Abstract
We introduce a novel isocyanide-based multicomponent reaction, the Passerini four component reaction (P-4CR), by replacing the carboxylic acid component of a conventional Passerini three component reaction (P-3CR) with an alcohol and CO2. Key to this approach is the use of a switchable solvent system, allowing the synthesis of a variety of α-carbonate-amides. The reaction was first investigated and optimized using butanol, isobutyraldehyde, tert-butyl isocyanide and CO2. Parameters investigated included the effect of reactant equivalents, reactant concentration, solvent, catalyst, catalyst concentration and CO2 pressure. Of the other parameters, the purity of the aldehyde and its tendency to oxidize was one of the most critical parameters for a successful P-4CR. After optimization, a total of twelve (12) P-4CR compounds were synthesized with conversions ranging between 16 and 82% and isolated yields between 18 and 43%. Their structures were confirmed via1H and 13C NMR, FT-IR and high resolution mass spectrometry (ESI-MS). In addition, three (3) hydrolysis products of P-4CR (α-hydroxyl-amides) were successfully isolated with yields between 23 and 63% and fully characterized (1H, 13C NMR, FT-IR and ESI-MS) as well.
Highlights
Multicomponent reactions (MCRs) are de ned as reactions involving more than two starting materials, while forming products in which most of the atoms of the starting materials are incorporated.[1]
As a starting point and to prove our hypothesis of a possible P4CR, we investigated the reaction of butanol, isobutyraldehyde, tert-butylisocyanide and CO2 in dichloromethane (DCM) as a solvent
As we observed in the further course of our investigations, the formation of the P-3CR product is due to the presence of the respective carboxylic acids originating from the oxidation of the used aldehyde component
Summary
1960 and involves a carboxylic acid, carbonyl component (aldehyde or ketone), an isocyanide and an amine as components, leading to the formation of a bis-amide.[5]. The idea is to utilize this in situ generated carbonate anion as an acid component (i.e. nucleophile) in a typical P-3CR and is the starting point of the reported results. In this case, the CO2 is able to activate the alcohols and is incorporated as C1 carbon source into the desired compound. The utilization of CO2 as a carbon source is both interesting from an environmental and sustainable perspective as well as to extend the scope and achievable structural variety of MCRs
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