Enantioselective addition of diphenyl phosphonate to ketimines derived from isatins catalyzed by binaphthyl-modified organocatalysts

Chiral binaphthyl-modified squaramide-catalyzed enantioselective addition of diphenyl phosphonate to ketimines derived from isatins has been achieved. This method affords practical and efficient access to chiral 3-amino-3-phosphonyl-substituted oxindole derivatives in high yields with excellent enantioselectivities (up to 99% ee).

Recently, there were a few reports on the synthesis of chiral 3-amino-3-phosphonyl-substituted oxindole derivatives by the catalytic enantioselective hydrophosphonation of ketimines [36,37]. The previous synthetic procedures suffered from several drawbacks, such as a high catalyst loading, long reaction time, and low temperature required for good enantioselectivity. Thus, new approaches for the organocatalytic enantioselective addition of diphenyl phosphonate to isatin imines are highly desired.

Results and Discussion
To determine suitable reaction conditions for the organocatalytic enantioselective addition reaction of diphenyl phosphonate to ketimines derived from isatins, we initially investigated a reaction system with ketimine 1a derived from N-allylisatin and diphenyl phosphonate (2) with organocatalyst in the presence of 4 Å molecular sieves. We first surveyed the effect of the structure of bifunctional organocatalysts I-VI ( Figure 1) on enantioselectivity in ethyl acetate at room temperature (Table 1, entries 1-6). Catalyst III, which is a binaphthyl-modified squaramide bifunctional organocatalyst, was the best catalyst for this enantioselective addition reaction (90% ee, Table 1, entry 3). In order to improve the selectivity, different solvents were tested in the presence of 10 mol % of catalyst III together with ketimine 1a and diphenyl phosphonate (2). We obtained excellent results in ethyl acetate (85% yield, 90% ee, Table 1, entry 3), while a slight decrease in enationselectivities was observed when dichloromethane, chloroform, tetrahydrofuran, toluene, and methanol were used as the solvent (Table 1, entries 7-11). Under low catalyst loading of 2.5 mol %, this enantioselective addition reaction proceeded successfully to give 3a without compromising the reactivity and enantioselectivity ( With the optimized conditions in hand, we proceeded to investigate the scope of the enantioselective addition of diphenyl phosphonate (2) with various ketimines 1 in the presence of 2.5 mol % of binaphthyl-modified squaramide-tertiary amine catalyst III in ethyl acetate at 0 °C ( Table 2). The corresponding addition products 3a-l were formed in high yields (74-94%) with excellent enantioselectivities (up to 99% ee). The reaction of diphenyl phosphonate (2) with N-allylated and
The stereochemical outcome in the above addition reaction was rationalized by a proposed stereochemical model. We propose that ketimine 1 is activated by the squaramide moiety through hydrogen bonding, and diphenyl phosphonate (2) is activated by the basic nitrogen atom in the tertiary amine of catalyst III. Then, diphenyl phosphonate (2) attacks the re-face of the carbon in ketimine 1 as shown in Figure 2.
To further demonstrate the synthetic potential of this method, we performed the addition reaction at the gram scale. As shown in Scheme 1, when ketimine 1a was treated with diphenyl phosphonate (2) in the presence of 2.5 mol % of catalyst III at 0 °C, the desired product 3a was obtained in 81% yield and 93% ee (Scheme 1).

Conclusion
In conclusion, we have developed a practical and efficient catalytic enantioselective addition reaction of diphenyl phosphonate (2) with various ketimines 1 derived from isatins. This transformation is catalyzed by binaphthyl-modified squaramide catalyst III with low catalyst loading (2.5 mol %). Chiral 3-amino-3-phosphonyl-substituted oxindole derivatives were obtained in high yields and excellent enantioselectivities were observed (up to 99% ee). This reaction affords valuable and easy access to chiral 3-amino-3-phosphonyl-substituted oxindole derivatives.

Experimental
General procedure for the enantioselective addition of diphenyl phosphonate (2) to ketimines derived from isatins 1: To a solution of ketimine 1 (0.3 mmol), diphenyl phosphonate (2, 0.45 mmol), and 4 Å molecular sieves (150 mg) in ethyl acetate (3 mL), the catalyst (III, 7.5 μmol) was added at 0 °C. The reaction mixture was stirred for 12-48 h. After completion of the reaction, the resulting solution was concentrated in vacuo and the obtained residue was purified by flash chromatography (EtOAc-hexane) to afford the corresponding adducts 3.

Supporting Information
Supporting Information File 1 Experimental and analytical data.