The Hantzsch Pyrrole Synthesis: Non-conventional Variations and Applications of a Neglected Classical Reaction

Abstract

Pyrrole is one of the most important one-ring heterocycles because of its widespread presence in natural products and unnatural bioactive compounds and drugs in clinical use. The preparation of pyrroles by reaction between primary amines, β-dicarbonyl compounds, and α-halo ketones, known as the Hantzsch pyrrole synthesis, is reviewed here for the first time. In spite of its age and its named reaction status, this method has received little attention in the literature. Recent work involving the use of non-conventional conditions has rejuvenated this classical reaction and this is emphasized in this review. Some applications of the Hantzsch reaction in target-oriented synthesis are also discussed.1 Introduction2 The Conventional Hantzsch Pyrrole Synthesis3 Hantzsch Pyrrole Synthesis under Non-conventional Conditions4 Applications of the Hantzsch Pyrrole Synthesis5 Conclusions

Synthesis of 1,4-Diazepanes and Benzo[b][1,4]diazepines by a Domino Process Involving theIn SituGeneration of an Aza-Nazarov Reagent

“…This reaction can be regarded a chemo-differentiating ABB′ three-component process, where one of the components has two different roles in the reaction . Again having in mind the synthetic application of our transformation, the fact that compound 8 contains a β-enaminoester structural fragment encouraged us to demonstrate its applicability as a synthetic intermediate, and to this end we chose to study 8 as a substrate for our mechanochemical generalization of the Hantsch pyrrole synthesis. , As shown in Scheme , phenacyl iodide ( 9 ) was obtained by mechanochemical α-iodination of acetophenone with N -iodosuccinimide in the presence of TsOH, in a solvent-free reaction promoted by ball milling (20 Hz, 1 h) . To this reaction mixture were added compound 8 , CAN as a catalyst and silver nitrate to capture the HI released in the alkylation of 8 by 9 , and ball milling was continued under the same conditions for an additional hour to furnish the highly functionalized pyrrole derivative 10 in moderate yield.…”

Synform Issue 2021/12

“…A recent review has reported the revival of the Hantzsch pyrrole synthesis under 'unconventional' conditions, including microwave irradiation and mechanochemistry. 6 The Hantzsch methods for the syntheses of nitrogen heterocycles with one heteroatom (pyridines and pyrroles) are summarized in Scheme 1. In these reactions, a β-keto ester 6 reacts with an α-chloro ketone 7 and ammonia (which react to form an α-amino ketone, 8) to give a densely substituted pyrrole 9, 4 or with ammonia and an aldehyde (usually an arom atic aldehyde, 10) to give a Hantzsch ester, 11, that contains a densely substituted 1,4-dihydropyridine ring.…”

Synthesis of unsymmetrically tetrasubstituted pyrroles and studies of AIEE in pyrrolo[1,2-a]pyrimidine derivatives

“…Classically, pyrroles can be synthesized by the Paal–Knorr reaction 3 or the Hantzsch reaction. 4 Many other syntheses of pyrroles have been established, 5 including powerful coupling strategies realized by transition-metals 5 and the van Leusen pyrrole synthesis. 6 However, the major disadvantages of these protocols lie in their requirement for substrate pre-functionalization, substituent deficiency and formation of by-products.…”