Reaction of heterocyclic enamines with nitrile oxide and nitrilimine precursors

Abstract

Alkylidenepyrrolidines 1, 21, 24 and 26 undergo reactions with nitrile oxides and nitrilimines or their precursors to give a range of novel heterocyclic compounds. With alkylidenepyrrolidine ester 1, nitrolic acids give products in which the liberated nitrous acid reacts with the alkylidenepyrrolidine, followed by two cycloadditions to give adducts 3. In contrast, hydroximoyl chlorides give isoxazoles 10, presumably by cycloaddition/elimination. With hydrazonyl chlorides, simple acylation of the alkylidenepyrrolidine occurs to give compounds 17. With sulfonyl alkylidenepyrrolidines 24 and 26, cycloaddition onto the imine tautomer is the preferred pathway, with a stereoselective reaction taking place in the latter case.

Combined experimental and theoretical studies of regio- and stereoselectivity in reactions of β-isoxazolyl- and β-imidazolyl enamines with nitrile oxides

“…In contrast to the reactions of these β-azolyl enamines, similar reactions of β-alkyl enamines as reported by Bujak et al [24] are regioselective and not stereospecific and therefore not concerted. We could propose stepwise (path 1) and concerted (path 2) reaction mechanisms for the formation of isoxazolines 3a–c as depicted in Scheme 3, in accordance with the proposed reaction mechanisms of heterocyclic enamines proposed earlier by Elliott and co-workers [36]. Path 1 includes the formation of intermediate A as a result of the electrophilic substitution of the β-H atom of the enamines 1a,b after treatment with hydroxamoyl chlorides 2a,d,g .…”

“…This kind of cyclization was ruled out by Elliott et al [36] because of a disfavored 5- endo -trig cyclization for the corresponding intermediate oxime.…”

Discovery of a Stress-Activated Protein Kinase Inhibitor for Lymphatic Filariasis

“…Microfilaria were used as a preliminary screen for efficacy because they are known to be more sensitive to oxidative stress compared to adults. 11,12 Previous work demonstrated that 1 was active at 10 μM using arsenateinduced ROS formation against both adult and microfilarial forms of B. malayi, 8 and lower concentrations of 1 did not inhibit parasite motility. 8 In this work, copper was employed to generate ROS, and in the heat map shown in Table 3, 1 shows microfilarial activity comparable to arsenate-mediated conditions.…”

“…In Scheme , commercially available thiomethyl pyrimidine 5 was deprotonated and reacted with commercially available Weinreb amide N -methoxy- N -methylacetamide affording a 43% yield of methyl ketone 6 . Following isoxazole formation with chlorophenyl oxime 7 , , the resulting sulfide was smoothly converted to sulfone 8 using oxone. Sulfone displacement by amines was accomplished in a straightforward manner in DMF at elevated temperature for up to 5 h, affording the Boc-protected intermediates 9a – h in good yield.…”

“…There is a strong enantioselective preference for (R)-3-aminopyrrolidine (9c) compared to the (S)-isomer (9d). It is likewise clear that trifluoromethyl substitution on the isoxazole is disfavored with an otherwise useful amine (12) and that replacement of the phenyl moiety with 2-or 3-pyridyl (14a,b) is detrimental for Bm-MPK1 potency (Table 1).…”