Multigram Synthesis of a Chiral Substituted Indoline Via Copper-Catalyzed Alkene Aminooxygenation

Abstract

(S)-5-Fluoro-2-(2,2,6,6-tetramethylpiperidin-1-yloxymethyl)-1-tosylindoline, a 2-methyleneoxy-substituted chiral indoline, was synthesized on multigram scale using an efficient copper-catalyzed enantioselective intramolecular alkene aminooxygenation. The synthesis is accomplished in four steps and the indoline is obtained in 89% ee (>98% after one recrystallization). Other highlights include efficient gram-scale synthesis of the (4R,5S)-di-Ph-box ligand and efficient separation of a monoallylaniline from its N,N-diallylaniline by-product by distillation under reduced pressure.

Key words

indoline - aminooxygenation - copper-catalyzed - alkene - TEMPO

• References

• 1 Anas S, Kagan HB. Tetrahedron: Asymmetry 2009; 20: 2193
• 2a Fuller PH, Kim J.-W, Chemler SR. J. Am. Chem. Soc. 2008; 130: 17638
• 2b Liwosz TW, Chemler SR. J. Am. Chem. Soc. 2012; 134: 2020
• 2c Bovino MT, Chemler SR. Angew. Chem. Int. Ed. 2012; 51: 3923
• 3a Seaman W, Norton AR, Woods JT, Bank HN. J. Am. Chem. Soc. 1945; 67: 1571
• 3b Goetz-Luthy N. J. Chem. Educ. 1949; 26: 271
• 3c Bannister WW, Pennace JR, Smith DW, Chelton CF, Wareing JA, Curby WA. J. Chem. Educ. 1973; 50: 578

Original synthesis of ligand 3:
• 4a Masamune S, Lowenthal RE. US Patent 5298623 A 19940329, 1994 ; Chem. Abstr. 1994, 121, 205742
• 4b Desimoni G, Faita G, Mella M. Tetrahedron 1996; 52: 13649
• 4c The method used in the present work: Denmark SE, Stiff CM. J. Org. Chem. 2000; 65: 5875
• 5a We believe loss of conversion upon scale-up is due to self-quenching of the TEMPO radical (disproportionation), which O₂ might prevent
• 5b TEMPO reactivity: Vogler T, Studer A. Synthesis 2008; 1979
• 6a These reactions, as performed (1 atm O₂, balloon), are not expected to pose a fire/explosion hazard, but use of 100% O₂ atmosphere with organic solvents can be an industrial concern. There is precedent for turning a batch process using O₂, balloon, into a continuous flow process that uses 8% O₂ in N₂: Ye X, Johnson MD, Diao T, Yates MH, Stahl SS. Green Chem. 2010; 12: 1180 ; and references cited therein
• 6b After these studies were completed, we found that under O₂ atmosphere the amount of TEMPO can be reduced to 1.5 equiv
• 7 Muniz K, Hovelmann CH, Streuff J. J. Am. Chem. Soc. 2008; 130: 763
• 8 Yip K.-T, Yang M, Law K.-L, Zhu N.-Y, Yang D. J. Am. Chem. Soc. 2006; 128: 3130