Communication pubs.acs.org/JACS
Asymmetric Nitrone Synthesis via Ligand-Enabled Copper-Catalyzed Cope-Type Hydroamination of Cyclopropene with Oxime Zhanyu Li, Jinbo Zhao,* Baozhen Sun, Tingting Zhou, Mingzhu Liu, Shuang Liu, Mengru Zhang, and Qian Zhang* Jilin Province Key Laboratory of Functional Organic Molecule Design & Synthesis, Department of Chemistry, Northeast Normal University, Changchun, Jilin 130024, China S Supporting Information *
most straightforward approach for the formation of N-alkyl nitrone, also offers the advantage of being amenable to asymmetric catalysis. However, such a process remains undefined so far (Scheme 1, iv). Cope-type hydroamination, a distinct subtype of hydroamination,16 has recently garnered much synthetic interest.17−24 However, since the seminal reports by Bishop25 and Grigg26 with their respective co-workers on the intramolecular thermal annulation of oxime with pendant olefin (Scheme 2, i), the
ABSTRACT: We report realization of the first enantioselective Cope-type hydroamination of oximes for asymmetric nitrone synthesis. The ligand promoted asymmetric cyclopropene “hydronitronylation” process employs a Cu-based catalytic system and readily available starting materials, operates under mild conditions and displays broad scope and exceptionally high enantio- and diastereocontrol. Preliminary mechanistic studies corroborate a CuI-catalytic profile featuring an olefin metallaretro-Cope aminocupration process as the key C−N bond forming event. This conceptually novel reactivity enables the first example of highly enantioselective catalytic nitrone formation process and will likely spur further developments that may significantly expedite chiral nitrone synthesis.
Scheme 2. Cope-Type Hydroamination of Oxime for the Synthesis of Nitrones
A
s a highly versatile linchpin in synthetic chemistry,1,2 nitrone has found widespread applications in 1,3-dipolar cycloaddition for heterocycle and natural product synthesis.3 Its multifaceted applications as spin trapping agents,4 bioorthogonal probes5 and efficacious therapeutic agents6 also render nitrone a heavily pursued synthetic target. Chiral nitrones also serve as important building blocks in asymmetric synthesis.7 In stark contrast to their versatile reactivity and prominent roles, routinely employed methods to synthesize nitrones still rely heavily on traditional strategies8−12 (Scheme 1, i−iii). Although
synthetic potential of the oxime version of Cope-type amination remains essentially untapped. Although a substoichiometric inorganic base was recently found to facilitate the process in favor of forging five-membered ring closure,27 lacking of a facile intermolecular process and an efficacious catalytic strategy amenable to stereochemical control pose significant challenges for this otherwise powerful nitrone formation process. On the basis of our long-standing interest in development of efficient C−N bond construction strategies,28 we envisioned a transitionmetal-catalyzed two-step process to address these challenges, wherein a transition-metal capable of ligating both oxime and olefin could first promote a retro-Cope aminometalation to afford cyclometalated species (the putative “metalla-retro-Cope” intermediate). Protonation of this intermediate then regenerates the catalyst and releases the formal olefin “hydronitronylation” product (Scheme 2, ii). Herein we present studies that validate
Scheme 1. Nitrone Formation Strategies
alternative strategies are emerging at an increasing rate in the past decade,13 none holds the prospect of enantiocontrol. The great majority of extant methods to access chiral nitrones rely on stoichiometric reaction of chiral precursors typically of natural origins,14,15 which significantly thwarted the application of chiral nitrones in organic chemistry and related fields. Coupling readily available oxime and electron-neutral olefin, an appealing and the © 2017 American Chemical Society
Received: June 29, 2017 Published: August 7, 2017 11702
DOI: 10.1021/jacs.7b06523 J. Am. Chem. Soc. 2017, 139, 11702−11705
Communication
Journal of the American Chemical Society Table 1. Scope of Cyclopropenea
the hypothesis, i.e., by identification of an earth-abundant CuIbased catalytic system, we realized an intermolecular desymmetritive “hydronitronylation” of cyclopropene under exceptionally mild conditions (Scheme 3). This unprecedented example of Scheme 3. Cu-Catalyzed Intermolecular Cope-Type Hydroamination of Cyclopropene
asymmetric Cope-type hydroamination with oximes displays several remarkable features, including starting material availability, ligand enabled base-metal catalysis, broad substrate scope, as well as remarkably high enantio- and diastereocontrol. To our knowledge, this process also constitutes the first example of a highly enantioselective nitrone formation process. Additionally, the role of nitrone as masked amine renders the process a potential route to cyclopropyl amine, an important pharmocophore. Direct cyclopropene hydroamination without ring-opening is challenging and has just been realized very lately with rare-earth metal catalysts.29 The initial scouting reaction was performed by reacting 3phenyl-3-methyl cyclopropene 1a with benzophenone oxime 2a using CuCl/dppbz as catalyst in the presence of a base at room temperature. We envisioned that a substoichiometric amount of base might suffice to initiate the process due to the basicity of the putative Cu(I) intermediates to regenerate the reactive species. Indeed, with only 30 mol % NaOt-Bu, the desired product 3a was isolated in 92% yield with full conversion being reached within 40 min in toluene at room temperature (Scheme 3, i). The control experiment without ligand resulted in no productive conversion, indicating of dramatic ligand-enabled reactivity (for detailed optimization, see Table S1 in the Supporting Information). This observation prompted us to evaluate the effect of stereochemical induction with chiral ligands. After a brief screening of commercially available ligands, solvents and temperature, we found the reaction with (R)DTBMSegPhos L6 delivered 3a in 95% yield and 92% ee in THF at −50 °C within 3 h. Remarkably, under all conditions the product was obtained as the exclusive diastereoisomer, suggesting of a very high diastereoselectivity control. The reaction also demonstrated good tolerance of air and moisture, as the reaction performed with minimal precautions (performed under air, without drying glassware, in wet solvents) still afforded product 3a in a good yield without erosion of enantioselection (75%, 92% ee). The reaction is also easily scaled up to 2 mmol, producing 3a in 98% yield with the same enantioselectivity (Scheme 3, iii). An evaluation of the generality of the reaction by variation of cyclopropenes with the optimized conditions (Table 1) demonstrates the robustness of the current hydronitronylation protocol. The great majority of examined 3-aryl-3-alkyl, 3,3diaryl, or 3,3-dialkyl cyclopropenes uneventfully produced the “hydronitronylation” products in high yields with excellent enantioselectivities. The reactivity and enantioselectivity is generally insensitive to electronic poperties of the aryl
a
Conditions: cyclopropene (0.20 mmol), oxime (1.2 equiv), CuCl (5 mol %), L6 (6 mol %) and NaOt-Bu (30 mol %) in THF (0.1 M).
substituents (3a−k). A slight decrease of enantioselectivities was observed for the sterically encumbered analogues (3l and 3m). Single crystal X-ray diffraction studies of 3n allowed for unequivocal determination of its structure and absolute configuration (Figure S8). Those of the other products are assigned by analogy. Improved enantioselectivities were observed with cyclopropenes bearing 3-alkyl substituents beyond methyl (3o). The reaction of more bulky i-Prsubstituted cyclopropene, however, turned out sluggish. 3p was isolated in a mere 5% yield with NHC ligand L10, with a reversed facial selectivity (Figures S1−S3), suggesting that diastereocontrol originates from steric differentiation. Substrates bearing meta-substituted 3-aryl and spirocyclic skeleton all delivered the corresponding nitrone products in high yields and enantioselectivities (3i−k, 3r). 3,3-Diaryl cyclopropane delivered the corresponding nitrone with a slightly reduced enantioselection control at room temperature (3q). Notably, unsymmetrical 3,3-dialkyl substituted nitrone 3s was obtained in a diatereomeric ratio of 4/1 under the racemic reaction conditions with dppbz as ligand. With the chiral ligand L6, however, the diastereomeric ratio was improved to 18.6/1, with the major diastereomer being formed in 96% ee (Figure S4). These results demonstrate that ligand exerts a decisive role in both enantio- and diastereocontrol and overrides the substrate control. We then turned to evaluate the scope with respect to oximes (Table 2). Oximes derived from substituted benzophenone afforded the products uneventfully in high yields and enantiocontrol (3t−3w). For Aryl alkyl ketone derived oximes, the employment of more electron-rich ligand was necessary, and MeO-BIPHEP derivative L7 as ligand achieved high efficiency and excellent selectivity. Notably, for these substrates Eproducts were formed as the predominant isomer (exemplified by the crystal structure of 3x′ in Figure S9) in high yields with good to high E/Z ratios (varying from E/Z = 5/1 to exclusive E).30 Reactions of propiophenone derived oximes bearing a variety of electronically distinct substituents afforded the corresponding hydronitronylation products with high yields and enantioselectivities (3x−3ze, 59−99% yields, 95−98% 11703
DOI: 10.1021/jacs.7b06523 J. Am. Chem. Soc. 2017, 139, 11702−11705
Communication
Journal of the American Chemical Society Table 2. Scope of Oximesa
rapidly hydrolyzes to oxime prior to coupling with cyclopropene. Furthermore, when MeOD was used as exogenous proton source in the reaction of oxime ester, product 3a-d was obtained in 93% yield with 71% deuterium incorporation, indicating of the intermediacy of cyclopropyl copper species (Scheme 4). The syn relationship of D (Ha) with Me in 3a-d was Scheme 4. Deuterium Labeling Experiment
assigned unequivocally by 2D NOESY studies of 3a combined with the isotope labeling experiment. Taken together, these observations corroborate a CuI-based catalytic profile featuring a putative inner-sphere cis aminocupration process (Figure 1).
Figure 1. Plausible CuI-based mechanistic profile.
a
Conditions: cyclopropene (0.20 mmol), oxime (1.2 equiv), CuCl (5 mol %), L (5 mol %) and NaOt-Bu (30 mol %) in toluene (0.1 M).
Similar to the hypothesis outlined above (Scheme 2, ii), it is proposed that the oxime ligated Cu(I) species engages cyclopropene to form π-complex C, which undergoes migratory insertion to generate the key cyclopropyl copper D (the metallaretro-Cope intermediate). We propose that this process proceeds via a five-membered metalla-retro-Cope transition state to forge the key C−N formation (TS, Figure 1).35 Protonation D with oxime 1a (path a) or t-BuOH (path b) releases the product 3a and regenerate the copper intermediates B (path a) or L*CuOt-Bu M (path b). In path b, M might be protonated by oxime to regenerate oxime-ligated copper intermediates B to close the catalytic loop. We have presented the first example of an intermolecular Cope-type hydroamination process of oximes using catalytic earth-abundant copper salts with the promotion of chiral ligands, allowing for a practical, straightforward access to valuable chiral nitrones in high enantio- and diastereoselectivities from readily available starting materials. The CuI-catalyzed process demonstrated broad scope and remarkable liganddirected stererocontrol, representing the first example of highly enantioselective nitrone formation process. Further developments of the conceptually novel reactivity mode are expected to significantly expedite chiral nitrone synthesis.
ee).31 Substrates bearing electron-rich heteroaryl (3zg) and various alkyls of different chain length and sterical requirements (3zh−3zm) also had negligible effect on reactivity or selectivity. Overall, the current hydronitronylation strategy demonstrated remarkably wide scope, granting efficient access to ketonitrones otherwise difficult to obtain from condensation of ketone with hydroxyamines.32 Furthermore, the reaction works equally well with aldoximes, affording a series of Z-products (see the crystal sturcutre of 4f in Figure S10) in high selectivities. The efficiency and selectivities are unanimously high across a diverse range of aldoximes bearing electronically distinct functional groups at 4and 3- positions of the phenyl group (4a−4j, 89−99%, 80− >99.9% ee). Again, sterically encumbered 1-naphthyl as well as pyridyl aldoximes worked equally efficiently with respect to both efficiency and selectivity (4l−4n). The high reactivity of the latter is remarkable considering usually strong catalyst poisoning caused by ligation of pyridine to metal center. To gain some mechanistic insights of the current transformation, we performed some preliminary mechanistic studies. Addition of radical inhibitor 2,6-di-tert-butyl-4-methyl-phenol (BHT) to the optimized conditions imparted negligible impact on the reaction efficiency (isolated yield: 79%), whereas the reaction performed under an atmosphere of O2 delivered the desired product 3a in a significantly lower yield of 15%. The insensitivity to radical inhibitors and susceptibility to oxygen suggest of a CuI-catalytic profile, rather than the most commonly invoked radical pathways involving single electron transfer (SET) between copper and oxime derivatives.33,34 A comparative study revealed that oxime and oxime acetate retrieved the same product in essentially identical yields and enantioselectivities (Table S3), suggesting that oxime ester
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ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/jacs.7b06523. Experimental procedures, analytical and spectral data (PDF) Crystal data for 3n (CIF) Crystal data for 3x′ (CIF) 11704
DOI: 10.1021/jacs.7b06523 J. Am. Chem. Soc. 2017, 139, 11702−11705
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Journal of the American Chemical Society
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Lett. 2014, 16, 4650−4653. (e) Fraboni, A. J.; Brenner-Moyer, S. E. Org. Lett. 2016, 18, 2146−2149. (f) Shi, W.-M.; Ma, X.-P.; Su, G.-F.; Mo, D.-L. Org. Chem. Front. 2016, 3, 116−130. (14) Schleiss, J.; Rollin, P.; Tatibouët, A. Angew. Chem., Int. Ed. 2010, 49, 577−580. (15) For selected recent examples of preparation of chiral nitrones for application in natural product synthesis, see: (a) Patel, S. K.; Murat, K.; Py, S.; Vallée, Y. Org. Lett. 2003, 5, 4081−4084. (b) Tamura, O.; Iyama, N.; Ishibashi, H. J. Org. Chem. 2004, 69, 1475−1480. (c) SánchezIzquierdo, F.; Blanco, P.; Busqué, F.; Alibés, R.; de March, P.; Figueredo, M.; Font, J.; Parella, T. Org. Lett. 2007, 9, 1769−1772. (d) Shibue, T.; Hirai, T.; Okamoto, I.; Morita, N.; Masu, H.; Azumaya, I.; Tamura, O. Chem. - Eur. J. 2010, 16, 11678−11688. (16) (a) For a recent comprehensive review, see: Organic Reactions, Denmark, S. E., Ed.; John Wiley & Sons: Hoboken, NJ, 2016, Vol. 88. (b) For an excellent representative example, see: Yu, F.; Chen, P.; Liu, G. Org. Chem. Front. 2015, 2, 819−822. (17) Beauchemin, A. M. Org. Biomol. Chem. 2013, 11, 7039−7050. (18) Krenske, E. H.; Davison, E. C.; Forbes, I. T.; Warner, J. A.; Smith, A. L.; Holmes, A. B.; Houk, K. N. J. Am. Chem. Soc. 2012, 134, 2434− 2441. (19) Moran, J.; Gorelsky, S. I.; Dimitrijevic, E.; Lebrun, M.-E.; Bédard, A.-C.; Séguin, C.; Beauchemin, A. M. J. Am. Chem. Soc. 2008, 130, 17893−17906. (20) Beauchemin, A. M.; Moran, J.; Lebrun, M.-E.; Séguin, C.; Dimitrijevic, E.; Zhang, L.; Gorelsky, S. I. Angew. Chem., Int. Ed. 2008, 47, 1410−1413. (21) Roveda, J.-G. g.; Clavette, C.; Hunt, A. D.; Gorelsky, S. I.; Whipp, C. J.; Beauchemin, A. M. J. Am. Chem. Soc. 2009, 131, 8740−8741. (22) Brown, A. R.; Uyeda, C.; Brotherton, C. A.; Jacobsen, E. N. J. Am. Chem. Soc. 2013, 135, 6747−6749. (23) MacDonald, M. J.; Schipper, D. J.; Ng, P. J.; Moran, J.; Beauchemin, A. M. J. Am. Chem. Soc. 2011, 133, 20100−20103. (24) Guimond, N.; MacDonald, M. J.; Lemieux, V.; Beauchemin, A. M. J. Am. Chem. Soc. 2012, 134, 16571−16577. (25) Bishop, R.; Brooks, P. R.; Hawkins, S. C. Synthesis 1988, 1988, 997−999. (26) Grigg, R.; Markandu, J.; Perrior, T.; Surendrakumar, S.; Warnock, W. J. Tetrahedron Lett. 1990, 31, 559−562. (27) Peng, X.; Tong, B. M. K.; Hirao, H.; Chiba, S. Angew. Chem., Int. Ed. 2014, 53, 1959−1962. (28) (a) Sun, K.; Li, Y.; Xiong, T.; Zhang, J.; Zhang, Q. J. Am. Chem. Soc. 2011, 133, 1694−1697. (b) Ni, Z.; Zhang, Q.; Xiong, T.; Zheng, Y.; Li, Y.; Zhang, H.; Zhang, J.; Liu, Q. Angew. Chem., Int. Ed. 2012, 51, 1244−1247. (c) Zhang, H.; Pu, W.; Xiong, T.; Zhou, X.; Sun, K.; Liu, Q.; Zhang, Q.; Li, Y. Angew. Chem., Int. Ed. 2013, 52, 2529−2533. (d) Zhang, H.; Song, Y.; Zhao, J.; Zhang, J.; Zhang, Q. Angew. Chem., Int. Ed. 2014, 53, 11079−11083. (e) Zheng, G.; Li, Y.; Han, J.; Xiong, T.; Zhang, Q. Nat. Commun. 2015, 6, 7011. (f) Zhang, G.; Xiong, T.; Wang, Z.; Xu, G.; Wang, X.; Zhang, Q. Angew. Chem., Int. Ed. 2015, 54, 12649−12653. (29) Teng, H.-L.; Luo, Y.; Wang, B.; Zhang, L.; Nishiura, M.; Hou, Z. Angew. Chem., Int. Ed. 2016, 55, 15406−15410. (30) See the compound characterization in SI for detailed E/Z ratio for each compound. (31) The moderate yield of 3zd was due to its mediocre stability upon isolation. (32) Huple, D. B.; Mokar, B. D.; Liu, R.-S. Angew. Chem., Int. Ed. 2015, 54, 14924−14928. (33) Liu, R.-H.; Wei, D.; Han, B.; Yu, W. ACS Catal. 2016, 6, 6525− 6530. (34) Huang, H.; Ji, X.; Wu, W.; Jiang, H. Chem. Soc. Rev. 2015, 44, 1155−1171. (35) For a stoichiometric intramolecular metalloamination with hydrazinoalkene, see: Sunsdahl, B.; Smith, A. R.; Livinghouse, T. Angew. Chem., Int. Ed. 2014, 53, 14352−14356.
Crystal data for 4f (CIF)
AUTHOR INFORMATION
Corresponding Authors
*[email protected] *[email protected] ORCID
Jinbo Zhao: 0000-0002-5261-7366 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS Financial support from NNSFC (21402025, 21372041), the Fundamental Research Funds for the Central Universities (2412017FZ014), and Changbai Mountain Scholarship Program are gratefully acknowledged.
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REFERENCES
(1) Grigorév, I. A. In Nitrile Oxides, Nitrones, and Nitronates in Organic Synthesis: Novel Strategies in Synthesis, 2nd ed.; Feuer, H., Ed.; John Wiley & Sons: Hoboken, NJ, 2008; pp 129−434. (2) Anderson, L. L. Asian J. Org. Chem. 2016, 5, 9−30. (3) For representative reviews, see: (a) Gothelf, K. V.; Jørgensen, K. A. Chem. Rev. 1998, 98, 863−909. (b) Nair, V.; Suja, T. D. Tetrahedron 2007, 63, 12247−12275. (c) Pellissier, H. Tetrahedron 2007, 63, 3235− 3285. (d) Stanley, L. M.; Sibi, M. P. Chem. Rev. 2008, 108, 2887−2902. (e) Hashimoto, T.; Maruoka, K. Chem. Rev. 2015, 115, 5366−5412. (4) Mason, R. P. Redox Biol. 2016, 8, 422−429. (5) MacKenzie, D. A.; Sherratt, A. R.; Chigrinova, M.; Cheung, L. L.; Pezacki, J. P. Curr. Opin. Chem. Biol. 2014, 21, 81−88. (6) (a) Floyd, R. A.; Kopke, R. D.; Choi, C. H.; Foster, S. B.; Doblas, S.; Towner, R. A. Free Radical Biol. Med. 2008, 45, 1361−1374. (b) Villamena, F. A.; Das, A.; Nash, K. M. Future Med. Chem. 2012, 4, 1171−1207. (c) Floyd, R. A.; Castro Faria Neto, H. C.; Zimmerman, G. A.; Hensley, K.; Towner, R. A. Free Radical Biol. Med. 2013, 62, 145− 156. (7) (a) Merino, P.; Franco, S.; Merchan, F. L.; Tejero, T. Synlett 2000, 2000, 442−454. (b) Brandi, A.; Revuelta, J.; Cicchi, S.; Goti, A. Synthesis 2007, 2007, 485−504. (8) For a comprehensive review on nitrone synthesis, see: Merino, P., in Science of Synthesis; Padwa, A., Ed.; Georg Thieme Verlag KG: Germany, 2004, Vol. 27, pp 511−580. (9) Oxidation of hydroxyamine: (a) Goti, A.; Cicchi, S.; Fedi, V.; Nannelli, L.; Brandi, A. J. Org. Chem. 1997, 62, 3119−3125. (b) Matassini, C.; Parmeggiani, C.; Cardona, F.; Goti, A. Org. Lett. 2015, 17, 4082−4085. (10) Oxidation of imine: (a) Christensen, D.; Jørgensen, K. A. J. Org. Chem. 1989, 54, 126−131. (b) Soldaini, G.; Cardona, F.; Goti, A. Org. Lett. 2007, 9, 473−476. (11) Oxidation of amine: (a) Murahashi, S.-I. Angew. Chem., Int. Ed. Engl. 1995, 34, 2443−2465. (b) Murahashi, S.-I.; Mitsui, H.; Shiota, T.; Tsuda, T.; Watanabe, S. J. Org. Chem. 1990, 55, 1736−1744. (c) Zonta, C.; Cazzola, E.; Mba, M.; Licini, G. Adv. Synth. Catal. 2008, 350, 2503− 2506. (12) N-alkylation: (a) Ma, X. P.; Shi, W. M.; Mo, X. L.; Li, X. H.; Li, L. G.; Pan, C. X.; Chen, B.; Su, G. F.; Mo, D. L. J. Org. Chem. 2015, 80, 10098−10107. (b) Smith, P. A. S.; Robertson, J. E. J. Am. Chem. Soc. 1962, 84, 1197−1204. (c) Buehler, E. J. Org. Chem. 1967, 32, 261−265. (d) Armstrong, P.; Grigg, R.; Heaney, F.; Surendrakumar, S.; Warnock, W. J. Tetrahedron 1991, 47, 4495−4518. (e) Nakama, K.; Seki, S.; Kanemasa, S. Tetrahedron Lett. 2002, 43, 829−832. (13) (a) Mo, D.-L.; Wink, D. A.; Anderson, L. L. Org. Lett. 2012, 14, 5180−5183. (b) Nakamura, I.; Okamoto, M.; Sato, Y.; Terada, M. Angew. Chem., Int. Ed. 2012, 51, 10816−10819. (c) Chavannavar, A. P.; Oliver, A. G.; Ashfeld, B. L. Chem. Commun. 2014, 50, 10853−10856. (d) Peng, X. X.; Deng, Y. J.; Yang, X. L.; Zhang, L.; Yu, W.; Han, B. Org. 11705
DOI: 10.1021/jacs.7b06523 J. Am. Chem. Soc. 2017, 139, 11702−11705
Asymmetric Nitrone Synthesis via Ligand-Enabled Copper-Catalyzed Cope-Type Hydroamination of Cyclopropene with Oxime Zhanyu Li, Jinbo Zhao,* Baozhen Sun, Tingting Zhou, Mingzhu Liu, Shuang Liu, Mengru Zhang, and Qian Zhang* Jilin Province Key Laboratory of Functional Organic Molecule Design & Synthesis, Department of Chemistry, Northeast Normal University, Changchun, Jilin 130024, China S Supporting Information *
most straightforward approach for the formation of N-alkyl nitrone, also offers the advantage of being amenable to asymmetric catalysis. However, such a process remains undefined so far (Scheme 1, iv). Cope-type hydroamination, a distinct subtype of hydroamination,16 has recently garnered much synthetic interest.17−24 However, since the seminal reports by Bishop25 and Grigg26 with their respective co-workers on the intramolecular thermal annulation of oxime with pendant olefin (Scheme 2, i), the
ABSTRACT: We report realization of the first enantioselective Cope-type hydroamination of oximes for asymmetric nitrone synthesis. The ligand promoted asymmetric cyclopropene “hydronitronylation” process employs a Cu-based catalytic system and readily available starting materials, operates under mild conditions and displays broad scope and exceptionally high enantio- and diastereocontrol. Preliminary mechanistic studies corroborate a CuI-catalytic profile featuring an olefin metallaretro-Cope aminocupration process as the key C−N bond forming event. This conceptually novel reactivity enables the first example of highly enantioselective catalytic nitrone formation process and will likely spur further developments that may significantly expedite chiral nitrone synthesis.
Scheme 2. Cope-Type Hydroamination of Oxime for the Synthesis of Nitrones
A
s a highly versatile linchpin in synthetic chemistry,1,2 nitrone has found widespread applications in 1,3-dipolar cycloaddition for heterocycle and natural product synthesis.3 Its multifaceted applications as spin trapping agents,4 bioorthogonal probes5 and efficacious therapeutic agents6 also render nitrone a heavily pursued synthetic target. Chiral nitrones also serve as important building blocks in asymmetric synthesis.7 In stark contrast to their versatile reactivity and prominent roles, routinely employed methods to synthesize nitrones still rely heavily on traditional strategies8−12 (Scheme 1, i−iii). Although
synthetic potential of the oxime version of Cope-type amination remains essentially untapped. Although a substoichiometric inorganic base was recently found to facilitate the process in favor of forging five-membered ring closure,27 lacking of a facile intermolecular process and an efficacious catalytic strategy amenable to stereochemical control pose significant challenges for this otherwise powerful nitrone formation process. On the basis of our long-standing interest in development of efficient C−N bond construction strategies,28 we envisioned a transitionmetal-catalyzed two-step process to address these challenges, wherein a transition-metal capable of ligating both oxime and olefin could first promote a retro-Cope aminometalation to afford cyclometalated species (the putative “metalla-retro-Cope” intermediate). Protonation of this intermediate then regenerates the catalyst and releases the formal olefin “hydronitronylation” product (Scheme 2, ii). Herein we present studies that validate
Scheme 1. Nitrone Formation Strategies
alternative strategies are emerging at an increasing rate in the past decade,13 none holds the prospect of enantiocontrol. The great majority of extant methods to access chiral nitrones rely on stoichiometric reaction of chiral precursors typically of natural origins,14,15 which significantly thwarted the application of chiral nitrones in organic chemistry and related fields. Coupling readily available oxime and electron-neutral olefin, an appealing and the © 2017 American Chemical Society
Received: June 29, 2017 Published: August 7, 2017 11702
DOI: 10.1021/jacs.7b06523 J. Am. Chem. Soc. 2017, 139, 11702−11705
Communication
Journal of the American Chemical Society Table 1. Scope of Cyclopropenea
the hypothesis, i.e., by identification of an earth-abundant CuIbased catalytic system, we realized an intermolecular desymmetritive “hydronitronylation” of cyclopropene under exceptionally mild conditions (Scheme 3). This unprecedented example of Scheme 3. Cu-Catalyzed Intermolecular Cope-Type Hydroamination of Cyclopropene
asymmetric Cope-type hydroamination with oximes displays several remarkable features, including starting material availability, ligand enabled base-metal catalysis, broad substrate scope, as well as remarkably high enantio- and diastereocontrol. To our knowledge, this process also constitutes the first example of a highly enantioselective nitrone formation process. Additionally, the role of nitrone as masked amine renders the process a potential route to cyclopropyl amine, an important pharmocophore. Direct cyclopropene hydroamination without ring-opening is challenging and has just been realized very lately with rare-earth metal catalysts.29 The initial scouting reaction was performed by reacting 3phenyl-3-methyl cyclopropene 1a with benzophenone oxime 2a using CuCl/dppbz as catalyst in the presence of a base at room temperature. We envisioned that a substoichiometric amount of base might suffice to initiate the process due to the basicity of the putative Cu(I) intermediates to regenerate the reactive species. Indeed, with only 30 mol % NaOt-Bu, the desired product 3a was isolated in 92% yield with full conversion being reached within 40 min in toluene at room temperature (Scheme 3, i). The control experiment without ligand resulted in no productive conversion, indicating of dramatic ligand-enabled reactivity (for detailed optimization, see Table S1 in the Supporting Information). This observation prompted us to evaluate the effect of stereochemical induction with chiral ligands. After a brief screening of commercially available ligands, solvents and temperature, we found the reaction with (R)DTBMSegPhos L6 delivered 3a in 95% yield and 92% ee in THF at −50 °C within 3 h. Remarkably, under all conditions the product was obtained as the exclusive diastereoisomer, suggesting of a very high diastereoselectivity control. The reaction also demonstrated good tolerance of air and moisture, as the reaction performed with minimal precautions (performed under air, without drying glassware, in wet solvents) still afforded product 3a in a good yield without erosion of enantioselection (75%, 92% ee). The reaction is also easily scaled up to 2 mmol, producing 3a in 98% yield with the same enantioselectivity (Scheme 3, iii). An evaluation of the generality of the reaction by variation of cyclopropenes with the optimized conditions (Table 1) demonstrates the robustness of the current hydronitronylation protocol. The great majority of examined 3-aryl-3-alkyl, 3,3diaryl, or 3,3-dialkyl cyclopropenes uneventfully produced the “hydronitronylation” products in high yields with excellent enantioselectivities. The reactivity and enantioselectivity is generally insensitive to electronic poperties of the aryl
a
Conditions: cyclopropene (0.20 mmol), oxime (1.2 equiv), CuCl (5 mol %), L6 (6 mol %) and NaOt-Bu (30 mol %) in THF (0.1 M).
substituents (3a−k). A slight decrease of enantioselectivities was observed for the sterically encumbered analogues (3l and 3m). Single crystal X-ray diffraction studies of 3n allowed for unequivocal determination of its structure and absolute configuration (Figure S8). Those of the other products are assigned by analogy. Improved enantioselectivities were observed with cyclopropenes bearing 3-alkyl substituents beyond methyl (3o). The reaction of more bulky i-Prsubstituted cyclopropene, however, turned out sluggish. 3p was isolated in a mere 5% yield with NHC ligand L10, with a reversed facial selectivity (Figures S1−S3), suggesting that diastereocontrol originates from steric differentiation. Substrates bearing meta-substituted 3-aryl and spirocyclic skeleton all delivered the corresponding nitrone products in high yields and enantioselectivities (3i−k, 3r). 3,3-Diaryl cyclopropane delivered the corresponding nitrone with a slightly reduced enantioselection control at room temperature (3q). Notably, unsymmetrical 3,3-dialkyl substituted nitrone 3s was obtained in a diatereomeric ratio of 4/1 under the racemic reaction conditions with dppbz as ligand. With the chiral ligand L6, however, the diastereomeric ratio was improved to 18.6/1, with the major diastereomer being formed in 96% ee (Figure S4). These results demonstrate that ligand exerts a decisive role in both enantio- and diastereocontrol and overrides the substrate control. We then turned to evaluate the scope with respect to oximes (Table 2). Oximes derived from substituted benzophenone afforded the products uneventfully in high yields and enantiocontrol (3t−3w). For Aryl alkyl ketone derived oximes, the employment of more electron-rich ligand was necessary, and MeO-BIPHEP derivative L7 as ligand achieved high efficiency and excellent selectivity. Notably, for these substrates Eproducts were formed as the predominant isomer (exemplified by the crystal structure of 3x′ in Figure S9) in high yields with good to high E/Z ratios (varying from E/Z = 5/1 to exclusive E).30 Reactions of propiophenone derived oximes bearing a variety of electronically distinct substituents afforded the corresponding hydronitronylation products with high yields and enantioselectivities (3x−3ze, 59−99% yields, 95−98% 11703
DOI: 10.1021/jacs.7b06523 J. Am. Chem. Soc. 2017, 139, 11702−11705
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Journal of the American Chemical Society Table 2. Scope of Oximesa
rapidly hydrolyzes to oxime prior to coupling with cyclopropene. Furthermore, when MeOD was used as exogenous proton source in the reaction of oxime ester, product 3a-d was obtained in 93% yield with 71% deuterium incorporation, indicating of the intermediacy of cyclopropyl copper species (Scheme 4). The syn relationship of D (Ha) with Me in 3a-d was Scheme 4. Deuterium Labeling Experiment
assigned unequivocally by 2D NOESY studies of 3a combined with the isotope labeling experiment. Taken together, these observations corroborate a CuI-based catalytic profile featuring a putative inner-sphere cis aminocupration process (Figure 1).
Figure 1. Plausible CuI-based mechanistic profile.
a
Conditions: cyclopropene (0.20 mmol), oxime (1.2 equiv), CuCl (5 mol %), L (5 mol %) and NaOt-Bu (30 mol %) in toluene (0.1 M).
Similar to the hypothesis outlined above (Scheme 2, ii), it is proposed that the oxime ligated Cu(I) species engages cyclopropene to form π-complex C, which undergoes migratory insertion to generate the key cyclopropyl copper D (the metallaretro-Cope intermediate). We propose that this process proceeds via a five-membered metalla-retro-Cope transition state to forge the key C−N formation (TS, Figure 1).35 Protonation D with oxime 1a (path a) or t-BuOH (path b) releases the product 3a and regenerate the copper intermediates B (path a) or L*CuOt-Bu M (path b). In path b, M might be protonated by oxime to regenerate oxime-ligated copper intermediates B to close the catalytic loop. We have presented the first example of an intermolecular Cope-type hydroamination process of oximes using catalytic earth-abundant copper salts with the promotion of chiral ligands, allowing for a practical, straightforward access to valuable chiral nitrones in high enantio- and diastereoselectivities from readily available starting materials. The CuI-catalyzed process demonstrated broad scope and remarkable liganddirected stererocontrol, representing the first example of highly enantioselective nitrone formation process. Further developments of the conceptually novel reactivity mode are expected to significantly expedite chiral nitrone synthesis.
ee).31 Substrates bearing electron-rich heteroaryl (3zg) and various alkyls of different chain length and sterical requirements (3zh−3zm) also had negligible effect on reactivity or selectivity. Overall, the current hydronitronylation strategy demonstrated remarkably wide scope, granting efficient access to ketonitrones otherwise difficult to obtain from condensation of ketone with hydroxyamines.32 Furthermore, the reaction works equally well with aldoximes, affording a series of Z-products (see the crystal sturcutre of 4f in Figure S10) in high selectivities. The efficiency and selectivities are unanimously high across a diverse range of aldoximes bearing electronically distinct functional groups at 4and 3- positions of the phenyl group (4a−4j, 89−99%, 80− >99.9% ee). Again, sterically encumbered 1-naphthyl as well as pyridyl aldoximes worked equally efficiently with respect to both efficiency and selectivity (4l−4n). The high reactivity of the latter is remarkable considering usually strong catalyst poisoning caused by ligation of pyridine to metal center. To gain some mechanistic insights of the current transformation, we performed some preliminary mechanistic studies. Addition of radical inhibitor 2,6-di-tert-butyl-4-methyl-phenol (BHT) to the optimized conditions imparted negligible impact on the reaction efficiency (isolated yield: 79%), whereas the reaction performed under an atmosphere of O2 delivered the desired product 3a in a significantly lower yield of 15%. The insensitivity to radical inhibitors and susceptibility to oxygen suggest of a CuI-catalytic profile, rather than the most commonly invoked radical pathways involving single electron transfer (SET) between copper and oxime derivatives.33,34 A comparative study revealed that oxime and oxime acetate retrieved the same product in essentially identical yields and enantioselectivities (Table S3), suggesting that oxime ester
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ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/jacs.7b06523. Experimental procedures, analytical and spectral data (PDF) Crystal data for 3n (CIF) Crystal data for 3x′ (CIF) 11704
DOI: 10.1021/jacs.7b06523 J. Am. Chem. Soc. 2017, 139, 11702−11705
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Crystal data for 4f (CIF)
AUTHOR INFORMATION
Corresponding Authors
*[email protected] *[email protected] ORCID
Jinbo Zhao: 0000-0002-5261-7366 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS Financial support from NNSFC (21402025, 21372041), the Fundamental Research Funds for the Central Universities (2412017FZ014), and Changbai Mountain Scholarship Program are gratefully acknowledged.
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