Manganese‐Catalyzed Multicomponent Synthesis of Pyrroles through Acceptorless Dehydrogenation Hydrogen Autotransfer Catalysis: Experiment and Computation

Abstract

An ew base metal catalyzed sustainable multicomponent synthesis of pyrroles from readily available substrates is reported. The developed protocolu tilizes an air-and moisture-stable catalyst system and enablest he replacement of themutagenic ahaloketones with readily abundant 1,2-diols. Moreover,the presented method is catalytic in base and the sole byproducts of this transformation are water and hydrogen gas. Experimental and computationalm echanistic studies indicatet hat the reactiont akes place through ac ombineda cceptorless dehydrogenation hydrogenautotransfermethodology.Multicomponent reactions are valuable sustainable processes for the construction of complex molecules in one pot from three or more substrates. This strategy merges severale lementary reaction steps, which leads to minimization of the amount of waste, and simplifies the workup and purifications teps. [1] Pyrroles represent prominent and important chemicalm otifs in medicinal, agro, and advanced materials chemistry.C lassical synthetic routes suffer from drawbacks mainly resultingf rom the generation of substantial amounts of waste produced during the multi-stepp re-functionalization of substrates or byproduct formation. [2] Accordingly,t here is ac ontinuous need to develop new catalytic systems that allow the direct and atom-economic conversion of renewable and readily available substrates to pyrroles.Alcohols can be obtained from renewable biomass resources and presentp romising sustainable feedstock chemicals. The utilization of alcohols as substrates in the synthesis of fine chemicals will hence contributen ot only to the reduction of toxic chemical waste but also to decrease CO 2 emissions by avoidingthe use of carbon fossil sources. [3] One of the key concepts for alcoholf unctionalization is hydrogen autotransfer (HA), which has become ap owerful tool for utilizing abundant alcohols as building blocks for environmentally benign CÀC and CÀNb ondf ormations, releasing water as the only byproduct (Scheme 1A). [4] Ar elatedc oncept is acceptorless dehydrogenation(AD), which permits the conversion of alcohols to car-Scheme1.Acceptorless dehydrogenation and hydrogen autotransfer catalysis.

Diastereoselective diazenyl formation: the key for manganese-catalysed alcohol conversion into (E)-alkenes

“…As it has been previously reported in similar homogeneous catalysts, 16,28 proton transfer from the hydroxyl group in the alcohol to the N in the catalyst is hypothesised as a barrier-less process for the step-wise mechanism (see Fig. S1 at the ESI †).…”

“…16 Definitively, these are just a few instances amongst the plethora of organic transformations catalysed by manganese that have been reported in the last lustrum. [17][18][19][20][21][22][23][24][25][26] Encouraged by our interests in the unravelling of the mechanistic aspects in the catalytic chemistry of manganese, [27][28][29][30] the recent work by Milstein et al, 31 reporting for first-time a manganese-catalysed coupling of alcohols and hydrazone to form alkenes, caught our attention. As an alternative to the classical approaches for the synthesis of olefins from carbonyl compounds (such as Wittig, 32 Peterson, 33 or Julia 34 olefinations), Milstein and co-workers offer an unprecedented base-and waste-free procedure for the direct transformation of alcohols into alkenes.…”

Manganese Catalyzed Acceptorless Dehydrogenative Coupling Reactions

“…Later, a multi‐component synthesis of highly substituted pyrroles 33 via the ADC of 1,2‐diols 28 , ketones 20 , and primary amines 2 in the presence of lutidine derived pincer complex Mn‐30 , and a catalytic amount of KO t Bu was developed (Scheme ) . Mechanistic studies showed that reaction takes place through a combined ADC and BH methodology ( vide infra ).…”

Manganese‐Catalysed Dehydrogenative Coupling – An Overview

“…A manganese‐pincer complex that catalysed the three‐component reaction of a 1,2‐diol, an α‐functionalised ketone, and a primary amine was introduced by same group for the synthesis of substituted pyrroles (Scheme ) . A stable manganese complex ( 105 ) is used with t‐ BuOK as base which generates the active catalyst and the reaction proceeds at 135 °C for 24 h. Various ketones, amines and diols worked well in this reaction protocol in which a bulky amine like adamantylamine and substituted as well as cyclic vicinal diols have lower reactivity.…”