Practical and regioselective amination of arenes using alkyl amines


The formation of carbon–nitrogen bonds for the preparation of aromatic amines is among the top five reactions carried out globally for the production of high-value materials, ranging from from bulk chemicals to pharmaceuticals and polymers. As a result of this ubiquity and diversity, methods for their preparation impact the full spectrum of chemical syntheses in academia and industry. In general, these molecules are assembled through the stepwise introduction of a reactivity handle in place of an aromatic C–H bond (that is, a nitro group, halogen or boronic acid) and a subsequent functionalization or cross-coupling. Here we show that aromatic amines can be constructed by direct reaction of arenes and alkyl amines using photocatalysis, without the need for pre-functionalization. The process enables the easy preparation of advanced building blocks, tolerates a broad range of functionalities, and multigram scale can be achieved via a batch-to-flow protocol. The merit of this strategy as a late-stage functionalization platform has been demonstrated by the modification of several drugs, agrochemicals, peptides, chiral catalysts, polymers and organometallic complexes.


Nitrogen-substituted aromatics are ubiquitous structural units in drugs, agrochemicals and organic materials1. Indeed, their preparation accounts for almost 30% of all nitrogen manipulations carried out in the pharmaceutical industry2,3. Traditionally, the introduction of nitrogen functionalities onto aromatics is conducted via nitration, followed by reduction and further multistep manipulation (Fig. 1a). The harsh conditions and low selectivity in the nitration step and the difficulties in the following functionalizations (for example, selective alkylations) have propelled the development of alternative approaches. The Buchwald–Hartwig, Ullmann and Chan–Lam cross-couplings have revolutionized this area and are routinely used in academia and industry4,5,6,7. Despite their versatility, these methodologies are viable only on pre-functionalized aromatics, such as aryl-halides or aryl-organoborons, as they need to undergo oxidative addition or transmetallation with the metal catalyst. While this ensures site-selectivity, the aromatic pre-functionalization requires extra steps and can be problematic. Furthermore, the application of metal-catalysed couplings in the assembly of sp2 C–N bonds on complex and multi-functionalized substrates is sometimes challenging, especially in the context of late-stage drug leads modification8.

Fig. 1: Amination of aromatics.

a, In general, classical approaches for the preparation of anilines require functionalized aromatics like nitro-arenes, aryl halides and aryl organoborons. b, The direct coupling of amines and aromatics is an elusive transformation. Such a method would complement current strategies, especially for the late-stage modification of complex and densely functionalized substrates. c, Outline of a general photoredox strategy for the direct coupling of unfunctionalized amines and aromatics.

Conversely, undirected arene C–H amination represents an attractive, cost-effective and atom-economical strategy for building these essential motifs. As such, considerable efforts have been made in the last few years towards the development of this type of reaction9. This has led to protocols enabling the introduction of specific N-containing fragments like imides10,11, 1,4-diazabicyclo[2.2.2]octane12 and azoles13,14 onto unfunctionalized arenes, frequently through the generation of nitrogen radicals15,16,17. The direct engagement of alkylamines (for example, piperidine) in related reactivities is, however, much more challenging owing to the enhanced instability of their corresponding nitrogen radicals. Indeed, these species are known to undergo very facile radical translocations, resulting in highly stabilized α-N carbon-radicals18. In an effort to overcome these reactivity issues, we have reported a method relying on the multistep preparation of pre-functionalized hydroxylamines as nitrogen-radical precursors19, and Nicewicz has identified conditions for the oxidation and nucleophilic trapping of highly electron-rich aromatics in the presence of primary alkyl amines20. Despite partially addressing some of the issues associated with the fundamental quest for aromatic C–H amination, both methodologies have restricted scope on both the amine/hydroxylamine and the aromatic coupling partners, which limits their application in target synthesis.

As such, a paramount synthetic challenge still stands, as the direct use of alkyl amines in C–H aminations in a general and regioselective manner is beyond what is currently possible (Fig. 1b). This gap in synthetic methodology is remarkable considering the fact that secondary amines are by far the most used class of reagents in medicinal chemistry21 and that 59% of small-molecule pharmaceuticals contain at least one N-heterocycle of which piperidine is the most prevalent22. As a result, a methodology able to selectively introduce amine functionalities onto drug leads in a single chemical step has the potential to bypass lengthy synthetic routes and, more importantly, to provide increased capacity for chemical space exploration around high-value molecules. We present here a photoredox strategy that achieves this goal and enables the direct and high site-selective coupling of alkylamines and aromatics (Fig. 1c). This process represents a general C–H functionalization platform for the fast preparation of aromatic amines and for the efficient generation of chemical diversity.

Results and discussion

Proposed strategy

As part of an overarching goal to develop novel methods for C–N bond formation, we conjectured that simple amines (A) could be doubly activated via in situ generation of a traceless N-electrophore and subsequent protonation (Fig. 2a). We reasoned that N-chlorination (B) by reaction with N-chlorosuccinimide (NCS), followed by the addition of a Brönsted acid would provide the N-chloroammonium (C), which ought to represent such a suitably activated species to directly engage in a redox pathway. For this strategy to be effective the usual reactivity of C has to be bypassed. These species display an amplified electrophilic character at the chlorine atom, making them excellent reagents in electrophilic aromatic chlorination (SEAr) (D)23,24. Thus the success of our proposal hinged on the identification of conditions able to suppress this normal ionic reactivity, diverting the reaction towards a radical process. Previous methods that have sought this transformation require the reactions to be run in concentrated sulfuric acid as the solvent, sometimes under high-energy ultraviolet irradiation with the arene partner in large excess25,26. Furthermore, as N-chloroamines are often unstable and difficult to handle, a synthetically useful method would require their transient generation with no elaboration.

Fig. 2: Development of a photocatalytic strategy for direct aromatic C–H amination.

a, Design plan and mechanistic proposal: the process starts with the in situ conversion of a primary and a secondary amine into an N-chloramine and its subsequent activation by protonation (A → B → C). As protonated N-chloroamines are strong electrophiles in Friedel–Craft reactions with aromatics, central to the success of this strategy is the diversion of their reactivity from ionic to radical. A photoredox cycle enables the redox formation of an aminium radical that undergoes highly polarized addition to an aromatic. The turnover of the photoredox cycle is coupled with the oxidation of the aminated cyclohexadienyl radical. The Brönsted acid has a dual role, activating the N-chloroamine and insulating the aniline from over-amination and photoredox oxidation. b, Development of photocatalytic C–H amination of aromatics using piperidine. The Brönsted acid–solvent combination modulates the reactivity of N-chloropiperidine, enabling the desired redox process. c, Cyclic voltammetry studies show that upon protonation the reduction potential of N-chloropiperidine is shifted towards positive values, which confirms its facile SET reduction. d, Stoichiometric UV–vis absorption studies using Ru(bpy)3Cl2 and protonated N-chloropiperidine demonstrate that SET takes place upon blue light irradiation. p:m, para:meta; p:o, para:ortho.

To address these challenges, our proposal for direct C–H amination was based on a strategy whereby a visible-light-excited photocatalyst (*PC)27 would promote single electron transfer (SET) reduction of in situ generated C to access the aminium radical E18,28. This highly electrophilic species would then undergo regioselective radical addition with the arene to form a stabilized cyclohexadienyl-type radical F. The site selectivity of this step is a mechanistic consequence of a highly polarized radical reaction whereby the natural nucleophilicity of the arene is harnessed to dictate the site of amination29. As such, the outcome of these reactions can be predicted in the same way as classical electrophilic aromatic substitutions. Finally, the low oxidation potential of F would enable SET, with the oxidized photocatalyst closing the photoredox cycle and forming G, which would aromatize by deprotonation to produce the protonated aniline H.

Optimization of photocatalytic amination of arenes and overcoming aromatic electrophilic chlorination

To validate this mechanistic hypothesis, we studied the reactions of piperidine (1) with tert-butylbenzene (2) and anisole (3) to model weakly and strongly electron-rich aromatics in the presence of NCS and the photocatalyst Ru(bpy)3Cl2 in acetonitrile (CH3CN) under irradiation with blue light-emitting diodes (LEDs) (Fig. 2b and Supplementary Tables 14). Using acetic acid (AcOH), neither amination nor chlorination was observed with either arene (entry 1, Fig. 2b). Trifluoroacetic acid (TFA) did not lead to any reactivity with 2 but provided the unwanted chloroanisole 5′ in moderate yield (entry 2). Analogously, while 3 underwent almost quantitative chlorination in the presence of stronger para-toluene sulfonic acid (p-TsOH), 2 did not react (entry 3). Conversely, perchloric acid (HClO4) completely suppressed the unwanted chlorination and produced the desired aminated products 4 and 5 with good-to-moderate para-selectivity (entry 4). Amine 4 was obtained in quantitative yield by switching the solvent to 1,1,1,3,3,3-hexafluoroisopropanol (HFIP)30; however, this led to chlorination of 331. In this solvent, the weaker acid TFA could also be used, albeit in slightly lower yields (entry 6). Overall, these experiments identified HClO4 as the optimum acid and CH3CN or HFIP as the solvent of choice depending on the electron density of the arene partner, CH3CN for highly electron-rich aromatics and HFIP for weakly electron-rich ones. These reactions proved very robust and reproducible and they could be conducted under open air without any erosion in yield. The aromatic partner does not need to be used in excess and equimolar reactions worked well with only a minimum decrease in the reaction yield (Supplementary Table 2).

Mechanistic investigations

To investigate the reaction mechanism we performed cyclic voltammetry (CV) studies to quantify the variation of redox properties of N-chloropiperidine 1-Cl upon protonation (Fig. 2c, Supplementary Fig. 11 and Supplementary Table 7). As the N-chloroammonium salt is expected to be a much stronger σ*-electrophore, this should translate into a more facile photoinduced SET. CV analysis of 1-Cl revealed a profile with Eox = +1.50 V and Ered = −1.80 V (versus saturated calomel electrode, SCE) in CH3CN, which precludes direct reduction from *Ru(ii) (*Eox = −0.81 V)27. On addition of HClO4, a change in the CV spectra was observed, resulting in progressive suppression of the oxidation peak and the appearance of a reduction peak with Ered = +0.43 V. A positive value of Ered means that, upon protonation, 1-Cl becomes a strong σ*-electrophore and should be easily reduced by *Ru(ii). Emission quenching experiments are in line with this observation, showing that the excited state of the photocatalyst is quenched by protonated 1-Cl at nearly the rate of diffusion (Stern–Volmer quenching constant: kq = 1.5 × 109 M s–1), while no effect was observed in the absence of acid (Supplementary Tables 8 and 9 and Supplementary Fig. 10). To rule out a Dexter energy transfer (that is, triplet sensitization) between *Ru(ii) and protonated 1-Cl, we performed UV–vis absorption studies. As shown in Fig. 2d, Ru(bpy)3Cl2 shows a maximum of absorption in the blue region (λ ≈ 450 nm). Addition of 1-Cl and HClO4 did not change this absorption profile when the sample was kept in the dark. However, following 10 s irradiation with blue light-emitting diodes the typical Ru(ii) absorbance disappeared and two bands matching the absorption of Ru(iii)(bpy)3 were observed together with an immediate colour change from orange [Ru(ii)] to green [Ru(iii)] (Supplementary Fig. 11). Overall, these investigations provide evidence for photoinduced SET as the mechanism for the aminium radical generation (Fig. 2a). Quantum yields Φ were determined for the reaction of 1 and 2 in CH3CN and HFIP. The experimental values of Φ(CH3CN) = 0.28 and Φ(HFIP) = 0.93 suggest that short-lived chain propagations might be present but should not be responsible for the overall reaction efficiency (Supplementary Table 10).

Evaluation of aromatic coupling partners and gram-scale reaction in flow

With the optimized protocol for arene amination we evaluated the aromatic scope using piperidine 1 (Table 1). Mono-substituted benzenes provided the para-products in high yields and selectivity (422). The strong preference for para-amination, especially in the case of halobenzenes (1821), is noteworthy as other C–H functionalizations normally provide isomeric mixtures. These results are a clear manifestation of how the polarized addition of highly electrophilic aminium radicals to arenes can efficiently channel the regioselectivity of the reaction and this can be readily rationalized and predicted by considering the Fukui indices for the aromatic coupling partner (Supplementary Fig. 12). Other aromatics with different functionalities were also compatible as demonstrated by the formation of 2339. The ability to tolerate halides and boron/silicon-functionalities shows that this process is fully orthogonal to classical cross-couplings and can enable further C–C, C–N and C–O bond formations to proceed.

Table 1 Aromatic scope for the photocatalytic aromatic C–H amination

Research conducted at AstraZeneca has showcased the feasibility of the method on a large scale. The preparative multigram synthesis of 21 via a batch-to-flow32,33 protocol operates in comparable yield and with a high productivity rate (5.7 g, 67%, in 1.5 h; Supplementary Figs. 28). Experiments monitoring the variation of internal pressure and temperature were conducted; these alleviate some of the concerns around the use of reactive N-chloroamines and HClO4 at scale. Overall, these studies provide promising results for further applications in industrial settings.

The reaction was then demonstrated on a range of substituted naphthalenes (3137) that, owing to their lower ionization potentials, enabled the presence of electron-withdrawing groups. The reaction was also successful on other heteroarenes including methoxylated (iso)quinolines (4044). In this case, the increased aromatic deactivation given by the N atom in the aromatic ring means that quinoline is not suitable with this protocol and represents a limitation of the method (Supplementary Table 6). Nevertheless, electron poor N-heterocycles (for example, pyridine) are compatible with the process and therefore molecules containing these motifs can be selectively aminated at the more electron-rich ring (38). As the amine is installed with para-selectivity, our reaction is orthogonal to established C–H activation strategies that, by harnessing the ability of the directing group, deliver products of ortho-functionalization34,35,36.

Evaluation of amine coupling partners

Next, we explored the amines scope in conjunction with benzene as a model of non-activated aromatics (Table 2). Because piperidine is the most prevalent N-heterocycle in pharmaceuticals2,22, and substituents on this heterocycles are often found at the C4 and C3 positions, we evaluated a broad range of functionalized derivatives. It was quickly discovered that substrates containing unprotected and polar functional groups were compatible (4559). These include free alcohols, esters, azide, alkyl halides, sulfonamides and ketones, which are sometimes troublesome in classical cross-coupling methodologies2,8.

Table 2 Secondary and primary amine scope for the photocatalytic aromatic C–H amination

Other N-heterocycles routinely used in medicinal chemistry programmes are also well tolerated (6071). These include perhydro-(iso)quinolines, pyrrolidines, including 3-azabicyclo[3.1.0]hexane, which is found in many antibiotics (for example, trovafloxacin), (benz)azepines and northropine. As many amines are commercially available as hydrochloride salts, we have adapted our methodology to their direct use in the process.

The introduction of small heterocycles is a popular strategy in medicinal chemistry programmes aimed at the exploration of chemical space around lead compounds2,37,38. As an example, the N-aryl-azetidine motif is found in more than 3,000 biologically active compounds including several commercially available drugs (for example, delafloxacin, an antibiotic used in the treatment of acute skin infections) according to the PubChem database. Despite this prominence, there are no reported examples of aromatic C–H functionalization with four-membered amines. We were pleased to see that our protocol enabled the installation of several azetidines (6971), including a spirocyclic bioisostere of morpholine (71). Acyclic dialkyl and primary amines were also suitable, as demonstrated by the successful formation of 7280, which contain labile functionalities. The formation of 77 and 80 is noteworthy, as efficient access to hindered anilines is important in medicinal chemistry, where it is frequently used to block oxidative metabolic pathways39, but remains challenging using other protocols. Finally, this method also enabled the use of commercial water solutions of gaseous dimethylamine and methylamine (81 and 82). The direct use of these two amines in C–H functionalization is unprecedented despite the fact that dimethyl amino-containing aromatics are one of the largest classes of bioactive anilines. Furthermore, this method gives direct access to products that are typically manufactured by aromatic nitration followed by reduction and selective alkylation at 250 °C over aluminium oxide40.

Application in late-stage functionalization and parallel screening

The identification of novel medicines as well as other high-value products greatly benefits from the ability to directly modify the core structure of natural products or existing lead molecules. Therefore, to demonstrate the potential of this reaction in medicinal chemistry, complex and bioactive molecules were subjected to our protocol (Fig. 3a). Strychnine (a Strychnos alkaloid), fenoprofen (Nalfon, a non-steroidal anti-inflammatory drug), dichlorprop (herbicide used on a tonne scale, worldwide) and ramipril (Altace, a top selling angiotensin converting enzyme inhibitor) display many redox-active and Lewis basic functionalities and underwent functionalization in good yields and selectivity (8388). We also prepared a structural analogue of AC-262536 (selective androgen receptor modulator) (89) and a truncated analogue of donepezil (Aricept, Alzheimer’s disease palliative) (90) from commercially available materials. Furthermore, using commercial building blocks we accessed 91, which can be converted into delamanid (Deltyba, used for treatment of multidrug-resistant tuberculosis) in just one step.

Fig. 3: Late-stage diversification of bioactive molecules via photoredox C–H amination.

a, The late-stage aminations of this series of complex molecules show predictable selectivity and compatibility with several reactive functionalities. b, Application of the amination strategy in microscale parallel screening shows the fast late-stage diversification of a blockbuster drug.

Microscale parallel experimentation is a growing field of research that is currently attracting significant interest across academia and the wider pharmaceutical industry owing to its ability to accelerate drug discovery41,42. To evaluate the feasibility of this process in small parallel screening settings, 24 different secondary and primary amines were reacted with equimolar amounts of the cough suppressant dextromethorphane (Robitussin) using a commercially available 24-well-plate photoredox reactor (Fig. 3b and Supplementary Figs. 9 and 10). All reactions tested provided the desired amination products, with yields higher than 50% in most cases. With this information in hand, we successfully translated three experiments on a higher scale and similar efficiency (9294). Overall, these examples indicate the presented method is a fast and powerful tool for drug discovery, with current development at AstraZeneca directed towards the automation of this reaction in a large high-throughput setting.

Peptides are an important class of biomolecules for which late-stage functionalization is highly desirable (Fig. 4a)43,44,45 and current methods target mostly cysteine, tryptophan, tyrosine and C-terminal residues46,47. Pleasingly, this reaction enables the underdeveloped functionalization of l-phenylalanine (95), which could also be performed on a tetrapeptide (97). As the azide functionality is tolerated, this approach allows the introduction of handles for bio-conjugation and/or stapling strategies (96 and 98).

Fig. 4: Applications of the aromatic C–H amination reaction.

a, Aromatic amination of phenyl alanine residues in the protected amino acid as well as a tetrapetide enables the preparation of unnatural amino acids and also the introduction of functionality handles for chemical ligation. b, Aromatic residues embedded into chiral auxiliary and catalyst scaffolds undergo selective amination. c, Reaction with commercial polystyrene beads leads to high degrees of polymer functionalization. d, The process is used to introduce amine groups onto the cyclometallated ligands of Ru- and Rh-organometallic complexes. The selectivity of the reaction is explained by the enhanced aromatic nucleophilicity at the carbon para to the site of cyclometallation.

The ability to add nitrogen functionality where needed may also prove useful in asymmetric catalysis when tuning the structure of a chiral ligand, because it bypasses the need for de novo ligand synthesis. As shown in Fig. 4b, we successfully performed diamination of 2,2′-dibromo-1,1′-binaphtyl (99 and 100), which is the precursor of Noyori’s BINAP, and modified Evans oxazolidinone (101). The level of functional group compatibility also enabled the modification of MacMillan imidazolidinone (102) and a PyBOX (103) ligand, two of the most used catalysts in asymmetric synthesis, as well as (+)-dihydroquinine (104), which is part of the AD-mix for the Sharpless asymmetric dihydroxylation.

Strategies for the post-polymerization functionalization of C–H bonds are highly sought after48, as they can provide access to high-value materials from inexpensive precursors. Using our methodology we obtained good degrees of functionalization on commercially available polystyrene beads with dimethylamine (Fig. 4c, 105).

Finally, we evaluated the late-stage amination on organometallic complexes and selected [Ru(ppy)(bpy)2](PF6), which has applications in solar energy storage49 (Fig. 4d). Pleasingly, our reaction enabled selective amination of the 2-phenylpyridine ligand in 37% yield (106). This modification improved the complex absorptivity in the visible–near-infrared regions, which is highly desirable for dye-sensitized solar cells (Supplementary Fig. 13). Cyclometallated rhodium complexes have applications as anticancer agents50 and we succeeded in the di-azetidination of [Rh(ppy)2(tbbpy)](PF6) (107). In both cases the amines are selectively installed at the most nucleophilic position para to the C-transition metal σ bond51. These examples pave the way for the development of unprecedented meta aminations of arenes by tandem C–H activation and nitrogen-radical addition.


We have reported the direct and selective coupling of amine and aromatics under photoredox conditions. This transformation has been applied to a range of poly-functionalized and structurally complex building blocks as well as being scaled effectively to multigram scale via batch-to-flow. The ability to tolerate halogen, boron and silicon functionality makes it orthogonal to cross-couplings. The potential in late-stage functionalization has been demonstrated by chemical space exploration around bioactive molecules. The versatility of the method has also been showcased by the direct amination of many high-value materials spanning small peptides, chiral catalysts, polymers and organometallic complexes. The operational ease, broad functional group tolerance and scalability of this reaction make it suitable for adoption in both academic and industrial settings.

Data availability

All data supporting the findings of this study are available within the Supplementary Information. These include reaction procedures, products characterization, the batch-to-flow experiment procedure, the microscale parallel screening procedure, cyclic voltammograms and UV–vis, density functional theory and NMR spectra.


  1. 1.

    Ricci, A. Amino Group Chemistry: From Synthesis to the Life Sciences (Wiley, Hoboken, 2008).

  2. 2.

    Blakemore, D. C. et al. Organic synthesis provides opportunities to transform drug discovery. Nat. Chem. 10, 383–394 (2018).

    CAS  Article  Google Scholar 

  3. 3.

    Roughley, S. D. & Jordan, A. M. The medicinal chemist’s toolbox: an analysis of reactions used in the pursuit of drug candidates. J. Med. Chem. 54, 3451–3479 (2011).

    CAS  Article  Google Scholar 

  4. 4.

    Ruiz-Castillo, P. & Buchwald, S. L. Applications of palladium-catalyzed C−N cross-coupling reactions. Chem. Rev. 116, 12564–12649 (2016).

    CAS  Article  Google Scholar 

  5. 5.

    Hartwig, J. F. Evolution of a fourth generation catalyst for the amination and thioetherification of aryl halides. Acc. Chem. Res. 41, 1534–1544 (2008).

    CAS  Article  Google Scholar 

  6. 6.

    Corcoran, E. B. et al. Aryl amination using ligand-free Ni(ii) salts and photoredox catalysis. Science 353, 279–283 (2016).

    CAS  Article  Google Scholar 

  7. 7.

    Creutz, S. E., Lotito, K. J., Fu, G. C., Peters, J. C. & Ullmann, C. –N. Photoinduced coupling: demonstrating the viability of a radical pathway. Science 338, 647–651 (2012).

    CAS  Article  Google Scholar 

  8. 8.

    Santanilla, A. B. et al. Nanomole-scale high-throughput chemistry for the synthesis of complex molecules. Science 347, 44–49 (2015).

    Article  Google Scholar 

  9. 9.

    Jiao, J., Murakami, K. & Itami, K. Catalytic methods for aromatic C–H amination: an ideal strategy for nitrogen-based functional molecules. ACS Catal. 6, 610–633 (2016).

    CAS  Article  Google Scholar 

  10. 10.

    Allen, L. J., Cabrera, P. J., Lee, M. & Sanford, M. S. N-Acyloxyphthalimides as nitrogen radical precursors in the visible light photocatalyzed room temperature C–H amination of arenes and heteroarenes. J. Am. Chem. Soc. 136, 5607–5610 (2014).

    CAS  Article  Google Scholar 

  11. 11.

    Foo, K., Sella, E., Thomé, I., Eastgate, M. D. & Baran, P. S. A mild, ferrocene-catalyzed C–H imidation of (hetero)arenes. J. Am. Chem. Soc. 136, 5279–5282 (2014).

    CAS  Article  Google Scholar 

  12. 12.

    Boursalian, G. B., Ham, W. S., Mazzotti, A. R. & Ritter, T. Charge-transfer-directed radical substitution enables para-selective C–H functionalization. Nat. Chem. 8, 810–815 (2016).

    CAS  Article  Google Scholar 

  13. 13.

    Romero, N. A., Margrey, K. A., Tay, N. E. & Nicewicz, D. A. Site-selective arene C-H amination via photoredox catalysis. Science 349, 1326–1330 (2015).

    CAS  Article  Google Scholar 

  14. 14.

    Morofuji, T., Shimizu, A. & Yoshida, J. Direct C–N coupling of imidazoles with aromatic and benzylic compounds via electrooxidative C–H functionalization. J. Am. Chem. Soc. 136, 4496–4499 (2014).

    CAS  Article  Google Scholar 

  15. 15.

    Paudyal, M. P. et al. Dirhodium-catalyzed C-H arene amination using hydroxylamines. Science 353, 1144–1147 (2016).

    CAS  Article  Google Scholar 

  16. 16.

    Legnani, L., Cerai, G. P. & Morandi, B. Direct and practical synthesis of primary anilines through iron-catalyzed C−H bond amination. ACS Catal. 6, 8162–8165 (2016).

    CAS  Article  Google Scholar 

  17. 17.

    An, X.-D. & Yu, S. Photoredox-catalyzed C(sp 2)–N coupling reactions. Tetrahedron Lett. 59, 1605 (2018).

    CAS  Article  Google Scholar 

  18. 18.

    Chow, Y. L., Danen, W. C., Nelsen, S. F. & Rosenblatt, D. H. Nonaromatic aminium radicals. Chem. Rev. 78, 243–274 (1978).

    CAS  Article  Google Scholar 

  19. 19.

    Svejstrup, T. D., Ruffoni, A., Julia, F., Aubert, V. M. & Leonori, D. Synthesis of arylamines via aminium radicals. Angew. Chem. Int. Ed. 56, 14948–14952 (2017).

    CAS  Article  Google Scholar 

  20. 20.

    Margrey, K. A., Levens, A. & Nicewicz, D. A. Direct aryl C–H amination with primary amines using organic photoredox catalysis. Angew. Chem. Int. Ed. 56, 15644–15648 (2017).

    CAS  Article  Google Scholar 

  21. 21.

    Goldberg, F. W., Kettle, J. G., Kogej, T., Perry, M. W. D. & Tomkinson, N. P. Designing novel building blocks is an overlooked strategy to improve compound quality. Drug Discov. Today 20, 11–17 (2015).

    Article  Google Scholar 

  22. 22.

    Vitaku, E., Smith, D. T. & Njardarson, J. T. Analysis of the structural diversity, substitution patterns, and frequency of nitrogen heterocycles among U.S. FDA approved pharmaceuticals. J. Med. Chem. 57, 10257–10274 (2014).

    CAS  Article  Google Scholar 

  23. 23.

    Lee, S. J., Terrazas, M. S., Pippel, D. J. & Beak, P. Mechanism of electrophilic chlorination: experimental determination of a geometrical requirement for chlorine transfer by the endocyclic restriction test. J. Am. Chem. Soc. 125, 7307–7312 (2003).

    CAS  Article  Google Scholar 

  24. 24.

    Xiong, X. & Yeung, Y.-Y. Highly ortho-selective chlorination of anilines using a secondary ammonium salt organocatalyst. Angew. Chem. Int. Ed. 55, 16101–16105 (2016).

    CAS  Article  Google Scholar 

  25. 25.

    Minisci, F. Novel applications of free-radical reactions in preparative organic chemistry. Synthesis 1973, 1–24 (1973).

    Article  Google Scholar 

  26. 26.

    Cosgrove, S. C., Plane, J. M. C. & Marsden, S. P. Radical-mediated direct C–H amination of arenes with secondary amines. Chem. Sci. 9, 6647–6652 (2018).

    CAS  Article  Google Scholar 

  27. 27.

    Prier, C. K., Rankic, D. A. & MacMillan, D. W. C. Visible light photoredox catalysis with transition metal complexes: applications in organic synthesis. Chem. Rev. 113, 5322–5363 (2013).

    CAS  Article  Google Scholar 

  28. 28.

    Musacchio, A. J. et al. Catalytic intermolecular hydroaminations of unactivated olefins with secondary alkyl amines. Science 355, 727 (2017).

    CAS  Article  Google Scholar 

  29. 29.

    Citterio, A. et al. Polar effects in fee radical reactions. homlytic aromatic amination by the amino radical cation, •+NH3: reactivity and selectivity. J. Org. Chem. 49, 4479–4482 (1984).

    CAS  Article  Google Scholar 

  30. 30.

    Colomer, I., Chamberlain, A. E. R., Haughey, M. B. & Donohoe, T. J. Hexafluoroisopropanol as a highly versatile solvent. Nat. Rev. Chem. 1, 0088 (2017).

    CAS  Article  Google Scholar 

  31. 31.

    Tang, R.-J., Milcent, T. & Crousse, B. Regioselective halogenation of arenes and heterocycles in hexafluoroisopropanol. J. Org. Chem. 83, 930–938 (2018).

    CAS  Article  Google Scholar 

  32. 32.

    Nguyen, J. D., Reiß, B., Dai, C. & Stephenson, C. R. J. Batch to flow deoxygenation using visible light photoredox catalysis. Chem. Commun. 49, 4352–4354 (2013).

    CAS  Article  Google Scholar 

  33. 33.

    Cambié, D., Bottecchia, C., Straathof, N. J. W., Hessel, V. & Noël, T. Applications of continuous-flow photochemistry in organic synthesis, material science, and water treatment. Chem. Rev. 116, 10276–10341 (2016).

    Article  Google Scholar 

  34. 34.

    Wang, H.-W. et al. Ligand-promoted rhodium(iii)-catalyzed ortho-C−H amination with free amines. Angew. Chem. Int. Ed. 56, 7449–7453 (2017).

    CAS  Article  Google Scholar 

  35. 35.

    Rosane, J. & Daugulis, O. A general method for aminoquinoline-directed, copper-catalyzed sp 2 C–H bond amination. J. Am. Chem. Soc. 138, 4601–4607 (2016).

    Article  Google Scholar 

  36. 36.

    Yoo, E. J., Ma, S., Mei, T.-S., Chan, K. S. L. & Yu, J.-Q. Pd-catalyzed Intermolecular C–H amination with alkylamines. J. Am. Chem. Soc. 133, 7652–7655 (2011).

    CAS  Article  Google Scholar 

  37. 37.

    Carreira, E. M. & Fessard, T. C. Four-membered ring-containing spirocycles: synthetic strategies and opportunities. Chem. Rev. 114, 8257–8322 (2014).

    CAS  Article  Google Scholar 

  38. 38.

    Willcox, D. et al. A general catalytic β-C–H carbonylation of aliphatic amines to β-lactams. Science 354, 851–857 (2016).

    CAS  Article  Google Scholar 

  39. 39.

    Wanka, L., Iqbal, K. & Schreiner, P. R. The lipophilic bullet hits the targets: medicinal chemistry of adamantane derivatives. Chem. Rev. 113, 3516–3604 (2013).

    CAS  Article  Google Scholar 

  40. 40.

    Immel, O. et al. Catalyst for the preparation of aniline. US patent 5,304,525A (1994).

  41. 41.

    Krska, S. W., DiRocco, D. A., Dreher, S. D. & Shevlin, M. The evolution of chemical high-throughput experimentation to address challenging problems in pharmaceutical synthesis. Acc. Chem. Res. 50, 2976–2985 (2017).

    CAS  Article  Google Scholar 

  42. 42.

    Gesmundo, N. J. et al. Nanoscale synthesis and affinity ranking. Nature 557, 228–232 (2018).

    CAS  Article  Google Scholar 

  43. 43.

    Vinogradova, E. V., Zhang, C., Spokoyny, A. M., Pentelute, B. L. & Buchwald, S. L. Organometallic palladium reagents for cysteine bioconjugation. Nature 526, 687–691 (2025).

    Article  Google Scholar 

  44. 44.

    Bloom, S. et al. Decarboxylative alkylation for site-selective bioconjugation of native proteins via oxidation potentials. Nat. Chem. 10, 205–211 (2018).

    CAS  Article  Google Scholar 

  45. 45.

    Osberger, T. J., Rogness, D. C., Kohrt, J. T., Stepan, A. F. & White, M. C. Oxidative diversification of amino acids and peptides by small-molecule iron catalysis. Nature 537, 214–219 (2016).

    CAS  Article  Google Scholar 

  46. 46.

    deGruyter, J. N., Malins, L. R. & Baran, P. S. Residue-specific peptide modification: a chemist’s guide. Biochemistry 56, 3863–3873 (2017).

    CAS  Article  Google Scholar 

  47. 47.

    Boutureira, O. & Bernardes, G. J. L. Advances in chemical protein modification. Chem. Rev. 115, 2174–2195 (2015).

    CAS  Article  Google Scholar 

  48. 48.

    Blasco, E., Sims, M. B., Goldmann, A. S., Sumerlin, B. S. & Barner-Kowollik, C. Polymer functionalization. Macromolecules 50, 5215–5252 (2017).

    CAS  Article  Google Scholar 

  49. 49.

    Bomben, P. G., Robson, K. C. D., Sedach, P. A. & Berlinguette, C. P. On the viability of cyclometalated Ru(ii) complexes for light-harvesting applications. Inorg. Chem. 48, 9631–9643 (2009).

    CAS  Article  Google Scholar 

  50. 50.

    Ma, D. L. et al. Antagonizing STAT3 dimerization with a rhodium(iii) complex. Angew. Chem. Int. Ed. 53, 9178–9182 (2014).

    CAS  Article  Google Scholar 

  51. 51.

    Gagliardo, M. et al. Organic transformations on σ-aryl organometallic complexes. Angew. Chem. Int. Ed. 46, 8558–8573 (2007).

    CAS  Article  Google Scholar 

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The authors thank M. Simonetti and F. Juliá-Hernandez for useful discussions. D.L. thanks EPSRC for a Fellowship (EP/P004997/1) and the European Research Council for a research grant (758427). A.R. thanks the Marie Curie Actions for a Fellowship (703238).

Author information




A.R., F.J. and D.L. designed the project. A.R., F.J., T.D.S. and A.J.M. performed all the synthetic experiments. J.J.D. performed the batch-to-flow optimization and scale-up. All authors analysed the results and wrote the manuscript.

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Correspondence to Daniele Leonori.

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Supplementary Information

Synthetic procedures; products characterization; electrochemical, UV–vis, emission quenching and DFT studies; NMR spectra.

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Ruffoni, A., Juliá, F., Svejstrup, T.D. et al. Practical and regioselective amination of arenes using alkyl amines. Nat. Chem. 11, 426–433 (2019).

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