The reaction of 1-ethylthio-3-iminopyrrolizines with hydroxylamine. A new synthesis of 3-aminoisoxazoles

The reaction of 1-ethylthio-3-iminopyrrolizine-2-carbonitriles with hydroxylamine leads to 1-hydroxylamino-3-iminopyrrolizine-2-carbonitriles, whereas 1-ethylthio-3-iminopyrrolizine-2-carboxamides and hydroxylamines give 3-aminoisoxazoles, as major products. The exchange of the ethylthio group for the hydroxylamine moiety is a side reaction of this approach.


Introduction
The pyrrolizine and indolizine alkaloids constitute a very large family of natural products having a wide range of biological activities and are isolated from a wide variety of plants, insects, animals, marine organisms and microbes. 1Derivatives of pyrrolizines are used for antiinflammation and analgesia, 2 as aromatase 3 and tumor 4 inhibitors.6][7][8] We have recently reported that 1ethylthio-3-iminopyrrolizines, the products of intramolecular cyclization of 2-(1-ethylthio-2cyanoethenyl)pyrroles, 9 when treated with secondary amines in methanol, readily exchange their ethylthio group for the amine moiety, thus forming the corresponding 1-aminopyrrolizines. 10 In the presence of water, the direction of the reaction of 1-ethylthio-3-iminopyrrolizines with secondary amines is determined by the nature of the substituents in the pyrrolizine cycle: pyrrolizine-2-carbonitriles exchange its ethylthio group for an amine residue only, whereas pyrrolizine-2-carboxamides undergo ring-opening to give the corresponding 2-(1-amino-2-carbamoyl-2-cyanoethenyl)pyrroles. 11With hydrazine hydrate as the amine component, both pyrrolizine-2-carbonitriles and pyrrolizine-2-carboxamides give 1-hydrazino-3iminopyrrolyzines in high yields. 12With the goal of further studying the reaction of 1ethylthiopyrrolizines with amines and establishing its scope and selectivity, as well as for the synthesis of new functionallized aminopyrrolizines with nitrile and carbamide substituents available for further modifications, we have investigated the interaction of 1-ethylthio-3iminopyrrolizines 1a,b and 1c-e with hydroxylamine.

Scheme 1
The reaction was found to be chemoselective: other products were not detected in the reaction mixture (the reaction was monitored by TLC).However, 1-hydroxylamino-3-iminopyrrolizines 2a,b are unstable in DMSO solutions and transform to 2-(2,2-dicyano-1-hydroxylaminoethenyl)pyrroles 3a,b, the concentration of which reaches 12% after 1 h ( 1 H NMR).However, it was impossible to reach completion of this transformation.
Under analogous conditions, with 1-ethyl-3-iminopyrrolizin-2-carboxamides 1c-e the reaction chemoselectivity breaches and 3-aminoisoxazoles 4c-e, as major products, are formed unexpectedly because of a different stability of the compounds in methanol compared to the nitrile analogues.The exchange of the ethylthio group for hydroxylamine in 3-iminopyrrolizines 1c-e, bearing a carbamoyl group, to form 1-hydroxylamino-3-iminopyrrolizines 5c-e is a side reaction of this approach.The ratio of products 4c-e : 5c-e is ~ 2.5 : 1. 3-Aminoisoxazoles 4c-e were isolated by column chromatography (Al 2 O 3 , eluent: methanol), while 1-hydroxylamino-3iminopyrrolizines 5c-e could not be isolated and were characterized by their 1 H NMR spectra in the reaction mixtures.

Scheme 2
The formation of 3-aminoisoxazoles is likely to be the result of the ring opening of the pyrrolizines 5c-e and formation of the pyrroles 6c-e with the syn-disposition of the nitrile function relative to the NH group of the pyrrole ring.Thus, pyrroles 6c-e add a second molecule of hydroxylamine at the nitrile group and the adducts 7c-e ring close to eliminate hydroxylamine giving the major products 3-aminoisoxazoles 4c-e (Scheme 3).
According to elemental analyses, 1-hydroxylamino-3-iminopyrrolizine 2b incorporates a molecule of acetone, which is also confirmed by 1 H NMR.
Structures of 3-aminoisoxazoles 4c-e were reliably confirmed by a series of 1 H and 13 C NMR experiments including homo-(NOESY, COSY) and heteronuclear (HMBC and HSQC) 2D correlations.Additionally, using the 2D HSQC technique optimized for the value of the direct 1 J(H,N) coupling constant, which equals 90 Hz, 15 N chemical shifts for nitrogen atoms in 3amino groups were obtained.They are in agreement with the known values. 13he 1 H NMR spectra of 3-aminoisoxazoles 4c-e show peaks of the pyrrole ring hydrogens (H-3) as a doublet as well as broadened peaks of NH hydrogens of pyrrole, amino and carbamoyl moieties.The amino group hydrogens in 3-aminoisoxazoles 4c-e resonate at 6.92-7.53ppm.
In the 2D HMBC spectrum of 3-aminoisoxazole 4e, the hydrogens of 3-amino group, representing a narrow singlet in 1 H NMR spectrum (in DMSO), show cross-peaks with the 13 C signals at 162.1 ppm (isoxazole C-3) and 98.52 ppm (isoxazole C-4).The peak of H-3 in the pyrrole ring has cross-peaks with the 13 C resonances of quaternary carbon atoms in the pyrrole ring and the signal at 162.95 ppm, assigned to C-5 in isoxazole.
Analysis of 2D NOESY spectra allows to determine exactly the position of CONH 2 group as C-4.This group shows a NOE effect with the H-3 hydrogen and the 3-amino group.
Physical constants and spectral characteristics of all compounds synthesized are given in the Experimental section.

Experimental Section
General Procedures.Melting points are uncorrected.IR spectra (400-4000 cm -1 ) were recorded in KBr pellets on a Bruker IFS-25 spectrometer. 1 H and 13 C NMR spectra were recorded on a Bruker DPX 250 [250.13 ( 1 H) and 62.9 ( 13 C) MHz, respectively] and Bruker DPX 400 [400.13 ( 1 H) MHz] instruments in DMSO-d 6 and referenced to internal HMDS.Structure of compounds was established by 1 H and 13 C NMR data obtained using 2D NMR techniques.Assignment of 13 C resonances was made by employing the 2D HSQC 15 and HMBC 16 heteronuclear correlation techniques.
For recording of 2D HMBC spectra, pulse sequence delays optimized for values of the direct 1 J(H,C) = 145 Hz and far n J(H,C) = 5 Hz coupling constants were used.
The starting 1-ethylthio-3-iminopyrrolizines were synthesized according to a procedure published in. 9Commercial hydroxylamine (Aldrich) was used as a 50% aqueous solution.