Mechanistic studies of an L-proline-catalyzed pyridazine formation involving a Diels–Alder reaction with inverse electron demand

Abstract

The mechanism of an L-proline-catalyzed pyridazine formation from acetone and aryl-substituted tetrazines via a Diels–Alder reaction with inverse electron demand has been studied with NMR and with electrospray ionization mass spectrometry. A catalytic cycle with three intermediates has been proposed. An enamine derived from L-proline and acetone acts as an electron-rich dienophile in a [4 + 2] cycloaddition with the electron-poor tetrazine forming a tetraazabicyclo[2.2.2]octadiene derivative which then eliminates N2 in a retro-Diels–Alder reaction to yield a 4,5-dihydropyridazine species. The reaction was studied in three variants: unmodified, with a charge-tagged substrate, and with a charge-tagged proline catalyst. The charge-tagging technique strongly increases the ESI response of the respective species and therefore enables to capture otherwise undetected reaction components. With the first two reaction variants, only small intensities of intermediates were found, but the temporal progress of reactants and products could be monitored very well. In experiments with the charge-tagged L-proline-derived catalyst, all three intermediates of the proposed catalytic cycle were detected and characterized by collision-induced dissociation (CID) experiments. Some of the CID pathways of intermediates mimic single steps of the proposed catalytic cycle in the gas phase. Thus, the charge-tagged catalyst proved one more time its superior effectiveness for the detection and study of reactive intermediates at low concentrations.

Reaction Monitoring and Structural Characterisation of Coordination Driven Self-Assembled Systems by Ion Mobility-Mass Spectrometry

“…The challenge of identifying and resolving occluded species is non-trivial to the study of dynamic libraries of self-assembling species in solution ( Figure 3 ) ( Misuraca et al, 2014 ). Mass spectrometry gives ready access to real time analysis of dynamic systems on a millisecond timescale ( Schalley and Springer, 2009 ; Hudgens et al, 2011 ; Pettibone and Hudgens, 2012 ; Olivares et al, 2014 ; Yunker et al, 2014 ; Ligare et al, 2017a ; Ligare et al, 2017b ; Ujma et al, 2017 ; Schnell et al, 2019 ; Mehara and Roithová, 2020 ; Zelenka and Roithová, 2020 ). The difficulties of occluded isobaric and isomeric species can be overcome by adding a filter for shape and size, in addition to m/z , namely, an ion-mobility spectrometer (IMS) ( Ujma et al, 2017 ; Polewski et al, 2021 ).…”

Dibromoisocyanuric Acid: Applications in Brominations and Oxidation Processes for the Synthesis of High Value Compounds

“…More recently, Engeser and co-workers employed Mattos's methodology to affect the bromination of a benzyl tetrazine 40 that was necessary for their work towards Diels-Alder chemistry. [29] In their studies, the benzyl bromide 41 (bearing a tetrazine motif) was formed in 45% yield; latterly transformed into a triphenylphosphine salt needed for their Diels-Alder applications (see scheme 13).…”