GAN Zi-Yun CAO Ri-Hui MA Qin GUO Ling②



Synthesis, Characterization and X-ray Crystal Structure of 2-Benzyl-7-butoxyl-9-isobutyl-1- methyl--carboline Bromide①

GAN Zi-YunaCAO Ri-HuibMA QinaGUO Lianga②

a(830011)b(510275)

2-Benzyl-7-butoxyl-9-isobutyl-1-methyl--carboline bromide (H-2-65) was synthe- sized by the reaction of Harmine with 1-iodobutane via9-alkylation, demethyl and2-qua- ternarization to obtain the new compound. The results demonstrate that H-2-65 has more remarkable anticancer activities in vitro. The results of1H NMR,13C NMR, DEPT, gCOSY, gHSQC, gHMBC, MS, single-crystal X-ray diffraction and elemental analysis showed that the title compound crystallizes in the triclinic system, space group1 with= 9.545(5),= 11.724(5),= 11.839(6) Å,= 77.530(6),= 87.169(6),= 72.823(5)o,= 2,= 1235.8(10) Å3,D= 1.294 g·cm-3,(000) = 504, the final= 0.0453,= 0.1262 and= 1.044.

2-benzyl-7-butoxyl-9-isobutyl-1-methyl--carboline bromide, synthesis, crystal structure;

1 INTRODUCTION

L., distributed in Uyghur na- tionality in Xinjiang, China, has been regarded as a traditional herb for medicinal or psychoactive therapy in water shortage deserts and grasslands for hundreds of years[1]. Moreover, it has been reported to possess a wide spectrum of pharmacological actions in different kinds of applications, including antibacterial, antifungal, antitumor treatments and effectiveness in the treatment of dermatosis[2-4]. Harmine (Fig. 1) was originally isolated from, and subsequent investigation confirmed that it was the most important active ingredients[5, 6].

Fig. 1. Structure of Harmine (A) and the title compound (B)

Previous investigations[7-14]were focused on the neuropharmacological effects of harmine on the central nervous system (CNS). Structure-activity relationship analysis demonstrated that the methoxy group at position-7 of harmine might play a very crucial role in determining their remarkable neuro- toxic effects;9-alkylated harmine derivatives exhibited strong cytotoxic effects;2-alkylated harmine derivatives displayed specific cytotoxic activities. Herein, we report the synthesis and single-crystal structure of 2-benzyl-7-butoxyl-9- isobutyl-1-methyl--carboline bromide (Fig. 1).

2 EXPERIMENTAL

2. 1 Materials and characterization

Melting points were determined in capillary tubes on an electrothermal WRS-3 apparatus without correction.1H NMR and13C NMR spectra were recorded on a Varian INOVA 400 spectrometer. Elemental analyses (C, H and N) were carried out on an Elementar Vario EL III Elemental Analyzer. ESI-MS spectra were obtained from Micromass ZQ4000 spectrometer.Crystal structure was deter- mined on a Bruker SMART CCD. All reagents purchased from commercial suppliers were dried and purified when necessary.

2. 2 Synthesis of the target compound

As shown in Scheme 1, a mixture of harmine (4.24 g, 20 mmol) and anhydrous DMF (80 mL) was stirred at room temperature, and then 95% NaH (0.75 g, 30 mmol) and isobutyl bromide (6.4 mL, 50 mmol) were added. The mixture was continued to stir at room temperature. After completion of the reaction, the solution was poured into H2O (200 mL), and extracted with ethyl acetate. After filtration and evaporation, the resulting product was crystallized from ethyl ether. Compound 2 (m. p. 111.4～113.5 ℃) was obtained as white solid. Then acetic acid (100 mL) and 40% hydrobromic acid (50 mL) were added, and the mixture was refluxed for 8～12 h to obtain compound 3. Compound 4 was afforded as the method of 2. At last, the mixture of compound 4 (2 mmol) and benzyl bromide (5～10 mmol) in ethyl acetate (50 mL) was refluxed for 5 h. After completion of the reaction, the solution was cooled and filtered to afford yellow solid and recrystallized from ethanol to give the pure solid compound 5: Yellow crystals, yield: 89%, m. p.: 245.3～247.9 ℃. The structure was characterized by NMR (Figs. 2～4), ESI-MS and elemental analysis. Anal. Calcd. (%) for C27H33BrN2O: C, 67.35; H, 6.91; N, 5.82. Found (%): C, 67.24; H, 6.96; N, 5.73.1H NMR (DMSO-d, 400 MHz)8.87 (1H, d,= 6.8 Hz, H-14), 8.68 (1H, d,= 6.4 Hz, H-15), 8.40 (1H, d,= 8.8 Hz, H-9), 7.48 (1H, d,= 2.0 Hz, H-6), 7.36～7.45 (2H, m, H-24, H-26), 7.19～7.21 (2H, m, H-23, H-27), 7.10 (1H, dd,= 8.8, 2.0 Hz, H-10), 6.07 (2H, s, H-21), 4.55 (2H, d,= 7.2 Hz, H-17), 4.20 (2H, t,= 6.4 Hz, H-4), 3.06 (3H, s, H-16), 2.04～2.07 (1H, m, H-18), 1.76～1.83(2H, m, H-3), 1.48～1.54(2H, m, H-2), 0.96 (3H, t,= 7.2 Hz, H-1), 0.83 (6H, d,= 6.8 Hz, H-19, H-20).13C NMR (DMSO-d, 100 MHz)162.7 (C-5), 148.1 (C-7), 139.4 (C-13), 135.7 (C-14), 134.7 (C-22), 134.6 (C-12), 133.2 (C-11), 129.1 (C-24, C-26), 128.3 (C-25), 126.5 (C-23, C-27), 124.4 (C-9), 114.2 (C-15), 113.2(C-10), 112.2 (C-8), 94.9 (C-6), 68.1 (C-4), 59.6 (C-21), 51.2 (C-17), 30.5 (C-3), 30.3 (C-18), 19.3 (C-19, C-20), 18.6 (C-2), 16.1 (C-16), 13.6 (C-1). ESI-MS/401 [M-Br].

2. 3 Single-crystal X-ray structure determination

A single crystal of compound 5 suitable for X-ray diffraction study was obtained from the mixsolutionof ethanol/acetone (V:V = 2:1) by slow evaporation at room temperature. A crystal with dimensions of 0.30mm × 0.25mm × 0.20mm was used. The crystal is of triclinic system,M= 481.47. X-ray diffraction intensity data were collected with a graphite-monochromatic Mo(= 0.71073 Å) radiation at 298(2) K. A total of 7587 reflections with 5473 independent ones (int= 0.0339) were collected in the range of 2.28≤≤27.51oby using an-2scan mode, in which 4304 were observed (> 2()) in the succeeding refinements with–12≤≤12, –14≤≤15 and –15≤≤12. The structure was solved by direct methods and refined by using difference Fourier techniques with SHELXS-97[15]and refinements on2were performed with SHELXL-97 program by full-matrix least-squares techniques with anisotropic thermal parameters for the non-hydrogen atoms. The positions of hydrogen atoms were located by the geometric calculation method.The final= 0.0453 and= 0.1262 (= 1/[2(F2) + (0.0828)2+ 0.2530], where= (F2+ 2F2)/3).= 1.044, (Δ)min= –0.918 and (Δ)max= 0.888 e·Å-3.

Scheme 1. Synthetic route of the target compound 5

Fig. 2. A section of the gradient correlated (1H-1H COSY) spectrum of the title compound

Fig. 3. A section of heteronuclear single-quantum coherence (HSQC) spectrum of the title compound

Fig. 4. A section of heteronuclear multiple-bond coherence (HMBC) spectrum of the title compound

3 RESULTS AND DISCUSSION

The NMR and X-ray diffraction data for the product are in good agreement with the structure of the title compound. The selected bond lengths, bond angles and torsion angles are listed in Tables 1 and 2, respectively. The molecular structure of compound 5with atomic numbering schemeis shown in Figs. 5 and 6.

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

Table 2. Selected Torsion Angles (°)

Fig. 5. Crystal structure of the title compound

Fig. 6. Packing diagram of the title compound

The compound 5 crystallizes in the triclinic space group1. In this molecule, there are two crys- tallographically independent but conformationally almost identical molecules in the asymmetric unit. Moreover, in each molecule, the-carboline moiety appears to be fully planar, but forms a dihedral angle of 76.0° with the benzyl phenyl ring. Consequently, the whole compound is not a planar molecule.

According to Fig. 5 and Table 1, the bond angles of C(6)–C(5)–C(10), C(15)–C(11)–C(12) and N(2)– C(13)–C(16) are close to the ideal 120°. In the crystal structure, the sum of C(7)–N(1)–C(12), C(7)–N(1)–C(17) and C(12)–N(1)–C(17) is 359.9°, which indicates2hybridization state of the N(1) atom. The C(7)–N(1), C(12)–N(1), C(13)–N(2) and C(14)–N(2) bond lengths are 1.388(3), 1.392(3), 1.368(3) and 1.370(4) Å, respectively, which is obviously shorter than the typical C–N bond (1.470 Å)[16], but close to the C=N double bond (1.38 Å)[17]due to the conjugative effect, which suggests thatelectrons are broadly distributed in the-carboline ring. The distance between the bromide anion and the-carboline ring centroid is 3.593 Å, and the sum of van der Waals radii of bromine and carbon is 3.55 Å, indicating the existence of···bromide anion interactions. Continuously sandwiched struc- tures are formed owing to these interactions between-carboline rings and bromide anion (Fig. 6). These interactions contribute to the stability of the struc- ture. The sum of these interactions results in the formation of a three-dimensional framework.

The introduction of substituents onto-carboline ring is considered to change the crystal structure due to the effect of nature and position of the sub- stituents. The formation of ordered structures from this compound is expected to have a potentially large impact on theirpharmacological properties[9].

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4 January 2015;

21 May 2015 (CCDC 921221)

the National Key Technology Research and Development Program of the Ministry of Science and Technology of China (No. 2012BAI30B00)

. Guo Liang, born in 1980, M.S., majoring in medicinal chemistry. E-mail: guoliang_xj@163.com

10.14102/j.cnki.0254-5861.2011-0622