Regioselective α-alkylation of benzo-fused cyclic amines via organic photoredox catalysis

Abstract

Addressing the synthetic challenge of regioselectively constructing benzo-fused 2-alkyl cyclic amines, this work presents an organophotoredox catalytic method for direct α-alkylation of tetrahydroquinolines, indolines, and related scaffolds with electronically unbiased styrenes. Employing a novel azafluoranthene-derived organic photosensitizer under visible-light irradiation, this transition-metal-free strategy enables efficient hydroaminoalkylation in mild conditions. The protocol exhibits exceptional substrate scope: diverse N-aryl and N-alkyl substituted benzo-fused amines (5–7 membered rings) couple with a series of olefins in up to 96% yield, while maintaining exclusive α-regioselectivity despite competitive C–H sites with near-identical bond dissociation energies. Gram-scale synthesis and concise routes to bioactive alkaloids (e.g., Galipeine, Cuspareine) underscore practical utility and adherence to green chemistry principles through high atom and step economy, and avoidance of precious metals.

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Introduction

2-Alkyl cyclic amines are privileged structural motifs prevalent in natural products and extensively utilized across pharmaceuticals, agrochemicals, and functional materials.¹ In particular, benzo-fused scaffolds exhibit unique significance as constrained molecular frameworks indispensable for bioactive drug design, exemplified by natural products like Angustureine, Galipeine, Guspareine and Galipinine isolated from Galipea officinalis (Scheme 1a).² Consequently, developing efficient synthetic routes to these N-heterocycles remains a high priority within synthetic and medicinal chemistry. Traditional methods typically rely on the catalytic hydrogenation of preformed 2-alkyl N-heteroarenes (Scheme 1b(i)).³ However, accessing these precursors often necessitates Suzuki–Miyaura coupling⁴ or Minisci⁵ heteroaryl α-C–H alkylation, methods constrained by their requirement for often challenging-to-access halogenated substrates or stoichiometric oxidants. Furthermore, the subsequent hydrogenation step generally demands pressurized H₂ gas. Notably, Zhang and co-workers recently disclosed an electroreductive α-alkylation of N-heteroarenes with styrenes using a sacrificial Zn anode, directly producing 2-alkyl tetrahydroquinolines (Scheme 1b(ii)).⁶ Alternatively, direct α-C(sp³)–H functionalization of readily available semi-saturated N-heterocycles via alkene insertion, known as hydroaminoalkylation (HAA), represents an atom- and step-economical route for catalytically assembling structurally diverse benzo-fused 2-alkyl cyclic amines.⁷ While early transition-metal catalysts have been widely explored for the catalytic HAA of non-electrophilic alkenes, reports predominantly focus on N-methyl group functionalization, often requiring high temperatures and struggling with achieving linear selectivity (Scheme 1b(iii)).⁸ Late transition-metal catalysis offers improved linear selectivity for non-electrophilic alkenes, but typically mandates specially tailored directing groups on the amine nitrogen (Scheme 1b(iv)).⁹ This persistent reliance on harsh conditions, specialized reactants, or intricate catalyst design underscores the critical need for the development of safe, environmentally friendly catalytic methods that enable the direct, diverse, and single-step synthesis of valuable benzo-fused 2-alkyl cyclic amines from abundant feedstocks.

Scheme 1 Representative bioactive molecules and the methods for access to benzo-fused 2-alkyl cyclic amines.

Photocatalytic hydroaminoalkylation of electron-deficient alkenes exploiting the nucleophilicity of α-aminoalkyl radicals has emerged over the past decade, typically affording linear (anti-Markovnikov) adducts (Scheme 1c).¹⁰ These key α-amino radicals are typically generated via direct deprotonation of amine cation radicals,¹¹ oxidative desilylation,¹² decarboxylation of α-carboxy amines,¹³ or direct HAT activation.¹⁴ While successful, this approach is largely restricted to activated alkenes (e.g., α,β-unsaturated carbonyls, acrylamides, acrylates), rendering the HAA of electronically unbiased styrenes challenging. In 2021, Cambeiro et al. achieved photocatalytic HAA of aryl alkenes with aniline derivatives using polypyridyl–Ir photocatalysts.¹⁵ Concurrently, Cresswell et al. reported HAA of styrenes with unprotected primary alkylamines using organophotoredox catalysis, involving an irreversible HAT step.¹⁶ However, despite these advances, a general and practical photocatalytic method for the direct HAA of electronically unbiased styrenes with benzo-fused cyclic amines (e.g., tetrahydroquinolines, indolines) to afford valuable benzo-fused 2-alkyl cyclic amines remains elusive. This represents a particularly challenging transformation due to the nearly identical bond dissociation energies (BDEs) for the α-C(sp³)–H and benzylic C–H bonds in these substrates,¹⁷ complicating selective functionalization compared to simple cyclic and acyclic amines.

Motivated by the significance of benzo-fused 2-alkyl cyclic amines and our ongoing research in photochemistry¹⁸ and N-heterocycle synthesis,¹⁹ we herein report a broadly applicable photocatalytic HAA of styrenes with diverse benzo-fused cyclic amines (Scheme 1d). This strategy leverages a new, readily available azafluoranthene-derived organic photosensitizer, enabling a direct and modular route to regioselectively access valuable benzo-fused 2-alkyl cyclic amines, including the synthesis of bioactive alkaloids such as Galipeine and Guspareine.

Results and discussion

Our optimization study commenced with N-phenyl-tetrahydroquinoline (1a) as the substrate and styrene (2a) as the radical acceptor to synthesize 2-alkyl-tetrahydroquinoline derivatives. Initial screening of commercially available photocatalysts (PCs), including expensive Ir- and Ru-based complexes and organic dyes, afforded the desired product 3aa only with low efficiency (Table 1, entries 2–7; see SI for details). Delightfully, a novel class of azafluoranthene-derived PCs, readily synthesized in a modular fashion,²⁰ demonstrated significantly enhanced reactivity. Employing 9-(1-methyl-1H-indol-6-yl)-7,10-diphenylacenaphtho[1,2-c]pyridine (MIDPAP) as the photosensitizer and potassium tris(3,5-dimethylpyrazolyl)borate (KTp*) as an additive in DMA (0.1 M) under irradiation with 420–430 nm blue LEDs at room temperature for 18 h delivered 3aa in 82% yield (entry 1). Subsequent solvent screening revealed that both DMSO and CH₃CN improved the yield (92% and 84%, respectively; entries 8 and 9), with DMSO being optimal. We then evaluated alternative additives. Inorganic bases (K₃PO₄, Na₂CO₃, Cs₂CO₃) afforded 3aa in moderate yields (35–70%; entry 10). In contrast, amine–borane or silanethiol compounds, employed as potential hydrogen atom transfer (HAT) reagents, failed to generate 3aa (entry 11). These results suggest that KTp* likely functions as a base to deprotonate intermediates within the system, rather than as a HAT reagent. Control experiments confirmed the essential roles of visible light, photosensitizer, and KTp*, as the reaction failed to proceed in the absence of any one component (entry 12).

Table 1 Optimization of reaction conditions^a

Entry	Deviation from above conditions	Yield (%)
a Conditions: 1a (0.1 mmol), 2a (0.2 mmol), MIDPAP (5 mol%), KTp* (12 mol%) and DMA (1.0 mL) were stirred at room temperature under N2 atmosphere, with irradiation by 45 W 420–430 nm LEDs for 18 h; yields were determined by ^1H NMR using CH2Br2 as the internal standard. b PC (1 mol%). c DMSO (1.0 mL). d Additive (20 mol%).
1	None	82
2^b	fac-Ir(ppy)3 as PC	n.d.
3^b	[Ir(dtbbpy)(ppy)2]PF6 as PC	42
4^b	[Ru(bpy)3]PF6 as PC	23
5	MesAcr^+BF4^− as PC	n.d.
6	4CzIPN as PC	47
7	Eosin Y as PC	15
8	DMSO instead of DMA	92
9	CH3CN instead of DMA	84
10^c^,^d	K3PO4/Na2CO3/Cs2CO3 as additive	35–70
11^c^,^d	BH3-NMe3/(Ph)3Si-SH/(i-Pr)3Si-SH	n.d.
12	Without PC, KTp* or light	n.d

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With the optimized conditions established, we explored the scope of radical acceptor with diverse alkenes (Scheme 2). Broadly, styrene derivatives underwent efficient hydroaminoalkylation with N-phenyl-tetrahydroquinoline (1a) to deliver 2-alkyl-tetrahydroquinolines 3aa–3aq in synthetically useful yields. Halogenated styrenes displayed distinct reactivity profiles: para-fluoro- (3ab, 78%), meta-fluoro- (3ac, 65%), and sterically demanding ortho-fluorostyrene (3ad, 73%) were well accommodated. In contrast, para-chloro- (3ae) and para-bromostyrene (3af) provided diminished yields, presumably due to their weaker electron-withdrawing inductive effects compared to fluorine. Strongly electron-withdrawing groups (p-CF₃, p-CN, p-CO₂Me) enhanced reactivity, furnishing 3ag–3ai in 51–96% yields, while moderately electron-donating substituents (p-Me, p-OBoc) also remained compatible with the reaction conditions. Intriguingly, the strongly donating p-methoxy group completely suppressed reactivity, whereas meta- and ortho-methoxystyrenes (3al–3am) proceeded efficiently. Fused-aromatic 2-vinylnaphthalene and heteroaromatic olefins, including 2-vinylthiophene and 2-vinylpyridine, reacted effectively (3an–3ap, 61–82%). Significantly, an L-menthol-functionalized styrene derivative yielded 3aq in 94% yield, highlighting late-stage modification potential. The protocol was successfully extended to electron-deficient alkenes: N,N-dimethylacrylamide (3ar), acrylates (3as–3at), and cyclohexenone (3au) furnished the corresponding products in 60–79% yields. Crucially, sterically encumbered 1,1-disubstituted alkenes were also successfully incorporated (3av–3ax, 61–74%), further underscoring the versatility of this methodology.

Scheme 2 Substrate scope of alkenes and amines. Reaction conditions: 1 (0.2 mmol), 2 (0.4 mmol), MIDPAP (5 mol%), KTp* (12 mol%) and DMSO (2.0 mL) were stirred at room temperature under N₂ atmosphere, with irradiation by 45 W 420–430 nm LEDs for 18 h, isolated yield. The diastereomeric ratio was determined by ¹H NMR spectroscopy.

Subsequently, the substrate scope of various tetrahydroquinoline derivatives was investigated (Scheme 2). N-Phenyl-tetrahydroquinolines bearing diverse substituents underwent efficient hydroaminoalkylation with 2-vinylpyridine to deliver products 3bp–3pp in consistently high yields. Both electron-donating (–Me, –OMe, –Ph) and electron-withdrawing groups (–F, –Cl, –Br) at ortho-, meta-, or para-positions of the N-phenyl ring exhibited no significant impact on efficiency, affording 3bp–3jp in 68–86% yields. Heteroaryl-substituted derivative (3kp) as well as dimethyl/dimethoxy analogues (3lp–3mp) were equally compatible. Modifications to the fused quinoline core at C6/C7 positions proceeded efficiently regardless of substituent electronics—halogens or methyl groups delivered 3np–3pp in 73–79% yields. Critically, N-alkyl-tetrahydroquinolines (N-methyl, 3qp; N-ethyl, 3rq; N-benzyl, 3sq) also proceeded smoothly under this reaction, exhibiting high regioselectivity that favored the α-ring position in alkylation over the acyclic sites. The protocol extended to benzo-fused N-heterocycles beyond six-membered rings: both seven-membered and five-membered analogues afforded products effectively (3tp–3vp, 65–86%). Notably, non-fused cyclic amines including N-phenylpiperidine (3wp, 66%) and N-phenylmorpholine (3xq, 78%) underwent smooth functionalization, while N,N-dimethylaniline yielded 3yp in 72% yield. Limitations were observed for heterocycles containing additional heteroatoms (oxygen/sulfur), which furnished 3zp–3z′q only in diminished yields, likely due to their lower inherent reactivity as well as the presence of competing reaction sites.

To establish practical utility, a gram-scale reaction was conducted under standard conditions, affording 3aa in 74% yield with retained efficiency (Scheme 3). Significantly, this protocol enables rapid access to bioactive alkaloids from readily available materials. Treatment of N-methyl-tetrahydroquinoline 1q with tert-butyl (2-methoxy-4-vinylphenyl) carbonate 2y under optimized photoredox conditions, followed by Boc deprotection under basic conditions, delivered Galipeine in 59% yield over two steps. Subsequent O-methylation of the phenolic hydroxyl group employing methyl iodide and sodium hydride in THF furnished Cuspareine in 80% yield, completing an efficient synthesis of both alkaloids, significantly reducing synthetic steps compared to literature routes.²¹

Scheme 3 Gram-scale synthesis and synthetic applications.

To gain insights into this hydroaminoalkylation reaction, a series of mechanistic investigations were carried out. The radical nature of this transformation was unambiguously confirmed through radical trapping and radical clock experiments (Scheme 4A). Specifically, no desired product 3ep was detected when the reaction was conducted in the presence of radical scavenger TEMPO. In the radical clock experiment, the reaction of N-phenyl-tetrahydroquinoline with cyclopropane-ring-containing alkene 2z afforded the ring-opened product 3az, providing direct evidence for the involvement of a radical pathway. To identify the ultimate proton source in this transformation, deuterium labeling studies were performed (Scheme 4B). When deuterated N-phenyl-tetrahydroquinoline (1e-d₂) was reacted with 2-vinylpyridine under standard conditions, no deuterium incorporation was observed at the benzylic position, indicating that the amine cation radical does not serve as a proton source in this system. Additionally, the reaction conducted in deuterated DMSO (DMSO-d₆) resulted in 0% deuterium incorporation, ruling out the solvent as a proton donor. In contrast, an 80% deuteration level at the benzylic position was achieved when the reaction was performed with 11 equivalents of D₂O. The minor hydrogen incorporation in the product is attributed to trace water present in the reaction system. These results suggest that the reaction may involve a benzyl anionic intermediate, with water in the system acting as the proton source. Light on/off experiments demonstrated that continuous irradiation is essential for sustaining the transformation, and combined with the quantum yield (φ = 0.76), the radical chain mechanism could be ruled out (Scheme 4C). Furthermore, fluorescence quenching experiments revealed that the excited-state photocatalyst (MIDPAP*) is quenched by N-phenyl-tetrahydroquinoline (1a) rather than styrene (2a) or KTp*, supporting a reductive quenching pathway (Scheme 4D). To determine whether C–H bond activation is the rate-determining step, deuterium kinetic isotope effect (KIE) experiments were conducted (Scheme 4E). A primary kinetic isotope effect (KIE = 4.0) was observed in intermolecular parallel experiments, confirming that C–H bond cleavage contributes significantly to the rate-determining step.

Scheme 4 Mechanistic studies.

Based on integrated mechanistic evidence and precedent studies,¹¹ the proposed photoredox catalytic cycle is depicted in Scheme 5. Photoexcitation of the catalyst PC generates the triplet excited state PC* (E_1/2(PC*/PC⁻) = +1.14 V vs. SCE), which subsequently undergoes reductive quenching by N-phenyl-tetrahydroquinoline (E_1/2 = +0.94 V vs. SCE) producing reduced catalyst PC˙⁻ and nitrogen-centered radical cation A. Concerted deprotonation of A releases the α-aminoalkyl radical B, which adds regioselectivity to styrene forming benzylic radical C. Single-electron reduction of C by PC˙⁻ generates carbanion D, followed by protonation via H₂O to afford the desired product 3aa while regenerating ground-state catalyst PC.

Scheme 5 Proposed mechanism.

Conclusions

In summary, we have developed an environmentally benign organophotoredox catalytic system for regioselective α-alkylation of benzo-fused cyclic amines, utilizing a novel azafluoranthene-derived organic photosensitizer under mild conditions. This strategy overcomes the selectivity challenges by differentiating nearly identical α-C(sp³)–H and benzylic C–H BDEs to achieve exclusive α-functionalization across diverse substrates. Mechanistic studies confirm a radical pathway with C–H cleavage as rate-determining, involving reductive quenching of the excited photocatalyst by the amine, and H₂O-mediated protonation of key intermediates. Gram-scale reactions and streamlined syntheses of bioactive alkaloids (Galipeine, Cuspareine) demonstrate practical utility with significant atom and step economy, providing general access to privileged 2-alkyl cyclic amine motifs from abundant feedstocks and advancing sustainable medicinal chemistry through elimination of precious catalyst and stoichiometric oxidant, and reduced synthetic complexity.

Author contributions

Y. C. and G.-J. D. conceived and supervised the project. J. C. provided the azafluoranthene-derived photosensitizers. Z. X. performed the experiments. R. W., C. L., and L. Z. participated in substrate synthesis and the analytical characterization. Y. C. and Z. X. wrote the manuscript and SI. All authors discussed the results and commented on the manuscript.

Conflicts of interest

There are no conflicts to declare.

Data availability

The data for this work are provided in the supplementary information (SI). Supplementary information: detailed optimization tables, experimental procedures, and characterization data for all compounds. See DOI: https://doi.org/10.1039/d5qo01322d.

Acknowledgements

Financial support from the National Natural Science Foundation of China (No. 22301256 and 22271244), the Scientific Research Fund of the Hunan Provincial Education Department (24C0070), the Open Research Fund of School of Chemistry and Chemical Engineering, Henan Normal University (2022C02), and the Hunan Provincial College Student Innovation Training Project (S202410530222) is gratefully acknowledged.

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