Organocatalytic asymmetric allylic amination of Morita–Baylis–Hillman carbonates of isatins

The investigation of a Lewis base catalyzed asymmetric allylic amination of Morita–Baylis–Hillman carbonates derived from isatins afforded an electrophilic pathway to access multifunctional oxindoles bearing a C3-quaternary stereocenter, provided with good to excellent enantioselectivity (up to 94% ee) and in high yields (up to 97%).


Results and Discussion
Based on the above considerations, we initially investigated the reaction of MBH carbonate 2a and a diversity of nucleophilic nitrogen sources by the catalysis of DABCO. No desired reaction occurred for phthalimide [25] or N-allyl p-toluenesulfon-Scheme 1: Allylic amination of MBH carbonates of isatins to access 3-amino-2-oxindoles. amide [27], which has been successfully applied in the asymmetric amination of MBH carbonates derived from aryl aldehydes. Pleasingly, the reaction took place smoothly to afford product 4a when hydroxylamine 3a with N-benzyloxycarbonyl and O-benzyl groups [29] was applied in diethyl ether ( Table 1, entry 1). Subsequently, an array of tertiary amines derived from quinidine was explored to introduce chirality into the product. While poor enantioselectivity was obtained when β-iso-  [14][15][16][17][18], and chlorobenzene was found to be the optimal selection (Table 1, entry 18). Finally, it was found that the reaction still proceeded smoothly at 0 °C, and a high ee value could be obtained in the catalysis by amine 1h, although a longer reaction time was required to give a better yield (Table 1,  entry 19). It should be noted that the reaction became sluggish when (S)-BINOL [32] was added, and even no reaction happened in the presence of other additives such as LiClO 4 or Ti(OiPr) 4 [33].
With the optimized conditions in hand, we explored a diversity of MBH carbonates derived from isatins in the reactions with protected hydroxylamine 3d by the catalysis of chiral amine 1h in chlorobenzene at 0 °C. The results are summarized in Table 2. A series of MBH carbonates 2 bearing either electrondonating or -withdrawing substituents on the aromatic moiety of 2-oxindoles were well tolerated. A higher reactivity was generally observed for MBH carbonates with electron-donating substitutions, and excellent yields and enantioselectivity were obtained ( Table 2, entries 2-4). On the other hand, MBH carbonates with electron-withdrawing groups exhibited a slower reaction rate, but both good yields and ee values were still obtained ( Table 2, entries 5-10).
As outlined in Scheme 2, some synthetic transformations were conducted with the multifunctional allylic amination product 4d. The N-O bond cleavage of 4d could be realized with Zn powder in acetic acid to produce compound 5, albeit in modest yield [34,35], whose absolute configuration has been determined by X-ray analysis [36]. The removal of the O-TBS unit proceeded efficiently in the presence of hydrofluoric acid, and an intramolecular transesterification process of intermediate 6 happened to afford a spirocyclic oxindole 7 without loss of enantiopurity [37].

Conclusion
We have developed a highly enantioselective allylic amination of Morita-Baylis-Hillman carbonates of isatins with N-silyloxycarbamates by the catalysis of a modified β-ICD derivative, which provides an electrophilic process to 3-amino-2-oxindoles with a C3-quaternary chiral center. A range of products with high molecular complexity were obtained with good to excellent enantioselectivity (up to 94% ee) and high yields (up to 97%). Currently, more studies on the catalytic asymmetric transformations of MBH carbonates of isatins are under way in our laboratory.

Supporting Information
General experimental procedures, copies of 1 H, 13 C NMR spectra and HPLC chromatograms for all new compounds, crystal data and structure refinement for enantiopure 5.

Supporting Information File 1
General procedures and analytical data.