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Regio- and stereoselective synthesis of new spiro-isoxazolidines via 1,3-dipolar cycloaddition
⁎Corresponding author. Tel.: +216 97339308. nafaa_jegham@yahoo.fr (Nafâa Jegham)
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Received: ,
Accepted: ,
This article was originally published by Elsevier and was migrated to Scientific Scholar after the change of Publisher.
Peer review under responsibility of King Saud University.
Abstract
New spiro-isoquinolinediones were prepared by regio- and stereoselective 1,3-dipolar cycloaddition of (E)-4-arylidene-N-methyl-isoquinoline-1,3-dione derivatives 1a–d with C-aryl-N-phenylnitrones 2e–g. NMR studies confirmed that only one regioisomer was formed selectively in the majority of cases. Regioselectivity of the reaction was established by 1H and 13C NMR assignments. The stereochemistry of spirannic compounds 3a–l and 4a–c has been corroborated by means of DFT calculations. The structures of all the products were characterized thoroughly by NMR and elemental analyses.
Keywords
1,3-Dipolar cycloaddition
Isoquinolinediones
Nitrones
Regiochemistry
Stereoselective
Spiroisoxazolidines
1 Introduction
The 1,3-dipolar cycloaddition reactions are among the most important synthetic reactions allowing the construction of five member ring carbocycles and heterocycles (Huisgen, 1984) Nitrile oxides and nitrones have been shown to be effective 1,3-dipoles and they undergo smooth reactions with substituted olefins (Torsell, 1990) to afford substituted isoxazolines and isoxazolidines, respectively. Both classes of heterocycle are versatile intermediates for the synthesis of natural products and biologically active compounds (Tice and Ganem, 1983; Vasella and Voeffray, 1983; Kasahara et al., 1989). The 1,3-dipolar cycloaddition reaction between nitrones and unsaturated systems is an efficient method for the organic synthesis of a wide variety of new heterocyclic derivatives structurally related to lactams, indolizidines (Cordero et al., 2013), and alkaloids (Omprakash et al., 2007) which have found application in the preparation of complex molecules with useful biological activities such as antibiotics and glycosidase inhibitors. As example (Barros et al., 2002) demonstrated that by conventional organic methods, chiral heterocycles with potential biological activity, can be synthesized, exploring the fact that addition of nucleophiles to a C⚌C double bond offers an attractive route for the creation of novel C—C, N—O and C—O bonds and for the generation of new isoxazolidine derivatives. These compounds have been used for many products’ syntheses and can be converted to efficient precursors for many synthetic intermediates including β-amino alcohols (Oukani et al., 2013), β-amino acids (Aouadi et al., 2012) and β-lactams (Zanobini et al., 2004), which are useful chiral building blocks for the synthesis of biologically active compounds. Although numerous reports are available for the synthesis of isoxazolidine derivatives (Kumar et al., 2010; Revuelta et al., 2008), relatively few work on spiro-isoxazolidine derivatives has been published.
In this context, our research group has been active in the synthesis of various spiro-cyclized isoxazolidines and isoxazolines (Jegham et al., 2010; Askri et al., 2007; Bahy et al., 2010). In continuation of our interest in cycloaddition reactions, we present here the first example where C-aryl-N-phenylnitrones 2e–g reacted with (E)-4-arylidene-isoquinoline-(2H,4H)-1,3-diones 1a–d in a regioselective manner.
2 Results and discussion
We have subjected dipolarophiles 1a–d (Ar⚌Ph, p-MeC6H4, p-MeOC6H4, p-NO2C6H4) to cycloaddition reactions (3 days at reflux in toluene) with the nitrones 2e–g (Ar⚌Ph, p-MeC6H4, p-MeOC6H4) according to Scheme 1.![[3 + 2] Cycloaddition reaction of C-aryl-N-phenylnitrones 2e–g with (E)-4-arylidene-(2H,4H)-isoquinoline-1,3-diones 1a–d.](/content/184/2017/10/2_suppl/img/10.1016_j.arabjc.2014.05.028-fig1.png)
[3 + 2] Cycloaddition reaction of C-aryl-N-phenylnitrones 2e–g with (E)-4-arylidene-(2H,4H)-isoquinoline-1,3-diones 1a–d.
The dipolarophiles 1a–d were obtained by the condensation of aromatic aldehydes with N-methylhomophthalimide (Jegham et al., 2012). The nitrones 2e–g were easily prepared from phenylhydoxylamine in ethanolic solution following a known procedure (Tufariello, 1984). The [3 + 2] cycloaddition reaction led to a single adduct 5-spiro-isoxazolidine in the major case, as evidenced by 1H NMR examination of the crude reaction mixture. The reaction yielded 100% regioselectively, unless otherwise was indicated. The regiochemistry of the reaction was not similar to that observed for the reaction of arylnitrile oxides with (E)-4-arylidene-N-phenyl-(2H,4H)-isoquinoline-1,3-diones in which we have obtained two regioisomers with comparable ratios. But for us the reactions are regiospecific in the majority of cases. The ratios were determined by the integration of the benzylic protons (3-H, 4-H and 5-H) signals in the NMR spectra of the crude mixture and closely correspond to those obtained after the separation (Table 1). The pairs of cycloadducts 3a–l and 4a–c are usually formed in fair yields and have been separated by column chromatography. In order to have better regioselectivity, the cycloaddition reactions have been performed in different solvents such as benzene, acetonitrile, toluene, and chloroform at reflux and room temperature. Unfortunately, we have found that variation of reaction conditions showed no modification in the ratios of formed regioisomers.
Entry
R
R′
Cycloadducts ¾
Ratios ¾
1H NMR δH4/δH5
13C NMR δC5,4′ and δC4,4′
1
H
H
3a/4a
30/70
4.07/6.26
86,0/69,0
2
Me
H
3b
100/0
4.04
86.5
3
OMe
H
3c
100/0
4.05
86.0
4
NO2
H
3d
100/0
4.28
86.2
5
H
Me
3e
100/0
4.08
86.3
6
Me
Me
3f/4b
75/25
4.02/6.22
85.9/69.2
7
OMe
Me
3 g
100/0
4.05
86.1
8
NO2
Me
3 h/4c
100/0
4.09
86.2
9
H
OMe
3i
100/0
4.24
90.3
10
Me
OMe
3j/4c
70/30
4.08/6.21
85.8/69.3
11
OMe
OMe
3 k
100/0
4,06
86.2
12
NO2
OMe
3 l
100/0
4,23
86.1
The structures of cycloadducts were established on the basis of spectroscopic data. The 1H NMR spectra of regioisomers 3a–l exhibited a doublet around 5.34 and 5.49 ppm attributed to the 3-H proton and a doublet between 4.03 and 4.29 ppm assigned to the 4-H proton. The 13C NMR data confirm this result. The chemical shifts of the spiro carbon atoms (C-5,4′) were found to be between 85.8 and 90.3 ppm because of the deshielding effect of the oxygen atom. In the case of structures 4a–c, the 1H NMR revealed a singlet around 6.20 and 6.27 ppm attributed to the 5-H proton and a singlet between 5.75 and 5.89 ppm assigned to the 3-H proton. In several other cycloadditions with comparable dipolarophiles (Molchanov et al., 2013; Wannasi et al., 2010) the inverse regioselectivity was observed leading only to 4-spiroisoxazolidine.
The cycloaddition of (E)-4-arylidene-N-methyl-(2H,4H)-isoquinoline-1,3-diones 1a–d with C-aryl-N-phenylnitrones 2e–g led to cycloadducts 3a–l and 4a–c with three new chiral centers of the isoxazolidine ring (Scheme 1). The relative stereochemistry of these carbons [rel-(3R, 5,4′R, 4R)] for 3a–l and [rel-(3R, 4,4′R, 5R)] for 4a–c results from (i) preservation of the (E) configuration of the initial olefin and (ii) concerted reaction of (Z)-nitrones 2e–g over 1a–d (Scheme 2). The formation of diastereoisomeric adducts has never been caused by any Z/E interconversion of nitrones (Rigolet et al., 2000; Cacciarini et al., 2000; Roussel et al., 2009). The relative configuration (Z) of the dipole is always being preserved in spiro-compounds (Scheme 2). For 3a–l the doublets observed in the NMR spectra, which correspond to protons 3-H and 4-H have a coupling constant of about 11 Hz which allows to conclude that these protons are in trans position. In the case of 4a–c the absence of correlation in NOESY spectra confirmed that the protons 3-H and 5-H are in trans position.
Approach modes (endo-C⚌O and exo-C⚌O).
One may consider different approaches during the course of the cycloaddition. The two approach modes (endo-C⚌O and exo-C⚌O) of the C-aryl-N-phenylnitrones 2e–g toward dipolarophiles 1a–d are depicted in Scheme 2.
In order to clarify the origin of the selective formation of the endo C⚌O product, we performed density functional theory (DFT) optimization of the complex of reactants in toluene at the B3LYP/6-31G (d) level of theory. In these calculations, the solvent was treated using the polarizable continuum dielectric model of Cossi et al., 2002.The calculations were performed with the Gaussian09 package (Frisch et al., 2009). We found that the reactants form a site-to-site complex of endo —C⚌O type (Fig. 1) that is very likely the precursor of an endo C⚌O transition state. It is well known that the site-to-site configuration is characteristic to complexes mainly stabilized by electrostatic interactions. In the present case the complex appears to be stabilized by hydrogen bonds involving the oxygen atoms carried by the two reactants. On the other hand, an analogous conformation of the complex of the exo C⚌O type was not identified in the calculations. We conclude that the endo C⚌O selectivity is due to a favorable electrostatic interaction between the two reactants.
The calculations show that the reactants form a site-to-site complex of endo C⚌O type.
3 Experimental
3.1 Materials
Reactions were carried out under an atmosphere of dry argon. Solvents were purified by standard methods and freshly distilled under nitrogen and dried before use. N-methylhomophthalimide was prepared according to the reported method (Horning et al., 1971). Melting points were determined by open capillary method and are uncorrected. NMR spectra were obtained on a Bruker-spectrospin AC-300 spectrometer operating at 300 MHz for 1H and at 75.64 for 13C using TMS as the internal standard in CDCl3 as solvent. Elemental analyses (C, H, N) were conducted on a Leco Elemental CHN 900; values were in satisfactory agreement with the calculated ones (0.30%). All the compounds were purified by column chromatography on silica gel (60–120 mesh), and crystallization from analytical grade solvents. The purity of the sample was checked by thin-layer chromatography (Merck Kieselgel 60F254).
3.2 Synthesis
A solution of dipolarophiles 1a–d (3 mmol) and C-aryl-N-phenylnitrones (3 mmol) 2e–g in dry toluene (10 mL), was stirred at reflux for 3 days. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography on silica gel eluted with cyclohexane/EtOAc (80:20) to afford compounds 3a–l and 4a–c.
3.2.1 Spiro[3,4-diphenylisoxazolidine-5:4′-(N-methyl)-isoquinoline-1′,3′-dione] (3a)
White solid (35%); m.p.126 °C. 1H NMR (300 MHz, CDCl3): δ (ppm) = 2.88(s, 3H, N-CH3), 5.43(d, 1H, H3, J = 11.1 Hz), 4.07(d, 1H, H4, J = 11.1 Hz), 6.80–8.08(m, 19H, H-arom). 13C NMR (75.5 MHz, CDCl3): δ (ppm) = 26.9(N-CH3), 71.0(C-3), 74.5(C-4), 86.0(C-5,4′), 118.2–151.0(C-arom), 163.4(C⚌O), 172.4(C⚌O). Anal. Calcd. for C30H24N2O3: C, 78.24; H, 5.25; N, 6.08. Found: C, 78.20; H, 5.19; N, 6.03.
3.2.2 Spiro[3,5-diphenylisoxazoline-4:4′-(N-methyl)-isoquinoline-1′,3′-dione] (4a)
White solid (52%); m.p.149 °C. 1H NMR (300 MHz, CDCl3): δ(ppm) = 3.48(s, 3H, N-CH3), 5.88(s, 1H, H3), 6.26(s, 1H, H5), 6.83–8.12(m, 19H, H-arom). 13C NMR (75.5 MHz, CDCl3): δ (ppm) = 27.8(N-CH3), 79.5(C-3), 90.2(C-5), 69.0(C-4,4′), 118.3–151.1(C-arom), 163.5(C⚌O), 171.2(C⚌O). Anal. Calcd. for C30H24N2O3: C, 78.24; H, 5.25; N, 6.08. Found: C, 78.21; H, 5.20; N, 6.02.
3.2.3 Spiro[3-phenyl-4-(p-tolyl)isoxazolidine-5:4′-(N-methyl)-isoquinoline-1′,3′-dione] (3b)
Orange solid (55%); m.p. 135 °C. 1H NMR (300 MHz, CDCl3): δ (ppm) = 2.23(s, 3H, CH3), 2.88(s, 3H, N-CH3), 5.39(d, 1H, H3, J = 11.2 Hz), 4.04(d, 1H, H4, J = 11.2 Hz), 6.68–8.24(m, 18H, H-arom). 13C NMR(75.5 MHz, CDCl3): δ (ppm) = 21.5(CH3), 27.0(N-CH3), 72.0(C-3), 74.3(C-4), 86.5(C-5,4′), 117.9–151.1(C-arom), 163.6(C⚌O), 172.6(C⚌O). Anal. Calcd. for C31H26N2O3: C, 78.46; H, 5.52; N, 5.90. Found: C, 78.49; H, 5.45; N, 5.86.
3.2.4 Spiro[4-(p-anisyl)-3-phenylisoxazolidine-5:4′-(N-methyl)-isoquinoline-1′,3′-dione] (3c)
White solid (46%); m.p. 185 °C. 1H NMR (300 MHz, CDCl3): δ (ppm) = 2.89(s, 3H, N-CH3), 3.77(s, 3H, OCH3), 5.35(d, 1H, H3, J = 11.1 Hz), 4.05 (d, 1H, H4, J = 11.1 Hz), 6.85–8.22(m, 18H, H-arom). 13C NMR (75.5 MHz, CDCl3): δ (ppm) = 27.1(N-CH3), 55.6(OCH3), 72.2(C-3), 74.2(C-4), 86.0(C-5,4′), 114.8–161.0(C arom), 163.7(C⚌O), 172.3(C⚌O). Anal. Calcd. for C31H26N2O4: C, 75.90; H, 5.34; N, 5.71. Found: C, 75.82; H, 5.28; N, 5.75.
3.2.5 Spiro[4-(p-nitrophenyl)-3-phenylisoxazolidine-5:4′-(N-methyl)-isoquinoline-1′,3′-dione] (3d)
Yellow solid (26%); m.p. 196 °C. 1H NMR (300 MHz, CDCl3) δ: (ppm) = 2.90(s, 3H, N-CH3), 5.48(d, 1H, H3, J = 11.1 Hz), 4.28(d, 1H, H4, J = 11.1 Hz), 6.86–8.35(m, 18H, H-arom). 13C NMR (75.5 MHz, CDCl3): δ (ppm) = 27.5(N-CH3), 72.4(C-3), 74.7(C-4), 86.2(C-5,4′), 118.2–156.0(C-arom), 163.5(C⚌O), 172.2(C⚌O). Anal. Calcd. for C30H23N3O5: C, 71.28; H, 4.59; N, 8.31. Found: C, 71.22; H, 4.51; N, 8.39.
3.2.6 Spiro[4-phenyl-3-(p-tolyl)isoxazolidine-5:4′-(N-methyl)-isoquinoline-1′,3′-dione] (3e)
White solid (60%); m.p. 190 °C. 1H NMR (300 MHz, CDCl3): δ (ppm) = 2.23(s, 3H, CH3), 2.88(s, 3H, N-CH3), 5.45 (d, 1H, H3, J = 11.2 Hz), 4.08(d, 1H, H4, J = 11.2 Hz), 6.79–8.24 (m, 18H, H-arom). 13C NMR (75.5 MHz, CDCl3): δ (ppm) = 21.5(CH3), 27.2(N-CH3), 71.9(C-3), 74.7(C-4), 86.3(C-5,4′), 118.7–151.1(C-arom), 163.7(C⚌O), 172.4(C⚌O). Anal. Calcd. for C31H26N2O3: C, 78.46; H, 5.52; N, 5.90. Found: C, 78.41; H, 5.48; N, 5.85.
3.2.7 Spiro[3,4-di(p-tolyl)isoxazolidine-5:4′-(N-methyl)-isoquinoline-1′,3′-dione] (3f)
Orange solid (50%); m.p. 245 °C. 1H NMR (300 MHz, CDCl3): δ (ppm) = 2.25(s, 3H, CH3), 2.26(s, 3H, CH3), 2.87(s, 3H, N-CH3), 5.36(d, 1H, H3, J = 11.1 Hz), 4.02(d, 1H, H4, J = 11.1 Hz), 6.75–8.01 (m, 17H, H-arom). 13C NMR (75.5 MHz, CDCl3): δ (ppm) = 21.5(CH3), 21.6(CH3), 27.0(N-CH3), 71.8(C-3), 74.2(C-4), 85.9(C-5,4′), 118.9–160.3(C-arom), 163.6(C⚌O), 172.6(C⚌O). Anal. Calcd. for C32H28N2O3: C, 78.67; H, 5.78; N, 5.73. Found: C, 78.62; H, 5.71; N, 5.69.
3.2.8 Spiro[3,5-di(p-tolyl)isoxazolidine-4:4′-(N-methyl)-isoquinoline-1′,3′-dione] (4b)
White solid (33%); m.p. 215 °C. 1H NMR (300 MHz, CDCl3): δ (ppm) = 2.24(s, 3H, CH3), 2.25(s, 3H, CH3), 2.86(s, 3H, N-CH3), 5.86(s, 1H, H3), 6.22(s, 1H, H5), 6.70–8.08 (m, 17H, H-arom).13C NMR (300 MHz, CDCl3): δ (ppm) = 21.4(CH3), 21.5(CH3), 27.0(N-CH3), 79.6(C-3), 90.2(C-5), 69.2(C-4,4′), 118.7–160.4(C-arom), 163.6(C⚌O), 171.4(C⚌O). Anal. Calcd. for C32H28N2O3: C, 78.67; H, 5.78; N, 5.73. Found: C, 78.61; H, 5.73; N, 5.70.
3.2.9 Spiro[4-(p-anisyl)-3-(p-tolyl)isoxazolidine-5:4′-(N-methyl)-isoquinoline-1′,3′-dione] (3g)
White solid (45%); m.p. 230 °C. 1H NMR (300 MHz, CDCl3): δ (ppm) = 2.25(s, 3H, CH3), 3.80(s, 3H, OCH3), 2.88(s, 3H, N-CH3), 5.38(d, 1H, H3, J = 11.1 Hz), 4.05 (d, 1H, H4, J = 11.1 Hz), 6.83–8.20(m, 17H, H-arom). 13C NMR (75.5 MHz, CDCl3): δ (ppm) = 21.2(CH3), 27.4(N-CH3), 55.6(OCH3), 72.3(C-3), 74.6(C-4), 86.1(C-5,4′), 118.0–161.2(C-arom), 163.3(C⚌O), 172.3(C⚌O). Anal. Calcd. for C32H28N2O4: C, 76.17; H, 5.59; N, 5.55. Found: C, 76.09; H, 5.51; N, 5.49.
3.2.10 Spiro[4-(p-nitrophenyl)-3-(p-tolyl)isoxazolidine-5:4′-(N-methyl)-isoquinoline-1′,3′-dione] (3h)
Yellow solid (35%); m.p. 225 °C. 1H NMR (300 MHz, CDCl3): δ (ppm) = 2.24(s, 3H, CH3), 2.90(s, 3H, N-CH3), 5.48(d, 1H, H3, J = 11.1 Hz), 4.09(d, 1H, H4, J = 11.1 Hz), 6.87–8,30(m, 17H, H-arom). 13C NMR(75.5 MHz, CDCl3,): δ (ppm) = 21.6(CH3), 27.3(N-CH3), 72.4(C-3), 74.5(C-4), 86.2(C-5,4′), 118.2–158.2(C-arom), 163.3(C⚌O), 172.3C⚌O). Anal. Calcd. for C31H25N3O5: C, 71.67; H, 4.85; N, 8.09. Found: C, 71.62; H, 4.78; N, 8.03.
3.2.11 Spiro[3-(p-anisyl)-4-phenylisoxazolidine-5:4′-(N-methyl)-isoquinoline-1′,3′-dione] (3i)
White solid (40%); m.p. 175 °C. 1H NMR (300 MHz, CDCl3): δ (ppm) = 3.35(s, 3H, N-CH3), 3.71(s, 3H, OCH3), 5.47(d, 1H, H3, J = 11.2 Hz), 4.24(d, 1H, H4, J = 11.2 Hz), 6.76–8.33(m, 18H, H-arom). 13C NMR (75.5 MHz, CDCl3): δ (ppm) = 27.5(N-CH3), 55.5(OCH3), 57.4(C-3), 63.7(C-4), 90.3(C-5,4′), 114.8–161.0(C-arom), 163.2(C⚌O), 172.3(C⚌O). Anal. Calcd. for C31H26N2O4: C, 75.90; H, 5.34; N, 5.71. Found: C, 75.83; H, 5.28; N, 5.67.
3.2.12 Spiro[3-(p-anisyl)-4-(p-tolyl)isoxazolidine-5:4′-(N-methyl)-isoquinoline-1′,3′-dione] (3j)
Orange solid (42%); m.p. 204 °C. 1H NMR (300 MHz, CDCl3): δ (ppm) = 2.23(s, 3H, CH3), 2.88 (s, 3H, N-CH3), 3.85(s, 3H, OCH3), 5.42 (d, 1H, H3, J = 11.2 Hz), 4.08 (d, 1H, H4, J = 11.2 Hz), 6.87–8.22(m, 17H, H-arom). 13C NMR (75.5 MHz, CDCl3): δ (ppm) = 21.4(CH3), 27.5(N-CH3), 55.8(OCH3), 71.7(C-3), 74.0(C-4), 85.8(C-5,4′), 114.8–161.2(C-arom), 163.8(C⚌O), 172.6(C⚌O). Anal. Calcd. for C32H28N2O4: C, 76.17; H, 5.59; N, 5.55. Found: C, 76.09; H, 5.50; N, 5.52.
3.2.13 Spiro[3-(p-anisyl)-5-(p-tolyl)isoxazolidine-4:4′-(N-methyl)-isoquinoline-1′,3′-dione] (4c)
White solid (30%); m.p. 227 °C. 1H NMR (300 MHz, CDCl3): δ (ppm) = 2.47(s, 3H, CH3), 3.11 (s, 3H, N-CH3), 3.96(s, 3H, OCH3), 5.76 (s, 1H, H3), 6.21(s, 1H, H5), 6.80–8.22(m, 17H, H-arom). 13C NMR (75.5 MHz, CDCl3): δ (ppm) = 21.4(CH3), 27.7(N-CH3), 55.5(OCH3), 79.4(C-3), 90.0(C-5), 69.3(C-4,4′), 114.6–161.2(C-arom), 163.4(C⚌O), 171.2(C⚌O). Anal. sssCalcd. for C32H28N2O4: C, 76.17; H, 5.59; N, 5.55. Found: C, 76.11; H, 5.52; N, 5.50.
3.2.14 Spiro[3,4-di(p-anisyl)isoxazolidine-5:4′-(N-methyl)-isoquinoline-1′,3′-dione] (3k)
White solid (28%); m.p. 256 °C.1H NMR (300 MHz, CDCl3): δ (ppm) = 2.89(s, 3H, N-CH3), 3.86(s, 3H, OCH3), 5.40(d, 1H, H3, J = 11.1 Hz), 4.06(d, 1H, H4, J = 11.1 Hz), 6.80–8.28(m, 17H, H-arom). 13C NMR (75.5 MHz, CDCl3): δ (ppm) = 27.7(N-CH3), 55.7(OCH3), 72.4(C-3), 74.3(C-4), 86.2(C-5,4′), 114.5–161.5(C-arom), 163.6(C⚌O), 172.3(C⚌O). Anal. Calcd. for C32H28N2O5: C, 73.83; H, 5.42; N, 5.38. Found: C, 73.78; H, 5.35; N, 5.32.
3.2.15 Spiro[3-(p-anisyl)-4-(p-nitrophenyl)isoxazolidine-5:4′-(N-methyl)isoquinoline-1′,3′-dione] (3l)
Yellow solid (26%); m.p. 246 °C. 1H NMR (300 MHz, CDCl3): δ (ppm) = 2.89 (s, 3H, N-CH3), 3.80 (s, 3H, OCH3), 5.44 (d, 1H, H3, J = 11.2 Hz), 4.23 (d, 1H, H4, J = 11.2 Hz), 6.85–8.30(m, 17H, H-arom). 13C NMR (75.5 MHz, CDCl3): δ (ppm) = 27.4(N-CH3), 55.4(OCH3), 72.2(C-3), 74.6(C-4), 86.1(C-5,4′), 114.7–161.2(C-arom), 163.3(C⚌O), 172.2(C⚌O). Anal. Calcd. for C31H25N2O6: C, 69.52; H, 4.71; N, 7.85. Found: C, 69.38; H, 4.65; N, 7.79.
4 Conclusion
In conclusion, an efficient synthesis of new spiro- isoxazolidines has been demonstrated by the highly regioselective 1,3-dipolar cycloaddition reaction of (E)-4-arylidene-N-methyl-(2H,4H)-isoquinoline-1,3-dione derivatives with C-aryl-N-phenylnitrones. The regiochemistry of the reaction depends on the electronic nature of the substituents at the para-position on the dipolarophile as well as on the dipole. The stereoselectivity of the reaction has been rationalized to be a consequence of combined electronic and steric interactions of the reagents during their approaches. The diasteroisomers are the result of the preferential approach directing the isoquinoline carbonyl group in the endo position relative to the dipolar linkage. The spiro-compounds prepared should be having potential biological activities.
Acknowledgments
The authors are grateful to DGRSRT (Direction Générale de la Recherche Scientifique et de la Rénovation Technologique) of the Tunisian of Higher Education, Scientific Research and Technology for the financial support.
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