Continuous-Flow Regioselective Reductive Alkylation of Oxindole with Alcohols and Aldehydes in a Fast and Economical Manner

András Mándoki; György Orsy; Zoltán Pászti; Márta Porcs-Makkay; Dóra Bogdán; Gyula Simig; István Mándity; Balázs Volk

doi:10.1055/a-2122-4080

Synthesis, Table of Contents

Synthesis 2023; 55(23): 4025-4033
DOI: 10.1055/a-2122-4080

paper

Continuous-Flow Regioselective Reductive Alkylation of Oxindole with Alcohols and Aldehydes in a Fast and Economical Manner

András Mándoki

^aArtificial Transporters Research Group, Research Centre for Natural Sciences, Magyar tudósok krt. 2, 1117 Budapest, Hungary

^bDepartment of Organic Chemistry, Faculty of Pharmacy, Semmelweis University, Hőgyes Endre u. 7, 1092 Budapest, Hungary

,

György Orsy

^aArtificial Transporters Research Group, Research Centre for Natural Sciences, Magyar tudósok krt. 2, 1117 Budapest, Hungary

,

Zoltán Pászti

^cRenewable Energy Research Group, Research Centre for Natural Sciences, Magyar tudósok krt. 2, 1117 Budapest, Hungary

,

Márta Porcs-Makkay

^dDirectorate of Drug Substance Development, Egis Pharmaceuticals Plc., P.O. Box 100, 1475 Budapest, Hungary

,

Dóra Bogdán

^aArtificial Transporters Research Group, Research Centre for Natural Sciences, Magyar tudósok krt. 2, 1117 Budapest, Hungary

^bDepartment of Organic Chemistry, Faculty of Pharmacy, Semmelweis University, Hőgyes Endre u. 7, 1092 Budapest, Hungary

,

Gyula Simig

^dDirectorate of Drug Substance Development, Egis Pharmaceuticals Plc., P.O. Box 100, 1475 Budapest, Hungary

,

István Mándity∗

^aArtificial Transporters Research Group, Research Centre for Natural Sciences, Magyar tudósok krt. 2, 1117 Budapest, Hungary

^bDepartment of Organic Chemistry, Faculty of Pharmacy, Semmelweis University, Hőgyes Endre u. 7, 1092 Budapest, Hungary

,

Balázs Volk ∗

^dDirectorate of Drug Substance Development, Egis Pharmaceuticals Plc., P.O. Box 100, 1475 Budapest, Hungary

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Abstract

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Abstract

Oxindole is a widely used scaffold in drug discovery, which can be found in several marketed drugs, among them sunitinib and ziprasidone. Thus, the derivatization of oxindole is of considerable current interest. The extreme reaction conditions (high temperature, high pressure) described in the literature for the batchwise regioselective multistep 3-alkylation of oxindole with alcohols in the presence of Raney nickel motivated us to develop a robust, time- and cost-efficient continuous-flow variant for this reaction. In addition, the continuous-flow technology was also extended to the reductive 3-alkylation of oxindole with aldehydes. The elaborated methodology allows the safe use of Raney nickel, an inexpensive and widely applied, albeit pyrophoric catalyst. Under the optimized reaction conditions, 10 oxindole derivatives were synthesized ranging from simple 3-alkyl to 3-aralkyl derivatives including two (trifluoromethyl)benzyl congeners. The technology is considerably robust and the catalyst showed a long-term usability. The model reaction between oxindole and acetaldehyde could be run for 16 hours uninterruptedly, rendering possible the efficient ethylation of about 20 g of oxindole utilizing only approximately 800 mg of Raney nickel.

Key words

continuous flow - reductive alkylation - oxindole - regioselectivity - Knoevenagel reaction

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References

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