modification of a medicinally relevant compound.

Scope of primary amines

As the use of aliphatic primary amines in hydrazide synthesis has not previously been reported, we explored this possibility using this CDC reaction (Fig. 5). The results demonstrate that primary amines with alkyl substituents (propyl amine (8a), isopropyl amine (8b), and butyl amine (8c)) provided the corresponding products (9a-9c) in higher yields (58–68%). Even in the case of the sterically demanding adamantyl amine (8d), which is used to treat dyskinesia65, the expected product (9d) was obtained in a similar isolated yield (48%). However, in the case of 2-phenylethylamine (8e), a much lower yield was observed (50%). In the case of cyclic primary amines (cyclopropyl amine (8f), cyclopentyl amine (8g), cyclohexylamine (8h)) varying yields (9f-9h, 13-44%) were obtained, possibly due to the steric effects associated with their cyclic structures. The yields of cyclopropyl amine (8f) and cyclohexylamine (8h) were enhanced when employing the reaction with benzamide 1r (9f′, 80% & 9h′, 78%). The R-enantiomer of 1-phenylethylamine (8i) behaved similarly, as expected (42%).Fig. 5 Scope of primary amines.

Reaction conditions: All yields are isolated. 1a/1r (0.37 mmol, 1 equiv.), 8 (0.74 mmol, 2 equiv.), PhI(OAc)2 (2 equiv.), K3PO4 (2 equiv.), in 1,2-DCE (2 mL) at 80 °C for 18 h under air.

Collectively, these results demonstrate this hydrazide-forming CDC-reaction’s broad tolerance of benzamides and primary and secondary amine cross-coupling partners makes it a potentially valuable tool for organic synthesis and its applications, e.g., for late-stage functionalization in drug discovery programs, as presented below (Fig. 6).Fig. 6 Late-stage functionalization of pharmaceuticals and drugs.

Reaction conditions: All yields are isolated. 1a/1r (0.37 mmol, 1 equiv.), 10 (0.74 mmol, 2 equiv.), PhI(OAc)2 (2 equiv.), K3PO4 (2 equiv.), in DCE (2 mL) at 80 °C for 18 h under air.

Scope of late-stage functionalization

Functionalization plays a pivotal role in medicinal chemistry, enabling the modification of existing drug scaffolds to create derivatives with enhanced properties66,67. Late-stage functionalization, is an important strategy for introducing functional and structural diversity when exploring chemical space in drug development programs68–72. To demonstrate the potential of hydrazine synthesis using our CDC-reaction in the late-stage functionalization of drugs, we employed a series of drugs as substrates (Fig. 6): Desloratadine (10a, second-generation antihistamine)73, Amoxapine (10b, atypical tricyclic antidepressant)74, Fluoxetine (10c, selective serotonin reuptake inhibitor (SSRI))75, Paroxetine (10d, SSRI)76, Buspirone (10e, anxiolytic agent)77, Troxipide (10f, systemic non-antisecretory gastric cytoprotective agent)78, Perospirone (10g, atypical antipsychotic)79, Donepezil (10h, cholinesterase inhibitor for Alzheimer’s disease)80, Sertraline (10i, SSRI)81, Bupivacaine (10j, anesthetic)82, Memantine (10k, NMDA receptor antagonist for Alzheimer’s disease)83, Leelamine (10l, anticancer agaent candidate)84, and Sitagliptin (10m dipeptidyl peptidase 4 inhibitor for type 2 diabetes)85. In all cases studied, late-stage functionalization using 4-methylbenzamide (1a) and 3,5-bis trifluoromethylbenzamide (1r) under the standardized reaction conditions was achieved, with low to good yields. The pharmacological activities of the late-stage functionalized compounds shall be investigated separately.

Proposed reaction mechanism

Based on the observed reactivity and literature precedence86–96 we proposed a mechanism for this reaction whereby the benzamide initially undergoes oxidative addition by PhI(OAc)2 and to provide the iodinium intermediate 12, with the concomitant loss of acetic acid (confirmed my LC-MS). The requirement of two equivalents of amine in the optimized reaction conditions reflects the necessity to the counter the protonation of amine by acetic acid. Next, the amine coordinates to the iodinium intermediate 12 to form the amide amine iodinium intermediate 13, which on reductive elimination affords the corresponding hydrazide product (Fig. 7).Fig. 7 Proposed mechanism for hydrazide formation.

Primary benzamides react with Lewis basic primary and secondary amines using PhI(OAc)2 as both a terminal oxidant and a cross-coupling mediator.

Mechanistic studies

To elucidate the preferred mechanism for formation of the amido/amino iodane intermediate (13), we conducted experiments using individual reactions with both amide and amine in the presence of PhI(OAc)2 in DCE (Fig. 8). Analysis of the crude reaction mixture using LC-MS for the amide reaction revealed the presence of a trace of homocoupled product, strongly indicative of the formation of the N-(phenylacetoxyiodo)amido species (12) (Fig. 8a and Supplementary Fig. 259). Despite our efforts, attempts to isolate the homocoupled product were unsuccessful. In the context of our study, the heightened reactivity observed with benzamide 1r prompted us to isolate the amido iodane species (13). However, our efforts yielded an unexpected product, N-methyl benzamide (14), suggesting a potential decarboxylation pathway (Fig. 8b). This observation provides additional support for our proposed reaction mechanism. In contrast, the amine reaction displayed no observable iodane formation, again providing support for the proposed pathway (Fig. 8c). Evidence of the formation of acetic acid during the reaction explains the need for two equivalents of amine in the optimized conditions. Collectively, these mechanistic studies reinforce the viability of the proposed simple pathway being the predominant route, which has parallels in previously reported work on metal-free C-N bond formation reactions86,96Fig. 8 Mechanistic studies.

a Homo-coupled product detection; b isolation of N-methyl benzamide (14), suggesting a potential decarboxylation pathway; c attempted amine homo-coupling.

In summary, we have developed a highly innovative and efficient method for the synthesis of hydrazides from primary amides and Lewis basic primary and secondary amines through intermolecular N-N cross-dehydrogenative coupling under mild reaction conditions. This approach can be considered a step-change over existing methodologies due to its several advantages, including: the use of readily available commercially available starting reagents, the elimination of transition metal catalysts, the use of high temperatures, and need for an inert atmosphere. By employing PhI(OAc)2 as a terminal oxidant and cross-coupling mediator, we successfully coupled primary benzamides with Lewis basic primary and secondary amines, though the generation of an iodinium intermediate, providing a sustainable and cost-effective alternative to traditional methods. The broad tolerance of functional groups on both the coupling partners is significant, as is their reaction’s compatibility with water, thus making this reaction a valuable tool for producing a broad range of hydrazides and allowing for the exploration of hydrazide chemical space in medicinal chemistry. The presence of strongly electron withdrawing groups, most notable 3,5-bistrifluoromethyl, can dramatically enhance yields of this versatile reaction. This protocol could be successfully applied to the late-stage modification of a range of important drug structures, highlighting the potential of this method in drug development. Finally, this transition metal-free CDC hydrazine synthesis through dehydrogenative hetero N-N bond formation constitutes a significant development in the synthesis of hydrazide derivative synthesis, and for the use of hydrazine synthesis in important application areas, such as drug development.

Methods

General procedure

Benzamide (1 equiv.), PhI(OAc)2 (2 equiv.), K3PO4 (2 equiv.), and the corresponding amine (2 equiv.) were combined in a 10 mL screw cap reaction tube under ambient conditions. If the amine was in solid form, it was also added at this stage. 1,2-dichloroethane (2 mL) was added and if the amine was a liquid and required dissolution in DCE. The reaction mixture was stirred at 80 °C for 18 h in an oil bath heated by an aluminum block heater. Subsequently, the reaction tube was cooled to room temperature, and silica gel was introduced (3 g). The crude product was then subjected to purification through either column chromatography with initial elution using petroleum ether (40-60) followed by elution with a petroleum ether and acetone (8.5:1.5, 8:2 or 7:3, v/v), or preparative by thin-layer chromatography.

Supplementary information

Supplementary Information

Peer Review File

Supplementary information

The online version contains supplementary material available at 10.1038/s41467-024-46890-9.

Acknowledgements

We thank Linnaeus University, the Swedish Research Council, (2014-4573 and 2023-03406), the Crafoord Foundation (2019-0925 and 2020-0775) and the Helge Ax:son Johnsons Foundation (2019-0318 and 2022-0317) for generous funding.

Author contributions

S.K. conceived the project. S.K. and I.A.N. designed the experiments. P.D. contributed to the characterization and analysis. T.Z. contributed to the reaction optimization studies. S.K. Performed most of the experiments and analysis. All authors contributed to the writing of the manuscript.

Peer review

Peer review information

Nature Communications thanks Jian Jin and the other anonymous reviewer(s) for their contribution to the peer review of this work. A peer review file is available.

Funding

Open access funding provided by Linnaeus University.

Data availability

The authors state that data generated in this study are provided within the article and Supplementary Information files. All data are available from the corresponding author upon request.

Competing interests

The authors declare no competing interests.

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
==== Refs
References

1. Li C-J Cross-Dehydrogenative Coupling (CDC): exploring C-C bond formations beyond functional group transformations Acc. Chem. Res. 2009 42 335 344 10.1021/ar800164n 19220064
2. Huang C-Y Kang H Li J Li C-J En route to intermolecular cross-dehydrogenative coupling reactions J. Org. Chem 2019 84 12705 12721 10.1021/acs.joc.9b01704 31441304
3. Tian T Li Z Li C-J Cross-dehydrogenative coupling: a sustainable reaction for C-C bond formations Green. Chem. 2021 23 6789 6862 10.1039/D1GC01871J
4. Wang H Gao X Lv Z Abdeliah T Lei A Recent advances in oxidative R1-H/R2-H cross coupling with hydrogen evolution via photo-/electrochemistry Chem. Rev. 2019 119 6769 6787 10.1021/acs.chemrev.9b00045 31074264
5. Röckl JL Pollok D Franke R Waldvogel SR A decade of electrochemical dehydrogenative C-C coupling of aryls Acc. Chem. Res. 2020 53 45 61 10.1021/acs.accounts.9b00511 31850730
6. Matcha K Antonchick AP Metal-free cross-dehydrogenative coupling of heterocycles with aldehydes Angew. Chem. Int. Ed. 2013 52 2082 2086 10.1002/anie.201208851
7. Zhu Y Chen T Li S Shimada S Han L-B Efficient Pd-catalysed dehydrogenative coupling of P(O)H with RSH: a precise construction of P(O)-S bonds J. Am. Chem. Soc. 2016 138 5825 5828 10.1021/jacs.6b03112 27128526
8. Au YK Lyu H Quan Y Xie Z Catalytic cascade dehydrogenative cross-coupling of BH/CH and BH/NH: one-pot process to carborano-isoquinolinone J. Am. Chem. Soc. 2019 141 12855 12862 10.1021/jacs.9b06204 31306583
9. Xu P Chen P-Y Xu H-C Scalable photoelectrochemical dehydrogenative cross-coupling of heteroarenes with aliphatic C-H bonds Angew. Chem. Int. Ed. 2020 59 14275 14280 10.1002/anie.202005724
10. Scheuermann, C. J. Beyond traditional cross couplings: The scope of the cross dehydrogenative coupling reactions. Chem. Asian. J. 5, 436–451 (2010).
11. Li, G., Qian, S., Wang, C. & You, J. Palladium(II)-catalysed dehydrogenative cross-coupling between two C-H bonds: Unexpected C=C bond formation. Angew. Chem. Int. Ed. 52, 7837–7840 (2013).
12. Yi H Recent advances in radical C−H activation/radical cross-coupling Chem. Rev. 2017 117 9016 9085 10.1021/acs.chemrev.6b00620 28639787
13. Park Y Kim Y Chang S Transition metal-catalyzed C−H amination: Scope, mechanism, and applications Chem. Rev. 2017 117 9247 9301 10.1021/acs.chemrev.6b00644 28051855
14. Krylov IB Vil’ VA Terent’ev AO Cross- dehydrogenative coupling for the intermolecular C−O bond formation Beilstein J. Org. Chem. 2015 11 92 146 10.3762/bjoc.11.13 25670997
15. Ke J Copper-catalyzed radical/radical C(sp3)-H/P-H cross-coupling: α-Phosphorylation of aryl ketone O-acetyloximes Angew. Chem., Int. Ed. 2015 54 6604 6607 10.1002/anie.201501287
16. Huang P Wang P Tang S Fu Z Lei A Electro- oxidative S-H/S-H cross-coupling with hydrogen evolution: facile access to unsymmetrical disulfides Angew. Chem. Int. Ed 2018 57 8115 8119 10.1002/anie.201803464
17. Qiu X Yang X Zhang Y Song S Jiao N Efficient and practical synthesis of unsymmetrical disulfides via base-catalyzed aerobic oxidative dehydrogenative coupling of thiols Org. Chem. Front. 2019 6 2220 2225 10.1039/C9QO00239A
18. Xu J Construction of tetracyclic 3-spirooxindole through cross-dehydrogentaion of pyridinium: applications in facile synthesis of (±)-Corynoxine and (±)-Corynoxine B J. Am. Chem. Soc. 2014 136 17962 17965 10.1021/ja5121343 25496352
19. Wu Z-J Xu H-C Synthesis of C3-fluorinated oxindoles through reagent-free cross-dehydrogenative coupling Angew. Chem. Int. Ed. 2017 56 4734 4738 10.1002/anie.201701329
20. Srimani D Ben-David Y Milstein D Direct synthesis of pyrroles by dehydrogenative coupling of β-aminoalcohols with secondary alcohols catalysed by ruthenium pincer complexes Angew. Chem. Int. Ed. 2013 52 4012 4015 10.1002/anie.201300574
21. Yeung CS Dong VM Catalytic dehydrogenative cross-coupling: Forming carbon-carbon bonds by oxidizing two carbon-hydrogen bonds Chem. Rev. 2011 111 1215 1292 10.1021/cr100280d 21391561
22. Liu C Oxidative coupling between two hydrocarbons. An update of recent C-H functionalizations Chem. Rev 2015 115 12138 12204 10.1021/cr500431s 26558751
23. Li W Cooperative Au/Ag dual-catalysed cross-dehydrogenative biaryl coupling: reaction development and mechanistic insight J. Am. Chem. Soc 2019 141 3187 3197 10.1021/jacs.8b12929 30681846
24. Gensch T Klauck FJR Glorius F Cobalt catalysed C-H thiolation through dehydrogenative cross-coupling Angew. Chem. Int. Ed. 2016 55 11287 11291 10.1002/anie.201605193
25. Dong J Rhodium or ruthenium catalysed oxidative C-H/C-H cross coupling. Direct access to π-conjugated systems Angew. Chem. Int. Ed. 2013 52 580 584 10.1002/anie.201207196
26. Morofuji T Shimizu A Yoshida J-I Metal- and chemical-oxidant-free C-H/C-H cross-coupling of aromatic compounds: the use of radical-cation pools Angew. Chem. Int. Ed 2012 51 7259 7262 10.1002/anie.201202788
27. Zhou Y Yuan J Yang Q Xiao Q Peng Y Directing-group-assisted transition-metal-catalyzed direct intermolecular C−H amidation and amination of arenes ChemCatChem 2016 8 2178 2192 10.1002/cctc.201600079
28. Blair LM Sperry J Natural products containing a nitrogen−nitrogen bond J. Nat. Prod. 2013 76 794 812 10.1021/np400124n 23577871
29. Rosen BR Werner EW O’Brien AG Baran PS Total synthesis of Dixiamycin B by electrochemical oxidation J. Am. Chem. Soc. 2014 136 5571 5574 10.1021/ja5013323 24697810
30. Waldman AJ Ng TL Wang P Balskus EP Heteroatom–heteroatom bond formation in natural product biosynthesis Chem. Rev. 2017 117 5784 5863 10.1021/acs.chemrev.6b00621 28375000
31. Merino E Synthesis of azobenzenes: the coloured pieces of molecular materials Chem. Soc. Rev. 2011 40 3835 3853 10.1039/c0cs00183j 21409258
32. Guo Q Lu Z Recent advances in nitrogen–nitrogen bond formation Synthesis 2017 49 3835 3847 10.1055/s-0036-1588512
33. Little DJ Smith MR Hamann TW Electrolysis of liquid ammonia for hydrogen generation Energy Environ. Sci. 2015 8 2775 2781 10.1039/C5EE01840D
34. Zhou C-H Wang Y Recent researches in triazole compounds as medicinal drugs Curr. Med. Chem. 2012 19 239 280 10.2174/092986712803414213 22320301
35. Hayashi H Hydrazine synthesis by a catalytic oxidation process Catal. Rev.-Sci. Eng. 1990 32 229 277 10.1080/01614949009351352
36. Ragnarsson U Synthetic methodology for alkyl substituted hydrazines Chem. Soc. Rev. 2001 30 205 213 10.1039/b010091a
37. Zhang C Jiao N Copper-catalyzed aerobic oxidative dehydrogenative coupling of anilines leading to aromatic azo compounds using dioxygen as an oxidant Angew. Chem. Int. Ed. 2010 49 6174 6177 10.1002/anie.201001651
38. Fritsche RF Theumer G Kataeva O Knoölker H-J Iron-catalyzed oxidative C−C and N−N coupling of diarylamines and synthesis of spiroacridines Angew. Chem. Int. Ed. 2017 56 549 553 10.1002/anie.201610168
39. Grirrane A Corma A García H Gold-catalyzed synthesis of aromatic azo compounds from anilines and nitroaromatics Science 2008 322 1661 1664 10.1126/science.1166401 19074342
40. Yu D-G Suri M Glorius F RhIII/CuII-cocatalyzed synthesis of 1H-indazoles through C–H amidation and N–N bond formation J. Am. Chem. Soc. 2013 135 8802 8805 10.1021/ja4033555 23711098
41. Ueda S Nagasawa H Facile synthesis of 1,2,4-triazoles via a copper-catalyzed tandem addition−oxidative cyclization J. Am. Chem. Soc 2009 131 15080 15081 10.1021/ja905056z 19799379
42. Wang F Mild Cu(OAc)2·H2O-catalyzed synthesis of multi-substituted 1,2,4-triazoles from amidines with nitriles via a N–N/C–N coupling RSC Adv. 2015 5 78422 78426 10.1039/C5RA15919A
43. Xu H Jiang Y Fu H Copper-catalyzed synthesis of 1,2,4-triazoles via sequential coupling and aerobic oxidative dehydrogenation of amidines Synlett 2013 24 125 129
44. Ryan M Martinelli JR Stahl SS Cu-catalyzed aerobic oxidative N–N coupling of carbazoles and diarylamines including selective cross-coupling J. Am. Chem. Soc 2018 140 9074 9077 10.1021/jacs.8b05245 29989813
45. Ryan MC Mechanistic insights into copper- catalyzed aerobic oxidative coupling of N−N bonds Chem. Sci. 2020 11 1170 1175 10.1039/C9SC04305E
46. Barbor JP Development of a nickel-catalyzed N–N coupling for the synthesis of hydrazides J. Am. Chem. Soc. 2023 145 15071 15077 10.1021/jacs.3c04834 37413695
47. Yan M Kawamata Y Baran PS Synthetic organic electrochemical methods since 2000: on the verge of a renaissance Chem. Rev. 2017 117 13230 13319 10.1021/acs.chemrev.7b00397 28991454
48. Yan M Kawamata Y Baran PS Synthetic organic electrochemistry: Calling all engineers Angew. Chem. Int. Ed. 2018 57 4149 4155 10.1002/anie.201707584
49. Wang H Nitrene-mediated intermolecular N–N coupling for efficient synthesis of hydrazides Nat. Chem. 2021 13 378 385 10.1038/s41557-021-00650-0 33753917
50. Vemuri PY Patureau FW Cross-dehydrogenative N−N coupling of aromatic and aliphatic methoxyamides with benzotriazoles Org. Lett. 2021 23 3902 3907 10.1021/acs.orglett.1c01034 33974802
51. Yin D Jin J Transition-metal-free dehydrogenative N−N coupling of secondary amines with KI/KIO4 Eur. J. Org. Chem. 2019 2019 5646 5649 10.1002/ejoc.201900763
52. Park SW IBX-mediated synthesis of indazolone via oxidative N−N bond formation and unexpected formation of quinazolin-4-one: in situ generation of formaldehyde from dimethoxyethane Arch. Pharm. Res. 2016 39 302 309 10.1007/s12272-016-0706-z 26780246
53. Monir K Ghosh M Mishra S Majee A Hajra A Phenyliodine(III) diacetate (PIDA) mediated synthesis of aromatic azo compounds through oxidative dehydrogenative coupling of anilines: Scope and mechanism Eur. J. Org. Chem. 2014 2014 1096 1102 10.1002/ejoc.201301209
54. Sajiki H Hattori K Sako M Hirota KA New synthesis of pyrazolo[3,4- d]pyrimidine-4,6(5H,7H)-diones by oxidative N-N bond formation of 6-Amino-5-(N-aryliminomethyl)uracils using iodobenzene diacetate Synlett 1997 12 1409 1410 10.1055/s-1997-1073
55. Correa A Tellitu I Dominguez E SanMartin R Novel alternative for the N−N bond formation through a PIFA-mediated oxidative cyclization and its application to the synthesis of indazol-3-ones J. Org. Chem. 2006 71 3501 3505 10.1021/jo060070+ 16626131
56. Blakemore DC Organic synthesis provides opportunities to transform drug discovery Nat. Chem. 2018 10 383 394 10.1038/s41557-018-0021-z 29568051
57. Vitaku E Smith DT Njardarson JT Analysis of the structural diversity, substitution patterns, and frequency of nitrogen heterocycles among U.S. FDA approved pharmaceuticals J. Med. Chem. 2014 57 10257 10274 10.1021/jm501100b 25255204
58. Roughley SD Jordan AM The medicinal chemist’s toolbox: An analysis of reactions used in the pursuit of drug candidates J. Med. Chem. 2011 54 3451 3479 10.1021/jm200187y 21504168
59. Ruiz-Castillo R Buchwald SL Applications of palladium-catalyzed C−N cross-coupling reactions Chem. Rev. 2016 116 12564 12649 10.1021/acs.chemrev.6b00512 27689804
60. Brullo C Design, synthesis, biological evaluation and structural characterization of novel GEBR library PDE4D inhibitors Eur. J. Med. Chem. 2021 223 113638 10.1016/j.ejmech.2021.113638 34171658
61. Zha G-F Rakesh KP Manukumar HM Shantharam CS Long L Pharmaceutical significance of azepane based motifs for drug discovery: a critical review Eur. J. Med. Chem. 2019 162 465 494 10.1016/j.ejmech.2018.11.031 30469042
62. Carreira EM Fessard TC Four-membered ring-containing spirocycles: synthetic strategies and opportunities Chem. Rev. 2014 114 8257 8322 10.1021/cr500127b 25003801
63. Willcox D A general catalytic β-C–H carbonylation of aliphatic amines to β-lactams Science 2016 354 851 857 10.1126/science.aaf9621 27856900
64. Ruffoni A Practical and regioselective amination of arenes using alkyl amines Nat. Chem. 2019 11 426 423 10.1038/s41557-019-0254-5 31011173
65. Caroff SN Jain R Morley JF Revisiting amantadine as a treatment for drug-induced movement disorders Ann. Clin. Psychiatry 2020 32 198 208 32722730
66. Guillemard L Kaplaneris N Ackermann L Johansson M Late-stage C–H functionalization offers new opportunities in drug discovery Nat. Rev. Chem. 2021 5 522 545 10.1038/s41570-021-00300-6 37117588
67. Sharma A Hartwig JF Metal-catalysed azidation of tertiary C–H bonds suitable for late-stage functionalization Nature 2015 517 600 604 10.1038/nature14127 25631448
68. Bellotti P Huang H-M Faber T Glorius F Photocatalytic late-stage C-H functionalization Chem. Rev. 2023 123 4237 4352 10.1021/acs.chemrev.2c00478 36692361
69. Lasso JD Durbis JC-P Li C-J Green chemistry meets medicinal chemistry: a perspective on modern metal-free late-stage functionalization reactions Chem. Soc. Rev. 2021 50 10955 10982 10.1039/D1CS00380A 34382989
70. Zhang L Ritter T A perspective on late-stage aromatic C-H bond functionalization J. Am. Chem. Soc. 2022 144 2399 2414 10.1021/jacs.1c10783 35084173
71. White MC Zhao J Aliphatic C-H oxidations for late-stage functionalization J. Am. Chem. Soc. 2018 140 13988 14009 10.1021/jacs.8b05195 30185033
72. Bai Z Late-stage functionalization and diversification of peptides by internal thiazole-enabled palladium catalysed C(sp3)-H arylation ACS Catal. 2021 11 15125 15134 10.1021/acscatal.1c05030
73. Murdoch D Goa KL Keam SJ Desloratadine: an update of its efficacy in the management of allergic disorders Drugs 2003 63 2051 2077 10.2165/00003495-200363190-00010 12962522
74. Kinney JL Evans RL Evaluation of amoxapine Clin. Pharm. 1982 1 417 424 6764165
75. Liu B The selective serotonin reuptake inhibitor fluoxetine has direct effects on beta cells, promoting insulin secretion and increasing beta‐cell mass Diabetes Obes. Metab. 2022 24 2038 2050 10.1111/dom.14791 35676820
76. Navels RM Gontkovsky ST Williams BE Paroxetine-The antidepressant from hell? Probably not, but caution required Psychopharmacol. Bull. 2016 46 77 104 27738376
77. Jann MW Buspirone: an update on a unique anxiolytic agent Pharmaotherapy 1988 8 100 116 10.1002/j.1875-9114.1988.tb03543.x
78. Dewan, B. & Balasubramanian, A. Troxipide in the management of grastritis: a randomized comparative trial in general practice. Gastroenterol. Res. Pract. 2010, 758397 (2010).
79. Yoshino T Nisijima K Shioda K Yui K Katoh S Perospirone, a novel atypical antipsychotic drug, potentiates fluoxetine-induced increases in dopamine levels via multireceptor actions in the rat medical prefrontal cortex Neurosci. Lett. 2004 364 16 21 10.1016/j.neulet.2004.03.079 15193747
80. Grossberg GT Cholinesterase inhibitors for the treatment of Alzheimer’s disease Curr. Ther. Res. Clin. Exp. 2003 64 216 235 10.1016/S0011-393X(03)00059-6 24944370
81. Sheehan DV Kamijima K An evidence based review of the clinical use of sertraline in mood and anxiety disorders Int. Clin. Psychopharmacol. 2009 24 43 60 10.1097/YIC.0b013e3282f4b616 21456103
82. Ma T-TD Liposomal bupivacaine versus traditional bupivacaine for pain control after total hip arthroplasty Medicine 2017 95 e7190 10.1097/MD.0000000000007190
83. Danysz, W. & Parsons, C. G. The NMDA recptor antagonist memantine as a symptomatological and neroprotective treatment for Alzheimer’s disease: preclinical evidence. Int. J. Geriatr. Psychiatry 18, S23-S32 (2003).
84. Gowda R Madhunapantula SV Kuzu OF Sharma A Roberson GP Targeting multiple key signaling pathways in melanoma using Leelamine Mol. Cancer. Ther. 2014 13 1679 1689 10.1158/1535-7163.MCT-13-0867 24688050
85. Karasik A Aschner P Katzeff H Davies MJ Stein PP Sitagliptin, a DPP-4 inhibitor for the treatment of patients with type 2 diabetes: a review of recent clinical trials Curr. Med. Res. Opin. 2008 24 489 496 10.1185/030079908X261069 18182122
86. Kantak AK Potavathri S Barhan RA Romano KM DeBoef B Metal-free intermolecular oxidative C-N bond formation via tandem C-H and N-H bond functionalization J. Am. Chem. Soc. 2011 133 19960 19965 10.1021/ja2087085 22010982
87. Lubriks D Sokolovs I Suna E Indirect C−H azidation of heterocycles via copper-catalyzed regioselective fragmentation of unsymmetrical λ3-iodanes J. Am. Chem. Soc. 2012 134 15436 15442 10.1021/ja305574k 22913396
88. Chan J Baucom KD Murry JA Rh(II)-catalyzed intermolecular oxidative sulfamidation of aldehydes: a mild efficient synthesis of N-sulfonylcarboxamides J. Am. Chem. Soc. 2007 129 14106 14107 10.1021/ja073872a 17967011
89. Souto JA Becker P Iglesias A Muniz K Metal-free iodine(III)-promoted direct intermolecular C−H amination reactions of acetylenes J. Am. Chem. Soc. 2012 134 15505 15511 10.1021/ja306211q 22909000
90. Sokolovs I Lubriks D Suna E Copper-catalyzed intermolecular C−H amination of (Hetero)arenes via transient unsymmetrical λ3-iodanes J. Am. Chem. Soc. 2014 136 6920 6928 10.1021/ja502174d 24739120
91. Purkait N Kervefors G Linde E Olofsson B Regiospecific N-arylation of aliphatic amines under mild and metal- free reaction conditions Angew. Chem. Int. Ed. 2018 57 11427 11431 10.1002/anie.201807001
92. Antonchick AP Samanta R Kulikov K Lagegahn J Organocatalytic, oxidative, intramolecular C-H bond amination and metal-free cross-amination of unactivated arenes at ambient temperature Angew. Chem. Int. Ed. 2011 50 8605 8608 10.1002/anie.201102984
93. Kiyokawa K Okumatsu D Minakata S Synthesis of hypervalent iodine(III) reagents containing a transferable (Diarylmethylene)amino group and their use in the oxidative amination of silyl ketene acetals Angew. Chem. Int. Ed. 2019 58 8907 8911 10.1002/anie.201904971
94. Souto JA Martinez C Velilla I Muniz K Defined hypervalent iodine(III) reagents incorporating transferable nitrogen groups: Nucleophilic amination through electrophilic activation Angew. Chem. Int. Ed. 2013 52 1324 1328 10.1002/anie.201206420
95. Allouche EMD Grinhagena E Waser J Hypervalent iodine-mediated late-stage peptide and protein functionalization Angew. Chem. Int. Ed. 2022 61 e202112287 10.1002/anie.202112287
96. Kim HJ Kim J Cho SH Chang S Intermolecular oxidative C-N bond formation under metal-free conditions: control of chemoselectivity between aryl sp2 and benzylic sp3 C-H bond imidation J. Am. Chem. Soc. 2011 133 16382 16385 10.1021/ja207296y 21928852
