diaza-Wittig reactions of diketoesters phosphazines: Synthesis of tetrasubstituted fluoroalkyl-containing pyridazines

Abstract

Pyridazines attract much attention due to their biological activity [1], some of them are used in the treatment of Parkinson, Alzheimer, and other neurodegenerative diseases [2,3]. Therefore the development of new methods of preparation of this class compounds is an urgent problem of the synthetic organic chemistry.In keeping with published reports 3,4,6-trisubstituted pyridazines can be synthesized in good yields from 2-vinyl derivatives of 2-diazoketones by the intramolecular diaza-Wittig reaction [4][5][6][7][8][9]. The only example of the synthesis of the tetrasubstituted pyridazine with the use of analogous procedure was described in [10], where by the diaza-Wittig reaction of the posphazine of 4-diazopyrrolidinetrione with ethyl acetoacetate bicyclic pyrrolo[3,4-c]pyridazine was obtained.The aim of our study was the elucidation of the possibility to obtain 3,4,5,6-tetrasubstituted pyridazines by the intermolecular diaza-Wittig reaction of phosphazines of acyclic diazoketoesters with 1,3-diketones and ketoesters .We used as diazo substrates methyl and ethyl 2-diazo-3-oxo-4,4,4-trifl uorobutanoates (Iа, Ib), аnd as 1,3-dicarbonyl compounds ketoesters IIa, IIb and diketones IIc, IId. In the preparation of the phosphazines from diazoketoesters I we applied the triphenylphosphine (IIIа) commonly used in the Staudinger reaction [11][12][13] and more nucleophilic [14] tris(dimethylamino)phosphine (IIIb).The reaction of diazoketoesters Iа, Ib with ketoester IIа was carried out similarly to procedure [10] using PPh 3 . It presumably proceeded with the intermediate formation of triphenylphosphazines IVа, IVb and was of low effi ciency. The monitoring of the reaction progress by 1 Н NMR spectroscopy showed that under these conditions a fairly complex mixture of products formed containing alongside the target compounds also a diazoacetic ester phosphazine and the other reaction products, and according to the data of 1 Н NMR spectrum of the reaction mixture the yield of pyridazines V did not exceed 30-32%.

Synthesis of α‐(Trifluoromethyl)pyridazine Derivatives

“…In 2011, the synthesis of bis(trifluoromethyl)pyridazines 78 using a diaza‐Wittig reaction was reported . More specifically, diazoketo esters 73 underwent a Staudinger reaction in the presence of tris(dimethylamino)phosphine, to form phosphazines 75 in excellent yields (96–97 %).…”

“…In 2011, the synthesis of bis(trifluoromethyl)pyridazines 78 using a diaza-Wittig reaction was reported. [19] action, releasing N 2 , represents one of the most common methods to obtain bis(trifluoromethyl)pyridazines as well as their derivatives. This reaction, under orbital control (LUMO diene / HOMO dienophile ), is favored by the presence of electron-withdrawing groups on the tetrazine and electron-donating groups on the dienophile.…”

Strategy for the Synthesis of Pyridazine Heterocycles and Their Derivatives

“…As part of an ongoing project on the synthesis of small heterocycles of pharmaceutical interest, a strategy for the synthesis of functionalized pyridazines by a diaza-Wittig reaction has been developed. In search for operationally simple synthetic processes, we have now developed a convenient and safe method for the synthesis of 6-substituted 4-hydroxy-3-methoxycarbonyl pyridazines starting from methyl acetoacetate.…”

TBAI/K2S2O8-Promoted [4 + 2] Annulation of Ketene N,S-Acetals and N-Tosylhydrazones toward Pyridazines

“…13 Recently, Zhai's group synthesized pyridazines from a ring-contractive extrusion reaction of thiadiazepine S-oxides. 14 He, 15 Volkova, 4b Mostafa, 2 and Nikolaev et al 16 also described colorful procedures to pyridazines. Although numerous efforts have been documented to synthesize pyridazines, most of these methods are limited to employing prefunctionalized substrates, utilizing toxic and unstable reagents, and multistep sequences.…”