Copper-Catalyzed Ligand-Controlled Selective Borocarbonylation of α-Substituted Styrenes Toward β-Boryl Aldehydes and Cyclopropyl Boronate Esters

Abstract

Open AccessCCS ChemistryRESEARCH ARTICLES18 Oct 2022Copper-Catalyzed Ligand-Controlled Selective Borocarbonylation of α-Substituted Styrenes Toward β-Boryl Aldehydes and Cyclopropyl Boronate Esters Yang Yuan†, Youcan Zhang†, Jian-Xing Xu and Xiao-Feng Wu Yang Yuan† Dalian National Laboratory for Clean Energy, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, 116023 Liaoning †Y. Yuan and Y. Zhang contributed equally to this work.Google Scholar More articles by this author , Youcan Zhang† Dalian National Laboratory for Clean Energy, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, 116023 Liaoning †Y. Yuan and Y. Zhang contributed equally to this work.Google Scholar More articles by this author , Jian-Xing Xu Dalian National Laboratory for Clean Energy, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, 116023 Liaoning Google Scholar More articles by this author and Xiao-Feng Wu *Corresponding authors: E-mail Address: [email protected] E-mail Address: [email protected] Dalian National Laboratory for Clean Energy, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian, 116023 Liaoning Leibniz-Institut für Katalyse e.V., Albert-Einstein-Straße 29a, Rostock 18059 Google Scholar More articles by this author https://doi.org/10.31635/ccschem.022.202202288 SectionsSupplemental MaterialAboutAbstractPDF ToolsAdd to favoritesDownload CitationsTrack Citations ShareFacebookTwitterLinked InEmail We report a copper-catalyzed ligand-controlled selective carbonylative borofunctionalization of α-substituted styrenes. This reaction provides a general and versatile procedure to synthesize a variety of synthetically useful β-boryl quaternary aldehydes and cyclopropyl boronate esters bearing a quaternary carbon center. With NHC (IMes= 1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene) as the ligand, the carbene intermediate reacts with O–H bond of alcohol while the carbene intermediate would undergo C–H bond insertion when using phosphine ligand [1,2-bis(diphenylphospino)ethane] as the ligand. Formation of a carbene intermediate has been proposed as the key step for this transformation. Download figure Download PowerPoint Introduction Carbenes or carbenoids are important reactive intermediates in organic synthesis that allow for the rapid construction of highly functionalized molecules.1–7 Among them, due to their electrophilic property, Fischer-type carbene and free carbene species can undergo insertion reactions.8,9 These insertion reactions, especially transition-metal-catalyzed carbene insertion reactions, represent one of the most fundamental and synthetically useful methods for forging C–C bonds or C–X bonds with high selectivity. Therefore, great effort has been devoted to the development of carbene insertions into C–H, N–H, O–H, S–H, and other X–H (e.g., B–H, Si–H, P–H…) bonds in past decades (Scheme 1a).10–23 Despite tremendous progress in this field, the selectively controlled X–H insertion under similar catalytic systems that allows for the structural diversity of final products, is still needed but remains challenging in current synthetic chemistry. Scheme 1 | Carbene insertion into X–H bond reactions. Download figure Download PowerPoint In recent years, borofunctionalization of unsaturated bonds has emerged as a remarkably versatile method to install boron (or boron and other functionalities) across π-systems.24–32 Among the possible procedures, transition-metal-catalyzed borocarbonylation33–39 is one of the most direct and efficient methods, introducing both the carbonyl group and the boryl group into a single molecule in one pot. Several approaches have been studied in our and other groups.40–42 Cu-catalyzed borocarbonylation in particular has been successfully demonstrated in diverse π-systems. These reactions generally involve the generation of Cu-Bpin species,43–46 which subsequently undergo addition to unsaturated bonds to afford boryl-alkyl/alkenyl copper intermediate. Then, the copper intermediate is followed by CO (carbon monoxide) insertion and the interception of the electrophile to generate the corresponding carbonyl-containing organoboron compounds. Interestingly, very recently our group reported a Cu-catalyzed carbonylative catenation and borylation of β-substituted styrenes.47 In this protocol, we proposed a carbene species as the key intermediate. Encouraged by this work, we wondered about further applications of this carbene intermediate to achieve selective X–H bond insertion from rather challenging α-substituted styrene substrates to build organoboronates bearing a quaternary carbon center. Herein, we disclose a copper-catalyzed borocarbonylation of α-substituted styrenes via ligand-controlled chemoselective carbene insertion into O–H bonds and C–H bonds. Specifically, with N-heterocyclic carbene (NHC) as the ligand, β-boryl quaternary aldehydes can be formed via carbene insertion into O–H bonds; While using phosphine ligand as the ligand, cyclopropylboronate esters bearing a quaternary carbon center can be obtained via carbene insertion into C–H bonds (Scheme 1b). Experimental Methods General procedure for borocarbonylation of α-substituted styrenes via carbene insertion into O–H bonds A vial (4 mL) was charged with SIMesCuCl (5.0 mol %), B2pin2 (76.2 mg, 1.5 equiv), KOtBu (67 mg, 3.0 equiv), and a stirring bar. The vial was closed by poly(tetrafluoroethylene) (PTFE)/white rubber septum (Wheaton 13 mm Septa) and a phenolic cap and connected with the atmosphere with a needle. The vial was evacuated under vacuum and recharged with argon three times. Then, tetrahydrofuran (THF; 1.0 mL) was injected under argon by using a syringe. After that tBuOH (0.4 mmol, 2.0 equiv) and α-substituted styrenes (0.2 mmol, 1.0 equiv) were added, and the vial (or several vials) was placed in an alloy plate, which was transferred into a 300 mL autoclave of the 4560 series from Parr Instruments (Moline, IL, USA). After flushing the autoclave three times with CO, a pressure of 5 bars of CO was adjusted at ambient temperature. Then, the reaction was performed for 16 h at 80 °C. After the reaction was complete, the autoclave was cooled down with ice water to room temperature, and the pressure was released carefully. The reaction was diluted with ethyl acetate (EA) and filtered through a pad of silica gel (a pipette with about 3 cm silica gel). The filtrate was concentrated under reduced pressure, and the residue was directly purified by column chromatography to afford the corresponding products 4. General procedure for borocarbonylation of α-substituted styrenes via carbene insertion into C–H bonds A vial (4 mL) was charged with 1,2-bis(diphenylphospino)ethane (DPPE) (10.0 mol %), Cu(OAc)2 (10.0 mol %), B2pin2 (101.6 mg, 2.0 equiv), KOtBu (67 mg, 3.0 equiv), and a stirring bar. The vial was closed by PTFE/white rubber septum (Wheaton 13 mm Septa) and phenolic cap and connected with the atmosphere with a needle. The vial was evacuated under vacuum and recharged with argon three times. Then, toluene (1.0 mL) was injected under argon by using a syringe. After that tBuOH (0.2 mmol, 1.0 equiv) and α-substituted styrenes (0.2 mmol, 1.0 equiv) were added, and the vial (or several vials) was placed in an alloy plate, which was transferred into a 300 mL autoclave of the 4560 series from Parr Instruments. After flushing the autoclave three times with CO, a pressure of 5 bar of CO was adjusted at ambient temperature. Then, the reaction was performed for 16 h at 60 °C. After the reaction was complete, the autoclave was cooled down with ice water to room temperature, and the pressure was released carefully. The reaction was diluted with EA and filtered through a pad of silica gel (a pipette with about 3 cm silica gel). The filtrate was concentrated under reduced pressure, and the residue was directly purified by column chromatography to afford the corresponding cyclopropylboronate esters 5. Results and Discussion Our initial optimization studies were conducted with α-methylstyrene 1a using stoichiometric amounts of bis(pinacolato)diboron (B2pin2), KOtBu, tBuOH, and THF as solvent under CO (5 bar) atmosphere at 80 °C. We found that the desired product β-borylated aldehyde 4a could be obtained in 71% gas chromatography (GC) yield when SIMesCuCl was used as the catalyst (Table 1, entry 1). A minor amount of the protoborated 3a formed as the byproduct. Copper catalyst ImesCuCl, IPrCuCl, and SIPrCuCl gave lower yields (18–48% yields, Table 1, entries 2–4), while 1,3-Bis (diphenylphosphino)propane (DPPP)/CuCl instead of ImesCuCl as the catalyst only afforded product 4a in 12% yield (Table 1, entry 5). The use of monodentate ligand PPh3 instead of DPPP as ligand did not generate 4a (Table 1, entries 6). Only byproduct 3a was delivered when KOMe was used as the base, and low yield (17%) of the product 4a was formed with NaOtBu as the base (Table 1, entries 7 and 8). Changing the solvent to CH3CN or N,N-Dimethylacetamide (DMAc) resulted in a trace amount of product 4a (Table 1, entry 9), and 1,4-dioxane only gave 4a in 25% yield (Table 1, entry 10). 38% yield of 4a was obtained when no tBuOH was added showing that a minor amount of water (likely introduced during the weighing process under air or from the reagents) existed in the system (Table 1, entry 11). Using 1.0 equiv of H2O or EtOH instead of tBuOH led to lower yields (Table 1, entries 12 and 13). Increasing the amount of tBuOH to 2.0 equiv gave the best result (78% yield, Table 1, entry 14). Here it is important to mention that due to the poor stability of β-borylated aldehyde 4a on silica, column chromatography should be performed quickly to prevent product decomposition during the purification process. Table 1 | Investigation of Reaction Conditionsa Entry Deviation from the Above Conditions Yield of 4a (%) 1 None 71 2 IMesCuCl instead of SIMesCuCl 48 3 IPrCuCl instead of SIMesCuCl 31 4 SIPrCuCl instead of SIMesCuCl 18 5 DPPP/CuCl instead of SIMesCuCl 12 6 PPh3/CuCl instead of SIMesCuCl Trace 7 KOMe instead of KOtBu Trace 8 NaOtBu instead of KOtBu 17 9 CH3CN, DMAc instead of THF Trace 10 1,4-Dioxane instead of THF 25 11 No tBuOH 38 12 H2O instead of tBuOH 55 13 EtOH instead of tBuOH 58 14 2.0 equiv tBuOH instead of 1.0 equiv 78 (63)b aReaction conditions: 1a (0.2 mmol, 1.0 equiv), B2pin2 (0.3 mmol, 1.5 equiv), tBuOH (1.0 equiv), SIMesCuCl (5.0 mol %), KOtBu (0.6 mmol, 3.0 equiv), CO (5 bar), 80 °C, THF (1.0 mL), 16 h. Yields are determined by GC with hexadecane as an internal standard. bIsolated yield. With the best conditions in hand, we next assessed the generality of this boroformylation reaction under the optimal reaction conditions. As shown in Scheme 2, α-methylstyrenes bearing different electron-rich or electron-deficient groups at the para position were all successfully converted into the desired products 4a–4h in moderate to good yields. -Me and -OMe groups at meta or ortho position also worked well to give 4i–4l in 49–61% yields. Disubstituted α-methylstyrenes also proceeded efficiently to give the corresponding β-boryl aldehydes 4m and 4n in 53% and 41% yields, respectively. Delightfully, the reaction worked smoothly with α-methylstyrenes containing 2,3-dihydrobenzofuran, benzo[d][1,3]dioxole, 1-naphthalene, and 2-MeO-naphthalene, delivering products 4o–4r in reasonable yields. Other α-alkylstyrenes were readily delivered to corresponding products ( 4s– 4x) in moderate yields, including bulky substitutions, such as isobutyl, cyclohexyl. Moreover, the cyclic boroformylated products 4y–4aa were isolated in 48–65% yields. Finally, the boroformylation of α-methylstyrene using a diboron reagent with a six-membered ring instead of B2pin2 provided 4ab in 45% yield. Unfortunately, 4-chloro-α-methylstyrene, 1,1-diphenylethylene, 1-methyl-3H-indene, 3-vinyl-1H-indole, styrene, and 2-methyl-1-pentene did not work under the present conditions. Scheme 2 | Substrates scope.aaReaction conditions: 1 (0.2 mmol, 1.0 equiv), B2pin2 (0.3 mmol, 1.5 equiv), tBuOH (2.0 equiv), SIMesCuCl (5.0 mol %), KOtBu (0.6 mmol, 3.0 equiv), CO (5 bar), 80 °C, THF (1.0 mL), 16 h, isolated yields. Download figure Download PowerPoint Surprisingly, during the screening of the above reaction conditions, we also found that the cyclopropylboronate ester 5a was formed by using phosphine ligands under certain conditions. To our delight, 5a was delivered in 62% yield with 2.5∶1 dr by employing DPPE/CuCl as the catalyst in toluene under 60 °C (Table 2, entry 1). Subsequently, various phosphine ligands were surveyed, such as Xantphos, 1,1-bis(diphenylphosphino)methane (DPPM), DPPP, 1,1′-bis (diphenyphosphino)ferrocene (DPPF), and 1,2-bis(diphenylphosphino)benzene (DPPBz). The yields of the desired 5a could not be further improved (entries 2–6). SIPrCuCl instead of DPPE/CuCl only resulted in a trace amount of 5a (entry 7) whereas SIMesCuCl led to β-boryl aldehyde 4a as the major product (entry 8). Although varying the copper precatalysts had limited impact on yields (Table 2, entries 9 and 10), Cu(OAc)2 was found to give better diastereoselectivity (3:1) and isolated in 58% yield. Table 2 | Investigation of Reaction Conditionsa Entry Deviation from the Above Conditions Yield of 5a (%) dr 1 None 62 2.5∶1 2 Xantphos instead of DPPE <5 / 3 DPPM instead of DPPE Trace / 4 DPPP instead of DPPE 60 1∶1.5 5 DPPF instead of DPPE 9 1.2∶1 6 DPPBz instead of DPPE 37 6∶1 7 SIPrCuCl instead of DPPE/CuCl Trace / 8 SIMesCuCl instead of DPPE/CuCl Traceb / 9 Cu(OAc)2 instead of CuCl 64 (58)c 3∶1 10 CuBr instead of CuCl 61 2.5∶1 aReaction conditions: 1a (0.2 mmol, 1.0 equiv), B2pin2 (0.3 mmol, 1.5 equiv), tBuOH (2.0 equiv), DPPE (10 mol %), CuCl (10 mol %), KOtBu (0.6 mmol, 3.0 equiv), CO (5 bar), 60 °C, toluene (1.0 mL), 16 h. Yields are determined by GC with hexadecane as an internal standard; diastereomeric ratios were determined by 1H NMR analysis. bMajor product was 4a. cIsolated yield. Using the optimized reaction conditions for this carbene insertion into the C–H bond reaction, we evaluated the substrate scope of this methodology. As summarized in Scheme 3, the reaction proceeded smoothly with a variety of α-substituted styrenes, affording the expected cyclopropylboronate esters in moderate yields. α-substituted styrenes bearing either electron-donating or electron-withdrawing groups at the para, meta, and ortho positions of the phenyl ring reacted well to give the products ( 5a–5i) in reasonable yields (41–60%) with indicated diastereomeric ratio (dr) values (1.2∶1–4∶1). The reaction was compatible with α-substituted styrenes containing two substituents on the aromatic ring, 2,3-dihydrobenzofuran, and benzo[d][1,3]dioxole, generating the corresponding products 5j–5m in 43–51% yields. α-Ethyl styrene and exocyclic styrenes were also tolerated under the catalytic system to deliver 5n–5p in 38–52% yields. Notably, the spiro product 5o was formed with outstanding diastereoselectivity (>20∶1 dr). The major diastereoisomers were determined by comparing the NMR spectra with Charette’s48 and Tortosa’s49 work. Scheme 3 | Substrates scope.aaReaction conditions: 1 (0.2 mmol, 1.0 equiv), B2pin2 (0.3 mmol, 1.5 equiv), tBuOH (2.0 equiv), DPPE (10 mol %), Cu(OAc)2 (10 mol %), KOtBu (0.6 mmol, 3.0 equiv), CO (5 bar), 60 °C, toluene (1.0 mL), 16 h; isolated yield; diastereomeric ratios were determined by 1H NMR analysis. Download figure Download PowerPoint To demonstrate the efficiency and practicability of the carbene insertion into O–H bond and C–H bond procedures, scale-up reactions were carried out with a reduced amount of catalyst loading. A 2.5 mol % loading of the copper catalyst was sufficient to perform the reaction on a 3 mmol scale (Scheme 4, I). Despite the reduced amounts of catalyst, 4a was produced in 55% yield (452 mg). Then, a 3 mmol-scale reaction of alkene 1a was also performed with 5.0 mol % CuCl/DPPE, delivering 5a in 50% yield with 2/1 dr. To showcase the synthetic utility of this methodology, some further transformations of product 4a were performed (Scheme 4, II). Oxidation of 4a with NaBO3 generated the β-hydroxy ketone 6 in 81% yield. Suzuki–Miyaura cross-coupling with iodobenzene using 4a as the nucleophile gave 7 in 74% yield. The product 4a was reduced by NaBH4 to afford the boroxole 8 in 86% yield, which also easily underwent oxidation, and Suzuki-Miyaura cross-coupling produced products 9 and 10, respectively. In addition, the cyclopropylboronate ester 5o can be effectively converted into other compounds through a series of derivatizations of the boronic ester group (Scheme 4, III). Arylation was successfully achieved using both palladium-catalyzed Suzuki–Miyaura coupling50 and transition-metal-free coupling51,52 reactions, providing good yields of 11 and 12, respectively. Compound 13 was prepared through an oxidation-benzoylation sequence. Finally, a C–C bond formation was achieved via Zweifel olefination,53 which provided alkene 14 in 63% yield. Scheme 4 | Scale-up reaction and derivatization. (a) NaBO3.4H2O (4.0 equiv), THF/H2O, rt, 5 h. (b) PhI (1.1 equiv), Pd(PPh3)4 (1.0 mol %), K2CO3 (1.5 equiv), N,N-dimethylformamide (DMF)/H2O, 80 °C, 3 h. (c) NaBH4 (2.0 equiv), MeOH, rt, 1 h. (d) NaBO3.4H2O (4.0 equiv), THF/H2O, rt, 3 h. (e) PhI (1.1 equiv), Pd(PPh3)4 (1.0 mol %), K2CO3 (1.5 equiv), DMF/H2O, 80 °C, 2 h. (f) PhBr (1.1 equiv), Pd(OAc)2 (1.0 mol %), RuPhos (1.0 mol %), KOH (3.0 equiv), THF/H2O, 70 °C, 12 h. (g) (I) NaBO3.4H2O (4.0 equiv), THF/H2O, rt, 5 h; (II) BzCl (1.5 equiv), Et3N (3.0 equiv), 4-dimethylaminopyridine (DMAP; 20.0 mol %), dichloromethane (DCM), rt. (h) (i) Furan (1.2 equiv), nBuLi (1.2 equiv), THF, −78 °C, 1 h; (ii) 5o (1.0 equiv), THF, −78 °C, 1 h, then N-bromosuccinimide (NBS; 1.2 equiv), −78 °C, 1 h. (i) (i) C2H3MgBr (4.0 equiv), THF, rt, 0.5 h; (ii) I2 (4.0 equiv), −78 °C, 0.5 h; (iii) NaOMe (8.0 equiv), MeOH, rt, 1 h. Download figure Download PowerPoint To gain insights into the reaction mechanism of the O–H bond carbene insertion. First, we investigated the stoichiometric experiment with intermediate C, which was prepared in situ from α-methylstyrene and Cu-Bpin under 5 bar of CO. Then, intermediate C further reacted with tBuOH and led to the formation of the expected product 4a containing a quaternary center in 26% yield (Scheme 5, I). Instead of tBuOH, deuterium tBuOD was used for the reaction, and 45% aldehyde hydrogen was deuterated. The result revealed that a minor amount of water from the reagents or the air could act as the proton sources as well. Next, deuterated substrates 1g-d2 and 1g-d5 were subjected separately to the reactions under standard conditions, and no significant H/D exchange was observed. Scheme 5 | Scale-up reaction and derivatizations. Download figure Download PowerPoint On the basis of our experimental observations as well as previous studies,47,54–57 a plausible reaction mechanism for O–H bond carbene insertion process is shown in Scheme 6. The (L’)Cu-Bpin species was formed by the reaction of B2pin2 with (L’)CuCl and tBuOK. Subsequent borocupration of the α-substituted styrenes generated the β-boroalkylcopper intermediate A. Next, CO was inserted into the C–Cu bond of intermediate A to afford the acyl-copper intermediate B, which underwent isomerization instantly to the key carbene intermediate C. Then, carbene intermediate C underwent O–H insertion with tBuOH to provide the intermediate D. The β-elimination from D produces 4, releasing the copper alkoxide species for the next catalytic cycle. Some control experiments and deuterium experiments were conducted for investigating the mechanism for the C–H bond insertion procedure (see Supporting Information Figure S1). The plausible mechanisms have been given in the Supporting Information (see Supporting Information Figure S2), and the computational study of the mechanism is ongoing in our lab.58–60 Concerning the selectivity between β-boryl aldehyde and boryl cyclopropane, we believe it is because the reactivity of the carbene intermediate C is tuned by the ligand added. Scheme 6 | Proposed mechanism for O–H bonds carbene insertion. Download figure Download PowerPoint Conclusion We have described a copper-catalyzed carbonylative borofunctionalization of α-substituted styrenes. The reaction proceeds via ligand-controlled selective carbene insertion into O–H and C–H bonds. This reaction provides a general and versatile procedure to synthesize a variety of synthetically useful β-boryl quaternary aldehydes and cyclopropylboronate esters bearing a quaternary carbon center. The formation of a carbene intermediate was proposed as the key step in this transformation. With NHC (IMes) as the ligand, the carbene intermediate reacts with the O–H bond of alcohol. Meanwhile, using phosphine ligand (DPPE) as the ligand, the carbene intermediate undergoes C–H bond insertion. We anticipate that the proposed carbene intermediates derived from this study will find broad applicability in carbonylation and organic chemistry. Supporting Information Supporting Information is available and includes general comments, general procedures, analytic data, and NMR spectra. Disclosures Because of the high toxicity of carbon monoxide, all the reactions should be performed in an autoclave. The laboratory should be well-equipped with a CO detector and alarm system. Conflict of Interest There is no conflict of interest to report. Funding Information The authors appreciate the financial support from DICP (Dalian Institute of Chemical Physics, CAS) and the K.C. Wong Education Foundation (grant no. GJTD-2020-08).