Copper-Catalyzed Highly Enantioselective 1,4-Protoboration of Terminal 1,3-Dienes

Abstract

Open AccessCCS ChemistryCOMMUNICATION1 May 2022Copper-Catalyzed Highly Enantioselective 1,4-Protoboration of Terminal 1,3-Dienes Qitao Guan, Yuqi Ji, Qian Zhao and Chun Zhang Qitao Guan Institute of Molecular Plus, Tianjin Key Laboratory of Molecular Optoelectronic Science, Department of Chemistry, School of Science, Tianjin University, Tianjin 300072 Google Scholar More articles by this author , Yuqi Ji Institute of Molecular Plus, Tianjin Key Laboratory of Molecular Optoelectronic Science, Department of Chemistry, School of Science, Tianjin University, Tianjin 300072 Google Scholar More articles by this author , Qian Zhao Institute of Molecular Plus, Tianjin Key Laboratory of Molecular Optoelectronic Science, Department of Chemistry, School of Science, Tianjin University, Tianjin 300072 Google Scholar More articles by this author and Chun Zhang *Corresponding author: E-mail Address: [email protected] Institute of Molecular Plus, Tianjin Key Laboratory of Molecular Optoelectronic Science, Department of Chemistry, School of Science, Tianjin University, Tianjin 300072 Google Scholar More articles by this author https://doi.org/10.31635/ccschem.021.202100947 SectionsSupplemental MaterialAboutAbstractPDF ToolsAdd to favoritesDownload CitationsTrack Citations ShareFacebookTwitterLinked InEmail The copper-catalyzed, highly enantioselective 1,4-protoboration of terminal 1,3-dienes with proton source and B2Pin2 has been developed. Chiral allylic boronate reagents, which are significant precursors for many well-established transformations, were prepared by this novel method with good functional group tolerance and enantioselectivity. Further studies indicated the products could be used as versatile precursors for asymmetric transformations and natural products syntheses. The mechanism of this reaction was investigated by control and reaction monitoring experiments. Download figure Download PowerPoint Introduction Due to the utility of allylic boron reagents in organic synthesis, chemists are increasingly attentive to their preparations.1–18 Usually, basic main-group organometallics, such as organolithium or Grignard reagent, are necessary for traditional methods to make allylboranes.19–25 The disadvantage of these strategies is their incompatibility with electrophilic functional groups. Since it was initially demonstrated by Suzuki and coworkers, catalytic 1,4-addition of 1,3-dienes using boron reagents has become a powerful synthetic tool to obtain allylic boronate systems (Figure 1a).26,27 In the initial stage, chemists focused on improving the 1,4-selectivity of this reaction, which was very challenging. Ritter group28 (Figure 1b) and Morken group29 (Figure 1c) described remarkable selectivity in the 1,4-hydroboration of 1- and 2-substituted dienes, respectively. Further elegant works were reported by several research groups (Figure 1).30–69 Notably, the Ito group reported the first copper-catalyzed 1,4-protoboration of cyclic 1,3-dienes to construct chiral C–B bonds (Figure 1d).70–78 However, using 1,4-boration to produce asymmetric tertiary carbon center containing products was not realized. Therefore, we developed the copper-catalyzed, highly enantioselective 1,4-addition of terminal 1,3-dienes with proton source and B2Pin2 to make asymmetric allylic boronate reagents that contain a distal tertiary carbon center (Figure 1e). Figure 1 | Strategy of 1,4-boration to produce allylic boronate reagents. (a) The first example for boration of 1,3-diene to prepare allylic boronate. (b) Work of Ritter group.28 (c) Work of Morken group.29 (d) Work of Ito group.70 (e) Enantioselective 1,4-protoboration of 1,3-dienes. Download figure Download PowerPoint The difunctionalization of conjugate dienes with high selectivity is an important class of transformation because it can control the formation of multiple complex isomeric products from simple precursors.32–69 Using the enantioselective 1,4-bifunctional reaction of acyclic 1,3-dienes to install at least one boron group is a powerful strategy to construct chiral allylic boronate reagents, which are versatile precursors for organic synthesis.32–45 Because of challenges, such as production of geometrical isomers of the residual double bond and possible 1,2-addition leading to achiral products, achievements with this strategy were limited to methods employing carbonyl reagents,79–82 imines,83,84 and boron reagents.85–87 Furthermore, previous studies of 1,4-hydroboration or 1,4-protoboration focused on the construction of an asymmetric C–B bond.70,88,89 Herein, the present reaction provided a novel method to construct asymmetric tertiary carbon center containing allylic boronate compounds by highly enantioselective 1,4-protoboration (Figure 1e).90–103 Results and Discussion Initial optimization of the reaction conditions Our study commenced with the copper-catalyzed reaction of [(2E)-penta-2,4-dien-2-yl]benzene ( 1a), LiOtBu, B2Pin2, and H2O. Interestingly, with L1 as ligand, this practical reaction afforded desired product 2a with 65% yield and 86% ee (Table 1, entry 1). Further studies indicated that alcohols could be used as the proton source for this transformation as well (Table 1, entries 2–5, and Supporting Information Table S6). Among them, 1,1,1,3,3,3-hexafluoropropan-2-ol (HFIP) was the best one, which afforded desired product with 74% yield and 97% ee (Table 1, entry 5). However, this chemistry did not work when acetic acid was used (Table 1, entry 6). Besides CuF2, other kinds of copper salts still worked but with lower efficiency (Table 1, entries 7 and 8, and Supporting Information Table S2). Without copper catalyst, this chemistry did not work (Table 1, entry 9). The efficiency of this reaction decreased when using other kinds of bases or solvents ( Supporting Information Tables S3 and S4). Further screening suggested base was necessary for this transformation (Table 1, entry 10). Compared with L1, other ligands lowered yield or enantioselectivity (Table 1, entries 11–13, and Supporting Information Table S5). Moreover, when the catalytic loading was reduced to 5%, this reaction still worked, but the yield and enantiomeric excess (ee) of desired product 2a were decreased slightly (Table 1, entry 14). The efficiency was poor under higher or lower reaction temperature ( Supporting Information Table S7). Finally, the entry 5 conditions, which afforded the desired product with 74% yield and 97% ee, were chosen as the optimal reaction conditions. Table 1 | The Effects of Different Reaction Conditionsa Entry [Cu] H+ Ligand Yield%b ee%c 1 CuF2 H2O L1 65 86 2 CuF2 CH3OH L1 65 58 3 CuF2 C2H5OH L1 67 68 4 CuF2 i-PrOH L1 70 74 5 CuF2 HFIP L1 74 97 6 CuF2 AcOH L1 0 – 7 CuCl HFIP L1 36 96 8 Cu(OH)2 HFIP L1 48 96 9 None HFIP L1 0 – 10d CuF2 HFIP L1 0 – 11 CuF2 HFIP L2 4 44 12 CuF2 HFIP L3 11 8 13 CuF2 HFIP L4 11 6 14e CuF2 HFIP L1 60 90 Note: HPLC, high-performance liquid chromatography; Pin, pinacol. a 1a (0.15 mmol), B2Pin2 (0.3 mmol), LiOtBu (0.3 mmol), [Cu] (10 mol %), ligand (11 mol %), proton source (0.45 mmol), THF (1.6 mL), 25 °C, 24 h, under N2 atmosphere, then NaBO3.4H2O (0.45 mmol), THF (2 mL), H2O (2 mL), 25 °C, 3 h. bIsolated yield, ratios of 1,4-addition:1,2-addition <25:1. cee was determined by HPLC. dThe reaction was performed without LiOtBu. eWith [Cu] (5 mol %), ligand (5.5 mol %). Scope of the reaction After the optimal reaction conditions were established, we then investigated the tolerance of different substituted phenyl groups (Table 2). In general, this chemistry afforded modest to good yields and high enantioselectivity with various phenyl substituents. First, different sizes of alkyl groups at the para-position did not affect the efficiency and selectivity (Table 2, 2b– 2g). But substitution at the ortho-position of the phenyl group induced lower yield (Table 2, 2i). Further studies indicated that electron-rich (–OPh, –OBn, and –OCF3), electron-neutral (–Ph), and electron-deficient (–F, –CF3, and –Cl) aryl-substituted 1,3-dienes performed well (Table 2, 2j– 2s). Notably, when bromo- and iodo-substituted aromatic 1,3-dienes were employed as substrate, the corresponding products, which can be used for further transformations, could be made smoothly (Table 2, 2t and 2u). Table 2 | Substrate Scope of 1-Aryl-Substituted Acyclic 1,3-Dienes (1)a Note: L1: 1,2-bis((2S,5S)-2,5-diphenylphospholano)ethane; Pin, pinacol. aStandard reaction condition: 1 (0.15 mmol), B2Pin2 (0.3 mmol), LiOtBu (0.3 mmol), CuF2 (10 mol %), L1 (11 mol %), HFIP (0.45 mmol), THF (1.6 mL), 25 °C, 24 h, under N2 condition, then NaBO3.4H2O (0.45 mmol), THF (2 mL), H2O (2 mL), 25 °C, 3 h. bIsolated yield, ratios of 1,4-addition:1,2-addition <25:1. cee was determined by HPLC. The substrate scope of the copper-catalyzed highly selective transformation was further expanded to a variety of more complicated dienes (Table 3). Besides normal phenyl dienes in Table 2, naphthyl and heterocyclic substrates worked well under these reaction conditions (Table 3, 4a– 4e). If the alkyl group was extended from methyl to ethyl or n-propyl, the desired product was afforded with lower efficiency (Table 3, 4f and 4g). Notably, a good performance of six-membered cyclic alkyl group containing 1,3-dienes was observed (Table 3, 4h– 4l). Further studies indicated that the substituent on the alkyl ring did not affect the efficiency of this transformation (Table 3, 4j). Importantly, this chemistry was used to make asymmetric oxygen-heterocycle containing allylic boronate compounds with good yield and great selectivity, even when a bromo-substituted compound was employed as the starting material (Table 3, 4k– 4n). Interestingly, the substrate scope could be expanded to nonaromatic alkyl 1,3-dienes which could be prepared from natural products by well-established methods (Table 3, 4o and 4p). For some reactions (Tables 2 and 3) , the conversions of dienes was nearly 100%, but the product yield was only 60% due to diene polymerization. Table 3 | Substrate Scope of 1,3-Dienes (3)a Note: dr, diastereomeric ratio; L1: 1,2-bis((2S,5S)-2,5-diphenylphospholano)ethane; Pin, pinacol. aStandard reaction conditions: 3 (0.15 mmol), B2Pin2 (0.3 mmol), LiOtBu (0.3 mmol), CuF2 (10 mol %), L1 (11 mol %), HFIP (0.45 mmol), THF (1.6 mL), 25 °C, 24 h, under N2 atmosphere, then NaBO3.4H2O (0.45 mmol), THF (2 mL), H2O (2 mL), 25 °C, 3 h. bIsolated yield, ratio of 1,4-addition:1,2-addition <25:1. cee was determined by HPLC. dH2O was used as proton source. Mechanistic studies To investigate the origin of the hydrogen atom of the newly formed C–H bond, tetrahydrofuran (THF)-d8 and D2O were used in the reaction independently (Scheme 1a, eqs 1 and 2). The reaction using THF-d8 as solvent did not afford the D-labeled product (Scheme 1a, eq 1). In contrast, with D2O as the D+ source, the product was labeled (Scheme 1a, eq 2, and Supporting Information). These results support that the new H atom of the product originated from the proton source in the reaction system. Furthermore, the rate-liming step was studied by kinetic isotope effect (KIE) experiments. As shown in Scheme 1b, eq 3, the KIE of Csp2-H converting into Csp3-H is 1.5:1 (KH:KD). This result implies that the addition of the Cu-BPin complex into 1,3-dienes is not the rate-liming step. However, the KIE of protonation is 9:1 (KH:KD) (Scheme 1b, eq 4), which suggests that the formation of the C–H bond is the rate-liming step of this reaction. Scheme 1 | Deuterium experiments and kinetic isotope studies. Download figure Download PowerPoint Then, the effect of steric hindrance was studied (Scheme 2, eqs 1 and 2). When 1,1,3-trisubstituted-1,3-dienes ( 3u) and 1,3-disubstituted-1,3-dienes ( 3v) were used as substrates, neither reaction worked. These data suggest that the Cu species generated from the addition of Cu–B complex into the C=C double bonds is incompatible with quaternary carbon centers because of the steric hindrance. Scheme 2 | The effect of steric hindrance. Download figure Download PowerPoint To probe the mechanism of this transformation, AcOH was used to quench the intermediates of the reaction system.104,105 In this study, seven parallel reactions were carried, and then they were quenched at different times. Interestingly, a signal related to the 1,2-addition product ( 6a) could be detected (Figure 2 and Supporting Information Figure S1). Based on the above data, we analyzed the kinetics of product and intermediate formation under optimal reaction conditions. First, as expected, with the extension of reaction time, the yield of desired product 5a increased steadily (Figure 2, 5a, and Supporting Information Figure S1). Interestingly, the concentration of compound 6a in this reaction increased steadily from the starting point to 6 h, and then obviously decreased after 8 h (Figure 2, 6a, and Supporting Information). Furthermore, only a trace amount of compound 6a could be detected under the optimal reaction conditions. The above result is evidence that 6a is generated from the reaction of active metal intermediate quenched by AcOH. Figure 2 | Reaction monitoring experiments of product and intermediate. Download figure Download PowerPoint Based on the above results, it can be proposed that 7a might exist in the reaction system and be generated from the copper-catalyzed reaction of 1a and B2Pin2 (Scheme 3).104–107 In addition, both compound 5a and 6a could originate from this Cu-complex ( 7a).106–111 Under the optimized reaction conditions, the intermediate 7a could convert into product 5a via a six-membered type transition state.108–112 Moreover, 7a could be quenched by AcOH to afford compound 6a without forming the desired product 5a (Table 1, entry 6).106,107 Furthermore, the consumption of 1a could induce the low concentration of 7a, which causes the signal of 6a to decrease in the late stage of the reaction process (Scheme 3 and Figure 2, 6a). The above analysis suggests that 7a is one of the key intermediates of the present reaction. Scheme 3 | Mechanism analysis. Download figure Download PowerPoint The substituent electronic effect on the reaction rate was studied. Compared with the electron neutral substrate 1a, the substrate with an electron withdrawing group ( 1r) reacted faster (Scheme 4, eq 1), and the substrate with an electron donating group ( 1j) reacted slower (Scheme 4, eq 2). These results were consistent with the characteristics of addition reactions of Cu–B complex into C=C double bonds. Scheme 4 | Substituent electronic effects. Download figure Download PowerPoint Based on the above studies, the proposed mechanism for this 1,4-protoboration is illustrated in Scheme 5. The active Cu-catalyst is generated as the first step of this transformation and reacts with B2Pin2 to form the LCu-BPin complex ( 10).104–107 Complex 10 can react with 1,3-dienes to afford the key intermediate 7a,104–107 as evidenced by mechanistic studies. As the key intermediate, 7a affords the desired product 5a via protonation.108–112 Scheme 5 | Possible reaction mechanism. Download figure Download PowerPoint The feasibility of 1 mmol scale reaction was established under standard reaction conditions. The above reaction afforded desired product 5a with 68% yield and 97% ee (Figure 3, (1), and Supporting Information). Importantly, this chemistry afforded a versatile intermediate for organic transformations. As shown in Figure 3, 5a reacted with benzaldehyde and nitrosobenzene to produce homoallylic alcohol 1129 and allylic alcohol product 12,113 respectively (Figure 3, (2) and (3), and Supporting Information). Furthermore, important compounds, such as α,β-unsaturated conjugate aldehyde 1362 and terminal alkene 14,62 could be synthesized from 5a under mild conditions (Figure 3, (4) and (5), and Supporting Information). Notably, all the above transformations worked well without diminished ee% of the original stereogenic centers from 5a. Figure 3 | The studies of further transformation. Download figure Download PowerPoint Furthermore, the significance of this novel reaction could be demonstrated by the utility toward the synthesis of natural products as well. The compound 2b, which was prepared by the present chemistry with 99% ee, can be converted into compound 15 by a mild reduction. Importantly, 15 can be used as a powerful intermediate to synthesize a series of nature products via well-established methods (Figure 4).114 Figure 4 | Synthesis of natural products. Download figure Download PowerPoint Conclusion We have demonstrated a novel copper-catalyzed highly enantioselective 1,4-protoboration of terminal 1,3-dienes with a proton source and B2Pin2. This chemistry provided a practical way to make asymmetric allylic boronate reagents with good functional group tolerance and enantioselectivity. The utility of the allyl boronate product was proved by the studies of further asymmetric transformations and formal syntheses of natural products. Furthermore, the intermediates of this reaction were investigated by control experiments and kinetic studies. Further investigations for mechanism studies and synthetic applications are ongoing in our laboratory. Supporting Information Supporting Information is available and includes experimental procedures and compound characterization data. Conflict of Interest There is no conflict of interest to report. Funding Information This research was made possible by a generous grant from Tianjin University, National Natural Science Foundation of China (no. 21801181).