Introduction

Benzene rings are crucial chemical structural components that are commonly found in pharmaceutical molecules and natural products1,2,3,4. However, in physiological conditions, drug molecules with multiple phenyl rings often undergo metabolic modifications that compromise their solubility and metabolic stability5. Therefore, enhancing key pharmacokinetic properties to broaden the range of potential drug molecules is crucial in clinical trials6,7,8,9,10,11. Scientists have discovered that by replacing a benzene group with different sp3-rich hydrocarbon bioisosteres12,13,14,15,16, such as bicyclo[1.1.1]pentane (BCP)17,18,19,20,21, bicyclo[2.1.1]hexane (BCH)22,23, bicyclo[3.1.1]heptane (BCHep)24,25,26,27, bicyclo[2.2.2]octane28,29, and cubane30,31, the properties of drugs can be significantly enhanced. For example, BCP-avagacestat32 and BCH-valsartan33 showed improved water solubility compared with the original drugs (Fig. 1a).

Fig. 1: Approaches for the synthesis bioisosteres of benzenes and stilbenes.
figure 1

a Bioisosteres of benzenes; b representative natural stilbenes; c Ti-catalyzed [2σ + 2π] cycloaddition to obtain stilbene bioisosteres.

Full size image

Natural stilbenes are an important class of polyphenolic phytochemicals characterized by two phenyl groups connected by a vinyl bridge34,35,36,37. Pharmacological research has demonstrated that stilbenes have significant potential in the prevention and treatment of diseases due to their anticancer, anti-inflammatory, neuroprotective, antibacterial, and antifungal properties38,39,40,41. Resveratrol, a well-known stilbene widely used in Chinese and Japanese folk medicine, has shown promise42,43,44,45. Nevertheless, its poor bioavailability has hindered its clinical progress. An intriguing strategy to significantly enhance the pharmacokinetic properties of resveratrol involves substituting the phenol ring with a BCP moiety (Fig. 1b)46. However, the synthesis requires 9-step reactions from a BCP-acid derivative. Given their wide range of biological activities and immense potential for diseases treatment, it is imperative to develop a general and efficient synthetic approach for exploring the bioisosteres of stilbenes.

The BCH scaffolds, which can imitate both ortho- and meta-substituted benzenoids, have gained significant interest. In addition to the intramolecular cycloaddition of 1,5-dienes23,47,48, the strain-release-driven [2σ + 2π] cycloaddition of bicyclo[1.1.0]-butanes (BCBs) with a single alkene becomes a popular approach for efficiently synthesizing BCH scaffolds. Very recently, significant advancements were made independently by Glorius22,49,50,51 and Brown52 in demonstrating the intermolecular [2π + 2σ]-photocycloaddition through triplet energy transfer. Procter disclosed elegant SmI2-catalysed insertion of electron-deficient alkenes into BCB ketones via radical relay mechanism53. Li54 and Wang55 reported the boryl radical-initiated cycloaddition of BCBs with simple alkenes. Additionally, Lewis acid catalyzed formal (3 + 2)-cycloaddition leads to the formation of diverse heteroatom-substituted BCH scaffolds56,57,58,59.

Among the various transition metals, titanium stands out as one of the most affordable options that are generally considered nontoxic and environmentally friendly58. The combination of these desirable characteristics, alongside its rich redox properties, makes titanium particularly appealing for medicinal chemistry60,61.

In this work, we present a mild and effective Ti-catalyzed intermolecular radical [2σ + 2π] cycloaddition of bicyclo[1.1.0]-butanes and 1,3-dienes (Fig. 1c). This transformation enables the synthesis of BCH scaffolds containing aryl vinyl groups with excellent regio- and trans-selectivity and broad functional group tolerence, thus offering rapid access to structurally diverse stilbene bioisosteres.

Results

Optimization of reaction conditions. The study began by using phenyl(3-phenylbicyclo[1.1.0]butan-1-yl)methanone 1a and a mixture of E/Z 1-phenyl-1,3-butadiene 2a as coupling partners. After making preliminary optimizations to the conditions, the reaction was conducted with the presence of Cp2TiCl2, Mn powder, and Et3N•HCl in 1,4-dioxane for a duration of 48 h at room temperature. Excitingly, this resulted in the desired trans-configuration product 3a with a moderate yield of 61% (Table 1, entry 1). The structure of 3a was unambiguously confirmed through X-ray analysis (for more details see the Supplementary Fig. 14). When CpTiCl3 was used instead of Cp2TiCl2, only 19% of the product 3a was obtained (entry 2). In order to further improve reaction efficiency, we have focused on the selection of salen-Ti as the catalyst. 1,2-diphenylethylenediamine-based salen-Ti I has been successfully used by Lin in the [3 + 2] cycloaddition of cyclopropyl ketones and alkenes62,63, however, this catalyst did not effectively increase the yield of product 3a (entry 3). Notably, the diamine backbone of the salen ligand was found to significantly influence the reaction and proved critical in achieving a high yield of the product. For instance, altering the diaminebackbone to a 2,2’-diamino-1,1’-binaphthyl, similar results were observed (entry 4). Nevertheless, employing a 1,2-cyclohexanediamine-based salen-Ti III led to an increased yield of 81% for compound 3a (entry 5), whereas a bulky salen-Ti IV resulted in a maximum yield of 89% (entry 6).Furthermore, other solvents were explored and it was found that the reaction proceeded, albeit with lower yields compared to 1,4-dioxane (entries 7-11). Replacing Et3N•HCl with 2,4,6-collidine•HCl led to a minimal amount of 3a being obtained (entry 12). It is worth noting that the reaction still achieved a satisfactory yield when Zn dust was used as a reductant (entry 13). Attempting to reduce the Mn loading from 2 equiv to 0.5 equiv resulted in significantly lower product yield (entry 14). In addition, lower yields were observed when reducing the amount of Et3N•HCl (entries 15 and 16). It should be noted that the reaction did not proceed in the absence of Ti catalysts and reductants (entries 17 and 18).

Table 1 Reaction optimizationa,b
Full size table

Substrate scope

Under optimized conditions, the present study investigated the compatibility of different 1,3-dienes with the salen-Ti IV catalyzed [2π + 2σ] cycloaddition reaction. The findings for substituted 1,3-dienes and BCB ketones are summarized in Fig. 2. The results indicate that a wide range of functionalized 1,3-dienes were tolerated, including aryl- and 1,1-disubstituted 1,3-dienes. This led to the production of a diverse series of 1,2,4-trisubstituted BCHs with comparable yields. Initially, the electronic effect of phenyl substituted 1,3-dienes was investigated. Surprisingly, phenyl derivatives with electron-neutral (-H), electron-donating (-Me, -OMe, -SMe or –NMe2), and electron-withdrawing (-F, -Cl, -Br, -CF3, -CN or -Ph) groups at the para-, meta-, or ortho-position were well tolerated (3a-3m). Additionally, naphthalene proved to be a competent partner, yielding the corresponding bicyclo[2.1.1]hexane in 61% yield (3n). Importantly, disubstituted phenyl 1,3-dienes with heteroatoms were all successfully accommodated (3o,3p and 3r), and the benzene ring containing active hydrogen also reacted smoothly, yielding product 3q in a 66% yield. Notably, the 2,4,6-trifluoro-substituted phenyl was able to proceed smoothly and afforded product 3 s in a 74% yield. Stilbenes bioisosteres with benzodioxole and benzodioxan groups were successfully synthesized (3t and 3 u). Subsequently, a series of heteroaromatic substituted 1,3-dienes were screened under the salen-Ti IV catalyzed [2π + 2σ] cycloaddition conditions. Excitingly, substrates containing O, N, and S atoms were accommodated well, resulting in the desired products with excellent yields (3v-3aa). Various 1,1-disubstituted 1,3-dienes were also investigated, demonstrating that aryl (4a-4e), diphenyl (4 f), and alkyl (4 g and 4 h) substituted 1,3-dienes were suitable coupling partners and proceeded smoothly. It is noteworthy that the elusive trans-configuration for the alkenes is observed in all of the aforementioned examples, including trisubstituted olefins, which were often challenging to acquire. 1,3-Cyclohexadiene was also well tolerated, producing tricyclo-decene 5a in an excellent yield. The reaction was successfully applied to both 1,3-butadiene and 2,3-dimethylbuta-1,3-diene (5b and 5c). 1-Alkyl substituted 1,3-dienes were converted to products 5d-5f in moderate yields as a mixture of E/Z-isomers. In addition, 1,4-disubstituted 1,3-dienes were also tolerated, yielding products 5 g and 5 h in a 73% and 68% yields as a mixture of two isomers. The scope of BCB ketones were also briefly examined. The results indicate that piperonyl, naphthyl, and butyl were all tolerated, gave the corresponding products 6a-6c in 53% to 97% yields. Furthermore, chlorophenyl substituted BCB ketones also reacted smoothly with 1-phenylbutadiene and butadiene (6d and 6e).

Fig. 2: Substrate scope towards1,3-dienes and BCB ketones.
figure 2

Reaction conditions: a 1 (0.2 mmol, 1 equiv), 2 (1.5 equiv), salen-Ti IV (5 mol%), Mn (2 equiv) and Et3N•HCl (2 equiv) in 1,4-dioxane (0.1 M) stirred for 48 h under N2 conditions; b E/Z ratio and d.r. were determined by 1H NMR analysis of crude products. c Isolated yield.

Full size image

Building on these success, we aimed to expand the scope of our study to include dienes with electron-withdrawing groups such as ester and amide. The outcome of our experiments is presented in Fig. 3. Notably, when using the standard conditions, we observed high yields in the reactions of a range of easily accessible 1,3-dienes with ester groups. Generally, the position of the substituent on the benzene ring did not have a significant impact on the reaction yields (9a-9d). Furthermore, we found that the presence of an aldehyde group was also compatible with the mild reaction conditions, resulting in a 73% yield of product 9e. The investigation of amide groups demonstrated that both secondary amide (9 f) and tertiary amides (9g-9i) were suitable substrates, leading to the formation of the corresponding products in favorable yields. Additionally, we were pleased to observe that amide 7j also reacted under the current conditions, resulting in a 74% yield of product 9j. 1,3-Enynes are readily available organic compounds and their functionalization has emerged as a powerful method for synthesizing propargyl derivatives64. Excitingly, when selected phenyl substituted 1,3-enyne was used as the coupling partner, alkynyl substituted BCH scaffold product 10a was isolated in 87% yield. To unfold the universality of the current reaction system to 1,3-enynes, we have extended the structures of several 1,3-enynes. The results indicate that substrates with -Me, -tBu or -F on the phenyl ring delivered the BCH products in high yields (10b-10d). Alkyl-substituted substrates could also be smoothly converted into the target product 10e in 94% yield. In addition, a late-stage functionalization of drug derivatives was conducted. Various structurally complex 1,3-dienes derived from natural products and active drugs, including bezafibrate 11a, febuxostat 11b, and oxaprozin 11c, were examined. All compounds proceeded well under optimal conditions, producing the corresponding products with comparable yields. These results highlight the robustness and utility of the current strategy in constructing various substituted bicyclo[2.1.1]hexane skeletons as structurally diverse stilbene bioisosteres.

Fig. 3: Substrate scope towards 1,3-diene substituted with electron-withdrawing groups.
figure 3

Reaction conditions: a 1a (0.2 mmol, 1 equiv), 7 or 8 (1.5 equiv), salen-Ti IV (5 mol%), Mn (2 equiv) and Et3N•HCl (2 equiv) in 1,4-dioxane (0.1 M) stirred for 48 h under N2 conditions. b Isolated yield.

Full size image

Synthetical application

To validate the practicality of the current methodology, a scale-up experiment and post-functionalization reactions were conducted (Fig. 4a). BCB ketone 1a (1.35 g) was reacted 1,3-butadiene in the presence of 5.0 mol% of salen-Ti IV, resulting in the desired product 5b with a yield of 78% (1.31 g). In order to demonstrate the synthetic potential of this approach, several transformations of product 5b were performed. For example, 5b was subjected to epoxidation of the terminal olefin using meta-chloroperbenzoic acid (m-CPBA), yielding the epoxide product 12 with an 84% yield. The carbonyl group of 5b could be efficiently reduced in the presence of NaBH4, affording the corresponding product 13 with a 98% yield (d.r. = 2:1). Additionally, a Wacker-type olefin oxidation of 5b was carried out under the same conditions as previously reported in the literature65, resulting in a 68% yield of the ketone 14. Methylthioether functional groups are well-known for their unique biological activity and significant value in the field of medicine66. Therefore, we successfully introduced the methylthio group into the BCH skeleton 15 by photocatalytic triplet-triplet energy transfer pathway67. Intriguingly, upon irradiation of the trans-configured alkene 3r using 400 nm LEDs for a duration of 12 h, the E/Z ratio transformed to 1.4:1, and product 3r’ was separated in a 41% yield as a cis-configuration alkene68. In addition to the aforementioned results, successful conversion from amide to ketone was also achieved (Fig. 4c), resulting in the corresponding product 9k with a yield of 95%. These successful application examples further demonstrate the practicality and applicability of the Ti-catalyzed [2σ + 2π] cycloaddition of BCB ketones with 1,3-dienes.

Fig. 4: Synthetic applications.
figure 4

a Grams scale synthesis and synthetic transformations. b Conversion of trans-alkene to cis-alkene under 400 nm LEDs irradiation. c Conversion of amide 9j to ketone 9k. m-CPBA meta-chloroperbenzoic acid, n-BuLi n-Butyllithium, DCE 1,2-Dichloroethane.

Full size image

Mechanistic studies

In addition, a radical trapping experiment was conducted to elucidate the reaction mechanism. Upon addition of the scavenger TEMPO, the formation of the desired product 3a was completely inhibited, and instead, the radical-trapping adduct 16 was detected by high-resolution mass spectrometry (HRMS) (Fig. 5a, for more details see the Supplementary Fig. 6). This finding provides further support for the involvement of radical intermediates in the salen-Ti IV catalyzed [2π + 2σ] cycloaddition reaction.

Fig. 5: Mechanistic studies.
figure 5

a Radical trapping experiment in the presence of 2,2,6,6-Tetramethylpiperidinooxy (TEMPO). b DFT calculations for the E/Z-selectivity of 1-phenyl-1,3-butadiene. c DFT calculations for the E/Z-selectivity of 1-cyclohexyl-1,3-butadiene. d DFT calculations for the regioselectivity of [4 + 2] vs [2 + 2]. Transition states are illustrated using CYLview2069.

Full size image

DFT calculations were also performed to gain more insights into the origin of E/Z-selectivity and regioselectivity ([4 + 2] vs [2 + 2]) at the ωB97XD/def2-TZVPP/SMD (solvent = 1,4-dioxane)//ωB97XD/def2-SVP level of theory. We set out to explore the trans-selectivity based on two model allyl radicals 17 and 18. With a free energy barrier of only 11.4 kcal/mol, the cis-configuration 17’ would convert predominantly to the thermodynamically more favorable trans-configuration 17, which was 3.8 kcal/mol more stable (Fig. 5b). Therefore, a rapid cis- to trans- isomerization would occur during the formation of allyl radicals D despite the initial presence of both E/Z isomers of 1-phenyl-1,3-butadiene 2a, leading to the exclusive formation of trans-configurations. Similarly, the trans-1-cyclohexyl-1,3-butadiene 18 was also calculated to be more stable, albeit to a smaller extent of 0.8 kcal/mol compared to 18’ (Fig. 5c), in consistent with experimental observations of products 5d (E/Z = 1.2:1), 5e (E/Z = 1.1:1) and 5 f (E/Z = 1.2:1).

The subsequent radical-enolate addition could potentially result in the formation of two regioisomeric products (Fig. 5d). In alignment with the experimental observations, our calculations on this step revealed a remarkable preference for the pathway leading to the [2 + 2] cycloaddition products E. This pathway, with a free energy barrier of 16.3 kcal/mol, was significantly more accessible compared to the [4 + 2] cycloaddition, which has a much higher energy barrier of 38.9 kcal/mol. Additionally, the [2 + 2] cycloaddition product E was thermodynamically more stable than its [4 + 2] product E’ counterparts by a substantial margin of 35.2 kcal/mol. This stability for both transition state and product was presumably due to the dihedral angle difference observed in double bonds: 171.9° for [2 + 2] and 121.3° for [4 + 2], respectively, suggesting a distorted alkene structure (atoms labeled in pink). In order to further examine the influence of different titanium catalysts on the energy profile and regioselectivity, calculations were also conducted using Cp2TiIVCl as the [Ti] component, and even with [Ti] = H by replacing the [Ti] moiety with a hypothetical hydrogen atom. Interestingly, computational results showed that the energy profiles and regioselectivity towards both [4 + 2] and [2 + 2] cycloaddition pathways remained largely unchanged, regardless of the nature of titanium catalyst used, indicating that the inherent regioselectivity of the reaction is primarily governed by the substrate structures. This conclusion underscores the robustness of the [2 + 2] cycloaddition preference under a variety of catalytic scenarios.

Proposed mechanism

Base on this result and previous reports62,63, A plausible reaction pathway is proposed in Fig. 6. Initially, by addition of an excess amount of Mn powder, the TiIV precursor can be reduced to obtain the species TiIII. A reversible single-electron transfer (SET) between the TiIII species A and the BCB ketone 1a results in the formation of a radical intermediate B. This intermediate undergoes reversible intramolecular ring opening to generate the enolate radical species C. Subsequently, intermolecular coupling with a mixture of E/Z isomers of 1-phenyl-1,3-butadiene 2a produces allyl radicals D. The allyl radicals then add to the TiIV–enolate moiety, leading to the formation of new ketyl allyl radicals E. Finally, the desired product 3a is obtained through an intramolecular SET of E, and the TiIII catalyst is regenerated, completing the catalytic cycle.

Fig. 6: Proposed catalytic mechanism.
figure 6

The corresponding mechanism for the selected model reaction between BCB 1a and 1-phenyl-1,3-butadiene 2a.

Full size image

Discussion

In summary, we have developed a reliable synthetic strategy for the Ti-catalyzed [2σ + 2π] cycloaddition of bicyclo[1.1.0]-butanes with 1,3-dienes or feedstock butadiene. The mildness of this protocol allows for the introduction of various substituents, including aryl, alkyl, 1,1- and 1,4-disubstituted 1,3-dienes, 1,3-enynes, ester and amide. The synthetic significance of this versatile approach is demonstrated through late-stage modification of pharmaceuticals, gram-scale synthesis, and subsequent conversion of the bicyclic hexane (BCH) skeletons. This method enables the efficient synthesis of 1,2,4-trisubstituted bicyclo[2.1.1]hexanes as bioisosteres of stilbenes.

Methods

General procedure

In a flame-dried 10 mL reaction tube equipped with a magnetic stirrer bar was charged sequentially with salen-Ti IV (0.05 equiv), Mn (2.0 equiv), Et3N•HCl (2.0 equiv). The Schlenk flask was transferred to an argon-filled glovebox and followed by the addition of 1,4-dioxane (2 mL), and the mixture was stirred at room temperature for 30 min in argon-filled glovebox. Then, to the resulting mixture were added 1,3-dienes (0.3 mmol, 1.5 equiv) and BCB ketones (0.2 mmol, 1.0 equiv). The resulting mixture was removed out the glovebox and stirred at room temperature for 48 h. After completion of the reaction, the mixture was filtered by silicone gasket. The solvent was evaporated in vacuo and the crude material was purified by flash column chromatography to furnish the desired product.