Ni–Al Bimetal-Catalyzed Tertiary C(sp 3 )–H Activation for Dual C–H Annulation of Formamides with Alkynes

Open AccessCCS ChemistryCOMMUNICATIONS26 Jul 2024Ni–Al Bimetal-Catalyzed Tertiary C(sp3)–H Activation for Dual C–H Annulation of Formamides with Alkynes Yi Li, Yu-Peng Liu, Mengying Xu, Weiwei Xu, Feng-Ping Zhang and Mengchun Ye Yi Li , Yu-Peng Liu , Mengying Xu , Weiwei Xu , Feng-Ping Zhang *Corresponding authors: E-mail Address: email protected E-mail Address: email protected and Mengchun Ye *Corresponding authors: E-mail Address: email protected E-mail Address: email protected Citation: CCS Chemistry. 2024;0:1–8https://doi.org/10.31635/ccschem.024.202404549 SectionsSupplemental MaterialAboutAbstractPDF ToolsAdd to favoritesDownload CitationsTrack Citations ShareFacebookTwitterLinked InEmail 3d-Metal-catalyzed tertiary C(sp3)–H bond activation has been a formidable challenge. Herein, a tertiary C(sp3)–H bond is smoothly activated by Ni–Al bimetallic catalysts for dual C–H annulation of formamides with alkynes, delivering a series of δ-lactams with a quaternary carbon up to 98% yield. Various tertiary C(sp3)–H bonds such as noncyclic, monocyclic and bridged-ring tertiary C(sp3)–H bonds are all compatible with the reaction. Download figure Download PowerPoint Introduction Transition metal-catalyzed aliphatic C(sp3)–H bond activation has been a formidable challenge in the field of C–H activation,1–6 due to the lack of an adjacent π-system rendering the interaction of C(sp3)–H bonds with metal catalysts quite weak, not only leading to low reactivity under regular reaction conditions, but also causing high sensitivity of C(sp3)–H metalation to steric hindrance. In general, primary C(sp3)–H bonds with low steric hindrance are relatively easy to activate by metal catalysts (Figure 1a), while the most sterically hindered tertiary C(sp3)–H bonds are quite resistant to direct C–H metalation. Until now, only a very limited number of tertiary C(sp3)–H bonds have been successfully activated by metals towards constructing a quaternary or tetra-substituted carbon (Figure 1b, top).7–11 For example, the installation of proper bidentate directing groups on cyclic substrates is capable of facilitating Pd-catalyzed tertiary C(sp3)–H bond activation, delivering alkylated or arylated products with a quaternary carbon center.12–15 The design of an allylic structure by incorporating an olefin motif adjacent to tertiary C(sp3)–H bonds also effectively enables Pd- or Ir-catalyzed C(sp3)–H alkylation or alkenylation reactions, providing alkylated or alkenylated products with a quaternary carbon center.16,17 In addition, the introduction of highly strained small rings proves effective in promoting Ir-catalyzed direct borylation of tertiary C(sp3)–H bonds, affording tetra-substituted carbon centers with a boryl group.18,19 Figure 1 | Tertiary C(sp3)–H bond activation via transition metal catalysis. Download figure Download PowerPoint Nevertheless, all these methods require the use of precious metals such as Pd and Ir as the catalysts, but are ineffective to 3d-metal catalysts that are often very picky to directing groups, ligands and reaction conditions in C–H bond activation (Figure 1b, bottom).20–23 Given attractive advantages of 3d-metal catalysts such as high abundance, low cost and good biocompatibility,24–29 the development of 3d metal-catalyzed tertiary C(sp3)–H bond activation would be in high demand, yet still remains an elusive challenge. Herein, we used a phosphine oxide-coordinated Ni and Al bimetallic catalyst to facilitate a Ni-catalyzed activation of the tertiary C(sp3)–H bond of formamides,30–74 providing a wide range of δ-lactams with a quaternary carbon center up to 98% yield (Figure 1c). The method tolerates noncyclic, monocyclic and bridged-ring tertiary C(sp3)–H bonds, demonstrating the unique catalytic ability of Ni–Al bimetallic catalyst. Results and Discussion Reaction proposal and optimization Following Nakao's work and our recent works on dual C–H annulation of formamides with alkynes via primary or secondary aliphatic C(sp3)–H bond activation,45,75–81 we envisioned to explore more challenging tertiary C(sp3)–H activation in such a dual C–H annulation reaction. So N-(2,6-diisopropylphenyl)-N-isobutylformamide ( 1a) and alkyne 2a were then selected as model substrates in the hope that the bulky 2,6-diisopropylphenyl group could not only inhibit direct hydrocarbamoylation of alkynes with formamides, but also promote tertiary C(sp3)–H activation by pushing the Ni intermediate near the isobutyl group for dual C–H annulation (Figure 2). A systematic survey of ligands revealed that traditional mono- or bi-dentate phosphines or N-heterocyclic carbenes were completely ineffective to the reaction, only affording side product from hydrocarbamoylation of alkynes. Moreover, a broad range of bifunctional phosphine oxides such as diphenyl- ( PO1), BINOL- ( PO2), Taddol- ( PO3 and PO4), diamine-derived ( PO5– PO10) phosphine oxides, which have proved powerful in previous aliphatic C(sp3)–H bond activation,59–74,77–81 all failed to facilitate the reaction, suggesting challenging reactivity of Ni-catalyzed tertiary C(sp3)–H bond activation. Figure 2 | Reaction development. 1a (0.2 mmol), 2a (0.6 mmol), toluene (1.0 mL) under N2 for 12 h; Yield was determined by 1H NMR analysis using CH2Br2 as the internal standard. aUsing n-octane as the solvent. Ar = 3,5-tBu2C6H3. Mes = mesityl. Download figure Download PowerPoint Fortunately, bulky diamine-derived phosphine oxide PO11 proved to be the sole suitable one among all screened ligands, providing δ-lactam 3a in 52% yield. A decrease in temperature to 60 °C gave a slight yield increase to 63%, while a higher or lower temperature diminished the yield. Besides temperature, Lewis acids with different Lewis acidities, loadings and steric hindrances had a strong influence on the yield (see the Supporting Information Tables S1–S8). Finally, 30 mol % of less sterically hindered AlMe3 proved optimal, delivering 3a in 82% yield. Surprisingly, nonpolar solvent also played a critical role in the reaction and a nearly quantitative yield was obtained in n-octane. Control experiments showed that previously optimized N-protecting groups were incompatible with the reaction, suggesting that tertiary C(sp3)–H bond activation was highly sensitive to steric hindrance of reaction sites. Scope of alkynes and formamides With optimal conditions in hand, the scope of alkynes was investigated first (Figure 3). A broad range of linear alkyl-substituted alkynes with varying chain length from two carbons to eight carbons were well compatible with the reaction, delivering the corresponding δ-lactams in 88%–98% yield ( 3a– 3f). Owing to the high sensitivity of the reactivity to steric hindrance, substituents on the alkyl chain cannot be attached to sites near triple bonds of alkynes. For example, the phenyl group at γ-position worked well, delivering the product in 92% yield ( 3g), while the phenyl group at the α- or β-position would be ineffective. O-containing functional groups such as OMe ( 3h), OPh ( 3i), easily-transformable OSEM ( 3j), OTHP ( 3k), and OMOM ( 3l) groups at the γ- or δ-position of the alkyl chain were all suitable substituents, giving 67%–90% yield. In addition, very bulky alkoxysilyl groups such as OTBS ( 3m and 3n), OTIPS ( 3o) and OTBDPS ( 3p) at the β, γ or δ-position of the alkyl chain were still well compatible with the reaction, providing 77%–96% yield. Besides O-containing groups, amine groups were also tolerated in the reaction, affording the corresponding product in 82% yield ( 3q). Not surprisingly, more sterically hindered alkynes such as rigid cyclic alkyne ( 3r) and diphenyl alkyne ( 3s) led to a decrease of yield. Beyond symmetrical alkynes, nonsymmetrical alkynes with two different linear alkyl groups proved to be good substrates, giving 98% yield yet with a low regioisomer ratio ( 3t). However, pleasingly, the regioisomer ratio can be greatly enhanced by introducing one bulkier substituent, such as a phenyl group ( 3u) or isopropyl group ( 3v), offering the sole isomer product, albeit with low yield. Figure 3 | Scope of alkynes. 1a (0.2 mmol), 2 (0.6 mmol), n-Octane (1.0 mL) under N2 for 12 h; yield of isolated products. PG, 2,6-diisopropylphenyl. a20 mol % of PO11 was used. nPr, n-propyl; nPent, n-pentyl; SEM, (trimethylsilyl) ethoxymethyl; THP, tetrahydro-2H-pyran-2-yl; MOM, methoxymethyl; TBS, tert-butyldimethylsilyl; TIPS, triisopropylsilyl; TBDPS, tert-butyldiphenylsilyl. Download figure Download PowerPoint Next, we examined the scope of formamides (Figure 4). A more easily removable N-2,6-diisopropyl-4-methoxyphenyl group was also a suitable protecting group, providing the corresponding product in 93% yield ( 4a), which allows for the versatile transformation of annulated products. Owing to the fact that tertiary C(sp3)–H bond activation is very sensitive to steric hindrance, noncyclic tertiary C(sp3)–H bonds are generally difficult to activate even by precious metals.12–19 However, pleasingly, the incorporation of an ethyl or n-propyl group instead of methyl group proved feasible in the current reaction ( 4b and 4c), providing the corresponding product in 53% and 39% yield, respectively. Figure 4 | Scope of formamides. 1 (0.2 mmol), 2a (0.6 mmol), n-Octane (1.0 mL) under N2 for 12 h; yield of isolated products. a20 mol % of PO11 was used. Download figure Download PowerPoint Beyond noncyclic tertiary C(sp3)–H bonds, various cyclic tertiary C(sp3)–H bonds such as cyclobutyl ( 4d), cyclopentyl ( 4e), and cyclohexyl ( 4f) C(sp3)–H bonds were well compatible with the reaction, delivering up to 98% yield. In addition, bridged-ring tertiary C(sp3)–H bonds were also investigated, and the result showed that rigid 2-adamantyl tertiary C(sp3)–H bonds can be smoothly activated, yet requiring a flexible alkyl group as the N-protecting group ( 4g and 4h). Synthetic utility To elucidate the utility of the reaction, we also investigated product transformations. Products 3a and 4a were smoothly obtained at gram scale with up to 81% yield (Figure 5a). When subjected to reducing reagent (LiAlH4) or oxidant (cerium ammonium nitrate), product 4a can be transformed into the corresponding piperidine ( 5) or piperidine-2,6-dione derivatives ( 6) in 80% and 55% yield, respectively (Figure 5b). Although direct removal of 2,6-diisopropylphenyl from the N atom is difficult, N-2,6-diisopropyl-4-methoxyphenyl group proved to be a removable group. When product 4a was treated with BBr3 and PhI(OAc)2 sequentially, the desired N–H δ-lactam 7 was obtained in 65% yield, which can be further protected by Boc2O into amide 8 in 98% yield or oxidized by ozone into β-amino ketone 9 in 85% yield. These transformations demonstrated that the current method provides a convenient method for the synthesis of various δ-lactams and derivatives from easily accessed formamides and alkynes. Figure 5 | Synthetic utility. Download figure Download PowerPoint Mechanistic discussion To gain more insights into the mechanism, relevant mechanistic experiments were carried out. Parallel experiments revealed a low kinetic isotope effect (KIE = 1.1) for formyl H (Figure 6a) and a little higher KIE (1.5) for tertiary H (Figure 6b), suggesting that the activation of C(sp2)–H bond and the activation of tertiary C(sp3)–H bond would not be involved in the rate-determining step. Besides deuterium-labeling experiments, a chiral formamide was also examined in the reaction and no significant racemization was observed (Figure 6c), indicating that a radical process or β-H elimination could be ruled out. Based on these results, a plausible mechanism was proposed (Figure 6d): the coordination of PO-ligated Ni−Al bimetallic catalyst with formamide forms the intermediate A, which undergoes the first formyl C−H bond activation via oxidative addition or ligand-to-ligand H transfer to give intermediate B.82–85 The following tertiary C(sp3)–H bond activation occurs to give intermediate C, which undergoes alkyne insertion, reductive elimination and de-coordination to provide the desired product. Figure 6 | Mechanistic experiments and proposed mechanism. Download figure Download PowerPoint Conclusion In conclusion, a Ni−Al bimetal-catalyzed tertiary C(sp3)–H bond activation of formamides with alkynes has been developed, providing a series of δ-lactams up to 98% yield. The phosphine oxide-ligated Ni–Al bimetallic catalyst and bulky N-protecting group prove critical in achieving the reactivity. A wide range of alkynes such as linear dialkyl alkynes with or without functional groups, diphenyl alkynes and nonasymmetrical alkynes were well tolerated, providing good to high yield and easily controlled regioselectivity. Likewise, various aliphatic tertiary C(sp3)–H bonds such as noncyclic, monocyclic and bridged-ring tertiary C(sp3)–H bonds can be smoothly activated, providing rapid and convenient access to a quaternary carbon center. Further investigation of wider applications of Ni–Al bimetallic catalysts in other challenging inert bond activation is under the way in the lab. Supporting Information Supporting Information is available, including additional experimental details and characteristic data of new compounds. Conflict of Interest There is no conflict of interest to report. Funding Information We thank the National Key R Shi Z.-J.Privileged Strategies for Direct Transformations of Inert Aliphatic C–H Bonds.Nat. Sci. Rev.2014, 1, 172–175. Google Scholar 3. Harwig J. 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