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Regio- and stereoselective synthesis of new spiro-isoxazolidines via 1,3-dipolar cycloaddition
Accepted Manuscript Original article Regio- and stereoselective synthesis of new spiro-isoxazolidines via 1,3-Dipolar Cycloaddition Nafâa Jegham, Amira Bahi, Nizar El Guesmi, Yakdhane Kacem, Béchir Ben Hassine PII: DOI: Reference:
S1878-5352(14)00104-X http://dx.doi.org/10.1016/j.arabjc.2014.05.028 ARABJC 1324
To appear in:
Arabian Journal of Chemistry
Received Date: Accepted Date:
4 June 2013 31 May 2014
Please cite this article as: N. Jegham, A. Bahi, N.E. Guesmi, Y. Kacem, B.B. Hassine, Regio- and stereoselective synthesis of new spiro-isoxazolidines via 1,3-Dipolar Cycloaddition, Arabian Journal of Chemistry (2014), doi: http://dx.doi.org/10.1016/j.arabjc.2014.05.028
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Regio- and stereoselective synthesis of new spiro-isoxazolidines via 1,3-Dipolar Cycloaddition Nafâa Jeghama,*, Amira Bahia, Nizar El Guesmib,c, Yakdhane Kacema, Béchir Ben Hassinea a
Laboratoire de Synthèse Organique Asymétrique et Catalyse Homogène (01UR1201),
Faculté des Sciences de Monastir, Avenue de l’Environnement, 5000 Monastir, Tunisia. b
Département de chimie, Faculté des Sciences de Monastir, Avenue de l’Environnement,
5000 Monastir, Tunisia. c
Department of Chemistry, Faculty of Applied Sciences, Umm Alqura University, P.O. Box
9569, Makkah, Saudi Arabia. * Corresponding author. Tel.: +216 97339308. E-mail address: [email protected]
Abstract New spiro-isoquinolinediones were prepared by regio- and stereoselctive 1,3-dipolar cycloaddition of (E)-4-arylidene-N-methyl-isoquinoline-1,3-dione derivatives 1a-d with Caryl-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 13
C NMR assignments. The stereochemistry of spirannic compounds 3a-l and 4a-c have been
corroborated by means of DFT calculations. The structures of all the products were characterized thoroughly by NMR and elemental analysis. Keywords: 1,3-dipolar cycloaddition, isoquinolinediones, nitrones, regiochemistry, stereoselctive, 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 1 / 13
smooth reactions with substituted olefins (Torsell, 1990) afforded substituted isoxazolines and isoxazolidines, respectively. Both classes of heterocycle are versatile intermediates for the synthesis of natural products and biologically active compounds (Tice et al., 1983; Vasella et al., 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), 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 (Charmier et al., 2002) demonstrated that by conventional organic methods, chiral heterocycles of 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 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 variously spiro-cyclized isoxazolidines and isoxazolines (Jegham et al., 2010; Askri et al., 2007; Bahi 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)-1,3diones 1a-d with 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, pMeC6H4, p-MeOC6H4) according to scheme 1. 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 2 / 13
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)-4arylidene-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 cycloadditions 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. The structures of cycloadducts were established on the basis of spectroscopic data. The 1
H NMR spectra of regioisomers 3a-l exhibited a doublet around 5.34 ppm and 5.49 ppm
attributed to the 3-H proton and a doublet between 4.03 ppm and 4.29 ppm assigned to the 4-H proton. The
13
C NMR data confirm this result. The chemical shifts of the spiro carbon
atoms (C-5,4’) were found to be between 85.8-90.3 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 ppm and 6.27 ppm attributed to the 5-H proton and a singlet between 5.75 ppm and 5.89 ppm assigned to the 3-H proton. In several other cycloadditions with comparable dipolarophiles (Molchanov et al., 2013 ; Wannassi 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 Caryl-N-phenylnitrones 2e-g led to cycloadducts 3a-l and 4a-c with three new chiral centers of 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., 1977). 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 11Hz 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. 3 / 13
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 towards 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 polarisable continum 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 (Figure 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.
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-methyl homophthalimide were prepared according to the reported method (Horning et al., 1971). Meltings 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 a 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 mech), and crystallisation 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 4 / 13
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. 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(Carom), 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. 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 ).
C NMR (75.5 MHz, CDCl3): δ (ppm)=
13
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. Spiro[3-phenyl-4-(p-tolyl)isoxazolidine-5:4’-(N-methyl)-isoquinoline-1’,3’-dione]
(3b):
orange solid (55%); m.p. 135°C. H NMR (300 MHz, CDCl3): δ (ppm) = 2.23(s, 3H, CH3), 1
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. 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(C3), 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. 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, NCH3), 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). C NMR (75.5 MHz, CDCl3): δ (ppm) = 27.5(N-CH3), 72.4(C-3), 74.7(C-4), 86.2(C-5,4’),
13
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. 5 / 13
Spiro[4-phenyl-3-(p-tolyl)isoxazolidine-5:4’-(N-methyl)-isoquinoline-1’,3’-dione]
(3e) :
white solid (60%) ; m.p. 190°C. H NMR (300 MHz, CDCl3): δ (ppm) = 2.23(s, 3H, CH3), 1
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. 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). 21.6(CH3),
27.0(N-CH3),
13
C NMR (75.5 MHz, CDCl3): δ (ppm) = 21.5(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. 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(C5), 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. Spiro[4-(p-anisyl)-3-(p-tolyl)isoxazolidine-5:4’-(N-methyl)-isoquinoline-1’,3’-dione]
(3g):
white solid (45%); m.p. 230°C. H NMR (300 MHz, CDCl3): δ (ppm) = 2.25(s, 3H, CH3), 1
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. 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), 6,878,30(m, 17H, H-arom ).13C NMR(75.5 MHz, CDCl3,): δ (ppm) = 21.6(CH3), 27.3(N-CH3),
6 / 13
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. Spiro[3-(p-anisyl)-4-phenylisoxazolidine-5:4’-(N-methyl)-isoquinoline-1’,3’-dione]
(3i):
white solid (40%); m.p. 175°C . H NMR (300 MHz, CDCl3): δ (ppm) = 3.35(s, 3H, N-CH3), 1
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(C3), 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. 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. Spiro[3-(p-anisyl)-5-(p-tolyl)isoxazolidine-4:4’-(N-methyl)-isoquinoline-1’,3’-dione]
(4c):
white solid (30%); m.p. 227°C. H NMR (300 MHz, CDCl3): δ (ppm) = 2.47(s, 3H, CH3), 1
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. 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(C3), 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. 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, NCH3), 3.80 (s, 3H, OCH3), 5.44 (d, 1H, H3, J = 11.2 Hz), 4.23 (d, 1H, H4, J = 11.2 Hz), 6.858.30(m, 17H, H-arom ). 13C NMR (75.5 MHz, CDCl3): δ (ppm) = 27.4(N-CH3), 55.4(OCH3), 7 / 13
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, efficient synthesis of new spiro- isoxazolidines have been demonstrated by the highly regioselective 1,3-dipolar cycloaddition reaction of (E)-4-arylidene-N-methyl(2H,4H)-isoquinoline-1,3-diones
derivatives
with
C-aryl-N-phenylnitrones.
The
regiochemistry of the reaction depends on the electronic nature of the substituants at the paraposition 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. References Aouadi ,K., Jeannau, E., Msaddek,M., Praly, J.P., 2012. 1,3-Dipolar cycloaddition of a chiral nitrone
to
(E)-1,4-dichloro-2-butene:
a new efficient synthesis of (2S,3S,4R)-4-
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8 / 13
Cacciarini, M., Cordero, F. M., Faggi, C. and Goti, A., 2000. Cycloaddition Reactions of CN-Diphenylnitrone to Methylene-γ-butyrolactones. Molecules. 5, 637-647.
Cordero ,F., Khairnar, B., Bonanno, P., Martinelli, A., Brandi,A., 2013. Copper-Catalyzed Synthesis of a Highly Hydroxy-Functionalized Benzo[e]indolizidine by Intramolecular NArylation. European Journal of Chemistry, Vol 2013, 4879-4886.
Cossi, M., Scalmani, G., Rega, N., and Barone, V., 2002. New Developments in the Polarizable Continuum Model for Quantum Mechanical and Classical Calculations on Molecules in Solution. J. Chem. Phys. 117, 43-54. Gaussian 09, Revision A.1, Frisch, M. J., Trucks, G.W., Schlegel, H.B., Scuseria, G.E., Robb, M.A., Cheeseman, J.R., Scalmani, G., Barone, V., Mennucci, B., Petersson, G.A., Nakatsuji, H., Caricato, M., Li, X., Hratchian, H.P., Izmaylov, A.F., Bloino, J., Zheng, G., J. L., Sonnenberg, M. Hada, Ehara, M., Toyota, K., Fukuda, R., Hasegawa, J., Ishida, M., Nakajima, T., Honda, Y., Kitao, O., Nakai, H., Vreven, T., Montgomery, J. A., Jr., Peralta, J. E., Ogliaro, F., Bearpark, M., Heyd, J. J., Brothers, E., Kudin, K. N., Staroverov, , V. N., Kobayashi, R., Normand, J., Raghavachari, K., Rendell, A., Burant, J. C., Iyengar, S. S., Tomasi, J., Cossi, M., Rega, N., Millam, J. M., Klene, M., Knox, J. E., Cross, J. B., V., Bakken, C. Adamo., Jaramillo, J., Gomperts, R., Stratmann, R. E., Yazyev, O., Austin, A. J., Cammi, R., Pomelli, C., Ochterski, J. W., Martin, R. L., Morokuma, K., Zakrzewski, V. G., Voth, G. A., Salvador, P., Dannenberg, J. J., Dapprich, S., Daniels, A. D., Farkas, Ö., Foresman, J. B., Cioslowski, J. V., Ortiz, J., and Fox, D. J., Gaussian, Inc., Wallingford CT, 2009. Horning, D.E., Lacasse,
G., and Muchowski, L.M., 1971. Spiroalkylation of some
Homophthalimides and oxindoles with 1-Bromo-2-chloroethane. Cand. J. Chem. 49, 246-254. Huisgen, R., 1984. 1.3-Dipolar cycloadditions chemistry. In: Padwa A.(ed) Wiley,.New York, vol.1. Jegham,N., Kacem,Y. and Hassine, B.B., 2010. Regioselective Synthesis and Structure of New Spiro-isoquinolinedione Derivatives. Heterocycles., Vol 81, 3, 707-715.
9 / 13
Jegham, N., Tka, N., Kacem, Y. and Hassine, B.B., 2012. New N-substituted (E)-4-Arylidene Isoquinoline-1,3-dione Derivatives: NMR Spectroscopic Investigation and Antibacterial Activity. Synthetic Commun. 42, 3328-3336. Kasahara, K., Iida, H. and Kibayashi, C., 1989. Asymmetric total synthesis of (+)-negamycin and (-)-3-epinegamycin via enantioselective 1,3-dipolar cycloaddition. J.Org.Chem. 54, 22252233. Kumar, R.S., Perumal., S., Shetty, K.A., Permual, Y and Sriram, D., 2010. 1,3-Dipolar cycloaddition
of
C-aryl-N-phenylnitrones
to
(R)-1-(1-phenylethyl)-3-[(E)-
arylmethylidene]tetrahydro-4(1H)-pyridinones: Synthesis and antimycobacterial evaluation of enantiomerically pure spiroisoxazolidines Eur.J.Med.Chem. 45,124.s
Molchanov ,A.P., Tran, T.Q.,
A. 2013. Regio- and stereoselective cyloaddition of C-
carbamoylnitrones to 1-benzylidene-3,3-dichloro-2,2-dimethylcyclopropane. Chemistry of Heterocyclic Compounds, Vol 49, 479-480.
Omprakash P, B., Vrushali, J., Vedavati G, P., Dilip D, D., 2007. 1,3-Dipolar cycloaddition reaction of a D-galactose derived nitrone with allyl alcohol : synthesis of polyhydroxylated perhydroazaazulene alkaloids. Tetrahedron asymmetry, 18, 1176-1182. Revuelta,J., Cicchi, A., De Meijere, A and Brandi, A., 2008. 3-Spirocyclopropanedihydroand -tetrahydropyridin-4-ones from Nitrone Cycloadducts of Bicyclopropylidene via 1-(1’Aminomethylcyclopropyl)- cyclopropanol under Pd II Catalysis. Eur.J.Org.Chem. 6, 1085. Oukani, H., Pelligrini-Moise, N., Jackowski, O., Chrétien, F., Chapleu, Yves., 2013. The 1,3dipolar cycloaddition reaction of chiral carbohydrate-derived nitrone and olefin: towards longchain sugars. Carbohydrate. Res. 361, 205-214. Rigolet S., Mélot, J. M., Vebrel, J., Chiaroni, A., and Riche, C., 2000. Influence of electronic and geometric factors on the steroseletivity of their 1,3-dipolar cycloaddition. J. Chem., Perkin Trans, 1, 1095-1103.
10 / 13
Roussel C., Ciamala, K., Vebrel, J. and Riche, C., 2009. Reactivity of arylnitrile oxides and C-aroyl-N-phenylnitrones
with
3-methylenedihydro-(3H)-furan-2-one
and
Itaconic
Anhydride. Heterocycles, 78, 1977-1991. Tufariello J. J., 1984. In 1,3-Dipolar Cycloaddition Chemistry; ed. by A. Padwa, John Wiley & Sons: New York. Tice C.M., Ganem, B., 1983. Chemistry of naturally occurring polyamines.8. Total synthesis of (+)-hypustin. J.Org.Chem, 48, 5048. Torsell, K.B.G., 1990. Nitrile oxides, Nitrones and nitronates in organic synthesis; Pergamon Press:Oxford. Vasella, A., Voeffray, R., 1983. Synthesis of D and L-5-oxaproline and of a new captopril analogue. Helv.Chim.Acta. 66, 1241-1252. Wannasi, N., Rammah, M.M, Boudriga, S., Rammah, M.B., Monnier-Jobé,K., Ciamala, K, Knorr,M., Mironel, Enescu., Rousselin, Y., Kubicki, M.M. 2010. Regio-and seteroselective 1,3-dipolar cycloaddition of C-aryl-N-phenylnitrones over (E)-aryldene-(2H)-indane-1-ones : ynthesis of highly substituted novel spiroioxazolidines. Heterocycles, 81, 2749-2762.
Zanobini ,A., Gensini, M., Magull, J., Vidovic, D., Kozhushkov, S., Brandi, A., Meijere, A., 2004. A Convenient New Synthesis of 3-Substituted β-Lactams Formally Derived from 1(Aminomethyl)cyclopropanecarboxylic Acids. European Journal of Chemistry, Vol 2004, 4158-4166.
Figure captions 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 Scheme 2 Approach modes (endo-C=O and exo-C=O) Figure 1 The calculations shows that the reactants form a site-to-site complex of endo C=O type 11 / 13
12 / 13
Table 1 Selected data for compounds 3a-l and 4a-c 1
H NMR
13
C NMR
Cycloadducts
Ratios
¾
¾
δH4/δH5
δC5,4’ and δC4,4’
Entry
R
R’
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
3g
100/0
4.05
86.1
8
NO2
Me
3h/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
3k
100/0
4,06
86.2
12
NO2
OMe
3l
100/0
4,23
86.1
13 / 13
S1878-5352(14)00104-X http://dx.doi.org/10.1016/j.arabjc.2014.05.028 ARABJC 1324
To appear in:
Arabian Journal of Chemistry
Received Date: Accepted Date:
4 June 2013 31 May 2014
Please cite this article as: N. Jegham, A. Bahi, N.E. Guesmi, Y. Kacem, B.B. Hassine, Regio- and stereoselective synthesis of new spiro-isoxazolidines via 1,3-Dipolar Cycloaddition, Arabian Journal of Chemistry (2014), doi: http://dx.doi.org/10.1016/j.arabjc.2014.05.028
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Regio- and stereoselective synthesis of new spiro-isoxazolidines via 1,3-Dipolar Cycloaddition Nafâa Jeghama,*, Amira Bahia, Nizar El Guesmib,c, Yakdhane Kacema, Béchir Ben Hassinea a
Laboratoire de Synthèse Organique Asymétrique et Catalyse Homogène (01UR1201),
Faculté des Sciences de Monastir, Avenue de l’Environnement, 5000 Monastir, Tunisia. b
Département de chimie, Faculté des Sciences de Monastir, Avenue de l’Environnement,
5000 Monastir, Tunisia. c
Department of Chemistry, Faculty of Applied Sciences, Umm Alqura University, P.O. Box
9569, Makkah, Saudi Arabia. * Corresponding author. Tel.: +216 97339308. E-mail address: [email protected]
Abstract New spiro-isoquinolinediones were prepared by regio- and stereoselctive 1,3-dipolar cycloaddition of (E)-4-arylidene-N-methyl-isoquinoline-1,3-dione derivatives 1a-d with Caryl-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 13
C NMR assignments. The stereochemistry of spirannic compounds 3a-l and 4a-c have been
corroborated by means of DFT calculations. The structures of all the products were characterized thoroughly by NMR and elemental analysis. Keywords: 1,3-dipolar cycloaddition, isoquinolinediones, nitrones, regiochemistry, stereoselctive, 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 1 / 13
smooth reactions with substituted olefins (Torsell, 1990) afforded substituted isoxazolines and isoxazolidines, respectively. Both classes of heterocycle are versatile intermediates for the synthesis of natural products and biologically active compounds (Tice et al., 1983; Vasella et al., 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), 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 (Charmier et al., 2002) demonstrated that by conventional organic methods, chiral heterocycles of 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 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 variously spiro-cyclized isoxazolidines and isoxazolines (Jegham et al., 2010; Askri et al., 2007; Bahi 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)-1,3diones 1a-d with 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, pMeC6H4, p-MeOC6H4) according to scheme 1. 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 2 / 13
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)-4arylidene-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 cycloadditions 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. The structures of cycloadducts were established on the basis of spectroscopic data. The 1
H NMR spectra of regioisomers 3a-l exhibited a doublet around 5.34 ppm and 5.49 ppm
attributed to the 3-H proton and a doublet between 4.03 ppm and 4.29 ppm assigned to the 4-H proton. The
13
C NMR data confirm this result. The chemical shifts of the spiro carbon
atoms (C-5,4’) were found to be between 85.8-90.3 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 ppm and 6.27 ppm attributed to the 5-H proton and a singlet between 5.75 ppm and 5.89 ppm assigned to the 3-H proton. In several other cycloadditions with comparable dipolarophiles (Molchanov et al., 2013 ; Wannassi 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 Caryl-N-phenylnitrones 2e-g led to cycloadducts 3a-l and 4a-c with three new chiral centers of 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., 1977). 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 11Hz 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. 3 / 13
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 towards 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 polarisable continum 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 (Figure 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.
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-methyl homophthalimide were prepared according to the reported method (Horning et al., 1971). Meltings 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 a 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 mech), and crystallisation 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 4 / 13
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. 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(Carom), 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. 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 ).
C NMR (75.5 MHz, CDCl3): δ (ppm)=
13
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. Spiro[3-phenyl-4-(p-tolyl)isoxazolidine-5:4’-(N-methyl)-isoquinoline-1’,3’-dione]
(3b):
orange solid (55%); m.p. 135°C. H NMR (300 MHz, CDCl3): δ (ppm) = 2.23(s, 3H, CH3), 1
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. 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(C3), 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. 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, NCH3), 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). C NMR (75.5 MHz, CDCl3): δ (ppm) = 27.5(N-CH3), 72.4(C-3), 74.7(C-4), 86.2(C-5,4’),
13
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. 5 / 13
Spiro[4-phenyl-3-(p-tolyl)isoxazolidine-5:4’-(N-methyl)-isoquinoline-1’,3’-dione]
(3e) :
white solid (60%) ; m.p. 190°C. H NMR (300 MHz, CDCl3): δ (ppm) = 2.23(s, 3H, CH3), 1
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. 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). 21.6(CH3),
27.0(N-CH3),
13
C NMR (75.5 MHz, CDCl3): δ (ppm) = 21.5(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. 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(C5), 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. Spiro[4-(p-anisyl)-3-(p-tolyl)isoxazolidine-5:4’-(N-methyl)-isoquinoline-1’,3’-dione]
(3g):
white solid (45%); m.p. 230°C. H NMR (300 MHz, CDCl3): δ (ppm) = 2.25(s, 3H, CH3), 1
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. 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), 6,878,30(m, 17H, H-arom ).13C NMR(75.5 MHz, CDCl3,): δ (ppm) = 21.6(CH3), 27.3(N-CH3),
6 / 13
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. Spiro[3-(p-anisyl)-4-phenylisoxazolidine-5:4’-(N-methyl)-isoquinoline-1’,3’-dione]
(3i):
white solid (40%); m.p. 175°C . H NMR (300 MHz, CDCl3): δ (ppm) = 3.35(s, 3H, N-CH3), 1
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(C3), 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. 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. Spiro[3-(p-anisyl)-5-(p-tolyl)isoxazolidine-4:4’-(N-methyl)-isoquinoline-1’,3’-dione]
(4c):
white solid (30%); m.p. 227°C. H NMR (300 MHz, CDCl3): δ (ppm) = 2.47(s, 3H, CH3), 1
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. 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(C3), 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. 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, NCH3), 3.80 (s, 3H, OCH3), 5.44 (d, 1H, H3, J = 11.2 Hz), 4.23 (d, 1H, H4, J = 11.2 Hz), 6.858.30(m, 17H, H-arom ). 13C NMR (75.5 MHz, CDCl3): δ (ppm) = 27.4(N-CH3), 55.4(OCH3), 7 / 13
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, efficient synthesis of new spiro- isoxazolidines have been demonstrated by the highly regioselective 1,3-dipolar cycloaddition reaction of (E)-4-arylidene-N-methyl(2H,4H)-isoquinoline-1,3-diones
derivatives
with
C-aryl-N-phenylnitrones.
The
regiochemistry of the reaction depends on the electronic nature of the substituants at the paraposition 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. References Aouadi ,K., Jeannau, E., Msaddek,M., Praly, J.P., 2012. 1,3-Dipolar cycloaddition of a chiral nitrone
to
(E)-1,4-dichloro-2-butene:
a new efficient synthesis of (2S,3S,4R)-4-
hydroxyisoleucine. Tetrahedron Lett. 53, 2817-2821. Askri, M., Jegham, N., Rammah, M., Ciamala, K., Monnier-Jobé,K., 2007. Spiroheterocycles from the Reaction of Arylnitrile oxides with some (Z)-3-Arylidene-2-(3H)-benzofuranones. New Acces to Orthohydroxyphenylisoxazoline Esters. Heterocycles, vol.71, No.2, 289-303. Bahy ,A., Kacem.Y. and Ben Hassine, .B., 2010. 1,3-Dipolar Cycloaddition of Nitrones With 5-Methylenehydantoins: Synthesis and transformation of New Spirohydantoin Derivatives. Synthetic Commu. vol.40, 1377-1390. Barros ,M.T., Januàrio-Charmier.M.O., Maycock, C.D and Michaud,T., 2002. An expedient stereoselective synthesis of polysubstituted piperidin-2-ones. Tetrahedron, vol.58, 1519.
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Cordero ,F., Khairnar, B., Bonanno, P., Martinelli, A., Brandi,A., 2013. Copper-Catalyzed Synthesis of a Highly Hydroxy-Functionalized Benzo[e]indolizidine by Intramolecular NArylation. European Journal of Chemistry, Vol 2013, 4879-4886.
Cossi, M., Scalmani, G., Rega, N., and Barone, V., 2002. New Developments in the Polarizable Continuum Model for Quantum Mechanical and Classical Calculations on Molecules in Solution. J. Chem. Phys. 117, 43-54. Gaussian 09, Revision A.1, Frisch, M. J., Trucks, G.W., Schlegel, H.B., Scuseria, G.E., Robb, M.A., Cheeseman, J.R., Scalmani, G., Barone, V., Mennucci, B., Petersson, G.A., Nakatsuji, H., Caricato, M., Li, X., Hratchian, H.P., Izmaylov, A.F., Bloino, J., Zheng, G., J. L., Sonnenberg, M. Hada, Ehara, M., Toyota, K., Fukuda, R., Hasegawa, J., Ishida, M., Nakajima, T., Honda, Y., Kitao, O., Nakai, H., Vreven, T., Montgomery, J. A., Jr., Peralta, J. E., Ogliaro, F., Bearpark, M., Heyd, J. J., Brothers, E., Kudin, K. N., Staroverov, , V. N., Kobayashi, R., Normand, J., Raghavachari, K., Rendell, A., Burant, J. C., Iyengar, S. S., Tomasi, J., Cossi, M., Rega, N., Millam, J. M., Klene, M., Knox, J. E., Cross, J. B., V., Bakken, C. Adamo., Jaramillo, J., Gomperts, R., Stratmann, R. E., Yazyev, O., Austin, A. J., Cammi, R., Pomelli, C., Ochterski, J. W., Martin, R. L., Morokuma, K., Zakrzewski, V. G., Voth, G. A., Salvador, P., Dannenberg, J. J., Dapprich, S., Daniels, A. D., Farkas, Ö., Foresman, J. B., Cioslowski, J. V., Ortiz, J., and Fox, D. J., Gaussian, Inc., Wallingford CT, 2009. Horning, D.E., Lacasse,
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Homophthalimides and oxindoles with 1-Bromo-2-chloroethane. Cand. J. Chem. 49, 246-254. Huisgen, R., 1984. 1.3-Dipolar cycloadditions chemistry. In: Padwa A.(ed) Wiley,.New York, vol.1. Jegham,N., Kacem,Y. and Hassine, B.B., 2010. Regioselective Synthesis and Structure of New Spiro-isoquinolinedione Derivatives. Heterocycles., Vol 81, 3, 707-715.
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Jegham, N., Tka, N., Kacem, Y. and Hassine, B.B., 2012. New N-substituted (E)-4-Arylidene Isoquinoline-1,3-dione Derivatives: NMR Spectroscopic Investigation and Antibacterial Activity. Synthetic Commun. 42, 3328-3336. Kasahara, K., Iida, H. and Kibayashi, C., 1989. Asymmetric total synthesis of (+)-negamycin and (-)-3-epinegamycin via enantioselective 1,3-dipolar cycloaddition. J.Org.Chem. 54, 22252233. Kumar, R.S., Perumal., S., Shetty, K.A., Permual, Y and Sriram, D., 2010. 1,3-Dipolar cycloaddition
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Molchanov ,A.P., Tran, T.Q.,
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Omprakash P, B., Vrushali, J., Vedavati G, P., Dilip D, D., 2007. 1,3-Dipolar cycloaddition reaction of a D-galactose derived nitrone with allyl alcohol : synthesis of polyhydroxylated perhydroazaazulene alkaloids. Tetrahedron asymmetry, 18, 1176-1182. Revuelta,J., Cicchi, A., De Meijere, A and Brandi, A., 2008. 3-Spirocyclopropanedihydroand -tetrahydropyridin-4-ones from Nitrone Cycloadducts of Bicyclopropylidene via 1-(1’Aminomethylcyclopropyl)- cyclopropanol under Pd II Catalysis. Eur.J.Org.Chem. 6, 1085. Oukani, H., Pelligrini-Moise, N., Jackowski, O., Chrétien, F., Chapleu, Yves., 2013. The 1,3dipolar cycloaddition reaction of chiral carbohydrate-derived nitrone and olefin: towards longchain sugars. Carbohydrate. Res. 361, 205-214. Rigolet S., Mélot, J. M., Vebrel, J., Chiaroni, A., and Riche, C., 2000. Influence of electronic and geometric factors on the steroseletivity of their 1,3-dipolar cycloaddition. J. Chem., Perkin Trans, 1, 1095-1103.
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Itaconic
Anhydride. Heterocycles, 78, 1977-1991. Tufariello J. J., 1984. In 1,3-Dipolar Cycloaddition Chemistry; ed. by A. Padwa, John Wiley & Sons: New York. Tice C.M., Ganem, B., 1983. Chemistry of naturally occurring polyamines.8. Total synthesis of (+)-hypustin. J.Org.Chem, 48, 5048. Torsell, K.B.G., 1990. Nitrile oxides, Nitrones and nitronates in organic synthesis; Pergamon Press:Oxford. Vasella, A., Voeffray, R., 1983. Synthesis of D and L-5-oxaproline and of a new captopril analogue. Helv.Chim.Acta. 66, 1241-1252. Wannasi, N., Rammah, M.M, Boudriga, S., Rammah, M.B., Monnier-Jobé,K., Ciamala, K, Knorr,M., Mironel, Enescu., Rousselin, Y., Kubicki, M.M. 2010. Regio-and seteroselective 1,3-dipolar cycloaddition of C-aryl-N-phenylnitrones over (E)-aryldene-(2H)-indane-1-ones : ynthesis of highly substituted novel spiroioxazolidines. Heterocycles, 81, 2749-2762.
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Figure captions 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 Scheme 2 Approach modes (endo-C=O and exo-C=O) Figure 1 The calculations shows that the reactants form a site-to-site complex of endo C=O type 11 / 13
12 / 13
Table 1 Selected data for compounds 3a-l and 4a-c 1
H NMR
13
C NMR
Cycloadducts
Ratios
¾
¾
δH4/δH5
δC5,4’ and δC4,4’
Entry
R
R’
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
3g
100/0
4.05
86.1
8
NO2
Me
3h/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
3k
100/0
4,06
86.2
12
NO2
OMe
3l
100/0
4,23
86.1
13 / 13