Design of Pyrazolo-pyrrolo-pyrazines and Pyrazolo-pyrrolo-diazepines via AuCl₃-Catalyzed and NaH-Supported Cyclization of N-Propargyl Pyrazoles

Abstract

A concise synthetic methodology for new heterocyclic scaffolds, such as pyrazolo-pyrrolo-pyrazine and pyrazolo-pyrrolo-diazepine skeletons, was developed. The key features of this method include (i) synthesis of pyrrole-derived α,β-alkynyl ketones, (ii) introduction of various substituents into the alkyne functionality by Sonogashira cross-coupling, (iii) synthesis of pyrazole units by the reaction of α,β-alkynyl compounds with hydrazine monohydrate, (iv) gold-catalyzed cyclization of pyrazoles with alkyne units, and (v) cyclization with NaH. Furthermore, this methodology allows various substituents to be introduced into all positions of the target compounds.

Transition-Metal-Free Synthesis of Pyrrolo[1,2-a]pyrazines via Intramolecular Cyclization of N-Propargyl(pyrrolyl)enaminones

“…21 Over the past decades, many synthetic methodologies to prepare pyrrolo[1,2-a]pyrazines have been reported. For example, Pd-catalyzed intramolecular cyclization of pyrrole-2-carboxamides, 22 TiCl 4 -catalyzed cyclization of 2-acetyl-N-propargylpyrrole, 23 reaction of pyrrole-2-carbaldehydes and vinyl azides, 24 Curtis reaction in Morita-Baylis-Hillman derivatives, 25 AuCl 3 -catalyzed intermolecular addition of pyrazoles to N-propargylpyrrole, 26 and reaction of propargylamines with pyrazine with subsequent Pd-catalyzed intramolecular cyclization of intermediate propargylpyrazines 10 have been documented. However, most of them require transition metals or are limited by substrate unavailability or complexity.…”

Recent Advances in Functionalization of Pyrroles and their Translational Potential

“…This synthetic technique speaks to a sensible approach for the development of heretofore obscure scaffold, pyrazolo‐pyrrolo‐diazepine and pyrazolo‐pyrrolo‐pyrazine in excellent yields (Scheme 63). [73] …”

Cycloisomerization of π‐Coupled Heteroatom Nucleophiles by Gold Catalysis: En Route to Regiochemically Defined Heterocycles

“…Similar sort of regiospecificity as a dependence of catalyst was also documented by Basceken et al . in the intramolecular hydroamination of N‐propargyl pyrazole/indole and pyrrole derivatives 260 [349,350] . As an illustrative example (Scheme 52, bottom panel), pyrazole lacking any substituent results in 6‐ exo ‐ dig cyclization after treatment with AuCl 3 forming 261 , whilst those containing substitution drives the cyclization in a 7‐ endo ‐ dig fashion to form 262 , as a consequence of different electronic nature of the alkyne residue.…”