Ligand-centered redox-driven Zn(II)-catalyzed anti-Markovnikov hydroamination of activated alkenes with primary aromatic amines via aminium radical cations

Abstract

A ligand-centered redox-driven strategy for anti-Markovnikov hydroamination of electron-deficient alkenes, including acrylates, acrylonitrile, and acrylamides, enabled by a well-defined Zn(II) catalyst bearing a redox-active arylazo–phenanthroline ligand, is reported. The azo-functionalized ligand serves as the key redox mediator, enabling single-electron transfer (SET) from primary aromatic amines to the low-lying π*-acceptor orbital of the ligand scaffold, generating aminium radical cation intermediates that engage in regioselective radical hydroamination under thermal conditions (100 °C), circumventing the need for precious metals, external oxidants, or photochemical activation. The protocol demonstrates broad substrate scope and functional group tolerance, efficiently transforming a variety of amines, including heteroaryl, electron-rich, and complex amines derived from natural products, into valuable hydroaminated products. Mechanistic studies support a radical pathway initiated by SET to the azo-functionalized catalyst, with the redox-active ligand mediating all key electron-transfer events, while the Zn(II) center acts as a coordination scaffold. This work highlights the potential of redox-active ligand systems to enable sustainable radical pathways for C–N bond formation, introducing a new catalytic paradigm for the selective hydroamination of electron-deficient alkenes to access linear alkylamine frameworks.

---

Introduction

Amine-containing molecular architectures are foundational motifs across pharmaceuticals, agrochemicals, natural products, and fine chemicals. The growing demand for structurally diverse amines has driven the need for efficient synthetic methods that enable both the construction and late-stage functionalization of these species.^1–16 Among the most direct and atom-economical strategies, hydroamination of alkenes installs nitrogen functionality across a C=C bond in a single step.^17–39

A persistent challenge in this area lies in controlling the regioselectivity of N–H additions to unsaturated substrates. Hydroamination reactions often favour Markovnikov selectivity, wherein the amine adds to the more substituted carbon of the alkene.^40–42 However, the development of anti-Markovnikov-selective processes remains a central challenge in catalysis.^43,44 Indeed, as early as 1993, anti-Markovnikov hydroamination was recognized as one of the top ten unsolved problems in this field.⁴⁵ While notable progress has been made, especially in the hydroamination of alkenes and alkynes, anti-Markovnikov selectivity remains difficult to achieve, particularly under intermolecular and catalytic conditions.

The fundamental difficulty arises from the electronic mismatch between the lone pair of the amine and the π-electron cloud of the alkene, which renders direct addition both kinetically and thermodynamically unfavourable. To address this, polarity inversion—or umpolung—strategies have emerged, wherein the intrinsic nucleophilicity of the amine is reversed through single-electron oxidation, generating electrophilic aminium radical cations (ARCs).^46–55 These ARCs are usually produced through N–X bond homolysis,⁵⁶ electrochemical,^57,58 and photochemical electron transfer processes.^59–68 A seminal advance in this area was the work by Knowles and co-workers, which demonstrated that photoinduced single-electron oxidation of amines using an iridium photocatalyst enables intramolecular hydroamination via ARC intermediates.^49,53 This concept was subsequently extended to intermolecular variants, allowing anti-Markovnikov hydroamination of alkenes with heteroaryl amines under mild photocatalytic conditions.⁴⁹ Despite these approaches, the broader application of ARC-mediated hydroamination has been constrained by several factors: reliance on precious metal catalysts, narrow substrate scopes, limited functional group tolerance, and dependence on organic solvents and external oxidants. Furthermore, while heterogeneous systems have been explored as a more sustainable alternative,^69–77 they often suffer from poor reactivity and selectivity.⁷⁸

In this work, we report a ligand-centered redox-driven Zn(II)-catalyzed anti-Markovnikov hydroamination of primary aromatic amines with electron-deficient alkenes, including acrylates, acrylonitrile, and acrylamides, under operationally simple and mild conditions (Scheme 1). This system exhibits broad substrate tolerance, transforming complex amine frameworks, such as phenanthroline-based amines, into valuable dihydroaminated products. Notably, ortho-phenylenediamine undergoes double hydroamination to yield a diacrylate intermediate, which can be further transformed under basic conditions to furnish benzodiazepin-2-one scaffolds. Additionally, late-stage hydroamination of tocopherol- and menthol-derived amines highlights the versatility and applicability of the protocol. Mechanistic investigations, including control experiments and literature precedent,^79,80 support a single-electron transfer (SET) mechanism wherein the redox-active arylazo ligand plays a pivotal role. The catalytic cycle is initiated by the ligand-centered reduction of the azo-functionalized Zn(II) catalyst via a single electron transfer from the amine, generating an electrophilic aminium radical cation (ARC). Notably, literature reports and electrochemical studies confirm that the reduction potential of the catalyst (−0.17 V vs. Ag/AgCl in MeCN) is sufficiently positive relative to the reduction potential of the amine (−0.43 V vs. Ag/AgCl in MeCN), making this electron transfer thermodynamically feasible.^81–83 During this process, the azo bond of the catalyst is reduced. The ARC subsequently undergoes regioselective addition to the alkene to furnish a C-centered radical intermediate. Subsequent electron transfer from the reduced catalyst to the C-centered radical intermediate, followed by protonation, completes the catalytic cycle and furnishes the hydroaminated products. Importantly, our results indicate that redox events are mediated exclusively by the azo ligand, with the Zn center serving primarily as a coordination template.^83–88 Taken together, this work establishes a sustainable, metal-templated yet ligand-controlled strategy for anti-Markovnikov hydroamination, expanding the synthetic toolkit for accessing linear alkylamines from simple olefin feedstocks under environmentally benign conditions.

Scheme 1 A comparison between the conventional approach and our approach.

Results and discussion

A five-coordinate Zn(II) complex (1), featuring a tridentate redox-active arylazo ligand, 2-((4-chlorophenyl)diazenyl)-1,10-phenanthroline (L), was used as a catalyst. Complex 1 was obtained in 94% yield by stirring an ethanolic solution of L with ZnCl₂ at room temperature under ambient conditions.⁸³

Our present study begins with optimizing the reaction conditions, taking aniline (2a) and ethyl acrylate (3a) as the model substrates. By varying the different reaction parameters such as the catalyst and loading of the additive, temperature, and time, it was found that the reaction proceeds best in the presence of 3.0 mol% of 1 and 10.0 mol% NaOTf, at 100 °C under an inert N₂ atmosphere, requiring only 6 h to produce 4a in the highest yield of 86% (Table 1, entry 4). The reaction also proceeds smoothly, with NaOAc as an additive, producing 4a in 79% yield (Table 1, entry 2). However, a drastic decrease in the product yield was observed when we replaced NaOAc with KOAc (Table 1, entry 3), while other additives, such as KO^tBu, NaO^tBu, and NaOH, failed to produce 4a (Table S1, entries 1–3). NaCl resulted in only trace amounts of products, and organic additives such as NEt₃, DABCO, and DIPEA produced the desired products in <14% yields (see SI, Table S1, entries 4–7). Using Na₂CO₃, Cs₂CO₃, and K₂CO₃ as additives, 4a was obtained in 31, 23, and 27% yields, respectively (see SI, Table S1, entries 8–10). Reducing the reaction temperature, time, amount of additive, and catalyst loading beyond the optimized conditions drastically lowered the product yield, while increasing these parameters did not improve the yield significantly (Table 1, entries 5–11). The reaction did not proceed when toluene or any other organic solvents were used as the solvent (Table 1, entries 12 and 13). A drastic drop in the product yield was observed when the reaction was conducted under air (Table 1, entry 14). The reaction produced only 5% of 4a in the absence of catalyst 1 (Table 1, entry 15). Without a catalyst and an additive, the reaction did not proceed (Table 1, entry 16). Commercially available ZnCl₂ failed to produce 4a (Table 1, entry 17). Interestingly, using 2-((4-chlorophenyl)diazenyl)-1,10-phenanthroline (L) as the catalyst, 48% of 4a was obtained (Table 1, entry 18) under the standard conditions, while the well-defined [Zn^II(phen)₂Cl₂] (phen = 1,10-phenanthroline) produced only 7% of 4a (Table 1, entry 19). Under 456 nm and 390 nm Kessil lamps, we did not obtain product 4a, suggesting that thermal excitation is required for this catalytic transformation (Table 1, entries 20 and 21). It is worth mentioning that we always obtained mono-N-substituted products, even when two equivalents of the alkenes were used (Table 1, entry 22).

Table 1 Optimization of the reaction conditions^{a,b,c,d,e,f,g,h}

Entry	Catalyst (mol%)	Additive (mol%)	Temperature	Time	Yield^h (%)
a Reaction conditions: aniline (1.0 mmol), ethyl acrylate (1.0 mmol); catalyst: 3.0 mol%; NaOTf: 10 mol%; temperature: 100 °C; time: 6 h; under an N2-filled glove box. b In the presence of toluene (2 mL). c In the presence of THF (2 mL). d Under air. e Under a 456 nm Kessil lamp. f Under a 390 nm Kessil lamp. g In the presence of two equivalents of 3a. h Isolated yield after column chromatography.
1	1 (3.0)	NaOAc (20)	100 °C	6 h	78
2	1 (3.0)	NaOAc (10)	100 °C	6 h	79
3	1 (3.0)	KOAc (10)	100 °C	6 h	49
4	1 (3.0)	NaOTf (10)	100 °C	6 h	86
5	1 (3.0)	NaOTf (10)	90 °C	6 h	71
6	1 (3.0)	NaOTf (10)	110 °C	6 h	84
7	1 (3.0)	NaOTf (5)	100 °C	6 h	61
8	1 (3.0)	NaOTf (10)	100 °C	9 h	86
9	1 (3.0)	NaOTf (10)	100 °C	3 h	53
10	1 (4.0)	NaOTf (10)	100 °C	6 h	87
11	1 (2.0)	NaOTf (10)	100 °C	6 h	57
12^b	1 (3.0)	NaOTf (10)	100 °C	6 h	0
13^c	1 (3.0)	NaOTf (10)	100 °C	6 h	0
14^d	1 (3.0)	NaOTf (10)	100 °C	6 h	41
15	—	NaOTf (10)	100 °C	6 h	5
16	—	—	100 °C	6 h	0
17	ZnCl2 (3.0)	NaOTf (10)	100 °C	6 h	0
18	L (3.0)	NaOTf (10)	100 °C	6 h	48
19	[Zn^II(phen)2Cl2] (3.0)	NaOTf (10)	100 °C	6 h	7
20^e	1 (3.0)	NaOTf (10)	100 °C	6 h	0
21^f	1 (3.0)	NaOTf (10)	100 °C	6 h	0
22^g	1 (3.0)	NaOTf (10)	100 °C	6 h	85

---

Having established the optimal reaction conditions, we evaluated the scope and generality of the transformation using a series of structurally diverse primary aromatic amines. Electron-rich anilines bearing alkyl or alkoxy substituents, such as –Me, –Et, –^tBu, and –SMe, furnished the desired hydroaminated products 4b–4e in 61–80% yields (Table 2, entries 2–5). Halogen-substituted anilines, including 4-chloroaniline and 4-fluoroaniline, were well tolerated, delivering products 4f and 4g in 76% and 69% yields, respectively (Table 2, entries 6 and 7). In the presence of a strongly electron-withdrawing –CF₃ group, the reaction efficiency declined slightly, as reflected by the lower yield of product 4h (Table 2, entry 8). Notably, heteroaryl amines containing pyridine motifs underwent smooth transformations, yielding 4i and 4j in 80% and 73% yields, respectively (Table 2, entries 9 and 10). Additionally, 8-aminoquinoline was amenable to the transformation, providing 4k in 68% yield (Table 2, entry 11).

Table 2 Substrate scope for various primary amines with ethyl acrylate^a,b

a Reaction conditions: aniline derivatives (1.0 mmol), ethyl acrylate (1.0 mmol), NaOTf (0.1 mmol), 1 (3.0 mol%), temperature: 100 °C, time: 6 h, and N₂ atmosphere. b Isolated yield in parentheses after column chromatography.

---

Next, we evaluated the compatibility of structurally varied acrylate esters under optimized reaction conditions. Methyl acrylate underwent smooth conversion to furnish product 5a in 77% yield (Table 3, entry 1). Acrylates bearing extended alkyl chains, including butyl, hexyl, and n-octyl acrylate, participated efficiently, affording products 5b–5d in 80–84% yields (Table 3, entries 2–4). The sterically hindered tert-butyl acrylate delivered 5e in 75% yield (Table 3, entry 5), indicating reasonable tolerance toward bulkier esters. However, when 2-ethylhexyl methacrylate was employed, the reaction furnished product 5f in a reduced yield of 57%, likely due to increased steric encumbrance near the olefinic moiety (Table 3, entry 6). Additionally, structurally diverse acrylates such as ethyl crotonate, a norbornane-based acrylate, and benzyl acrylate produced the desired products 5g–5i, in 78%, 63%, and 71% yields, respectively (Table 3, entries 7–9), further demonstrating the adaptability of the protocol to a range of acrylate frameworks.

Table 3 Substrate scope for primary amines with various acrylate derivatives^a,b

a Reaction conditions: aniline (1.0 mmol), acrylate derivatives (1.0 mmol), NaOTf (0.1 mmol), 1 (3.0 mol%), temperature: 100 °C, time: 6 h, and N₂ atmosphere. b Isolated yield in parentheses after column chromatography.

---

The versatility of the catalytic system was further demonstrated using acrylonitrile as the Michael acceptor in reactions with a variety of substituted anilines (Table 4). A broad spectrum of aniline derivatives bearing electron-donating and electron-withdrawing substituents, regardless of their substitution pattern on the aromatic ring, underwent efficient transformations to furnish the corresponding hydroaminated products 6b–6i in yields of up to 72% (Table 4, entries 2–9). Notably, our method also tolerated heteroaromatic amines; for example, 8-aminoquinoline afforded the desired product 6j in 59% yield (Table 4, entry 10).

Table 4 Substrate scope for various primary amines with acrylonitrile^a,b

a Reaction conditions: aniline derivatives (1.0 mmol), acrylonitrile (1.0 mmol), NaOTf (0.1 mmol), 1 (3.0 mol%), temperature: 100 °C, time: 6 h, and N₂ atmosphere. b Isolated yield in parentheses after column chromatography.

---

Encouraged by the successful application of our protocol to acrylonitrile, we next explored the scope of acrylamide derivatives under optimized conditions (Table 5). A diverse array of primary aromatic amines underwent efficient hydroamination with acrylamides, affording the corresponding products in yields of up to 71% (Table 5, entries 1–9). Electron-donating substituents such as –Me, –^tBu, –OMe, and –SMe were well accommodated, affording products in 61–68% yields (Table 5, entries 2–5). Anilines bearing halogen substituents, including –F and –Cl, also reacted efficiently, providing 7f and 7g in 62% and 68% yields, respectively (Table 5, entries 6 and 7). Notably, N-phenylacrylamide delivered the desired product 7h in 62% yield (Table 5, entry 8). Furthermore, N,N-dimethylacrylamide underwent successful hydroamination with aniline, producing 7i in 64% yield (Table 5, entry 9).

Table 5 Substrate scope for various primary amines with acrylamide^a,b

a Reaction conditions: aniline derivatives (1.0 mmol), acrylamide derivatives (1.0 mmol), NaOTf (0.1 mmol), 1 (3.0 mol%), temperature: 100 °C, time: 6 h, and N₂ atmosphere. b Isolated yield in parentheses after column chromatography.

---

To further probe the catalytic competence of our system, polyfunctionalized nitrogen nucleophiles 1,10-phenanthrolin-2-amine and 1,10-phenanthroline-2,9-diamine were subjected to hydroamination with ethyl acrylate and acrylonitrile under the standard conditions. Remarkably, these reactions led to the formation of di- and tetra-hydroaminated products 9, 10, 12, and 13, respectively (Scheme 2, entries 1 and 2), highlighting the catalyst's ability to accommodate multiple reactive sites. The resulting polyaminated phenanthroline derivatives represent valuable intermediates for developing structurally diverse ligand frameworks, with promising utility in coordination chemistry and the design of functional organometallic complexes. Unlike aniline derivatives, during the hydroamination reactions with phenanthroline-based amines, we always obtained the corresponding di-N-substituted products selectively.

Scheme 2 Application towards synthesis of the precursor for the phenanthroline-based ligand moiety.

Under the optimized catalytic conditions, o-phenylenediamine (14′) underwent a double hydroamination with ethyl acrylate to furnish the dihydroaminated intermediate 14. Subsequent base-induced cyclization of 14 using KO^tBu in toluene at 80 °C for 5 hours under aerobic conditions led to the formation of 1,3,4,5-tetrahydro-2H-benzo[b][1,4]diazepin-2-one (15) in 81% yield (Scheme 3). Notably, compound 15 is a core structural motif in bioactive molecules and is known for its potential pharmacological activity as an arginine vasopressin antagonist.⁸⁹

Scheme 3 Synthesis of an arginine vasopressin antagonist drug.

To demonstrate the applicability of the protocol to complex, biologically relevant scaffolds, DL-α-tocopherol-derived amine (DL-16) was subjected to hydroamination with ethyl acrylate and acrylonitrile in the presence of catalyst 1. These reactions afforded the corresponding adducts DL-17 and DL-18 in 61% and 52% yields, respectively (Scheme 4, entry 1). Similarly, (±)-menthol-derived amine ((±)-19) underwent smooth hydroamination with acrylonitrile to furnish product (±)-20 in 56% yield (Scheme 4, entry 2). These results underscore the functional group tolerance and synthetic utility of the method in late-stage functionalization of natural product-based amines.

Scheme 4 Functionalization of tocopherol- and menthol-derived amines.

Notably, the in situ generated hydroaminated products derived from aniline and acrylate derivatives can be readily converted to the corresponding amino acids upon treatment of the reaction mixture with KOH in methanol for 2 hours under aerial conditions at room temperature (Scheme 5). This transformation offers a straightforward route to structurally diverse aromatic amino acid derivatives, underscoring the synthetic utility of the methodology for accessing value-added building blocks.

Scheme 5 Straightforward synthesis of aromatic amino acids.

Our protocol is not compatible with secondary amines, such as N-methylaniline. The reaction of N-methylaniline with ethyl acrylate, acrylonitrile, and acrylamides under our standard reaction conditions failed to yield the corresponding hydroaminated products, even after repeated attempts (see SI, Scheme S1).

To gain deeper insights into the mechanism of the reaction, a series of control reactions were conducted. Treatment of aniline with catalyst 1 and NaOTf in the presence of the radical scavenger BHT at 100 °C under a nitrogen atmosphere led to the formation of a BHT-trapped aminium radical cation (21), as confirmed by high-resolution mass spectrometry (HRMS), suggesting the involvement of a radical pathway (Scheme 6, entry 1a). In the presence of BHT, the reaction between aniline and ethyl acrylate did not proceed (Scheme 6, entry 1b). Furthermore, analysis of this reaction mixture using HRMS indicated the formation of radical-trapped intermediates 2a–3a-BHT (22) and 1-BHT (23), further substantiating the presence of discrete radical species during the reaction (Scheme 6, entry 1b).

Scheme 6 Control experiments.

To probe the proton transfer events during the transformation, we conducted an isotopic labeling experiment using deuterated aniline (2a-D). Upon reaction with ethyl acrylate, the corresponding hydroaminated product 4a-D was obtained in 75% yield, with deuterium incorporation of 31% at the –NH site and 30% at the α-position of the ester side chain (Scheme 6, entry 2). These results suggest that the amine serves not only as a nucleophile but also as a proton source, implicating a potential intramolecular proton transfer to the α-position of the acrylate.

Furthermore, when the catalysis was performed using the one-electron reduced form of the catalyst ([1]⁻), no hydroaminated product was observed in the reaction between 2a and 3a (Scheme 6, entry 3). This result emphasizes the essential role of the unreduced native form of the redox-active catalyst in enabling the catalytic turnover. Electrochemical data further support this mechanistic proposal. The reduction potential of the catalyst (−0.17 V vs. Ag/AgCl in MeCN) is sufficiently positive compared to that of the amine (−0.43 V vs. Ag/AgCl in MeCN), rendering the initial single-electron transfer (SET) from the amine to the catalyst thermodynamically favourable. This electron transfer event generates the aminium radical cation, which was independently trapped in the presence of BHT, demonstrating that electron transfer from the amine to the catalyst is necessary to initiate the catalytic cycle. Together, these findings and the radical trapping and isotopic labeling experiments provide compelling evidence for a SET-driven mechanism, in which the redox-active azo ligand mediates the key electron transfer steps.

Based on the existing literature^46–55 and control experiments, a plausible mechanism is depicted in Scheme 7. The reaction is initiated by a single-electron transfer (SET) from the amine to the redox-active azo functionality of catalyst 1, generating an aminium radical cation (ARC) intermediate A. During this process, the low-lying ligand-centered π* acceptor orbitals of catalyst 1 accept the single electron, transforming it to the corresponding azo-anion radical intermediate [1]⁻.⁸¹ The thermodynamic viability of this step is supported by the relative reduction potentials of the catalyst (−0.17 V vs. Ag/AgCl in MeCN) and the amine (−0.43 V vs. Ag/AgCl in MeCN).^81–83 The formation of ARC intermediates was validated through HRMS analysis. During the photochemical generation of the aminium radical cation, it has been reported that the triflate anion acts as a stabilizer, enhancing the lifetime of the aminium cation radical.⁴⁹ In our case, in the absence of any concrete experimental evidence, we speculate that the triflate anion present in the reaction medium possibly stabilizes the cationic radical intermediate. Intermediate A undergoes regioselective radical addition to the acrylate derivative, affording a new carbon-centered radical intermediate B, as identified by HRMS analysis of the BHT-trapped intermediate. Transfer of the single electron, stored in the azo-aromatic ligand backbone during the generation of ARCs, to intermediate B furnishes intermediate C with the regeneration of catalyst 1. Finally, a proton transfer from the aniline moiety to the α-position of the acrylate unit results in the formation of the hydroaminated product D. The deuterium labeling experiments support this pathway, indicating that the amine functions not only as a nucleophile but also as a key proton source in the final step of the catalytic cycle. During the catalytic process, the Zn(II) center acts as a template, while the redox-active arylazo scaffold 2-((4-chlorophenyl)diazenyl)-1,10-phenanthroline (L) plays a key role, acting as a reservoir of electrons, accepting electrons to generate aminium radical cation intermediates and donating the ‘stored’ electron to intermediate B to form the key intermediate C.

Scheme 7 Plausible mechanism.

Conclusion

In summary, we have developed a practical and general strategy for anti-Markovnikov hydroamination of activated alkenes using a well-defined Zn(II) catalyst 1 bearing a redox-active arylazo–phenanthroline ligand, 2-((4-chlorophenyl)diazenyl)-1,10-phenanthroline. Taking advantage of the low-lying azo-based vacant acceptor orbitals in catalyst 1, aminium radical cations were generated via single electron transfer from the primary aromatic amines to catalyst 1 under thermal reaction conditions and subsequently utilized for hydroamination of a wide range of activated alkenes. This catalytic protocol efficiently engages a broad range of primary aromatic amines with various acrylates, acrylonitrile, and acrylamides to deliver structurally diverse hydroaminated products. The method exhibits broad substrate compatibility, including electron-rich and electron-deficient anilines, heteroaryl amines, and amines derived from natural products and phenanthroline frameworks, highlighting its synthetic versatility. These adducts can be further transformed into valuable building blocks, including aromatic amino acid derivatives and phenanthroline-based ligand frameworks, underscoring the synthetic utility of the current protocol. Mechanistic investigations, including radical trapping, isotopic labeling, and electrochemical studies, support a radical pathway involving an aminium radical cation intermediate. All the key steps of the catalytic cycle were experimentally identified, including single-electron transfer, radical addition, and proton transfer events, with the redox-noninnocent azo moiety playing a decisive role, acting as a reservoir of electrons during the catalytic turnover. This work not only demonstrates a rare example of ligand-centered, redox-driven Zn(II)-catalyzed radical-type hydroamination but also underscores the potential of redox-responsive ligand platforms in enabling sustainable and selective C–N bond-forming processes without requiring expensive and scarce Ru- or Ir-based photosensitizers.

Author contributions

S. P. performed all the catalysis work. S. C. and A. P. participated in mechanistic investigations and NMR studies. N. D. P. supervised and coordinated the project. N. D. P. and S. P. contributed to manuscript writing.

Conflicts of interest

The authors declare no competing financial interest.

Data availability

The data underlying this study are available in the published article and its supplementary information (SI). Supplementary information: supplementary figures and tables, characterization data of the synthesized compounds, and copies of ¹H, ¹³C, and ¹⁹F NMR spectra. The authors have cited additional references within the supplementary information.⁹⁰ See DOI: https://doi.org/10.1039/d5qo01248a.

Acknowledgements

The research was supported by the Anusandhan National Research Foundation (ANRF, erstwhile DST-SERB) (grant to NDP; Project: CRG/2023/003413). SP, SC and AP thank IIESTS for fellowship support. Financial assistance from IIESTS is acknowledged. DST sponsored SAIF, IIESTS, is acknowledged for providing HRMS and NMR facilities.

References

1. S. Qi, D. Yin, L. Hu, C. Huang, R. Xie, G. Lu and J. Wang, Iron-Catalyzed Reductive Allylic C–H Amination of Olefin with Nitroarenes via Intermolecular Nitroso Ene Reaction, Angew. Chem., Int. Ed., 2025, 64, e202504750.
2. S. Hu, X. Wang, T. Wu, Z. Ding, M. Wang and W. Kong, Ni-Catalyzed Enantioselective Reductive Cyclization/Amidation and Amination of 1,6-Enynes and 1,7-Enynes, Angew. Chem., Int. Ed., 2025, 64, e202413892.
3. C. M. Marshall, J. G. Federice, C. N. Bell, P. B. Cox and J. T. Njardarson, An Update on the Nitrogen Heterocycle Compositions and Properties of U.S. FDA-Approved Pharmaceuticals (2013–2023), J. Med. Chem., 2024, 67, 11622–11655.
4. Z. Cao, Q. Wang, H. Neumann and M. Beller, Modular and Diverse Synthesis of Acrylamides by Palladium-Catalyzed Hydroaminocarbonylation of Acetylene, Angew. Chem., Int. Ed., 2024, 63, e202410597.
5. V. Pozhydaiev, A. Paparesta, J. Moran and D. Lebœuf, Iron(II)-Catalyzed 1,2-Diamination of Styrenes Installing a Terminal NH₂ Group Alongside Unprotected Amines, Angew. Chem., Int. Ed., 2024, 63, e202411992.
6. S. Ma and J. F. Hartwig, Progression of Hydroamination Catalyzed by Late Transition-Metal Complexes from Activated to Unactivated Alkenes, Acc. Chem. Res., 2023, 56, 1565–1577.
7. V. Pozhydaiev, C. Muller, J. Moran and D. Lebœuf, Catalytic Synthesis of β-(Hetero)arylethylamines: Modern Strategies and Advances, Angew. Chem., Int. Ed., 2023, 62, e202309289.
8. A. Trowbridge, S. M. Walton and M. J. Gaunt, New Strategies for the Transition-Metal Catalyzed Synthesis of Aliphatic Amines, Chem. Rev., 2020, 120, 2613–2692.
9. P. Ruiz-Castillo and S. L. Buchwald, Applications of Palladium-Catalyzed C–N Cross-Coupling Reactions, Chem. Rev., 2016, 116, 12564–12649.
10. L. Xing, J. Klug-Mcleod, B. Rai and E. A. Lunney, Kinase Hinge Binding Scaffolds and Their Hydrogen Bond Patterns, Bioorg. Med. Chem., 2015, 23, 6520–6527.
11. E. Vitaku, D. T. Smith and J. T. Njardarson, 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.
12. J. Bariwal and E. V. der Eycken, C–N Bond Forming Cross-Coupling Reactions: An Overview, Chem. Soc. Rev., 2013, 42, 9283–9303.
13. J. Schranck, A. Tlili and M. Beller, More Sustainable Formation of C–N and C–C Bonds for the Synthesis of N-Heterocycles, Angew. Chem., Int. Ed., 2013, 52, 7642–7644.
14. C. C. Marvin, Synthesis of Amines and Ammonium Salt, in Comprehensive Organic Synthesis, Elsevier, 2014, vol. 6, pp. 34–99.
15. A. Ricci, Amino Group Chemistry: From Synthesis to the Life Sciences, Wiley, Weinheim, 2008.
16. S. A. Lawrence, Amines: Synthesis Properties and Applications, Cambridge University Press, Cambridge, UK, 2004, pp. 265–308.
17. Y.-W. Sun, H.-T. Tan, S.-N. Sun and B.-J. Li, Iridium-Catalyzed Asymmetric β-Selective Hydroamination of Enamides for the Synthesis of 1,2-Diamines, Angew. Chem., Int. Ed., 2025, e202507200.
18. C. Lee, H.-J. Kang and S. Hong, NiH-catalyzed C–N Bond Formation: Insights and Advancements in Hydroamination of Unsaturated Hydrocarbons, Chem. Sci., 2024, 15, 442–457.
19. A. Artasensi, S. Mazzotta, I. Sanz, L. Lin, G. Vistoli, L. Fumagalli and L. Regazzoni, Exploring Secondary Amine Carnosine Derivatives: Design, Synthesis, and Properties, Molecules, 2024, 29, 5083.
20. W. Harrison, G. Jiang, Z. Zhang, M. L. H. Chen and H. Zhao, Photoenzymatic Asymmetric Hydroamination for Chiral Alkyl Amine Synthesis, J. Am. Chem. Soc., 2024, 146, 10716–10722.
21. J. M. Phelps, R. Kumar, J. D. Robinson, J. C. K. Chu, N. J. Flodén, S. Beaton and M. J. Gaunt, Multicomponent Synthesis of α-Branched Amines via a Zinc-Mediated Carbonyl Alkylative Amination Reaction, J. Am. Chem. Soc., 2024, 146, 9045–9062.
22. R. Maiti, J. Chakraborty, P. K. Sahoo, I. Nath, X. Dai, J. Rabeah, N. De Geyter, R. Morent, P. V. D. Voort and S. Das, A Covalent Triazine Framework for Photocatalytic Anti-Markovnikov Hydrofunctionalizations, Angew. Chem., Int. Ed., 2024, 63, e202415624.
23. C. Sharma, S. Kumari, D. Sharma, A. K. Srivastava and R. K. Joshi, Selenated NHC-Pd(II) Pincer Complex Catalyzed, Temperature-Dependent Selective Hydroamination and Oxidative Amination of Olefins: Formation of Enamine Esters and β-Amino Esters under Solvent-Free and Aerobic Conditions, J. Org. Chem., 2024, 89, 701–709.
24. A. Tyagi, S. Mondal, Anmol, V. Tiwari, T. Karmakar and S. Kundu, Understanding Cyclic(Alkyl)(Amino)Carbene–Copper Complex Catalysed N–H And O–H Bond Addition to Electron Deficient Olefins, Chem. Commun., 2023, 59, 110–113.
25. M. A. Allen, H. M. Ly, G. F. O'Keefe and A. M. Beauchemin, A Redox-Enabled Strategy for Intramolecular Hydroamination, Chem. Sci., 2022, 13, 7264–7268.
26. S. Ma, Y. Xi, H. Fan, S. Roediger and J. F. Hartwig, Enantioselective Hydroamination of Unactivated Terminal Alkenes, Chem, 2022, 8, 532–542.
27. S.-M. Jia, Y.-H. Huang, Z.-L. Wang, F.-X. Fan, B.-H. Fan, H.-X. Sun, H. Wang and F. Wang, Hydroamination of Unactivated Alkenes with Aliphatic Azides, J. Am. Chem. Soc., 2022, 144, 16316–16324.
28. Y.-D. Du, B.-H. Chen and W. Shu, Direct Access to Primary Amines from Alkenes by Selective Metal-Free Hydroamination, Angew. Chem., Int. Ed., 2021, 60, 9875–9880.
29. S. Streiffa and F. Jérôme, Hydroamination of Non-Activated Alkenes with Ammonia: A Holy Grail in Catalysis, Chem. Soc. Rev., 2021, 50, 1512–1521.
30. A. J. Musacchio, B. C. Lainhart, X. Zhang, S. G. Naguib, T. C. Sherwood and R. R. Knowles, Catalytic Intermolecular Hydro-aminations of Unactivated Olefins with Secondary Alkyl Amines, Science, 2017, 355, 727–730.
31. L. Huang, M. Arndt, K. Gooßen, H. Heydt and L. J. Gooßen, Late Transition Metal-Catalyzed Hydroamination and Hydroamidation, Chem. Rev., 2015, 115, 2596–2697.
32. S. C. Ensign, E. P. Vanable, G. D. Kortman, L. J. Weir and K. L. Hull, Anti-Markovnikov Hydroamination of Homoallylic Amines, J. Am. Chem. Soc., 2015, 137, 13748–13751.
33. S. Zhu and S. L. Buchwald, Enantioselective CuH-Catalyzed Anti-Markovnikov Hydroamination of 1,1-Disubstituted Alkenes, J. Am. Chem. Soc., 2014, 136, 15913–15916.
34. T. M. Nguyen and D. A. Nicewicz, Anti-Markovnikov Hydro-amination of Alkenes Catalyzed by an Organic Photoredox System, J. Am. Chem. Soc., 2013, 135, 9588–9591.
35. K. D. Hesp and M. Stradiotto, Rhodium- and Iridium-Catalyzed Hydroamination of Alkenes, ChemCatChem, 2010, 2, 1192.
36. T. E. Müller, K. C. Hultzsch, M. Yus, F. Foubelo and M. Tada, Hydroamination: Direct Addition of Amines to Alkenes and Alkynes, Chem. Rev., 2008, 108, 3795–3892.
37. R. Severin and S. Doye, The Catalytic Hydroamination of Alkynes, Chem. Soc. Rev., 2007, 36, 1407–1420.
38. A. L. Seligson and W. C. Trogler, Protonolysis Approach to the Catalytic Amination of Olefins with Bis(phosphine) palladium(II) Dialkyls, Organometallics, 1993, 12, 744–751.
39. K. De, J. Legros, B. Crousse and D. Bonnet-Delpon, Solvent-Promoted and -Controlled Aza-Michael Reaction with Aromatic Amines, J. Org. Chem., 2009, 74, 6260–6265.
40. H. Miao, H. Dong, Q. Meng, C. Feng, Y. Chen, G. Zhang and Q. Zhang, Photoredox and Cobalt-Catalyzed Markovnikov-Selective Radical Hydroamination of Unactivated Alkenes with Anilines, Org. Lett., 2025, 27, 3296–3301.
41. J. Escorihuela, A. Lledós and G. Ujaque, Anti-Markovnikov Intermolecular Hydroamination of Alkenes and Alkynes: A Mechanistic View, Chem. Rev., 2023, 123, 9139–9203.
42. D. C. Miller, J. M. Ganley, A. J. Musacchio, T. C. Sherwood, W. R. Ewing and R. R. Knowles, Anti-Markovnikov Hydroamination of Unactivated Alkenes with Primary Alkyl Amines, J. Am. Chem. Soc., 2019, 141, 16590–16594.
43. C. Nájera, I. P. Beletskaya and M. Yus, Metal-Catalyzed Regiodivergent Organic Reactions, Chem. Soc. Rev., 2019, 48, 4515–4618.
44. J. C.-H. Yim and L. L. Schafer, Efficient Anti-Markovnikov-Selective Catalysts for Intermolecular Alkyne Hydroamination: Recent Advances and Synthetic Applications, Eur. J. Org. Chem., 2014, 6825–6840.
45. J. Haggin, Chemists Seek Greater Recognition for Catalysis, Chem. Eng. News, 1993, 71, 23–27.
46. S.-S. Yan, R. Jackstell and M. Beller, Copper-Catalyzed Selective Amino-alkoxycarbonylation of Unactivated Alkenes with CO, J. Am. Chem. Soc., 2025, 147, 6464–6471.
47. C. Pratley, S. Fenner and J. A. Murphy, Ground State Generation and Cyclization of Aminium Radicals in the Formation of Tetrahydroquinolines, Org. Lett., 2024, 26, 1287–1292.
48. B. Singh, S. Kashyap, S. Singh, S. Gupta and M. K. Ghorai, Catalytic Aminium Radical-Cation Salt (Magic Blue)-Initiated SN²-Type Nucleophilic Ring-Opening Transformations of Aziridines, J. Org. Chem., 2024, 89, 2247–2263.
49. E. P. Geunes, J. M. Meinhardt, E. J. Wu and R. R. Knowles, Photocatalytic Anti-Markovnikov Hydroamination of Alkenes with Primary Heteroaryl Amines, J. Am. Chem. Soc., 2023, 145, 21738–21744.
50. Y. Jiang, D. Liu, M. E. Rotella, G. Deng, Z. Liu, W. Chen, H. Zhang, M. C. Kozlowski, P. J. Walsh and X. Yang, Net-1,2-Hydrogen Atom Transfer of Amidyl Radicals: Toward the Synthesis of 1,2-Diamine Derivatives, J. Am. Chem. Soc., 2023, 145, 16045–16057.
51. C. Pratley, S. Fenner and J. A. Murphy, Nitrogen-Centered Radicals in Functionalization of sp² Systems: Generation, Reactivity, and Applications in Synthesis, Chem. Rev., 2022, 122, 8181–8260.
52. J. M. Ganley, P. R. D. Murray and R. R. Knowles, Photocatalytic Generation of Aminium Radical Cations for C–N Bond Formation, ACS Catal., 2020, 10, 11712–11738.
53. A. J. Musacchio, L. Q. Nguyen, G. H. Beard and R. R. Knowles, Catalytic Olefin Hydroamination with Aminium Radical Cations: A Photoredox Method for Direct C–N Bond Formation, J. Am. Chem. Soc., 2014, 136, 12217–12220.
54. W. C. Danen and F. A. Neugebauer, Aminyl Free Radicals, Angew. Chem., Int. Ed. Engl., 1975, 14, 783–789.
55. M. E. Wolff, Cyclization of N-Halogenated Amines (The Hofmann-Löffler Reaction), Chem. Rev., 1963, 63, 55–64.
56. L. C. Portis, V. V. Bhat and C. K. Mann, Electrochemical Dealkylation of Aliphatic Tertiary and Secondary Amines, J. Org. Chem., 1970, 35, 2175–2178.
57. P. L. Norcott, C. L. Hammill, B. B. Noble, J. C. Robertson, A. Olding, A. C. Bissember and M. L. Coote, TEMPO-Me: An Electrochemically Activated Methylating Agent, J. Am. Chem. Soc., 2019, 141, 15450–15455.
58. J. A. Leitch, T. Rossolini, T. Rogova, J. A. P. Maitland and D. J. Dixon, α-Amino Radicals via Photocatalytic Single-Electron Reduction of Imine Derivatives, ACS Catal., 2020, 10, 2009–2025.
59. T. Yang, W. Xiong, G. Sun, W. Yang, M. Lu and M. J. Koh, Multicomponent Construction of Tertiary Alkylamines by Photoredox/Nickel-Catalyzed Aminoalkylation of Organohalides, J. Am. Chem. Soc., 2024, 146, 29177–29188.
60. W. Xiong, G. Sun, M. Zhou, M. Lu, M. J. Koh and T. Yang, Accessing Fluorinated Tertiary Homoallylamines via Photocatalytic Defluorinative Aminoalkylation of Fluoroalkyl-Substituted Alkenes, ACS Catal., 2024, 14, 8252–8260.
61. T. Morofuji, A. Shimizu and J.-i. Yoshida, Electrochemical C–H Amination: Synthesis of Aromatic Primary Amines via N-Arylpyridinium Ions, J. Am. Chem. Soc., 2013, 135, 5000–5003.
62. Y. Harabuchi, H. Hayashi, H. Takano, T. Mita and S. Maeda, Oxidation and Reduction Pathways in the Knowles Hydroamination via a Photoredox-Catalyzed Radical Reaction, Angew. Chem., Int. Ed., 2023, 62, e202211936.
63. S. Wang, Y. Gao, Z. Liu, D. Ren, H. Sun, L. Niu, D. Yang, D. Zhang, X. Liang, R. Shi, X. Qi and A. Lei, Site-Selective Amination Towards Tertiary Aliphatic Allylamines, Nat. Catal., 2022, 5, 642–651.
64. S. Govaerts, L. Angelini, C. Hampton, L. Malet-Sanz, A. Ruffoni and D. Leonori, Photoinduced Olefin Diamination with Alkylamines, Angew. Chem., Int. Ed., 2020, 59, 15021–15028.
65. T. D. Svejstrup, A. Ruffoni, F. Julia, V. M. Aubert and D. Leonori, Synthesis of Arylamines via Aminium Radicals, Angew. Chem., Int. Ed., 2017, 56, 14948–14952.
66. D. Uraguchi, N. Kinoshita, T. Kizu and T. Ooi, Synergistic Catalysis of Ionic Brønsted Acid and Photosensitizer for a Redox Neutral Asymmetric α-Coupling of N-Arylaminomethanes with Aldimines, J. Am. Chem. Soc., 2015, 137, 13768–13771.
67. N. A. Romero, K. A. Margrey, N. E. Tay and D. A. Nicewicz, Site-Selective Arene C-H Amination via Photoredox Catalysis, Science, 2015, 349, 1326–1330.
68. S. Maity and N. Zheng, A Visible-Light-Mediated Oxidative C–N Bond Formation/Aromatization Cascade: Photocatalytic Preparation of N-Arylindoles, Angew. Chem., Int. Ed., 2012, 51, 9562–9566.
69. M. Sengupta, S. Das, Sk. M. Islam and A. Bordoloi, Heterogeneously Catalysed Hydroamination, ChemCatChem, 2021, 13, 1089–1104.
70. T. Joseph, G. V. Shanbhag, D. P. Sawant and S. B. Halligudi, Chemoselective anti-Markovnikov Hydroamination of α,β-Ethylenic Compounds with Amines Using Montmorillonite Clay, J. Mol. Catal. A: Chem., 2006, 250, 210–217.
71. J. Horniakova, K. Komura, H. Osakia, Y. Kubota and Y. Sugi, The Hydroamination of Methyl Acrylates with Amines Over Zeolites, Catal. Lett., 2005, 102, 191–196.
72. M. R. Saidi, Y. Pourshojaei and F. Aryanasab, Highly Efficient Michael Addition Reaction of Amines Catalyzed by Silica-Supported Aluminum Chloride, Synth. Commun., 2009, 39, 1109–1119.
73. S. Sharma and S. Banerjee, Sheet-Like CuCo₂O₄-Catalyzed Efficient Aza-Michael Addition Reactions of Aromatic Amines to Conjugated Alkenes, ChemistrySelect, 2025, 10, e202500512.
74. G. Bosica, J. Spiteri and C. Borg, Aza-Michael Reaction: Selective Mono- Versus Bis-Addition Under Environmentally-Friendly Conditions, Tetrahedron, 2014, 70, 2449–2454.
75. Y. Zhang, M. Shamzhy, M. Kubů and J. Čejka, Nanosponge Hierarchical Micro-Mesoporous MFI Zeolites as a High-Performance Catalyst for the Hydroamination of Methyl Acrylate with Aniline, Microporous Mesoporous Mater., 2022, 341, 112087.
76. G. Bosica and R. Saliba, Aza-Michael Mono- and Bis-Addition of Primary and Secondary Amines Promoted by Silica-Supported Polyphosphoric Acid, PPA/SiO₂, ChemistrySelect, 2022, 7, e202104359.
77. C. J. Fui, T. X. Ting, M. S. Sarjadi, S. M. Sarkar, B. Musta and M. L. Rahman, Bio-Heterogeneous Cu(0)NC@PHA for n-Aryl/Alkylation at Room Temperature, Polyhedron, 2021, 206, 115310.
78. D. J. Cole-Hamilton and R. P. Tooze, Homogeneous Catalysis – Advantages and Problems, in Catalyst Separation, Recovery and Recycling, 2006, vol. 30, pp. 1–8.
79. N. D. Paul, T. Krämer, J. E. McGrady and S. Goswami, Dioxygen Activation by Mixed-Valent Dirhodium Complexes of Redox Non-innocent Azoaromatic Ligands, Chem. Commun., 2010, 46, 7124–7126.
80. R. Mondal, G. Chakraborty, A. K. Guin, S. Sarkar and N. D. Paul, Iron-Catalyzed Alkyne-Based Multicomponent Synthesis of Pyrimidines Under Air, J. Org. Chem., 2021, 86, 13186–13197.
81. J. Colucci, V. Montalvo, R. Hernandez and C. Poullet, Electrochemical Oxidation Potential of Photocatalyst Reducing Agents, Electrochim. Acta, 1999, 44, 2507–2514.
82. A. S. Pavitt, E. J. Bylaska and P. G. Tratnyek, Oxidation Potentials of Phenols and Anilines: Correlation Analysis of Electrochemical and Theoretical Values, Environ. Sci.: Processes Impacts, 2017, 19, 339–349.
83. S. Das, R. Mondal, G. Chakraborty, A. K. Guin, A. Das and N. D. Paul, Zinc Stabilized Azo-anion Radical in Dehydrogenative Synthesis of N-Heterocycles. An Exclusively Ligand Centered Redox Controlled Approach, ACS Catal., 2021, 11, 7498–7512.
84. S. Pal, S. Mondal, A. K. Guin and N. D. Paul, Zn(II)-Stabilized Radical Ligand Enabled Radical-Type C(sp³)-H Activation-Cascade Cyclization to Imidazopyridines, Chem. – Eur. J., 2025, e202500359.
85. S. Pal, A. K. Guin, S. Khanra and N. D. Paul, Zn(II)-Stabilized Azo-Anion Radical-Catalyzed Dehydrogenative Synthesis of Olefins, J. Org. Chem., 2025, 90, 225–239.
86. S. Pal, A. K. Guin, S. Chakraborty and N. D. Paul, Zn(II)-Stabilized Azo-Anion Radical Catalyzed Sustainable C–C Bond Formation: Regioselective Alkylation of Fluorene, Oxindole, and Indoles, ChemCatChem, 2024, e202400026.
87. S. Chakraborty, R. Mondal, S. Pal, A. K. Guin, L. Roy and N. D. Paul, Zn(II)-Catalyzed Selective N-Alkylation of Amines with Alcohols Using Redox Noninnocent Azo-Aromatic Ligand as Electron and Hydrogen Reservoir, J. Org. Chem., 2023, 88, 771–787.
88. S. Pal, S. Das, S. Chakraborty, S. Khanra and N. D. Paul, Zn(II)-Catalyzed Multicomponent Sustainable Synthesis of Pyridines in Air, J. Org. Chem., 2023, 88, 3650–3665.
89. A. Matsuhisa, H. Koshio, K. Sakamoto, N. Taniguchi, T. Yatsu and A. Tanaka, Nonpeptide Arginine Vasopressin Antagonists for Both V_1A and V₂ Receptors: Synthesis and Pharmacological Properties of 2-Phenyl-4′-(2,3,4,5-tetrahydro-1H-1,5-benzodiazepine-1-carnonyl)benzanilide Derivatives, Chem. Pharm. Bull., 1998, 46, 1566–1579.
90. M. Vellakkaran, K. Singh and D. Banerjee, An Efficient and Selective Nickel-Catalyzed Direct N-Alkylation of Anilines with Alcohols, ACS Catal., 2017, 7, 8152–8158.

---