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 [4–9]. 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 [11–13] 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 PPh3. It presumably proceeded with the intermediate formation of triphenylphosphazines IVа, IVb and was of low effi ciency. The monitoring of the reaction progress by 1Н 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 1Н NMR spectrum of the reaction mixture the yield of pyridazines V did not exceed 30–32%.