A Modular Strategy for the Direct Catalytic Asymmetric α-Amination of Carbonyl Compounds

Abstract

•Direct asymmetric introduction of non-protected amino group at α-position of carbonyl•Use of N-alkyl or N-aryl hydroxylamines as an electrophilic amine source•Straightforward access to a variety of chiral α-aminocarbonyl compounds•Stereocontrol enabled by chiral 1,2,3-triazolium catalysts Chiral α-aminocarbonyl compounds represent a ubiquitous structural motif in a large family of biologically active compounds. A representative example is 3-aminooxindoles, which are commonly found in therapeutic agents, such as gastrin/CCK-B receptor agonist AG-041R, vasopressin receptor antagonist SSR-149415, and antimalarial NITD609. Discovering new candidates for pharmaceuticals requires judicious modification of not only the structure of the organic framework around the carbonyl group but also the nitrogen substituents given the binding properties of the amine components, whose steric and electronic features have a profound effect on the biological activity. One of the most efficient protocols to address this issue is the direct catalytic stereoselective introduction of structurally diverse, non-protected amines at the α-position of carbonyl compounds. However, such a transformation remains unrealized, and here we report a method to fill this gap. Direct catalytic methods for the stereoselective introduction of various non-protected amines at the carbon atom adjacent to a carbonyl group remain elusive in synthetic chemistry, even though they offer the most straightforward entry to chiral α-aminocarbonyl compounds. Here, we demonstrate that the in situ activation of hydroxylamines with trichloroacetonitrile enables direct transfer of their amine moieties to the C-3 position of oxindoles with rigorous enantiocontrol under the catalysis of chiral 1,2,3-triazolium salts. This protocol provides a powerful and practical means of accessing optically active 3-aminooxindoles with a wide array of alkyl and aryl substituents on nitrogen. Other carbonyl compounds, such as β-ketoesters and α-cyanoesters, can also be directly transformed into the corresponding α-aminocarbonyls with high enantioselectivity. Direct catalytic methods for the stereoselective introduction of various non-protected amines at the carbon atom adjacent to a carbonyl group remain elusive in synthetic chemistry, even though they offer the most straightforward entry to chiral α-aminocarbonyl compounds. Here, we demonstrate that the in situ activation of hydroxylamines with trichloroacetonitrile enables direct transfer of their amine moieties to the C-3 position of oxindoles with rigorous enantiocontrol under the catalysis of chiral 1,2,3-triazolium salts. This protocol provides a powerful and practical means of accessing optically active 3-aminooxindoles with a wide array of alkyl and aryl substituents on nitrogen. Other carbonyl compounds, such as β-ketoesters and α-cyanoesters, can also be directly transformed into the corresponding α-aminocarbonyls with high enantioselectivity. The development of general methods for the stereoselective construction of chiral aminocarbonyls with sufficient structural variation of the nitrogen substituents represents an enduring challenge in chemical synthesis.1Ricci A. Amino Group Chemistry: From Synthesis to the Life Sciences. Wiley-VCH, 2008Google Scholar, 2Hili R. Yudin A.K. Making carbon-nitrogen bonds in biological and chemical synthesis.Nat. Chem. Biol. 2006; 2: 284-287Crossref PubMed Scopus (586) Google Scholar, 3Ochi M. Kawasaki K. Kataoka H. Uchio Y. Nishi H. AG-041R, a gastrin/CCK-B antagonist, stimulates chondrocyte proliferation and metabolism in vitro.Biochem. Biophys. Res. Commun. 2001; 283: 1118-1123Crossref PubMed Scopus (167) Google Scholar, 4Bernard K. Bogliolo S. Ehrenfeld J. Vasotocin and vasopressin stimulation of the chloride secretion in the human bronchial epithelial cell line, 16HBE14o-.Br. J. Pharmacol. 2005; 144: 1037-1050Crossref Scopus (119) Google Scholar, 5Rottmann M. McNamara C. Yeung B.K. Lee M.C. Zou B. Russell B. Seitz P. Plouffe D.M. Dharia N.V. Tan J. et al.Spiroindolones, a potent compound class for the treatment of malaria.Science. 2010; 329: 1175-1180Crossref PubMed Scopus (930) Google Scholar, 6Randolph J.T. Flentge C.A. Huang P.P. Hutchinson D.K. Klein L.L. Lim H.B. Mondal R. Reisch T. Montgomery D.A. Jiang W.W. et al.Synthesis and biological characterization of b-ring amino analogues of potent benzothiadiazine hepatitis C virus polymerase inhibitors.J. Med. Chem. 2009; 52: 3174-3183Crossref Scopus (34) Google Scholar Among the manifold transformations that are conceivable for the assembly of chiral α-aminocarbonyls, the catalytic asymmetric α-amination of carbonyl compounds is one of the most efficient and straightforward methods, and a multitude of stereoselective C–N bond-forming reactions have been reported.7Janey J.M. Recent advances in catalytic, enantioselective α aminations and α oxygenations of carbonyl compounds.Angew. Chem. Int. Ed. Engl. 2005; 44: 4292-4300Crossref Scopus (319) Google Scholar, 8Smith A.M.R. Hii K.K. Transition metal catalyzed enantioselective α heterofunctionalization of carbonyl compounds.Chem. Rev. 2011; 111: 1637-1656Crossref Scopus (307) Google Scholar, 9Zhou F. Liao F.-M. Yu J.-S. Zhou J. Catalytic asymmetric electrophilic amination reactions to form nitrogen-bearing tetrasubstituted carbon stereocenters.Synthesis. 2014; 46: 2983-3003Crossref Scopus (95) Google Scholar, 10Maji B. Yamamoto H. Use of in situ generated nitrosocarbonyl compounds in catalytic asymmetric α-hydroxylation and α-amination reactions.Bull. Chem. Soc. Jpn. 2015; 88: 753-762Crossref Scopus (42) Google Scholar However, the direct enantioselective installation of a diverse range of non-protected amines onto carbonyl α-carbons still remains unrealized.11Tian J.-S. Ng K.W.J. Wong J.-R. Loh T.-P. α-Amination of aldehydes catalyzed by in situ generated hypoiodite.Angew. Chem. Int. Ed. Engl. 2012; 51: 9105-9109Crossref Scopus (92) Google Scholar, 12Lamani M. Prabhu K.R. NIS-catalyzed reactions: amidation of acetophenones and oxidative amination of propiophenones.Chem. Eur. J. 2012; 18: 14638-14642Crossref Scopus (139) Google Scholar, 13Jia W.-G. Li D.-D. Dai Y.-C. Zhang H. Yan L.-Q. Sheng E.-H. Wei Y. Mu X.-L. Huang K.-W. Synthesis and characterization of bisoxazolines and pybox-copper(II) complexes and their application in the coupling of α-carbonyls with functionalized amines.Org. Biomol. Chem. 2014; 12: 5509-5516Crossref Scopus (22) Google Scholar, 14Jiang Q. Xu B. Zhao A. Jia J. Liu T. Guo C. Transition-metal-free oxidative α-C−H amination of ketones via a radical mechanism: mild synthesis of α-amino ketones.J. Org. Chem. 2014; 79: 8750-8756Crossref Scopus (90) Google Scholar, 15Tokumasu K. Yazaki R. Ohshima T. Direct catalytic chemoselective α-amination of acylpyrazoles: a concise route to unnatural α-amino acid derivatives.J. Am. Chem. Soc. 2016; 138: 2664-2669Crossref PubMed Scopus (67) Google Scholar, 16Tona V. de la Torre A. Padmanaban M. Ruider S. González L. Maulide N. Chemo- and stereoselective transition-metal-free amination of amides with azides.J. Am. Chem. Soc. 2016; 138: 8348-8351Crossref Scopus (88) Google Scholar The main obstacle to achieving this goal stems from the structural and functional-group requirements for electrophilic nitrogen sources to be competent to forge a C–N bond yet compatible with the respective catalytic system. Only a few reagents, such as azodicarboxylates,17Gennari C. Colombo L. Bertolini G. Asymmetric electrophilic amination: synthesis of α-amino and α-hydrazino acids with high optical purity.J. Am. Chem. Soc. 1986; 108: 6394-6395Crossref Scopus (210) Google Scholar, 18Evans D.A. Nelson S.G. Chiral magnesium bis(sulfonamide) complexes as catalysts for the merged enolization and enantioselective amination of N-acyloxazolidinones. A catalytic approach to the synthesis of arylglycines.J. Am. Chem. Soc. 1997; 119: 6452-6453Crossref Scopus (245) Google Scholar, 19Cheng L. Liu L. Wang D. Chen Y.-J. Highly enantioselective and organocatalytic α-amination of 2-oxindoles.Org. Lett. 2009; 11: 3874-3877Crossref Scopus (187) Google Scholar, 20Qian Z.-Q. Zhou F. Du T.-P. Wang B.-L. Ding M. Zhao X.-L. Zhou J. Asymmetric construction of quaternary stereocenters by direct organocatalytic amination of 3-substituted oxindoles.Chem. Commun. 2009; : 6753-6755Crossref Scopus (162) Google Scholar, 21Bui T. Borregan M. Barbas III, C.F. Expanding the scope of cinchona alkaloid-catalyzed enantioselective α-aminations of oxindoles: a versatile approach to optically active 3-amino-2-oxindole derivatives.J. Org. Chem. 2009; 74: 8935-8938Crossref Scopus (112) Google Scholar, 22Mouri S. Chen Z. Mitsunuma H. Furutachi M. Matsunaga S. Shibasaki M. Catalytic asymmetric synthesis of 3-aminooxindoles: enantiofacial selectivity switch in bimetallic vs monometallic Schiff base catalysis.J. Am. Chem. Soc. 2010; 132: 1255-1257Crossref Scopus (244) Google Scholar, 23Yang Z. Wang Z. Bai S. Shen K. Chen D. Liu X. Lin L. Feng X. Highly enantioselective synthesis of 3-amino-2-oxindole derivatives: catalytic asymmetric α-amination of 3-substituted 2-oxindoles with a chiral scandium complex.Chem. Eur. J. 2010; 16: 6632-6637Crossref Scopus (107) Google Scholar, 24Bui T. Hernández-Torres G. Milite C. Barbas III, C.F. Highly enantioselective organocatalytic α-amination reactions of aryl oxindoles: developing designer multifunctional alkaloid catalysts.Org. Lett. 2010; 12: 5696-5699Crossref Scopus (107) Google Scholar, 25Zhou F. Ding M. Liu Y.-L. Wang C.-H. Ji C.-B. Zhang Y.-Y. Zhou J. Organocatalytic asymmetric α-amination of unprotected 3-aryl and 3-aliphatic substituted oxindoles using di-tert-butyl azodicarboxylate.Adv. Synth. Catal. 2011; 353: 2945-2952Crossref Scopus (72) Google Scholar, 26Mouri S. Chen Z. Matsunaga S. Shibasaki M. Catalytic asymmetric amination of oxindoles under dinuclear nickel Schiff base catalysis.Heterocycles. 2012; 84: 879-892Crossref Scopus (13) Google Scholar, 27Jumde R.P. Mandoli A. Long-lived polymer-supported dimeric cinchona alkaloid organocatalyst in the asymmetric α-amination of 2-oxindoles.ACS Catal. 2016; 6: 4281-4285Crossref Scopus (32) Google Scholar, 28Saaby S. Bella M. Jørgensen K.A. Asymmetric construction of quaternary stereocenters by direct organocatalytic amination of α-substituted α-cyanoacetates and β-dicarbonyl compounds.J. Am. Chem. Soc. 2004; 126: 8120-8121Crossref Scopus (270) Google Scholar, 29Liu X. Li H. Deng L. Highly enantioselective amination of α-substituted α-cyanoacetates with chiral catalysts accessible from both quinine and quinidine.Org. Lett. 2005; 7: 167-169Crossref Scopus (190) Google Scholar nitroso arenes30Momiyama N. Yamamoto H. Enantioselective O- and N-nitroso aldol synthesis of tin enolates. Isolation of three binap-silver complexes and their role in regio- and enantioselectivity.J. Am. Chem. Soc. 2004; 126: 5360-5361Crossref Scopus (172) Google Scholar, 31Zhang T. Cheng L. Liu L. Wang D. Chen Y.-J. Asymmetric organocatalytic N-nitroso-aldol reaction of oxindoles.Tetrahedron Asymmetry. 2010; 21: 2800-2806Crossref Scopus (54) Google Scholar, 32Shen K. Liu X. Wang G. Lin L. Feng X. Facile and efficient enantioselective hydroxyamination reaction: synthesis of 3-hydroxyamino-2-oxindoles using nitrosoarenes.Angew. Chem. Int. Ed. Engl. 2011; 50: 4684-4688Crossref Scopus (145) Google Scholar, 33Jia L.-N. Huang J. Peng L. Wang L.-L. Bai J.-F. Tian F. He G.-Y. Xu X.-Y. Wang L.-X. Asymmetric hydroxyamination of oxindoles catalyzed by chiral bifunctional tertiary amine thiourea: construction of 3-amino-2-oxindoles with quaternary stereocenters.Org. Biomol. Chem. 2012; 10: 236-239Crossref Google Scholar, 34Companyo X. Valero G. Pineda O. Calvet T. Font-Bardia M. Moyano A. Rios R. Enantioselective organocatalytic oxyamination of unprotected 3-substituted oxindoles.Org. Biomol. Chem. 2012; 10: 431-439Crossref Google Scholar and carbonyls,35Sandoval D. Frazier C.P. Bugarin A. Read de Alaniz J. Electrophilic α-amination reaction of β-ketoesters using N-hydroxycarbamates: merging aerobic oxidation and Lewis acid catalysis.J. Am. Chem. Soc. 2012; 134: 18948-18951Crossref Scopus (66) Google Scholar, 36Xu C. Zhang L. Luo S. Merging aerobic oxidation and enamine catalysis in the asymmetric α-amination of β-ketocarbonyls using N-hydroxycarbamates as nitrogen sources.Angew. Chem. Int. Ed. Engl. 2014; 53: 4149-4153Crossref Scopus (98) Google Scholar azidoiodinanes,37Deng Q.-H. Bleith T. Wadepohl H. Gade L.H. Enantioselective iron-catalyzed azidation of β-keto esters and oxindoles.J. Am. Chem. Soc. 2013; 135: 5356-5359Crossref Scopus (192) Google Scholar or sulfonyloxycarbamates,38Cecere G. König C.M. Alleva J.L. MacMillan D.W.C. Enantioselective direct α-amination of aldehydes via a photoredox mechanism: a strategy for asymmetric amine fragment coupling.J. Am. Chem. Soc. 2013; 135: 11521-11524Crossref Scopus (191) Google Scholar have been used for implementing asymmetric amination strategies. Consequently, subsequent reductive N–N or N–O bond cleavage and/or deacylation is necessary for generating unmasked amine functionalities (Figure 1A ). Very recently, electron-acceptor-substituted aryl aminyl radicals generated from the corresponding aryl azides were utilized for achieving direct asymmetric α-amination of 2-acyl imidazoles.39Huang X. Webster R.D. Harms K. Meggers E. Asymmetric catalysis with organic azides and diazo compounds initiated by photoinduced electron transfer.J. Am. Chem. Soc. 2016; 138: 12636-12642Crossref Scopus (128) Google Scholar However, in all of these approaches, the scope of substituents on nitrogen is strictly limited by the nature of the electrophilic nitrogen sources, which renders it difficult to introduce various amines directly at the α-carbon atom of carbonyls with rigorous stereocontrol in a single synthetic operation. We designed a modular strategy for the catalytic asymmetric α-amination of carbonyl compounds based on the use of hydroxylamines as an amine source.40Murru S. Lott C.S. Fronczek F.R. Srivastava R.S. Fe-catalyzed direct α C−H amination of carbonyl compounds.Org. Lett. 2015; 17: 2122-2125Crossref Scopus (21) Google Scholar Although hydroxylamines themselves are nucleophilic, their derivatives containing O-electron-withdrawing substituents, such as benzoyl or phosphinyl groups, have classically been used as electrophilic nitrogen sources in α-amination reactions.41Sheradsky T. Nir Z. The amination of carbanions.Tetrahedron Lett. 1969; 10: 77-78Crossref Scopus (26) Google Scholar, 42Colvin E.W. Kirby G.W. Wilson A.C. O-(Diphenylphosphinyl)hydroxylamine: a new reagent for electrophilic C-amination.Tetrahedron Lett. 1982; 23: 3835-3836Crossref Scopus (72) Google Scholar The problem associated with this type of methodology is the insufficient reactivity of O-substituted hydroxylamines, which react only with highly nucleophilic organometallic species.43Berman A.M. Johnson J.S. Copper-catalyzed electrophilic amination of diorganozinc reagents.J. Am. Chem. Soc. 2004; 126: 5680-5681Crossref PubMed Scopus (235) Google Scholar, 44Matsuda N. Hirano K. Satoh T. Miura M. Copper-catalyzed amination of ketene silyl acetals with hydroxylamines: electrophilic amination approach to α-amino acids.Angew. Chem. Int. Ed. Engl. 2012; 51: 11827-11831Crossref Scopus (81) Google Scholar The introduction of a strongly electron-withdrawing substituent on oxygen, e.g., a sulfonyl group, would enhance the electrophilicity, but this class of hydroxylamines is thermally labile and decomposes immediately at room temperature.45Tamura Y. Minamikawa J. Ikeda M. O-Mesitylenesulfonylhydroxylamine and related compounds – powerful aminating reagents.Synthesis. 1977; : 1-17Crossref Scopus (100) Google Scholar Our approach is to activate simple hydroxylamines in situ via treatment with trichloroacetonitrile under mildly basic conditions,46Patai S. The Chemistry of Amidines and Imidates. Wiley, 1975Crossref Scopus (223) Google Scholar, 47Payne G.B. Deming P.H. Williams P.H. Reactions of hydrogen peroxide. VII. alkali-catalyzed epoxidation and oxidation using a nitrile as co-reactant.J. Org. Chem. 1961; 26: 659-663Crossref Scopus (312) Google Scholar, 48Schmidt R.R. New methods for the synthesis of glycosides and oligosaccharides: are there alternatives to the Koenigs-Knorr method?.Angew. Chem. Int. Ed. Engl. 1986; 25: 212-235Crossref Scopus (1545) Google Scholar where phase-transfer catalysis of chiral onium salts can be operative.49Shirakawa S. Maruoka K. Recent developments in asymmetric phase-transfer reactions.Angew. Chem. Int. Ed. Engl. 2013; 52: 4312-4348Crossref Scopus (536) Google Scholar We speculated that the hydroxylamine nitrogen atom of an in-situ-formed O-trichloroacetimino hydroxylamine would be sufficiently electrophilic to engage in bond connection with a catalytically generated chiral onium enolate of the carbonyl compound, thereby allowing stereocontrolled transfer of the amine component (Figure 1B). Here, we report on the realization of highly enantioselective α-amination of several carbonyl compounds, namely, oxindoles, β-ketoesters, and α-cyanoesters, with the use of this strategy and chiral 1,2,3-triazolium salts as the requisite catalysts. Considering the structural diversity of the readily available hydroxylamines, this protocol provides a powerful and practical tool for the straightforward synthesis of optically active α-aminocarbonyls with a wide array of alkyl and aryl substituents on nitrogen. Initially, our study focused on assessing the viability of the α-amination of oxindoles by using N-substituted hydroxylamines as the amine source in combination with trichloroacetonitrile. For this purpose, N-Boc-3-phenyloxindole (3a) and N-cyclohexylhydroxylamine (4a) were selected as model substrates because the asymmetric incorporation of a bulky N-alkylamino group at the α-carbon atom in relation to the carbonyl group remains unexplored. An initial experiment involved treating 3a with 4a and trichloroacetonitrile in the presence of powdered potassium carbonate and a catalytic amount of tetrabutylammonium bromide or benzyltrimethylammonium bromide in toluene at 0°C. However, these common phase-transfer catalysts proved to be inactive for the targeted C–N bond formation, and the starting materials were recovered together with several unidentified products (entries 1 and 2 in Table 1). In contrast, the reaction using 1,2,3-triazolium bromide 1a·Br as a catalyst under otherwise identical conditions afforded the desired 3-aminooxindole 5a, albeit in very low yield (entry 3). Because the structurally similar catalyst 1b·Br, bearing a methyl instead of a hydrogen substituent at the C-5 carbon, did not induce any reactivity (entry 4), we presumed that the hydrogen-bond-donating ability of the triazolium ion was essential for promoting this amination. Encouraged by the feasibility of a direct transfer of the amine component of N-cyclohexylhydroxylamine, we applied chiral 1,2,3-triazolium bromides of type 2·Br, which feature ample structural modularity,50Ohmatsu K. Kiyokawa M. Ooi T. Chiral 1,2,3-triazoliums as new cationic organic catalysts with anion-recognition ability: application to asymmetric alkylation of oxindoles.J. Am. Chem. Soc. 2011; 133: 1307-1309Crossref Scopus (147) Google Scholar to the amination with the aim of enhancing the reactivity and achieving absolute stereocontrol. L-Alanine-derived catalyst 2a·Br afforded 5a in significantly increased yield with an excellent level of enantiocontrol. A subsequent pertinent modification of the triazolium structure allowed us to identify 2b·Br as the optimal catalyst, which delivered 5a (Figures S8, S9, and S72) in critically improved yield with virtually complete stereochemical control (entry 6). The 2b·Br-catalyzed reaction did not afford any product in the absence of trichloroacetonitrile (entry 7). In addition, the amination did not proceed when O-benzoyl hydroxylamine 4b was used as the sole electrophilic nitrogen source (entry 8). These results corroborate the critical importance of combining hydroxylamine and trichloroacetonitrile to promote the stereoselective direct α-amination of 3a. Meanwhile, we confirmed the in situ generation of an O-imino hydroxylamine by a nuclear magnetic resonance (NMR) spectroscopic analysis of a solution of trichloroacetonitrile and hydroxylamine 4a in toluene-d8 (Figure S1). Even though the imino hydroxylamine could be purified by chromatography on silica gel, it was not stable enough to be stored. But more importantly, when the isolated imino hydroxylamine was used immediately for the asymmetric amination under the influence of 2b·Br, 5a was produced with similarly high efficiency and enantiopurity. This result unambiguously demonstrated that the imino hydroxylamine was an actual reactive intermediate.Table 1Direct Enantioselective Amination of Oxindole 3a with Hydroxylamine 4EntryCatalyst4Yield (%)aIsolated yield.ee (%)bDetermined by high-performance liquid chromatography analysis.1cPerformed using 10 mol % of catalyst.n-Bu4N·Br4a0–2cPerformed using 10 mol % of catalyst.BnNMe3·Br4a0–3cPerformed using 10 mol % of catalyst.1a·Br4a10–4cPerformed using 10 mol % of catalyst.1b·Br4a0–52a·Br4a419662b·Br4a80997dPerformed in the absence of Cl3CCN.2b·Br4a0–8dPerformed in the absence of Cl3CCN.2b·Br4b0–Unless otherwise noted, the following reaction conditions were used: 0.10 mmol of 3a, 0.15 mmol of 4, 0.10 mmol of Cl3CCN, and 0.10 mmol of K2CO3 in the presence of catalyst (5.0 mol %) in 1.0 mL of toluene at 0°C for 24 hr.a Isolated yield.b Determined by high-performance liquid chromatography analysis.c Performed using 10 mol % of catalyst.d Performed in the absence of Cl3CCN. Open table in a new tab Unless otherwise noted, the following reaction conditions were used: 0.10 mmol of 3a, 0.15 mmol of 4, 0.10 mmol of Cl3CCN, and 0.10 mmol of K2CO3 in the presence of catalyst (5.0 mol %) in 1.0 mL of toluene at 0°C for 24 hr. We next explored the scope of this asymmetric α-amination protocol with regard to hydroxylamines (4). As illustrated in Figure 2, a wide range of amines could be directly introduced at the C-3 carbon of oxindole 3a from the parent hydroxylamines in a highly stereoselective fashion. Not only sterically hindered N-cycloalkyl hydroxylamines but also N-benzylic and other simple alkyl-substituted hydroxylamines could be used as viable amine sources, producing the corresponding 3-aminooxindoles (5b–5h; Figures S10–S23 and S72–S73) with uniformly excellent enantioselectivity. For the reactions with N-isopropyl, allylic, and alkoxycarbonylmethyl hydroxylamines, increased catalyst loading was required to produce 5i, 5j, and 5k in satisfactory yield (Figures S24–S29 and S74). Furthermore, the direct incorporation of unmasked aniline derivatives was possible with comparable degrees of efficiency and selectivity, where the 1,2,3-triazolium salt 2a·Br proved to be a superior catalyst, and various functional groups on the aryl moiety, e.g., bromine, ester, or nitrile, were tolerated well (5l–5o; Figures S30–S37, S74, and S75). It should be noted that 2c·Br, an L-leucine-derived analog of 2a·Br, exhibited higher catalytic activity in the reaction with a hydroxylamine bearing a 4-vinylphenyl substituent on nitrogen, which afforded the desired product (5p; Figures S38, S39, and S75) with high optical purity in a synthetically useful yield. As carbonyl nucleophiles, not only 3-substituted oxindoles but also other cyclic and acyclic carbonyl compounds could be used through the appropriate tuning of the triazolium structure and reaction conditions (Figure 3). With respect to oxindoles, the incorporation of different aromatic and aliphatic substituents at the 3-position was amenable to amination with either 2a·Br or 2c·Br as a catalyst, as evident from the representative results shown in Figure 3A (Figures S40–49, S76, and S77). In the presence of the suitable catalyst 2d·Br, 1-indanone derivative 6 also underwent smooth amination with N-phenylhydroxylamine or N-benzylhydroxylamine to produce α-amino β-ketoester 7a or 7b with high enantioselectivity (Figures 3B, S50–S53, and S77). Moreover, a series of cyanoesters 8 could be directly aminated under the conditions optimized for this type of acyclic substrate to give the corresponding aminoesters 9a–9e (Figures S54–S63 and S77–S78) in uniformly good yield with high enantiomeric excess. The reaction of α-phenyl cyanoester with N-2-chlorophenylhydroxylamine was particularly efficient, and the resultant enantioenriched α-amino α-cyanoester 9f (Figures S64, S65, and S79) was readily converted into tetrahydroquinoxaline derivative 10 (Figures S66, S67, and S79) without loss of stereochemical integrity; the chiral ring system is found in potential therapeutics such as promising anti-HIV agents (Figure 3C).51Singh G.S. Desta Z.Y. Isatins as privileged molecules in design and synthesis of spiro-fused cyclic frameworks.Chem. Rev. 2012; 112: 6104-6155Crossref PubMed Scopus (1310) Google Scholar We further applied the present method to asymmetric intramolecular C–N bond formation. An attempted reaction of oxindole 11a, containing an N-hydroxylaminopropyl side chain, merely afforded trace amounts of the 5-membered cyclic product 12a, most likely as a result of the ready protonation of the oxindole enolate intermediate by the amino N–H functionality. As expected, treatment of 11b, bearing an N-hydroxyl-N-methylamino group, with catalyst 2d·Br induced facile intramolecular ring closure to furnish pyrrolidinyl spirooxindole 12b (Figures S68, S69, and S79) of high enantiomeric purity, which is of particular importance as a key structural motif in several natural alkaloids with distinct bioactivity profiles.52Patel M. Mc Hugh Jr., R.J. Cordova B.C. Klabe R.M. Erickson-Vitanen S. Trainor G.L. Rodgers J.D. Synthesis and evaluation of quinoxalinones as HIV-1 reverse transcriptase inhibitors.Bioorg. Med. Chem. Lett. 2000; 10: 1729-1731Crossref Scopus (92) Google Scholar Chiral piperidinyl spirooxindole 12c (Figures S70, S71, and S79) was also obtained with a good level of enantiocontrol in the reaction of 11c, which has one carbon-elongated side chain (Figure 3D). In conclusion, we have developed a strategy for the direct incorporation of structurally diverse non-protected amines at the carbon atom adjacent to a carbonyl group with high levels of enantiocontrol in a single synthetic operation. This system is based on the in situ activation of readily available hydroxylamines by trichloroacetonitrile under mild conditions that are compatible with the phase-transfer catalysis of chiral 1,2,3-triazolium salts. We anticipate that this modular and operationally simple method, which provides access to optically active α-amino carbonyl compounds, will find numerous applications in chemical synthesis. A solution of 2b·Br (4.85 mg, 0.005 mmol), oxindole 3a (30.9 mg, 0.10 mmol), hydroxylamine 4a (17.3 mg, 0.15 mmol), and K2CO3 (13.8 mg, 0.10 mmol) in toluene (1.0 mL) was degassed by alternating vacuum evacuation and Ar backfill. Then, the resulting mixture was cooled to 0°C. After the introduction of trichloroacetonitrile (10 μL, 0.10 mmol) into the reaction flask, stirring was maintained for 24 hr at the same temperature. The reaction was quenched with a saturated aqueous solution of NH4Cl, and the extractive workup was performed with EtOAc. After drying over Na2SO4, filtration, and removal of solvent, the crude residue was purified by column chromatography on silica gel to afford 5a as a colorless oil (32.5 mg, 0.080 mmol, 80% yield, 99% ee). 5a: purified by column chromatography on CHROMATOREX NH; [α]D24Bui T. Hernández-Torres G. Milite C. Barbas III, C.F. Highly enantioselective organocatalytic α-amination reactions of aryl oxindoles: developing designer multifunctional alkaloid catalysts.Org. Lett. 2010; 12: 5696-5699Crossref Scopus (107) Google Scholar = +68.5 (c = 1.3, CHCl3) for 99% ee; 1H-NMR (400 MHz, CDCl3): δ 7.88 (1H, dd, J = 8.0, 2.0 Hz), 7.43 (2H, dd, J = 8.2, 1.8 Hz), 7.34 (1H, td, J = 7.2, 1.2 Hz), 7.32 (1H, d, J = 8.0 Hz), 7.30–7.23 (3H, m), 7.17 (1H, td, J = 8.2, 1.2 Hz), 2.36–2.30 (1H, m), 2.17 (1H, br s), 1.76–1.45 (5H, m), 1.64 (9H, s), 1.19–1.01 (5H, m); 13C-NMR (101 MHz, CDCl3): δ 178.7, 149.3, 141.7, 139.5, 130.4, 129.2, 128.7, 128.2, 126.3, 126.0, 124.6, 115.4, 84.6, 69.4, 53.3, 35.8, 35.1, 28.3, 25.8, 25.3, 25.1; IR: 3327, 2928, 2853, 1767, 1728, 1607, 1472, 1342, 1287, 1146, 1001, 754 cm−1; HRMS (ESI): calcd for C25H31N2O3+ ([M + H]+) 407.2329, found 407.2327; HPLC IE3, Hex/IPA = 10:1, flow rate = 1.0 mL/min, λ = 210 nm, 7.8 min (minor isomer), 14.2 min (major isomer). K.O. and T.O. conceived and designed the study and co-wrote the paper. Y.A. and T.N. performed the experiments and analyzed the data together with K.O. All authors discussed the results and commented on the manuscript. Financial support was provided by CREST (JST), a JSPS KAKENHI grant (JP16H01015) for Precisely Designed Catalysts with Customized Scaffolding, and the Program for Leading Graduate Schools, “Integrative Graduate Education and Research Program in Green Natural Sciences,” at Nagoya University. Download .pdf (5.37 MB) Help with pdf files Document S1. Supplemental Experimental Procedures, Figures S1–S79, and Tables S1–S3 Download .zip (.06 MB) Help with zip files Data S1. CIF Data for Compound S6 Download .zip (.11 MB) Help with zip files Data S2. CIF Data for Compound S7 Download .zip (.13 MB) Help with zip files Data S3. CIF Data for Compound S9