Supramolecular Template-Assisted Catalytic [2+2] Photocycloaddition in Homogeneous Solution

Abstract

Open AccessCCS ChemistryRESEARCH ARTICLE22 Apr 2022Supramolecular Template-Assisted Catalytic [2+2] Photocycloaddition in Homogeneous Solution Fang Wang, Sha Bai, Qing-Wen Zhu, Zi-Hang Wei and Ying-Feng Han Fang Wang Key Laboratory of Synthetic and Natural Functional Molecule of the Ministry of Education, Xi’an Key Laboratory of Functional Supramolecular Structure and Materials, College of Chemistry and Materials Science, Northwest University, Xi’an 710127 Google Scholar More articles by this author , Sha Bai *Corresponding authors: E-mail Address: [email protected] E-mail Address: [email protected] Key Laboratory of Synthetic and Natural Functional Molecule of the Ministry of Education, Xi’an Key Laboratory of Functional Supramolecular Structure and Materials, College of Chemistry and Materials Science, Northwest University, Xi’an 710127 Google Scholar More articles by this author , Qing-Wen Zhu Key Laboratory of Synthetic and Natural Functional Molecule of the Ministry of Education, Xi’an Key Laboratory of Functional Supramolecular Structure and Materials, College of Chemistry and Materials Science, Northwest University, Xi’an 710127 Google Scholar More articles by this author , Zi-Hang Wei Key Laboratory of Synthetic and Natural Functional Molecule of the Ministry of Education, Xi’an Key Laboratory of Functional Supramolecular Structure and Materials, College of Chemistry and Materials Science, Northwest University, Xi’an 710127 Google Scholar More articles by this author and Ying-Feng Han *Corresponding authors: E-mail Address: [email protected] E-mail Address: [email protected] Key Laboratory of Synthetic and Natural Functional Molecule of the Ministry of Education, Xi’an Key Laboratory of Functional Supramolecular Structure and Materials, College of Chemistry and Materials Science, Northwest University, Xi’an 710127 Google Scholar More articles by this author https://doi.org/10.31635/ccschem.022.202201919 SectionsSupplemental MaterialAboutAbstractPDF ToolsAdd to favoritesDownload CitationsTrack Citations ShareFacebookTwitterLinked InEmail Supramolecular interactions can help recognize and organize substrates around an enzyme’s active sites and subsequently assemble a new molecule in a certain way. Inspired by nature’s control of reactions, in this work we designed a template catalyst equipped with ditopic Au(I)–N-heterocyclic carbene (NHC) functional sites that direct olefin substrates into reactive geometries via collaboration of coordination-driven interactions. Notably, this catalyst enables the realization of catalytic [2+2] photocycloadditions with as low as 2 mol % catalyst loading in homogeneous solution and the delivery of a series of cyclobutane derivatives with excellent conversions and stereoselectivities. The success of gram-scale reactions further demonstrates the feasibility of this strategy, which lays a solid foundation for the large-scale preparation of cyclobutane derivatives in the future. Download figure Download PowerPoint Introduction Photochemical reaction is a powerful tool in contemporary synthetic chemistry.1,2 Among photochemical reactions, [2+2] photocycloaddition has emerged as an essential and synthetically direct process to construct strained cyclobutanes, which are core scaffolds of many natural products and bioactive compounds.3–5 Despite numerous efforts devoted to this reaction,6–14 exploiting a practical method of cyclobutane formation capable of circumventing the kinetically favored trans/cis isomerization of olefins in solution remains an inherent challenge.15–19 Supramolecular templated reaction has emerged as a powerful strategy to enhance the efficiency and topochemistry of photocycloadditions in solution. However, the current scope is substantially hindered by stoichiometric reactions and generally yields mixtures of products.20–24 A methodology that enables consecutive photocycloaddition in a manner reminiscent of biology’s enzymatic catalysis is highly desired. Recently, we have developed a supramolecular strategy to enhance the efficiency and topochemistry of photochemical [2+2] and [4+4] reactions in homogeneous solution.25–27 By taking advantage of metal-N-heterocyclic carbene (NHC) templates, photoreactive units can be preorganized within NHC-based assemblies to achieve photocycloadditions of high purity. Owing to the relatively strong σ-donating ability of NHCs,28 the subtle difference of bond strength between M–CNHC bonds and M–N/O bonds (Werner-type metal centers) provides us with an opportunity to dissociate and release the formed cyclobutane products in situ, however, only confined to stoichiometric reactions.26 We found that after the completion of the reaction, the ditopic NHC templates tended to assemble into a more stable species and stop further catalytic cycling. We hypothesized that a rational design of the NHC template, including the introduction of sterically hindered groups and relatively rigid structure, may inhibit the generation of inactive species and make the reaction catalytic (Figure 1). Hence, we devised a supramolecular templated catalysis capable of synthesizing a wide range of cyclobutane derivatives with high precision and activity in homogeneous solution by virtue of rationally designing a ditopic Au(I)-NHC catalyst. Figure 1 | Conception of catalytic [2+2] photocycloaddition in solution using metal-NHC templates. Download figure Download PowerPoint Experimental Methods General procedure for catalytic [2+2] photocycloaddition of bidentate substrates using complex 3 as catalyst A solution of substrate L a –L h (0.10 mmol) and 3 (13.0 mg, 0.01 mmol) in dimethyl sulfoxide (DMSO; 5 mL) in a silica tube was irradiated under UV light (λ = 365 nm) at ambient temperature for an appropriate time [detected by thin-layer chromatography (TLC) and 1H NMR spectroscopy]. After the reaction finished, a saturated aqueous solution (50 mL) of NaOAc or NH4Cl was added to the tube, and the mixture was stirred at room temperature for another 10 min. The solvent was removed by filtration. The residue solid was collected and extracted with dichloromethane (3 × 20 mL). The combined organic phase was concentrated and purified by column chromatography on neutral alumina using a mixture of dichlormethane and methanol (v/v, 100/1) as the eluent to give the cyclobutane product. General procedure for catalytic [2+2] photocycloaddition of 4-styrylpyridine derivatives using complex 3 as catalyst A solution of substrate L i– L r (0.10 mmol) and complex 3 (2.6 mg, 2.0 × 10−3 mmol) in DMSO (1.5 mL) in an silica tube was irradiated under UV light (λ = 365 nm) at ambient temperature for an appropriate time (detected by TLC and 1H NMR spectroscopy). After the reaction finished, water (10 mL) was added to the tube and extracted with dichloromethane (3 × 5 mL). The combined organic phase was concentrated and purified by column chromatography on neutral alumina using a mixture of dichlormethane and methanol (v/v, 100/1) as the eluent to give cyclobutane products. Computational methods All calculations were performed with the Gaussian(R) 09 program optimizer. The theoretical approach was based on the framework of density functional theory (DFT). The geometry optimizations were performed at B3LYP level using the LANL2DZ basis set for the Au element and the 6-31G* basis set for all of the other atoms. All of the calculated bond dissociation energy (BDE) was averaged bond dissociation energy. X-ray structural determination and crystallographic data All data for crystal structure determinations were measured on a Bruker D8 VENTURE diffractometer (Karlsruhe, Germany), using graphite monochromated Mo Kα radiation (λ = 0.71073 Å). Reduction of data and semiempirical absorption correction were done using the SADABS program. The structures were solved by direct methods, which revealed the position of all nonhydrogen atoms. These atoms were refined on F2 by a full matrix least-squares procedure using anisotropic displacement parameters. X-ray crystallographic data for 1, 3, 4a, 4b, 4c, 4i, 4j, 4k, 4l, 4m, 4n, 4o, 4p, and 5 ( Supporting Information Tables S1–S14). CCDC number 2097108, 2142106–2142108, 2142110–2142118, and 2142120. Results and Discussion At first, a Calix-type bis-NHC precursor 1 embedded with two sterically hindered benzimidazolone moieties was prepared from commercially available 2-hydroxybenzimidazole (Figure 2a and Supporting Information Scheme S1). Afterward, the reaction of 1 with AuCl(THT) (THT = tetrahydrothiophene) afforded complex 2 ( Supporting Information Figure S1). As illustrated in Figure 2b, we initially proposed in the presence of pyridyl-based olefins that the intermediate I with two vacant coordinative sites would anchor a pair of olefins via a reversible coordination mode to form supramolecular assembly II. Thus, adjacent substrates were controlled in suitable topochemistry within NHC assembly II and facilitated subsequent dimerization to generate III. Eventually, dissociating the ditopic NHC template from III through a selective rupture of pyridyl nitrogen-metal bonds would provide photoproduct while retaining the robust carbene-metal bonds, thereby allowing intermediate I to reenter the catalytic cycle. In the current system, the functional sites can be preinstalled within the catalyst to emulate enzyme active sites and orient substrates into reactive geometries via the cumulative influence of supramolecular interactions.29–35 Figure 2 | (a) The synthesis of Au(I)-NHC catalyst 3 and the side view of the single-crystal structure of NHC precursor 1 (color code: gray, carbon; blue, nitrogen; red, oxygen; hydrogen atoms are omitted for clarity). (b) The proposed catalytic cycle of supramolecular [2+2] photocycloaddition. Download figure Download PowerPoint As a proof-of-principle, the [2+2] photocycloaddition of trans-1,2-bis(4-pyridyl)ethylene ( L a) was selected as a model reaction to validate our hypothesis.10,36–38 In general, L a did not dimerize but underwent a trans/cis isomerization upon photoirradiation in solution ( Supporting Information Figure S56).39,40 We carried out a reaction by irradiating a solution of L a and in situ-generated intermediate I (20 mol % catalyst loading) from complex 2 and AgOTf in DMSO-d6 for 1 h with UV light (λ = 365 nm). To our delight, the desired cyclobutane product 4a was obtained in a moderate yield. However, the active Au(I)-NHC intermediate I slowly transformed into an inactive species and inhibited further catalytic cycling. After manipulation of the reaction conditions, we realized that the addition of a weak base was essential for achieving high catalytic efficiency. In the presence of a weak base, intermediate I assembled to the base reversibly, was temporarily stable and thus reentered the catalytic cycle. As expected, by employing pyridine as an additive, a satisfied yield (88%) of the desired product 4a was obtained in the presence of Au(I)-NHC template 3 (20 mol % catalyst loading) under standard conditions. The conversion was easily monitored by in situ 1H NMR spectra based on the decrease of signals assigned to olefin protons of L a and the rise of characteristic resonance for the newly formed cyclobutane ring of 4a ( Supporting Information Figure S3). These processes were also monitored by time-dependent UV–vis spectroscopy ( Supporting Information Figure S4). Furthermore, 4-Cl and 4-CF3 substituted pyridines were selected to stabilize intermediate I and afford photoproduct 4a in 85% and 82% yields, respectively ( Supporting Information Scheme S2). Contrary to this, pyridine additive with more electronegative substituent (4-N(CH3)2) significantly quenched the catalytic cycle ( Supporting Information Scheme S2, 6% yield), presumably caused by the disturbance of the reversible coordination mode between pyridyl and intermediate I. In addition, the homolytic Au–N BDE of these templates was investigated ( Supporting Information Table S17). The Au–N BDE of intermediate I with different pyridine derivatives was found to be average 50.7, 43.3, 45.2, and 59.6 kcal/mol for template 3 and templates with 4-CF3-, 4-Cl-, and 4-N(CH3)2-substituented pyridines ( Supporting Information Figure S66 and Tables S26–S33), which provided further information about their different catalytic activities in the photochemical [2+2] reactions of L a. After screening reaction parameters, template 3 bearing pyridyl groups was established as the optimal candidate. In each case, product 4a was identified as rctt-cyclobutane (r = regio, c = cis, and t = trans) by 1H NMR and X-ray crystallography analyses ( Supporting Information Figures S6 and S34). With an optimal catalyst 3 identified, it is worth mentioning that reducing the catalyst loading of 3 to 10 mol % can also afford cyclobutane product 4a in 84% yield (Figure 3). Figure 3 | Catalytic [2+2] photocycloaddition of bidentate olefin substrates catalyzed by 3 and the single-crystal structures of products 4a, 4b, and 4g (color code: gray, carbon; blue, nitrogen; hydrogen atoms are omitted for clarity). Reaction conditions (unless otherwise noted): L a−L h(0.1 mmol), 3 (10 mol %), DMSO (5 mL), and hν 365 nm under air atmosphere at room temperature; the isolated yields are given. aThe reaction time was 1 h. bThe catalyst loading was 2 mol %, and the reaction time was 24 h. Download figure Download PowerPoint The pyridine-adduct 3 can be prepared by treatment of 2 with AgOTf and pyridine successively in high yield. The formation of complex 3 was confirmed by NMR spectroscopy, electrospray ionization mass spectrometry, and X-ray crystallography analysis ( Supporting Information Figures S2 and S16–S33). Notably, in the crystal structure, two pyridyl units located on the same side of 3, and the distances between Au•••Au atoms and the centroid of pyridyl units were measured 4.53 and 3.87 Å, respectively, providing prerequisites for expected photochemical reaction.41 With the optimal reaction condition in hand, a suite of bis-azole functionalized olefin substrates ( L b− L h) was then investigated (Figure 3 and Supporting Information Schemes S3–S5). A satisfactory result was achieved when applying 1,2-bis(4-(1H-imidazol-1-yl)phenyl)ethane ( L b) as substrate (c = 0.02 M), affording head-to-head (HH) cyclobutane product 4b in 99% yield in 5 h ( Supporting Information Figure S7). Substituents (Me, Et, i-Pr) at the C2 position of imidazole rings displayed a great influence on reactivity, delivering the corresponding rctt-products 4c– 4e in 95%, 75%, and 65% yields, respectively ( Supporting Information Figures S35 and S36). We attributed this, in part, to the insufficient orientation between neighboring olefins hindered by bulky substituents. Further investigation revealed that olefin substrates with different classes of heterocycles were tolerated in this strategy. L f and L g bearing 1,2,4-triazole and benzimidazole groups, respectively generated cyclobutane products 4f and 4g in 72% and 86% yields ( Supporting Information Figure S8). Similarly, substituted L g by Me groups on the C2 position of benzimidazole rings ( L h) resulted in a lower yield of product 4h after irradiation for 5 h (65%) ( Supporting Information Figure S37). With the above promising results in hand, a gram scale reaction was further conducted for ligand L a with 2 mol % catalyst loading, isolating rctt-cyclobutane product 4a in 76% yield without any loss of stereoselectivity (see the Supporting Information for details). This result evidently confirms the high efficiency and practicability of the catalytic process mediated by 3. To further explore the scope of this method, we then turned our attention to monodentate 4-styrylpyridine derivatives (Figure 4). We were pleased that this strategy was effective for L i− L r even under 2 mol % catalyst loading and exclusively provided the desired HH-cyclobutane products 4i– 4r as rctt-isomers ( Supporting Information Schemes S3 and S5), suggesting a synergistic action of template effect and intermolecular π–π interactions between two adjacent olefin substrates. As shown in Figure 4, simple 4-styrylpyridine ( 4i) and those bearing halogen groups ( L k and L l; Cl, Br; c = 0.067 M) provided the cyclobutane products 4k and 4l in excellent yields (75 and 80%) in 15 h, whereas a slight decrease in reactivity (67%) was observed in the 4-F derived substrate L j. Substrates bearing trifluoromethyl-, cyano- and acetyl-groups ( L o– L q) were also tolerated, giving the corresponding products in excellent to good yields (80%, 81%, and 56%). In order to further examine the substituent effect of the reaction, an electron-donating group (Me) was introduced to substrate L n that could also isolate the product 4n with an 81% yield. Naphthyl-substituted substrate L r was compatible albeit giving a lower yield (31%) due to inhibition by a competing isomerization, presumably due to unfavorable steric hindrance between neighboring naphthyl rings. To demonstrate the practicability of the method, we conducted the [2+2] photocycloaddition of L l on a 1.0-g scale with 2 mol % of catalyst 3 in DMSO, producing the desired rctt-cyclobutane product 4l in 73% isolated yield without any loss of stereoselectivity (see the Supporting Information for details). Figure 4 | Catalytic [2+2] photocycloaddition of 4-styrylpyridine derivatives catalyzed by 3 and the single-crystal structures of products 4i−4p (color code: gray, carbon; blue, nitrogen; fluorine, cyan; chlorine, green; bromine, brown; hydrogen atoms are omitted for clarity). Reaction conditions: L i−L r(0.1 mmol), 3 (2 mol %), DMSO (1.5 mL), and hν 365 nm under air atmosphere at room temperature (reaction time in parentheses); the isolated yields are given. Download figure Download PowerPoint Single crystals of 4i– 4p were grown by slow diffusion of diethyl ether into their saturated solution of acetonitrile or DMF at ambient temperature, respectively. X-ray diffraction analyses explicitly confirmed the rctt conformation of cyclobutane products, with the assistance of NMR spectroscopy and high-resolution mass spectrometry ( Supporting Information Figures S9–S15 and S38–S55). To our delight, the single crystal of the intermediate II-type assembly 5, suitable for X-ray diffraction analysis, was obtained ( Supporting Information Figure S5). Within the assembly, two C=C bonds of L k lay crisscrossed and were separated by 3.94 Å, the orientation of which displayed a strong tendency to participate in photocycloaddition. In the process, the crossed spatial arrangement of adjacent C=C bonds was more or less fixed to conform well to the topochemical postulate for an expected photocycloaddition upon irradiation in solution.42,43 In addition, DFT was used to model the binding of [ NHC] and L k/ 4k to Au(I) ions within [ 5]2+ and intermediate III-type assembly [ 6]2+ ( Supporting Information Figure S65 and Tables S15, S16, and S18–S25). The calculated structure of [ 5]2+ possesses average CNHC–Au and N–Au bond lengths of 2.01 and 2.10 Å, which agree well with those of the crystal structure for 5. The calculated homolytic Au–CNHC BDE was found to be average 88.9 kcal/mol in [ 6]2+ and larger than the mean Au–N BDE, which is in line with preferential dissociation of photoproduct from intermediate III and the retention of Au–CNHC bonds at the same time.28,44 To provide further insights into the reaction mechanism, we decided to study their time-dependent reaction profiles (see the Supporting Information). Figure 5 shows the profile for photocyclization of L o catalyzed by 3. In the beginning, photocycloaddition proceeded rapidly together with competing isomerization (the ratio is about 3:1), delivering cyclobutane product 4o with a sole byproduct cis- L o. However, instead of cis-geometry products, selective formation of rctt-cyclobutane 4o was observed upon completion of the reaction, which is the same as photoproduct stemming from L o. Since a kinetic cis/trans isomerization would occur when irradiating a solution of cis- L o, we then conducted a control experiment by mixing newly isolated cis- L o with catalyst 3 (10 mol %) in DMSO-d6 upon irradiation for 5 h. As expected, rctt-cyclobutane 4o was exclusively generated in 54%, monitored by in situ 1H NMR spectroscopy ( Supporting Information Figure S57), which is consistent with the gradual consumption of cis- L o and the progressive generation of 4o upon continuous irradiation shown in Figure 5, indicating an equilibrium shift toward the templated product. Furthermore, this phenomenon can be explained by the formation of a metastable diradical state during the reaction, in which the σ-bonds of the diradical intermediate experience a rotation from cis-geometry to the desired trans-isomer suitable for subsequent photocycloaddition.35,45 Similar phenomena can also be observed in the cases of L i− L r ( Supporting Information Figures S58–S64). Figure 5 | Time-dependent reaction profiles for [2+2] photocycloaddition of L o assistant with catalyst 3. Yields were determined by 1H NMR. Download figure Download PowerPoint Conclusion We have developed a facile route to realize catalytic [2+2] photocycloadditions of a series of olefin substrates in homogeneous solution based on a properly designed ditopic Au(I)-NHC template. The templated catalysis facilitates both mono- and bidentate substrates to produce a suite of rctt-HH cyclobutane derivatives in moderate to excellent yields with relatively low catalyst loadings. Based on experiments and DFT calculations, we identified that the flexible supramolecular interactions within supramolecular assemblies are crucial for steering and preorganizing photoreactive units to match well with the topochemical postulate for expected photocycloadditions. We believe that this strategy will pave the way for developing a wide variety of supramolecular catalysts that require shorter reaction time and lower catalyst amounts for direct covalent bond-forming processes. Supporting Information Supporting Information is available and includes the general information, experimental methods, DFT calculation details, characterization data, and NMR spectra. Conflict of Interest The authors declare no conflict of interest. Funding Information Financial support from the National Natural Science Fund for Distinguished Young Scholars of China (grant no. 22025107), the National Youth Top-notch Talent Support Program of China, the Key Science and Technology Innovation Team of Shaanxi Province (grant nos. 2019TD-007 and 2019JLZ-02), and the FM&EM International Joint Laboratory of Northwest University is gratefully acknowledged.