Nanoporous gold-catalyzed borylation of C(sp3)–O bonds in dialkyl ethers and its mechanistic elucidation

Nanoporous gold-catalyzed borylation of C(sp3)–O bonds in dialkyl ethers and its mechanistic elucidation | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Nanoporous gold-catalyzed borylation of C(sp 3 )–O bonds in dialkyl ethers and its mechanistic elucidation Tienan Jin, Yuhui Zhao, Charlie Lacroix, Takuma Sato, Masahiro Terada This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6249124/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Selective cleavage and functionalization of C–O bonds in ethers is a longstanding challenge in organic synthesis due to their inherent stability. This is particularly significant for synthesizing alkylboron compounds, which serve as versatile intermediates in diverse transformations. However, the high chemical stability of dialkyl ethers makes their successful borylation rare. Herein, we present a heterogeneous catalytic borylation of various dialkyl ethers with B₂pin₂ using an unsupported nanoporous gold catalyst (AuNPore). The nanosized, sponge-like catalyst operates without the need for metal oxide supports or bases, efficiently converting a wide range of acyclic and cyclic ethers, as well as acetals, into alkyl monoboronates and diboronates. Mechanistic studies indicate that AuNPore promotes B–B bond cleavage, leading to deoxygenative carbocation formation. This enables an unprecedented borylation pathway via the formation of a C(sp 3 )–Au–Bpin organogold species, which undergoes reductive elimination to yield alkylboron products. Physical sciences/Chemistry/Catalysis/Heterogeneous catalysis Biological sciences/Drug discovery/Medicinal chemistry/Drug discovery and development Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Introduction Selective cleavage and functionalization of C–O bonds in ethers, 1-3 which are prevalent in biological molecules and fine chemicals, have been a longstanding challenge in organic synthesis due to their inherent stability and resistance to activation. 4-6 This challenge is particularly significant in the synthesis of alkylboron compounds, 7-14 which offer diverse reactivity for late-stage functionalization and potential applications in chemical biology with increased molecular complexity. 15-20 In this context, the direct borylation of activated C(sp³)–O bonds has emerged as a novel strategy for the selective synthesis of alkylboron compounds. In general, the preactivation of unreactive alkyl alcohols 21-25 or the use of active alkyl alcohol derivatives, 26-35 such as benzylic, allylic, and propargylic alkyls, is indispensable in these transition metal (TM)-catalyzed and photochemical borylations, facilitating the conversion of activated C(sp 3 )–O bonds to C(sp 3 )–B bonds (Fig. 1a). On the other hand, in 2021, the Dong group conducted pioneering work on the borylation of a limited number of alkyl aryl ethers, achieving moderate efficiency in yielding alkylborates, thereby paving the way for further developments in the field. 36,37 This direct borylation approach overcomes the limitations in regioselectivity and functional-group compatibility associated with traditional methods, such as hydroboration of alkenes 7-9 and transmetalation of Grignard and organolithium reagents with boron electrophiles. 38,39 Moreover, this method can be extended to cyclic ethers and acetals, enabling the convenient synthesis of hydroxy-functionalized alkyl monoborates and geminal alkyl diborates. However, the efficient borylation of inert C(sp 3 )–O bonds in dialkyl ethers remains rare due to the high chemical stability of ethers, resulting from their large bond dissociation energy, as well as the challenging regioselectivity in cleaving two different C(sp 3 )–O bonds. During our study, only one example has been reported most recently by the Shishido group on the borylation of inert dialkyl ethers catalyzed by α-Fe 2 O 3 -supported gold nanoparticles. 40 In this case, the Lewis acidic metal oxide support plays an important role in activating the C(sp 3 )–O bonds. Given the principles of green synthesis, such as waste minimization, energy efficiency, and reduced environmental impact, the development of sustainable and robust catalytic systems for the efficient functionalization of naturally abundant, inert chemical bonds still remains a significant challenge. Over the past decade, we have explored the unique heterogeneous catalytic performance of nanoporous gold (AuNPore) in activating various covalent bonds to develop green synthetic methods. 41 In particular, we discovered that homolytic B–B bond cleavage of bis(pinacolato)diboron (B 2 pin 2 ) on AuNPore led to stereoselective diborylation of alkynes (Fig. 1b). 42 We further demonstrated that the regioselective catalytic diborylation of methylenecyclopropanes (MCPs) proceeds via cleavage of both the distal C–C single bond of MCPs and the B–B bond of B 2 pin 2 on AuNPore to form alkyl diborates (Fig. 1b). 43 The three-dimensional, high-surface-area nanoporous structure of AuNPore is composed of nanosized hyperboloid-like ligaments ranging from 30 to 40 nm, with low-coordinated, catalytically active gold atoms present on both the positively and negatively curved ligaments (Fig. 1c). 44,45 In addition, as shown in Fig. 1c, AuNPore is superior to metal nanoparticles in terms of its bulk metal shape, which prevents aggregation-induced catalyst deactivation and enables convenient experimental manipulation, and catalyst recovery and reuse. Importantly, the metal oxide support-free AuNPore catalyst may simplify the theoretical mechanistic studies of intermediates and transition states by eliminating support effects. 43 Inspired by previous studies, we devised that the borylation of dialkyl ethers with B 2 pin 2 could be achieved through deoxygenation of the C(sp 3 )–O bond by the Lewis acidic Bpin unit, generated in situ over the AuNPore catalyst. Herein, we present a heterogeneous catalytic method for the borylation of C(sp³)–O bonds in various acyclic and cyclic dialkyl ethers, as well as acetals, using the unsupported AuNPore catalyst (Fig. 1d). This catalytic process operates without the need for additives such as metal oxide supports or bases and exhibits a broad substrate scope with high functional group tolerance. Consequently, a diverse range of alkyl monoborates and diborates can be obtained in good to high yields. Notably, both experimental and theoretical studies suggest that a carbocation intermediate, generated via C(sp³)–O bond cleavage, plays a key role in forming an energetically favorable C(sp 3 )–Au–Bpin organogold species. Results and discussion As shown in Fig. 1 b, our previous studies on the diborylation of alkynes and MCPs have demonstrated that AuNPore is a unique catalyst for the B–B bond cleavage of B₂pin₂, outperforming other nanoporous metal catalysts (Pt, Pd, Ag, Cu), which exhibited no activity. 42 , 43 Encouraged by these findings, we selected AuNPore as the catalyst for the borylation of secondary alkyl methyl ether 1a to synthesize secondary alkylboronic ester 2a without any additives, using the widely used and stable B₂pin₂ as the boron reagent (Fig. 2 a). The unsupported AuNPore catalyst was prepared using a well-established dealloying method, in which an Au 30 Ag 70 alloy was treated with concentrated nitric acid at room temperature to remove silver atoms. 45 To our delight, a brief optimization study revealed that the reaction proceeded efficiently in toluene at both 100°C and 85°C for 6 hours, with the former temperature giving slightly higher yield of 2a . Reducing the catalyst loading from 10 mol% to 5 mol% decreased the yield of 2a to 79%. Furthermore, a gram-scale reaction using 1.0 g of 1a produced 2 a with no loss of efficiency. It was noted that CH₃OBpin was consistently observed as a byproduct, while the CH 3 –O bond cleavage product, CH 3 Bpin, was not detected in this reaction. Ethyl ether 1a' was less reactive under standard conditions compared to the methyl ether 1a , yielding the corresponding 2a in moderate yield, along with the formation of EtOBpin and the recovery of 1a' (44%). To determine whether the leached Au atoms in the solution function as the actual catalyst, control experiments were conducted (Fig. 2 b). For instance, after carrying out the borylation of 1a with B 2 pin 2 under standard conditions for 1 h, the separated reaction mixture, devoid of the AuNPore catalyst, did not exhibit any further increase in the yield of 2a after an additional 5 h of heating. In contrast, the residue containing the AuNPore catalyst led to a further improvement in the yield of 2a , reaching 91%. Furthermore, inductively coupled plasma mass (ICP-MS) analysis detected no leached Au atoms in the solution. These results clearly demonstrate that the borylation reaction catalyzed by AuNPore proceeds through a heterogeneous catalytic process. The AuNPore catalyst, recovered from the borylation of 1a through simple filtration, demonstrated exceptional reusability without any loss of catalytic activity; the yield of 2a remained consistently at 90% even after four additional reuses (Fig. 2 c). These experimental results combined with the non-toxic nature of gold metal highlight the high regioselectivity, robustness, and environmentally friendly catalytic performance of AuNPore. With this remarkable catalytic performance, a wide range of acyclic methyl ethers was examined for direct borylation with B 2 pin 2 using 10 mol% AuNPore in toluene at 100°C (Fig. 3 ). Secondary linear alkyl methyl ethers bearing halogens such as F, Cl, and Br at the para -position of the phenyl ring showed excellent compatibility with the AuNPore catalyst, affording the corresponding secondary alkylboronic esters 2b - 2d in good to high yields (73–86%) without dehalogenation and metal-catalyzed cross-coupling side reactions. Borylation of a substrate with an electron-donating methoxy group on the phenyl ring proceeded chemoselectively at the secondary C(sp 3 )-O bond, yielding product 2e in high yield while preserving methoxy group. In contrast, a substrate bearing a strong electron-donating N , N -dimethylamino group on the phenyl ring provided the corresponding product 2f in moderated yield, with partial recovery of the ether substrate (50%) even after prolonged reaction times. Additionally, alkylboronic acids tethered to naphthyl ( 2g ) and heteroaromatics such as furan ( 2h ) and thiophene ( 2i ), were successfully obtained under standard conditions without catalyst poisoning. Notably, boronic ester 2j , tethered to an acyl-protected alcohol, was synthesized with exclusive chemoselectivity without any cleavage of the active ester C(sp 3 )-O bond. This result suggests that this borylation preferentially occurs at the inert ether C(sp 3 )-O bond. This borylation process was also applied to the synthesis of one-carbon-shortened propyl ( 2k ) and homoallyl ( 2l ) boronic esters. The moderate yield of 2k was attributed to the increased formation of the elimination byproduct ( E )-prop-1-en-1-ylbenzene (33%). Further studies on inert alkyl methyl ether substrates revealed that the primary ether exhibited low regioselectivity in forming the desired product 2m , primarily due to the formation of CH 3 Bpin as the major product via cleavage of the O-CH 3 bond. Meanwhile, tertiary alkyl ethers were largely unreactive toward borylation, as exemplified by 2n , likely due to steric hinderance between the bulky tertiary alkyl group and the AuNPore surface. In contrast, methyl ethers with bulkier secondary cyclic alkyl groups, such as 2,3-dihydro-1 H -indene, adamantane, and cyclododecane, underwent borylation uneventfully, affording the desired products 2o - 2q in high yields. Additionally, this borylation was successful with various active alkyl methyl ethers. Both active primary and secondary benzyl ethers bearing cyclopropyl or benzothienyl groups reacted efficiently, giving the corresponding products 2r - 2v in good to high yields. Active secondary allyl ethers also underwent borylation efficiently, affording the corresponding primary ( 2w ) and secondary ( 2x ) alkylboronic esters in high yields, where 2w was formed from the secondary allyl ether 1w via a double bond shift. Encouraged by this remarkable catalytic activity observed with acyclic ethers, we further investigated cyclic alkyl ethers to access difunctional alkylboronic esters via ring-opening borylation (Fig. 4 ). A range of cyclic ethers having various sizes reacted smoothly with B 2 pin 2 in the presence of 2.5 mol% of AuNPore in toluene at 80°C, yielding the corresponding ring-opened linear alkylboronic esters in moderate to high yields. Aryl epoxides 3a and 3b , bearing an unsubstituted phenyl group and an electron-rich p -tolyl group, respectively, reacted efficiently to yield the corresponding products 4a and 4b . However, 3c with an electron-withdrawing chlorine on the phenyl ring afforded 4c in moderate yield due to the formation of a 1-chloro-4-vinylbenzene by-product via deoxygenative elimination. These initially formed products 4a - 4c were hydrolyzed to hydroxyl-substituted boronic esters 4a' - 4c' under Condition A for isolation, as they underwent partial O-B bond hydrolysis during silica gel chromatography. Phenyl-substituted oxetanes 3d and 3e with strained four-membered rings, also underwent efficient borylation, providing the corresponding products 4d and 4e in high yields via cleavage of the active and inactive C-O bonds, respectively. The borylation of 2-phenyltetrahydrofuran ( 3f ) occurred preferentially at the more reactive 2-position of the tetrahydrofuran moiety, affording the corresponding product 4f in good yield. The products 4d - 4f were further converted to the corresponding 1,n-diols 4d" - 4f" under Condition B due to their low stability during silica gel chromatography. Interestingly, the sequential diborylation of 1,3-dihydroisobenzofuran ( 3g ), which contains two active C–O bonds, proceeded smoothly with an excess of B 2 pin 2 , producing the diboronic ester product 4g in 75% isolated yield. Similarly, the less strained six-membered cyclic ethers such as 2-phenyltetrahydro-2 H -pyran ( 3h ) and isochromane ( 3i ), also exhibited good reactivity toward selective borylation at the benzylic position, affording the expected products 4h and 4i in high yields. Furthermore, 4-phenyltetrahydro-2 H -pyran 3j containing two inert C(sp 3 )–O bond could undergo the ring-opening borylation using 10 mol% of AuNPore, affording the corresponding difunctional boronic ester 4j in good yield. To further broaden this approach in the synthesis of 1,n-diboronic esters, we investigated diethers and acetals containing two C(sp 3 )-O bonds within a single molecule (Fig. 5 ). As expected, the diborylation of 1,4- and 1,3-dimethyl diethers 5a and 5b having both active benzylic and inactive C(sp 3 )–O bonds, with 3 equivalents of B 2 pin 2 afforded the corresponding 1,4- and 1,3-diboronic esters 6a and 6b in 75% and 46% isolated yields, respectively. Notably, 5a , a mixture of syn - and anti -isomers, and 5b , a single anti -isomer, were both converted to 6a and 6b as a mixture of syn -and anti -isomers, suggesting that the reaction likely involves the formation of a carbocation intermediate. Additionally, 1,4-bis(methoxymethyl)benzene ( 5c ) with two active C-O bonds was well accommodated, yielding the diborylation product 6c in 85% isolated yield. In recent years, gem -diborylalkanes have been widely employed as versatile bifunctional reagents in various chemical transformations, including sequential cross-coupling, asymmetric functionalization, and other orthogonal reaction. 46 Although several synthetic approaches have been developed to synthesize gem -diborylalkanes, direct borylation using simple and readily available acetals has never been reported. In this context, we explored the use of acetal substrates for the synthesis of gem -diborylalkanes via direct diborylation of two C(sp 3 )-O bonds. To our delight, the diborylation of benzaldehyde dimethyl acetal ( 7a ) efficiently yielded the desired gem -diborylalkane 8a under standard conditions. Furthermore, 2-phenylacetaldehyde dimethyl acetal ( 7b ) and 3-phenylpropanal dimethyl acetal ( 7c ) exhibited high reactivity, affording the corresponding gem -diborylalkanes 8b and 8c in 72% and 53% isolated yields, respectively. This selective approach successfully expands the scope of C–O bond borylation to previously unexplored substrates. Regarding synthetic utility, the derivatization of the resulting mono- and diboronic esters was carried out according to reported methods (Fig. 6 a). For example, the addition of 2-lithiofuran, prepared from furan and n -BuLi at low temperature, to monoboronic ester 2a , followed by treatment of the resulting borate complex with N -bromosuccinimide (NBS), furnished the coupling product 9a in 76% yield. 47 In addition, the α-C − H bond adjacent to the diboron moiety of gem -diboronic ester 8b was readily lithiated with LiTMP (2,2,6,6-tetramethylpiperidyl lithium). 48 The resulting lithiated 8b underwent subsequent nucleophilic substitution with 1-bromo-3-methylbut-2-ene or nucleophilic addition to benzophenone, affording the functionalized diboronic ester 9b and monoboronic ester 9c , respectively, in good yields. These resulting mono- and dibonic esters can be further functionalized via cross-coupling reactions. To gain mechanistic insight into the present borylation, several control experiments were performed (Fig. 6 b). Partial racemization was observed during the borylation of S -1a with an enantiopurity of 99% ee, leading to the formation of the stereo-inverted product R -2a as the major enantiomer under standard conditions. The enantiopurity of R -2a was determined by its conversion to the alcohol product R -10a in 60% ee. It was confirmed that racemization of S -1a and R -2a did not occur under standard conditions, either in the presence or absence of B 2 pin 2 . Additionally, the borylation of trans - 1y having an equatorial methoxy group, exhibited low reactivity and selectivity, affording a mixture of the corresponding products, cis - 2y and trans - 2y , in low yields with the stereo-inverted cis - 2y as the major isomer. These experimental evidences, particularly the low stereoselectivity, suggest that the borylation likely proceeds through the formation of a carbocation intermediate. In contrast, the borylation of cis - 1y having an axial methoxy group, produced the stereo-inverted product trans - 2y as a single isomer in 44% isolated yield, along with the elimination alkene byproduct 1y' . However, these experimental results do not provide definitive evidence to elucidate the mechanism, and it seems that the reaction mechanism may not be strictly limited to either an S N 1- or S N 2-type pathway. To elucidate the detailed reaction mechanism, density functional theory (DFT) calculations were carried out using isopropyl methyl ether as a model substrate to optimize the energetically favorable pathways, including intermediates ( IMs ) and transition states ( TSs ) (Fig. 7 , Supplementary Tables S1 and S2). Additionally, considering that the low-coordinated gold atoms in AuNPore serve as catalytically active sites, an Au 20 – cluster with a tetrahedral structure was used as a catalyst model system. 49 The B–B bond cleavage of B 2 pin 2 on AuNPore has been demonstrated in our previous experimental and theoretical studies. 42 , 43 Similarly, in this study, the adsorption of B 2 pin 2 on the Au 20 - cluster ( IM0' ) induces B–B bond cleavage via TS 0 , forming the Au diboryl complex IM0 . The activation free energy (ΔG ‡ ) of TS 0 is relatively high at 27.4 kcal/mol, corresponding to the experimentally observed heating conditions in the range of 80–100°C. Next, the cleaved Bpin unit on Au binds to the ether oxygen in IM1 , forming the boryloxonium complex IM2 via acid-base complexation ( TS 1-2 ). The desorption of boryloxonium species in IM2 leads to the formation of a more energetically stable intermediate IM3 . At this stage, an S N 2-type C–B bond formation could be considered as a possible subsequent pathway. However, the calculated results indicate that the Bpin units on Au act as Lewis acids to form IM2 and IM3 , which contradicts the expected nucleophilic behavior of the Bpin unit in S N 2-type borylation. Consistently, our DFT calculations were unable to optimize the transition state corresponding to this S N 2-type borylation, likely due to the high ΔG ‡ . Instead, IM3 undergoes facile deoxygenation via TS 3-4 with a low ΔG ‡ of 3.1 kcal/mol, generating the energetically much stable carbocation intermediate IM4 along with MeOBpin. To support the mechanistic pathway involving a carbocation intermediate, DFT calculations on secondary kinetic isotope effects (SKIEs) were performed (Fig. 6 c, Supplementary Table S3). The calculated α- and β-SKIE values for the conversion of IM3 to IM4 , corresponding to the α-C-D and β-C-D bonds, were 1.22 and 1.08, respectively, suggesting the formation of a carbocation intermediate. To further verify this computational outcome, intermolecular competition reactions were conducted using a 1:1 mixture of protonated and deuterated ethers under standard conditions in the same vessel for 30 min (Fig. 6 d). As a result, the experimentally obtained α- and β-SKIE values for the borylation of 1a and 1a- d , as well as 1a and 1a- d 3 , were 1.28 and 1.17, respectively. These values are in remarkable agreement with the calculated values, further supporting the carbocation formation and the validity of our DFT calculation method. This carbocation formation led us to consider the possibility of a subsequent S N 1-type borylation pathway. However, probably due to the electrophilic nature of the Bpin unit on Au, the calculations were unable to optimize a reasonable transition state for the S N 1-type borylation. Unexpectedly, our DFT calculations suggest that the most energetically favorable pathway proceeds via TS 4-5 , leading to the formation of the organogold species IM5 ( i Pr–Au–Bpin), with a low ΔG ‡ of 4.5 kcal/mol. It was noted that the Wiberg bond index of 0.2872 between Au and the carbocation center (Au-C), calculated for the carbocation in IM4 , indicates the noncovalent nature of the Au-C interaction (Supplementary Fig. S1 ). This carbocation could be stabilized by the Au surface from the backside of the methoxy leaving group, favoring the generation of the formally stereo-inverted i Pr–Au–Bpin species ( IM5 ). Finally, the reductive elimination of the i Pr–Au–Bpin species in IM5 via TS 5-6 forms a C(sp 3 )–B bond on Au ( IM6 ), 50 , 51 which then desorbs to release the corresponding alkylboronic esters. In general, reductive elimination proceeds in a stereoretentive manner, 51 so the borylation of enantioenriched ethers is expected to afford the corresponding boronic ester products with inverted stereochemistry. However, a decrease in the enantiopurity of the stereoinversion product R -2a was observed upon chiral transfer borylation of enantioenriched S -1a , as shown in Fig. 6 b. This partial racemization is probably due to the weak noncovalent Au-C interaction in IM4 , which may lead to partial desorption of the carbocation from the Au surface. Additionally, the energy barrier between TS 4-5 and IM5 (1.7 kcal/mol) is lower compared to that of TS 5-6 in the reductive elimination of IM5 (3.7 kcal/mol), implying a fast reversible reaction from IM5 to IM4 via TS 4-5 . Moreover, IM4 (-29.4 kcal/mol) is more stable than IM5 (-26.5 kcal/mol). This reversible reaction, which is both kinetically and thermodynamically favorable for IM4 , can also lead to partial racemization. In conclusion, we have established an efficient and practicable heterogeneous borylation method for various dialkyl ethers using a highly reusable and robust AuNPore nanostructure catalyst. This strategy enables the conversion of a wide range of dialkyl ethers, including both acyclic and cyclic ethers, as well as acetal substrates containing inactive and active C(sp 3 )–O bonds, into synthetically valuable alkyl boronic monoesters and diesters in moderate to high chemical yields and broad functional group compatibility. Notably, an unprecedented heterogeneous catalytic borylation mechanism, involving the formation of carbocation and organogold species followed by reductive elimination through C(sp 3 )–Au–Bpin intermediates, was proposed for the first time through DFT calculations combined with experimental outcomes, diverging from traditional S N 1- and S N 2-type boryl substitution pathways. By leveraging the unique property of AuNPore, this approach offers a green, efficient, and scalable solution to a traditionally challenging transformation, highlighting the potential of heterogeneous AuNPore catalysis in sustainable synthetic chemistry. Methods General procedure for the borylation of ethers To a solution of dialkyl ether 1a (0.3 mmol, 1.0 equiv) and B 2 pin 2 (0.42 mmol, 1.4 equiv) in toluene (1 M, 0.3 mL) was added AuNPore (10 mol%, 5.9 mg) in a 3 mL reactor vial with screwed cap at room temperature. The reaction mixture was stirred under nitrogen atmosphere on an aluminum-block for 6 h at 100 ºC. After cooling to room temperature, the AuNPore catalyst was recovered by simple filtration and the filtrate was evaporated. The resulting residual was purified by silica gel chromatography to afford 2a in 80% yield (62.4 mg) as a colorless oil. The recovered AuNPore catalyst was washed with acetone and dried under vacuum for reuse. Declarations Acknowledgements This research was supported by a Grant-in-Aid for Scientific Research on Innovative Areas “Hybrid Catalysis for Enabling Molecular Synthesis on Demand” (JP17H06447) from MEXT (Japan) and a Grant-in-Aid for Scientific Research (S) (JP22H04969) from the JSPS. The computation was performed using Research Center for Computational Science, Okazaki, Japan (Project: 24-IMS-C110). Y.Z. thanks the China Scholarship Council (202208210181) for financial support. Author contributions T.J. and M.T. conceived and designed the project and wrote the manuscript with the assistance of other authors. Y.Z. and C.L conducted experiments and contributed equally. T.S. performed theoretical calculations. All the authors analyzed the data and discussed the results. Competing interests The authors declare no competing interests. Additional information Supplementary information The online version contains supplementary material available at http:// Correspondence and requests for materials should be addressed to Tienan Jin. Data availability Experimental procedures, computational data, and characterization of related compounds are available in the Supplementary Information. All data are available from the corresponding author upon request. References Cornella J, Zarate C, Martin R (2014) Metal-catalyzed activation of ethers via C–O bond cleavage: a new strategy for molecular diversity. Chem Soc Rev 43:8081–8097 Tobisu M, Chatani N (2015) Cross-Couplings Using Aryl Ethers via C – O Bond Activation Enabled by Nickel Catalysts. Acc Chem Res 48:1717–1726 Tollefson EJ, Hanna LE, Jarvo ER (2015) Stereospecific Nickel-Catalyzed Cross-Coupling Reactions of Benzylic Ethers and Esters. Acc Chem Res 48:2344–2353 Benton FL, Dillon TE (1942) The Cleavage of Ethers with Boron Bromide. I. Some Common Ethers. 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Nat Chem 6:584–589 Teo WJ, Ge S (2018) Cobalt-Catalyzed Enantioselective Synthesis of Chiral gem -Bis(boryl)alkanes. Angew Chem Int Ed 57:12935–12939 Bobuatong K, Karanjit S, Fukuda R, Ehara M, Sakurai H (2012) Aerobic oxidation of methanol to formic acid on Au 20 – : a theoretical study on the reaction mechanism. Phys Chem Chem Phys 14:3103–3111 Portugués A, Martínez-Nortes MA, Bautista D, González-Herrero P, Gil-Rubio J (2023) Reductive Elimination Reactions in Gold(III) Complexes Leading to C(sp 3 ) – X (X = C, N, P, O, Halogen) Bond Formation: Inner-Sphere vs S N 2 Pathways. Inorg Chem 62:1708–1718 Mankad NP, Toste F, D. (2012) C(sp 3 )–F reductive elimination from alkylgold(III) fluoride complexes. Chem Sci 3:72–76 Additional Declarations There is NO Competing Interest. Supplementary Files SI.pdf Supplementary Infromation GraphicalAbstract.png Graphical Abstract Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6249124","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":435446796,"identity":"75aa6577-d09b-4946-a695-9fd18ca9c9dd","order_by":0,"name":"Tienan Jin","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABEElEQVRIie3RsUrEMBjA8S8EUoTU+ZNI7xVSCtWD43yVK4FzdutwQ6e4iK4Vi76C082VQlz6AN1vdSgUXBSx5U5UaAu3ieQ/hFLyo/kaAJvtDydZt9Zx+wRs+4ok/Vs50G9C0lLuQbqFHugfZKgz56ZoeAzBoUhIQ+7fvRNHLxFWc6B3/Z/hvGCClxCy45yKi7UMplfGIBgFJMv7CSpGXQ0zhgsQt2sZPVbnGoHl7WSLfjLZ0GZH6JubfZGPEYIUREvCljDhJh1ZGiR6hJQqPMpKDBhGepqaIJClUafRteJDsziXT5v6JZ75D6kqqnrlefJZ+1X9Ovf8gT+2C+H31bVH4n46Jnqb4N7EZrPZ/mefJuFRWKM1yuEAAAAASUVORK5CYII=","orcid":"https://orcid.org/0000-0003-1150-7299","institution":"Tohoku University","correspondingAuthor":true,"prefix":"","firstName":"Tienan","middleName":"","lastName":"Jin","suffix":""},{"id":435446797,"identity":"512523e5-9e40-44e6-926d-8aff9bcf62c5","order_by":1,"name":"Yuhui Zhao","email":"","orcid":"","institution":"Tohoku University","correspondingAuthor":false,"prefix":"","firstName":"Yuhui","middleName":"","lastName":"Zhao","suffix":""},{"id":435446798,"identity":"739404ff-510c-4bef-bb78-836eb3f1dc1f","order_by":2,"name":"Charlie Lacroix","email":"","orcid":"","institution":"Tohoku University","correspondingAuthor":false,"prefix":"","firstName":"Charlie","middleName":"","lastName":"Lacroix","suffix":""},{"id":435446799,"identity":"d5898013-ab21-446e-81e5-3863d5389d11","order_by":3,"name":"Takuma Sato","email":"","orcid":"","institution":"Tohoku University","correspondingAuthor":false,"prefix":"","firstName":"Takuma","middleName":"","lastName":"Sato","suffix":""},{"id":435446800,"identity":"72b7a8e7-cf27-4231-a1ef-521733ca20f6","order_by":4,"name":"Masahiro Terada","email":"","orcid":"","institution":"Tohoku University","correspondingAuthor":false,"prefix":"","firstName":"Masahiro","middleName":"","lastName":"Terada","suffix":""}],"badges":[],"createdAt":"2025-03-18 03:55:55","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6249124/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6249124/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":79644262,"identity":"615e8fc0-d30b-4896-a0b4-554ed9976ae9","added_by":"auto","created_at":"2025-04-01 06:41:46","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":229666,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eBorylation of C(sp\u003c/strong\u003e\u003csup\u003e\u003cstrong\u003e3\u003c/strong\u003e\u003c/sup\u003e\u003cstrong\u003e)-O bonds to access alkylboron compounds. \u003c/strong\u003ea) Reported examples of the borylation of various activated C(sp\u003csup\u003e3\u003c/sup\u003e)-O bonds by transition-metal (TM)-catalyzed and photochemical methods. b) Our previous studies on AuNPore-catalyzed diborylations via B-B and C-C bond cleavage. c) Scanning electron microscopy (SEM) image of the nanoporous structure of AuNPore. The exact bulk metal shape and size of the used AuNPore catalyst is shown in the top right corner. d) This study on the AuNPore-catalyzed borylation of C(sp\u003csup\u003e3\u003c/sup\u003e)-O bonds in various dialkyl ethers and acetals.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-6249124/v1/ac0e6bce7e16bb7ba9e9b636.png"},{"id":79644266,"identity":"4f45e2ce-b8e6-4c54-978c-39b7f02ff874","added_by":"auto","created_at":"2025-04-01 06:41:46","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":65224,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eEstablishment of nanostructured AuNpore-catalyzed borylation, leaching experiments, and reusability of AuNPore.\u003c/strong\u003e Reaction conditions: \u003cstrong\u003e1a\u003c/strong\u003e (0.3 mmol), B\u003csub\u003e2\u003c/sub\u003epin\u003csub\u003e2\u003c/sub\u003e (1.4 equiv), AuNPore (10 mol%), toluene (1.0 M, 0.3 mL), at 100 \u003csup\u003e°\u003c/sup\u003eC for 6 h. a) Examination of AuNpore-catalyzed borylation of dialkyl ether \u003cstrong\u003e1a\u003c/strong\u003e with B\u003csub\u003e2\u003c/sub\u003epin\u003csub\u003e2\u003c/sub\u003e. b) Leaching experiments of the AuNPore-catalyzed borylation. c) Reusability of the AuNPore catalyst for the borylation of \u003cstrong\u003e1a\u003c/strong\u003e with B\u003csub\u003e2\u003c/sub\u003epin\u003csub\u003e2\u003c/sub\u003e. \u003csup\u003e\u003cem\u003ea\u003c/em\u003e\u003c/sup\u003e Isolated yields in parentheses are shown after silica gel chromatography. \u003csup\u003e1\u003c/sup\u003eH NMR yields determined using dibromomethane as an internal standard. \u003csup\u003e\u003cem\u003eb\u003c/em\u003e\u003c/sup\u003e 2.2 equiv of B\u003csub\u003e2\u003c/sub\u003epin\u003csub\u003e2\u003c/sub\u003e was used. \u003csup\u003e\u003cem\u003ec\u003c/em\u003e\u003c/sup\u003e \u003cstrong\u003e1a'\u003c/strong\u003e was recovered in 44% yield.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-6249124/v1/587f9a9ca6b135db5564886a.png"},{"id":79645568,"identity":"85a9d4b3-55c7-42e8-8dac-8b98a4042852","added_by":"auto","created_at":"2025-04-01 06:57:46","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":99898,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSubstrate scope of alkyl methyl acyclic ethers.\u003c/strong\u003e Isolated yields are shown after silica gel chromatography. \u003csup\u003e1\u003c/sup\u003eH NMR yields in parentheses determined using dibromomethane as an internal standard.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-6249124/v1/945d131044dab5c0ac90b8f5.png"},{"id":79644264,"identity":"99b64e19-b5d0-4761-b175-c7c5934febe1","added_by":"auto","created_at":"2025-04-01 06:41:46","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":103879,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSubstrate scope of alkyl cyclic ethers.\u003c/strong\u003e \u003csup\u003e\u003cem\u003ea\u003c/em\u003e\u003c/sup\u003e \u003csup\u003e1\u003c/sup\u003eH NMR yields determined using dibromomethane as an internal standard. Isolated yields are shown in parentheses after silica gel chromatography. \u003csup\u003e\u003cem\u003eb\u003c/em\u003e\u003c/sup\u003e Condition A: aq. HCl (0.1 M), EtOAc, rt, 1 h. Condition B: aq. HCl (0.1 M), EtOAc, rt, 1 h, then H\u003csub\u003e2\u003c/sub\u003eO\u003csub\u003e2\u003c/sub\u003e (30%), aq. NaOH (2 M), THF, 0 °C, 1 h. The isolated yields are shown after silica gel chromatography. \u003csup\u003e\u003cem\u003ec\u003c/em\u003e\u003c/sup\u003e 3 equiv. B\u003csub\u003e2\u003c/sub\u003epin\u003csub\u003e2\u003c/sub\u003e was used. \u003csup\u003e\u003cem\u003ed\u003c/em\u003e\u003c/sup\u003e 5 mol% AuNPore was used. \u003csup\u003e\u003cem\u003ee\u003c/em\u003e\u003c/sup\u003e 10 mol% AuNPore was used.\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-6249124/v1/1470379a3e4836824e960ae2.png"},{"id":79644276,"identity":"4ec9cb3b-46f8-4734-9c41-76ad15078d9c","added_by":"auto","created_at":"2025-04-01 06:41:46","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":78921,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSubstrate scope of diethers and acetals.\u003c/strong\u003e Isolated yields are shown after silica gel chromatography. \u003csup\u003e1\u003c/sup\u003eH NMR yields in parentheses determined using dibromomethane as an internal standard.\u003c/p\u003e","description":"","filename":"5.png","url":"https://assets-eu.researchsquare.com/files/rs-6249124/v1/75294770c445be801eda2363.png"},{"id":79644283,"identity":"7bbb4293-6db1-4c50-88dc-a61e4e8d598a","added_by":"auto","created_at":"2025-04-01 06:41:46","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":98345,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eDerivatization of alkylborates and mechanistic studies.\u003c/strong\u003e a) Derivatization of the alkylboronic esters. b) Control experiments for stereoselectivity. c) Theoretical calculation of the SKIEs using isopropyl methyl ether as a model substrate. d) Study of secondary kinetic isotope effects (SKIEs) using deuterated dialkyl ethers. \u003csup\u003e\u003cem\u003ea\u003c/em\u003e\u003c/sup\u003e Isolated yields are shown after silica gel chromatography. \u003csup\u003e\u003cem\u003eb\u003c/em\u003e\u003c/sup\u003e \u003csup\u003e1\u003c/sup\u003eH NMR yields are shown in parenthesis. \u003csup\u003e\u003cem\u003ec\u003c/em\u003e\u003c/sup\u003e SKIE values were calculated based on \u003csup\u003e1\u003c/sup\u003eH NMR yields of the products.\u003c/p\u003e","description":"","filename":"6.png","url":"https://assets-eu.researchsquare.com/files/rs-6249124/v1/51e84a7d420fd6c1c8d111dc.png"},{"id":79644275,"identity":"5473db87-0e2a-4103-93c6-f37d3e554986","added_by":"auto","created_at":"2025-04-01 06:41:46","extension":"png","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":618119,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003ePlausible reaction mechanism.\u003c/strong\u003e a) Computed Gibbs energy profiles for the AuNPore-catalyzed borylation using isopropyl methyl ether as a model substrate and Au\u003csub\u003e20\u003c/sub\u003e\u003csup\u003e–\u003c/sup\u003e cluster as a catalyst model system. b) Optimized structures of intermediates\u003cstrong\u003e IM0'\u003c/strong\u003e-\u003cstrong\u003eIM6\u003c/strong\u003e on Au\u003csub\u003e20\u003c/sub\u003e\u003csup\u003e–\u003c/sup\u003e cluster. Calculations were performed at the M06/def2-SVP level.\u003c/p\u003e","description":"","filename":"7.png","url":"https://assets-eu.researchsquare.com/files/rs-6249124/v1/80378a5c7dbdc72c8d0c2fd6.png"},{"id":81311596,"identity":"f7bb0f8a-4348-47b0-871b-10580e2a00c8","added_by":"auto","created_at":"2025-04-24 15:34:58","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1930621,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6249124/v1/6b5b42ff-bbe8-40a0-aa68-6a38470beee7.pdf"},{"id":79644569,"identity":"90ca7c7c-1b9c-4c37-b626-064966a4d1f6","added_by":"auto","created_at":"2025-04-01 06:49:46","extension":"pdf","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":17199006,"visible":true,"origin":"","legend":"Supplementary Infromation","description":"","filename":"SI.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6249124/v1/0503c7c6c7368f507d37b926.pdf"},{"id":79644560,"identity":"1beb42c6-5889-4420-8441-19ee26320459","added_by":"auto","created_at":"2025-04-01 06:49:46","extension":"png","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":193862,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eGraphical Abstract\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"GraphicalAbstract.png","url":"https://assets-eu.researchsquare.com/files/rs-6249124/v1/f66d7d84f1d54c4dc97faeae.png"}],"financialInterests":"There is \u003cb\u003eNO\u003c/b\u003e Competing Interest.","formattedTitle":"\u003cp\u003e\u003cstrong\u003eNanoporous gold-catalyzed borylation of C(sp\u003c/strong\u003e\u003csup\u003e\u003cstrong\u003e3\u003c/strong\u003e\u003c/sup\u003e\u003cstrong\u003e)–O bonds in dialkyl ethers and its mechanistic elucidation\u003c/strong\u003e\u003c/p\u003e","fulltext":[{"header":"Introduction","content":"\u003cp\u003eSelective cleavage and functionalization of C\u0026ndash;O bonds in ethers,\u003csup\u003e1-3\u003c/sup\u003e which are prevalent in biological molecules and fine chemicals, have been a longstanding challenge in organic synthesis due to their inherent stability and resistance to activation.\u003csup\u003e4-6\u003c/sup\u003e This challenge is particularly significant in the synthesis of alkylboron compounds,\u003csup\u003e7-14\u003c/sup\u003e which offer diverse reactivity for late-stage functionalization and potential applications in chemical biology with increased molecular complexity.\u003csup\u003e15-20\u003c/sup\u003e In this context, the direct borylation of activated C(sp\u0026sup3;)\u0026ndash;O bonds has emerged as a novel strategy for the selective synthesis of alkylboron compounds. In general, the preactivation of unreactive alkyl alcohols\u003csup\u003e21-25\u003c/sup\u003e or the use of active alkyl alcohol derivatives,\u003csup\u003e26-35\u003c/sup\u003e such as benzylic, allylic, and propargylic alkyls, is indispensable in these transition metal (TM)-catalyzed and photochemical borylations, facilitating the conversion of activated C(sp\u003csup\u003e3\u003c/sup\u003e)\u0026ndash;O bonds to C(sp\u003csup\u003e3\u003c/sup\u003e)\u0026ndash;B bonds (Fig. 1a). On the other hand, in 2021, the Dong group conducted pioneering work on the borylation of a limited number of alkyl aryl ethers, achieving moderate efficiency in yielding alkylborates, thereby paving the way for further developments in the field.\u003csup\u003e36,37\u003c/sup\u003e This direct borylation approach overcomes the limitations in regioselectivity and functional-group compatibility associated with traditional methods, such as hydroboration of alkenes\u003csup\u003e7-9\u003c/sup\u003e and transmetalation of Grignard and organolithium reagents with boron electrophiles.\u003csup\u003e38,39\u003c/sup\u003e Moreover, this method can be extended to cyclic ethers and acetals, enabling the convenient synthesis of hydroxy-functionalized alkyl monoborates and geminal alkyl diborates. However, the efficient borylation of inert C(sp\u003csup\u003e3\u003c/sup\u003e)\u0026ndash;O bonds in dialkyl ethers remains rare due to the high chemical stability of ethers, resulting from their large bond dissociation energy, as well as the challenging regioselectivity in cleaving two different C(sp\u003csup\u003e3\u003c/sup\u003e)\u0026ndash;O bonds. During our study, only one example has been reported most recently by the Shishido group on the borylation of inert dialkyl ethers catalyzed by \u0026alpha;-Fe\u003csub\u003e2\u003c/sub\u003eO\u003csub\u003e3\u003c/sub\u003e-supported gold nanoparticles.\u003csup\u003e40\u003c/sup\u003e In this case, the Lewis acidic metal oxide support plays an important role in activating the C(sp\u003csup\u003e3\u003c/sup\u003e)\u0026ndash;O bonds. Given the principles of green synthesis, such as waste minimization, energy efficiency, and reduced environmental impact, the development of sustainable and robust catalytic systems for the efficient functionalization of naturally abundant, inert chemical bonds still remains a significant challenge.\u003c/p\u003e\n\u003cp\u003eOver the past decade, we have explored the unique heterogeneous catalytic performance of nanoporous gold (AuNPore) in activating various covalent bonds to develop green synthetic methods.\u003csup\u003e41\u003c/sup\u003e In particular, we discovered that homolytic B\u0026ndash;B bond cleavage of bis(pinacolato)diboron (B\u003csub\u003e2\u003c/sub\u003epin\u003csub\u003e2\u003c/sub\u003e) on AuNPore led to stereoselective diborylation of alkynes (Fig. 1b).\u003csup\u003e42\u003c/sup\u003e We further demonstrated that the regioselective catalytic diborylation of methylenecyclopropanes (MCPs) proceeds via cleavage of both the distal C\u0026ndash;C single bond of MCPs and the B\u0026ndash;B bond of B\u003csub\u003e2\u003c/sub\u003epin\u003csub\u003e2\u003c/sub\u003e on AuNPore to form alkyl diborates (Fig. 1b).\u003csup\u003e43\u003c/sup\u003e The three-dimensional, high-surface-area nanoporous structure of AuNPore is composed of nanosized hyperboloid-like ligaments ranging from 30 to 40 nm, with low-coordinated, catalytically active gold atoms present on both the positively and negatively curved ligaments (Fig. 1c).\u003csup\u003e44,45\u003c/sup\u003e In addition, as shown in Fig. 1c, AuNPore is superior to metal nanoparticles in terms of its bulk metal shape, which prevents aggregation-induced catalyst deactivation and enables convenient experimental manipulation, and catalyst recovery and reuse. Importantly, the metal oxide support-free AuNPore catalyst may simplify the theoretical mechanistic studies of intermediates and transition states by eliminating support effects.\u003csup\u003e43\u003c/sup\u003e Inspired by previous studies, we devised that the borylation of dialkyl ethers with B\u003csub\u003e2\u003c/sub\u003epin\u003csub\u003e2\u003c/sub\u003e could be achieved through deoxygenation of the C(sp\u003csup\u003e3\u003c/sup\u003e)\u0026ndash;O bond by the Lewis acidic Bpin unit, generated in situ over the AuNPore catalyst. Herein, we present a heterogeneous catalytic method for the borylation of C(sp\u0026sup3;)\u0026ndash;O bonds in various acyclic and cyclic dialkyl ethers, as well as acetals, using the unsupported AuNPore catalyst (Fig. 1d). This catalytic process operates without the need for additives such as metal oxide supports or bases and exhibits a broad substrate scope with high functional group tolerance. Consequently, a diverse range of alkyl monoborates and diborates can be obtained in good to high yields. Notably, both experimental and theoretical studies suggest that a carbocation intermediate, generated via C(sp\u0026sup3;)\u0026ndash;O bond cleavage, plays a key role in forming an energetically favorable C(sp\u003csup\u003e3\u003c/sup\u003e)\u0026ndash;Au\u0026ndash;Bpin organogold species.\u003c/p\u003e"},{"header":"Results and discussion","content":"\u003cp\u003eAs shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eb, our previous studies on the diborylation of alkynes and MCPs have demonstrated that AuNPore is a unique catalyst for the B\u0026ndash;B bond cleavage of B₂pin₂, outperforming other nanoporous metal catalysts (Pt, Pd, Ag, Cu), which exhibited no activity.\u003csup\u003e\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e,\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e\u003c/sup\u003e Encouraged by these findings, we selected AuNPore as the catalyst for the borylation of secondary alkyl methyl ether \u003cb\u003e1a\u003c/b\u003e to synthesize secondary alkylboronic ester \u003cb\u003e2a\u003c/b\u003e without any additives, using the widely used and stable B₂pin₂ as the boron reagent (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ea). The unsupported AuNPore catalyst was prepared using a well-established dealloying method, in which an Au\u003csub\u003e30\u003c/sub\u003eAg\u003csub\u003e70\u003c/sub\u003e alloy was treated with concentrated nitric acid at room temperature to remove silver atoms.\u003csup\u003e\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e\u003c/sup\u003e To our delight, a brief optimization study revealed that the reaction proceeded efficiently in toluene at both 100\u0026deg;C and 85\u0026deg;C for 6 hours, with the former temperature giving slightly higher yield of \u003cb\u003e2a\u003c/b\u003e. Reducing the catalyst loading from 10 mol% to 5 mol% decreased the yield of \u003cb\u003e2a\u003c/b\u003e to 79%. Furthermore, a gram-scale reaction using 1.0 g of \u003cb\u003e1a\u003c/b\u003e produced \u003cb\u003e2\u003c/b\u003ea with no loss of efficiency. It was noted that CH₃OBpin was consistently observed as a byproduct, while the CH\u003csub\u003e3\u003c/sub\u003e\u0026ndash;O bond cleavage product, CH\u003csub\u003e3\u003c/sub\u003eBpin, was not detected in this reaction. Ethyl ether \u003cb\u003e1a'\u003c/b\u003e was less reactive under standard conditions compared to the methyl ether \u003cb\u003e1a\u003c/b\u003e, yielding the corresponding \u003cb\u003e2a\u003c/b\u003e in moderate yield, along with the formation of EtOBpin and the recovery of \u003cb\u003e1a'\u003c/b\u003e (44%). To determine whether the leached Au atoms in the solution function as the actual catalyst, control experiments were conducted (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eb). For instance, after carrying out the borylation of \u003cb\u003e1a\u003c/b\u003e with B\u003csub\u003e2\u003c/sub\u003epin\u003csub\u003e2\u003c/sub\u003e under standard conditions for 1 h, the separated reaction mixture, devoid of the AuNPore catalyst, did not exhibit any further increase in the yield of \u003cb\u003e2a\u003c/b\u003e after an additional 5 h of heating. In contrast, the residue containing the AuNPore catalyst led to a further improvement in the yield of \u003cb\u003e2a\u003c/b\u003e, reaching 91%. Furthermore, inductively coupled plasma mass (ICP-MS) analysis detected no leached Au atoms in the solution. These results clearly demonstrate that the borylation reaction catalyzed by AuNPore proceeds through a heterogeneous catalytic process. The AuNPore catalyst, recovered from the borylation of \u003cb\u003e1a\u003c/b\u003e through simple filtration, demonstrated exceptional reusability without any loss of catalytic activity; the yield of \u003cb\u003e2a\u003c/b\u003e remained consistently at 90% even after four additional reuses (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003ec). These experimental results combined with the non-toxic nature of gold metal highlight the high regioselectivity, robustness, and environmentally friendly catalytic performance of AuNPore.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eWith this remarkable catalytic performance, a wide range of acyclic methyl ethers was examined for direct borylation with B\u003csub\u003e2\u003c/sub\u003epin\u003csub\u003e2\u003c/sub\u003e using 10 mol% AuNPore in toluene at 100\u0026deg;C (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e). Secondary linear alkyl methyl ethers bearing halogens such as F, Cl, and Br at the \u003cem\u003epara\u003c/em\u003e-position of the phenyl ring showed excellent compatibility with the AuNPore catalyst, affording the corresponding secondary alkylboronic esters \u003cb\u003e2b\u003c/b\u003e-\u003cb\u003e2d\u003c/b\u003e in good to high yields (73\u0026ndash;86%) without dehalogenation and metal-catalyzed cross-coupling side reactions. Borylation of a substrate with an electron-donating methoxy group on the phenyl ring proceeded chemoselectively at the secondary C(sp\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e)-O bond, yielding product \u003cb\u003e2e\u003c/b\u003e in high yield while preserving methoxy group. In contrast, a substrate bearing a strong electron-donating \u003cem\u003eN\u003c/em\u003e,\u003cem\u003eN\u003c/em\u003e-dimethylamino group on the phenyl ring provided the corresponding product \u003cb\u003e2f\u003c/b\u003e in moderated yield, with partial recovery of the ether substrate (50%) even after prolonged reaction times. Additionally, alkylboronic acids tethered to naphthyl (\u003cb\u003e2g\u003c/b\u003e) and heteroaromatics such as furan (\u003cb\u003e2h\u003c/b\u003e) and thiophene (\u003cb\u003e2i\u003c/b\u003e), were successfully obtained under standard conditions without catalyst poisoning. Notably, boronic ester \u003cb\u003e2j\u003c/b\u003e, tethered to an acyl-protected alcohol, was synthesized with exclusive chemoselectivity without any cleavage of the active ester C(sp\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e)-O bond. This result suggests that this borylation preferentially occurs at the inert ether C(sp\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e)-O bond. This borylation process was also applied to the synthesis of one-carbon-shortened propyl (\u003cb\u003e2k\u003c/b\u003e) and homoallyl (\u003cb\u003e2l\u003c/b\u003e) boronic esters. The moderate yield of \u003cb\u003e2k\u003c/b\u003e was attributed to the increased formation of the elimination byproduct (\u003cem\u003eE\u003c/em\u003e)-prop-1-en-1-ylbenzene (33%). Further studies on inert alkyl methyl ether substrates revealed that the primary ether exhibited low regioselectivity in forming the desired product \u003cb\u003e2m\u003c/b\u003e, primarily due to the formation of CH\u003csub\u003e3\u003c/sub\u003eBpin as the major product via cleavage of the O-CH\u003csub\u003e3\u003c/sub\u003e bond. Meanwhile, tertiary alkyl ethers were largely unreactive toward borylation, as exemplified by \u003cb\u003e2n\u003c/b\u003e, likely due to steric hinderance between the bulky tertiary alkyl group and the AuNPore surface. In contrast, methyl ethers with bulkier secondary cyclic alkyl groups, such as 2,3-dihydro-1\u003cem\u003eH\u003c/em\u003e-indene, adamantane, and cyclododecane, underwent borylation uneventfully, affording the desired products \u003cb\u003e2o\u003c/b\u003e-\u003cb\u003e2q\u003c/b\u003e in high yields. Additionally, this borylation was successful with various active alkyl methyl ethers. Both active primary and secondary benzyl ethers bearing cyclopropyl or benzothienyl groups reacted efficiently, giving the corresponding products \u003cb\u003e2r\u003c/b\u003e-\u003cb\u003e2v\u003c/b\u003e in good to high yields. Active secondary allyl ethers also underwent borylation efficiently, affording the corresponding primary (\u003cb\u003e2w\u003c/b\u003e) and secondary (\u003cb\u003e2x\u003c/b\u003e) alkylboronic esters in high yields, where \u003cb\u003e2w\u003c/b\u003e was formed from the secondary allyl ether \u003cb\u003e1w\u003c/b\u003e via a double bond shift.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eEncouraged by this remarkable catalytic activity observed with acyclic ethers, we further investigated cyclic alkyl ethers to access difunctional alkylboronic esters via ring-opening borylation (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e). A range of cyclic ethers having various sizes reacted smoothly with B\u003csub\u003e2\u003c/sub\u003epin\u003csub\u003e2\u003c/sub\u003e in the presence of 2.5 mol% of AuNPore in toluene at 80\u0026deg;C, yielding the corresponding ring-opened linear alkylboronic esters in moderate to high yields. Aryl epoxides \u003cb\u003e3a\u003c/b\u003e and \u003cb\u003e3b\u003c/b\u003e, bearing an unsubstituted phenyl group and an electron-rich \u003cem\u003ep\u003c/em\u003e-tolyl group, respectively, reacted efficiently to yield the corresponding products \u003cb\u003e4a\u003c/b\u003e and \u003cb\u003e4b\u003c/b\u003e. However, \u003cb\u003e3c\u003c/b\u003e with an electron-withdrawing chlorine on the phenyl ring afforded \u003cb\u003e4c\u003c/b\u003e in moderate yield due to the formation of a 1-chloro-4-vinylbenzene by-product via deoxygenative elimination. These initially formed products \u003cb\u003e4a\u003c/b\u003e-\u003cb\u003e4c\u003c/b\u003e were hydrolyzed to hydroxyl-substituted boronic esters \u003cb\u003e4a'\u003c/b\u003e-\u003cb\u003e4c'\u003c/b\u003e under Condition A for isolation, as they underwent partial O-B bond hydrolysis during silica gel chromatography. Phenyl-substituted oxetanes \u003cb\u003e3d\u003c/b\u003e and \u003cb\u003e3e\u003c/b\u003e with strained four-membered rings, also underwent efficient borylation, providing the corresponding products \u003cb\u003e4d\u003c/b\u003e and \u003cb\u003e4e\u003c/b\u003e in high yields via cleavage of the active and inactive C-O bonds, respectively. The borylation of 2-phenyltetrahydrofuran (\u003cb\u003e3f\u003c/b\u003e) occurred preferentially at the more reactive 2-position of the tetrahydrofuran moiety, affording the corresponding product \u003cb\u003e4f\u003c/b\u003e in good yield. The products \u003cb\u003e4d\u003c/b\u003e-\u003cb\u003e4f\u003c/b\u003e were further converted to the corresponding 1,n-diols \u003cb\u003e4d\"\u003c/b\u003e-\u003cb\u003e4f\"\u003c/b\u003e under Condition B due to their low stability during silica gel chromatography. Interestingly, the sequential diborylation of 1,3-dihydroisobenzofuran (\u003cb\u003e3g\u003c/b\u003e), which contains two active C\u0026ndash;O bonds, proceeded smoothly with an excess of B\u003csub\u003e2\u003c/sub\u003epin\u003csub\u003e2\u003c/sub\u003e, producing the diboronic ester product \u003cb\u003e4g\u003c/b\u003e in 75% isolated yield. Similarly, the less strained six-membered cyclic ethers such as 2-phenyltetrahydro-2\u003cem\u003eH\u003c/em\u003e-pyran (\u003cb\u003e3h\u003c/b\u003e) and isochromane (\u003cb\u003e3i\u003c/b\u003e), also exhibited good reactivity toward selective borylation at the benzylic position, affording the expected products \u003cb\u003e4h\u003c/b\u003e and \u003cb\u003e4i\u003c/b\u003e in high yields. Furthermore, 4-phenyltetrahydro-2\u003cem\u003eH\u003c/em\u003e-pyran \u003cb\u003e3j\u003c/b\u003e containing two inert C(sp\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e)\u0026ndash;O bond could undergo the ring-opening borylation using 10 mol% of AuNPore, affording the corresponding difunctional boronic ester \u003cb\u003e4j\u003c/b\u003e in good yield.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eTo further broaden this approach in the synthesis of 1,n-diboronic esters, we investigated diethers and acetals containing two C(sp\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e)-O bonds within a single molecule (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e). As expected, the diborylation of 1,4- and 1,3-dimethyl diethers \u003cb\u003e5a\u003c/b\u003e and \u003cb\u003e5b\u003c/b\u003e having both active benzylic and inactive C(sp\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e)\u0026ndash;O bonds, with 3 equivalents of B\u003csub\u003e2\u003c/sub\u003epin\u003csub\u003e2\u003c/sub\u003e afforded the corresponding 1,4- and 1,3-diboronic esters \u003cb\u003e6a\u003c/b\u003e and \u003cb\u003e6b\u003c/b\u003e in 75% and 46% isolated yields, respectively. Notably, \u003cb\u003e5a\u003c/b\u003e, a mixture of \u003cem\u003esyn\u003c/em\u003e- and \u003cem\u003eanti\u003c/em\u003e-isomers, and \u003cb\u003e5b\u003c/b\u003e, a single \u003cem\u003eanti\u003c/em\u003e-isomer, were both converted to \u003cb\u003e6a\u003c/b\u003e and \u003cb\u003e6b\u003c/b\u003e as a mixture of \u003cem\u003esyn\u003c/em\u003e-and \u003cem\u003eanti\u003c/em\u003e-isomers, suggesting that the reaction likely involves the formation of a carbocation intermediate. Additionally, 1,4-bis(methoxymethyl)benzene (\u003cb\u003e5c\u003c/b\u003e) with two active C-O bonds was well accommodated, yielding the diborylation product \u003cb\u003e6c\u003c/b\u003e in 85% isolated yield. In recent years, \u003cem\u003egem\u003c/em\u003e-diborylalkanes have been widely employed as versatile bifunctional reagents in various chemical transformations, including sequential cross-coupling, asymmetric functionalization, and other orthogonal reaction.\u003csup\u003e\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e\u003c/sup\u003e Although several synthetic approaches have been developed to synthesize \u003cem\u003egem\u003c/em\u003e-diborylalkanes, direct borylation using simple and readily available acetals has never been reported. In this context, we explored the use of acetal substrates for the synthesis of \u003cem\u003egem\u003c/em\u003e-diborylalkanes via direct diborylation of two C(sp\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e)-O bonds. To our delight, the diborylation of benzaldehyde dimethyl acetal (\u003cb\u003e7a\u003c/b\u003e) efficiently yielded the desired \u003cem\u003egem\u003c/em\u003e-diborylalkane \u003cb\u003e8a\u003c/b\u003e under standard conditions. Furthermore, 2-phenylacetaldehyde dimethyl acetal (\u003cb\u003e7b\u003c/b\u003e) and 3-phenylpropanal dimethyl acetal (\u003cb\u003e7c\u003c/b\u003e) exhibited high reactivity, affording the corresponding \u003cem\u003egem\u003c/em\u003e-diborylalkanes \u003cb\u003e8b\u003c/b\u003e and \u003cb\u003e8c\u003c/b\u003e in 72% and 53% isolated yields, respectively. This selective approach successfully expands the scope of C\u0026ndash;O bond borylation to previously unexplored substrates.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eRegarding synthetic utility, the derivatization of the resulting mono- and diboronic esters was carried out according to reported methods (Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003ea). For example, the addition of 2-lithiofuran, prepared from furan and \u003cem\u003en\u003c/em\u003e-BuLi at low temperature, to monoboronic ester \u003cb\u003e2a\u003c/b\u003e, followed by treatment of the resulting borate complex with \u003cem\u003eN\u003c/em\u003e-bromosuccinimide (NBS), furnished the coupling product \u003cb\u003e9a\u003c/b\u003e in 76% yield.\u003csup\u003e47\u003c/sup\u003e In addition, the α-C\u0026thinsp;\u0026minus;\u0026thinsp;H bond adjacent to the diboron moiety of \u003cem\u003egem\u003c/em\u003e-diboronic ester \u003cb\u003e8b\u003c/b\u003e was readily lithiated with LiTMP (2,2,6,6-tetramethylpiperidyl lithium).\u003csup\u003e\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e\u003c/sup\u003e The resulting lithiated \u003cb\u003e8b\u003c/b\u003e underwent subsequent nucleophilic substitution with 1-bromo-3-methylbut-2-ene or nucleophilic addition to benzophenone, affording the functionalized diboronic ester \u003cb\u003e9b\u003c/b\u003e and monoboronic ester \u003cb\u003e9c\u003c/b\u003e, respectively, in good yields. These resulting mono- and dibonic esters can be further functionalized via cross-coupling reactions.\u003c/p\u003e \u003cp\u003eTo gain mechanistic insight into the present borylation, several control experiments were performed (Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003eb). Partial racemization was observed during the borylation of \u003cb\u003eS\u003c/b\u003e\u003cb\u003e-1a\u003c/b\u003e with an enantiopurity of 99% ee, leading to the formation of the stereo-inverted product \u003cb\u003eR\u003c/b\u003e\u003cb\u003e-2a\u003c/b\u003e as the major enantiomer under standard conditions. The enantiopurity of \u003cb\u003eR\u003c/b\u003e\u003cb\u003e-2a\u003c/b\u003e was determined by its conversion to the alcohol product \u003cb\u003eR\u003c/b\u003e\u003cb\u003e-10a\u003c/b\u003e in 60% ee. It was confirmed that racemization of \u003cb\u003eS\u003c/b\u003e\u003cb\u003e-1a\u003c/b\u003e and \u003cb\u003eR\u003c/b\u003e\u003cb\u003e-2a\u003c/b\u003e did not occur under standard conditions, either in the presence or absence of B\u003csub\u003e2\u003c/sub\u003epin\u003csub\u003e2\u003c/sub\u003e. Additionally, the borylation of \u003cem\u003etrans\u003c/em\u003e-\u003cb\u003e1y\u003c/b\u003e having an equatorial methoxy group, exhibited low reactivity and selectivity, affording a mixture of the corresponding products, \u003cem\u003ecis\u003c/em\u003e-\u003cb\u003e2y\u003c/b\u003e and \u003cem\u003etrans\u003c/em\u003e-\u003cb\u003e2y\u003c/b\u003e, in low yields with the stereo-inverted \u003cem\u003ecis\u003c/em\u003e-\u003cb\u003e2y\u003c/b\u003e as the major isomer. These experimental evidences, particularly the low stereoselectivity, suggest that the borylation likely proceeds through the formation of a carbocation intermediate. In contrast, the borylation of \u003cem\u003ecis\u003c/em\u003e-\u003cb\u003e1y\u003c/b\u003e having an axial methoxy group, produced the stereo-inverted product \u003cem\u003etrans\u003c/em\u003e-\u003cb\u003e2y\u003c/b\u003e as a single isomer in 44% isolated yield, along with the elimination alkene byproduct \u003cb\u003e1y'\u003c/b\u003e. However, these experimental results do not provide definitive evidence to elucidate the mechanism, and it seems that the reaction mechanism may not be strictly limited to either an S\u003csub\u003eN\u003c/sub\u003e1- or S\u003csub\u003eN\u003c/sub\u003e2-type pathway.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eTo elucidate the detailed reaction mechanism, density functional theory (DFT) calculations were carried out using isopropyl methyl ether as a model substrate to optimize the energetically favorable pathways, including intermediates (\u003cb\u003eIMs\u003c/b\u003e) and transition states (\u003cb\u003eTSs\u003c/b\u003e) (Fig.\u0026nbsp;\u003cspan refid=\"Fig7\" class=\"InternalRef\"\u003e7\u003c/span\u003e, Supplementary Tables S1 and S2). Additionally, considering that the low-coordinated gold atoms in AuNPore serve as catalytically active sites, an Au\u003csub\u003e20\u003c/sub\u003e\u003csup\u003e\u0026ndash;\u003c/sup\u003e cluster with a tetrahedral structure was used as a catalyst model system.\u003csup\u003e\u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e\u003c/sup\u003e The B\u0026ndash;B bond cleavage of B\u003csub\u003e2\u003c/sub\u003epin\u003csub\u003e2\u003c/sub\u003e on AuNPore has been demonstrated in our previous experimental and theoretical studies.\u003csup\u003e\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e,\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e\u003c/sup\u003e Similarly, in this study, the adsorption of B\u003csub\u003e2\u003c/sub\u003epin\u003csub\u003e2\u003c/sub\u003e on the Au\u003csub\u003e20\u003c/sub\u003e\u003csup\u003e-\u003c/sup\u003e cluster (\u003cb\u003eIM0'\u003c/b\u003e) induces B\u0026ndash;B bond cleavage via \u003cb\u003eTS\u003c/b\u003e\u003csub\u003e\u003cb\u003e0\u003c/b\u003e\u003c/sub\u003e, forming the Au diboryl complex \u003cb\u003eIM0\u003c/b\u003e. The activation free energy (ΔG\u003csup\u003e\u0026Dagger;\u003c/sup\u003e) of \u003cb\u003eTS\u003c/b\u003e\u003csub\u003e\u003cb\u003e0\u003c/b\u003e\u003c/sub\u003e is relatively high at 27.4 kcal/mol, corresponding to the experimentally observed heating conditions in the range of 80\u0026ndash;100\u0026deg;C. Next, the cleaved Bpin unit on Au binds to the ether oxygen in \u003cb\u003eIM1\u003c/b\u003e, forming the boryloxonium complex \u003cb\u003eIM2\u003c/b\u003e via acid-base complexation (\u003cb\u003eTS\u003c/b\u003e\u003csub\u003e\u003cb\u003e1-2\u003c/b\u003e\u003c/sub\u003e). The desorption of boryloxonium species in \u003cb\u003eIM2\u003c/b\u003e leads to the formation of a more energetically stable intermediate \u003cb\u003eIM3\u003c/b\u003e. At this stage, an S\u003csub\u003eN\u003c/sub\u003e2-type C\u0026ndash;B bond formation could be considered as a possible subsequent pathway. However, the calculated results indicate that the Bpin units on Au act as Lewis acids to form \u003cb\u003eIM2\u003c/b\u003e and \u003cb\u003eIM3\u003c/b\u003e, which contradicts the expected nucleophilic behavior of the Bpin unit in S\u003csub\u003eN\u003c/sub\u003e2-type borylation. Consistently, our DFT calculations were unable to optimize the transition state corresponding to this S\u003csub\u003eN\u003c/sub\u003e2-type borylation, likely due to the high ΔG\u003csup\u003e\u0026Dagger;\u003c/sup\u003e. Instead, \u003cb\u003eIM3\u003c/b\u003e undergoes facile deoxygenation via \u003cb\u003eTS\u003c/b\u003e\u003csub\u003e\u003cb\u003e3-4\u003c/b\u003e\u003c/sub\u003e with a low ΔG\u003csup\u003e\u0026Dagger;\u003c/sup\u003e of 3.1 kcal/mol, generating the energetically much stable carbocation intermediate \u003cb\u003eIM4\u003c/b\u003e along with MeOBpin. To support the mechanistic pathway involving a carbocation intermediate, DFT calculations on secondary kinetic isotope effects (SKIEs) were performed (Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003ec, Supplementary Table S3). The calculated α- and β-SKIE values for the conversion of \u003cb\u003eIM3\u003c/b\u003e to \u003cb\u003eIM4\u003c/b\u003e, corresponding to the α-C-D and β-C-D bonds, were 1.22 and 1.08, respectively, suggesting the formation of a carbocation intermediate. To further verify this computational outcome, intermolecular competition reactions were conducted using a 1:1 mixture of protonated and deuterated ethers under standard conditions in the same vessel for 30 min (Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003ed). As a result, the experimentally obtained α- and β-SKIE values for the borylation of \u003cb\u003e1a\u003c/b\u003e and \u003cb\u003e1a-\u003c/b\u003e\u003cb\u003ed\u003c/b\u003e, as well as \u003cb\u003e1a\u003c/b\u003e and \u003cb\u003e1a-\u003c/b\u003e\u003cb\u003ed\u003c/b\u003e\u003cb\u003e3\u003c/b\u003e, were 1.28 and 1.17, respectively. These values are in remarkable agreement with the calculated values, further supporting the carbocation formation and the validity of our DFT calculation method. This carbocation formation led us to consider the possibility of a subsequent S\u003csub\u003eN\u003c/sub\u003e1-type borylation pathway. However, probably due to the electrophilic nature of the Bpin unit on Au, the calculations were unable to optimize a reasonable transition state for the S\u003csub\u003eN\u003c/sub\u003e1-type borylation. Unexpectedly, our DFT calculations suggest that the most energetically favorable pathway proceeds via \u003cb\u003eTS\u003c/b\u003e\u003csub\u003e\u003cb\u003e4-5\u003c/b\u003e\u003c/sub\u003e, leading to the formation of the organogold species \u003cb\u003eIM5\u003c/b\u003e (\u003cem\u003ei\u003c/em\u003ePr\u0026ndash;Au\u0026ndash;Bpin), with a low ΔG\u003csup\u003e\u0026Dagger;\u003c/sup\u003e of 4.5 kcal/mol. It was noted that the Wiberg bond index of 0.2872 between Au and the carbocation center (Au-C), calculated for the carbocation in \u003cb\u003eIM4\u003c/b\u003e, indicates the noncovalent nature of the Au-C interaction (Supplementary Fig. \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e). This carbocation could be stabilized by the Au surface from the backside of the methoxy leaving group, favoring the generation of the formally stereo-inverted \u003cem\u003ei\u003c/em\u003ePr\u0026ndash;Au\u0026ndash;Bpin species (\u003cb\u003eIM5\u003c/b\u003e). Finally, the reductive elimination of the \u003cem\u003ei\u003c/em\u003ePr\u0026ndash;Au\u0026ndash;Bpin species in \u003cb\u003eIM5\u003c/b\u003e via \u003cb\u003eTS\u003c/b\u003e\u003csub\u003e\u003cb\u003e5-6\u003c/b\u003e\u003c/sub\u003e forms a C(sp\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e)\u0026ndash;B bond on Au (\u003cb\u003eIM6\u003c/b\u003e),\u003csup\u003e\u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e,\u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e\u003c/sup\u003e which then desorbs to release the corresponding alkylboronic esters. In general, reductive elimination proceeds in a stereoretentive manner,\u003csup\u003e\u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e\u003c/sup\u003e so the borylation of enantioenriched ethers is expected to afford the corresponding boronic ester products with inverted stereochemistry. However, a decrease in the enantiopurity of the stereoinversion product \u003cb\u003eR\u003c/b\u003e\u003cb\u003e-2a\u003c/b\u003e was observed upon chiral transfer borylation of enantioenriched \u003cb\u003eS\u003c/b\u003e\u003cb\u003e-1a\u003c/b\u003e, as shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003eb. This partial racemization is probably due to the weak noncovalent Au-C interaction in \u003cb\u003eIM4\u003c/b\u003e, which may lead to partial desorption of the carbocation from the Au surface. Additionally, the energy barrier between \u003cb\u003eTS\u003c/b\u003e\u003csub\u003e\u003cb\u003e4-5\u003c/b\u003e\u003c/sub\u003e and \u003cb\u003eIM5\u003c/b\u003e (1.7 kcal/mol) is lower compared to that of \u003cb\u003eTS\u003c/b\u003e\u003csub\u003e\u003cb\u003e5-6\u003c/b\u003e\u003c/sub\u003e in the reductive elimination of \u003cb\u003eIM5\u003c/b\u003e (3.7 kcal/mol), implying a fast reversible reaction from \u003cb\u003eIM5\u003c/b\u003e to \u003cb\u003eIM4\u003c/b\u003e via \u003cb\u003eTS\u003c/b\u003e\u003csub\u003e\u003cb\u003e4-5\u003c/b\u003e\u003c/sub\u003e. Moreover, \u003cb\u003eIM4\u003c/b\u003e (-29.4 kcal/mol) is more stable than \u003cb\u003eIM5\u003c/b\u003e (-26.5 kcal/mol). This reversible reaction, which is both kinetically and thermodynamically favorable for \u003cb\u003eIM4\u003c/b\u003e, can also lead to partial racemization.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eIn conclusion, we have established an efficient and practicable heterogeneous borylation method for various dialkyl ethers using a highly reusable and robust AuNPore nanostructure catalyst. This strategy enables the conversion of a wide range of dialkyl ethers, including both acyclic and cyclic ethers, as well as acetal substrates containing inactive and active C(sp\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e)\u0026ndash;O bonds, into synthetically valuable alkyl boronic monoesters and diesters in moderate to high chemical yields and broad functional group compatibility. Notably, an unprecedented heterogeneous catalytic borylation mechanism, involving the formation of carbocation and organogold species followed by reductive elimination through C(sp\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e)\u0026ndash;Au\u0026ndash;Bpin intermediates, was proposed for the first time through DFT calculations combined with experimental outcomes, diverging from traditional S\u003csub\u003eN\u003c/sub\u003e1- and S\u003csub\u003eN\u003c/sub\u003e2-type boryl substitution pathways. By leveraging the unique property of AuNPore, this approach offers a green, efficient, and scalable solution to a traditionally challenging transformation, highlighting the potential of heterogeneous AuNPore catalysis in sustainable synthetic chemistry.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eGeneral procedure for the borylation of ethers\u003c/h2\u003e \u003cp\u003eTo a solution of dialkyl ether \u003cb\u003e1a\u003c/b\u003e (0.3 mmol, 1.0 equiv) and B\u003csub\u003e2\u003c/sub\u003epin\u003csub\u003e2\u003c/sub\u003e (0.42 mmol, 1.4 equiv) in toluene (1 M, 0.3 mL) was added AuNPore (10 mol%, 5.9 mg) in a 3 mL reactor vial with screwed cap at room temperature. The reaction mixture was stirred under nitrogen atmosphere on an aluminum-block for 6 h at 100 \u0026ordm;C. After cooling to room temperature, the AuNPore catalyst was recovered by simple filtration and the filtrate was evaporated. The resulting residual was purified by silica gel chromatography to afford \u003cb\u003e2a\u003c/b\u003e in 80% yield (62.4 mg) as a colorless oil. The recovered AuNPore catalyst was washed with acetone and dried under vacuum for reuse.\u003c/p\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis research was supported by a Grant-in-Aid for Scientific Research on Innovative Areas “Hybrid Catalysis for Enabling Molecular Synthesis on Demand” (JP17H06447) from MEXT (Japan) and a Grant-in-Aid for Scientific Research (S) (JP22H04969) from the JSPS. The computation was performed using Research Center for Computational Science, Okazaki, Japan (Project: 24-IMS-C110). Y.Z. thanks the China Scholarship Council (202208210181) for financial support.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eT.J. and M.T. conceived and designed the project and wrote the manuscript with the assistance of other authors. Y.Z. and C.L conducted experiments and contributed equally. T.S. performed theoretical calculations. All the authors analyzed the data and discussed the results.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAdditional information\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSupplementary information\u003c/strong\u003e The online version contains supplementary material available at\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ehttp://\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCorrespondence\u003c/strong\u003e and requests for materials should be addressed to Tienan Jin.\u003c/p\u003e\u003ch2\u003eData availability\u003c/h2\u003e \u003cp\u003eExperimental procedures, computational data, and characterization of related compounds are available in the Supplementary Information. All data are available from the corresponding author upon request.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eCornella J, Zarate C, Martin R (2014) Metal-catalyzed activation of ethers via C\u0026ndash;O bond cleavage: a new strategy for molecular diversity. Chem Soc Rev 43:8081\u0026ndash;8097\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTobisu M, Chatani N (2015) Cross-Couplings Using Aryl Ethers via C\u0026thinsp;\u0026ndash;\u0026thinsp;O Bond Activation Enabled by Nickel Catalysts. Acc Chem Res 48:1717\u0026ndash;1726\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTollefson EJ, Hanna LE, Jarvo ER (2015) Stereospecific Nickel-Catalyzed Cross-Coupling Reactions of Benzylic Ethers and Esters. Acc Chem Res 48:2344\u0026ndash;2353\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBenton FL, Dillon TE (1942) The Cleavage of Ethers with Boron Bromide. I. Some Common Ethers. 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Chem Sci 3:72\u0026ndash;76\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-6249124/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6249124/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eSelective cleavage and functionalization of C–O bonds in ethers is a longstanding challenge in organic synthesis due to their inherent stability. This is particularly significant for synthesizing alkylboron compounds, which serve as versatile intermediates in diverse transformations. However, the high chemical stability of dialkyl ethers makes their successful borylation rare. Herein, we present a heterogeneous catalytic borylation of various dialkyl ethers with B₂pin₂ using an unsupported nanoporous gold catalyst (AuNPore). The nanosized, sponge-like catalyst operates without the need for metal oxide supports or bases, efficiently converting a wide range of acyclic and cyclic ethers, as well as acetals, into alkyl monoboronates and diboronates. Mechanistic studies indicate that AuNPore promotes B–B bond cleavage, leading to deoxygenative carbocation formation. This enables an unprecedented borylation pathway via the formation of a C(sp\u003csup\u003e3\u003c/sup\u003e)–Au–Bpin organogold species, which undergoes reductive elimination to yield alkylboron products.\u003c/p\u003e","manuscriptTitle":"Nanoporous gold-catalyzed borylation of C(sp3)–O bonds in dialkyl ethers and its mechanistic elucidation","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-04-01 06:41:41","doi":"10.21203/rs.3.rs-6249124/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"c1addda9-a880-483e-8824-9a55a5330e12","owner":[],"postedDate":"April 1st, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":46496467,"name":"Physical sciences/Chemistry/Catalysis/Heterogeneous catalysis"},{"id":46496468,"name":"Biological sciences/Drug discovery/Medicinal chemistry/Drug discovery and development"}],"tags":[],"updatedAt":"2025-04-24T15:26:51+00:00","versionOfRecord":[],"versionCreatedAt":"2025-04-01 06:41:41","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6249124","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6249124","identity":"rs-6249124","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}