Radical Sorting as a General Framework for Deaminative C(sp³)–C(sp²) Cross-Coupling

SUMMARY

Radical-based transition-metal-catalyzed cross-couplings are invaluable tools in synthetic medicinal chemistry. Although carboxylic acids are now routinely used as radical precursors, aliphatic primary amines—an equally abundant class of building blocks—are less commonly used in radical coupling. We present a general method for deaminative cross-coupling relying on a dual-catalytic system that generates geminate pairs of non-identical alkyl radicals via photosensitization of unsymmetrical 1,2-dialkyldiazenes, then selectively engages the desired radical species in C(sp³)–C(sp²) bond formation. This Ni-mediated ‘radical sorting’ of geminate radical pairs is key in obtaining high yields and avoiding side products. This approach capitalizes on the versatility of the Sulfur(VI) Fluoride Exchange (SuFEx) click reaction combined with the aza-Ramberg-Bäcklund reaction and enables the functionalization of a broad array of structurally diverse primary amines—including peptide derivatives and synthetic pharmaceutical intermediates. Mechanistic insights from this work open unique avenues for radical-based cross-couplings.

eTOC blurb

A general strategy has been developed to replace C–N bonds with C–C bonds in readily available substrates, including peptide derivatives. This radical cross-coupling strategy relies on unsymmetrical 1,2-dialkyldiazenes as universal radical precursors through dinitrogen extrusion in mild conditions (room temperature, blue light), and a dual iridium/nickel catalytic system.

Graphical Abstract

INTRODUCTION

Transition-metal-catalyzed cross-couplings are among the most widely used disconnections in modern synthetic chemistry, spanning applications from drug discovery to materials science. Within this field, radical-based processes have experienced a resurgence over the past decade, driven by efforts to move away from noble transition metals and toward coupling partners beyond those utilized in the traditional Pd-catalyzed cross-couplings.^1–6 This paradigm shift has challenged the perception that transient alkyl radicals are inherently unsuitable for productive intermolecular bond-forming mechanisms.^7,8 The development of mild and selective methods to generate and harness carbon-centered radicals is crucial for expanding the scope of electrophiles amenable to cross-couplings. A longstanding challenge in scaffold diversification lies in the development of general deaminative cross-coupling methodologies. Despite their abundance, affordability,⁹ and structural diversity as alkyl building blocks (Figure 1A), aliphatic primary amines are rarely employed as radical precursors compared to aliphatic halides^9,10 and carboxylic acid derivatives.^6,11 Notably, amines are ubiquitous across a diverse array of structurally complex biomolecules, including amino acids and peptides, biogenic neurotransmitters and signaling molecules, lipids, and amino sugars, as well as alkaloid secondary metabolites.¹² However, the intrinsic stability of the C–N bond typically necessitates modification of the amine group to facilitate the deaminative formation of the desired C–C bond (Figure 1B).^13–15 Katritzky salts can undergo single-electron transfer to generate alkyl radicals for Ni-catalyzed cross-couplings. While effective for a variety of transformations, this method has drawbacks, including poor atom economy and a substrate scope limited by the steric hindrance of the activating group.^16–22 Rovis recently developed an alternative approach using photoinduced oxidation of 2,4,6-trimethoxyphenylimines to generate alkyl radical exclusively from α−3° primary amines.^23,24 Both methods produce organic byproducts from the activating groups, which can affect yield and purification. Although they demonstrate the potential of C–N activation in radical cross-coupling, neither tap the vast reservoir of alkyl primary amines. During the preparation of the manuscript, an elegant electrochemically mediated C–N bond activation via bistriflimidation of primary amines was reported.²⁵

Figure 1. Overview of deaminative C(sp³)–C(sp²) cross-couplings.

(A) Abundance of aliphatic primary amines compared with common sources of alkyl radicals. (B) C–N bond activation via 1,2-dialkyldiazenes vs. prior art. (C) Universal deaminative cross-coupling through sorting of alkyl radicals arising from photosensitized unsymmetrical 1,2-dialkyldiazenes. Ph, phenyl; OMe, methoxy; Me, methyl; TCCA, trichloroisocyanuric acid; DBU, 1,8-diazabicyclo[5.4.0]undec-7-ene; PC, photocatalyst; Ni, nickel.

Inspired by the storied use of 1,2-dialkyldiazenes, such as AIBN, as radical initiators, we surmised that these intermediates, underutilized as synthetic building blocks, could serve as a general source of alkyl radicals for Ni-mediated cross-coupling upon N₂ expulsion and cage escape. Initial exploration relying on symmetrical 1,2-dialkyldiazenes demonstrated the feasibility of this approach, but it also revealed significant limitations that hinder its broader application.²⁶ While a variety of 2° benzylic diazenes fragmented under mild conditions (blue light, room temperature), unactivated α−1° and α−2° 1,2-dialkyldiazenes with high bond-dissociation energy (BDE) were found unreactive, and radical pair recombination outcompeted the desired cross-coupling pathway when using α−3° diazenes including AIBN (Figure S1). We envisioned that the stepwise photoinduced decomposition^27,28 of a tailored unsymmetrical 1,2-dialkyldiazene might circumvent these issues (Figure 1B). Specifically, a sacrificial 3° alkyl group appended to the diazene motif would provide a weaker linkage for homolytic cleavage (low BDE), which would readily fragment upon excitation leading to a fleeting diazenyl radical. A subsequent homolytic cleavage driven by N₂ expulsion would generate the desired radical precursor, regardless of its BDE. Importantly, the sacrificial group must be carefully designed to promote the desired reaction pathway while preventing the typically prevalent in- and out-of-cage radical recombination,^29–32 and disproportionation, ²⁷ as well as nonselective alkyl radical capture by the Ni catalyst. Successfully identifying reaction conditions to address these anticipated pitfalls and to achieve the desired C–C bond construction would help demonstrate the untapped potential of diazene-type intermediates in cross-coupling, following recently reported platforms including Baran’s sulfonyl hydrazides,³³ Li’s work with hydrazones,^34–36 and Levin’s nitrogen deletion through isomeric isodiazenes.³⁷

RESULTS AND DISCUSSION

The implementation of our strategy is depicted in Figure 1C. Leveraging the mildness and modularity of Sulfur(VI) Fluoride Exchange (SuFEx) click chemistry^38–40 and the aza-Ramberg-Bäcklund reaction (aza-RB)^26,41 provided expedient access to diverse 1,2-dialkyldiazenes 2 containing a cumyl sacrificial group. Bench-stable sulfamoyl fluoride 1 was prepared in multi-gram scale in a single step without column chromatography, and diazenes 2 were readily purified and stored in the dark at –20 °C for extended periods of time⁴² (Figures S14–17, Table S5). Energy transfer (EnT) from a suitable photocatalyst (PC) under blue light would induce diazene fragmentation and lead to the formation of geminate radical pair. We hypothesized that the Ni catalyst would selectively triage various transient alkyl radicals to promote cross-coupling between the desired fragments amid multiple reactive intermediates. The flat and sterically hindered sacrificial cumyl radical being less likely to bind^43,44 would undergo radical recombination affording the non-toxic molecule 5, used as fire retardant, which can be easily removed via column chromatography and does not interfere with the Ni catalysis. The subtle differences in the reactivity of alkyl radicals toward transition-metal catalysts has recently been exploited in decarboxylative cross-couplings,^45–47 which selectively merge 1° and 3° radicals through a process coined ‘radical sorting’ by MacMillan and coworkers.^48,49 Unlike these elegant systems, however, our reaction design does not rely on distinct radical sources that converge through interdependent catalytic cycles. Instead, the light-mediated radical generation is decoupled from the C–C bond-forming event, eliminating the need to precisely match the redox potentials of catalytic intermediates and substrates.

The cumyl moiety was identified as the ideal sacrificial group by evaluating the fragmentation of substrates 6–9 and 2a (see also Figure S3) with Ir-1 (1 mol%)—selected for its high triplet energy⁵⁰—in acetonitrile, a low-viscosity, photochemically inert solvent⁵¹ that facilitates cage escape and radical diffusion⁵² (Figure 2A). While pyran-based diazene 6 and tert-butyl derivative 7 were not efficiently decomposed, trityl diazene 8 was too unstable for practical handling. Gratifyingly, irradiation of cumyldiazene 2a resulted in complete fragmentation consistent with the calculated low BDE of the cumyl–nitrogen bond (Figure S18, Tables S6–S10). While diazene 9 underwent clean fragmentation, the resulting benzyl radical was not discriminated by the Ni catalyst (Figure S2). Following the development of a general deamination strategy, we turned our attention to the development of the Ni catalytic system (Figure 2B). Extensive screening of reaction conditions revealed that a combination of Ir-1 (1 mol%), NiBr₂•(di-OMe-bpy) (Ni-1) (15 mol%), and Zn in a 95:5 mixture of MeCN and DMAc (Table S2) delivered the desired cross-coupling product 4a from diazene 2a and 4-bromoacetophenone (3a) in 88% yield. Notably, undesired side products 10, 11, and 12 were not detected in the optimized conditions; however, homodimer 12 was formed at lower catalyst loading (5 mol%, Table S3). This highlights the importance of efficient radical capture by the Ni catalyst and the role of photosensitization in suppressing in-cage reactivity. The efficient recombination of the cumyl radical⁵³ avoided the formation of α-methylstyrene via disproportionation that could interfere with the Ni catalysis. Other Ir photocatalysts including Ir-2 or Ir-3 resulted in decreased cross-coupling yields (Entries 2 and 3). Using organic dye 4CzIPN afforded 48% of arylated compound 4a while obviating the need for expensive Ir-based photocatalysts (Entry 4 and Table S1). The use of dianionic nickel complexes such as Ni-2 and Ni-3 (Entries 5 and 6) and Mn as reducing agent (Entry 7) were less efficient. A small amount of DMAc was essential for efficient cross-coupling (Entry 8), potentially coordinating key Ni species as seen in related cross-couplings.^54,55 Control experiments revealed that only minimal background decomposition occurred at room temperature in the dark, but neither cross-coupling nor cumyl recombination were detected (Entry 9). Impressively, even after 24 h at 120 °C, 42% of diazene 2a remained alongside only 16% of 4a (Entry 10). In the absence of photocatalyst Ir-1, 4a was not isolated using either blue light or high-energy UV light (300 nm) (Entries 11 and 12). These control experiments underscore the importance of the photosensitization step to furnish high yields of the desired product and the identification of solvent and Ni catalyst (Entries 6 and 8) to maximize ‘radical sorting’.

Figure 2. Reaction development.

(A) Only one sacrificial group delivered efficient radical generation. (B) Optimized reaction conditions for the deaminative cross-coupling. Ac, acyl; Zn, zinc; MeCN, acetonitrile; DMAc, N,N-dimethylacetamide. ^aSide product 12 was detected only in entries 6 and 8.

Substrate scope exploration

With optimized conditions in hand, the scope of primary amines amenable to this deaminative arylation was explored using 3a as coupling partner (Figure 3). A wide range of α−1° amines containing a variety of functional groups—including acetal, ether, ester, amide, carbamate, and protected indoles—were transformed in moderate to excellent yields. Benzylic (4b–4d), homobenzylic (4a and 4e), and linear aliphatic (4f–4g) products were obtained in high yields. Impressively, neopentyl-type compound 4h was obtained in 51% yield despite the steric hindrance. Electron-rich aromatic amide derivative 4i was isolated in 66% yield. Notably, the alkene in cyclohexene derivative 4j was tolerated and might serve as linchpin for further functionalization. Arylated derivatives of lysine, β-alanine, and GABA were synthesized (4k–4m) paving the way for the production of diverse non-canonical amino acids. Similarly, Boc-tryptamine 4n underwent arylation in 76% yield. This strategy was also effective in functionalizing aminated intermediates of drug molecules, such as mosapride (4o) and Lipitor^® (4p), highlighting its potential in medicinal chemistry. Unactivated cyclic α−2° amine substrates were shown to engage in the deaminative cross-coupling in synthetically useful yields (products 4q–4u, 53–81% yield). Acyclic α−2° amine substrates were also found to be compatible partners (products 4v–4x). Ni(TMHD)₂ (Ni-3) proved advantageous compared to Ni-1 for these secondary alkyl radical substrates, as previously shown by Molander and Gutierrez.⁴³ Drug molecule mexiletine was arylated in moderate yields under these slightly modified conditions (4x). Successful transformation of cyclic α−3° amines (4y–4ab) demonstrated the suitability of this method to form synthetically challenging quaternary centers. Notably, bicyclo[1.1.1]pentane derivative 4y was isolated in 67% yield and methyloxetane compound 4aa was produced in 58% yield with Ni-3. This method now adds a new tool to the arsenal of medicinal chemists, since bicyclo[1.1.1]pentane and oxetane are increasingly used as bioisosteres in drug discovery campaigns, the former for para-substituted benzene groups,⁵⁶ and the latter for gem-dimethyl or carbonyl motifs.⁵⁷ Finally, acyclic α−3° tert-butylamine was transformed into 4ac, albeit in a lower yield. Nonetheless, this result illustrates the unique lack of reactivity of the cumyl radical toward Ni capture, underscoring its crucial role as a sacrificial group. Overall, unlike other C–N activation approaches, the developed cross-coupling demonstrates broad compatibility with α−1°, 2°, and 3° aliphatic primary amines and thereby provides a universal platform for deaminative reactions.

Figure 3. Substrate scope of deaminative cross-coupling.

All reactions were performed on a 0.13 mmol scale. All yields reported are isolated yields. ^aNi-3 was used in lieu of Ni-1. ^b95:5 1,4-dioxane:DMAc was used as solvent. Ir, iridium; ^tBu, tert-butyl; Boc, tert-butyloxycarbonyl.

The scope of the aryl bromide partner (Figure S5) was screened with an eye toward applications in medicinal chemistry. Good yields were obtained in the synthesis of cross-coupled products bearing electron-deficient (4ad–4ag) and electron-rich aryl groups (4ah–4aj) and meta (4aj) and ortho (4ak) substituents were both tolerated. Selective coupling at the bromide position was observed in the presence of typical cross-coupling handles such as triflate 4al and pinacol boronate 4am. This orthogonal reactivity should allow for the expedient construction of complex scaffolds. A range of heteroaryl bromides were also incorporated including pyridine at the C2 (4an), C3 (4ao–4aq), and C4 (4ar) positions, as well as heterocycles like pyrimidine (4as) and quinoline (4at). Of note, replacing MeCN with 1,4-dioxane helped improve the yield for pyridine congeners 4aq and 4ar. Finally, densely functionalized aryl bromides were used including bioactive D-galactose (4au) and indomethacin derivative (4av).

Mechanistic investigation

Several experiments were conducted to probe the mechanism postulated in the design stage, and more specifically the Ni-mediated ‘radical sorting’ steps following the diazene fragmentation through EnT. Collection of the UV-visible absorption spectra of diazene 2a, aryl bromide 3a, Ni-1, and Ir-1 confirmed that only the photocatalyst exhibits any meaningful absorption within the blue LED spectral window (425–475 nm) (Figure 4A). Additionally, measurement of the photoluminescence of Ir-1 in the presence of various amounts of diazene 2a revealed a Stern-Volmer behavior characterized by bimolecular rate constant k_q = 9.4 × 10⁸ M⁻¹•s⁻¹ (Figure 4B and Figure S6). To distinguish between an SET or EnT mechanism between Ir-1 and 2a, cyclic voltammetry (CV) of 2a was performed (Figure 4C). The cyclic voltammogram of diazene 2a indicated an irreversible oxidative cycle with an oxidation potential of 1.13 V vs Ag/Ag⁺ reference electrode in MeCN (1.47 V vs SCE in MeCN) and a silent reductive cycle (Figure S9).⁵⁸ This value is ~0.3 V higher than the excited state redox potential of Ir-1 (E_1/2^red[*Ir^III/Ir^II] = +1.21 V vs SCE in MeCN),⁵⁹ suggesting that EnT is more likely than SET.

Figure 4. Mechanistic experiments.

(A) UV-visisble absorption profile of the cross-coupling reaction components. (B) Photoluminescence quenching, and (C) cyclic voltammetry (CV) measurements of diazene 2a. (D) Radical clock experiment using cyclopropyl 2b. (E) Monitoring reaction kinetics via ¹H NMR using phenyltrimethylsilane as an internal standard. (F) Experiments with stoichiometric Ni(II) prepared from oxidative addition to 4-CF₃C₆H₄Br. (G) Postulated mechanism including two independent cycles. K_SV, Stern-Volmer constant; k_q, quenching rate constant.

Next, a radical-clock experiment using diazene 2b resulted in the exclusive formation of alkene 13 as a 3:1 mixture of diastereomers following cyclopropyl ring opening (Figure 4D). The fate of the posited alkyl radicals with and without Ni catalyst was monitored via ¹H NMR spectroscopy using diazene 2c (Figure 4E and Figures S10–S13). Irradiation of a mixture of 2c and Ir-1 led to the formation of the three possible radical recombination products (5, 15, and 16), along with some minor unidentified products. The concomitant formation and partitioning of all three products align with a mechanism dominated by out-of-cage recombination of transient radicals. Importantly, the predominance of 5 relative to 16 suggests an efficient cage escape process, likely facilitated by the formation of a triplet-triplet pair,^60–63 and the lack of persistent radical effect.⁶⁴ In contrast, addition of Ni-1, aryl bromide 3a, and Zn powder completely suppressed the formation of 15 and 16 in favor of 5 and arylated product 4b, highlighting the sorting role of the Ni catalyst. The stoichiometric reaction of Ni_ox•(di-OMe-bpy) with diazene 2a, without Zn, delivered comparable yield of 4af as in the catalytic conditions, while arylation of symmetrical diazene 2d failed in the same conditions (Figure 4F, Table S4). These experiments support our hypothesis that binding of the planar cumyl radical to a Ni(II) intermediate is unfavorable, thereby enabling selective ‘radical sorting’.

A proposed mechanism is illustrated in Figure 4G. Upon excitation, the photocatalyst induces fragmentation of diazene 2 via EnT, generating the geminate radical pair [I•, •II]. It is hypothesized that photosensitization leads to the formation of a triplet radical pair ³[I•, •II], precluding rapid in-cage recombination,⁶³ which typically occurs on a sub-picosecond time for a singlet pair generated from the direct excitation of 1,2-dialkyldiazenes.^65,66 Upon cage escape and diffusion, the radicals follow distinct fates. The cumyl radical (II•), with its resonance stabilization and resulting planarity, is less likely to bind to the Ni center, favoring dimerization through recombination. Conversely, capture of I• by the oxidative addition complex III would initiate the productive cross-coupling pathway via a radical-chain mechanism. Reductive elimination then forms the desired cross-coupling product 4, and one-electron reduction of V by Zn completes the catalytic cycle. Although Ni(COD)₂, a Ni(0) complex, was suitable for the reaction (Table S3), an alternative sequential-reduction pathway involving Ni(I)/Ni(II)/Ni(III) intermediates may also operate (see gray arrows for a simplified mechanism).⁶⁷ This pathway could proceed through SET from Zn or through comproportionation of Ni(III) and Ni(I) species.⁶⁸ Finally, while quenching of Ir-1 photoluminescence was not observed in the presence of NiBr₂•(di-OMe-bpy) or Ni_ox•(di-Ome-bpy) (Figures S7 and S8), sensitization of other Ni intermediates cannot be ruled out.

Synthetic applications

The mildness and generality of our deaminative process motivated us to explore its potential in the modification of peptidic substrates. Peptides are an intriguing class of drug molecules due to their high specificity, potency, and biocompatibility; however, they often require late-stage functionalization to address pharmacokinetics issues caused by enzymatic degradation.^69,70 Dipeptide Boc-Lys-Leu-OMe (18) was successfully transformed into diazene 2e following our procedure (Figure 5A). Gratifyingly, arylation of 2e under standard conditions delivered derivative 19 in 47% yield. Given that each electrophile is activated in independent catalytic cycles in our postulated mechanism, we hypothesized that other classes of coupling partners could be utilized without major changes to the standard conditions. Indeed, acylation of diazene 2e with acyl succinimide 20 afforded product 21 in 39% yield. Switching the coupling partner to isocrotyl bromide (22) furnished the alkenylated product 23. Notably, while Katritzky salts have been employed to install (hetero)aryl⁷¹ and acyl groups⁷² onto lysine-containing peptides, the incorporation of an alkene handle via deamination is, to the best of our knowledge, unprecedented. Given the versatility of alkenes as synthons for scaffold modification—including as click chemistry handles—this deaminative alkenylation provides a convenient strategy for the diversification of lysine residues.

Figure 5. Synthetic Applications.

(A) Dipeptide editing via deaminative cross-coupling. ^aphen was used as ligand in lieu of di-OMe-bpy (B) Synthesis of medicinally relevant two-carbon (C2) linchpins. ^b(ref. 33). All yields are isolated. See the supplemental information for detailed reaction 566 conditions. Lys, Lysine; Leu, Leucine.

In another application of C–N bond activation, two-carbon linchpins for the construction of valuable fine chemicals and drugs were synthesized from inexpensive starting materials (Figure 5B). Capitalizing on the selectivity of the SuFEx click reaction, ethanolamine 24 was converted into diazene 2f without requiring protection of the primary alcohol. Deaminative arylation with 3-bromopyridine derivative 3b furnished hydroxyethylated pyridine 25—a valuable yet expensive building block³³—in 81% yield. This deceptively simple approach provides an efficient alternative to common hydroxyethyl surrogates such as 26, 27, and 28, which are often burdened by challenging synthesis, difficult isolation, and low-yield couplings, as demonstrated in prior work.³³ Similarly, nitrogenated analog 2g was prepared from the corresponding primary amine 29 and subsequently transformed into Boc-protected betahistine (30), a drug used to treat vertigo symptoms. In addition to offering a streamlined route to betahistine, this sequence provides a practical method for synthesizing numerous analogs by varying the heteroaryl bromide coupling partner.

In conclusion, this work establishes a general approach for deaminative cross-coupling through the intermediacy of unsymmetrical 1,2-dialkyldiazenes fragmented via photocatalyzed energy transfer. A wide range of unactivated primary amines were functionalized owing to the robustness and modularity of SuFEx click chemistry and the mild cross-coupling conditions. A key advance in this study is the discovery that a geminate pair of transient carbon-centered radicals can be efficiently sorted by a Ni catalyst to ensure the desired productive pathway. Mechanistic investigations support the presence of two independent catalytic cycles: a redox-neutral Ir-catalyzed photosensitization cycle that generates the geminate radical pair and a second Ni-catalyzed cycle that governs radical sorting and C–C bond formation. The development, optimization, and application of this deaminative arylation were demonstrated across diverse substrates, including sensitive dipeptides. Furthermore, the methodology was extended to deaminative acylation and alkenylation reactions, showcasing its versatility. This new class of C–C bond-forming reactions provides a powerful platform for leveraging primary amines—a ubiquitous motif in natural and synthetic molecules—for late-stage scaffold diversification.

METHODS

General procedure for deaminative cross-coupling

A flame-dried and argon-purged 3 mL vial equipped with a bean-shaped PTFE-coated stir bar was charged with aryl bromide 3 (0.19 mmol, 1.5 equiv), diazene 2 (if in solid form, 1 equiv) photocatalyst Ir-1 (1.4 mg, 1 mol%), Ni-1 (8.2 mg, 15 mol%), KH₂PO₄ (34 mg, 0.25 mmol, 2.0 equiv), and activated zinc powder (see Supplemental Information for activation procedure) (16.5 mg, 2.0 equiv). Upon addition of all the solids, the vial was evacuated under high vacuum for 15 min and then backfilled with argon. Anhydrous degassed MeCN (0.57 mL) was added with a syringe under an argon atmosphere followed by anhydrous degassed DMAc (0.03 mL) with a micro-syringe and diazenes 2 (if in liquid form, 1 equiv). The vial was then irradiated using blue LEDs (30 W, 450 nm), while the reaction was stirred at 350 rpm (Figure S4). After 24 h of irradiation, the reaction mixture was diluted with EtOAc (2 mL) and filtered through a silica plug (~2.0 cm), which was subsequently flushed with additional EtOAc (50 mL). The volatiles were removed in vacuo, and the crude residues were purified by silica gel column chromatography. Further details regarding the methods can be found in the Supplemental Methods.

RESOURCE AVAILABILITY

Lead Contact

Requests for further information and resources should be directed to and will be fulfilled by the lead contact, Quentin Michaudel (quentin.michaudel@chem.tamu.edu).

Materials Availability

All products described in this study can be prepared from commercially available starting materials using the procedures described in the supplemental information.

Supplementary Material

SUPPLEMENTAL INFORMATION

Supplemental methods, Figures S1 to S19, Tables S1 to S18

NMR spectra of the synthesized diazenes and cross-coupling products

The bigger picture.

Reactions forging C–C bond through the action of a metal catalyst are ubiquitous in modern synthetic chemistry, with far-reaching impact across pharmaceuticals, agrochemicals, and materials science. As chemists seek to engage more diverse feedstock reagents in these powerful transformations, there has been a renewed interest in radical-based cross-coupling strategies. Amines are an especially interesting class of building blocks due to their abundance, yet C–N bonds are notoriously difficult to engage in chemical processes. Herein, we report a general strategy to activate the C–N bond of readily available primary amines for a subsequent C–C bond formation via a radical cross-coupling reaction. This reaction leverages the unique reactivity of unsymmetrical 1,2-dialkyldiazenes as universal radical precursors through the expulsion of dinitrogen (N₂). The effectiveness of this cross-coupling, which accommodates a wide range of substrates including peptide derivatives, arises from the mild reaction conditions (room temperature and blue light) and a dual iridium/nickel catalytic system. This catalyst combination enables a unique ‘radical sorting’ mechanism that selectively directs the desired intermediates toward C–C bond formation, while avoiding typical side reactions of 1,2-dialkyldiazenes such as radical-pair recombination or disproportionation, which have previously limited the use of these reagents in organic synthesis.

Highlights.

• General C–N bond activation via SuFEx click and the aza-Ramberg–Bäcklund reaction

• Deaminative Ni-catalyzed coupling via Ir-induced 1,2-dialkyldiazene photocleavage

• Ni-mediated sorting of productive vs sacrificial radicals from geminate pairs

• Broad scope of primary amines, including peptides, and diverse coupling partners

Data and Code Availability

Crystal structure data for compound 4i (Figure S19, Tables S11–S18) has been submitted to Cambridge Crystallographic Data Center (CDCC) with the deposition number CCDC 2418415.