Unveiling the mechanism of N-methylation of indole with dimethylcarbonate using either DABCO or DBU as catalyst

Pedro H Vendramini; Lucas A Zeoly; Rodrigo A Cormanich; Michael Buehl; Marcos N Eberlin; Bruno R V Ferreira

doi:10.1002/jms.4707

Unveiling the mechanism of N-methylation of indole with dimethylcarbonate using either DABCO or DBU as catalyst

J Mass Spectrom. 2021 Mar;56(3):e4707. doi: 10.1002/jms.4707.

Authors

Pedro H Vendramini¹, Lucas A Zeoly², Rodrigo A Cormanich³, Michael Buehl⁴, Marcos N Eberlin^{1

5}, Bruno R V Ferreira⁶

Affiliations

¹ Thomson Mass Spectrometry Laboratory, Institute of Chemistry, University of Campinas-UNICAMP, PO Box 6154, Campinas, São Paulo, 13083-970, Brazil.
² Laboratory of Synthesis of Natural Products and Drugs, Institute of Chemistry, University of Campinas-UNICAMP, PO Box 6154, Campinas, São Paulo, 13083-970, Brazil.
³ Institute of Chemistry, University of Campinas-UNICAMP, PO Box 6154, Campinas, São Paulo, 13083-970, Brazil.
⁴ EaStCHEM School of Chemistry, University of St Andrews, North Haugh, St Andrews, KY16 9ST, UK.
⁵ MackMass Laboratory, School of Engineering-PPGEMN, Mackenzie Presbyterian University, Rua da Consolação, 896, São Paulo, São Paulo, 01302-907, Brazil.
⁶ Federal Institute of Education, Science and Technology of Northern Minas Gerais-IFNMG, PO Box 71, Salinas, Minas Gerais, 39560-000, Brazil.

PMID: 33590578
DOI: 10.1002/jms.4707

Abstract

Depending on the catalyst used, N-methylation of indole with dimethylcarbonate (DMC)-an environmentally friendly alkylation agent-yields different products. With 1,4-diazabicyclo[2.2.2]octane (DABCO), the reaction forms only N-methylated indole, but with 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU), both N-methylated and N-methoxycarbonylated indole are formed. Using direct ESI(+)-MS monitoring to collect actual snapshots of the changing ionic composition of the reaction solution, we report on the interception and characterization of key intermediates for such reactions. Although a mechanism has been proposed with methoxycarbonylated base as the key intermediate for both DBU and DABCO, the ESI(+)-MS data and B3LYP-D3/6-311+G** calculations suggest that the reaction of DMC with indole under either DABCO or DBU catalysis follows contrasting mechanisms.

Keywords: ESI(+)-MS/MS; N-methylation; density functional theory calculations; indole; mechanism.

Abstract

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