Synthesis of α‐(Trifluoromethyl)pyridazine Derivatives

Abstract

Over the last decades, an increasing interest in α‐(trifluoromethyl)pyridazines in medicinal chemistry has been noticed. This interest stems firstly from the recent development of biologically active pyridazines as well as from the capacity of the pyridazine ring to be a bioisoster of other heterocycles. Secondly, due to the influence of a fluorine atom on the chemical and physico‐chemical properties of organic compounds, fluorinated pyridazines have been an attractive scaffold for medicinal chemists. Consequently, the methods that allow the synthesis of fluorinated pyridazines, and more specifically pyridazines possessing either one or two CF3 groups α to the nitrogen atoms, are of great interest and are reported in this review.

Diels–Alder Reaction in the Synthesis of Fluorinated (Hetero)Aromatic Compounds

“…Most of the chemistry towards products I was recently reviewed by Cossy et al [31] [32] Similar ring-opening products were also isolated in the case of reaction with oxazole and 4-methyl imidazole (products 75 and 76, respectively), while in the case of 1methyl-pyrazole the fused product 77 was isolated. In a similar way, compound 71 reacted also with some methoxysubstituted pyridine and quinoline derivatives, in which the corresponding fused pyridazines were isolated in low yields even after prolonged heating in chlorobenzene at 130°C (12-18 d).…”

“…Most of the chemistry towards products I was recently reviewed by Cossy et al Therefore, only selected examples of application of compound 71 are presented here. Compound 71 easily reacts with electron‐rich heteroaromatic compounds.…”

Bicyclic Aziridinium Ions in Azaheterocyclic Chemistry – Preparation and Synthetic Application of 1‐Azoniabicyclo[n.1.0]alkanes

“…Besides the overwhelming number of examples dealing with 1‐azoniabicyclo[3.1.0]hexane‐interceded pyrrolidine‐to‐piperidine transformations, ring‐contraction reactions from 3‐substituted piperidines to 2‐substituted pyrrolidines, involving analogous bicyclic intermediates, are known in the literature as well. Recently, Cossy and co‐workers have developed a general protocol for the ring contraction of 3‐hydroxy‐3‐(trifluoromethyl)piperidines 137 into a broad library of 2‐substituted 2‐(trifluoromethyl)pyrrolidines 139 , using a variety of halogen, nitrogen, oxygen, carbon and sulfur nucleophiles to trigger this ring transformation (Scheme ) . Herein, treatment of 3‐hydroxypiperidines 137 with 1.5 equiv.…”

Construction of Unusual Indole-Based Heterocycles from Tetrahydro-1H-pyridazino[3,4-b]indoles

“…Given the intriguing structures and the medicinal importance of polycyclic indole-based molecules [ 1 , 2 , 3 , 4 , 5 , 6 , 7 ], we envisioned that the amalgamation of the indole moiety [ 8 , 9 , 10 , 11 , 12 , 13 ] with the pyridazine ring [ 14 , 15 , 16 , 17 , 18 , 19 ] that potentially generates different isomeric scaffolds ( a – c ) would lead to entities endowed with either amplified or new biological activities ( Figure 1 ). A large number of reports dedicated to the synthesis of these appealing frameworks and studies on their pharmacologic activities appeared in the literature in the past few decades [ 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 ].…”