Synthesis
DOI: 10.1055/s-0036-1590880
paper
© Georg Thieme Verlag Stuttgart · New York

Synthesis of 3,3-Disubstituted 2-Oxindoles by Deacylative Alkylation of 3-Acetyl-2-oxindoles

Aitor Ortega-Martíneza, b, Cynthia Molinaa, b, Cristina Moreno-Cabrerizoa, b, José M. Sansano*a, b, Carmen Nájera*a
  • aDepartamento de Química Orgánica and Centro de Innovación en Química Avanzada (ORFEO-CINQA), Facultad de Ciencias, Universidad de Alicante, 03080-Alicante, Spain   Email: jmsansano@ua.es   Email: cnajera@ua.es
  • bInstituto de Síntesis Orgánica, Facultad de Ciencias, Universidad de Alicante, 03080-Alicante, Spain
We gratefully acknowledge financial support from the Spanish Ministerio de Ciencia e Innovación (MICINN) (projects CTQ2010-20387 and Consolider Ingenio 2010, CSD2007-00006), the Spanish Ministerio de Economía y Competitividad (MINECO) (projects CTQ2013-43446-P and CTQ2014-51912-REDC), the Spanish Ministerio de Economía, Industria y Competitividad, Agencia Estatal de Investigación (AEI) and Fondo Europeo de Desarrollo Regional (FEDER, EU) (projects CTQ2016-76782-P and CTQ2016-81797-REDC), the Generalitat Valenciana (PROMETEO2009/039 and PROMETEOII/ 2014/017) and the University of Alicante. A.O.-M. thanks MINECO for a predoctoral fellowship.
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Publication History

Received: 09 June 2017

Accepted after revision: 22 July 2017

Publication Date:
22 August 2017 (eFirst)

Abstract

An innovative and efficient monoalkylation and nonsymmetrical 3,3-dialkylation of oxindoles has been achieved. First, the monoalkylation of 3-acetyl-2-oxindoles can be performed in good yields under mild reaction conditions using alkyl halides and benzyltrimethylammonium hydroxide (Triton B) as base at room temperature. This methodology is applied to construct the synthetically challenging compound 1,3-dimethyl-2-oxindole. Subsequent deacylative alkylation (DaA) of the alkylated 3-acetyl-2-oxindoles with alkyl halides takes place efficiently using LiOEt or by conjugate addition with electron-deficient alkenes in the presence of Triton B at room temperature under argon, affording the corresponding unsymmetrically 3,3-disubstituted 2-oxindoles. This simple methodology has been applied to the synthesis of precursors of horsfiline, esermethole, physostigmine, and phenserine alkaloids.

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