Iron-Catalyzed Borylation and Silylation of Unactivated Tertiary, Secondary, and Primary Alkyl Chlorides

Abstract

Open AccessCCS ChemistryCOMMUNICATION1 Sep 2021Iron-Catalyzed Borylation and Silylation of Unactivated Tertiary, Secondary, and Primary Alkyl Chlorides Siyu Wang†, Minghui Sun†, Huan Zhang, Juan Zhang, Yun He and Zhang Feng Siyu Wang† Chongqing Key Laboratory of Natural Product Synthesis and Drug Research, School of Pharmaceutical Sciences, Chongqing University, Chongqing 401331 , Minghui Sun† Chongqing Key Laboratory of Natural Product Synthesis and Drug Research, School of Pharmaceutical Sciences, Chongqing University, Chongqing 401331 , Huan Zhang Chongqing Key Laboratory of Natural Product Synthesis and Drug Research, School of Pharmaceutical Sciences, Chongqing University, Chongqing 401331 , Juan Zhang Chongqing Key Laboratory of Natural Product Synthesis and Drug Research, School of Pharmaceutical Sciences, Chongqing University, Chongqing 401331 , Yun He Chongqing Key Laboratory of Natural Product Synthesis and Drug Research, School of Pharmaceutical Sciences, Chongqing University, Chongqing 401331 and Zhang Feng *Corresponding author: E-mail Address: [email protected] Chongqing Key Laboratory of Natural Product Synthesis and Drug Research, School of Pharmaceutical Sciences, Chongqing University, Chongqing 401331 Sichuan Key Laboratory of Medical Imaging, Department of Chemistry, School of Preclinical Medicine, North Sichuan Medical College, Sichuan 637000 https://doi.org/10.31635/ccschem.020.202000447 SectionsSupplemental MaterialAboutAbstractPDF ToolsAdd to favoritesDownload CitationsTrack Citations ShareFacebookTwitterLinked InEmail Herein, we describe an iron-catalyzed borylation and silylation of unactivated alkyl chlorides, delivering the tertiary, secondary, and primary alkylboronic esters, and secondary, primary alkylsilanes with high efficiency. This protocol exhibits broad substrate scope and good functional group compatibility, allowing the efficient late-stage borylation of biorelevant compounds, thus offering an excellent platform in drug discovery and development. Preliminary mechanistic studies suggest that an alkyl radical was involved in this catalytic system. Download figure Download PowerPoint Introduction Alkylboronic esters are the classical synthetic intermediates in chemical synthesis due to the smooth transformation of the C–B bond.1–4 Hydroboration of alkenes5–8 and electrophilic substitution of boron species with organometallic reagents9,10 are the most common methods for the preparation of alkyl boranes. However, these methods still have some limitations, such as the regioselectivity issue in the hydroboration reactions and the poor functional group compatibility in the case of electrophilic substitution. In the past several years, synthetic protocols for their preparation using alkyl halides,11–22 carboxylic acids,23–25 amines,26–29 and alcohols30,31 have been reported. Primary and secondary alkylboronic esters can be obtained by these protocols. However, the general methods to access tertiary alkylboronic esters have seldom been achieved, except for the special substrates, such as adamantane halides.15 Thus far, there are very few general methods for the synthesis of tertiary alkylboronic esters (Scheme 1). The borylation of unactivated tertiary alkyl bromides/iodides and chlorides was documented by Dudnik and Fu32 and Atack and Cook,33 respectively. In 2017, Li et al.34 and Fawcett et al.35 developed the decarboxylative methods for the preparation of tertiary alkylboronic esters. Very recently, deoxygenative borylation was also disclosed by Friese and Studer.36 However, some limitations still exist in these reactions, such as the nonapplication of unactivated alkyl chlorides,32 the requirement of organometallic reagents,33 and the prefunctionalization of substrates.34–36 Therefore, developing an economical and efficient method for synthesizing tertiary alkylboronic esters is increasingly in demand. Scheme 1 | The general methods for the synthesis of tertiary alkylboronic esters. Download figure Download PowerPoint Iron catalysts have become more attractive and are widely employed in organic synthesis for their abundance, low cost, and nontoxicity.37–39 In past decades, the iron-catalyzed classical cross-coupling reactions using organometallic reagents as coupling partners have been extensively explored.40–42 Until recent years, the iron-catalyzed carbon–heteroatom bond formation has drawn some attention, but these catalytic systems are still not general, in which the additional organometallic reagents are always required to in situ generate the low-oxidation-state iron catalyst through reductive elimination.43–46 To date, the borylation of alkyl halides via iron catalysis has scarcely been documented. In 2014, Atack et al.45 and Bedford et al.46 developed the borylation of alkyl halides via iron catalysis, respectively, in which the tertiary halides and unactivated alkyl chlorides exhibited low efficiency. Moreover, in these reactions, the highly reactive ethylmagnesium bromide or tert-butyllithium was required to in situ generate the highly reactive iron catalyst. Although alkyl chlorides are the most common raw materials in organic synthesis, the use of alkyl chlorides as coupling partners has been less documented due to the problem of C–Cl bond cleavage.32,45,47,48 Therefore, the development of a general, mild, and simple catalytic system for the preparation of tertiary, secondary, and primary alkylboronic esters from alkyl chlorides without the use of organometallic reagents is more attractive.49–54 With our continuing studies on iron catalysis,55–61 herein, we describe a general method for the borylation and silylation of tertiary, secondary, and primary unactivated alkyl chlorides through an iron-catalyzed organometallic reagents-free cross-coupling reaction. Experimental Methods The Experimental Methods are available in the Supporting Information. General Procedure for the borylation of tertiary and secondary alkyl chloride A 25 mL flame-dried Schlenk tube equipped with a magnetic stir bar was charged with FeI2 (0.02 mmol, 0.1 equiv), B2pin2 (0.5 mmol, 2.5 equiv), t-BuOLi (0.6 mmol, 3.0 equiv) in glove box. Alkyl chloride (0.2 mmol, 1.0 equiv), TMEDA (0.02 mmol, 0.1 equiv), fresh distilled DME (1.0 mL) were then added under nitrogen atmosphere. The reaction mixture was allowed to stir at 70 °C for 10 h. The reaction mixture was then concentrated, and purified by silica gel flash chromatography to afford the corresponding products. Experimental details and characterization methods are available in Supporting Information. Results and Discussion In our previous work,58,59 we found that the iron-boronate complex with high reduction potential could promote the borylation of unactivated Csp2–O bonds. Inspired by this finding, we envisioned that the iron-boron ate complex might also induce the C–Cl bond cleavage, and this catalytic system could avoid the use of organometallic reagents to produce the low-valent iron species. With these considerations in mind, we initiated our study by subjecting an unactivated tertiary chloride 1a to a diboron reagent 2aa in the presence of iron catalysts and various ligands (for details, see Supporting Information). As shown in Table 1, the best result, 80% yield of the desired product, was obtained when FeI2 (10 mol %), TMEDA (N,N,N′,N′-Tetramethylethane-1,2-diamine) (10 mol %), and t-BuOLi (3.0 equiv) were employed (Table 1, Entry 1). Other iron catalysts were evaluated, and FeI2 was demonstrated as the best choice, delivering the desired product in moderate to good yields (Table 1, Entries 2–4). N,N,N′,N′-Tetramethyldiaminomethane (TMMDA) could promote this transformation smoothly and yielded the corresponding product in 64% yield (Table 1, Entry 5). The electron-rich phosphine ligand, P(Cy)3 was examined as well, providing 1 in 63% yield (Table 1, Entry 6). Then, various solvents were investigated, and DME (1,2-Ethanediol dimethyl ether) was superior (Table 1, Entries 7 and 8). Control experiments confirmed the necessity of iron catalyst and base (Table 1, Entries 9 and 11). No desired product was observed in the absence of an iron catalyst (Table 1, Entry 9), and moderate yield was afforded without a ligand (Table 1, Entry 10). The trace-metal effect was investigated as well (for details, see Supporting Information). The comparable yield was obtained by using a high-purity iron catalyst; copper and nickel catalysts could not promote this transformation. Table 1 | Optimization of the Reaction Conditionsa Entry Deviation from Standard Condition Yield (%)b 1 None 80(77) 2 FeCl2, instead of FeI2 79 3 FeCl3, instead of FeI2 59 4 Fe(OTf)2, instead of FeI2 72 5 TMMDA, instead of TMEDA 64 6 P(Cy)3, instead of TMEDA 63 7 THF, instead of DME 60 8 Diglyme, instead of DME 51 9 Without FeI2 0 10 Without TMEDA 56 11 Without t-BuOLi 0 aDetermined by 1H NMR using mesitylene as an internal standard. bThe isolated yield is shown in parentheses. TMMDA = N,N,N′,N′-Tetramethyldiaminomethane. Under optimized conditions, the substrate scope of this borylation reaction was tested. The tertiary, secondary, and primary alkyl chlorides underwent this transformation smoothly (Table 2), which was in sharp contrast to the previous work,32 in which the tertiary alkyl chlorides always exhibited very low efficiency. Functional groups, such as trifluoromethyl, fluoro, chloro, pivaloyl, carbamate, tert-Butyldimethylsilyl, tert-butoxycarbonyl, Triisopropylsilyl (TIPS), ketal, amide, boryl, and alkenyl, were well tolerated. Substrates with a long carbon chain performed this transformation well, and the borylated products were obtained in moderate to good yields. Importantly, substrates ( 8a– 9a, 18a– 20a, 23a– 24a, and 32a– 33a) bearing a β-chloro group could easily conduct the base-promoted elimination process, which also reacted well, providing the desired products in moderate to good yields (50–80%). Moreover, this reaction showed good regioselectivity. The chloro group on the aromatic ring could be tolerated ( 9, 56%; 19, 53%). The substrate ( 10a) containing a primary and a tertiary chloro group could also exhibit chemoselectivity albeit in low yield ( 10, 36%), and 15% of diborylated product 10′ was obtained as well (see Supporting Information). It should be noted that the substrate ( 22a) with two bulky alkyl groups could undergo this reaction and obtained the desired product in reasonable yield ( 22, 47%). Both the cyclic and acyclic secondary chlorides underwent this transformation smoothly, and the substrate ( 30a) containing a big ring could deliver the product in excellent yield ( 30, 94%). The heteroaromatic ring could also be compatible in this catalytic system and provided the desired products in moderate yields ( 33, 57%; 40, 54%). It should be mentioned that some byproducts were also observed in this reaction, such as base-promoted elimination compounds and hydrogenated products (for details, see Supporting Information). Table 2 | Scope of the Iron-Catalyzed Borylation of Alkyl Chloridesa aReaction conditions (unless otherwise specified): Alkyl chlorides (0.2 mmol, 1.0 equiv), FeI2 (10 mol %), TMEDA (10 mol %), B2pin2 (2.5 equiv), t-BuOLi (3.0 equiv), DME (1.0 mL), 70 °C, 10 h. bTMMDA (10 mol %) was used, 80 °C. cTMMDA (10 mol %) was used, 90 °C. Alkylsilanes as the significant building blocks in organic synthesis are widely presented in materials and agrochemicals.62–66 Thus far, the synthesis of alkylsilanes has been a long-standing challenge, especially for the secondary and tertiary alkylsilanes, owing to the large steric hindrance of the silicon group.67–86 Recently, an iron-catalyzed silylation of primary and secondary alkyl bromides has been realized by Xue et al.87 using silicon Grignard reagents. Encouraged by the borylation reaction, the iron-catalyzed silylation of unactivated alkyl chlorides was also evaluated, as shown in Table 3. To our delight, 91% yield of 31s was obtained when this silylation reaction was carried out with Fe(OAc)2 (10 mol %), TMEDA (10 mol %), and t-BuONa (2.5 equiv) in tetrahydrofuran (THF) at 80 °C. The secondary alkyl chlorides ( 14a, 19a, and 24a) could also undergo this reaction with good efficiency ( 14s– 24s; 46–65%). Instead of base-promoted elimination, the silylation proceeded well when substrates ( 19a and 24a) with a β-chloro group were used ( 19s and 24s; 46–50%). The primary alkyl chlorides ( 31a– 34a, 36a– 40a, and 42a–45a) showed good reactivity, and moderate to excellent yields were obtained ( 31s– 34s, 36s– 40s, and 42s–45s; 46–92%). Functional groups, such as trifluoromethyl, ketal, TIPS, and fluoro, could be tolerated in this transformation. The heteroaromatic derivatives ( 33a and 40a) reacted well, and the desired products were afforded in moderate to good yields ( 33s, 46%; 40s, 82%). However, this protocol was not suitable for the tertiary alkyl chlorides. When 1a was used as a substrate, no silylated product 1s was observed; instead, many undesired products, such as alkenes ( 46 and 47), hydrogenated product ( 48), and dimeric compound ( 49), were obtained. Silylboron reagent, Ph(Me)2Si-Bpin, was also evaluated, but no desired product was found. Other electrophilic reagents, including alkyl iodides, alkyl bromides, and alcohol derivatives, could also perform this transformation, but with very low efficiency (for details, see Supporting Information). Table 3 | Iron-Catalyzed Silylation of Alkyl Chloridesa aReaction conditions: Alkyl chlorides (0.2 mmol, 1.0 equiv), Et3Si-Bpin (2.5 equiv), Fe(OAc)2 (10 mol %), TMEDA (10 mol %), t-BuONa (2.5 equiv), THF (1.0 mL), 80 °C, 10 h. bMeONa (2.5 equiv) and Methyl tert-butyl ether (MTBE) (1.0 mL) were used. Isolated yields are reported (for details, see Supporting Information). The inherent value of this method was further exhibited by the late-stage borylation of biomolecules, as shown in Scheme 2. Substrates derived from l-menthol and isoborneol with the large steric hindrance reacted well, and afforded the desired products in moderate yields ( 51, 64%; 52, 63%). Interestingly, terpineol, cholesterol, and diosgenin derivatives, containing an alkene group could also convert to their corresponding products in accepted yields ( 53– 55, 34–51%). These results suggest this protocol can provide facile access to the diverse biorelevant compounds. Moreover, a gram scale could be conducted, and 60% yield of 2 was obtained (Scheme 2). Furthermore, inspired by the diverse transformation of the C–B bonds developed by Bonet et al.88 and Armstrong et al.89, the alkene and furan derivatives bearing a quaternary-carbon center were generated in moderate yields ( 56, 76%; 57, 51%). The Csp–C and Csp3–C bonds could also be formed efficiently from the tertiary alkyl boronic esters and secondary alkyl boronic acid, respectively ( 59, 83%; 61, 70%).90,91 Scheme 2 | Applications and transformations. Download figure Download PowerPoint During our investigation of the scope of the iron-catalyzed borylation of alkyl chlorides, we found that substrates 10a containing a primary and a tertiary chloro group exhibited chemoselectivity, and the tertiary chloride was more reactive than the primary chloro group. Therefore, to evaluate the reactivity of tertiary, secondary, and primary alkyl chlorides, the competition experiments were carried out (Scheme 3a). These results are consistent with the nickel-catalyzed borylation of alkyl bromides documented by Dudnik and Fu.32 The mixture of tertiary alkyl chloride 1a and secondary alkyl chloride 14a reacted with B2pin2 for 1 h, generating a 2∶1 mixture of borylated products 1 and 14 ( 1, 55%; 14, 27%). Similarly, a 4.9∶1 ratio of 1– 31 was provided when the mixture of tertiary alkyl chloride 1a and primary alkyl chloride 31a was tested. The reaction of secondary alkyl chloride 14a and primary alkyl chloride 31a with B2pin2 was also conducted and offered a similar result ( 14/ 31 = 1.6/1). Based on the kinetic studies (Scheme 3a), we found that the rate of the iron-catalyzed borylation was tertiary > secondary > primary, which was consistent with the stability of alkyl radicals. Therefore, the radical pathway might be involved in this catalytic system. Furthermore, when the primary substrate 31a reacted with B2pin2 in the presence of TEMPO (2,2,6,6-Tetramethylpiperidinooxy) (1.0 equiv), the TEMPO-trapped product 62 was obtained in 12% yield (Scheme 3b). The electron paramagnetic resonance (EPR) experiment was also carried out, and a broad triplet spectrum was successfully observed, which confirmed that the alkyl radical existed in the reaction. Interestingly, when we conducted the radical clock experiment using tertiary alkyl chloride 1a as substrate (Scheme 3c), the borylated ring-opening product 64 was afforded in 66% yield.92,93 In addition, when the chiral substrate, (R)-(3-chlorobutyl)benzene, underwent this transformation, the racemic product 14′ was obtained. Scheme 3 | (a–d) Mechanistic studies. Download figure Download PowerPoint Next, to investigate how to initiate this transformation, the sequential experiments were carried out (Scheme 3d). We found that 77% of 1a could be recovered, along with the elimination product ( 47, 19%), and no protonated product 48 was obtained without the use of B2pin2, revealing that the FeI2, TMEDA, and t-BuOLi catalytic system could not lead the cleavage of the strong C–Cl bond. However, 0.5 h later, when tertiary alkyl chloride 1a was added to the mixture of FeI2, TMEDA, t-BuOLi, and B2pin2, 63% of 1 was afforded, suggesting that B2pin2 might play a vital role in the initiation of this transformation. Moreover, the mixture of this reaction was monitored by 11B NMR, and a suspected iron-boron complex94 was observed (11B NMR, δ = 22; for details, see Supporting Information). On the basis of these preliminary results and our previous studies,58,59 a mechanism was proposed in Scheme 4. An iron alkoxide ate complex I was obtained through the reaction of t-BuOLi with FeI2.95 Subsequently, the newly generated iron species I transmetalated with B2pin2, and produced an iron-boron species II having high reduction potential.96 Then, the iron-boron complex II reacted with alkyl chlorides through a single electron transfer pathway, affording the complex III. Finally, the alkylboronic ester was obtained along with the iron species IV through reductive elimination. Scheme 4 | Proposed mechanism. Download figure Download PowerPoint Conclusion We have reported a general iron-catalyzed method for the synthesis of alkylboronic esters and alkylsilanes, especially for the tertiary alkylboronic esters. This reaction proceeds under mild conditions without the use of organometallic reagents, and exhibits a broad substrate scope and good functional group tolerance. A notable feature of this protocol is its late-stage functionalization of biomolecules, which will provide good applications in medicinal chemistry. The detailed mechanism of this transformation is still in progress in our lab. Supporting Information Supporting Information is available. Conflict of Interest There is no conflict of interest to report. Funding Information The authors are grateful for the financial support from the National Natural Science Foundation of China (no. 21801029), the Fundamental Research Funds for the Central Universities (no. 2020CDJQY-A043), the Sichuan Key Laboratory of Medical Imaging (North Sichuan Medical College, no. SKLMI201901), the Strategic Cooperation of Science and Technology between Nanchong City and North Sichuan Medical College (nos. 19SXHZ0441 and 19SXHZ0227), the Chongqing Postdoctoral Science Foundation (no. cstc2020jcyj-bsh0061), the China Postdoctoral Science Foundation (no. 2020M673121), and the Natural Science Foundation of Chongqing (no. cstc2019jcyj-msxmX0048). Acknowledgments The authors thank Prof. Xingang Zhang (Shanghai Institute of Organic Chemistry (SIOC)) for helpful discussions. The authors also thank Prof. Jian Jin (SIOC) and Mr. Qiaoqiao Min (SIOC) for their kind help on the synthesis of compound 59 and EPR experiments analysis. References 1. 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