Synthesis of Bi‐ and Polyfunctional Isoxazoles from Amino Acid Derived Halogenoximes and Active Methylene Nitriles

Abstract

The reaction of chloroximes that have a protected amino group and active methylene nitriles under basic conditions has been shown to give functionalized 5‐aminoisoxazoles in yields of 37–81 %. This method has a broad substrate scope, including nitriles that contain either an electron‐withdrawing (i.e., CO2Me, CN, or SO2Me) or a heteroaryl group at the α‐position. Moreover, a malononitrile dimer was employed in analogous transformations, which led to the formation of polyfunctional isoxazolo[5,4‐b]pyridines. The selective removal of the protecting groups contained in the product demonstrated the utility of these compounds as advanced building blocks in early drug discovery programs.

Synthesis of 5-(Fluoroalkyl)isoxazole Building Blocks by Regioselective Reactions of Functionalized Halogenoximes

“…Our previous experience with [ 3 + 2] cycloadditions showed that regioselectivity of the reaction can be controlled by using alkenes bearing a leaving group (e.g., bromo or dialkylamino substituents) as the starting materials. 51 To date, only a few examples of similar reactions with trifluoromethyl-substituted substrates were described in the literature, being limited to simple alkyl-or benzonitrile oxides and α,β-unsaturated esters (Scheme 2). 33,34,52 ■ RESULTS AND DISCUSSION Synthesis of isoxazoles.…”

Synthesis of functionalized 4,5-dihydroisoxazoles decorated with the dimethylphosphinoyl group

“…Having intermediate halogenoximes, we started studying their interaction with dimethyl(vinyl)phosphine oxide (13). For the reaction, we chose conditions that previously proved themselves as efficient and reliable ones for a wide range of substrates [30]. Precisely, the reactions were carried out using a 1-to-1 ratio of the starting materials in the presence of a 1.3-fold excess of a weakly basic sodium bicarbonate in the ethyl acetate medium at room temperature.…”

“…One should note that our research group has a profound experience in construction of polysubstituted isoxazoles and 4,5-dihydro analogs [30,31]. We have devised new and optimized known methods towards the heterocyclic platforms, which rely on 1,3-dipolar addition of in situ generated nitrile oxides from halogenoximes to diverse unsaturated partners.…”

Synthesis of 4‐Hetarylisoxazoles from Amino Acid‐Derived Halogenoximes and Push‐Pull Enamines

“…The starting chloroximes 5 – 9 [both ( R )‐ and ( S )‐isomers were used in the case of chiral compounds] and enamines 10 – 18 were prepared according to the known procedures. Existing literature protocols for the [3+2] cycloaddition of halogenoximes and “push‐pull“ enamines varied in the reaction conditions, including AcOH in dioxane–H 2 O, neat Et 3 N, NaHCO 3 in EtOAc,, , and no promoter in dioxane , . In this work, we have used the conditions described in our previous works for similar transformations of the chloroximes 5 – 9 , , .…”

“…Existing literature protocols for the [3+2] cycloaddition of halogenoximes and “push‐pull“ enamines varied in the reaction conditions, including AcOH in dioxane–H 2 O, neat Et 3 N, NaHCO 3 in EtOAc,, , and no promoter in dioxane , . In this work, we have used the conditions described in our previous works for similar transformations of the chloroximes 5 – 9 , , . Thus, treatment of 5 – 9 with NaHCO 3 in EtOAc at room temp., followed by addition of 10 – 18 and subsequent stirring at room temp.…”