This journal is © The Royal Society of Chemistry and the Centre National de la Recherche Scientifique 2017 New J. Chem. Cite this: DOI: 10.1039/c7nj01395g Organocatalytic enantioselective construction of isatin-derived N-alkoxycarbonyl 1,3-aminonaphthols via sterically encumbered hydrocarbon-substituted quinine-based squaramide† Seda Karahan and Cihangir Tanyeli * Herein, an illustrative example to synthesize chiral naphthoxazepine precursors via the aza-Friedel–Crafts reaction of N-alkoxycarbonyl isatin ketimines with naphthol using a new 2-adamantyl-substituted quinine- derived squaramide catalyst is presented; the reaction afforded the chiral-tetrasubstituted 3-amino-2- oxindoles with excellent enantioselectivity of greater than 99% ee and quantitative yields. To the best of our knowledge, this methodology is featured for being representative of the efficiency of sterically hindered hydrocarbon substituents in squaramide organocatalysts in terms of stereoselectivity. Introduction Numerous research efforts have been made in recent years for the synthesis of stereochemically complex molecules via economically and environmentally benign stereoselective C–C bond forming reactions. 1 In this respect, development of mild methodologies for the synthesis of chiral amines or func- tional groups derived from them is crucial for pharmacy and agrochemistry. 2 Direct nucleophilic addition to imines is one of the straightforward methods leading to chiral amines. 2 More specifically, optically active aminonaphthols with two func- tional groups are important synthons for the synthesis of new heterocycles. 3,4 Betti proposed a protocol in which 2-naphthol as a carbon nucleophile, which is sufficiently acidic to promote tautomerization, attacks imine obtained from benzaldehyde and aniline; the adduct aminobenzylnaphthol derivatives are known as the Betti base. 5 Besides these, a 3-amino-2-oxindole skeleton exists in many biologically active natural products. 6 An enantioselective aza-Friedel–Crafts reaction of naphthols with isatin-derived ketimines is be a direct strategy of combining valuable aminonaphthol and tetrasubstituted 3-amino-2-oxindole units in one. Montesinos-Magraner et al. reported a study related to quinine-derived thiourea-catalyzed asymmetric addition of naphthols and electron-rich phenols to 1-substituted-N-Boc- protected isatin-derived ketimines for the first time. They obtained excellent yields and enantioselectivities (up to 99% yield and 99% ee). 7 After this, Khan and Ganguly 8 reported a computational study clarifying the efficiency of a quinine thiourea catalyst, which is common to both studies. 7,8 Herein, as a part of our ongoing study on organocatalytic asymmetric construction of spirooxindoles, we explored an alternative and supplementary study comprising transformation of various N-alkoxycarbonyl ketimines derived from isatins into Betti bases. Distinctively, we also exhibit that presence of substituents at 1-position of isatin-derived ketimine does not play a critical role in stereoselectivity and reactions of unsubstituted derivatives almost as selective as substituted ones by the catalysis of 2-adamantyl substituted quinine derived squaramide organocatalyst IIb. Previously, catalytic activities of 2-aminoDMAP/squaramides, 9 and quinine-based squaramides with sterically encumbered 1-adamantyl, 2-adamantyl and tert- butyl units 10 have been described by our group. Results and discussion Subsequent to the overwhelming success of chiral ureas and thioureas in organocatalysis, the utility of squaramides as rigid H-bonding catalysts was recognized with the pioneering study of Rawal. 11 From the following asymmetric organocatalytic applica- tions reported hereto, 12 we are familiar with CF 3 -substituted aryl squaramides with increased acidity of N-H protons. Therefore, we surveyed squaramides Ia, Ib, IIa–d, as well as quinine-based thiourea and urea, IIIa and IIIb, respectively, as bifunctional organocatalysts in model reaction of 2a with 1-naphthol (1) (Table 1). Although aza- Friedel–Crafts reaction catalyzed by 2-aminoDMAP cored squar- amide catalysts Ia and Ib led to adduct 3a in good yields, it was nearly a racemate (Table 1, entries 1 and 2). When quinine- derived squaramides IIa–d were compared with thiourea and urea, IIIa and IIIb, respectively, the former revealed better stereo- selectivity (entries 3–8). Quinine-derived thiourea catalyst IIIa, Department of Chemistry, Middle East Technical University, 06800, Ankara, Turkey. E-mail: tanyeli@metu.edu.tr † Electronic supplementary information (ESI) available. See DOI: 10.1039/c7nj01395g Received 26th April 2017, Accepted 16th July 2017 DOI: 10.1039/c7nj01395g rsc.li/njc NJC PAPER Published on 17 July 2017. Downloaded by Middle East Technical University (Orta Dogu Teknik U) on 01/08/2017 08:57:51. View Article Online View Journal