Asymmetric Borylative Coupling of Vinylazaarenes and Ketones Catalyzed by a Copper(I) Complex
Xu-cheng Gan, Liang Yin
Abstract
Open AccessCCS ChemistryCOMMUNICATION1 Apr 2020Asymmetric Borylative Coupling of Vinylazaarenes and Ketones Catalyzed by a Copper(I) Complex Xu-Cheng Gan and Liang Yin Xu-Cheng Gan CAS Key Laboratory of Synthetic Chemistry of Natural Substances, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200032 (China) and Liang Yin *Corresponding author: E-mail Address: [email protected] CAS Key Laboratory of Synthetic Chemistry of Natural Substances, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200032 (China) https://doi.org/10.31635/ccschem.020.201900102 SectionsSupplemental MaterialAboutAbstractPDF ToolsAdd to favoritesTrack Citations ShareFacebookTwitterLinked InEmail Azaarenes are attractive structural units widely found in chiral pharmaceuticals, agrochemicals, and biologically active natural products. An ongoing strategy has been the construction of new chiral molecules containing azaarenes by virtue of the electron-deficient properties of azaarenes. Herein, an asymmetric three-component coupling of vinylazaarenes, B2Pin2, and ketones was achieved in the presence of a chiral copper(I) catalyst. The reaction favored a broad substrate scope of either vinylazaarenes or ketones. High enantioselectivity was observed in this reaction together with moderate diastereoselectivity, attributable to the relatively small difference of steric repulsion between two proposed transition states. Finally, the synthetic utilities of the product were demonstrated by several beneficial transformation reactions. Download figure Download PowerPoint Introduction N-Containing aromatic heterocycles (azaarenes) are extremely important structure motifs in biologically active molecules, which is reflected by the fact that functionalized azaarenes distribute widely in pharmaceutically active ingredients (such as Voriconazole, Ravuconazole, and Bedaquiline, Scheme 1a) and alkaloids.1–4 Moreover, nearly half of these materials are chiral.1 Therefore, it is extremely desirable for organic chemists to develop efficient methodologies for the preparation of chiral building blocks containing azaarenes.5 However, the coordinating nature of azaarenes (such as pyridines) provides obstacles to transition metal-catalyzed asymmetric reactions.6–8 Aside from the classical methods used with azaarenes as nonparticipating bystanders, new methods which utilize the chemical properties of the azaarenes themselves have emerged, contributing to the asymmetric synthesis of chiral derivatives.5 Among such methods, the reactions of alkenyl-substituted aromatic N-heterocycles are particularly appealing due to their partial shared similarities of the classical Michael acceptors (such as, α,β-unsaturated carbonyl compounds).9,a Scheme 1 | Chiral pharmaceutical molecules with azaarenes, borylative coupling of vinylazaarenes and aldimines, and our working hypothesis. Download figure Download PowerPoint In 2009, Lam and co-workers10 disclosed an exciting enantioselective reduction of β,β-disubstituted alkenylazaarenes with a copper catalyst. It was particularly remarkable that the activation of conjugate carbon–carbon double bonds by azaarenes enabled the catalytic reduction of sterically hindered trisubstituted olefin with high to excellent enantioselectivity. Since then, significant efforts have been dedicated by the Lam group11–14, Harutyunyan group15,16, and others17–25,b to the efficient synthesis of various chiral molecules containing azaarenes through transition metal catalysis or organocatalysis. Among the various vigorous reactions, copper-catalyzed borylation of alkenyl-substituted azaarenes leading to chiral azaarenes with C-BPin moieties have been particularly notable, as the C-BPin served as a synthetic handle to enable further structural elaboration.26–28 In 2016, copper-catalyzed nonenantioselective three-component reaction, including vinylazaarenes, B2Pin2, and N-Boc imines was published by the Lam group, which generated azaarenes-containing, Boc-protected, amino alcohols, with moderate diastereoselectivity, after an oxidative workup (Scheme 1b).29 Later, Meng and co-workers30 investigated a copper-catalyzed enantioselective addition of B2Pin2 to N-heteroaryl-substituted alkenes, and the chiral borylated product was transformed successfully to functionalized molecules constructed with C-BPin moiety. Apart from Lam's nonenantioselective reaction with aldimines, there are no reports on the challenging three-component reaction between B2Pin2, vinylazaarenes, and carbonyl compounds, which play vital roles in numerous asymmetric catalytic reactions. Compared with aldehydes, simple ketones are rather inert in the presence of nucleophiles.31,32 Moreover, they are more complicated to employ in asymmetric catalysis due to the relatively small difference in steric hindrance between the two substituents on the carbonyl group.31 Accordingly, the asymmetric catalytic reaction of simple ketones remains a substantial challenge. Based on our previous work on catalytic asymmetric borylative coupling of 1,3-enynes and ketones,33,34 we reasoned that borylative coupling 2-vinylazaarenes and simple ketones might favor the delivery of azaarene-contained chiral alkyl boronates, and enable further, their structural derivatization (Scheme 1c). However, significant challenges exist: First, copper(I)-species A (with an azaarene group) would have to undergo an equilibrium with B, which, we envisaged, might potentially lead to more complicated asymmetric induction than benzyl copper(I) species would. Second, the nucleophilicity of chiral alkyl copper(I)-species A would be extenuated due to the electron-withdrawing nature of azaarene. Third, the addition of copper(I)-species A or B would be remarkably difficult due to the steric hindrances caused by their bearing BPin group, N-containing heterocycles with substituents, and a bulky bisphosphine ligand. Here, we disclose a copper(I)-catalyzed three-component coupling of vinylazaarenes, B2Pin2, and simple ketones, which afforded chiral molecules containing azaarenes with excellent enantioselectivity. Results and Discussion The reaction of 2-vinylquinoline ( 1a), B2Pin2 ( 2), and acetophenone ( 3a) were employed as a model reaction (Table 1). In the presence of 5 mol % of Cu(CH3CN)4PF6, 6 mol % of (R)-BINAP, and 1.5 equiv of NaOtBu, the borylative coupling of 2-vinylquinoline and acetophenone proceeded smoothly to afford 4aa in 42% yield with 3/1 dr, after an oxidative workup (entry 1). Unfortunately, the enantioselectivity for the major diastereoisomer was rather low (< 1%). (R)-SEGPHOS, (R)-DTBM-SEGPHOS, (R,R)-Me-DUPHOS, and (R,R)-Ph-BPE proved unsuitable (entries 2–5). The ferrocene-embedded bisphosphines such as (R)-(S)-JOSIPHOS and (R,RP)-TANIAPHOS led to 4aa in moderate yields, but low to moderate diastereoselectivity, respectively (entries 6 and 7). A high yield (81%) and the best enantioselectivity (73%) were observed when (R,R)-QUINOXP* was used as a ligand, although the diastereoselectivity (4/1) was still moderate (entry 8). Switching NaOtBu to KOMe resulted in a slight increase in enantioselectivity (78%) but a considerable reduction in yield (60%) (entry 9). Employing 1.5 equiv KOtBu as the base with (R,R)-QUINOXP* led to the overall highest yield (86%) and moderate enantioselectivity (80%) of 4aa (entry 10). Reducing the amount of KOtBu from 1.5 equiv to 1.2 equiv, and finally to 1.0 equiv, further enhanced the enantiomeric excess from 80% to 86%, and 95%, respectively (entries 11 and 12).c (R,R)-BENZP*, which is structurally similar to (R,R)-QUINOXP*, was also a suitable ligand in this reaction (entry 13), generating moderate yield (75%), but high enantioselectivity (93%). Table 1 | Optimization of the Reaction Conditions for the Synthesis of Stereoselective Vinylazaarenes Derivativesa Subsequently, the substrate scope of ketones was evaluated under our optimized reaction conditions (Table 2). Acetophenones with various substituents were acceptable with moderate isolated yield (59–72%) and excellent enantioselectivity (90–96%) ( 4aa– 4al). Thus, the electron-donating nature or the electron-withdrawing group of substituents did not have a considerable impact on the reaction outcomes. Moreover, the position of a substituent on the phenyl ring did not affect the asymmetric nature of the reaction. The borylative coupling of 2-acetonaphthone with 2-vinylquinoline proceeded nicely in moderate isolated yield (67%) with excellent enantioselectivity (94%) ( 4am). Notably, ketones with heterocycles served as appropriate substrates, too, with average yields and excellent enantioselectivity ( 4an– 4ar). The heteroatoms in these ketones might potentially coordinate to the copper complex, and thus, lead to the deactivation of the catalyst. Fortunately, an α,β-unsaturated ketone selectively led to the product 4as without considerably disturbing by the copper-catalyzed 1,4-borylation. At last, ketones with fluoromethyl or difluoromethyl ( 4at– 4au), which might have acidic protons, were also identified as suitable substrates in moderate isolated yields (70–72%) with excellent enantioselectivity (90–91%). Although the diastereoselectivities were moderate, the major diastereoisomers were easily isolated from the minor diastereoisomers in pure form through silica gel column chromatography. Table 2 | Substrate Scope of Ketonesa Furthermore, various vinylazaarenes were investigated under optimized reaction conditions (Table 3). Several 2-vinylquinolines with substituents (including both electron-donating groups and electron-withdrawing groups) at 6-position were identified as competent substrates ( 4aa– 4fa). Two 2-vinylquinolines with fluorine and chlorine at 7-position coupled smoothly with B2Pin2 and acetophenone to give the products ( 4ga and 4ha) in moderate diastereoselectivity and excellent enantioselectivity for the major diastereoisomer. Other heterocycles, such as benzoxazole ( 4ia), benzothiazole ( 4ja), pyrazine ( 4ka), quinoxaline ( 4la), pyrimidine ( 4ma and 4na), pyridazine ( 4oa), and pyridine ( 4pa and 4qa), were well tolerated under our present reaction conditions. It was gratifying that propiophenone also reacted with 2-vinylpyridine and B2Pin2 to give the product ( 4qv) in excellent enantioselectivity. Moreover, dialkyl ketones underwent smoothly coupling with 5-cyano-2-vinylpyridine and B2Pin2 to generate the products ( 4qw, 4qx, and 4qy) in excellent enantioselectivity. The absolute configuration of 4ea was determined through X-ray crystallography (CCDC 1902952; UK). The absolute configurations of other products ( 4) were deduced by analogy. Table 3 | Substrate Scope of Vinylazaarenesa The excellent enantioselectivity achieved with cyclohexanone and acetone indicates that the stereo-recognition on the trisubstituted carbon was very high. The low diastereoselectivity of our current reaction indicates that stereo-recognition on the tetrasubstituted carbon was problematic, which was explained by two proposed six-membered ring transition states (TS 1 and TS 2, based on the borylative coupling of 1a and 3a), as shown in Scheme 2. In TS 1, which furnished the major diastereoisomer, steric repulsion existed between the N-containing heterocycle and a methyl group. In TS 2, leading to the minor diastereoisomer, a larger repulsion existed between the N-containing heterocycle and phenyl group (note: the phenyl group was larger than the methyl group). Nonetheless, the relatively small difference in steric repulsion between TS 1 and TS 2 resulted in low diastereoselectivity. Scheme 2 | Two proposed transition states of borylative coupling of vinylazaarenes. TS 1, diastereoisomer with normal steric repulsion; TS 2, diastereoisomer with a larger steric repulsion. Download figure Download PowerPoint Finally, when the catalytic loading was decreased further to 2.0 mol%, this alteration in the reaction condition enabled a successful gram-scale preparation of 4aa, as shown in Scheme 3. A 4aa of 1.05 g was isolated in 60% yield with > 20/1 dr and 93% ee. In 2010, Baran and co-workers35 reported a simple but efficient methodology for the direct coupling of arylboronic acids to electron-deficient heterocycles using an inexpensive silver catalyst and a co-oxidant. By following the protocol, the regioselective coupling of 4aa and phenylboronic acid was carried out successfully to furnish product 5 in 67% yield. The primary hydroxyl group in 4aa served as a synthetic handle for further transformations. For example, 4aa was transformed into 6 in 71% yield by a two-step reaction involving mesylation and subsequent SN2 substitution with NaN3. Then, following a reported procedure,36 a click reaction37,d was performed between 6 and 7, which occurred smoothly in the presence of a copper catalyst, affording the complex 1,2,3-triazole derivative ( 8) in excellent yield (98%). Scheme 3 | Gram-scale reaction and transformations of 4aa. Download figure Download PowerPoint Conclusion A catalytic asymmetric borylative coupling of vinylazaarenes to ketones was achieved with excellent enantioselectivity. An array of azaarenes, including quinoline, benzoxazole, benzothiazole, pyrazine, quinoxaline, pyrimidine, pyridazine, and pyridine, were well tolerated. Moreover, various ketones, including both aromatic and alkyl ketones, were applicable. The moderate diastereoselectivity was explained reasonably with two proposed transition states. Finally, the utilities of the product were showcased by several transformations. Currently, further optimization of our developed system toward high diastereoselectivity with new strategies is an ongoing project in our laboratory. Footnotes a For a review on the employment of vinylazaarenes as electrophiles in organic reactions, refer to the study by Klumpp.9 b Krische group17 reported a rhodium-catalyzed diastereoselective reductive coupling of 2-vinylpyridines and aldimines under hydrogen atmosphere. c At present, we are not fully aware of the exact reason for the dependence of the enantiomeric excess on both the nature and equivalents of the base employed. d For a review on click chemistry, refer to Kolb et al.37 Supporting Information Supporting Information is available. Conflict of Interest There is no conflict of interest to report. Funding Information This research was funded by the National Natural Science Foundation of China (grant nos. 21672235, 21871287, and 21922114). 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Issue AssignmentVolume 2Issue 2Page: 203-208Supporting Information Copyright & Permissions© 2020 Chinese Chemical SocietyKeywordscopper catalystborylative couplingasymmetric catalysisvinylazaareneketoneAcknowledgmentsWe gratefully acknowledge the financial support from the "Thousand Youth Talents Plan," the Strategic Priority Research Program of the Chinese Academy of Sciences (no. XDB20000000), CAS Key Laboratory of Synthetic Chemistry of Natural Substances, and Shanghai Institute of Organic Chemistry. Downloaded 2,595 times Loading ...