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Enantioselective Synthesis of Quaternary Oxindoles: Desymmetrizing Staudinger-Aza-Wittig Reaction Enabled by a Bespoke HypPhos Oxide Catalyst

Changmin Xie, Jacob Kim, Binh Khanh Mai, Shixuan Cao, Rong Ye, Xin-Yi Wang, Peng Liu* and Ohyun Kwon*

*University of Pittsburgh, Pittsburgh, Pennsylvania 15260; University of California, Los Angeles, California 90095-1569, United States, Email:,

C. Xie, J. Kim, B. K. Mai, S. Cao, R. Ye, X.-Y. Wang, P. Liu, O. Kwon, J. Am. Chem. Soc., 2022, 144, 21318-21327.

DOI: 10.1021/jacs.2c09421

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A chiral phosphine oxide catalyzes an asymmetric Staudinger-aza-Wittig reaction of (o-azidoaryl)malonates to provide chiral quaternary oxindoles in the presence of a silane reductant and an IrI-based Lewis acid. The reaction occurs under mild conditions, with good functional group tolerance, a wide substrate scope, and excellent enantioselectivity.

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synthetic applications

Standard Conditions for the Asymmetric Staudinger-Aza-Wittig Reaction

An oven-dried reaction tube equipped with a magnetic stirrer bar was charged with a mixture of 3 (0.05 mmol), the phosphine oxide 2[O] (3.0 mg, 0.01 mmol, 10 mol%), [Ir(cod)Cl]2 (1.7 mg, 0.025 mmol, 5 mol%), tetrabutylammonium tetrafluoroborate (TBABF4, 1.7 mg, 0.01 mmol, 10 mol%), and 4- molecular sieves (5 mg). The tube was evacuated and filled with N2 three times. Cyclohexane (1 mL) was added and then the mixture was stirred at rt for 15 min. PhSiH3 (18.4 L, 0.15 mmol) was added and then the mixture was stirred at rt for another 15 min, before warming to 45 C. After 48 h (with complete consumption of 3, as monitored using TLC), silica gel (2 g/mmol) or PTSA (5 mol%) was added to assist the hydrolysis of the imidate to the oxindole. The mixture was then loaded onto a silica gel column and purified through FCC (hex/EtOAc) to give the desired oxindole 4 or imidate 11.

[Notes: (1) Generally, the imidate 11 was observed as the product after the aza-Wittig reaction, based on analyses using TLC and crude 1H NMR spectroscopy. After silica gel FCC, the oxindole 4 was isolated. (2) In some situations the imidate could be isolated through FCC using NEt3-neutralized silica gel. In these cases, silica gel or PTS-promoted hydrolysis was omitted. (3) After the reactions had reached completion, only two peaks appeared in the 31P NMR spectra of the crude reaction mixtures in most cases: at -22 ppm for 2 and at 47.2 ppm for 2[O]. The results indicate that our catalyst was conformationally stable under the reaction conditions.]

Key Words

oxindoles, Staudinger reaction, phenylsilane

ID: J48-Y2022