Spectral Assignment in the [3 + 2] Cycloadditions of Methyl (2E)-3-(Acridin-4-yl)-prop-2-enoate and 4-[(E)-2-Phenylethenyl]acridin with Unstable Nitrile N-Oxides

The investigation of cycloaddition reactions involving acridine-based dipolarophiles revealed distinct regioselectivity patterns influenced mainly by the electronic factor. Specifically, the reactions of methyl-(2E)-3-(acridin-4-yl)-prop-2-enoate and 4-[(1E)-2-phenylethenyl]acridine with unstable benzonitrile N-oxides were studied. For methyl-(2E)-3-(acridin-4-yl)-prop-2-enoate, the formation of two regioisomers favoured the 5-(acridin-4-yl)-4,5-dihydro-1,2-oxazole-4-carboxylates, with remarkable exclusivity in the case of 4-methoxybenzonitrile oxide. Conversely, 4-[(1E)-2-phenylethenyl]acridine displayed reversed regioselectivity, favouring products 4-[3-(substituted phenyl)-5-phenyl-4,5-dihydro-1,2-oxazol-4-yl]acridine. Subsequent hydrolysis of isolated methyl 5-(acridin-4-yl)-3-phenyl-4,5-dihydro-1,2-oxazole-4-carboxylates resulted in the production of carboxylic acids, with nearly complete conversion. During NMR measurements of carboxylic acids in CDCl3, decarboxylation was observed, indicating the formation of a new prochiral carbon centre C-4, further confirmed by a noticeable colour change. Overall, this investigation provides valuable insights into regioselectivity in cycloaddition reactions and subsequent transformations, suggesting potential applications across diverse scientific domains.

Our previous investigation [13,14] unveiled the fascinating chemistry of acridinealkene when paired with relatively stable nitrile N-oxides.The outcomes were not only synthetically valuable but also provided insights into the mechanistic intricacies of such transformations.Building upon this foundation, the present study represents a natural extension, delving deeper into the reactivity and spectral nuances encountered when these acridine dipolarophiles meet their less-stable counterparts-unstable nitrile N-oxides.
Unstable nitrile N-oxides have remained relatively underexplored in [3 + 2] cycloaddition chemistry, primarily due to their rapid dimerization, which brings with it challenges in their creation and manipulation.Because of the rapid dimerization, unstable nitrile N-oxides are usually synthesised in situ from hydroximoyl halides [24,25], aldoximes or from primary nitroalkanes [26,27], which often limits their use in organic synthesis.The inherent reactivity of unstable nitrile oxides poses intriguing questions: How does their fleeting existence influence the outcome of the cycloaddition?What insights can we gain from the elucidation of their reaction pathways?
In this context, nuclear magnetic resonance (NMR) spectroscopy emerges as an invaluable tool.It allows us to scrutinise the subtle spectral changes.By employing these advanced analytical methods, we aim to shed light on the unique challenges and opportunities presented by this intriguing class of compounds.
This study represents not only a continuation of our prior work but also a significant stride toward comprehending the broader landscape of [3 + 2] cycloadditions with nitrile N-oxides.The insights gained herein promise to enrich our understanding of the reactivity patterns of acridine-based systems and pave the way for the development of innovative synthetic strategies in organic chemistry.

Result and Discussion
2.1.[3 + 2] Cycloaddition Reactions of Methyl (2E)-3-(Acridin-4-yl)-acrylate (1) and 4-[(E)-2-Phenylethenyl]acridin (2) with Nitrile N-Oxides 4a-e Our investigation focused on the cycloaddition reactions of acridine-alkenes, namely methyl (2E)-3-(acridin-4-yl)-prop-2-enoate (1) and 4-[(1E)-2-phenylethenyl]acridine (2) [13], with unstable nitrile N-oxides 4a-e.Both alkene substrates 1 and 2 possess electronaccepting substituents.Identical reaction conditions were maintained across all ten reactions.The reactions involved dissolving acridine-alkene 1 or 2 in ethanol and subsequently adding a six-fold excess of the precursor of the three-atom-component (TAC)-Nhydroxybenzenecarbonimidoyl chloride 3a-e.As the major limitation of the chemistry of isoxazolines is the propensity of nitrile N-oxides to undergo rapid dimerization to furoxan N-oxides [28,29], we circumvent this problem by generating the nitrile N-oxide species in situ, and an ethanolic solution of triethylamine was added dropwise over 8 days to generate the corresponding nitrile N-oxide 4a-e (Scheme 1).Benzonitrile N-oxide 4 partially reacted with dipolarophiles, the remainder dimerized into furoxane.Experiments demonstrated that the use of less than a six-fold excess of oxime 3 led to exceedingly slow conversion to cycloadducts.To maintain a sufficiently low concentration of nitrile oxide 4a-e during the slow cycloaddition reaction, triethylamine had to be added very slowly.Consequently, the concentration of the generated unstable nitrile N-oxide 4a-e remained only slightly more than that of the alkene 1 or 2 throughout the experiment.
Remarkably, our approach achieved nearly complete conversion of alkenes 1 or 2 to cycloadducts without the need for specific optimization of nitrile N-oxide 4a-e formation for cycloaddition rates versus dimerization.
The progression of the cycloaddition was monitored using 1 H NMR spectra.These spectra revealed the complete absence of alkenes 1 and 2, confirming their near 100% conversion.Nonetheless, two pairs of doublets in the 4.00-7.00ppm range, corresponding to the methine protons H-4 and H-5 of new regioisomers 5/6 and 7/8, were observed.
In contrast, no regioselectivity was reversed in the reactions of alkene 2 with nitrile oxides 4a-e.The reactions slightly favour the formation of products 7c-e.Interestingly, a major 8a isoxazoline was observed in the reaction of 2 with 4a, indicating a distinct regioselectivity pattern.Remarkably, our approach achieved nearly complete conversion of alkenes 1 or 2 to cycloadducts without the need for specific optimization of nitrile N-oxide 4a-e formation for cycloaddition rates versus dimerization.
The progression of the cycloaddition was monitored using 1 H NMR spectra.These spectra revealed the complete absence of alkenes 1 and 2, confirming their near 100% conversion.Nonetheless, two pairs of doublets in the 4.00-7.00ppm range, corresponding to the methine protons H-4 and H-5 of new regioisomers 5/6 and 7/8, were observed.
In contrast, no regioselectivity was reversed in the reactions of alkene 2 with nitrile oxides 4a-e.The reactions slightly favour the formation of products 7c-e.Interestingly, a major 8a isoxazoline was observed in the reaction of 2 with 4a, indicating a distinct regioselectivity pattern.
It is well known that the regioselectivity of [3 + 2] cycloadditions depends on both steric and electronic effects.We propose that the regioselectivity of described reactions is highly governed by the electronic factors of the alkene which can be found from the magnitudes of their 13 C chemical shifts.In the case of (2E)-3-(acridin-4-yl)-prop-2-enoate (1), the presence of a mildly polar acridine ring and a strongly electron-accepting methoxycarbonyl group results in a highly polarized C3=C2 double bond with chemical shifts 141.8 ppm for C-3 (closer to acridine) and 120.3 ppm for C-2 (distant from acridine).This polarization facilitates an attack by the nitrile oxide oxygen, thereby favouring the formation of product 6.Conversely, in 4-[(1E)-2-phenyletenyl]acridine (2), the non-polar C1=C2 double bond with chemical shifts 130.5 ppm for C-1 (distant from acridine) and 125.2 ppm for C-2 (closer to acridine), owing to substituents with equivalent electron effects, leads to nearly equal preferences for either regioisomer (Table 1) [6,14].It is well known that the regioselectivity of [3 + 2] cycloadditions depends on both steric and electronic effects.We propose that the regioselectivity of described reactions is highly governed by the electronic factors of the alkene which can be found from the magnitudes of their 13 C chemical shifts.In the case of (2E)-3-(acridin-4-yl)-prop-2-enoate (1), the presence of a mildly polar acridine ring and a strongly electron-accepting methoxycarbonyl group results in a highly polarized C3=C2 double bond with chemical shifts 141.8 ppm for C-3 (closer to acridine) and 120.3 ppm for C-2 (distant from acridine).This polarization facilitates an attack by the nitrile oxide oxygen, thereby favouring the formation of product 6.Conversely, in 4-[(1E)-2-phenyletenyl]acridine (2), the non-polar C1=C2 double bond with chemical shifts 130.5 ppm for C-1 (distant from acridine) and 125.2 ppm for C-2 (closer to acridine), owing to substituents with equivalent electron effects, leads to nearly equal preferences for either regioisomer (Table 1) [6,14].
The separation of cycloadducts from the reaction mixture proved to be labourious and time-consuming.Small quantities of sufficiently pure isoxazolines 5b, 6a,b,d,e, 7b, 8a-c for NMR analysis through multiple-column chromatography separations were obtained.However, it was unable to isolate adequate amounts of isoxazolines 5a,d,e, and  7a,d,e.Consequently, high-quality NMR spectra for these compounds could not be obtained, and their full characterisation remained elusive.However, their existence was confirmed by observing their presence in the 1 H NMR spectra of the reaction mixture.Regioisomeric isoxazolines 7d/8d and 7e/8e could not be separated, and their structures were determined from the NMR spectra of these mixtures.
The complete structural characterisation of isolated compounds was achieved by the combined use of 1D and 2D NMR techniques (NMR spectra are included in Supplementary Materials).The procedures used to assign NMR data to compounds 7d and 8d are explained in detail here.The 1 H NMR spectrum (Figure 1) suggested the presence of two acridin-4-yl rings, two 1,3-disubstituted phenyl units, three types of protons with doubletshaped signals, and one proton with a broad singlet-shaped signal.The separation of cycloadducts from the reaction mixture proved to be labourious and time-consuming.Small quantities of sufficiently pure isoxazolines 5b, 6a,b,d,e, 7b, 8a-c for NMR analysis through multiple-column chromatography separations were obtained.However, it was unable to isolate adequate amounts of isoxazolines 5a,d,e, and 7a,d,e.Consequently, high-quality NMR spectra for these compounds could not be obtained, and their full characterisation remained elusive.However, their existence was confirmed by observing their presence in the 1 H NMR spectra of the reaction mixture.Regioisomeric isoxazolines 7d/8d and 7e/8e could not be separated, and their structures were determined from the NMR spectra of these mixtures.
The complete structural characterisation of isolated compounds was achieved by the combined use of 1D and 2D NMR techniques (NMR spectra are included in Supplementary Materials).The procedures used to assign NMR data to compounds 7d and 8d are explained in detail here.The 1 H NMR spectrum (Figure 1) suggested the presence of two acridin-4-yl rings, two 1,3-disubstituted phenyl units, three types of protons with doublet-shaped signals, and one proton with a broad singlet-shaped signal.

ones Z-10e and E-10e
The subsequent step involved the hydrolysis of isolated esters 6a,b,d,e to produce carboxylic acids 9a,b,d,e.These reactions were carried out in ethanol with a 10-fold excess of the base over 4 h, resulting in nearly 100% conversion of starting substances 6a,b,d,e.Hydrolysis of derivative 6e yielded three products: acid 9e (81%) and two isoxazole-5-one stereoisomers, Z-10e (14%) and E-10e (5%) (Scheme 2) [13].The separation and purification of isoxazole-5-ones Z-10e, and E-10e proved challenging, yielding only a mixture of isoxazole-5-one Z-10e (87%) along with the E-10e derivative (13%) after repeated crystallization.While proton and carbon signals of the major Z-10e were successfully assigned based on NMR experiments, the minor derivative E-10e proton and carbon signals could not be assigned.The preliminary analysis of the 1 H NMR spectrum of the mixture of stereoisomers Z-10e and E-10e in CDCl3 revealed signals with no overlap, facilitating the direct measurement of chemical shifts and J values and the correct determination of their multiplicities.The 1 H and 13 C NMR chemical shifts measured in CDCl3 are in reasonable agreement with those measured previously [13].
The acridine proton-proton connectivity was traced starting from NOESY correlations between proton H-9′ and protons H-1′/H-8′.The standard gCOSY experiment revealed H1′-H3′ and H5′-H8′ connectivities.The chemical shifts of protons attached to acridine carbon atoms were assigned through a straightforward application of the gHSQC experiment.The nonprotonated carbons C-4′, C-4′a/C-10′a, and C-8′a/C-9′a of acridin-4-yl moiety were assigned using their HMBC connectivities with the protons three-bonds The acridine proton-proton connectivity was traced starting from NOESY correlations between proton H-9 ′ and protons H-1 ′ /H-8 ′ .The standard gCOSY experiment revealed H1 ′ -H3 ′ and H5 ′ -H8 ′ connectivities.The chemical shifts of protons attached to acridine carbon atoms were assigned through a straightforward application of the gHSQC experiment.The nonprotonated carbons C-4 ′ , C-4 ′ a/C-10 ′ a, and C-8 ′ a/C-9 ′ a of acridin-4-yl moiety were assigned using their HMBC connectivities with the protons three-bonds distant.Additionally, the assignments of unprotonated carbons C-3, C-4, and C-5 of isoxazolone moiety were unequivocally accomplished through their observed HMBC connectivities with H-6 and H-2 ′′ ,6 ′′ protons (Figures 5 and 6) [6].For isoxazole-5-one Z-10e, the magnetic anisotropy effect on the acridine proton H-3's chemical shift was evident.The high chemical shift (9.73 ppm) of the proton doublet H-3 ′ can be attributed to the magnetic anisotropic effect of the spatially close C=O group.In addition, a synergic effect of two electron-acceptor groups, C=O and C=N, elicited a strong deshielding of proton H-6 to 9.85 ppm.For isoxazole-5-one Z-10e, the magnetic anisotropy effect on the acridine proton H-3's chemical shift was evident.The high chemical shift (9.73 ppm) of the proton doublet H-3′ can be attributed to the magnetic anisotropic effect of the spatially close C=O group.In addition, a synergic effect of two electron-acceptor groups, C=O and C=N, elicited a strong deshielding of proton H-6 to 9.85 ppm.
It appears that the possibility of isoxazolone formation depends on the electron-withdrawing character of the phenyl substituent.The electron-withdrawing nitro group favoured the formation of isoxazole-5-one 10e, while the presence of unsubstituted phenyl, the electron-donor methoxy group or the nitro group in position 3 on the phenyl ring inhibited the formation of isoxazole-5-one.

Carboxylic Acids 9a,b,d,e Decarboxylation and Formation of 4-(3-Phenyl-4,5-Dihydro-1,2-Oxazol-5-yl)Acridines 11a,b,d,e
During NMR measurements of carboxylic acids 9a,b,d,e in CDCl3, it was observed that decarboxylation occurred, resulting in NMR spectra featuring two distinct sets of signals (Figure 7).The most prominent indication of decarboxylation was the appearance of three new signals corresponding to the protons H-4a, H-4b and H-5.With the formation of the new prochiral carbon centre C-4, the two signals for protons H-4a and H-4b became It appears that the possibility of isoxazolone formation depends on the electronwithdrawing character of the phenyl substituent.The electron-withdrawing nitro group favoured the formation of isoxazole-5-one 10e, while the presence of unsubstituted phenyl, the electron-donor methoxy group or the nitro group in position 3 on the phenyl ring inhibited the formation of isoxazole-5-one.9a,b,d,e.The only noticeable difference in all these substances was the presence of three signals corresponding to protons H-4a, H-4b and H-5, with chemical shifts of 4.20 ppm, 3.40 ppm, and 6.90 ppm, respectively.The relative stereochemistry of the prochiral carbon centre C-4 was determined through 2D NOESY spectra, where a NOESY cross peak between protons H-5 (6.9 ppm) and H-4a (4.2 ppm) was observed as well as through homonuclear coupling constants (Figure 8).As was written by Thomas, it is clear that as well as the dependence on dihedral angle, vicinal coupling constants depend on the electronegativity and orientation of substituents on the H-C-C-H fragment with both α and β effects, the H-C-C bond angles, overlap of orbitals from adjacent nuclei, and possibly on lone pairs and hyperconjugative effects.The lone pairs on nitrogen and oxygen have specific The only noticeable difference in all these substances was the presence of three signals corresponding to protons H-4a, H-4b and H-5, with chemical shifts of 4.20 ppm, 3.40 ppm, and 6.90 ppm, respectively.The relative stereochemistry of the prochiral carbon centre C-4 was determined through 2D NOESY spectra, where a NOESY cross peak between protons H-5 (6.9 ppm) and H-4a (4.2 ppm) was observed as well as through homonuclear coupling constants (Figure 8).As was written by Thomas, it is clear that as well as the dependence on dihedral angle, vicinal coupling constants depend on the electronegativity and orientation of substituents on the H-C-C-H fragment with both α and β effects, the H-C-C bond angles, overlap of orbitals from adjacent nuclei, and possibly on lone pairs and hyperconjugative effects.The lone pairs on nitrogen and oxygen have specific effects on both chemical shifts and coupling constants for protons on adjacent carbons [25].The coupling constant 3 J for the protons H-5 and H-4a, situated on the opposite side of the five-membered isoxazoline ring, falls within the 11.2-11.5Hz range.However, the coupling constant 3 J between protons H-5 and H-4b on the same side is in the 7.5-7.9Hz range.
9a,b,d,e.The only noticeable difference in all these substances was the presence of three signals corresponding to protons H-4a, H-4b and H-5, with chemical shifts of 4.20 ppm, 3.40 ppm, and 6.90 ppm, respectively.The relative stereochemistry of the prochiral carbon centre C-4 was determined through 2D NOESY spectra, where a NOESY cross peak between protons H-5 (6.9 ppm) and H-4a (4.2 ppm) was observed as well as through homonuclear coupling constants (Figure 8).As was written by Thomas, it is clear that as well as the dependence on dihedral angle, vicinal coupling constants depend on the electronegativity and orientation of substituents on the H-C-C-H fragment with both α and β effects, the H-C-C bond angles, overlap of orbitals from adjacent nuclei, and possibly on lone pairs and hyperconjugative effects.The lone pairs on nitrogen and oxygen have specific effects on both chemical shifts and coupling constants for protons on adjacent carbons.[25] The coupling constant 3 J for the protons H-5 and H-4a, situated on the opposite side of the five-membered isoxazoline ring, falls within the 11.2-11.5Hz range.However, the coupling constant 3 J between protons H-5 and H-4b on the same side is in the 7.5-7.9Hz range.

General
All reagents (Merck, Darmstadt, Germany) were used as supplied without prior purification.The progression of the reaction was monitored by analytical thin-layer chromatography using TLC sheets ALUGRAM-SIL G/UV254 (Macherey Nagel, Düren, Germany).Purification by flash chromatography was performed using silica gel (60 Å, 230-400 mesh, Merck, Darmstadt, Germany) with the indicated eluent.

Melting Point Determination
The melting points of the synthesised derivatives were determined using a Stuart TM melting point apparatus SMP10 (Bibby Scientific Ltd., Staffordshire, UK).

NMR Spectroscopy
NMR spectra were acquired using a Varian VNMRS spectrometer (Palo Alto, CA, USA) operating at 599.87 MHz for 1 H, 150.84 MHz for 13 C, and Varian Mercury spectrometer (Palo Alto, CA, USA) operating at 400.13 MHz for 1 H and 100.62 MHz for 13 C.These experiments were conducted at a temperature of 299.15 K, and a 5 mm inverse-detection H-X probe with a z-gradient coil was used.Pulse programs from the Varian sequence library were employed.Chemical shifts (δ in ppm) were referenced to internal solvent standard CDCl 3 77.0ppm for 13 C, while a partially deuterated signal of CHD 2 Cl 7.26 ppm was used for 1 H referencing.MestReNova v. 15.0.1 (Mestrelab Research, Santiago de Compostela, Spain) was utilized for NMR spectra processing and analysis.

IR Spectroscopy
The infrared spectra of prepared compounds were recorded with Avatar FT−IR 6700 (Fourier transform infrared spectroscopy) spectrometer in the range from 400 to 4000 cm −1 with 64 repetitions for a single spectrum using the ATR (attenuated total reflectance) technique.All obtained data were analysed using Omnic 8.2.0.387 (2010) software, and the structure of all new compounds was confirmed by analysis of FT-IR spectrum by functional group identification.
The compounds Z-10e and E-10e were separated from the mixture of 6e and 9e using column chromatography (SiO 2 , CHCl 3 /MeOH, 4:1).The ratio of isomers Z-10e and E-10e was determined to be 1.00:0.14based on 1 H NMR spectra.

a
Ratios of regioisomeric isoxazolines were determined by integration of H-4 and H-5 proton signals of reaction mixture 1 H NMR spectra.

2. 2 .
Basic Hydrolysis of 6a,b,d,e and Formation of Carboxylic Acids 9a,b,d,e and Isoxazole-5-ones Z-10e and E-10eThe subsequent step involved the hydrolysis of isolated esters 6a,b,d,e to produce carboxylic acids 9a,b,d,e.These reactions were carried out in ethanol with a 10-fold excess of the base over 4 h, resulting in nearly 100% conversion of starting substances 6a,b,d,e.Hydrolysis of derivative 6e yielded three products: acid 9e (81%) and two isoxazole-5-one stereoisomers, Z-10e (14%) and E-10e (5%) (Scheme 2)[13].The 1 H chemical shift, splitting patterns, and intensities of proton signals for derivatives 9a,b,d,e were consistent with those of the starting esters6a,b,d,e.The only noticeable difference in all these substances was the absence of the 1 H NMR singlet signal of the methyl ester group around 3.90 ppm.In addition, the13 C NMR spectra of all products 9a,b,d,e exhibited a slight shift (approximately 0.9-2.1 ppm) of the C=O group signal to lower ppm values compared to the starting esters 6a,b,d,e.

The 1 H
chemical shift, splitting patterns, and intensities of proton signals for derivatives 9a,b,d,e were consistent with those of the starting esters 6a,b,d,e.The only noticeable difference in all these substances was the absence of the 1 H NMR singlet signal of the methyl ester group around 3.90 ppm.In addition, the 13 C NMR spectra of all products 9a,b,d,e exhibited a slight shift (approximately 0.9-2.1 ppm) of the C=O group signal to lower ppm values compared to the starting esters 6a,b,d,e.

2. 3 .
Carboxylic Acids 9a,b,d,e Decarboxylation and Formation of 4-(3-Phenyl-4,5-dihydro-1,2-oxazol-5-yl)acridines 11a,b,d,eDuring NMR measurements of carboxylic acids 9a,b,d,e in CDCl 3 , it was observed that decarboxylation occurred, resulting in NMR spectra featuring two distinct sets of signals (Figure7).The most prominent indication of decarboxylation was the appearance of three new signals corresponding to the protons H-4a, H-4b and H-5.With the formation of the new prochiral carbon centre C-4, the two signals for protons H-4a and H-4b became non-equivalent.The occurrence of decarboxylation was further evidenced by a noticeable colour change from light yellow to dark green[30].Molecules 2024, 29, 2756 9 of 18 non-equivalent.The occurrence of decarboxylation was further evidenced by a noticeable colour change from light yellow to dark green.[30]

Figure 7 .
Figure 7.The comparison of 1 H (400 MHz, CDCl3) NMR spectra of derivatives 9b and 11b.The structures of the non-purified decarboxylated products 11a,b,d,e were elucidated using 1D and 2D (TOCSY, H2BC, HMBC) NMR spectra and compared with those of carboxylic acids 9a,b,d,e.The 1 H chemical shift, splitting patterns, and intensities of proton signals for derivatives 11a,b,d,e were consistent with those of the starting acids 9a,b,d,e.The only noticeable difference in all these substances was the presence of three signals corresponding to protons H-4a, H-4b and H-5, with chemical shifts of 4.20 ppm, 3.40 ppm, and 6.90 ppm, respectively.The relative stereochemistry of the prochiral carbon centre C-4 was determined through 2D NOESY spectra, where a NOESY cross peak between protons H-5 (6.9 ppm) and H-4a (4.2 ppm) was observed as well as through homonuclear coupling constants (Figure8).As was written by Thomas, it is clear that as well as the dependence on dihedral angle, vicinal coupling constants depend on the electronegativity and orientation of substituents on the H-C-C-H fragment with both α and β effects, the H-C-C bond angles, overlap of orbitals from adjacent nuclei, and possibly on lone pairs and hyperconjugative effects.The lone pairs on nitrogen and oxygen have specific

Figure 7 .
Figure 7.The comparison of 1 H (400 MHz, CDCl 3 ) NMR spectra of derivatives 9b and 11b.The structures of the non-purified decarboxylated products 11a,b,d,e were elucidated using 1D and 2D (TOCSY, H2BC, HMBC) NMR spectra and compared with those of carboxylic acids 9a,b,d,e.The 1 H chemical shift, splitting patterns, and intensities of proton signals for derivatives 11a,b,d,e were consistent with those of the starting acids 9a,b,d,e.The only noticeable difference in all these substances was the presence of three signals corresponding to protons H-4a, H-4b and H-5, with chemical shifts of 4.20 ppm, 3.40 ppm, and 6.90 ppm, respectively.The relative stereochemistry of the prochiral carbon centre C-4 was determined through 2D NOESY spectra, where a NOESY cross peak between protons H-5 (6.9 ppm) and H-4a (4.2 ppm) was observed as well as through homonuclear

Ratio of Regioisomers a 5:6 Reactants R R 1 Ratio of Regioisomers a 7:8 1 +
a Ratios of regioisomeric isoxazolines were determined by integration of H-4 and H-5 proton signals of reaction mixture 1 H NMR spectra.