Synthesis and Crystal Structure of 3?-Ethyl 5?-Methyl 1-Benzyl-4?-methyl-2-oxo-3?,4?-dihydrospiro-[indoline-3,2?-pyrrole]-3?,5?-dicarboxylate①

ZHENG Hu-Fei MENG Xiang-Suo

YUAN Wei SHI De-Qing②

(Key Laboratory of Pesticide and Chemical Biology of Ministry of Education,College of Chemistry, Central China Normal University, Wuhan 430079, China)

1 INTRODUCTION

Spirocyclic oxindoles are the structural motifs in many natural products[1]and biologically active molecules[2]. It is not surprising that these compounds have been the focus of many chemists, in part because of their biological activities, but also of the challenge of the simultaneous creation of spiro quaternary centers and multiple chiral centers[3].Recently, 1,3-dipolar cycloadditions of azomethine ylides to electron-deficient olefins were well explored, providing an effective method to access pyrrolidine-containing compounds[4]. In this context, most of dipolarophiles are electron-deficient alkenes[5],imines[6], and alkynes[7]. Very recently, Gong and co-workers have reported the first 1,3-dipolar cycloaddition between 2,3-butadienoates and azomethine ylides to access 3-methylenepyrrolidine derivatives with excellent enantioselectivity using a chiral bisphosphoric acid as the catalyst[8a], and subsequent its application in the kinetic resolution of racemic 2,3-butadienoate[8b]. As part of our ongoing interest in developing concise, convenient and environmentally benign methods for the synthesis of carbon- and hetero-cycles with potential biologically active heterocycles[9], in this paper, we investigate the cascade reaction involving 2,3-butadienoate,isatins, and glycinate hydrogen chloride salt, in which two major products were obtained. One is the expected 1,3-dipolar cycloaddition product 4;however, the structure of another product 5 is not clear. In order to confirm its structure absolutely, a single crystal of 5 was obtained from the mixture of dichloromethane and n-hexane (v:v = 1:1)and the molecular structure was determined by X-ray diffraction.

Scheme 1. Synthetic route of the target compound 5

2 EXPERIMENTAL

2. 1 Synthesis of 3?-ethyl 5?-methyl 1-benzyl-4?-methyl-2-oxo-3?,4?-dihydrospiro

[indoline-3,2?-pyrrole]-3?,5?-dicarboxylate 5

Under a nitrogen atmosphere, to a 10 mL flask equipped with reflux condenser was added 1 (0.12 g,0.5 mmol), 2 (0.08 g, 0.75 mmol), 3 (0.09 g, 0.75 mmol), 3 ? molecular sieve (100 mg), Et3N (0.1 g,1.0 mmol), and MeOH (4.0 mL). This solution was stirred at room temperature for several hours till the reaction completed or no further improvement of the yields appeared (monitored by TLC). Then the reaction mixture was concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel (silica: 200～300;eluant:petroleum ether/ethyl acetate 12:1～6:1)to afford product 4 (white solid, m.p. 130～131 ℃,yield: 30%)and 5 (white sold, m.p. 161～162 ℃,yield: 20%).

Data for compound 51H NMR (600 MHz,CDCl3)δ (ppm)7.38 (d, J = 7.2 Hz, 2H), 7.32 (t, J =7.5 Hz, 2H), 7.28 (d, J = 7.2 Hz, 1H), 7.16～7.18 (m,1H), 6.93 (d, J = 4.8 Hz, 2H), 6.71 (d, J = 8.4 Hz,1H), 5.26 (d, J = 15.6 Hz, 1H), 4.67 (d, J = 15.6 Hz,1H), 4.11～4.16 (m, J = 7.5 Hz, 1H), 3.89 (s, 3H),3.75～3.79 (m, 1H), 3.61～3.65 (m, 1H), 3.58 (d, J= 7.8 Hz, 1H), 1.55 (d, J = 7.2 Hz, 3H), 0.46 (t, J =7.2 Hz, 3H);13C NMR (100 MHz, CDCl3)δ (ppm)174.8, 172.8, 169.2, 162.0, 142.9, 135.1, 130.0,128.5, 127.6, 127.3, 125.9, 124.1, 122.8, 109.3, 81.3,60.8, 56.9, 52.7, 46.8, 44.1, 17.1, 13.0; MS (EI)(70 eV): m/z = 420 (M+, 25.7), 347 (13.9), 315 (24.6),301 (3.9), 225 (16.1), 198 (5.8), 105 (3.9), 91 (100);H RMS (ESI)for C24H25N2O5[M+H]+: calcd.421.1758. Found: 421.1760.

2. 2 Structure determination

A colorless needle crystal cultured from the mixture of dicholomethane and n-hexane (1:1 v/v)with dimensions of 0.20mm × 0.10mm × 0.10mm was selected for X-ray diffraction analysis. The determination of unit cell and the data collection were performed with MoKα radiation (λ = 0.71073 ?)on a Bruker APEX-II CCD diffractometer equipped with a graphite-monochromator situated in the incident beam. A total of 8220 reflections were collected in the range of 1.82≤θ≤26.00° by using an ω-2θ scan mode at 298(2)K, in which 4185 were independent with Rint= 0.0205 and 3379 observed reflections with I ＞ 2σ(I)were used in the structure determination and refinements. The structure was solved by direct methods with SHELXS-97[10], and refined on F2by full-matrix least-squares techniques with SHELXL-97 programs[11]. All hydrogen atoms were placed by calculation geometry and took part in refinement. The non-hydrogen atoms were located from an E-map and refined anisotropically to the final R = 0.0466, wR = 0.1507 (w = 1/[σ2(Fo2)+(0.1246P)2+ 0.1495P], where P = (Fo2+ 2Fc2)/3)and goodness-of-fit on F2is 1.041. (Δρ)max= 0.260,(Δρ)min= –0.321 e/?3, (Δ/σ)max= 0.000 and (Δ/σ)mean= 0.000.

3 RESULTS AND DISCUSSION

The title compound was prepared according to Scheme 1.

We investigated the reaction involving 1-benzyl isatin 1, methyl glycinate hydrochloride 2, and ethyl 2,3-butadienoate 3 in the presence of Et3N (2.0 equiv)and 3 ? molecular sieve (100 mg)in MeOH(4.0 mL)at room temperature. The expected [3+2]cycloaddition product 4 (yield: 30%)and another isomer 5 (yield: 20%)were isolated. The1H NMR,13C NMR and high resolution MS for the product 5 are in good agreement with the title compound. In order to confirm the structure of 5 absolutely, a single crystal of the title compound 5 was cultured for X-ray diffraction analysis. The selected bond lengths and bond angles are listed in Table 1. As shown in Table 1, in the dihydrogen pyrrole ring, the C(16)–N(2)bond is close to the value for a C=N bond (1.28 ?)[12], and the C(8)–N(2)bond is close to the value for a normal single C–N bond (1.47 ?)[13].The C(8)–C(18), C(16)–C(17), C(17)–C(18)and C(17)–C(21)bond lengths are in the range of a normal single C–C bond. These results indicated that compound 5 is the isomerized product of the 1,3-dipolar cycloaddition product 4. The molecular structure of the title compound with atomic numbering scheme is shown in Fig. 1. Fig. 2 depicts the molecular packing in the unit cell. The benzene ring of the benzyl group and the indole ring, the dihydrogen pyrrole and the indole ring are almost perpendicular to each other with dihedral angles of 87.1(1)and 87.8(1)°, respectively. The X-ray diffraction indicated that the methyl and ethoxycarbonyl group in the dihydrogen pyrrole ring adopt trans configurations, which can be due to the stability in the cyclization process.

Table 1. Selected Bond Lengths (?)and Bond Angles (°)

Table 2. Bond Lengths (?)and Bond Angles (°)of Hydrogen Bonds and C–H··π Interaction

Fig. 1. Structure of the title compound 5

Fig. 2. Packing diagram of the title compound of a unit cell

Moreover, the single-crystal X-ray diffraction shows intermolecular C(17)–H(17)··O(4)and C(5)–H(5)··O(4)hydrogen bonds and C–H··π (benzene ring)interactions in the structure (see Table 2). By a combination of the C–H··π and C–H··O hydrogen bonding interactions, a one-dimensional chain structure was formed along the axis of [101], and no apparent interactions are observed between the adjacent chains.

4 BIOLOGICAL ACTIVITIES

The biological (insecticidal, herbicidal and fungicidal)activity evaluation (in vitro, in vivo)of the target compound are ongoing at the Syngenta bioassay platform (Syngenta Jealott?s Hill International Research Centre, Bracknell, Berkshire, RG42 6EY, United Kingdom)and will be reported in due course.

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