Cyclic aldimine derivatives are significant intermediates, attributed to their diverse biological effects and their function as essential reagents or intermediates in organic synthesis.^[1] As a result, cyclic aldimines have been extensively modified through diverse chemical transformations in previous studies.^[2] Given that the C=N double bonds in imines are the primary reactive sites, the reported methodologies mainly focus on nucleophilic addition,^[3] ring- expansion,^[4] and annulation reactions.^[5] In contrast, the unsaturated C=N bond in cyclic aldimines must be maintained for the synthesis of many desired molecules, which is typically achieved through C—H functionalization. However, research in this area is constrained due to the inherent stability of the C—H bond (Scheme 1, a).^[6] The radical- mediated three-component C—H functionalization remains underexplored and has not been thoroughly investigated.

Strained small sp³-rich rings are frequently employed as unique bioisosteres in modern medicinal chemistry, mainly because their small size and structural rigidity often lead to enhanced pharmacological properties compared to their parent molecules, such as aqueous solubility and metabolic stability.^[7] For instance, 1,3-disubstituted bicyclo[1.1.1]- pentanes (BCPs) are frequently used as bioisosteres for alkynes and para-substituted aromatic rings.^[8] Likewise, mono-substituted bicyclo[1.1.1]pentanes (BCPs) are sought after as replacements for tertiary butyl and phenyl groups.^[9] Consequently, significant efforts have been conducted to develop versatile and effective strategies for synthesizing the strained bicyclo[1.1.1]pentanes (BCPs) rings.

Recently, the development of radical-mediated multicomponent reaction has received considerable attention due to their multifaceted technical advantages, significantly simplifying the cumbersome purification steps inherent in traditional multi-step synthesis.^[10-11] On the other hand, the hypervalent iodine is commonly employed in these systems, which eliminates the need for transition metal catalysts, simultaneously resolving heavy metal contamination concerns.^[12] These multicomponent reactions also have emer- ged as promising approaches for the rapid synthesis of 1,3-disubstituted bicyclo[1.1.1]pentanes (BCPs).^[13-15]

To address the research shortcomings and to continue our work on the functionalization of [1.1.1]propellane and green synthesis,^[16] herein, we disclose a practical method for direct 1,3-azidoheteroarylation of [1.1.1]propellane with cyclic aldimines and azidotrimethylsilane (TMSN₃) under mild conditions. Importantly, the resulting functionalized strained rings act as synthetically flexible building blocks for a variety of transformations, making this method particularly appealing for constructing complex medicinal skeletons.

To achieve the transformation, N-sulfonyl ketimine (1a), [1.1.1]propellane (2), and azidotrimethylsilane (TMSN₃) (3) were selected as the initial reactants. The optimal reaction conditions were determined through a systematic evaluation involving the selection of an appropriate oxidant, solvent, reaction atmosphere and temperature (Table 1). When the reaction was conducted in MeCN under a nitrogen atmosphere with (diacetoxyiodo)benzene (PIDA) serving as the oxidant, the target 1-azido-3-heteroaryl bicyclo[1.1.1]pentane (BCP) (4a) was synthesized with a yield of 40%. Alternative oxidant, including bis(trifluoro- acetoxyiodo)benzene (PIFA), 3-chloroperbenzoic acid (m-CPBA), and hydrogen peroxide (H₂O₂), demonstrated negligible catalytic activity in the reactions (Table 1, Entries 2~4). Control experiment showed that the presence of an oxidant was a crucial and essential element for the successful execution of this transformation. To enhance the yield of corresponding product, a wide range of organic solvents including dimethylsulfoxide (DMSO), N-methyl- pyrrolidone (NMP), dimethyl formamide (DMF), ethyl acetate (EA), methyl alcohol (MeOH), and dichloromethane (DCM) were explored (Table 1, Entries 6~11), and it was found that dimethyl formamide (DMF) was the optimal solvent for 1,3-azidoheteroarylation of [1.1.1]propellane.

To further improve the yields, the dosage of azidotrimethylsilane (TMSN₃) (3) was then studied. Increasing the dosage of TMSN₃ (3) did not significantly influence the azidoheteroarylation process (Table 1, Entry 12). Conversely, decreasing the dosage of azidotrimethylsilane (TMSN₃) (3) markedly diminished the efficiency of the azidoheteroarylation reaction (Table 1, Entry 13). Of note, excluding azidotrimethylsilane (TMSN₃) (3) from the reaction mixture led to the absence of any product (Table 1, Entry 14). Further evaluation of reaction atmosphere and temperature did not obviously improve the reactivity of the reaction.

Armed with the optimal reaction conditions, the range of substrates suitable for the azidoheteroarylation of [1.1.1]- propellane was then explored. As shown in Table 2, cyclic aldimine derivatives with a variety of substituents were found to be suitable for the reaction, yielding the corresponding products 4a~4t in moderate to excellent yields. Substrates featuring electron-donating groups, such as Me, ^tBu, MeO, and CF₃O at the C(6)-position exhibited good reactivity, resulting in products (4a~4e) with satisfactory yields. Additionally, cyclic aldimines with C(6)-halogen substituents, which are valuable for subsequent synthetic modifications, were well compatible under optimal conditions, producing target products (4f~4h) in 55%~62% yields. Moreover, the azidoheteroarylation of [1.1.1]pro- pellane using cyclic aldimines with Me, MeO, EtO, BnO, F, Cl, Br, and MeO₂C groups at the C(7)- or C(8)-positions led to the formation of the corresponding products (4i~4r) with 50%~77% yields. Of note, substrate with electron- withdrawing group provided corresponding product in lower yield probably due to the low reactivity. Furthermore, bifunctionalized cyclic aldimines also proved to be effective substrates, delivering the desired products (4s and 4t) in acceptable yields. Other substrates with iodo- (1u), alkenyl- (1v), and alkyl aldehyde moiey (1w) were not compatible under standard condition.

To evaluate the synthetic capabilities of this approach, gram-scale reactions, product transformations, and late- stage modifications of pharmaceuticals were conducted. The product (4a) was synthesized in 69% yield, during large-scale reaction under optimized conditions (Scheme 2, a). Furthermore, a reduction-protection sequence led to the formation of 1-amino-3-heteroaryl bicyclo[1.1.1]pentane (BCPs) (6) with 70% yield (Scheme 2, b. The 1-amino- 3-heteroaryl bicyclo[1.1.1]pentane (BCP) (4a) could also undergo click chemistry with phenylacetylene (7) to yield the corresponding bicyclo[1.1.1]pentane (BCP)-containing triazole (8). Additionally, the developed azidoheteroarylation reaction-click chemistry sequence was successfully applied for the late-stage functionalization of valuable molecules. The ibuprofen, flurbiprofen, indomethacin, ke- toprofen, naproxen, and isoxepac were effectively modified, resulting in the desired products (9a~9f) with 75%~90% yields (Scheme 2, c.

To elucidate the mechanisms underlying the solvent- controlled difunctionalization of [1.1.1]propellane, a series of control experiments were executed. Initially, the introduction of 2,2,6,6-tetramethyl-1-piperidinyloxyl (TEMPO) into the catalytic systems resulted in the complete inhibition of azidoheteroarylation reaction of [1.1.1]propellane (Scheme 3). Additionally, the formation of the corresponding radical adduct (10) was detected by high-resolution mass spectrometry (HRMS). Moreover, the formation of azido radical (•N₃) was confirmed by electron spin resonance (ESR) spectroscopy. These observations robustly indicate that a radical-mediated process is pivotal to the reaction.

Based on the aforementioned results and existing literature,^[17] we have proposed single-electron transfer (SET) mechanisms for these two reactions as depicted in Scheme 4. Initially, the reaction between (diacetoxyiodo)benzene (PIDA) and azidotrimethylsilane (TMSN₃) (3) gave an unstable acyclic azido hypoiodite intermediate, which promptly decomposed to produce an azido radical (•N₃). In the azidoheteroarylation reaction of [1.1.1]propellane, the azido radical (•N₃) directly inserted into [1.1.1]propellane, resulting in the formation of the metastable N₃-BCP-radical A, which then reacted with cyclic aldimine 1a to deliver a nitrogen radical intermediate B. In path a, the nitrogen radical intermediate B underwent a 1,2-hydrogen shift to generate a carbon radical intermediate C, which was further oxidized by (diacetoxyiodo)benzene (PIDA) to produce a carbon cation intermediate D.^[6a,17b] In path b, the nitrogen radical intermediate B was directly oxidized by (diacetoxyiodo)benzene (PIDA) to produce a nitrogen cation intermediate E. Finally, the desired 1-azido-3-heteroaryl bicyclo[1.1.1]pentane (BCP) (4a) was obtained via deprotonation of the carbon cation intermediate D or nitrogen cation intermediate E.

In conclusion, an efficient protocol for direct 1,3-azido- heteroarylation of [1.1.1]propellane with cyclic aldimines and TMSN₃ was developed. This approach is distinguished by its mild reaction conditions and independence from transition-metal catalysts, offering an environmentally benign and efficient route for the synthesis of a range of cyclic aldimine derivatives that incorporate the structurally advantageous bicyclo[1.1.1]pentane (BCP) motif. Our control experiments have elucidated the participation of a radical- relay mechanism in the reaction cascade.