Application of the ring-closing metathesis to the formation of 2-aryl-1H-pyrrole-3-carboxylates as building blocks for biologically active compounds

Abstract

Ring-closing metathesis (RCM) is a powerful tool for the preparation of cyclic organic compounds. Yet, one of the major limitations of this method is the difficulty to prepare large quantities of target molecules. Herein we describe a comprehensive study regarding the gram-scale synthesis of 2-aryl-1H-pyrrole-3-carboxylates based on the ring-closing metathesis of the corresponding b-amino esters as a key step. This study includes evaluation of solvent and catalyst as well as reaction kinetics on the RCM. After an aromatization step, this methodology allowed for an efficient generation of variously substituted and unprecedented 2-aryl-1H-pyrrole-3-carboxylates in good yields and cost-effectiveness. The resulting molecules might serve as key building blocks for the generation of CNS-oriented compound libraries.

Continuous flow ring-closing metathesis, an environmentally-friendly route to 2,5-dihydro-1H-pyrrole-3-carboxylates

“…These compounds were then converted efficiently into the corresponding pyrroles, which are highly versatile building blocks for biologically active compounds (Scheme 1). 8 We also demonstrated that the 2,5-dihydro-1H-pyrrole-3-carboxylate 2a was a highly significant intermediate in the synthesis of pyrroloquinolines, 9 which behave as 5-HT 6 receptor neutral antagonists. These compounds, displaying pro-cognitive properties, might be useful in the treatment of the cognitive decline associated with Alzheimer's disease and cognitive disorders caused by genetic abnormalities.…”

“…28 In addition, these solvents were classified as non-toxic for the industrial synthesis of API. 29 Since it was an appropriate solvent for the RCM of 1a in batch, 8 ethyl acetate was first tested (Table 1, entry 2). Reactions using HG-II, M5 1 and M2 2 gave interesting HPLC conversions (>85%) in AcOEt, but the results were not better than those in dichloromethane.…”

“…In comparison, RCM of 15 g of 1a in batch gave less satisfying results. 8 To confirm that the RCM reaction proceeded in the reaction coil and not in the reservoir bottle before pumping into the coil, the conversion was checked, in the reservoir solution, after 37 min. Less than 5% conversion was measured, demonstrating that the RCM process required heating at 120°C in continuous flow.…”

Recent Advancements in Pyrrole Synthesis

“…Lamaty demonstrated a strategy using nitro-Grela as the ruthenium ring-closing metathesis catalyst to form substituted pyrrolines 14 from -amino esters 13. 30 The ensuing deprotection-aromatization step with NaOt-Bu furnished 2-aryl-1H-pyrrole-3-carboxylates 15. The second example by Wu and Li reported the preparation of N-sulfonyl-and N-acylpyrroles 17 and 18.…”

2-Phenyl-1H-pyrrole-3-carboxamide as a New Scaffold for Developing 5-HT6 Receptor Inverse Agonists with Cognition-Enhancing Activity

“…The general synthetic route used to prepare final compounds 7 – 32 is summarized in Scheme . By use of our previously optimized procedures, , intermediates 1 – 4 were synthesized via a four-step sequence involving ( i ) aza-Baylis–Hillman reaction, ( ii ) N-allylation, ( iii ) ring-closing metathesis, and ( iv ) removal of the tosyl group with simultaneous aromatization. Next, saponification of the esters 4a – c in a refluxing aqueous solution of NaOH furnished the carboxylic acids 5a – c .…”