Synthesis of perfluoroalkylated heterocyclic phosphonates

Abstract

Perfluoroalkylated heterocyclic phosphonates have been conveniently synthesized by 1,3-dipolar cycloaddition of aromatic nitrile oxides (or ethyl diazoacetate or tert-butyl azidoacetate) and perfluoroalkylated alkynylphosphonates in good to excellent yields with high regioselectivity.A large number of phosphonic acids and their derivatives have been shown to exhibit important biological properties, including antibiotic, antileukaemic and insecticidal activity, depending on the nature of substituent on the phosphonic group.' Introduction of a fluorine atom or perfluoroalkyl group into compounds with biological properties often leads to pronounced activity enhancement, and organofluorine compounds have been applied increasingly in pharmaceuticals, agrichemicals and other fields. Furthermore heterocyclic compounds, particularly fluorine-containing heterocyclic species, play important roles in the fields of medicinal and agricultural ~hemistry.~ Therefore, it is of interest to develop a convenient method for the synthesis of the title compounds since they may be expected to possess biological activity.

Reaction of benzohydroximinoyl chlorides and β‐(trifluoromethyl)‐acetylenic esters: Synthesis of regioisomeric (trifluoromethyl)‐isoxazolecarboxylate esters and oxime addition products

“…Trisubstituted isoxazoles can be prepared directly by dipolar cycloadditions, which give 5-trifluoromethyl isomers as the major product from addition of nitrile oxides to perfluoroalkyl substituted β-ketoesters, acetylenes and acrylates. Small amounts (5 -10%) of the regioisomeric 4-trifluoromethylisoxazoles have been proposed based on the analysis of crude reaction mixtures, however these minor products have not been previously isolated or characterized [15,18]. A notable exception is the addition of 1aryl-3-trifluoromethylacetylenes to nitrile oxides which gives 4-trifluoromethylisoxazoles as the major product [19].…”

Capture of 3‐Amino‐4‐oxycyanofurazan and Characterization of Isoxazole Product

“…To 600-mL diethyl ether solution of 3-amino-4-chloroximinofurazan (48 g, 0.295 mol) in a three-necked, round-bottomed flask fitted with a mechanical stirrer and a dropping funnel, 490-mL 3% aqueous solution of sodium carbonate was added dropwise at 0∼3°C (Scheme 5). 1 H NMR (DMSO-d 6 , 500 MHz) δ, ppm: 6.61(s, 4H, NH 2 ); 13 Selected bond lengths (nm × 10 −1 ) for compound 4 crystal structure parameters. The solution was evaporated to dryness under reduced pressure, and the residue was recrystallized from ethanol and afforded the product 27.5 g with a yield of 73.6%.…”

“…Unfortunately, the procedure suffered from low yield of the last step. However, the mechanism was unproved, because AOCF was unstable even at low temperature and could not be isolated from the reaction system [13][14][15][16][17][18]. To our knowledge, only a primitive mechanism was reported, which proposed an intermediate, 3-amino-4-oxycyanofurazan (AOCF) [11,12], presenting before the formation of DATF (Scheme 2).…”

“…To our knowledge, only a primitive mechanism was reported, which proposed an intermediate, 3-amino-4-oxycyanofurazan (AOCF) [11,12], presenting before the formation of DATF (Scheme 2). However, the mechanism was unproved, because AOCF was unstable even at low temperature and could not be isolated from the reaction system [13][14][15][16][17][18].…”

Fluorinated Triazoles and Tetrazoles

“…Such an approach made it possible to perform a regioselective synthesis of nucleosides analogs containing in their molecular structure a trifl uoromethyl-1,2,3-triazolyl fragment 35 [ 42 ]. The reaction of tert -butyl azidoacetate with diisopropyl-3,3,3-trifl uoroprop-1-ynylphosphonate gave regioisomeric diisopropyl(1-tert -butoxycarbonylmethyl-4-trifl uoromethyl-1 H -l,2,3-triazol-5-yl)phosphonate 36 and disopropyl(l-tert -but oxycarbonylmethyl-5-fl uoromethyl-lH-l,2,3-triazol-4-yl)phosphonate 37 in 75:25 ratio (90 % overall yield) [ 43 ]. Pentamethylcyclopentadienylrhodium (or iridium) azido complexes 38 react with ditrifl uoromethylacetylene to give the corresponding 1,2,3-triazole rhodium complex 39 .…”