Indian Journal of Chemistry Vol. 57B, January 2018, pp. 108-119

Experimental and DFT studies for substituent effects on cycloadditions of C,N-disubstituted nitrones to cinnamoyl piperidine

Sutapa Mandala, Kaustabh K Maitib, Avijit Banerjic, Thierry Prangéd, Alain Neumane & Nivedita Acharjeea* a Department of Chemistry, Durgapur Government College, Durgapur 713 214, India

b CSIR-National Institute for Interdisciplinary Science and Technology, Industrial Estate PO, Pappanamcode, Thiruvananthapuram 695 019, India

c Retired Professor, Centre of Advanced Studies on Natural Products Including Organic Synthesis, Department of Chemistry, University of Calcutta, 92, Acharya Prafulla Chandra Road, Kolkata 700 009, India

d Laboratoire de Cristallographie et RMN, Biologiques, Faculté de pharmacie, 4, Av de-l’ Observatoire, 75006 Paris, France e UFR SMBH - Université Paris 13, 74, rue Marcel Cachin 93000 Bobigny, France

E-mail: nivchem@gmail.com; nivedita_acharjee@gmail.com

Received 30 June 2017; accepted (revised) 21 November 2017

Cycloaddition reactions of C-aryl-N-methyl nitrones (with varied electron demand character) to cinnamoyl piperidines have been studied by both experimental and theoretical approaches. The reactions are completely regioselective. Endo/meta selectivity of the major isomer has been confirmed on the basis of UV-Vis, IR, NMR and X-ray studies. Global properties of the reactants have been analyzed. Delocalization and activation energies of the located transition states have been calculated. Concerted mechanism of the reactions has been confirmed from trajectory simulations. Computational studies have rationalized the preferred endo stereoselectivity and have also indicated that increase in electron withdrawing character of nitrone C-aryl substituent decreases the activation energies and increases the diastereomeric excess along the reaction pathway.

Keywords: Cycloadditions, computational chemistry, density functional theory, activation energy, transition state

1,3-Dipolar cycloadditions are one of the classic reactions of synthetic organic chemistry which generate regio- and stereochemically defined heterocycles of vital importance for both academia and industry1. Like Diels Alder reactions, 1,3-dipolar cycloadditions depend on the electrophilic and nucleophilic character of the reagents and the reaction process is influenced by substituent effects of dipoles and dipolarophiles. The first theoretical study based on FMO approach was reported by Sustmann et al.2 for substituent effects on dipolar cycloadditions. Nowadays, DFT calculations are generally used to present the semiquantitative theoretical rationalization of organic reactions. Domingo et al.3 recently reviewed the applications of conceptual DFT studies for rationalization of different organic reactions. Houk et al.4 have reported DFT analysis of substituent effects on Diels Alder reactions. Braida et al.5 correlated the diradical character of 1,3-dipoles and their reactivity towards cycloaddition reactions to ethylene or propene. A 2015 study by Emamian et al.6 analyzed the reactivity of azomethine betaines in

terms of singlet diradical character descriptors. These investigations highlighted the influence of substituents on reactivities of dipoles and consequently on the reaction pathway.

Nitrones are widely used as radical scavengers and we have recently reported the radical capture energetics of C,N-disubstituted nitrones7. These nitrones can be used as dipoles to synthesize regio- and stereochemically defined tetrasubstituted isoxazolidines. With this in mind, we have attempted to present a consolidated experimental and theoretical investigation to highlight the influence of substituent effects on the selectivities of such reactions. Theoretical studies to analyze the substituent effects on synthesis of tetrasubstituted isoxazolidines has not been addressed so far in literature to the best of our knowledge. C-aryl -N-methyl nitrones (1-4, Figure 1) have been selected as the dipoles for the study with varied electron demand character (p-H, p-Cl, p-NO2 and p-OMe substitution) of C-aryl substituents. Nitrones 1-4 have been allowed to react with cinnamoyl piperidine derivatives (5,6, Figure 1) to

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generate tetrasubstituted isoxazolidines. UV, IR, NMR and X-ray crystallographic studies were carried out to determine the yield, diastereomeric ratios and structures of the isolated cycloadducts. Then, a comparative analysis has been presented in terms of conceptual DFT studies. Global properties3 (electronic chemical potentials, global hardness, electrophilicity and nucleophilicity indices), and activation energies of the located transition states were calculated and analyzed at DFT/B3LYP/6-31G(d) level of theory. Domingo et al.8 reported the comparative analysis of activation enthalpies and singlet diradical character of 1,3-dipoles for different reactions. In the present study, singlet diradical character of the nitrone series was analyzed from magnitude of total spin operator

calculations and compared with the activation energies. Wiberg Bond indices, atom-atom overlap weighted NAO bond orders and asymmetry indices were calculated to rationalize the extent of bond formation and nature of transition states of the investigated reactions. Results and Discussion Experimental results

Experimental data for the investigated reactions (Figure 1) have been collected in Table I. The reactions were carried out in toluene as the solvent. The reactions were completely meta-regioselective. Each reaction generated two cycloadducts and the endo/meta stereoisomer was isolated as the major

NOH

Me

R1

N

O

R2

R1 = H (1), Cl (2), NO2 (3), OMe(4)

NO

HH

H

Me

R1

N

O

R2

NO

HH

H

Me

R1

NO

R2

NO

HH

H

Me

R1

NO

R2

R2 = Cl (5), H(6)

Ortho channel

Meta channel

NO

HH

H

Me

R1

N

O

R2

NOT OBSERVED EXPERIMENTALLY

R1 R

2

7 H Cl 9 Cl Cl 11 NO2 Cl 13 OMe Cl 15 H H 17 Cl H

R1 R

2

8 H Cl 10 Cl Cl 12 NO2 Cl 14 OMe Cl 16 H H 18 Cl H

Endo- Exo-

Figure 1 — Nitrone cycloadditions to cinnamoyl piperidine derivative

Table I — Experimental results for 1,3DCs of C-aryl-N-methyl nitrones to cinnamoyl piperidines

Nitrone Ketone Reaction Time (h) Product Ratio Total Conversion

1 5 17 7: 8 = 75:25 66%

2 5 15 9: 10 = 78:22 74%

3 5 13 11: 12 = 85:15 79%

4 5 18 13:14 = 77:23 65%

1 6 16 15:16 = 76:24 67% 2 6 15 17:18 = 77:23 66%

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product in each case. The yield and diastereomeric ratio were determined from the 1H NMR spectra of the crude reaction mixtures. Cycloaddition reaction of C-phenyl-N-methyl nitrone 1 to 5 yielded two cycloadducts 7 and 8 with the diastereoisomeric ratio 75:25. Reactions of nitrones 2, 3 and 4 to dipolarophile 5 yielded two cycloadducts in each case with diastereomeric ratios of 78:22, 85:15 and 77:23. It is evident from the experimental studies that endo stereoselectivity of the reaction involving C-(4-nitrophenyl)-N-methyl nitrone is highest along the series. Total 12 cycloadducts were isolated during the study by column chromatography over neutral alumina.

H-3, H-4 and H-5 of the isoxazolidine ring in 7 showed signals at δ 4.00 (d, J = 9.1), 3.62 (dist t, J = 7.4) and 5.45 (d, J = 7.3). For cycloadducts 8, the corresponding signals for H3, H4 and H5 appeared at δ 3.81 (d, J = 10.2), 3.49 (dist t, J = 7.7) and 5.90 (d, J = 7.6). Coupling constants indicated 3,4-trans-4,5-trans stereochemistry of the major adducts and 3,4-cis-4,5-trans of the minor isomers in line with our previous investigations9-11. Finally, the stereochemistry of cycloadducts was confirmed by X-ray crystallographic studies of minor adduct 8 and major adduct 9. X-ray structures of minor adduct 8 with 3,4-cis-4,5-trans stereochemistry and major adduct 9, with 3,4-trans-4,5-trans stereochemistry are shown in Figure 2.

Figure 2 — X-ray Crystallographic structure of cycloadducts 8 and 9

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Analysis of global properties Global properties of reactants 1-5 are listed in

Table II. The influence of C-aryl substitution is reflected in these properties. Nitrone 3 shows the lowest HOMO and LUMO energies along the series owing to the presence of strong electron withdrawing nitro substituent. On the other hand, presence of electron donating methoxy substituent in 4 results in the highest HOMO and LUMO energies along the series. The electronic chemical potential (µ) values of nitrones 1, 2 and 4 are greater than that of dipolarophile 5. This indicates charge transfer from nitrone to the dipolarophile and normal electron demand character of the cycloadditions. For nitrone 3, µ value is greater than that of 5 and therefore predicts the inverse electron demand character. The global electrophilicity3, ω, follows the trend 3>5>2>1>4 and the nucleophilicity index N, varies as, 4>1>2>5>3. These values predict that nitrone 3 is the most electrophilic and nitrone 4 is the most nucleophilic reactant along the series. ∆ω values for reaction systems 1/5, 2/5, 3/5 and 4/5 are calculated as 0.231, 0.108, 0.432 and 0.339 respectively which indicates low polar character of the cycloadditions.

Nature of transition states and analysis of activation parameters

The orientation complexes (r), products (p) and transition states (t) for endo and exo modes are indicated by n and x for the reaction channel, each prefixed by 1, 2, 3 and 4 for 1/5, 2/5, 3/5 and 4/5 respectively in accordance to our previous communications9-11. Transition state optimizations for the ortho regioisomeric channel were attempted. However, these computations resulted in unrealistic structures. The inability of DFT studies for regioselectivity predictions of nitrone cycloadditions has also been pointed out by Domingo et al.12. We have also reported some instances9,10 in this context. The bond lengths, Wiberg bond indices (a), atom-atom overlap weighted NAO bond orders (b) and asymmetry indices (∆a) calculated according to the works of Barański and coworkers13,14 are listed in Table III.

Bond orders for forming C-C bonds are greater than that of the forming C-O bonds for all the transition states. Wiberg bond indices aC3-C4 and aC5-O1 and atom-atom overlap weighted NAO bond orders bC3-C4 and bC5-O1 for transition states 1tnm and 4tnm

Table II — DFT/B3LYP/6-31G(d) calculated global properties

S. No EHOMO (eV) ELUMO (eV) µ (au) η (au) S (au) ω (eV) N (eV)

1 −5.496 −1.253 −0.125 0.296 1.692 0.718 3.582 2 −5.660 −1.524 −0.133 0.286 1.748 0.841 3.419 3 −6.204 −2.612 −0.164 0.265 1.884 1.381 2.875 4 −5.143 −1.007 −0.113 0.285 1.757 0.610 3.936 5 −-6.149 −1.551 −0.142 0.289 1.732 0.949 2.929

EHOMO and ELUMO are the HOMO and LUMO energies. Electronic chemical potential,µ and global hardness, η of the reactants are calculated3 from the computed ionization potentials and electron affinities. Global electrophilicity index3, ω, is calculated as, ω = µ2/2η.Global softness is given by S = 1/2η. Nucleophilicity index3, N is calculated from the HOMO energies and given by EHOMO(Nu) − EHOMO(TCE), where TCE is tetracyanoethylene

Table III — DFT/B3LYP/6-31G(d) calculated bond lengths, bond indices (a, b) and asymmetry indices (∆a) of the transition states

Ts O1-N1 N2-C3 C3-C4 C4-C5 C5-O1 aC3-C4 aC5-O1 bC3-C4 bC5-O1 IC3-C4 IC5-O1 ∆a

1tnm 1.310 1.361 2.105 1.413 2.058 0.437 0.367 0.355 0.239 0.650 0.558 0.092 1txm 1.315 1.367 2.027 1.421 2.052 0.492 0.396 0.408 0.241 0.708 0.562 0.146 2tnm 1.388 1.445 2.100 1.432 2.100 0.694 0.581 0.476 0.292 0.652 0.545 0.107 2txm 1.412 1.440 2.100 1.424 2.100 0.686 0.626 0.475 0.305 0.669 0.443 0.226 3tnm 1.382 1.438 2.200 1.417 2.200 0.596 0.495 0.405 0.239 0.601 0.598 0.003 3txm 1.382 1.357 2.170 1.411 2.078 0.404 0.012 0.322 0.233 0.627 0.567 0.060 4tnm 1.312 1.362 2.109 1.413 2.045 0.433 0.382 0.352 0.245 0.647 0.567 0.080 4txm 1.316 1.368 2.038 1.420 2.036 0.484 0.402 0.401 0.248 0.701 0.573 0.128

aC3-C4,aC5-O1: Wiberg Bond indices bC3-C4, bC5-O1: Atom-atom overlap weighted NAO bond orders IC3-C4 = 1- ({rTS

C3-C4 - rP

C3-C4 }/rPC3-C4) IC5-O1 = 1- ({rTS

C5-O1 - rP

C5-O1}/rPC5-O1)

rTS and rP are the bond distances of transition states and products ∆a = IC3-C4 - IC5-O1

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are comparable to each other and lower than that of 2tnm and 3tnm. This indicates that introduction of electron donating substituent in the C-aryl ring shows nominal effect on the extent of bond formation. aC3-

C4,aC5-O1, bC3-C4 and bC5-O1 values of 2/5 are highest along the series. Global electrophilicity of the nitrones follow the order, 3>2>1>4 and electron donating mesomeric effect follows the order, OMe > Cl > H > NO2. Chlorine shows greater global electrophilicity than 1 and 4 and it shows greater electron donating mesomeric effect than -NO2. The highest bond order for 2tnm can be attributed to the combined positive influence of both these factors on the extent of bond formation with global electrophilicity being the predominant factor. This combined positive influence is underlined by the observation that 4tnm with OMe substituent shows similar magnitude of bond order as 1tnm with H substituent. If global electrophilicity was the only factor to dictate the extent of bond formation, then bond order of 4tnm should be less than 1tnm and not equal. The endo transition states for all the reaction systems show lower values of asymmetry indices than their exo counterparts. Transition state 3tnm with lowest activation energy (Table IV) also shows lowest asymmetry index along the series.

The optimized transition states are collected in Figure 3. Huisgen proposed the concerted mechanism of cycloadditions15. Firestone reported the stepwise

mechanism involving diradical intermediate for dipolar cycloadditions16. Although most of the reactions reported in literature indicate concerted mechanism for cycloadditions, some reactions have also been reported to follow the two-step mechanism17. Therefore, a dynamics calculation18 was carried out to establish the mechanism of the investigated reactions. We have also reported19 trajectory calculations for other cycloadditions to establish the mechanism. Single trajectory calculations were carried out for endo/meta mode of 3/5 reaction system as the representative example. The time gaps between the formation of two bonds were calculated in single trajectories. Snapshots for trajectory analysis are shown in Figure 4. Two bonding definitions were employed for the study. The first bond length value used is 1.8Ǻ in single trajectory simulations. This value is longer than the product distance. The second value of 2.0Ǻ was used which is close to the forming bond distances of transition states (Table III). For endo/meta mode of 3/5 reaction system, the time gaps were 1.6 fs (for 1.8Ǻ) and 0.9 fs (for 2.0Ǻ). The calculated time gaps are much lower than the C-C, C-N and C-O vibrational periods of 30 fs.

These values indicate a concerted mechanism where C-O and C-C bonds are formed within a vibrational period. Cyclo-diradical mechanism is not supported for these reactions since no diradical is formed on surface which shows greater lifetime than the time required by those atoms to undergo a vibration required for bond formation. The reactions thus follow a concerted mechanism.

Relative energies of products and transition states are listed in Table IV and that of orientation complexes are shown in Figure 4. For 1tnm, activation energy ∆E = 97.2 kJ/mol and for 1txm, ∆E = 113.8 kJ/mol. This indicates a clear preference for the endo channel. The endo transition state for other reaction systems also show lower activation energies than their exo counterparts. Experimentally, endo/exo ratios follow the order 3/5 (85:15) >2/5 (78:22) >4/5 (77:23) >1/5 (75:25). The difference in activation energies {1tnm−1txm}; {2tnm−2txm}; {3tnm−3txm} and {4tnm−4txm} are calculated as 16.6kJ/mol; 30.9kJ/mol; 43.0kJ/mol and 16.9kJ/mol in gas phase and 15.2 kJ/mol; 27.9 kJ/mol; 40.7kJ/mol and 15.8kJ/mol in toluene. The difference in reaction energies {1pnm−1pxm}; {2pnm−2pxm}; {3pnm−3pxm} and {4pnm−4pxm} are calculated as −7.3 kJ/mol;

Table IV — DFT/B3LYP/6-31G(d) calculated activation and reaction energies

∆E B3LYP/6-31G(d)

(kJ/mol)

∆E B3LYP/6-31G(d)//PCM

(Toluene) (kJ/mol)

1pnm −47.6 −34.0 1pxm −40.3 −27.6 1tnm 97.2 107.7 1txm 113.8 122.8 2pnm −46.2 −32.9 2pxm −32.6 −20.6 2tnm 85.0 97.240 2txm 115.9 125.2 3pnm −49.9 −36.9 3pxm −30.9 −16.9 3tnm 64.5 77.2 3txm 107.5 117.9 4pnm −45.1 −31.1 4pxm −37.5 −25.3 4tnm 97.6 107.8 4txm 114.5 123.6

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−13.6 kJ/mol; −18.9 kJ/mol and −7.6 kJ/mol in gas phase and −6.4 kJ/mol; −12.3 kJ/mol; −20.0 kJ/mol and −5.8 kJ/mol in toluene. The predicted trend of activation and reaction energies follow the endo/exo selectivity order 3/5 >2/5 >4/5 >1/5 and is in agreement with the experimental observations (Figure 5).

Optimizations of reactants, products, orientation complexes and the transition states for the present

study were carried out in gas phase and these geometries were used to calculate the single point energies in toluene using PCM model20,21. Similar calculations have been reported by Domingo et al.12 to rationalize the conformational preference of methacrolein in dipolar cycloadditions.

The activation energies of the preferred endo/meta channel for the reaction systems follow the order

Figure 3 — DFT/B3LYP/6-31G(d) optimized products and transition states

Figure 4 — Snapshots for trajectory analysis (1.8Ǻ) for endo/meta channel (3 + 5)

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∆E3tnm (64.5 kJ/mol) < ∆E2tnm (85.0 kJ/mol) < ∆E1tnm

(97.2 kJ/mol) ≈ ∆E4tnm (97.6 kJ/mol)

Experimentally, reaction 3/5 is completed in 13 h (total conversion 79%) and reactions 1/5, 2/5 and 4/5 are completed in 17, 15 and 18 h respectively with total conversions 66%, 75% and 65% (Table I). This trend is also reflected in the stability of optimized orientation complexes (Figure 4). Orientation complexes for the investigated reaction channels are more stabilized than the reactants in each case. Introduction of p-chloro and p-nitro substituents in the C-aryl ring of the nitrone stabilizes the orientation complex compared to the unsubstituted nitrone. When we introduce electron donating p-methoxy group in the C-aryl ring, then energy of orientation complexes is comparable to the unsubstituted system.

The predicted trend indicates the influence of global electrophilicities of the nitrones on activation energies. Global electrophilicity, ω (Table IV) of the nitrones follow the order 3 (1.381 eV) >2 (0.841eV) >1(0.718 eV) >4(0.610 eV). As the global electrophilicity of nitrone increases, the activation

energy decreases. Reaction 3/5 with highest ω of the nitrone shows lowest activation energies along the series. Although ω is the predominating factor in this context, but the impact of electron donating mesomeric effect on the relative energies cannot be ignored. It is because, global electrophilicity (Table IV) of 1 is 0.718 and 4 is 0.610 and they show almost comparable relative energies of products and transition states. If global electrophilicity was the only factor, then reaction system 4/5 should show higher activation energy than 1/5. It is worth mentioning that the electron donating mesomeric effect of −OMe in 4 cannot overcome the influence of high global electrophilicity of −Cl in 2 and −NO2 in 3 and therefore 4/5 shows higher activation energy than these systems.

The predicted trend of activation and reaction energies can be correlated with the singlet diradical character of the series of investigated nitrones.

The magnitude of total spin operator <S2> is the measure of singlet diradical character of the three atom components8. The total spin operator <S2> was calculated as 1.1642, 1.1879, 1.6811 and 1.1110 for

Figure 5 — Reaction profiles for the cycloaddition reactions

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nitrones 1, 2, 3 and 4 respectively. The investigated reactions involve non-polar character as evident from differences in global electrophilicity (Table II) of the nitrones and dipolarophile. As the total spin operator values of the nitrones increase, activation energies of the cycloadditions decrease. This suggests that when we vary C-aryl substitution of the nitrone from electron donating (−OMe) to electron withdrawing (NO2) moiety, the total spin operator increases. This indicates the increase in tendency of the nitrone to have a singlet diradical character and is characterized by increase in reactivity of the nitrone. This results in lowering of activation energies.

Second Order Perturbation theory analysis Merino et al.22 suggested the contribution of inter-

reactant delocalizations for the generation of preferred isomer by second order perturbation theory (SOPT) analysis. For the present study, delocalization energies of natural bond orbitals were calculated from SOPT analysis. For transition state 1tnm and 1txm, the calculated delocalization energies for σO1-Cβ- σ*C3-Cα transition, were 27.279 and 22.688 kJ/mol, for σ C3-Cα- σ*O1-Cβ transition, were 103.855 and 87.194 kJ/mol, for σ C3-Cα- σ*Cα-CO (piperidinyl) transition, were 71.581 and 56.971 kJ/mol, for n (N2)- σ*O1-Cβ transition, were 103.855 and 87.194 kJ/mol and for n (N2)- σ*C3-Cα

transition, were 115.282 and 104.148 kJ/mol. Similar trends were also observed for reaction systems 2/5, 3/5 and 4/5 respectively. Thus, SOPT analysis indicated appreciable delocalization and increased stability of endo transition state in each case.

Experimental methods Melting points of the isolated cycloadducts were

recorded on an electrically heated Kofler Block apparatus. UV-Vis spectra were recorded in methanol using Shimadzu UV-3101 PC spectrophotometer. IR spectra were recorded in KBr pellets using a Perkin-Elmer RX-9 FT-IR spectrophotometer. 1H and 13C NMR spectra were recorded in CDCl3 using a Bruker AV-300 NMR spectrometer at 300 and 75.5 MHz. 13C NMR assignments were confirmed by DEPT spectra. COSY experiments were also performed during the study to confirm the assignments. Chemical shifts for NMR are reported in parts per million, downfield from tetramethylsilane (TMS). Mass spectra are recorded with a JEOL JMS600 H mass spectrometer.

Cycloaddition procedure Equimolar amounts (0.009 mol) of nitrones and

dipolarophiles were refluxed in 5cm3 dry thiophene

free toluene under nitrogen atmosphere. The reactions were monitored by thin layer chromatography using benzene-ethyl acetate (4:1) solvent system. Excess toluene was removed from the post reaction mixtures under reduced pressure in a Büchi rotary evaporator. Column chromatography was performed to purify the crude post reaction mixtures over neutral alumina (Activity I-II, Merck) using petroleum ether, benzene and ethyl acetate mixtures as the eluents. Solvents used for thin layer chromatography and column chromatography were distilled prior to use. Anhydrous sodium sulfate was used to dry the organic extracts.

X-ray crystallography A crystal of compound 8 of size 0.5 × 0.2 × 0.2 mm,

was selected under microscope and glued on top of a glass fibre and mounted on a goniometer head. A PHILIPS PW1100 automatic four-circle diffractometer was used for recording the different data. The wavelength of CuKα was selected with a graphite monochromator (λ=1.5418 Å). First, the crystal was oriented using a set of 25 randomly measured reflections within a two-theta range of 7-20°. The orientation matrix was then refined by centering reflections at higher angle of diffraction. Second, each reflection was measured within the 3-65° two-theta range at a speed of 0.04 s over a scanning angle of 1°2. The step-scan method was used (30 steps per reflection). The background was estimated on both sides of the reflection as the mean of the two first and the two last channels of the step-scan, then subtracted to the integrated sum. In a first round, all non hydrogen atoms were modelled as thermal isotropic scatters. At the end of the isotropic refinement, hydrogen atoms were located on difference-Fourier maps. They were introduced in the refined model with isotropic thermal factors riding on the bonded atom (usually carbon). In a second round, isotropic thermal factors for non-hydrogen atoms were progressively replaced by anisotropic thermal factors. The hydrogens were all kept isotropic. They were allowed to refine only in the last steps of the refinement with constrained C-H distances. The structure was solved by direct methods (SHELXS86 program). and refined by full-matrix least squares techniques (SHELXL program).

Compound 9 crystallises as very small colourless elongated rods. A crystal (0.3 × 0.15 × 0.15 mm) was selected and mounted on a PHILIPS PW1100 diffractometer operating the CuKα wavelength,

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selected by a graphite monochromator. The cell parameters were deduced from the refinement of angular positions of 25 randomly distributed reflections, selected within the range 30°≤ 2Ɵ ≤ 60°. The data set consists of 3716 reflections among which only 2570 were observed (criteria: I ≥2σ(I)). Isotropic, then anisotropic thermal parameters were employed for non-hydrogen atoms. Hydrogen atoms were located on difference-Fourier maps and introduced with an isotropic thermal factor equal to that of the bonded atom (ridding refinement). The final R factors are: 7.6% (all F data); 6.2% (observed F data); 19% (all F2 data); 16% (observed F2data). The structure was solved by direct methods with SHELXS program and refined with the SHELXL program.

X-ray data of 8 and 9 are deposited at the Cambridge Structural Data Centre under CCDC number 1478412 and 233193 respectively. The data can be obtained free of charge via www.ccdc. cam.ac.uk/data_request/cif. It can be obtained by e-mailing data_request@ccdc.cam.ac.uk.

Computational Methods Geometries of the reactants, products, orientation

complexes and transition states were optimized at DFT/B3LYP/6-31G(d) level of theory. The stationary points were characterized through vibrational frequency calculations and definitely identified for minima (number of imaginary frequencies = 0) or transition states (number of imaginary frequencies = 1). For the nitrones, the stability of restricted wave-functions were checked by STABLE keyword. Instability was found at HF/6-31G(d) level and the values of total spin operator <S2> were obtained HF-6-31G(d) STABLE = opt on the optimized geometries. IRC calculations24 were performed to check the energy profile which connects the transition state to the two associated minima of the proposed mechanism. The electron affinity and ionization potential were obtained at DFT level using UB3LYP/6-31G(d) theory for the anion and cation. Geometries of the neutral species were used to calculate the electronic structure of the charged species. Solvent effects were considered by DFT/B3LYP/6-31G(d) single point energy calculations at the gas phase geometries using Polarized Continuum Model of Tomasi and coworkers20,21 (CPCM24) in toluene. Gaussian jobs with the sampled initial conditions were automatically generated to propagate the trajectories (ADMP25 keyword). The

trajectories were run at 298K using the default step size. All calculations were carried out using Gaussian 2003 set of programs25 with Gauss view interface.

Experimental Section (3α,4β,5α)-5-(4-Chlorophenyl)-2-methyl-3-phenyl-

4-piperidinyloxo-isoxazolidine (7, C22H25N2O2Cl): White crystalline solid. Yield 1.78 g (58%). m.p.133°C. Isolated from benzene eluates. Rf = 0.58 (silica gel, benzene: ethyl acetate - 4:1); 1H NMR (300 MHz, CDCl3): δ 4.00 (d, J = 9.1, H3), 3.62 (dist. t, J = 7.4, H4), 5.45 (d, J = 7.3, H5), 6.90-7.37 (m, H2,3,4,5,6(A), H2,3,5,6(B), 3.29 (m, H2A(C), 2.99 (m, H2B(C), 1.51 (br.s, H3(C), 1.17 (br.s, H4(C), 0.59 (m, H5A(C), 0.50 (m, H5B(C), 2.54 (m, H-6(C), 2.67 (s, NCH3);

13C NMR (75.5 MHz, CDCl3): δ 78.38 (C3), 62.88 (C4), 81.55 (C5), 137.25 (C-1(A), 127.13 (C-2,6(A), 128.69 (C-3,5(A), 128.04 (C-4(A), 133.78 (C-1(B), 128.16 (C-2,6(B), 129.23 (C-3,5(B), 134.94 (C-4(B), 46.22 (C-2(C), 24.76 (C-3(C), 24.41 (C-4(C), 25.94 (C-5(C), 43.19 (C-6(C), 167.48 (C=O), 42.29 (NCH3); UV-Vis: (methanol: C = 5 × 10−5 mol dm−3) λmax(logϵ) = 264(3.96) nm; IR (KBr): 2840-2920 (w), 1635 (s), 1030(w), 850(w), 830(w), 740(s), 700(w) cm−1; MS: m/z 384(C22H25N2O2Cl, M+), 271(C16H14NOCl), 265 (C14H16NO2Cl), 249 (C14H16NOCl), 159 (C10H9NO), 134 (C8H8NO), 135 (C8H9NO), 119 (C8H9N), 104 (C7H6N).

(3α,4α,5β)-5-(4-Chlorophenyl)-2-methyl-3-phenyl-4-piperidinyloxo isoxazolidine (8, C22H25N2O2Cl): White needle shaped crystals. Yield 0.15 g (5%). m.p.122°C. Isolated from 2% ethyl acetate in benzene eluates. Rf = 0.62 (silica gel, benzene: ethyl acetate - 4:1); 1H NMR (300 MHz, CDCl3): δ 3.81 (d, J = 10.2, H3), 3.49 (dist. t, J = 7.7, H4), 5.90 (d, J = 7.6, H5), 7.19-7.38 (m, H2,3,4,5,6 (A), H2,3,5,6(B), 3.20 (m, H2A(C), 3.00 (m, H2B(C), 1.50 (m, H3(C), 1.19 (m, H4(C), 0.97 (m, H5A(C); 0.66 (m, H5B(C), 2.54 (m, H-6(C), 2.58 (s, NCH3);

13C NMR (75.5 MHz, CDCl3): δ 76.58 (C3), 58.96 (C4), 81.25 (C5), 138.55 (C-1(A), 127.90 (C-2,6(A), 128.48 (C-3,5(A), 128.20 (C-4(A), 133.66 (C-1(B), 128.64 (C-2,6(B), 129.51 (C-3,5(B), 135.13 (C-4(B), 46.06 (C-2(C), 24.58 (C-3(C), 24.03 (C-4(C), 25.61 (C-5(C), 42.50 (C-6(C), 167.24 (C=O), 43.02(NCH3); UV-Vis: (methanol: C = 5 × 10−5 mol dm−3) λmax

(logϵ) = 219(4.15) nm; IR (KBr): 2880-2960 (w), 1640 (s), 1020 (w), 860 (w), 840 (w), 750 (s), 700 (w) cm−1; MS: m/z 384 (C22H25N2O2Cl, M+), 271 (C16H14NOCl), 265 (C14H16NO2Cl), 249 (C14H16NOCl), 159 (C10H9NO), 134 (C8H8NO), 135 (C8H9NO), 119 (C8H9N), 104(C7H6N).

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(3α,4β,5α)-3-(4-Chlorophenyl)-5-(4-chlorophenyl)-2-methyl-4-piperidinyloxo isoxazolidine (9, C22H24N2O2Cl2): White crystalline solid. Yield 1.64 g (56%). m.p.126°C. Isolated from benzene eluates. Rf = 0.63 (silica gel, benzene: ethyl acetate - 4:1); 1H NMR (300 MHz, CDCl3): δ 4.14 (d, J = 8.9, H3), 3.62 (dist. t,H4), 5.46 (d, J = 7.4, H5), 7.32 (m, H2,6 (A), H2,6 (B), 7.39 (m, H3,5 (A), H3,5 (B) 3.54 (m, H2(C), 1.44 (m, H3,4(C), 0.94 (m, H5A(C); 0.78 (m, H5B(C), 3.54 (m, H6(C), 2.75 (s, NCH3);

13C NMR (75.5 MHz, CDCl3): δ 76.57 (C3), 63.17 (C4), 81.92 (C5), 139.87 (C-1(A)), 127.42 (C-2,6(A)), 129.08 (C-3,5(A), 136.73 (C-4(A), 134.12 (C-1(B), 128.77 (C-2,6(B), 128.87 (C-3,5(B), 133.78 (C-4(B), 46.91 (C-2,6(C), 25.79 (C-3(C), 24.28 (C-4(C), 26.34 (C-5(C), 167.57 (C=O), 46.88 (NCH3); UV-Vis: (methanol: C = 5 × 10−5 mol dm−3) λmax(logϵ) = 286 (5.53) nm; IR (KBr): 2850-2920 (w), 1640 (s), 1020(w), 850(s) cm−1; MS: m/z 418 (C22H24N2O2Cl2, M+), 305 (M+-C6H10NO+H.), 249 (M+-C8H8NOCl), 193 (305-C6H4Cl- H.), 168 (C8H8NOCl), 153 (M+-C14H17NO2Cl+H.), 265 (M+-C8H7NCl-H.), 138 (153-CH3), 84 (C5H10N).

(3α,4α,5β)-3-(4-Chlorophenyl)-5-(4-chlorophenyl)-2-methyl-4-piperidinyloxo isoxazolidine (10, C22H24N2O2Cl2): White crystalline solid. Yield 0.11 g (4%). m.p.146°C. Isolated from 2% ethyl acetate in benzene eluates. Rf = 0.71 (silica gel, benzene: ethyl acetate - 4:1); 1H NMR (300 MHz, CDCl3): δ 3.80 (d, J = 10.3, H3), 3.48 (dd, J = 10.3,7.8,H4), 5.46 (d, J = 7.8, H5), 7.23 (m, H2,6 (A), H2,6 (B), 7.30 (m, H3,5 (A), H3,5 (B) 3.30 (m, H2(C), 1.26 (m, H3,4(C), 1.03 (m, H5A(C); 0.82 (m, H5B(C), 3.04 (m, H6A(C), 2.94 (m, H6B(C), 2.56 (s, NCH3);

13C NMR (75.5 MHz, CDCl3): δ 76.38 (C3), 58.91(C4), 81.38 (C5), 138.22 (C-1(A), 127.82 (C-2,6(A), 130.07 (C-3,5(A), 134.78 (C-4(A), 134.53 (C-1(B), 128.42 (C-2,6(B), 128.70 (C-3,5(B), 133.78 (C-4(B), 46.24 (C-2 (C), 25.16 (C-3(C), 24.11 (C-4(C), 25.94 (C-5(C), 42.89 (C-6(C), 166.99 (C=O), 43.05 (NCH3); UV-Vis: (methanol: C = 5 × 10−5 mol dm−3) λmax(logϵ) = 220(5.72) nm; IR (KBr): 2860-2920 (w), 1625 (s), 1015 (s), 860, 830 (w) cm−1; MS: m/z 418 (C22H24N2O2Cl2, M+), 305 (M+-C6H10NO+H.), 249 (M+-C8H8NOCl), 193 (305-C6H4Cl- H.), 168 (C8H8NOCl), 153 (M+-C14H17NO2Cl+H.), 265 (M+-C8H7NCl-H.), 138 (153-CH3), 84 (C5H10N).

(3α,4β,5α)-3-(4-Nitrophenyl)-5-(4-chlorophenyl)-2-methyl-4-piperidinyloxo isoxazolidine (11, C22H24N3O4Cl): Pale yellow crystalline solid. Yield

2.00 g (52%). m.p.140°C. Isolated from 2% ethyl acetate in benzene eluates. Rf = 0.57 (silica gel, benzene: ethyl acetate - 4:1); 1H NMR (300 MHz, CDCl3): δ 4.44 (d, J = 8.6, H3), 3.61 (t, J = 8.2,H4), 5.62 (d, J = 7.8, H5), 7.61 (d, J = 8.7, H2,6 (A), 8.21 (d, J = 8.7, H3,5 (A), 7.32-7.39 (m, H-2,3,5.6 (B), 3.54 (br.s, H2(C), 1.44 (m, H3,4(C), 0.91 (m, H5A(C); 0.83 (m, H5B(C), 2.73 (H6 (C), 2.83 (s, NCH3); 13C NMR (75.5 MHz, CDCl3): δ 76.57 (C3), 53.35 (C4), 82.29 (C5), 146.35 (C-1(A), 127.54 (C-2,6(A), 124.06 (C-3,5(A), 148.26 (C-4(A), 138.72 (C-1(B), 128.05 (C-2,6(B), 129.01 (C-3,5(B), 134.19 (C-4(B), 43.79 (m, C-2 (C), 25.77 (m, C-3(C), 24.19 (m, C-4(C), 26.47 (m, C-5(C), 46.92 (m, C-6(C), 167.05 (C=O), 44.27 (NCH3); UV-Vis: (methanol: C = 5 × 10−5 mol dm−3) λmax(logϵ) = 276 (4.26) nm; IR (KBr): 2860-2950 (w), 1640 (s), 1530 (s), 1360 (s), 1100(w), 860,830(w) cm−1; MS: m/z 429(C22H24N3O4Cl, M+), 413(M+-CH3), (C21H21N3O4Cl), 317(M+-C6H10NO), 249(M+-C8H8N2O3), 164 (M+-C14H17NO2Cl + H.), 84(C5H10N

+).

(3α,4α,5β)-3-(4-Nitrophenyl)-5-(4-chlorophenyl)-2-methyl-4-piperidinyloxo isoxazolidine (12, C22H24N3O4Cl): White crystalline solid. Yield 0.19 g (5%). m.p.116°C. Isolated from 2% ethyl acetate in benzene eluates. Rf = 0.64 (silica gel, benzene: ethyl acetate - 4:1); 1H NMR (300 MHz, CDCl3): δ 4.04 (d, J = 10.4, H3), 3.65 (dd, J = 8.0, 10.4,H4), 5.92 (d, J = 8.0, H5), 7.62 (d, J = 8.6, H2,6 (A), 8.21 (d, J = 8.6, H3,5 (A), 7.31-7.40 (m, H-2,3,5.6(B), 3.42 (m, H2A(C), 2.90 (m, H2A(C), 1.25-1.35 (m, H3,4(C), 1.02 (m, H5(C); 3.20 (m, H6(C), 2.68 (s, NCH3); 13C NMR (75.5 MHz, CDCl3): δ 75.9(C3), 58.92(C4), 81.71 (C5), 145.21 (C-1(A), 127.76 (C-2,6(A), 123.27 (C-3,5(A), 148.26 (C-4(A), 139.10 (C-1(B), 128.82 (C-2,6(B), 130.27 (C-3,5(B), 134.20 (C-4(B), 46.44 (C-2 (C), 25.26 (C-3(C), 24.08 (C-4(C), 26.18 (C-5(C), 43.37 (C-6(C), 166.48 (C=O), 42.81 (NCH3); UV-Vis: (methanol: C = 5 × 10−5 mol dm−3) λmax(logϵ) = 268 (4.10) nm; IR (KBr): 2865-2950 (w), 1630 (s), 1530 (s), 1350 (s), 1100(w), 850, 830 (w) cm−1; MS: m/z 429 (C22H24N3O4Cl, M+), 317 (M+-C6H10NO), 249 (M+-C8H8N2O3), 164 (M+-C14H17NO2Cl + H.), 84 (C5H10N

+). (3α,4β,5α)-3-(4-Methoxyphenyl)-5-(4-chlorophenyl)-

2-methyl-4-piperidinyloxo isoxazolidine (13, C23H27N2O3Cl): White crystals. Yield 2.19 g (49%). m.p.143°C. Isolated benzene eluates. Rf = 0.49 (silica gel, benzene: ethyl acetate - 4:1); 1H NMR (300 MHz, CDCl3): δ 3.85 (d, J = 9.3, H3), 3.53 (dist. t,

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J = 7.7,H4), 5.95 (d, J = 7.8, H5), 7.28 (m, H2,6 (A), 6.86 (m, H3,5 (A), 7.32-7.39 (m, H-2,3,5.6(B), 3.34 (m, H2(C), 1.32 (m, H3,4(C), 1.16 (m, H5(C), 3.08 (H6(C), 2.67 (s, NCH3), 3.80 (s, OCH3);

13C NMR (75.5 MHz, CDCl3): δ 76.37 (C3), 58.53 (C4), 80.97 (C5), 133.35 (C-1(A), 128.64 (C-2,6(A), 115.70 (C-3,5(A)), 159.74 (C-4(A), 136.23 (C-1(B), 127.71 (C-2,6(B), 128.39 (C-3,5(B), 134.07 (C-4(B), 42.67 (m, C-2 (C), 24.85 (m, C-3(C), 23.82 (m, C-4(C), 25.46(m, C-5(C), 45.91 (m, C-6(C), 167.25 (C=O), 42.40 (NCH3), 57.21 (OCH3); UV-Vis: (methanol: C = 5 × 10−5 mol dm−3) λmax(logϵ) = 274 (3.12) nm; IR (KBr): 2860-2920 (w), 1630 (s), 1040 (w), 850,830(w) cm−1; MS: m/z 414(C23H27N2O3Cl, M+), 302(M+-C6H10NO), 249(M+-C9H11NO2), 190 (302- C6H5Cl+H.), 165 (249-C5H10N), 150 (M+-C14H17NO2Cl + 2H.), 84(C5H10N

+).

(3α,4α,5β)-3-(4-Methoxyphenyl)-5-(4-chlorophenyl)-2-methyl-4-piperidinyloxo isoxazolidine (14, C23H27N2O3Cl): White amorphous powder. Yield 0.18 g (4%). Isolated from 2% ethyl acetate in benzene eluates. Rf = 0.56 (silica gel, benzene: ethyl acetate - 4:1); 1H NMR (300 MHz, CDCl3): δ 4.72 (d, J = 10.2, H3), 3.60 (dd, J = 7.9, 10.2,H4), 5.95 (d, J = 7.9, H5), 7.25 (m, H2,6 (A), 6.80 (m, H3,5 (A), 7.30-7.37 (m, H-2,3,5.6(B), 3.30 (m, H2(C), 1.26 (m, H3,4(C), 1.18 (m, H5(C), 3.00 (H6(C), 2.69 (s, NCH3), 3.78 (s, OCH3);

13C NMR (75.5 MHz, CDCl3): δ 76.40 (C3), 54.51 (C4), 80.81 (C5), 132.32 (C-1(A), 128.49 (C-2,6(A), 116.82(C-3,5(A), 159.65 (C-4(A), 136.42 (C-1(B), 126.95 (C-2,6(B), 128.25 (C-3,5(B), 134.11 (C-4(B), 42.54 (m, C-2 (C), 24.79 (m, C-3(C), 23.69 (m, C-4(C), 25.24(m, C-5(C), 45.74 (m, C-6(C), 167.32 (C=O), 42.50 (NCH3), 57.69 (OCH3); UV-Vis: (methanol: C = 5 × 10−5 mol dm−3) λmax(logϵ) = 226 (4.40) nm; IR (KBr): 2860-2920 (w), 1625 (s), 1035 (w), 860, 830(w) cm−1; MS: m/z 414(C23H27N2O3Cl, M+), 302 (M+-C6H10NO), 249(M+-C9H11NO2), 190 (302- C6H5Cl+H.), 165 (249-C5H10N), 150 (M+-C14H17NO2Cl + 2H.), 84(C5H10N

+).

(3α,4β,5α)-2-Methyl-3,5-diphenyl-4-piperidinyloxo isoxazolidine (15, C22H26N2O2): White crystalline solid. Yield 1.57 g (56%). m.p.128°C. Isolated from benzene eluates. Rf = 0.58 (silica gel, benzene: ethyl acetate - 4:1); 1H NMR (300 MHz, CDCl3): δ 4.17 (d, J = 8.9, H3), 3.77 (dist. t, J = 7.6, H4), 5.52 (d, J = 7.5, H5), 7.50-7.54 (m, H2,6 (A), H2,6(B), 7.33-7.37 (m, H3,4,5(A), H3,4,5(B)), 3.19 (m, H2 (C), 1.34 (m, H3,4(C), 0.88 (m, H5A(C), 0.82 (m,

H5B(C), 3.00 (m, H-6(C), 2.79 (s, NCH3); 13C NMR

(75.5 MHz, CDCl3): δ 78.15 (C3), 60.55(C4), 81.65 (C5), 138.14(C-1(A), 127.25 (C-2,6(A), 128.54 (C-3,5(A), 128.04 (C-4(A), 140.00 (C-1(B)), 128.20 (C-2,6(B), 129.20 (C-3,5(B), 128.03 (C-4(B), 46.56 (C-2(C), 24.72 (C-3(C), 25.51 (C-4(C), 25.91 (C-5(C), 42.91(C-6(C), 168.15(C=O), 42.50(NCH3); UV-Vis: (methanol: C = 5 × 10−5 mol dm−3) λmax(logϵ) = 268.5(4.74); IR (KBr): 2840-2920 (w), 1630 (s), 760(s), 700(s) cm−1; MS: m/z 350(C22H26N2O2, M+), 237(C16H15NO), 231(C14H17NO2), 215(C14H17NO), 134 (C8H8NO), 135 (C8H9NO), 119 (C8H9N), 104 (C7H6N).

(3α,4α,5β)-2-Methyl-3,5-diphenyl-4-piperidinyloxo isoxazolidine (16, C22H26N2O2): Grey coloured crystalline solid. Yield 0.14 g (5%). m.p.110°C. Isolated from 5% ethyl acetate in benzene eluates. Rf = 0.61 (silica gel, benzene: ethyl acetate - 4:1); 1H NMR (300 MHz, CDCl3): δ 3.81 (d, J = 10.2, H3), 3.56 (dist. t, J = 7.4, H4), 5.91 (d, J = 7.4, H5), 7.37 (m, H2,6 (A), 7.30 (m, H2,6 (B), 7.22 (m, H3,4,5(A), H3,4,5(B), 3.17 (m, H2 (C), 1.18 (m, H3,4(C), 0.99 (m, H5A(C), 0.61 (m, H5B(C), 2.98 (m, H-6(C), 2.55 (s, NCH3);

13C NMR (75.5 MHz, CDCl3): δ 78.21 (C3), 60.84(C4), 81.57 (C5), 138.22(C-1(A), 127.30 (C-2,6(A), 128.20 (C-3,5(A), 128.01 (C-4(A), 140.10 (C-1(B), 128.19(C-2,6(B), 129.19 (C-3,5(B), 128.04 (C-4(B), 46.60 (C-2(C), 24.81 (C-3(C), 25.49 (C-4(C), 25.84 (C-5(C), 42.84 (C-6(C), 168.25(C=O), 42.37(NCH3); UV-Vis: (methanol: C = 5 × 10−5 mol dm−3) λmax(logϵ) = 217(4.37) nm; IR (KBr): 2860-2920 (w), 1640 (s), 770(s), 700(w) cm−1; MS: m/z 350(C22H26N2O2, M+), 237 (C16H15NO), 231 (C14H17NO2), 215 (C14H17NO), 134 (C8H8NO), 135 (C8H9NO), 119 (C8H9N), 104 (C7H6N).

(3α,4β,5α)-3-(4-Chlorophenyl)-2-methyl-5-phenyl-4-piperidinyloxo isoxazolidine (17, C22H25N2O2Cl): White needle shaped crystals. Yield 1.69 g (58%). m.p.144°C. Isolated from 2% ethyl acetate in benzene eluates. Rf = 0.68 (silica gel, benzene: ethyl acetate - 4:1); 1H NMR (300 MHz, CDCl3): δ 4.16 (d, J = 8.8, H3), 3.63 (dist. t, J = 8.3, H4), 5.39 (d, J = 7.7, H5), 7.25-7.54 (m, H2,3,5,6 (A), H2,3,4,5,6(B), 3.48(m, H2(C), 1.60 (m, H3(C), 1.54(m, H4(C) 0.79 (m, H5A(C); 0.80 (m, H5B(C), 2.66 (m, H6(C), 2.75 (s, NCH3);

13C NMR (75.5 MHz, CDCl3): δ 77.28 (C3), 63.11(C4), 82.66 (C5), 140.80 (C-1(A), 127.62 (C-2,6(A), 128.95 (C-3,5(A), 133.83 (C-4(A), 137.07 (C-1(B), 128.69 (C-2,6(B), 126.09 (C-3,5(B), 129.30 (C-4(B), 46.78 (C-2(C), 25.71 (C-3(C), 24.25

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(C-4(C), 26.21(C-5(C), 43.59(C6(C), 167.63 (C=O), 44.02(NCH3); UV-Vis: (methanol: C = 5 × 10−5 mol dm−3) λmax(logϵ) = 271.5(3.31) nm; IR (KBr): 2860-2920 (w), 1630 (s), 840,820(w), 760,700(w) cm−1; MS: m/z 384(C22H25N2O2Cl, M+), 271 (M+-C6H10NO+H.), 231 (M+-C8H8NCl), 215 (M+-C8H8NClO), 168 (C8H8NOCl), 153 (C8H8NCl), 265 (M+-C8H7NCl-H.), 138 (153-CH3), 79 (271-C6H6).

(3α,4α,5β)-3-(4-Chlorophenyl)-2-methyl-5-phenyl-4-piperidinyloxo isoxazolidine (18, C22H25N2O2Cl): White flakes. Yield 0.18 g (6%). m.p.128°C. Isolated from 2% ethyl acetate in benzene eluates. Rf = 0.61 (silica gel, benzene: ethyl acetate - 4:1); 1H NMR (300 MHz, CDCl3): δ 3.88 (d, J = 10.2, H3), 3.65 (dist. t, J = 7.7, H4), 5.96 (d, J = 7.4, H5), 7.26-7.46 (m, H2,3,5,6 (A), H2,3,4,5,6(B), 3.35(m, H2(C), 1.35 (m, H3(C), 1.18 (m, H4(C) 0.87 (m, H5(C), 3.06 (m, H6(C), 2.68 (s, NCH3);

13C NMR (75.5 MHz, CDCl3): δ 76.15 (C3), 58.64 (C4), 82.04 (C5), 139.58 (C-1(A), 127.90 (C-2,6(A), 128.35 (C-3,5(A), 134.39 (C-4(A), 134.85 (C-1(B), 128.38 (C-2,6(B), 126.55 (C-3,5(B), 130.67 (C-4(B), 42.63 (C-2,6(C), 25.46 (C-3(C), 24.11 (C-4(C), 25.88 (C-5(C), 46.19 (C6(C), 167.63 (C=O), 46.22 (NCH3); UV-Vis: (methanol: C = 5 × 10−5 mol dm−3) λmax(logϵ) = 258(3.45) nm; IR (KBr): 2860-2940 (w), 1640 (s), 840 (w), 760, 710 (w) cm−1; MS: m/z 384 (C22H25N2O2Cl, M+), 271 (M+-C6H10NO+H.), 231 (M+-C8H8NCl), 215 (M+-C8H8NClO), 168 (C8H8NOCl), 153 (C8H8NCl), 265 (M+-C8H7NCl-H.), 138 (153-CH3), 79 (271-C6H6).

Conclusion Cycloaddition reactions of C-aryl-N-methyl

nitrones (with different global electrophilicities) to cinnamoyl piperidine have been studied in this report by both experimental and computational methods. Activation energy calculations indicated endo-stereoselectivity, which is in complete agreement with the experimental findings.

Concerted mechanism was indicated by ADMP trajectory following from the time-gaps between the formation of C-C and C-O bonds.

Activation energies for reactions of unsubstituted and methoxy substituted nitrone were comparable. Cycloaddition involving electron withdrawing nitro substituted nitrone showed sharp decrease in activation energies both in gas phase as well as in toluene. The predicted trend along the series was in agreement with the experiments.

Analysis of global properties and bond orders indicated that the predominant factor determining the extent of bond formation and activation energies is the global electrophilicity of nitrones. However, the effect of electron donating mesomeric effect on the bond-formation process cannot be neglected. Acknowledgements

The authors are grateful to Prof. Manas Banerjee, Burdwan University, India for kind cooperation. References 1 Feuer H, Nitrile Oxides, Nitrones and Nitronates in Organic

Synthesis, 2nd Edn (John Wiley and Sons, New York, United States) (2008) 129.

2 Sustmann R, Tetrahedron Letters, 29 (1971) 2717. 3 Domingo L R, Gutiérrez M R & Patricia P, Molecules, 21

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