Transition-metal-, oxidant- and additive-free multi-component synthesis of alkyl heteroaryl BCPs enabled by visible-light-induced phosphine-catalyzed halogen-atom transfer

Abstract

Alkyl heteroaryl bicyclo[1.1.1]pentanes (BCPs) are an important class of bioisosteres, playing a crucial role in the realm of drug discovery. The quest for their synthesis, however, has been hindered by the limitations of existing protocols, which are characterized by the need for multiple reagents and a poor atom economy. This has prompted an urgent need for the development of more sustainable and efficient synthetic methodologies. Our contribution addresses this challenge by unveiling a novel, sustainable, and highly practical multi-component coupling reaction. This breakthrough process facilitates the direct alkylation/heteroarylation of [1.1.1]propellane through a photoinduced phosphine-catalyzed halogen-atom transfer mechanism. Notably, this innovative reaction is conducted under conditions devoid of transition metals, ligands, oxidants, and additives, thereby embodying the tenets of green chemistry. The versatility of our method is underscored by its remarkable tolerance towards a wide spectrum of heteroarenes and its seamless compatibility with diversely activated alkyl radical precursors, ranging from polyhalides to halides of tertiary, secondary, and primary alkyl groups. Moreover, the practicality of our protocol is further elaborated by its ability for late-stage functionalization of pharmaceutically relevant compounds, paving the way for large-scale synthesis and facile product derivatization. Our mechanistic studies have elucidated a radical-relay pathway, providing a solid foundation for the robustness of this synthetic strategy. We are confident that this sustainable and adaptable synthetic platform will significantly expand the toolkit available in drug discovery, offering a promising avenue for the development of novel therapeutic agents.

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Introduction

As versatile bioisosteres of functionalized biaryl frameworks, (hetero)aryl bicyclo[1.1.1]pentanes (BCPs) have made significant inroads in the pharmaceutical landscape, conferring improved aqueous solubility, metabolic stability, and enhanced passive permeability to a multitude of drug molecules (Scheme 1a).¹ Therefore, numerous methodologies have been developed for the synthesis of diverse (hetero)aryl BCPs, such as thio heteroaryl BCPs,² amino heteroaryl BCPs,³ and alkyl heteroaryl BCPs. Among them, the development of novel methods for the rapid construction of alkyl heteroaryl BCPs has received much more attention. The traditional synthesis of these compounds is often mired in complexity, necessitating multi-step couplings that rely heavily on metal catalysts, ancillary additives, and prefunctionalized substrates.⁴ These limitations have impeded their broader application in industrial-scale chemical processes. In the quest for more streamlined and efficient synthetic methodologies, radical multi-component coupling reactions have come to the fore, celebrated for their exceptional efficiency and minimized environmental footprint.⁵ In 2022, Gutierrez and colleagues harnessed the reactivity of Grignard reagents, [1.1.1]propellane, and tertiary-alkyl halides to forge a new method for the synthesis of tertiary-alkyl aryl BCPs, employing an iron-catalyzed strategy.⁶ Simultaneously, the Molander group made a significant contribution by introducing a metallaphotoredox catalysis approach for the construction of alkyl aryl BCPs, utilizing potassium tertiary-alkyl trifluoroborate salts, [1.1.1]propellane, and bromoheteroarenes as key reactants.⁷ Besides, Jiang and our group independently reported an electron donor–acceptor (EDA) photoactivation strategy to synthesize perfluoroalkyl heteroaryl BCPs.⁸ Ding and coworkers disclosed a visible-light-induced two-component strategy for the synthesis of trifluoromethyl heteroaryl BCPs using BCP thianthrenium salts as starting materials.⁹ However, these methodologies are constrained by the substrate scope toward tertiary alkyl or perfluoroalkyl radical precursors and prefunctionalized (hetero)aromatics. To surmount these hurdles, Molander's team advanced the field by reporting a photocatalytic multi-component desulfonative protocol, offering a novel avenue for BCP synthesis.¹⁰ Concurrently, our research group introduced an α-aminoalkyl radical-mediated halogen-atom transfer strategy, marking a significant step towards the synthesis of these biologically relevant compounds.¹¹ Despite the broad substrate tolerance in these methodologies, the persistent reliance on prefunctionalized heteroarenes, transition-metal catalysts, organic ligands, oxidants, and additives remains a stumbling block to achieving the lofty goals of green chemistry (Scheme 1b).¹² Therein lies the requirement for the development of a user-friendly, practical, and environmentally benign catalytic system that can orchestrate the sustainable synthesis of a diverse spectrum of alkyl (hetero)aryl BCPs, thereby propelling the field of pharmaceutical chemistry towards a more sustainable future.

Scheme 1 Alkyl (hetero)aryl BCP cores in pharmaceuticals and their synthesis.

In the vanguard of sustainable organic synthesis, photocatalyzed transformations have captured the spotlight for their eco-friendliness and energy efficiency.¹³ Among these green methodologies, phosphine-based photocatalysis stands out as a versatile and powerful tool for the creation of a myriad of chemical bonds.¹⁴ Historically, phosphine-mediated reactions have predominantly traversed the path of nucleophilic attack,¹⁵ with phosphine-catalyzed radical couplings emerging as a rare but promising phenomenon.¹⁶ A cornerstone of this field is halogen-atom transfer (XAT),¹⁷ a process where the C–X bond's lowest unoccupied molecular orbital (LUMO) (X = halogen) intersects with the phosphine's highest occupied molecular orbital (HOMO), leading to the formation of an electron donor–acceptor (EDA) complex.¹⁸ The photochemical activation of this EDA complex is a pivotal step, capable of generating both phosphine halide radicals and the corresponding alkyl radicals (Scheme 1c). A seminal example of this is the work by Czekelius and colleagues, who elegantly demonstrated a photoinduced phosphine-catalyzed difunctionalization of olefins through XAT, utilizing alkyl iodides.¹⁹ However, this activation mode is found to be exclusive to alkyl iodides in their system, potentially due to the relatively elevated LUMO energy level of alkyl chlorides or bromides, which attenuates the HOMO–LUMO interaction.²⁰ This insight highlights a critical gap in the field: the urgent need for a catalytic system that can extend its reach to a diverse array of alkyl halides, thereby expanding the synthetic horizons and offering a more inclusive approach to chemical synthesis. The development of such a system would not only address a significant synthetic challenge but also inject a new lease of life into the synthetic industry, opening avenues for the production of complex molecules with greater efficiency and less environmental impact.

Motivated by the profound implications of sustainable chemistry and propelled by our steadfast commitment to the development of eco-friendly catalytic systems,²¹ we have embarked on a quest to revolutionize the synthesis of alkyl heteroaryl BCPs. With a vision to surmount the existing synthetic barriers, we present a pioneering visible-light-induced phosphine-catalyzed halogen-atom transfer (XAT) strategy that heralds a new era in the difunctionalization of [1.1.1]propellane (Scheme 1d). This innovative method stands out for its minimalist yet powerful approach, eschewing the need for transition metals, ligands, oxidants, and additives. By harnessing the power of light and the reductive elegance of phosphine catalysis, we have crafted a pathway that is not only operationally straightforward but also intrinsically aligned with the principles of sustainability, offering a blueprint for future endeavors in the synthesis of biologically and pharmaceutically relevant molecules.

Results and discussion

In our quest to optimize the synthesis of alkyl heteroaryl BCPs, we embarked on a strategic exploration of the multi-component reaction conditions. As meticulously documented in Table 1, the optimal synthesis of the desired product (4) was realized in a commendable 70% yield. This was achieved through the judicious combination of azauracil (1a), [1.1.1]propellane (2), perfluorobutyl iodide (3a), and triphenylphosphine (PPh₃) in the solvent N-methylpyrrolidone (NMP), under 455 nm LED irradiation for 6 h (Table 1, entry 1). The pivotal role of triphenylphosphine (PPh₃) and light irradiation in the reaction was unambiguously confirmed, as no product was formed in their absence, underscoring the indispensable role of photosensitization in this transformative process (Table 1, entries 2 and 3). Other phosphine catalysts, such as triethyl phosphite (P(EtO)₃), triphenyl phosphite (P(PhO)₃), and tri-tert-butylphosphine (P^tBu₃), were explored in an attempt to catalyze the reaction, and they yielded the product (4) with less impressive efficiency, highlighting the unique efficacy of PPh₃ (Table 1, entries 4–6). Solvent influence was also meticulously evaluated, with methanol (MeOH) and acetone falling short in comparison with the optimal performance observed with NMP. Notably, acetonitrile (MeCN) was found to be an ineffective medium for this reaction, further emphasizing the critical interplay between solvent and reaction dynamics (Table 1, entries 7–9). Intriguingly, the extension of the reaction time beyond the optimal 6 h did not culminate in a higher yield, suggesting a saturation point in the reaction kinetics (Table 1, entry 10).

Table 1 Screening of reaction conditions^a

Entry	Variation from the given conditions	Yield^b (%)
a Reaction conditions: 1a (0.2 mmol), 2 (0.5 mmol), 3a (0.4 mmol), PPh3 (20 mol%), NMP (2 mL), blue LEDs, rt, 6 h. b Isolated yield.
1	None	70
2	w/o PPh3	Trace
3	w/o blue LEDs	0
4	P(EtO)3 instead of PPh3	31
5	P(PhO)3 instead of PPh3	39
6	P^tBu3 instead of PPh3	20
7	MeOH instead of NMP	29
8	Acetone instead of NMP	40
9	MeCN instead of NMP	Trace
10	Performed in 3 h or 12 h	53/68

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Having established the viability of the multi-component reaction, we proceeded to investigate the substrate scope with respect to heteroarenes. As shown in Table 2, a diverse array of azauracils, each featuring distinct N-substituted groups such as benzyl, methyl, ethyl, p-methylbenzyl, and keto, were successfully transformed into the desired products (4–8) in yields ranging from 62–70%. Notably, azauracils harboring sensitive functional groups like allyl (9) and propargyl (10) emerged as excellent substrates for this transformation. Furthermore, a broad spectrum of pyrazinones, adorned with both stable and sensitive unsaturated groups, demonstrated remarkable compatibility under the standard conditions, yielding the corresponding products (11–19) with satisfactory efficiency. The versatility of the reaction was further underscored by the successful incorporation of quinoxalinones with nitrogen-substituted groups, including methyl, benzyl, keto, ester, phenyl, allyl, and propargyl, which were smoothly converted to the target products (20–26) in yields of 39–75%. Encouraged by these promising results, the reaction's scope was expanded to include quinoxalinones with both single and multiple functional groups on the phenyl ring. These substrates actively participated in the multi-component reaction, yielding the coupling products (27–32) in yields ranging from 50–72%. Driven by our success, we extended our investigation to other heteroarenes under the standard conditions. The quinoxalinone with a fused ring was found to participate in the reaction seamlessly, affording the desired product (33) in 60% yield. Intriguingly, this method proved equally adept for multi-component transformations involving quinoxaline derivatives, [1.1.1]propellane, and perfluorobutyl iodide, leading to the formation of the corresponding perfluorobutyl heteroaryl BCPs (34–36) in yields ranging between 28–46%. Additionally, other heteroarenes, such as 2H-1,4-benzoxazin-2-one and cinnolin-4(1H)-one, were successfully converted into their corresponding products (37–39), achieving acceptable yields. Unfortunately, the quinoline derivatives (1bb–1be) with both electron-donating and electron-withdrawing groups could not been converted into the corresponding products due to their low reactivity (see the ESI†).

Table 2 Substrate scope of heteroarenes^a,b

a Reaction conditions: 1 (0.2 mmol), 2 (0.5 mmol), 3a (0.4 mmol), PPh₃ (20 mol%), NMP (2 mL), blue LEDs, rt, 6 h. b Isolated yield.

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Building upon the established success of our multi-component reaction, we delved into the realm of organic polyhalides to further expand the synthetic horizons of our visible-light-induced, phosphine-catalyzed approach (Table 3). We were delighted to discover that a spectrum of pharmaceutically relevant polyhaloalkyl groups (ⁱC₃F₇, C₆F₁₃, C₈F₁₇, CF₂CO₂Et, CF₂P(O)(OEt)₂, CHCl₂, CCl₃, CFBr₂, and CHBr₂) could be seamlessly incorporated onto the BCP framework (40–48). This was accomplished through a strategic multi-component transformation involving quinoxalinone, [1.1.1]propellane, and the corresponding polyhalides. While the perfluoroalkyl bromides exhibited a marginally reduced reactivity relative to their iodide analogs, this observation provided valuable insights into the underlying reactivity trends. The diminished reactivity can be rationalized by considering the higher bond dissociation energy (BDEC-Br > BDEC-I)^13a and the attenuated HOMO–LUMO interaction (ΔH_P⋯Br > ΔH_P⋯I).¹⁶ These findings underscore the influence of bond strength on the reaction's efficacy and highlight the subtle interplay between reactivity and substrate structure. In a testament to the robustness of our method, we found that ethyl chlorodifluoroacetate, despite its higher C–Cl bond dissociation energy, was still amenable to the reaction, affording the corresponding product (43) in 30% yield. This observation is particularly encouraging, as it suggests that our method may be adaptable to a broader range of polyhalide substrates, each with their unique bond energetics. Further investigation found that different heteroarenes could also react with diverse polyhalides to give the corresponding products (49–63) in 43–74% yields.

Table 3 Substrate scope of organic polyhalides^a,b

a Reaction conditions: 1 (0.2 mmol), 2 (0.5 mmol), 3 (0.4 mmol), PPh₃ (20 mol%), NMP (2 mL), blue LEDs, rt, 6 h. b Isolated yield.

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In our relentless endeavor to expand the arsenal of organic halides for synthetic endeavors, we redirected our focus toward the employment of a diverse array of monohalides as precursors for carbon radicals (Table 4). Our exploration was fruitful, with primary alkyl halides bearing an assortment of functional groups exhibiting robust reactivity and culminating in the synthesis of a diverse array of alkyl heteroaryl BCPs (64–68) with yields acceptably ranging from 32–58%. A significant revelation that emerged was that in addition to alkyl iodides, alkyl bromides were also equally competent radical precursors, thus broadening the horizons of our method's applicability. Inspired by these promising findings, we extended our investigation to secondary alkyl halides, each bearing a unique set of substituent groups. These were effortlessly integrated into our reaction framework (69–71), further enriching the library of attainable BCPs. Regrettably, non-activated cyclohexyl bromide was not compatible under the standard conditions. We then delved into the realm of tertiary alkyl halides, which, to our delight, participated in the multi-component reaction, yielding the desired products (74–78) in yields that were deemed acceptable.

Table 4 Substrate scope of organic monohalides^a,b

a Reaction conditions: 1 (0.2 mmol), 2 (0.5 mmol), 3 (0.4 mmol), PPh₃ (20 mol%), NMP (2 mL), blue LEDs, rt, 6 h. b Isolated yield.

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The practical utility of our protocol was then highlighted through its application in the direct late-stage modification of a variety of valuable molecules with pharmaceutical relevance. Prominent among these were ibuprofen, indomethacin, flurbiprofen, loxoprofen, epiandrosterone, menthol, citronellol, aspirin, and perphenazine. The corresponding products (79–87) were successfully isolated in 34–61% yields under the standard conditions (Scheme 2a), illustrating the method's significant potential for pharmaceutical innovation. To further highlight the scalability and industrial viability of our approach, we embarked on a large-scale synthesis of perfluorobutyl heteroaryl BCP (4). This endeavor successfully yielded the product in 64% yield (1.1 g) via a modest extension of the reaction time to 12 h (Scheme 2b), a testament to the method's robustness on a larger scale. Moreover, to showcase the synthetic versatility of our BCPs, we utilized the perfluorobutyl heteroaryl BCP 26, endowed with a terminal alkyne group, in a Click chemistry reaction with the anti-HIV pharmaceutical zidovudine. This innovative coupling successfully delivered a novel organic molecule (88) in 73% yield (Scheme 2c), thereby demonstrating the remarkable potential for product derivatization and the synthetic malleability of our BCPs. Alkyl heteroaryl BCPs are considered to be an important source of drug candidate molecules that must meet strict impurity residue limits. Therefore, after purification by column chromatography, the purity analysis of product 4 was performed by HPLC. It was found that no phosphine residues were present in the final product (see the ESI†).

Scheme 2 Synthetic application.

In our pursuit of demystifying the underlying mechanism of this multi-component reaction, we embarked on performing a series of judiciously crafted control experiments. The introduction of 2,2,6,6-tetramethyl-1-piperidinyloxyl (TEMPO) into the catalytic system led to a profound suppression of the reaction, as shown in Scheme 3a. This observation was complemented by the detection of the radical adducts C₄F₉-TEMPO (89) and C₄F₉-BCP-TEMPO (90) via high-resolution mass spectrometry (HRMS) in the absence of heteroarenes, as shown in Schemes 3b and c. These compelling results demonstrated that the radical-relay pathway was at the heart of the multi-component reaction, with the heteroarene playing no role in the radical generation process. On/off irradiation studies provided a pivotal insight that uninterrupted LED irradiation was indispensable for the multi-component transformation, effectively excluding the possibility of a radical chain propagation mechanism, as shown in Fig. S1.† The UV-visible absorption spectra hinted at a subtle augmentation in the absorption of triphenylphosphine (PPh₃) upon the introduction of perfluorobutyl iodide. However, the absence of pronounced visible changes suggested the formation of only a minor quantity of a weak electron donor–acceptor (EDA) complex, which was undetected by direct detection methods, as shown in Fig. 1.²² Nonetheless, the ³¹P NMR spectra of the reaction mixture revealed a new signal at approximately 31 ppm under the standard conditions, indirectly confirming the formation of the EDA complex, as shown in Fig. 2.

Scheme 3 Control experiments.

Fig. 1 UV/Vis absorption spectra of PPh₃, C₄F₉I, and their mixture.

Fig. 2 Monitoring of the reaction by ³¹P NMR.

Armed with these mechanistic insights and in alignment with previous scholarly work,^5,16 we propose a coherent mechanism for the visible-light-induced, phosphine-catalyzed multi-component reaction, as shown in Scheme 4. The process begins with the coordination of triphenylphosphine (PPh₃) with alkyl halide 3 to form the EDA complex A. This complex then undergoes a visible-light-induced halogen-atom transfer, yielding the halogenated triphenylphosphine radical species B and the nascent alkyl radical C.²⁰ The alkyl radical C subsequently reacts with [1.1.1]propellane (2), forming the R-BCP radical D. This radical then initiates an attack on the heteroarene 1a, leading to the formation of the aminyl radical E.¹¹ The final act of this mechanistic play involves the reaction of the halogenated triphenylphosphine radical species B with the aminyl radical E, resulting in the formation of the final product and the liberation of HX. A possible mechanism that is initiated by an EDA complex formed by the interaction of a heteroarene with an alkyl halide was also proposed (see the ESI†).²³

Scheme 4 Proposed mechanism.

Conclusions

In conclusion, we have developed a photoinduced phosphine-catalyzed halogen-atom transfer strategy that elegantly constructs alkyl heteroaryl BCPs. This synthetic innovation is notable for eliminating the need for transition metals, ligands, oxidants, and additives, thus heralding a new era of green chemistry and providing an efficient route for the direct difunctionalization of [1.1.1]propellane. Our method has been proven to be exceptionally versatile, accommodating a diverse range of activated alkyl halides, heteroarenes, and molecules of pharmaceutical significance under the refined reaction conditions. Control experiments have meticulously shown the radical-relay mechanism at play, offering deep insights into the reaction's intricacies and setting the stage for the evolution of synthetic strategies. With its demonstrated versatility and environmental benignity, this approach is set to make a lasting impact, offering chemists a robust and eco-friendly toolkit for the assembly of complex molecular architectures with precision and elegance.

Data availability

The data supporting this article have been included as part of the ESI.†

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

We thank the Key Research & Development Project of the Science Technology Department of Zhejiang Province (No. 2024C01203) and the Natural Science Foundation of Zhejiang Province (No. LY21B060009) for financial support.

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Footnote

† Electronic supplementary information (ESI) available: Detailed experimental procedures and analytical data. See DOI: https://doi.org/10.1039/d4qo01351d

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