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• W3036745971 abstract "•First enantioselective ring-closing C(sp3)–H amination of urea derivatives•Simple access to chiral 2-imidazolidinones which can be converted to vicinal diamines•Applications to the synthesis of pharmaceuticals, natural products, and a chiral catalyst•Chiral-at-metal catalyst used in challenging asymmetric nitrenoid insertion chemistry Direct C–H functionalization offers the prospect for streamlined synthesis with high atom economy. In this respect, the transition-metal-catalyzed enantioselective insertion of nitrenoids into prochiral sp3 C–H bonds is a powerful tool for the efficient construction of non-racemic chiral nitrogen-containing molecules. Intramolecular versions have been used to synthesize chiral nitrogen heterocycles, but cyclic urea is still elusive through enantioselective nitrenoid insertion chemistry. Here, we fill this gap and report an enantioselective intramolecular C(sp3)–H amination of N-benzoyloxyurea to provide chiral 2-imidazolidinones in high yields and with high enantioselectivities. The synthetic utility of this new method is illustrated with the catalytic asymmetric synthesis of medicinal agents, natural products, and a chiral organocatalyst. Our work emphasizes the usefulness of transition-metal-controlled asymmetric nitrene chemistry and the importance of tailored catalyst design. An enantioselective intramolecular C(sp3)–H amination of N-benzoyloxyurea by using a chiral-at-metal ruthenium catalyst is reported, providing chiral 2-imidazolidinones in yields of up to 99% and with up to 99% ee. Catalyst loadings down to 0.05 mol % are feasible. Control experiments support a stepwise nitrene insertion mechanism through hydrogen atom transfer of a ruthenium nitrenoid intermediate followed by a radical recombination. Chiral 2-imidazolidinones are prevalent in bioactive compounds and can be converted to chiral vicinal diamines in a single step. The synthetic value of the new method is demonstrated for the synthesis of intermediates of the drugs levamisole and dexamisole, the bisindole alkaloids topsentine D and spongotine A, and a chiral organocatalyst. An enantioselective intramolecular C(sp3)–H amination of N-benzoyloxyurea by using a chiral-at-metal ruthenium catalyst is reported, providing chiral 2-imidazolidinones in yields of up to 99% and with up to 99% ee. Catalyst loadings down to 0.05 mol % are feasible. Control experiments support a stepwise nitrene insertion mechanism through hydrogen atom transfer of a ruthenium nitrenoid intermediate followed by a radical recombination. Chiral 2-imidazolidinones are prevalent in bioactive compounds and can be converted to chiral vicinal diamines in a single step. The synthetic value of the new method is demonstrated for the synthesis of intermediates of the drugs levamisole and dexamisole, the bisindole alkaloids topsentine D and spongotine A, and a chiral organocatalyst. The direct catalytic asymmetric conversion of prochiral C(sp3)–H into C–N bonds offers an efficient synthetic route to non-racemic chiral nitrogen-containing molecules.1Park Y. Kim Y. Chang S. Transition metal-catalyzed C–H amination: scope, mechanism, and applications.Chem. Rev. 2017; 117: 9247-9301Crossref PubMed Scopus (1087) Google Scholar, 2Collet F. Dodd R.H. Dauban P. Catalytic C–H amination: recent progress and future directions.Chem. Commun. (Camb.). 2009; : 5061-5074Crossref PubMed Scopus (638) Google Scholar, 3Hazelard D. Nocquet P.-A. Compain P. Catalytic C-H amination at its limits: challenges and solutions.Org. Chem. 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Cui X. et al.Enantioselective radical construction of 5-membered cyclic sulfonamides by metalloradical C–H amination.J. Am. Chem. Soc. 2019; 141: 18160-18169Crossref PubMed Scopus (39) Google Scholar carbamates,19Reddy R.P. Davies H.M.L. Dirhodium tetracarboxylates derived from adamantylglycine as chiral catalysts for enantioselective C−H aminations.Org. Lett. 2006; 8: 5013-5016Crossref PubMed Scopus (183) Google Scholar,20Lebel H. Huard K. Lectard S. N-Tosyloxycarbamates as a source of metal nitrenes: rhodium-catalyzed C-H insertion and aziridination reactions.J. Am. Chem. Soc. 2005; 127: 14198-14199Crossref PubMed Scopus (239) Google Scholar lactams,21Park Y. Chang S. Asymmetric formation of γ-lactams via C–H amidation enabled by chiral hydrogen-bond-donor catalysts.Nat. Catal. 2019; 2: 219-227Crossref Scopus (82) Google Scholar, 22Xing Q. Chan C.M. Yeung Y.W. Yu W.Y. Ruthenium(II)-catalyzed enantioselective γ-lactams formation by intramolecular C–H amidation of 1,4,2-dioxazol-5-ones.J. Am. Chem. Soc. 2019; 141: 3849-3853Crossref PubMed Scopus (53) Google Scholar, 23Wang H. Park Y. Bai Z. Chang S. He G. Chen G. Iridium-catalyzed enantioselective C(sp3)-H amidation controlled by attractive noncovalent interactions.J. Am. Chem. Soc. 2019; 141: 7194-7201Crossref PubMed Scopus (68) Google Scholar, 24Zhou Z. Chen S. Hong Y. Winterling E. Tan Y. Hemming M. Harms K. Houk K.N. Meggers E. Non-C2-symmetric chiral-at-ruthenium catalyst for highly efficient enantioselective intramolecular C(sp3)-H amidation.J. Am. Chem. Soc. 2019; 141: 19048-19057Crossref PubMed Scopus (37) Google Scholar Boc-protected pyrrolidines,25Kuijpers P.F. Tiekink M.J. Breukelaar W.B. Broere D.L.J. van Leest N.P. van der Vlugt J.I. et al.Cobalt-porphyrin-catalysed intramolecular ring-closing C−H amination of aliphatic azides: a nitrene-radical approach to saturated heterocycles.Chem. Eur. J. 2017; 23: 7945-7952Crossref PubMed Scopus (80) Google Scholar,26Qin J. Zhou Z. Cui T. Hemming M. Meggers E. Enantioselective intramolecular C–H amination of aliphatic azides by dual ruthenium and phosphine catalysis.Chem. Sci. 2019; 10: 3202-3207Crossref PubMed Scopus (25) Google Scholar and related Boc-protected heterocycles (Figure 1B).27Zhou Z. Chen S. Qin J. Nie X. Zheng X. Harms K. Riedel R. Houk K.N. Meggers E. Catalytic enantioselective intramolecular C(sp3 )-H amination of 2-azidoacetamides.Angew. Chem. Int. Ed. 2019; 58: 1088-1093Crossref PubMed Scopus (36) Google Scholar However, interestingly, urea derivatives as nitrene precursors leading to chiral cyclic urea, specifically 2-imidazolidinones, are absent from this list.28Kim M. Mulcahy J.V. Espino C.G. Du Bois J. Expanding the substrate scope for C−H amination reactions: oxidative cyclization of urea and guanidine derivatives.Org. Lett. 2006; 8: 1073-1076Crossref PubMed Scopus (159) Google Scholar This is unfortunate considering the prevalence of chiral 2-imidazolidinones in bioactive compounds and their use as chiral auxiliaries.29Swain S.P. Mohanty S. Imidazolidinones and imidazolidine-2,4-diones as antiviral agents.ChemMedChem. 2019; 14: 291-302Crossref PubMed Scopus (8) Google Scholar,30Lu C. Hu L. Yang G. Chen Z. 2-Imidazolidinones as chiral auxiliaries in asymmetric synthesis.Curr. Org. Chem. 2012; 16: 2802-2817Crossref Scopus (16) Google Scholar Furthermore, chiral 2-imidazolidinones can be converted in a single step to chiral vicinal diamines, which are valuable building blocks for the synthesis of medicinal agents, natural products, chiral ligands, and chiral catalysts.31Lucet D. Le Gall T. Mioskowski C. The chemistry of vicinal diamines.Angew. Chem. Int. Ed. 1998; 37: 2580-2627Crossref PubMed Scopus (827) Google Scholar, 32Saibabu Kotti S.R.S. Timmons C. Li G. Vicinal diamino functionalities as privileged structural elements in biologically active compounds and exploitation of their synthetic chemistry.Chem. Biol. Drug Des. 2006; 67: 101-114Crossref PubMed Scopus (290) Google Scholar, 33Kizirian J.C. Chiral tertiary diamines in asymmetric synthesis.Chem. Rev. 2008; 108: 140-205Crossref PubMed Scopus (286) Google Scholar Here, we report an intramolecular asymmetric C(sp3)–H amination of N-benzoyloxyurea (Figure 1C). The enantioselective cyclization is highly efficient with catalyst loadings down to 0.05 mol %. To our knowledge, this is the first example of chiral cyclic urea synthesized through a catalytic enantioselective nitrene C–H insertion strategy. We recently disclosed enantioselective nitrene insertion chemistry of organic azides and 1,4,2-dioxazol-5-ones by using “chiral-at-metal” ruthenium catalysts with exclusive metal-centered chirality (only achiral ligands).24Zhou Z. Chen S. Hong Y. Winterling E. Tan Y. Hemming M. Harms K. Houk K.N. Meggers E. Non-C2-symmetric chiral-at-ruthenium catalyst for highly efficient enantioselective intramolecular C(sp3)-H amidation.J. Am. Chem. Soc. 2019; 141: 19048-19057Crossref PubMed Scopus (37) Google Scholar,26Qin J. Zhou Z. Cui T. Hemming M. Meggers E. Enantioselective intramolecular C–H amination of aliphatic azides by dual ruthenium and phosphine catalysis.Chem. Sci. 2019; 10: 3202-3207Crossref PubMed Scopus (25) Google Scholar,27Zhou Z. Chen S. Qin J. Nie X. Zheng X. Harms K. Riedel R. Houk K.N. Meggers E. Catalytic enantioselective intramolecular C(sp3 )-H amination of 2-azidoacetamides.Angew. Chem. Int. Ed. 2019; 58: 1088-1093Crossref PubMed Scopus (36) Google Scholar We anticipated that this novel class of catalysts would allow us to address the challenge of accessing chiral 2-imidazolidinones by enantioselective C(sp3)–H amination from judiciously chosen urea derivatives. We initiated our study with the N-benzoyloxyurea 1aa (see Scheme S1 for substrate preparation) and envisioned that after release of the benzoate leaving group, an intermediate ruthenium nitrenoid would form and engage in an intramolecular C–H amination.34Huh S. Hong S.Y. Chang S. Synthetic utility of N-benzoyloxyamides as an alternative precursor of acylnitrenoids for γ-lactam formation.Org. Lett. 2019; 21: 2808-2812Crossref PubMed Scopus (14) Google Scholar Indeed, in the presence of 1 mol % ruthenium catalyst (Ru1) and K2CO3 (3 equiv) in CH2Cl2 at room temperature for 16 h, the 2-imidazolidinone 2a was formed in quantitative yield and with 86% enantiomeric excess (ee) (Table 1, entry 1). Optimization of the chiral-at-metal ruthenium catalyst (Ru2–Ru5,26Qin J. Zhou Z. Cui T. Hemming M. Meggers E. Enantioselective intramolecular C–H amination of aliphatic azides by dual ruthenium and phosphine catalysis.Chem. Sci. 2019; 10: 3202-3207Crossref PubMed Scopus (25) Google Scholar,27Zhou Z. Chen S. Qin J. Nie X. Zheng X. Harms K. Riedel R. Houk K.N. Meggers E. Catalytic enantioselective intramolecular C(sp3 )-H amination of 2-azidoacetamides.Angew. Chem. Int. Ed. 2019; 58: 1088-1093Crossref PubMed Scopus (36) Google Scholar,35Zheng Y. Tan Y. Harms K. Marsch M. Riedel R. Zhang L. Meggers E. Octahedral ruthenium complex with exclusive metal-centered chirality for highly effective asymmetric catalysis.J. Am. Chem. Soc. 2017; 139: 4322-4325Crossref PubMed Scopus (64) Google Scholar,36Zheng Y. Zhang L. Meggers E. Catalytic enantioselective synthesis of key propargylic alcohol intermediates of the anti-HIV drug efavirenz.Org. Process Res. Dev. 2018; 22: 103-107Crossref Scopus (9) Google Scholar entries 2–5) improved the enantioselectivity to 95% ee by using the trimethylsilyl-modified ruthenium catalyst Ru5 (see Scheme S2 for catalyst preparation). Functionalization of the benzoate leaving group with an electron-donating methoxy (1ab) (entry 6) or electron-withdrawing CF3-group (1ac) (entry 7) slightly affected the enantioselectivity. A pivaloate leaving group (1ad) only provided the 2-imidazolidinone in 27% yield with 91% ee (entry 8). Interestingly, the catalyst loading can be reduced down to 0.05 mol % upon increasing the reaction time to 24 h and the temperature to 40°C. (entries 9–11.) The addition of a base is not required but increases the rate of reaction (entry 12) (see Table S1 for additional conditions).37It is worth noting that other chiral-at-metal catalysts developed in our laboratory, IrS, RhS, or rNHCRu, do not catalyze this reaction under the reaction conditions shown in Table 1.Table 1Evaluation of the C(sp3)–H Amination ReactionaStandard conditions: Substrate 1aa–1ad (0.2 mmol), K2CO3 (0.6 mmol), Ru catalyst (0.002 mmol) in CH2Cl2 (2 mL) stirred at the indicated temperature for 16 h under N2 unless noted otherwise.EntryCatalystsXConditionsaStandard conditions: Substrate 1aa–1ad (0.2 mmol), K2CO3 (0.6 mmol), Ru catalyst (0.002 mmol) in CH2Cl2 (2 mL) stirred at the indicated temperature for 16 h under N2 unless noted otherwise.,bDeviations from standard conditions are shown.Yield (%)cDetermined by 1H NMR of the crude products using Cl2CHCHCl2 as internal standard.ee (%)dEnantiomeric excess determined by HPLC analysis of the crude main product on a chiral stationary phase.1Λ-Ru11aaStandard100862Λ-Ru21aaStandard100943Λ-Ru31aaStandard100954Λ-Ru41aaStandard100945Λ-Ru51aaStandard100 (99)eIsolated yield in brackets.956Λ-Ru51abStandard100947Λ-Ru51acStandard100948Λ-Ru51adStandard27919Λ-Ru51aa0.5 mol % catalyst)1009410Λ-Ru51aa0.1 mol % catalystfReaction executed at 40°C for 24 h.1009411Λ-Ru51aa0.05 mol % catalystfReaction executed at 40°C for 24 h.669312Λ-Ru51aano basegIncreased reaction time of 48 h.10094a Standard conditions: Substrate 1aa–1ad (0.2 mmol), K2CO3 (0.6 mmol), Ru catalyst (0.002 mmol) in CH2Cl2 (2 mL) stirred at the indicated temperature for 16 h under N2 unless noted otherwise.b Deviations from standard conditions are shown.c Determined by 1H NMR of the crude products using Cl2CHCHCl2 as internal standard.d Enantiomeric excess determined by HPLC analysis of the crude main product on a chiral stationary phase.e Isolated yield in brackets.f Reaction executed at 40°C for 24 h.g Increased reaction time of 48 h. Open table in a new tab It is worth noting that other chiral-at-metal catalysts developed in our laboratory, IrS, RhS, or rNHCRu, do not catalyze this reaction under the reaction conditions shown in Table 1. The proposed mechanism is shown in Figure 2. Upon release of benzoic acid from the N-benzoyloxyurea, the ruthenium catalyst forms a ruthenium nitrenoid intermediate (I). The ruthenium nitrenoid from its triplet state subsequently performs a 1,5-hydrogen atom transfer (HAT) to provide the radical intermediate II. This is followed by C–N bond formation through radical-radical recombination to provide the ruthenium-coordinated product (III), which is released to regenerate the active catalyst for a new catalytic cycle. The radical mechanism is supported by a significant kinetic isotope effect (KIE) of 4.35, which we determined with an intramolecular competition experiment by using the deuterated substrate 1aa' to provide the cyclized products 2a' and 2a'' with a ratio of 4.35:1 (Figures 3A and S1).38Harvey M.E. Musaev D.G. Du Bois J. A diruthenium catalyst for selective, intramolecular allylic C−H amination: reaction development and mechanistic insight gained through experiment and theory.J. Am. Chem. Soc. 2011; 133: 17207-17216Crossref PubMed Scopus (226) Google Scholar, 39Hennessy E.T. Betley T.A. Complex N-heterocycle synthesis via iron-catalyzed, direct C–H bond amination.Science. 2013; 340: 591-595Crossref PubMed Scopus (384) Google Scholar, 40Lu H.-J. Jiang H.-L. Hu Y. Wojtas L. Zhang X.P. Chemoselective intramolecular allylic C-H amination versus C-C aziridination through Co(II)-based metalloradical catalysis.Chem. Sci. 2011; 2: 2361-2366Crossref Scopus (79) Google Scholar, 41Paradine S.M. Griffin J.R. Zhao J. Petronico A.L. Miller S.M. Christina White M. A manganese catalyst for highly reactive yet chemoselective intramolecular C(sp(3))-H amination.Nat. Chem. 2015; 7: 987-994Crossref PubMed Scopus (164) Google Scholar The high KIE value obtained is a strong indication for the formation of a triplet nitrene intermediate, which then engages in radical chemistry. This is in contrast to our previous work on nitrene insertion of 2-azidoacetamides in which a KIE value of 1.5 was determined by an analogous intramolecular competition experiment.27Zhou Z. Chen S. Qin J. Nie X. Zheng X. Harms K. Riedel R. Houk K.N. Meggers E. Catalytic enantioselective intramolecular C(sp3 )-H amination of 2-azidoacetamides.Angew. Chem. Int. Ed. 2019; 58: 1088-1093Crossref PubMed Scopus (36) Google Scholar The assumption that the mechanism proceeds through intermediate radicals is further indicated by an experiment performed with the diastereomeric substrates (Z)-1b and (E)-1b (Figures 3B and S2–S4). Whereas (E)-1b formed (E)-2b under complete retention of the alkene configuration (80% yield, 76% ee), (Z)-1b (E:Z ratio > 20:1) was converted to 2b with an eroded Z:E diastereomeric ratio of just 4.4:1 (73% yield, 91% ee). This can be rationalized with an isomerization from the thermodynamically less stable Z-isomer to the preferred E-isomer in the course of the C–H amination at the stage of the allyl radical intermediate. However, the radical is apparently short-lived so that no complete isomerization can occur. As expected, the Z:E-ratio is temperature dependent with a higher Z:E-ratio at lower temperature (5.1:1 at 4°C) and a lower Z:E-ratio at higher temperature (2.9:1 at 40°C). Finally, a radical mechanism is also supported by the ring-closing C–H amination of the chiral non-racemic substrate (S)-1c (89% ee) to provide (R)-2c under retention of configuration for both catalyst enantiomers (Figure 3C). However, although the Δ-catalyst provides (R)-2c with only slightly decreased enantioselectivity (85% ee), the mismatched Λ-catalyst leads to a strong erosion of the enantiomeric excess of (R)-2c (40% ee). This decrease in enantiomeric excess is not consistent with a concerted C–H insertion mechanism but rather indicates a radical pathway in which the Δ-catalyst matches the S-configuration of the chiral substrate whereas the Λ-catalyst constitutes a mismatch, thus resulting in a slower radical recombination and subsequent partial racemization. To explore the scope of this new method, we applied the reaction conditions to a variety of N-benzoyloxyurea as shown in Figure 4. Benzylic C(sp3)–H aminations to chiral 2-imidazolidinones occurred with high yields and high enantioselectivities. For example, a para-, meta-, and even a sterically very hindering ortho-methyl group in the phenyl moiety are well tolerated (products 2d–2f, 92%–99% yield, 95%–97% ee), as well as an electron-withdrawing fluorine (2g) and chlorine substituent (2h, for crystallographic data see Table S2; Figure S34, CCDC number 1972573), and an electron-donating methoxy group (2i). A 1-naphthyl group provided the cyclic urea 2j with 99% yield and 99% ee, whereas a 2-naphthyl group afforded the cyclic urea 2k with 97% yield and 90% ee. The smaller 2-thiophene moiety provided the cyclic urea 2l with 99% yield but a somewhat reduced 88% ee. We obtained 2-Imidazolidinone 2m with stereocenters in the 4- and 5-position in sluggish 29% yield but 89% ee by desymmetrization of an indane substrate by using the ruthenium catalyst Λ-Ru4 instead of Λ-Ru5. However, the desymmetrization of a N-benzoyloxyurea derived from 1,3-diphenyl-2-propanamine provided the 4,5-difunctionalized 2-imidazolidinones 2n with two adjacent stereocenters as a single diastereomer in 93% yield with 94% ee (see Table S3; Figures S35–S38 for the assignment of the relative configuration by NMR). Besides C(sp3)–H aminations at benzylic and allylic positions (see Figure 3B), ring-closing C(sp3)–H amination is also possible at a propargylic position in 89% yield and with 87% ee (2o). However, methylene groups without any adjacent activation group do not provide significant amounts of cyclization product (see Supplemental Information for more details). The substrate was completely consumed but did not provide any significant amount of useful product (e.g., 6-membered ring-close urea and nitrene reduction side-product). The ring-closing C(sp3)–H amination to 2-imidazolidinones tolerates different N-alkyl substituents as shown in Figure 5. Ethyl, n-butyl, isobutyl, and phenethyl substituents are well tolerated providing the corresponding N-alkylated 2-imidazolidinones 2p–2s in 68%–99% yield and with 92%–95% ee. However, a benzyl substituents results in reduced yields of 37% yield for 2t (93% ee). Importantly, the ring-closing C(sp3)–H amination is applicable to non-alkylated substrates as demonstrated with the product 2u containing two N–H groups which was afforded in 91% yield and 91% ee. It is worth noting that a substrate bearing a N-phenyl substituent (1v) only provided the corresponding C(sp2)–H amination product (2v), which is not desired in this context but by itself a useful transformation. Chiral 2-imidazolidinones are highly valuable building blocks for the synthesis of bioactive compounds, such as medicinal agents and natural products. For example, (S)-4-phenyl-2-imidazolidinone [(S)-2u] can be obtained from the N-benzoyloxyurea 1u and just 0.2 mol % Λ-Ru5 in a yield of 74% with almost perfect enantioselectivity of 99.6% ee after a single recrystallization step (Figure 6A). According to reported procedures, this enantiomerically pure 2-imidazolidinone (S)-2u can be converted to the drug levamisole42Amery W.K.P. Bruynseels J.P.J.M. Levamisole, the story and the lessons.Int. J. Immunopharmacol. 1992; 14: 481-486Crossref PubMed Scopus (66) Google Scholar by first thiation of the urea with Lawesson’s reagent43Sharma V.K. Lee K.-C. Joo C. Sharma N. Jung S.-H. Importance of imidazolidinone motif in 4-phenyl-N-arylsulfonylimidazolidinone for their anticancer activity.Bull. Korean Chem. Soc. 2011; 32: 3009-3016Crossref Scopus (4) Google Scholar followed by cycloalkylation with 1,2-dibromoethane.44Raeymaekers A.H.M. Roevens L.F.C. Janssen P.A.J. The absolute configurations of the optical isomers of the broad spectrum anthelmintic tetramisole.Tetrahedron Lett. 1967; 16: 1467-1470Crossref PubMed Scopus (34) Google Scholar,45Röben C. Souto J.A. González Y. Lishchynskyi A. Muñiz K. Enantioselective metal-free diamination of styrenes.Angew. Chem. Int. Ed. 2011; 50: 9478-9482Crossref PubMed Scopus (226) Google Scholar Analogously, the drug dexamisole, which is the enantiomer of levamisole,46Keszei S. Simándi B. Székely E. Fogassy E. János Sawinsky S. Kemény S. Supercritical fluid extraction: a novel method for the resolution of tetramisole.Tetrahedron: Asymmetry. 1999; 10: 1275-1281Crossref Scopus (29) Google Scholar can be synthesized from (R)-2u, which we obtained from 1u by using Δ-Ru5 instead of Λ-Ru5.47Birman V.B. Li X. Benzotetramisole: a remarkably enantioselective acyl transfer catalyst.Org. Lett. 2006; 8: 1351-1354Crossref PubMed Scopus (281) Google Scholar, 48Abbasov M.E. Alvariño R. Chaheine C.M. Alonso E. Sánchez J.A. Conner M.L. Alfonso A. Jaspars M. Botana L.M. Romo D. Simplified immunosuppressive and neuroprotective agents based on gracilin A.Nat. Chem. 2019; 11: 342-350Crossref PubMed Scopus (17) Google Scholar, 49Schuppe A.W. Zhao Y. Liu Y. Newhouse T.R. Total synthesis of (+)-granatumine A and related bislactone limonoid alkaloids via a pyran to pyridine interconversion.J. Am. Chem. Soc. 2019; 141: 9191-9196Crossref PubMed Scopus (18) Google Scholar A second example provides a concise route to the bisindole alkaloids topsentine D and spongotine A (Figure 6B). Accordingly, ring-closing C(sp3)–H amination of the indole-containing substrates 1w and 1x provided, under standard conditions, the 4-indolyl-2-imidazolidinones 2w and 2x, respectively, in high yields and with high ee. These 2-imidazolidinones can be hydrolyzed with concentrated HCl in AcOH at 85°C under microwave conditions50Vasanthakumar G.R. Bhor V.M. Surolia A. Hydrolysis of cyclic ureas under microwave irradiation: synthesis and characterization of 7,8-diaminopelargonic acid.Synth. Commun. 2007; 37: 2633-2639Crossref Scopus (9) Google Scholar for 10 min to the respective vicinal diamines 3a and 3b with almost unchanged enantiomeric excess and constitute intermediates of the natural products topsentine D51Ji X. Wang Z. Dong J. Liu Y. Lu A. Wang Q. Discovery of topsentin alkaloids and their derivatives as novel antiviral and anti-phytopathogenic fungus agents.J. Agric. Food Chem. 2016; 64: 9143-9151Crossref PubMed Scopus (23) Google Scholar and spongotine A,52Murai K. Morishita M. Nakatani R. Kubo O. Fujioka H. Kita Y. Concise total synthesis of (−)-spongotine A.J. Org. Chem. 2007; 72: 8947-8949Crossref PubMed Scopus (32) Google Scholar respectively. A third example provides access to the mono-N-methylated 1,2-diamine 3c, which was reported as an intermediate for the synthesis of a chiral organocatalyst (Figure 6C).53Sheshenev A.E. Boltukhina E.V. White A.J.P. Hii K.K.M. Methylene-bridged bis(imidazoline)-derived 2-oxopyrimidinium salts as catalysts for asymmetric Michael reactions.Angew. Chem. Int. Ed. 2013; 52: 6988-6991Crossref PubMed Scopus (38) Google Scholar Our method, introduced here, to access chiral vicinal diamines complements a catalytic, enantioselective syn-diamination of alkenes to 1,3-ditosylimidazolidin-2-ones recently reported by Denmark54Tao Z. Gilbert B.B. Denmark S.E. Catalytic, enantioselective syn-diamination of alkenes.J. Am. Chem. Soc. 2019; 141: 19161-19170Crossref PubMed Scopus (28) Google Scholar and related work by Muñiz,55Muñiz K. Barreiro L. Romero R.M. Martínez C. Catalytic Asymmetric diamination of styrenes.J. Am. Chem. Soc. 2017; 139: 4354-4357Crossref PubMed Scopus (127) Google Scholar,56Muñiz K. Promoting intermolecular C–N bond formation under the auspices of iodine(III).Acc. Chem. Res. 2018; 51: 1507-1519Crossref PubMed Scopus (69) Google Scholar but which all require the use of sulfonyl protection groups. Furthermore, Arnold recently reported an enzymatic C(sp3)–H amination platform for the enantioselective synthesis of cyclic sulfamides as building blocks for diverse chiral 1,2- and 1,3-diamines.14Yang Y. Cho I. Qi X. Liu P. Arnold F.H. An enzymatic platform for the asymmetric amination of primary, secondary and tertiary C(sp3)-H bonds.Nat. Chem. 2019; 11: 987-993Crossref PubMed Scopus (54) Google Scholar Although the described method is very powerful, diamines with two primary amines are apparently not accessible, and therefore, Arnold’s enzymatic method through sulfamides is not suitable for the applications shown in Figure 6. To conclude, here, we reported the first example of a ring-closing C(sp3)–H amination of urea substrates to chiral 2-imidazolidinones in a catalytic enantioselective fashion. Starting from abundant primary or secondary amines, N-benzoyloxyurea can be synthesized in just two steps and enantioselectively cyclized to cyclic urea under mild reaction conditions and by using low loadings of a chiral-at-metal ruthenium catalyst. We anticipate that this method will be of significant synthetic interest because the furnished chiral 2-imidazolidinones and their corresponding chiral 1,2-diamines, obtained through efficient hydrolysis with HCl, are highly valuable chiral building blocks. Further information and requests for resources and reagents should be directed to and will be fulfilled by the Lead Contact, Eric Meggers ( [email protected] ). Unique and stable reagents generated in this study will be made available on request, but we might require a payment and/or a completed materials transfer agreement if there is potential for commercial application. The crystal structure data of compound (S)-2h has been deposited in the Cambridge structural database under reference number 1972573. A dry Schlenk tube (10 mL) was charged with substrate 1aa (59.6 mg, 0.2 mmol), chiral ruthenium catalyst Ru5 (0.002 mmol, 1.0 mol %), and K2CO3 (82.8 mg, 0.6 mmol) under an atmosphere of N2. Freshly distilled dichloromethane (2.0 mL) was added via syringe. The reaction mixture was stirred at ambient temperature for 16 h under an atmosphere of N2. Thereafter, the mixture was transferred to a column and purified by flash chromatography on silica gel (EtOAc:n-hexane = 2:1 to EtOAc:MeOH 95:5) to afford the analytical pure product (S)-2a (34.9 mg, 99% yield) as a white solid. An enantiomeric excess of 95% ee was determined by high performance liquid chromatography (HPLC) analysis on a chiral stationary phase (column: Daicel Chiralpak IA 250 × 4.6 mm, absorption: λ = 220 nm, mobile phase: n-hexane:isopropanol = 90:10, flow rate: 1.0 mL/min, column temperature: 30°C, retention times: tr (major) = 13.2 min, tr (minor) = 11.4 min). E.M. is grateful for funding from the Deutsche Forschungsgemeinschaft , Germany ( ME 1805/15-1 ). M.K. is grateful for funding from the JSPS Program for Fostering Globally Talented Researchers, Japan. E.M. and M.K. coordinated the project; E.M. and Z.Z. wrote the manuscript with the help of all co-authors; E.M. and Z.Z. conceived the project and designed the majority of the experiments; Z.Z. carried out the majority of the experiments; Y.T., T.Y., and M.H. contributed to the catalyst synthesis and synthesized some substrates; X.X. assigned the relative configuration of product 2n by NMR experiments; S.I. and R.R. collected the crystallographic data and solved and refined the X-ray crystal structure of 2h. The authors declare no competing interests. Download .pdf (9.73 MB) Help with pdf files Document S1. Supplemental Experimental Procedures, Figures S1–S95, Tables S1–S3, Schemes S1–S8, and Supplemental References It is worth noting that other chiral-at-metal catalysts developed in our laboratory, IrS, RhS, or rNHCRu, do not catalyze this reaction under the reaction conditions shown in Table 1." @default.
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• W3036745971 title "Enantioselective Ring-Closing C–H Amination of Urea Derivatives" @default.
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