Synthesis of condensed isoxazolines and isoxazolidines via cycloaddition to furan-2(5 H )-ones

Cycloadditions of nitrone 1 and pyridylnitrile oxide 4 to furanones 2 and 3 afford tetrahydrofuro[3’,4’:4,5]isoxazolo[2,3-a ]dibenzo[ c,f ]azepin-1(3 H )-ones and furo[3,4-d ]isoxazolin-4( H )-ones, respectively, in a totally regioselective manner. The resulting adducts evolve into the corresponding pyrroloisoxazole systems by treatment with ammonium hydroxide and hydrazine hydrate in good yield. The N-O bond of isoxazolo[2,3-a ]dibenzo[ c,f ]azepin-1(3 H )-ones is not cleaved by LiAlH 4 .


Introduction
The valuable and diverse biological activity of molecules containing isoxazoline/isoxazolidine rings, 1 pyrroloazepines, 2 pyrrolinones, 3 or 2, 3,3a,8-tetrahydrodibenzo[c,f]isoxazolo [2,3a]azepines, 4 confers on them a high pharmacological value.1,3-Dipolar cycloadditions, by using nitrile oxides and nitrones as dipoles, are one of the best reported methods for building isoxazoline and isoxazolidine skeletons, respectively. 5,6In an earlier work we reported the efficiency of 5-alkoxyfuran-2(5H)-ones as dipolarophiles in reactions with diazoalkanes, 7 alkyl-, bromo-or benzonitrile oxides, 8 azomethine ylides, 9 nitrones, 10 and carbonyl ylides. 11One of the most significant features of adducts formed in these reactions is the versatility of their functionalities, which allows the subsequent synthesis of other heterocyclic systems, that are not easily obtained from other precursors.In this sense, we have reported the regioselective synthesis of functionalized pyrroloazepines and isoxazolo [4,5-d]pyridazin-4(5H) [and 7(6H)]-ones from the adducts obtained from reactions of 5-alkoxyfuran-2(5H)-ones with 11H-dibenzo [b,e]azepine 5-oxide (1) 10b and nitrile oxides, 8b respectively.With these precedents, we reasoned that it would be interesting to develop some strategies involving the use of furanones with the aim of obtaining new pyrrolo [3,4-d]isoxazole 12 structures bearing diverse functionalities.In this paper we report the results obtained in the reactions of commercially available furan-2(5H)-one 2 and methoxyfuranone (3) 13 with nitrone 1 4 and pyridylnitrile oxides 4 and 5 (Scheme 1), and the transformation of the resulting adducts into the corresponding pyrrolinones.

Results and Discussion
The 1,3-dipolar cycloaddition at room temperature of nitrone 1 to commercially available furanone 2 afforded 6 in 92% yield after 18 hours (Scheme 2).The reaction was totally regioselective.Similar results were obtained from reaction of 1 with methoxyfuranone 3, affording 7 in 84% yield.10b With the adducts 6 and 7 in hand, their reactions with LiAlH4 (LAH) were studied.In the presence of an excess of the reagent (1.5 equiv mol), 6 and 7 afforded diol 8 10b in 89% and 93% yield, respectively (Scheme 2).Diol 8 can be used as the starting material in the synthesis of racemic pyrroloazepines.10b However, when the reduction of 7 was carried out by using 0.7 equiv mol of LAH and the reaction was quenched after 5 min, a 35:65 mixture of diol 8 and hemiacetal 9 was obtained in almost quantitative yield.Upon chromatographic separation, compounds 9 and 8 were isolated in 63% and 24% yield, respectively.10a ISSN 1551-7012 Page 305
According to the structure assigned to 9, it is the carbonyl group of compound 7 which suffers the reduction under the latter conditions.It contrasts with the well-documented reduction of 5-alkoxyfuran-2(5H)-ones with NaBH4, which affords products resulting from the reduction of the acetal moiety C-5 (C-3 in compound 9).The formation of the stable hemiacetal 9 can be explained by assuming the nucleophilic hydride addition to the carbonyl group at 7, followed by ring opening of lactone, reduction of the aldehyde with simultaneous elimination of methanol, and final cyclization into the hemiacetal 9 (Scheme 3).

Scheme 3
The cleavage of the N-O bond in isoxazolidines 6 and 8 into aminoalcoholes 10-11 was satisfactorily carried out by hydrogenolysis with H2/Pd(C) 10% in ethanol (Scheme 4), under conditions similar to those that we had previously reported for related compounds.

Scheme 4
Isoxazolidine 8 was transformed into pyrrolo [3',4':4,5]isoxazolo[2,3-a]dibenzo[c,f]azepine 12 by double mesylation followed by reaction with benzylamine (Scheme 4).Pyrrolo[3',4':4,5]isoxazolo[2,3-a]dibenzo[c,f]azepin-1-one derivatives were obtained by reaction of 7 with nitrogenated nucleophiles (Scheme 5).When the reactions were carried out under heterogeneous phase with ammonium hydroxide or hydrazine hydrate, 13a or 14a were isolated in good yields as the sole products.However, inseparable mixtures of steroisomers a and b (epimer at hemiaminal carbon) of compounds 13 and 14 were obtained when the reactions were performed in THF or ethanol as the solvents.Under these conditions, reaction times are shorter than those required under heterogeneous phase.The formation of isomers a and b can be rationalized by assuming that the opening of the lactone ring by the amine and subsequent elimination of methanol generates aldehyde I, which can adopt two plausible conformations around the C-CHO bond (I-A and I-B).The subsequent attack of nitrogen to each one of these conformations (I-A and I-B) would afford isomers a and b, respectively.The higher stability of conformation A (B must be less stable due to electrostatic repulsion between both oxygen atoms, Scheme 5) can account for the major or sole formation of the a isomers.

Scheme 5
Next we studied some reactions of the furanones with nitrile oxides.The reaction of 3 with nicotinonitrile oxide 4, 15 generated "in situ" by slow addition of triethylamine (with a syringe pump) on to 3-[chloro(hydroxymino)methyl]pyridinium chloride, afforded 15 as the sole adduct in good yield after 4 hours (Scheme 6).The complete regioselectivity and stereoselectivity observed in this reaction are not unexpected, since a similar behavior had been observed in reactions of 3 with other nitrile oxides.8c By contrast, reactions of nitrile oxide 5 with furanone 3 afforded mixtures of regioisomers 16 and 17 under all experimental conditions assayed (Scheme 6), although the stereoselectivity remains complete (anti with respect to the methoxy group at 3).Both 16 and 17 could be isolated as pure compounds by column chromatography.8c,17 It can be rationalized by assuming that the electronwithdrawing effect of the 2-pyridinyl group lowers the energy at the HOMO of the nitrile oxide, thus modifying the type of cycloadition 18 (II or III instead I, according to the Sutsman clasification) 19 .A similar effect can be invoked in order to justify the higher regioselectivity observed in acetonitrile (it must provoke a higher stabilization of the HOMO than toluene).Reactions of furo [3,4-d]isoxazole 15 with nitrogenated nucleophiles provided compounds exhibiting isoxazoline-pyrrolidine condensed rings (Scheme 7).Hence, 15 reacted at room temperature with ammonium hydroxide and hydrazine hydrate, without solvent, giving compounds 18 and 19, respectively, as the sole products in good yields.Under similar conditions, benzylamine afforded a mixture of pyrrolinones 20 and 21 (Scheme 7).The results obtained in reactions of 15 and 7 with nitrogenated nucleophiles described in this paper, are in agreement with those reported by us for 6-methoxy-3-methylfuro [3,4-d]isoxazol-4(3aH)-one, 20 but contrast with those reported by Fišera for the 6-ethoxy-3-phenylderivative, 16a which evolves into a 50:50 mixture of epimers at C-6 of pyrrolo [3,4-d]isoxazolones by treatment with ammonia (in MeOH), or tetrahydroisoxazolo [3,4-d]pyridazin-4(3H)-ones by reaction with hydrazine hydrate (refluxing water/AcOH, 9:7).
The formation of isoxazolopyrrolinones 18-20 can be explained according to sequence depicted in Scheme 5.The formation of compound 21 can be rationalized also from intermediate I at Scheme 5 through of corresponding intermediate imine and subsequent cyclization by nucleophilic attack of amide nitrogen to iminic carbon.
The structures of the compounds 13, 14, 18, 19, and 20, were established on the basis of their spectroscopic parameters.In Table 1 are collected the most significant ones.The IR absorption frequency (> 1680 cm -1 ) and the 13 C chemical shift (>165 ppm) of the C=O group, as well as the value of the coupling constant J6,6a (ca.0 Hz) confirm the pyrrolinone structure assigned to these compounds.

Reduction of the furanone ring
Method A. To a solution of isoxazolidines 6 or 7 10b (0.33 mmol) in THF (5.5 mL), vigorously stirred at room temperature, was added LAH (0.82 mmol) in small portions.The reaction mixture was stirred for 30 minutes and then ethyl acetate (10 mL) and water (10 mL) were added.The layers were separated and the aqueous phase was extracted with ethyl acetate (3 x 20 mL).The organic phase was dried over Na2SO4 and evaporated at reduced pressure.Method B. To a stirred solution of isoxazolidine 7 (0.33 mmol) in THF (5.5 mL) at room temperature was added in small portions 0.24 mmol of LAH.After 30 minutes a mixture of ethyl acetate (10 mL) and water (10 mL) were added.The organic layer was separated and the aqueous phase was extracted with ethyl acetate (3 x 20 mL).The combined organic layers was dried (Na2SO4) and the solvent was removed under reduced pressure to give a 35:65 mixture of ()-8 and ()-

Cleavage of the N-O bond
To a solution of 0.52 mmol of isoxazolidine ()-6 or ()-8 in ethyl acetate (or ethanol) (9 mL) was added 55 mg (0.052 mmol, 10% mol) of Pd/(C) (10%).The mixture was stirred at room temperature under hydrogen pressure for 20 or 12 hours.The reaction mixture was filtered through a Celite pad, and the cake washed with the solvent.The filtrate was concentrated at reduced pressure.

Reaction with benzylamine A)
A mixture of furoisoxazoline 15 (88 mg, 0.38 mmol) and benzylamine (415 μL, 3.8 mmol) was stirred at room temperature for 3 hours.The reaction mixture was dissolved in dichloromethane and washed with water.The aqueous layer was extracted with dichloromethane and the combined organic layers were dried (Na2SO4).The solvent was removed under reduced pressure and the crude product was analyzed by 1 H NMR (91:9 of pyrroloisoxazolones 20 and 21) and purified by column chromatography (hexane/ethyl acetate, 1:2).Combined yield 71%. B) To a solution of 15 (91 mg, 0.39 mmol) in CH2Cl2 (1 mL) was added benzylamine (85 μL, 0.78 mmol) at room temperature.After 3 hours under stirring the reaction mixture was washed with water.The aqueous layer was extracted with dichloromethane.The combined organic layers were dried (Na2SO4) and the solvent was removed under reduced pressure.The crude solid was analyzed by 1 H NMR (74:26 of pyrroloisoxazolones 20 and 21) and purified by column chromatography (hexane/ethyl acetate, 1:2).Combined yield 84%.

Table 1 .
Significant NMR data for compounds 13

, 14, 18, 19, and 20.
13and13C NMR spectra were recorded on Brucker AC-300 and Bruker WP-200-SY spectrometers.Chemical shifts (δ) are reported in ppm, coupling constant in Hz.Microanalyses were carried out on a LECO CHNS-932 in Laboratory of elemental analyses of SIDI of Universidad Autónoma de Madrid, and were in good agreement with the calculated values.IR spectra were recorded on a Bruker Vector 22 spectrometer.

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was separated and the aqueous phase was extracted with dichloromethane.The combined organic layers were washed with water, dried (Na2SO4) and the solvent was removed in vacuo.The brown oil obtained was purified by column chromatography (hexane/ethyl acetate, 1:1) to give 328 mg of furoisoxazolone 15.Yield 63%.Mp 110-111 ºC (from ethyl acetate).Anal.calcd.