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. 2025 Sep 4;147(37):33700–33710. doi: 10.1021/jacs.5c09500

Divergent Synthesis of 1‑Azabicyclo[n.1.1]alkane Bioisosteres via Photoinduced Palladium Catalysis

Ying Zhang †, Kai-Dian Li †, Song Yu ‡, Kangyin Pan §, Hongtao Xu §, Huan-Ming Huang †,*
PMCID: PMC12447495  PMID: 40905730

Abstract

Nitrogen heterocycles are indispensable structural motifs in pharmaceuticals, agrochemicals, and materials science. However, the development of new synthetic methods to access these frameworks remains a significant challenge. Here, we describe a switchable radical approach for the synthesis of 1-azabicyclo[2.1.1]­hexanes and 1-azabicyclo[4.1.1]­octenes through the coupling of azabicyclo[1.1.0]­butanes with 1,3-dienes, mediated by a visible-light-driven palladium photocatalytic system. This method exhibits a broad substrate scope, excellent functional group compatibility, and the capacity to assemble complex architectures, underscoring its utility in accessing valuable aza-bioisosteres. The strategy has also been employed successfully in DNA-encoded library (DEL) synthesis. Mechanistic studies, synthetic applications, and computational analyses corroborate the proposed open-shell pathway, revealing that allylic palladium intermediate formation and regiodivergent nucleophilic addition are key to achieving divergent synthesis.

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Introduction

Nitrogen heterocycles are widely present in pharmaceuticals, agrochemicals, natural products, and material science. , Pyridine, for example, ranks as the second most common ring system in marketed drugs, underscoring the enduring demand for innovative synthetic methods to access these scaffolds. , Driven by the “escape from flatland” paradigm, , three-dimensional (3D) aza-bioisosteressuch as 1-, 2-, and 3-aza-bioisostereshave emerged as compelling alternatives to planar pyridine motifs in medicinal chemistry − and as versatile building blocks in synthesis (Figure A). − These sp3-rich architectures offer enhanced spatial and electronic profiles, improved aqueous solubility, and reduced lipophilicity, making them attractive, patent-free candidates for drug discovery with optimized physicochemical properties. − Despite their potential, synthetic routes to 1-azabicyclo[2.1.1]­hexanes (1-aza-BCHs) remain scarce. − In 1985, Malpass et al. reported a formal dyotropic rearrangement of N-chloroamines catalyzed by alumina, yielding C-chloroamines. Later, Heimgartner and Mloston disclosed a polar [2π+2σ] cycloaddition of azabicyclo[1.1.0]­butanes (ABBs) with olefins, though only two limited examples were demonstrated. Most recently, Aggarwal and his team achieved an elegant intramolecular Friedel–Crafts spirocyclization of ABBs to construct complex sp3-rich frameworks. Given these sparse precedents, general and modular strategies for 1-aza-BCH synthesis remain a critical unmet need.

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Background and reaction design.

Recent advances in strain-release chemistry have provided efficient routes to (hetero)­bioisosteres. ,,− For example, Leitch, Brown & Fessard, Bach, Feng & Wang, and Zheng have independently demonstrated the synthesis of 2-azabicyclo[2.1.1]­hexanes (2-aza-BCHs, I in Figure A) via (3 + 2) cycloadditions of bicyclo[1.1.0]­butanes (BCBs). Similarly, Zheng and Wang & Li developed methods for constructing 2-azabicyclo[3.1.1]­heptenes (2-aza-BCHeps, II in Figure A) through titanium-catalyzed or pyridine-boryl radical-mediated reactions of BCBs with vinyl azides. Mykhailiuk et al. reported a general approach to 3-azabicyclo[3.1.1]­heptanes (3-aza-BCHeps, III in Figure A) via reductive ring-opening of spirocyclic oxetanyl nitriles, while Li et al. achieved the asymmetric synthesis of chiral 3-aza-BCHeps through copper-catalyzed formal [4π+2σ] cycloadditions. Glorius et al. disclosed a silver-mediated cycloaddition of bicyclobutanes with isocyanides to access polysubstituted 3-azabicyclo[3.1.1]­heptanes, and Deng & Zhang reported an elegant example of Eu­(OTf)3-catalyzed formal polar [4π+2σ] cycloaddition of bicyclo[1.1.0]­butanes with nitrones to access polysubstituted 2-oxa-3-azabicyclo[3.1.1]­heptanes (IV in Figure A). Soon after, Zhou and his team developed an elegant example of copper-catalyzed enantioselective [4π+2σ] cycloaddition of bicyclobutanes with nitrones. In contrast, the transformation of azabicyclo[1.1.0]­butanes (ABBs) into 1-azabicyclo[2.1.1]­hexanes (1-aza-BCHs, V in Figure A) remains underdeveloped, with only two reported examples. , Saha and coworkers described a formal [3 + 2] cycloaddition of ABBs with (aza)­oxyallyl cations, affording bridged bicyclic azetidines via a two-step sequence (Figure B). More recently, Aggarwal and Noble achieved the synthesis of 1-aza-BCHs through a polar-radical-polar relay strategy under photochemical conditions (Figure C). Given the scarcity of methods, the development of general and efficient approaches to 1-aza-bioisosteres remains an urgent challenge.

Recent advances in photoinduced palladium catalysis have established its dual capacity to mediate both radical and polar transformations, emerging as a versatile platform for complex molecule synthesis. − Building upon principles of divergent synthesis, which offer sustainable access to structural diversity from common precursors, we hypothesized that azabicyclo[1.1.0]­butanes (ABBs) could serve as ideal radical precursors. − Under visible light irradiation, photoexcited palladium catalysts may activate ABBs to generate stabilized α-keto radicals, − which could undergo regioselective addition to 1,3-dienes. − Subsequent formation of allylic palladium intermediates − would then enable divergent functionalization through nucleophilic trapping by nitrogen-centered anions, with reaction parameters dictating product selectivity (Figure D). This unprecedented radical strategy establishes a versatile platform for the divergent synthesis of 1-aza-bioisosteres.

Results and Discussion

Reaction Design and Optimization

Our investigation of the photoinduced Pd-catalyzed synthesis of 1-aza-BCHs began with ABB 1a and 1,3-diene 2a as model substrates, employing Pd­(PPh3)4 as the catalyst and MeCN as the solvent in a water-cooled photoreactor. Initial efforts at 40 °C yielded no product 3 after 6 h (Table , entry 1). Removing the cooling bath to raise the temperature to 60 °C significantly improved the reactivity, affording 3 in 26% yield after 6 h, likely due to enhanced nucleophilic attack (entry 2). Increasing photon flux further boosted efficiency: light intensities of 1 W/cm2 and 1.3 W/cm2 increased yields to 47% (entry 3) and 71% (entry 5), respectively, highlighting light’s critical role in sustaining the catalytic cycle. Solvent choice proved crucialreplacing MeCN (bp 81–82 °C) with DMA (bp 164–166 °C) dramatically improved the yield to 95% NMR yield (88% isolated yield, entry 6). Screening alternative Pd catalysts (PdCl2: 67%, entry 7; Pd­(OAc)2: 68%, entry 8) or phosphine ligand (BINAP, 64%, entry 9) underperformed compared to Pd­(PPh3)4. The photocatalyst [Ir­(dtbbpy)­(ppy)2]­PF6 was evaluated, previously reported by Aggarwal and Noble as highly reactive in their work, with no target product detected (entry 15). Deviations from optimal substrate stoichiometry (entry 10), Pd loading (entries 13–14), or light source (405 nm LED, 0.5 W/cm2, entry 19) reduced efficiency, while alternative bromine salts maintained good yields (entry 11). Temporal analysis showed that yields plateaued after 6 h (entry 12). Further screening of bases, solvents, K2CO3/LiBr ratios, and DMA concentrations confirmed that the conditions in entry 6 remained optimal (entries 16–18, 20–21). Control experiments confirmed the necessity of palladium, Xantphos, LiBr, and K2CO3 and high photon flux light for high yields (entries 22–24).

1. Reaction Optimization for the Synthesis of 1-Azabicyclo[2.1.1]­hexanesa .

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a

Optimized reaction conditions: 1a (0.4 mmol, 2.0 equiv), 2a (0.2 mmol, 1.0 equiv), Pd­(PPh3)4 (5 mol %), Xantphos (6 mol %), LiBr (80 mol %), K2CO3 (2.0 equiv) in DMA (2.0 mL, 0.1 M) at 60 °C under irradiation of 450 nm LEDs (1.3 W/cm2) in a water-cooled aluminum heat block for 6 h.

b

Yields determined by 1H NMR with dibromomethane as the internal standard.

c

Yields of the isolated product 3.

Substrate Scope for the Synthesis of 1-Azabicyclo[2.1.1]­hexanes

Following the establishment of optimal reaction conditions, we investigated the substrate scope to construct various 1-azabicyclo[2.1.1]­hexanes (Figure ). First, various substituted ABBs were examined. For aryl-substituted ABB derivatives, electron-withdrawing substituents such as fluoro (4), chloro (5), and trifluoromethyl (11) groups exhibited satisfactory performance, yielding products in 52–92% efficiency. Electron-donating groups, including tert-butyl (6), methyl (7–9), dimethylamino (10), and methoxy (12), demonstrated good reactivity, affording the corresponding products in 40–91% yields. Heteroaromatic variants of ABB bearing thiophene (13) and furan (14) substituents were successfully transformed into products with 85% and 65% yields, respectively. Additionally, both linear alkyl ABBs (15–17) and cyclic alkyl ABBs (18–20) proved to be compatible with the current catalytic system, delivering target products in 44–85% yields.

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Substrate scope of 1-azabicyclo[2.1.1]­hexanes. Reaction conditions: 1 (0.4 mmol, 2.0 equiv), 2 (0.2 mmol, 1.0 equiv), Pd­(PPh3)4 (5 mol %), Xantphos (6 mol %), LiBr (80 mol %), K2CO3 (2.0 equiv) in DMA (2.0 mL, 0.1 M) at 60 °C under irradiation of 450 nm LEDs (1.3 W/cm2) in a water-cooled aluminum heat block for 6 h.

Subsequently, we investigated the expansion of 1,3-dienes. For 1-aryl-1,3-dienes, substrates bearing electron-withdrawing groups such as fluoro (21), chloro (22), amide (30), and ester (31) substitutions demonstrated excellent reactivity, affording the corresponding products in 74–89% yields. Notably, electron-donating substituents, including phenyl (23), tert-butyl (24), methyl (25, 27, 29), and methoxy (26,28) groups, also exhibited good reactivity with yields ranging from 69% to 92%. Alteration of substitution patterns to the m-methyl (27), m-methoxy (28), or o-methyl (29) positions resulted in slightly diminished but still satisfactory efficiencies (73–78%). Polysubstituted aromatic systems such as m-dimethoxy (32) and 2,4,6-trimethyl (33) benzene rings were well tolerated, providing products in 83% and 73% yields, respectively. The protocol proved effective for heteroaromatic and fused aromatic substituted diene groups, such as furoyl (34), pyridine (35), and naphthyl (36) moieties, yielding products in 71–87% yields. Furthermore, alkyl-substituted diene (37) and polysubstituted diene (38) systems were successfully transformed into the desired products, demonstrating the broad applicability of this methodology.

Reaction Optimization of 1-Azabicyclo[4.1.1]­octenes

Building upon the optimization of the synthesis of 1-azabicyclo[2.1.1]­hexanes, we observed that substitution of 1-aryl-1,3-diene with 2-aryl-1,3-diene 2aa led to the formation of a mixture containing both 1-azabicyclo[4.1.1]­octenes 39 and 1-azabicyclo[2.1.1]­hexanes 40 in a 2.7:1 ratio (Table ). This outcome prompted systematic optimization efforts to selectively access the more structurally distinctive product 39. Through ligand screening, we identified that the alkyl-bidentate phosphine ligand L 4 enabled the exclusive formation of product 39 with excellent chemoselectivity (entry 1). Further optimization revealed that replacement of bromide with iodide ions (entries 2 and 3), coupled with increased stoichiometric equivalents, significantly accelerated the palladium-mediated activation of substrate 1a. This modification, combined with an extended reaction time, enhanced the process efficiency from an initial 64% (entry 3) to 75% NMR yield (68% isolated yield, entry 7). Notably, attempts to improve catalyst loading adjustments proved to be ineffective (entry 8), demonstrating the critical balance required in catalytic system design.

2. Reaction Optimization for the Synthesis of 1-Azabicyclo[4.1.1]­octenes .

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a

Optimized reaction conditions: 1a (0.4 mmol, 2.0 equiv), 2aa (0.2 mmol, 1.0 equiv), Pd (PPh3)4 (5 mol %), L4 (6 mol %), KI (1.5 equiv), K2CO3 (2.0 equiv) in DMA (2.0 mL, 0.1 M) at 60 °C under irradiation of 450 nm LEDs (1.3 W/cm2) in a water-cooled aluminum heat block for 15 h.

b

Yields determined by 1H NMR with dibromomethane as the internal standard.

c

Yields of the isolated product.

d

Ratio of 39 and 40.

Substrate Scope for the Synthesis of 1-Azabicyclo[4.1.1]­octenes

Building upon our synthetic methodology, we conducted comprehensive substrate investigations for the synthesis of 1-azabicyclo[4.1.1]­octenes (Figure ). The reaction demonstrated excellent compatibility with electron-withdrawing groups, including fluorine (41) and chlorine (42). Electron-donating aryl-substituted ABBs, such as tert-butyl (43), methyl (44), and methoxy (45) substituents, could also be tolerated with the current catalytic reaction. Heteroaromatic systems such as a furan-substituted substrate (46) could also exhibit good compatibility in 62% yield. Notably, alkyl-substituted ABBs (47–49) and cycloalkyl ABBs (50–52) displayed superior performance with yields ranging from 62 to 93%. In the 2-aryl-1,3-diene substrate 2 investigation, various aromatic and aliphatic substitutions generally afforded products (53–58) in moderate to excellent yields.

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Substrate scope of 1-azabicyclo[4.1.1]­octenes. Reaction conditions: 1 (0.4 mmol, 2.0 equiv), 2 (0.2 mmol, 1.0 equiv), Pd (PPh3)4 (5 mol %), dcypb (6 mol %), KI (1.5 equiv), K2CO3 (2.0 equiv) in DMA (2.0 mL, 0.1 M) at 60 °C under irradiation of 450 nm LEDs (1.3 W/cm2) in a water-cooled aluminum heat block for 15 h. Ar = 4-phenyl-substituted aromatic ring (4-Ph-Ph).

Manipulation of 1-Aza-bioisosteres and DNA-Encoded Library (DEL) Synthesis

To demonstrate the practical applicability of this methodology, we successfully executed a gram-scale reaction at a 4.5 mmol scale, obtaining the desired product 3 as a brown oil in 86% isolated yield (1.12 g) (Figure A). The synthetic versatility of 1-azabicyclo[2.1.1]­hexane 3 was further showcased through diverse derivatizations: bridged bicyclic azetidine (59), olefin (60) via a Wittig reaction, primary amine (61) via reductive amination, and alcohol (62) under suitable reaction conditions. In addition, 1-azabicyclo[4.1.1]­octene 39 could also undergo reductive amination to afford primary amine (63). These conversions collectively highlight the compound’s potential as a versatile synthetic building block for further application. Building upon these findings, we further extended the methodology to DNA-encoded library (DEL) synthesis (Figure B). , Through amide condensation-mediated conjugation of 1,3-diene at the amine terminus of the DNA headpiece, we successfully implemented the 1-azabicyclo[2.1.1]­hexane incorporation strategy under our established mild reaction conditions. This platform demonstrated efficient coupling with diverse ABBs (65–72), enabling precise installation of bicyclic architectures onto DNA scaffolds to expand the structural diversity of DNA-encoded libraries. The successful implementation not only confirms the excellent functional group compatibility and operational mildness of our protocol but also establishes a versatile platform for combinatorial library construction, demonstrating significant potential for broad applicability.

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Gram-scale synthesis, further applications, and DNA-encoded library (DEL) synthesis.

Mechanistic Studies

To elucidate the mechanism of this unprecedented divergent synthesis, we conducted mechanistic studies (Figure ). Radical inhibition experiments using 2,2,6,6-tetramethylpiperidin-1-oxyl (TEMPO) fully suppressed the formation of product 3 (Figure A, upper). Trapping with methyl 2-((phenylsulfonyl)­methyl)­acrylate (73) afforded radical adduct 74 (19% yield), confirming the presence of radical intermediate II (Figure A, down). Exposing cyclopropane-containing diene 2t to standard conditions yielded the ring-opened product 75 (11%), supporting a radical ring-opening step (Figure B). Intermediate 76, when subjected to the reaction, delivered 3 in 58% yield, consistent with its formation in situ from 1a and LiBr (Figure C). Electron paramagnetic resonance (EPR) study with phenyl tert-butyl nitrone (PBN) spin-trapping identified oxygen-centered radical 77, further verifying the mechanism (Figure D). These collective findings demonstrate the generation of α-carbonyl radical II during the reaction process. UV–vis absorption analysis demonstrates light absorption by Pd­(PPh3)4 at the reaction wavelength (450 nm), thereby confirming the photoactivation of Pd­(PPh3)4 as the operative photocatalyst in this system (Figure E). Furthermore, Stern–Volmer quenching studies integrated into our mechanistic investigations revealed that the palladium catalyst was exclusively quenched by alkyl bromide I, with no observable interaction with 2a (Figure F). When only substrate 1a and Pd­(PPh3)4 are present, the photocatalyst undergoes quenching, albeit inefficiently. This observation indicates a low electron transfer efficiency between 1a and Pd­(PPh3)4, resulting in diminished reaction yield. Based on these studies, we propose the following mechanisms for the unprecedented divergent synthesis of 1-aza-bioisosteres enabled by photoinduced palladium catalyst − under visible light condition (Figure G). The bromide intermediate I, generated in situ from ABB 1a and LiBr, undergoes single-electron reduction via photoexcited palladium catalyst (E 1/2([PdI]/[Pd0]*) = −2.76 V vs Fc+/Fc in THF) to form the α-carbonyl radical II under visible light condition. Subsequent trapping by 1,3-dienes 2a generates allylic radical III, − which combines with Pd­(I) species to form π-allyl Pd­(II) intermediate IV. − Intramolecular nucleophilic attack by the nitrogen anion in IV then delivers the 1-azabicyclo[2.1.1]­hexane product 3 (Figure G, left). Alternatively, when KI is employed, iodide intermediate V forms and is reduced to azetidinyl radical anion II. With 2-substituted 1,3-dienes 2, this pathway proceeds via allylic radical VI and Pd­(I) species to generate intermediate VIII, ultimately furnishing 1-azabicyclo[4.1.1]­octene derivative 53 through intramolecular cyclization (Figure G, right). A density functional theory (DFT) investigation (see Supporting Information for computational details) was conducted to elucidate the origin of the observed selectivity, as illustrated in Figure H. Coupling reactions involving 1-substituted 1,3-butadienes consistently yield the strained bicyclic products 3–38, whereas reactions with 2-substituted analogues afford products 39 and 41–58, which feature larger ring systems. To rationalize this divergence in product distribution, transition states and products for two competing ring-closing pathways were computed for intermediates IV and VIII, respectively (Figure G). For intermediate IV (derived from 1-phenyl-1,3-butadiene, left side of Figure H), the ring-closing transition state TS_IV, leading to the desired product 3, is strongly favored kinetically over its competing pathway via transition state TS_IV′ (ΔΔG ‡ = −21.2 kcal mol–1). This pronounced kinetic preference arises from significant steric repulsion between the terminal phenyl substituent and the palladium ligand in TS_IV′, which is absent in TS_IV. Although TS_IV leads to a strained and thus slightly less thermodynamically favored product 3 compared to 3′, the marked kinetic disparity is the key factor influencing selectivity. In contrast, for intermediate VIII (derived from 2-phenyl-1,3-butadiene, right side of Figure H), the reaction is both kinetically and thermodynamically favored via TS_VIII over TS_VIII′ (ΔΔG ‡ = −8.9 kcal mol–1; ΔΔG = −10.7 kcal mol–1), resulting in preferential formation of product 53 over 53′. This selectivity is attributed to minimal steric interactions involving the backbone substituent in both pathways. However, the pathway via TS_VIII leads to a less strained scaffold, thus favoring TS_VIII and the formation of 53. We also investigated the effect of the ligand on the reaction outcome by comparing two competing pathways for intermediate VIII using Xantphos in place of the selectivity-optimal ligand L4. Interestingly, the calculated kinetic preference is significantly reduced: the activation barrier difference between TS_VIII­(Xantphos) (leading to 53) and TS_VIII′(Xantphos) (leading to 53′) narrows to just −2.9 kcal mol–1 (see Supporting Information). This computational result is consistent with experimental observations (Table ), where the selectivity decreased upon switching to Xantphos. These findings further support the validity of our computational analysis in elucidating the origin of the selectivity.

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Mechanistic and computational studies. Optimized geometries of the transition states and products correspond to the two competing ring-closing pathways for intermediates IV and VIII, with computed relative Gibbs energies (ΔΔG ‡) and electronic energies (ΔΔE ‡) between the respective pathways.

Conclusions

In summary, we have developed a novel visible-light-driven palladium catalytic platform that enables the unprecedented divergent synthesis of two distinct classes of nitrogen-containing bioisosteres from common azabicyclo[1.1.0]­butane precursors. Key mechanistic insightsobtained through radical trapping experiments, EPR spectroscopy, and computational studiesconfirm an open-shell pathway with excellent regioselective control over product formation. Our investigations reveal that the divergent synthesis is governed by the structure of phosphine ligands and the substitution pattern on 1,3-diene derivatives. This radical-polar crossover catalytic system exhibits exceptional synthetic utility, including a broad substrate scope with excellent functional group tolerance, high-yielding access to valuable 3D aza-bioisosteric scaffolds, successful application in complex molecule synthesis, and compatibility with DNA-encoded library technology. The methodology not only advances the synthesis of sp3-rich nitrogen heterocycles but also establishes a versatile platform for future developments in selective radical chemistry and bioisostere design.

Supplementary Material

ja5c09500_si_001.pdf (17MB, pdf)

Acknowledgments

We are grateful for financial support from the National Natural Science Foundation of China (22201179 & 22471168 to H.-M.H.) and the startup funding from ShanghaiTech University (H.-M.H.). We thank the HPC Platform of ShanghaiTech University for computing time. We sincerely thank Prof. Chaodan Pu and Zhuo Zhao for their help with mechanistic studies.

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/jacs.5c09500

  • Experimental procedures, NMR spectra for the products, X-ray crystallographic data, and computational details (PDF)

The authors declare no competing financial interest.

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