Copper-Catalyzed Ring-Opening/Borylation of Cyclopropenes

Abstract

Open AccessCCS ChemistryCOMMUNICATION1 Apr 2022Copper-Catalyzed Ring-Opening/Borylation of Cyclopropenes Ming-Yao Huang†, Yu-Tao Zhao†, Hao Chai, Cheng-Da Zhang and Shou-Fei Zhu Ming-Yao Huang† The State Key Laboratory and Institute of Elemento-Organic Chemistry, College of Chemistry, Nankai University, Tianjin 300071 , Yu-Tao Zhao† The State Key Laboratory and Institute of Elemento-Organic Chemistry, College of Chemistry, Nankai University, Tianjin 300071 , Hao Chai The State Key Laboratory and Institute of Elemento-Organic Chemistry, College of Chemistry, Nankai University, Tianjin 300071 , Cheng-Da Zhang The State Key Laboratory and Institute of Elemento-Organic Chemistry, College of Chemistry, Nankai University, Tianjin 300071 and Shou-Fei Zhu *Corresponding author: E-mail Address: [email protected] The State Key Laboratory and Institute of Elemento-Organic Chemistry, College of Chemistry, Nankai University, Tianjin 300071 https://doi.org/10.31635/ccschem.021.202100921 SectionsSupplemental MaterialAboutAbstractPDF ToolsAdd to favoritesDownload CitationsTrack Citations ShareFacebookTwitterLinked InEmail Since organoboron compounds readily undergo a diverse array of transformations and are widely used in various fields, the development of C–B-bond-forming reactions have attracted considerable attention. Herein, we report a new method for forming C–B bonds by means of Cu-catalyzed ring-opening/borylation reactions of cyclopropenes. This method provides efficient access to a new type of stable allylborane–Lewis base adduct, which is a versatile synthon. The configuration of the products can be well controlled with this method, and some of the configurations we obtained are inaccessible by other catalytic methods for generating allylborons. Mechanistic studies indicated that the reactions proceed via insertion of an alkenyl Cu carbene—generated in situ by cyclopropene ring opening—into the B–H bond; the ring-opening step determines both the rate and stereochemistry. Download figure Download PowerPoint Introduction Organoboron compounds have broad applications in organic synthesis,1,2 medicinal chemistry,3,4 and materials science.5,6 Therefore, the development of new methods to form C–B bonds has been an area of longstanding interest in the field of synthetic chemistry. Since transition metal-catalyzed insertion of carbenes into B–H bonds was first disclosed in 2013, it has become a good method for the construction of C–B bonds.7–10 When diazo compounds,11–17 alkynes,18,19 or sulfoxonium ylides20,21 are used as carbene precursors, this method enables the construction of many novel organoboranes in high yields with high regioselectivity and, in some cases, high enantioselectivity (Scheme 1a). Quite recently, insertion of unsaturated carbenes into B–H bonds has also been established as a method to construct C(sp2)–B bonds.22 The development of new carbene precursors will undoubtedly increase the utility of this method for constructing organoboranes that are inaccessible by other known methods, which can, in turn, be expected to provide new opportunities for investigating the bioactivity and material properties of organoboranes. Scheme 1 | (a) Known transition metal-catalyzed B–H bond insertion reactions. (b) Copper-catalyzed ring-opening/borylation of cyclopropenes. Download figure Download PowerPoint Cyclopropenes23–27 are useful carbene precursors: transition metal-promoted ring opening of these compounds is a well-established method for metal carbene generation, and related carbene-transfer reactions have been widely used in organic synthesis.28–33 Herein, we report a protocol for Cu-catalyzed insertion of copper carbenoids, which were generated in situ by the ring opening of cyclopropenes, into the B–H bonds of borane–Lewis base adducts (Scheme 1b). This protocol not only represents the first demonstration that carbenoids generated from ring opening of cyclopropenes can be inserted into B–H bonds but also provides efficient access to a new type of stable allylborane–Lewis base adduct, which is a versatile synthon. The configuration of the allylborane product can be well controlled with this method, and some of the configurations were only accessible using this methodology. Results and Discussion We began our study by investigating the reaction of cyclopropene 1a and trimethylamine–borane adduct 2a in dichloromethane (DCM) at 25 °C with catalysis using Cu(MeCN)4PF6 (Table 1). In the absence of a ligand, only a trace amount of the desired insertion product was detected, and dimerization was observed instead (entry 1). The addition of a bisphosphine ligand failed to improve the yield of the desired product (entries 2 and 3); however, reaction in the presence of the monophosphine ligand JohnPhos ( L3) afforded 3aa in 83% yield by NMR spectroscopy (entry 4). The lower activity of biphosphine ligand modified copper complex might contribute to its higher steric hindrance and weaker Lewis acidity compared to the monophosphine-modified copper complex. Changing the substituent on the biphenyl skeleton or phosphorous atom of the ligand did not improve the yield (entries 5–10). Solvent effects were also investigated with ligand L3, and all of the tested solvents, except dichloroethane (DCE), dramatically decreased the yield (entries 11–15). When the reaction temperature was increased to 40 °C, the yield was slightly increased, and the reaction time required for full conversion decreased (entry 16). Notably, the reaction was sensitive to the steric bulk and Lewis basicity of the Lewis base. Specifically, only borane trimethylamine adducts afforded good yields; other Lewis bases, including secondary and tertiary amines, pyridines, phosphines, and N-heterocarbenes, displayed moderate or poor yields ( Supporting Information Table S1). Table 1 | Copper-Catalyzed Ring-Opening/Borylation Reaction of Cyclopropene 1a: Optimization of Reaction Conditions Entrya L Solv. Conv. (%)b Yield (%)b 1 None DCM 100 Trace 2 L1 DCM 100 Trace 3 L2 DCM 100 Trace 4 L3 DCM 96 83 5 L4 DCM 100 69 6 L5 DCM 100 49 7 L6 DCM 100 Trace 8 L7 DCM 100 14 9 L8 DCM 100 81 10 L9 DCM 100 70 11 L3 DCE 100 79 12 L3 CHCl3 100 25 13 L3 Toluene 88 45 14 L3 THF 100 21 15 L3 cHexanes 66 18 16c L3 DCM 100 85 (82) aReaction conditions: 1a/ 2a/Cu(MeCN)4PF6/ L = 0.2/0.8/0.01/0.012 (mmol), in 2 mL of solvent. bConversion and yield were determined by 1H NMR analysis using 1,3,5-trimethoxylbenzene as an internal standard. The main byproduct was dimer 4. Value in parentheses was isolated yield in a 0.3 mmol scale. cReaction was performed at 40 °C for 12 h. Using optimized conditions (Table 1, entry 16), we assessed the scope of the transformation by carrying out reactions of 3,3-dialkyl substituted cyclopropenes 1 with 2a (Scheme 2). Symmetrical 3,3-dialkyl-substituted cyclopropenes afforded good yields of the corresponding allylboranes ( 3aa– 3da). The stereoselectivity of reactions of asymmetrical cyclopropenes could be regulated by changing the ligand, owing to differences in steric bulk between the two C3 substituents. Under standard conditions with L3 as the ligand, a 3-methyl-3-adamantyl-substituted cyclopropene gave only E-allylborane 3ea (65% yield). In contrast, reactions of cyclopropenes with smaller steric bias, such as 3-methyl-3-cyclohexyl cyclopropene, 3-ethyl-3-cyclohexyl cyclopropene, and 3-methyl-3-cyclopentyl cyclopropene, showed good E stereoselectivity ( 3fa– 3ha) in the presence of the more hindered ligand L9. A cyclopropene with methyl and benzyl substituents, which are similar in size, gave an E/Z mixture of 3ia in the presence of ligand L9. Scheme 2 | Copper-catalyzed ring-opening/borylation reaction of 3,3-dialkyl cyclopropenes with trimethylamine-borane. Reaction conditions: 1/2a/Cu(MeCN)4PF6/L3 = 0.3/1.2/0.015/0.018 (mmol), in 3 mL of DCM. Isolated yields were given. The E/Z ratio of the product is >20:1 unless otherwise noted. Ad = adamantyl. aL9 was used at 25 °C for 16 h. Download figure Download PowerPoint We then attempted to expand the scope of the reaction to 3-aryl-3-alkyl-substituted cyclopropenes 5. We found that reaction of 3-methyl-3-phenyl cyclopropene ( 5a) with 2a under the conditions used for the 3,3-dialkyl cyclopropenes only gave a 38% yield of E-allylboron product 6aa, along with an intramolecular C–H insertion byproduct ( Supporting Information Table S2, entry 1). However, ligand optimization revealed that the results could be improved by using ligand L9, which afforded a 71% isolated yield of E- 6aa ( Supporting Information Table S2, entry 5). Notably, the E selectivity of this reaction is unique: other transition metal-catalyzed reactions usually afford Z-allylboron compounds.34,35 With the newly optimized conditions in hand, we systematically evaluated a variety of 3-alkyl-3-aryl cyclopropenes (Scheme 3). Introduction of para-methyl or -methoxyl groups on the phenyl ring slightly decreased the yield (compare the yields of 6ba and 6ca to that of 6aa), whereas para-F and -Cl atoms had little influence on the yield or stereoselectivity ( 6da and 6ea). The introduction of a strongly electron-withdrawing para-trifluoromethyl group on the phenyl ring markedly reduced the yield and stereoselectivity ( 6fa). Substrates with a meta substituency showed reduced yields, but such substituents had no effect on the stereoselectivity ( 6ga and 6ha). The reaction was highly sensitive to the steric bulk of the 3-phenyl group; the reaction of a cyclopropene with an ortho-phenyl ring afforded only a trace of desired product 6ia. Cyclopropenes with fused rings (i.e., 3-benzo[d][1,3]dioxole and 3-naphthyl) also afforded the desired products ( 6ja and 6ka) with acceptable yields and selectivities. In addition to a 3-methyl group, 3-ethyl and 3-cyclopropyl substituents were tolerated ( 6la and 6ma). Fused cyclopropenes afforded good yields of the corresponding products ( 6na and 6oa), but the stereoselectivity decreased with decreasing ring size. Hydroxyl and ester groups were well tolerated ( 6pa and 6qa), whereas sulfonyl and phthalimido amide groups inhibited the reaction and thus decreased yields ( 6ra and 6sa). Cyclopropenes bearing a C3 vinyl group were also tested and found to afford moderate yields of conjugated vinyl allylic boranes in the E configuration ( 6ta and 6ua). Finally, 3,3-diaryl-substituted cyclopropenes, either with phenyl or electron-rich 4-methoxylphenyl groups, gave only a trace of allylboron product 6va or 6wa; byproducts generated by intramolecular C–H insertion were obtained instead (not shown). Scheme 3 | Copper-catalyzed ring-opening/borylation reaction of aryl- or alkenyl-substituted cyclopropenes with trimethylamine-borane. Reaction conditions: 5/2a/Cu(MeCN)4PF6/L9 = 0.3/1.2/0.015/0.018 (mmol), in 3 mL of DCM. Isolated yields were given. The E/Z ratio of the product is >20:1 unless otherwise noted. Ms = methanesulfonyl, NPht = phthalimido. Download figure Download PowerPoint To illustrate the potential synthetic utility of this novel protocol, we performed a set of transformations on one of the allylborane products. First, we carried out a gram-scale reaction to obtain allylborane 6aa (71% yield, E/Z > 20:1; Scheme 4a). Borane adduct 6aa was easily transformed into boronates 7 and 8 by reaction with pinacol or N-methyl imidodiacetic acid, respectively (Scheme 4b). Heating aqueous 6aa in air efficiently oxidized the borane group to a hydroxyl group ( 9). Stereospecific allylboration reactions of 6aa with benzaldehyde and phenylpropyl aldehyde in the presence of water afforded corresponding homoallylic alcohols 10 and 11 with high diastereoselectivity. Interestingly, reaction of 6aa with N-chlorosuccinimide efficiently chlorinated the allylborane to afford a novel, highly stable chloro-borane amine adduct ( 12). Scheme 4 | Gram-scale experiment and transformations of product 6aa. (1) pinacol, THF, 70 °C, 2 h; (2) N-methyl imidodiacetic acid, toluene/DMSO = 5:1, 70 °C, 4 h; (3) H2O, air, THF, 60 °C, 12 h; (4) H2O, PhCHO, THF, 60 °C, 6 h; (5) H2O, THF, 70 °C, 4 h, then phenylpropyl aldehyde, 4Å molecular sieves, 4 h; (6) N-chlorosuccinimide, DCM, room temperature, 5 min. THF, tetrahydrofuran; DMSO, dimethyl sulfoxide. Download figure Download PowerPoint Finally, we performed some control experiments to shed light on the mechanism of this reaction. A deuterium-labeling experiment showed that boron and deuterium were added to the same carbon (Scheme 5a). A kinetic isotope experiment gave a negligible kinetic isotope effect (1.1), indicating that the hydrogen-transfer step was fast (Scheme 5b). Reaction of cyclopropene 5a with a mixture of deuterated and protonated borane adducts revealed that the H–D exchange did not occur (Scheme 5c). Moreover, the separate reactions of cyclopropene 5a with three different borane adducts gave almost identical distributions of the products of intermolecular B–H insertion and byproducts produced by intramolecular C–H insertion; this result demonstrated that the nature of the borane adduct had no influence on the selectivity of cyclopropene ring opening (Scheme 5d). Scheme 5 | Control experiments and proposed mechanism. Download figure Download PowerPoint On the basis of these control experiments, we propose the mechanism shown in Scheme 5e. Cyclopropene 5a undergoes Cu(I)-catalyzed ring opening to form an E- or Z-vinyl Cu(I) carbene intermediate. This step is probably the rate-determining step according to the kinetic isotope effect experiment (Scheme 5b) and determines the stereochemistry of the alkenyl of the carbene intermediate (the ratio of Z- and E-carbene). The E-carbene intermediate is subsequently captured by the borane adduct via a three-membered-ring transition state to form the allylboron product, while the Z-carbene tends to undergo intramolecular electrophilic attack on the phenyl ring to afford the product of a formal intramolecular C–H insertion reaction. This mechanism can explain the lower E/Z ratios observed for 6fa and 6oa. The electron-deficient nature of the para-trifluoromethylphenyl ring of 6fa decreases the rate of the intramolecular electrophilic attack on the Z-carbene, such that a portion of it is captured by the borane adduct to generate a small amount of the Z-allylboron product. In the case of 6oa, ring strain in the byproduct inhibits the intramolecular C–H insertion reaction and instead favors the B–H insertion reaction of the Z-carbene. Conclusions We have developed a protocol for Cu(I)-catalyzed ring-opening/borylation reactions of cyclopropenes. The mild protocol has a broad substrate scope and can be used to synthesize a variety of novel γ,γ-disubstituted allylborane–Lewis base adducts. These adducts are stable in air and can readily undergo various transformations, illustrating the great potential of this protocol for synthetic chemistry. Mechanistic studies show that the reaction proceeds via insertion of a vinyl Cu(I) carbene, generated by opening of the cyclopropene ring, into the B–H bond. This method will undoubtedly facilitate the structurally diverse synthesis of organoborons. Supporting Information Supporting Information is available and includes the general procedures for Cu(I)-catalyzed ring-opening/borylation of cylcopropenes, evaluation results of different Lewis base-borane adducts, additional optimization results, characteristic data, and spectra of new compounds. Conflict of Interest There is no conflict of interest to report. Funding Information This research was made possible as a result of a generous grant from the National Natural Science Foundation of China (nos. 21625204 and 21971119), the "111" project (B06005) of the Ministry of Education of China, National Program for Support of Top-notch Young Professionals, and Key-Area Research and Development Program of Guangdong Province (no. 2020B010188001) for financial support. Acknowledgments This work was dedicated to the 100th Anniversary of Chemistry at Nankai University. References 1. Miyaura N.; Suzuki A.Palladium-Catalyzed Cross-Coupling Reactions of Organoboron Compounds.Chem. Rev.1995, 95, 2457–2483. Google Scholar 2. Leonori D.; Aggarwal V. K.Stereospecific Couplings of Secondary and Tertiary Boronic Esters.Angew. Chem. Int. Ed.2015, 54, 1082–1096. Google Scholar 3. Trippier P. C.; McGuigan C.Boronic Acids in Medicinal Chemistry: Anticancer, Antibacterial and Antiviral Applications.Med. Chem. Commun.2010, 1, 183–198. Google Scholar 4. Dembitsky V. 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