Lewis Acid‐Catalyzed Synthesis of Functionalized Pyrroles

Abstract

The synthesis of highly functionalized pyrroles is described. The sequence involves the preliminary preparation of a-aminohydrazones by Michael addition of primary amines to 1,2-diaza-1,3-butadienes. The treatment of these compounds with dialkyl acetylenedicarboxylates produces a-(Nenamino)-hydrazones that were converted into the corresponding pyrroles by Lewis acid-catalyzed ring closure. A screening of several Lewis/Brønsted acid catalysts was also performed.Keywords: alkynes; 1,2-diaza-1,3-butadienes; hydroamination; Lewis acids; Michael addition; pyrroles Pyrroles are among the most studied heterocyclic ring systems due to their diverse biological activities and applications in materials science. [1,2] As a consequence, much attention has been paid to their preparation by classical methods such as the Knorr, [3] Hantzsch, [4] and Paal-Knorr [5] syntheses. However, these approaches usually present significant limitations in terms of substituents that can be introduced, the substitution pattern, or regioselectivity. Several recent variations in the formation of pyrrole rings are based on metal-catalyzed reactions [6] and catalytic multicomponent coupling methodologies [7] which can improve usefully the classical synthetic approaches.We have demonstrated that the reactions between 1,2-diaza-1,3-butadienes and carbonyl compounds [8] or enol silyl derivatives [9] represent useful and convenient entries to 1-aminopyrroles. Here, we report a new and flexible Knorr-related strategy for the construction of amply functionalized pyrroles. The typical Knorr approach utilizes a-amino ketones and carbonyl derivatives containing an activated methylene group as starting materials.[3] A variation of this synthesis provides for the use of alkynes as reagents rather than carbonyl compounds.[10] In our methodology, the a-amino ketones are replaced with a-aminohydrazones. Their easy and flexible preparation involves the 1,2-diaza-1,3-butadienes 1a-d that readily react with different primary amines 2a, b in tetrahydrofuran at room temperature in the case of 1a-c, or under reflux for 1d producing the desired a-aminohydrazones 3a-f. The reaction takes place by means of 1,4-hydroamination (Michael-type) of the amino derivatives 2a, b to the azo-ene system of the 1,2-diaza-1,3-butadienes 1a-d. (Scheme 1, Table 1). [8b,11] It is noteworthy that a-aminohydrazones are solid compounds and are appreciably more stable to storage and handling than a-amino ketones. In fact, no self-condensation of compounds 3 was observed.In turn, the a-aminohydrazones 3a-f reacted with dialkyl acetylenedicarboxylates 4a-c in ethanol under reflux to give a-(N-enamino)-hydrazones 5a-i in 2-Scheme 1. Synthesis of the a-aminohydrazones 3a-f, and a-(N-enamino)-hydrazones 5a-i. i: THF, room temperature for 1a-c; THF, reflux for 1d. ii: EtOH, reflux.

Zinc(II) Triflate‐Catalyzed Divergent Synthesis of Polyfunctionalized Pyrroles

“…3 J C,H of Z isomers 3.4-3.6 Hz). [17] We have observed that the N-cyclohexyl a-(N-enamino)-hydrazono compounds 5a-f are only in the E forms, while the N-benzyl a-(N-enamino)-hydrazones 5g-j are obtained as a mixture of E/Z isomers (E 55-80%, Z 14-28%). [17] The X-ray diffraction study of (E)-5h (Figure 1) unambiguously supports the assigned structure.…”

“…[17] We have observed that the N-cyclohexyl a-(N-enamino)-hydrazono compounds 5a-f are only in the E forms, while the N-benzyl a-(N-enamino)-hydrazones 5g-j are obtained as a mixture of E/Z isomers (E 55-80%, Z 14-28%). [17] The X-ray diffraction study of (E)-5h (Figure 1) unambiguously supports the assigned structure. [21] We have then explored the conversion of the aaminocarbonyl-a-(N-enamino)-hydrazones 5a-j into the corresponding pyrroles 8a-g by acid-catalyzed intramolecular ring closure.…”

“…[21] We have then explored the conversion of the aaminocarbonyl-a-(N-enamino)-hydrazones 5a-j into the corresponding pyrroles 8a-g by acid-catalyzed intramolecular ring closure. Among the different types of the tested Lewis/Brønsted acids, [17] only the Lewis ones exhibit remarkable catalytic activity, and this occurrence is probably due to the chelation effect of the N-carbonylhydrazones towards metal catalysts (Scheme 2). [22] The discovered optimized conditions for this conversion require a catalytic amount (20%) of ZnA C H T U N G T R E N N U N G (OTf) 2 in dichloromethane under reflux.…”

“…More recently, we have introduced a new and flexible Knorrrelated strategy for the construction of amply functionalized pyrroles A (Scheme 1). [17] The typical Knorr approach utilizes a-amino ketones and carbonyl derivatives containing an activated methylene group as starting materials. [10] A variation of this synthesis implicates the use of alkynes as reagents rather than carbonyl compounds.…”

A Novel Assembly of Substituted Pyrroles by Acid‐Catalyzed Sequential Three‐Component Reaction of Amines, Alkynoates, and 1,2‐Diaza‐1,3‐dienes

“…Pursuing our long-standing interest in the chemistry of heterocycles, we have recently reported a novel synthetic route to highly functionalized pyrroles. [14] Specifically, the process was realized by a preliminary addition of a primary amine to a 1,2-diaza-1,3-diene (DD), [15] a hydroamination reaction with an activated alkyne producing an a-(N-enamino)-hydrazone and a subsequent Lewis acid-catalyzed ring closure by means of intramolecular C-nucleophilic attack to give the pyrrole heterocycle (El 1 + Nu!I 1 + El 2 !4'; Scheme 1, A).…”