Diastereoselectivity of nitrone 1,3-dipolar cycloaddition to Baylis-Hillman adducts

1,3-Dipolar cycloadditions of C -phenyl- N -methylnitrone to Baylis-Hillman adducts ( β -hydroxy- α -methylene esters) proceed with complete regioselectivity in good yields to afford the corresponding diastereomeric 3,5,5-trisubstituted isoxazolidines. Attack of the dipole from the less sterically hindered side of the dipolarophiles affords C-3/C-5 cis isoxazolidines as the predominant isomers. Addition of Lewis acids and microwave irradiation produce only a small effect on the diastereoisomeric product ratio. Microwave irradiation accelerates the reaction.


Introduction
2][3] Regio-and stereoselective nitrone cycloaddition, followed by reduction of the N-O bond to produce both an amino and a hydroxy function, allows the synthesis of many products of potential interest.Diastereoselectivity of the cycloadditions depends mainly upon the nature of dipole and dipolarophile; several models that allow the prediction of the major product diastereomer, have been published. 4hen 1,3-dipolar cycloaddition is to be used in any synthesis of a complex target molecule, a method that accommodates change or even reversal of the ratio of diastereoisomers would be a desirable.However, one cannot change the dipole and/or the dipolarophile (except changing the protecting group in the suitable dipolarophile), since they are determined by the structure and the strategy of the synthesis of the target molecule.
Lewis acids are often used as catalysts in 1,3-dipolar cycloadditions of nitrones. 5Recently we have described (i) the reversal of diastereoselectivity of mesitonitrile oxide 1,3-dipolar cycloadditions to Baylis-Hillman adducts that is brought about by added Mg(II) as well (ii) the acceleration of this cycloaddition by microwave irradiation. 6In the present communication, we report the investigation of the effect of the addition of Mg(II) additive upon the stereoselectivity of reactions of C-phenyl-N-methylnitrone (1) with Baylis-Hillman adducts 2-4.

Results and Discussion
Baylis-Hillman adducts 2-4 were chosen as electron deficient dipolarophiles.Adducts 2 and 4 were prepared via Baylis-Hillman reactions by using an appropriate aldehyde and methyl acrylate. 7,8Dipolarophile 3 was obtained by the silylation of 2. The cycloadditions of nitrone 1 with 2-4 are completely regioselective; only the 5-substituted isoxazolidines 5-7 are isolated irrespective of the presence or absence of Mg(II).Change of solvent, alteration of reaction temperature or microwave irradiation have no influence on the regioselectivity of the reaction.The cycloadditions were first carried out in the absence of any Lewis acid.Reaction of nitrone 1 and isopropyl Baylis-Hillman adduct 2 formed mixtures of diastereoisomers (Table 1).Isoxazolidine 5a was formed as a major product.It is noterworthy to mention that at room temperature no cycloaddition has been observed; after 14 days only the unreacted starting materials were detected (entry 1, Table 1).Since nitrone 1 shows no reactivity in the non-catalyzed reactions at room temperature, higher reaction temperatures are needed to effect complete reaction.On the other hand, when the reaction was performed in the presence of MgI 2 -I 2 catalyst, a mixture of cycloadducts 5a-c was formed in 28% yield in diastereomeric ratio of 94 : 4 : 2 (entry 2, Table 1).The lowest diastereomeric ratio has been achieved by the performing the reaction in boiling toluene (entries 6 and 7, Table 1).Reaction of nitrone 1 and phenyl Baylis-Hillman adduct 4 proceeded in analogous fashion; isoxazolidine 7a was formed as major product (entry 9, Table 1).A complete selectivity is observed with compound 3 in which the silyl protected hydroxy group prevents the possible coordination.The low chemical yield in this case may be due to steric reasons.
The addition of a Grignard reagent (MeMgBr) as a Lewis acid in contrast to mesitonitrile oxide cycloaddition exerts a slight influence on the stereoselectivity of the reaction (entries 3 and 5, Table 1).The observed reversal of the stereoselectivity of the mesitonitrile oxide cycloaddition with dipolarophile 2 has been rationalised in terms of the presence of a chelated transition state with a geometry different from a "nonchelated" transition state. 6We have presumed that Mg(II) coordinates with alcoholate as well as with the methoxycarbonyl group, and therefore the conformation of a magnesium alcoholate differs from that of the corresponding free Baylis-Hillman adduct. 6n the other hand, the stereoselectivity was not improved in the reaction between nitrone 1 and dipolarophile 2 even under catalyzed conditions, a result that suggests insufficient coordination between the Lewis acid and the dipolarophile 2. A Lewis acid catalyst can be incorporated both in nitrone 1 and bidentate ester 2. It is clear that the catalyst is mostly incorporated in the dipole complex rather than the dipolarophile complex.5a Yields of the cycloaddition in the presence of Mg(II) additive are lower when compared with the yields of the reaction performed without the Mg(II) additive (Table 1).
Our attempts to accelerate the cycloaddition by microwave irradiation were successful.For example, the reaction of Baylis-Hillman adduct 2 was complete in seven days when performed in refluxing CCl 4 without irradiation, whereas the same cycloaddition under microwave irradiation could be completed in only 1 h (entries 3 and 4, Table 1).In this case, the diastereomeric excess was nearly unchanged.Dipolarophile 4 reacted under microwave irradiation reacted analogous fashion and the corresponding reaction time also decreased from 7 days to 1 hour (entries 9 and 10, Table 1).
Purification by flash chromatography allowed the isolation of the pure major diastereoisomers 5a, 6a, 7a as well as minor isomer 7b, while the isolation and/or characterization of the other minor isomers was not possible.All structures described were characterized via analysis of their respective 1 H-and 13 C-NMR spectra.The ratio of diastereoisomers was determined from quantitative 13 C NMR spectra, by integration of the peaks from C-5 of the isoxazolidines.
Moreover, no thermal interconversion among cycloadducts occurred in refluxing toluene, thus indicating that the cycloaddition proceeded irreversibly under the reaction conditions to give the kinetically controlled products 5-7.The structural assignments of the products are based on analysis of NMR spectra.The stereochemistries of the cycloadducts were deduced by n.O.e.experiments.The most important and decisive information obtained from these experiments is the presence or absence of the n.O.e.interaction between the protons H-4/H-3, H-4/H-1´ and H-3/H-1´ in the corresponding cycloadducts.For instance the cis relationship of the phenyl substituent at C-3 and methoxycarbonyl substituent at C-5 in 7a has been assigned on the basis of NOEDS.The enhancement on signal H-4 B and the enhancement on signal H-3 and H-1´ following saturation of signal H-4 A show a cis relationship between the aforementioned substituents at C-3 and C-5; irradiation of H-4 B causes only enhancement on H-4 A .Moreover, the missing interactions between H-4 B and H-3 and between H-4 B and H-1´ confirm this cis relationship.
In conclusion, 1,3-dipolar cycloadditions of C-phenyl-N-methylnitrone to Baylis-Hillman adducts (β-hydroxy-α-methylene esters) proceed with complete regioselectivity in good yields to afford the corresponding diastereomeric 3,5,5-trisubstituted isoxazolidines.Attack of the dipole from the less sterically hindered side of the dipolarophiles affords C-3/C-5 cis isoxazolidines as major products.Addition of Lewis acids and microwave irradiation produce only a small effect on the diastereoisomeric product ratio, moreover the microwave irradiation accelerates the reaction.

Experimental Section
General Procedures.All starting materials and reagents are commercially available (Fluka, Merck, Avocado or Aldrich) and were used without further purification.Solvents were dried before use.Thin-layer chromatography (TLC glass plates coated with silica 60 F 254 Merck) was used for monitoring of reaction courses, eluents are given in the text.For column chromatography the flash chromatography technique was employed using silica 60 (0.040-0.063 mm, Merck).Melting points (mp) were determined on a Kofler hot plate apparatus and are uncorrected.
IR spectra were recorded on FTIR NICOLET MAGNA 750 instrument.The 1 H and 13 C NMR spectra of deuterochloroform solutions were obtained using Varian VXR-300 (300 MHz) and Bruker DRX-400 (400 MHz) instruments, tetramethylsilane (TMS) being the internal reference.
C-Phenyl-N-methylnitrone (1) was prepared from the benzaldehyde by the reaction with Nmethylhydroxylamine according to the procedure already described in the literature. 9The Baylis-Hillman alkenes 2, 4 were prepared by the reaction of isobutyraldehyde and benzaldehyde with methylacrylate in the presence of catalytic amount of DABCO respectively. 7,8Alkene 3 was obtained by the silylation of 2 with TBDPSCl and imidazole in CH 2 Cl 2 .MeMgBr as 1.4M solution in THF used for cycloadditions is commercially available reagent.The MgI 2 -I 2 was freshly prepared prior to use.

General procedures
Method A. To the round-bottom flask equipped with magnetic stirring bar were nitrone 1, corresponding alkene 2-4 (1 eq) and solvent added.The appropriate solvent, reaction time and temperature for each reaction are listed in Table 1.The reaction mixture was stirred until complete conversion of nitrone 1 (monitored by TLC) alternatively, when the conversion was not complete, the reaction was stopped after 14 days.The solvent was evaporated and quantitative 13 C NMR of crude reaction mixture was recorded.The reaction mixture was then column chromatographed.The yields of the isolated mixtures of cycloadducts for each experiment are given in Table 1.Method B. Cycloadditions in the presence of Lewis acids.The reactions were carried out under argon atmosphere.To the dry round-bottom flask equipped with magnetic stirring bar and rubber septum was alkene 2 or 4 (1 eq) added.The solution of Lewis acid (1 eq) was at room temperature dropwise added and the mixture was stirred for 15-30 min at the same temperature.The solution of nitrone 1 (1 eq) was then with syringe dropwise added.The appropriate solvent, reaction time and temperature are listed in Table 1.The mixture was stirred until complete conversion of nitrone 1 (monitored by TLC).The reaction was quenched with saturated NH 4 Cl water solution, extracted with CH 2 Cl 2 (in the case of MgI 2 -I 2 mediated cycloadditions the collected organic layers were washed with 10% Na 2 S 2 O 7 water solution to remove I 2 ), dried over Na 2 SO 4 and the solvent was removed by rotary evaporation.Method C. Microwave mediated cycloadditions.The reactions were carried out in conventional kitchen microwave oven at the rate of 1000 W. The equimolar solution of nitrone 1 and alkene 2 or 4 in CCl 4 was put into the 100 ml Erlenmayer flask, cooled to 0 °C, flask was inserted to microwave oven and the mixture was irradiated for 5 min.The flask was than taken out and the reaction course was monitored.The mixture was again cooled down to 0 °C and whole sequence was repeated until complete conversion of nitrone 1 (12 times).The solution was then transferred to the round-bottom flask and the solvent was removed by rotary evaporation.