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19Crown Ethers
Краун-эфиры
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http://macroheterocycles.isuct.ru
Paper
Статья
DOI: 10.6060/mhc140493l
Synthesis and Molecular Structure of Dibenzo [4-(a-Thienyl-and «-Pyrrolyl)pyrido]aza-14-crown-4 Ethers
Anh T. Le,a@ Hieu H. Truong,b Phuong T. T. Nguyen,a Ha T. Pham,a Vasily E. Kotsuba,c Anatoly T. Soldatenkov,c Viktor N. Khrustalev,d and Ayalew T. Wodajoe
aVietnam National University, University of Science, Ha Noi, Viet Nam
bInstitute of Chemistry, Vietnam Academy of Science and Technology, Ha Noi, Viet Nam
c Peoples' Friendship University of Russia, 117198 Moscow, Russia
dNesmeyanov Institute of Organoelemental Compounds, Russian Academy of Sciences, 119991 Moscow, Russia eCollege of Natural and Computational Sciences, University of Gondar, 196 Gondar, Ethiopia @Corresponding author E-mail:[email protected]
An effective synthesis of dibenzo[4-(heteroaryl)pyrido]aza-14-crown-4 ethers was elaborated by one-step domino condensation of 1,4-bis(2-acetylphenoxy)-3-oxapentane, thiophene- andpyrrolcarbaldehyde and ammonia, in acetic acid. Molecular structure of dibenzo[4-(2-thienyl)pyrido]aza-14-crown-4 ether was established by X-ray analysis.
Keywords: Azacrown ethers, dibenzo and pyrido fused crown ethers, 2-formyl substituted thiophene and pyrrole, synthesis, X-ray analysis.
Синтез и молекулярная структура дибензо[4-(а-тиенил и а-пирролил)пиридо]аза-14-краун-4 эфиров
А. Т. Ле^@ Х. Х. ЧЬЮШ\ь Ф. Т. Т. Нгуен^ Х. Т. Фам^ В. Е. Коцюба^ А. Т. Солдатенков^ В. Н. Хрусталёв^ А. Т. Водажоe
аУниверситет наук Вьетнамского национального университета, 144 Ханой, Вьетнам ъИнститут химии Вьетнамской академии наук и технологий, 136 Ханой, Вьетнам сРоссийский университет дружбы народов, 117198 Москва, Россия
АИнститут элементорганических соединений имени А.Н. Несмеянова, 119991 Москва, Россия еКолледж естественных и компьютерных наук университета Гондора, 196 Гондор, Эфиопия ®E-mail:[email protected]
Дибензо[4-(гетарил)пиридо]аза-14-краун-4-эфиры были получены с высоким выходом в ходе однореакторной домино-конденсации в среде уксусной кислоты 1,4-бис(2-ацетилфенокси)-3-оксапентана, тиофен- и пирролкарбальдегидов и аммиака. Строение молекулы дибензо[4-(2-тиенил)пиридо]аза-14-краун-4-эфира было подтверждено методом РСА.
Ключевые слова: Азакраун-эфиры, дибензо- и пиридо-аннелированные краун-эфиры, 2-формилтиофен, 2-формилпиррол, синтез, рештеноструктурный анализ.
Azacrown ethers have found widespread application in science and technology.11,21 Recently, the synthesis of azacrown ethers bearing fused nitrogen-containing heterocyclic rings has drawn the interest of scientists because such combination can enhance the properties of both components, including biological activity.[2-7] By using domino reactions in the synthesis of azacrown ethers, we had earlier obtained dibenzo[(y-phenyl)pyrido)]aza-14-crown-4 ether from benzaldehyde, 1,4-bis(2-acetylphenoxy)-3-oxapentane (1) and ammonium acetate. In addition we had established that such compounds containing y-phenylpyridine ring exhibited cytotoxicity to several cancer cell lines: Hepatocellular carcinoma (Hep-G2); Rhabdosarcoma (RD), Human Uterine (FL); Human Breast adenocarcinoma (MCF7).[8] Therefore, we continued our studies with the aim to obtain analogs bearing other aryl groups in y-position. In this communication we report the synthesis of thienyl (compound 4a) and pyrrolyl (compound 4b) azacrown derivatives, as well as the results of X-ray analysis of the molecular structure of dibenzo[4-(a-thienyl)pyrido)aza-14-crown-4 ether (4a).
Condensation of 2-formylthiophene (2a) or 2-formyl-pyrrol (2b), with 1,4-bis(2-acetylphenoxy)-3-oxapentane (1) and ammonium acetate (3) was conducted under heating
(reflux for 6 h in acetic acid in air). The expected aza-14-crown-4 ethers (4a,b) were prepared and isolated in good yields.
The structures of the products 4a,b were determined by NMR, MS and IR spectrometry and X-ray analysis as well. 'H NMR spectrum of compound 4a showed multiplets at 3.83 and 4.13 ppm (4H each) for 8 protons of the polyether moiety and a singlet at 7.50 ppm for two P-protons belonging to the pyridine ring (H-22, H-24). Eight protons of the two benzene rings showed four signals at 6.95; 7.01; 7.33 and 7.36 ppm. Three protons of the y-thienyl group gave three signals (1H each) at 7.13, 7.40 and 7.54 ppm, respectively.
The structural formula of compound 4a was unequivocally confirmed by X-ray crystallography. The general shape of the molecule 4a and the packing of its molecules in the crystal are shown below (the atoms are presented with their crystallographic numbering).
In the crystal, one molecule of 4a forms a complex with one water molecule via two hydrogen bonds (O-H... N25 and O-H...O11). The molecule 4a possesses y-thienyl substituted pyridine ring which has one nitrogen atom with ./¿-configuration and a 14-crown-4 ether ring which includes three oxygen atoms. Lengths of valence and hydrogen
Scheme 1.
Figure 1. Molecular structure and crystal packing of compound 4a. Макрогетер0циmbl /Macroheterocycles 2014 7(4) 386-390
Table 1. Lengths (l, A) of valence and hydrogen bond in the units D-H.. .A in compound 4a, distance (d, A) between atoms D and A, angles (0, deg).
Unit D-H...A l(D-H) l(H...A) ¿(D...A) 0<(DHA)
O(1W)-H(1WA)...O(11)i 0.90 1.98 2.857(2) 166
O(1W)-H(1WB)...N(25)i 0.90 2.00 2.868(2) 163
O(2W)-H(2WA)...N(25A)ii 0.90 2.03 2.922(2) 170
O(2W)-H(2WB)...O(11A)ii 0.90 2.13 2.936(2) 149
Relative symmetry operation: (i) x, y+1, z; (ii) x+1, y, z.
bonds, and also angles between them in the fragments of the complex water/compound 4a (D-H...A, where D - donor atom, A - acceptor atom) are given in Table 1. The basic crystallographic data are presented in Table 2.
The structure of compound 4a was unambiguously established by X-ray diffraction analysis. The molecular structure of compound 4a is shown in Figure 1 along with the atomic numbering scheme. Compound 4a crystallizes in the triclinic space group P-1 with the two crystallographi-cally independent molecules in the unit cell. The geometries of the two crystallographically independent molecules are very similar.
Compound 4a comprises the aza-14-crown-3 ether skeletal moiety and adopts a bowl conformation (Figure 1). The configuration of the C7-08-C9-C10-011-C12-C13-O14-C15 polyether chain is t-g(-)-t-t-g(+)-t (t = trans, 180°; g = gauche, ±60°). The dihedral angle between the planes of the benzene rings fused to the aza-14-crown-3 ether moiety is 61.8(2) and 60.3(2)° for the two crystallographically independent molecules, respectively. Due to the presence of conjugation the thienyl substituent lies practically within the pyridine ring plane.
In the crystal, the molecules of compound 4a form quite steady associates with the solvate water molecules by
Table 2. Basic crystallographic data and parameters for the refinement of compound 4a.
Compound 4a
C H NO S
Empirical formula C25H.NO3S.H2O
Molecular mass 433.50
Temperature (K) 120(2)
Crystal system Triclinic
Space group P-1
a, A 6.8631 (3)
b, A 19.9169 (10)
c, A 20.0634 (10)
a, deg 61.596 (1)
P, deg 80.624 (1)
y, deg 80.478 (1)
Volume (V), A3 2367.9 (2)
No. of molecules in a unit cell (Z) 4
¡i, mm-1 0.166
No. of measured reflexions 31720
No. of independent reflexions 13817
the intermolecular hydrogen bonds (Table 1). The H-bonded associates are further linked into doubled columns along the a axis by the n-n stacking interactions between the thiophene and pyridine fragments {the (S1-C26-C27-C28-C29)/ (C21A-C22A-C23A-C24A-C1A-N25A) interplane distance is 3.363(2) A; the (C21-C22-C23-C24-C1-N25)/ (S1A-C26A-C27A-C28A-C29A) [1+x, y, z] interplane distance is 3.358(2) A; the shortest C...C distances are 3.254(2) A (C22A...C28') and 3.276(2) A (C22...C28B)} (Figure 2). The columns are arranged at van-der-Waals distances.
The assumed reaction mechanism for the synthesis of compounds 4a,b is presented below. The domino reaction is supposed to proceed via Michael additions, aldol condensation, dehydration and, finally, oxidation-aromatization with the formation of the pyridine ring.
The proposed reaction mechanism is very similar to Hantzsch dihydropyridine synthesis,[9] however, the nature of the final oxidative step requires additional research. We suggest air oxygen to be the oxidative agent, but a Zelin-sky type conjugate hydration-dehydration[9] process can also take place.
The PASS software,[10] designed to predict biological activity of novel substances, estimated that compounds 4a,b could possess valuable bioactivities such as imidazoline receptor agonist (70.7 % probability), membrane permeability inhibitor (67.9 %) and phobic disorders treatment (69.6 %).
X-Ray Structure Determination
Data were collected on a Bruker SMART APEX II CCD diffractometer (A(MoKa)-radiation, graphite monochromator, m and q> scan mode) and corrected for absorption using the SADABS program.[11] For details, see Table 2. The structure of 4a was solved by direct methods and refined by the full-matrix least squares technique on F2 with anisotropic displacement parameters for non-hydrogen atoms. The crystal contains two crystallographically independent molecules in the unit cell. The two thienyl substituents of the two independent molecules of 4a are disordered over two sites related by rotation on 180o around the C-CPy bond, with the occupancies of 0.80:0.20 each. The independent part of the unit cell of 4a contains two water and two chloroform solvate molecules. The chloroform solvate molecules were found to be strongly disordered and could not be modeled satisfactorily. The contribution to the scattering by these molecules was removed by the use of the utility SQUEEZE in PLATON98.[u] The hydrogen atoms of the solvate water molecules were localized in the difference-Fourier map and included in the refinement with fixed positional (the rider mode) and isotropic displacement parameters. The other hydrogen atoms were placed in calculated positions and refined within the riding model with fixed isotropic displacement parameters (Uiso(H) = 1.2Ueq(C)). All calculations were carried out using the SHELXTL program.[13] Crystallo-graphic data for 4a-H2O-CHCl3 have been deposited with the Cambridge Crystallographic Data Center. CCDC 979537 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from the Director, CCDC, 12 Union Road, Cambridge CB2 1EZ, UK (Fax: +44 1223 336033; e-mail: [email protected] or www.ccdc. cam.ac.uk).
Experimental
Melting points were determined in open capillary tubes on a digital Stuart SMP3 apparatus. Elemental analysis was conducted on a EuroVector EA-3000 analyzer. The IR spectra were recorded in KBr disks on an Infralum FT-801 spectrometer. The 'H NMR spectra were recorded on a Bruker WP-400 instrument in CDCl3, TMS as internal standard. LC/MS analysis was performed using an Agilent 1100 series chromatograph equipped with Agilent 1100 series DAD (wavelength 254±4 nm was used for detection), Sedex 75 ELSD and Agilent LC/MSD VL mass spectrometer (ionization in ESI mode). X-Ray structural analysis of compound 4a was measured on an APEX2 (Bruker, 2005). All X-ray related analyses and calculations were carried out with SAINT (Bruker, 2001) and SHELXTL (Sheldrick, 2008).
23-(2-Thienyl)-8,11,14-trioxa-25-azatetracyclo-[19.3.02 7.01520]pentacosa-1 (25),2,4,6,15(20),16,18,21,23)nonaene (4a). A mixture of diketone 1 (1.71 g, 5.00 mmol), 2-thienylalde-hyde (2a) (0.53 g, 5.00 mmol) and ammonium acetate (10 g, 0.13 mol) was refluxed in acetic acid (50 ml) for 6 hours. The reaction mixture was left to cool to room temperature and then neutralized with aqueous sodium carbonate. Afterward, the product was extracted with ethyl acetate (3x50 ml). The solvent was then evaporated under vacuum. The product 4a was then purified by column chromatography (eluting with CHCl3-hexane 1:1) and recrystallized from ethanol. Single crystals for X-ray studies were grown from ethanol (96 % non-absolute). Yield 0.96 g (46 %), white crystals. M.p. = 198-199 oC. Found: C 72.19; H 5.12; N 3.35. C25H21NO3S requires: C 72.27; H 5.09; N 3.37. Mass spectrum, (LCMS), m/z (IreP %): 416 [M+1]+ (100). IR (KBr) vmax cm4: 1596 s, 1250 s. 1H NMR (CDCl3, 300 K) SH ppm: 3.83 and 4.13 (4H each, m each, (0CH2CH2)20); 6.95 (2H, d, J = 8.0 Hz, H-6 and H-16); 7.01 (2H, t, J = 7.5 Hz, H-4 and H-18); 7.13 (1H, t, J = 5.0 and 3.5 Hz, H-4' thienyl); 7.33 (2H, d.d, J = 7.9 and 1.5 Hz, H-3 and H-19); 7.36 (2H, t.d, J = 8.0 and 1.5 Hz, H-5 and H-17); 7.40 (1H, d.d, J = 5 and 1.0 Hz, H-3' thienyl); 7.50 (2H, s, H-22 and H-24); 7.54 (1H, d.d, J = 3.5 and 1.0 Hz, H-5' thienyl).
23-(2-Pyrrolyl)-8,11,14-trioxa-25-azatetracyclo-[19.3.027.01520]pentacosa-1 (25),2,4,6,15(20),16,18,21,23)nonaene (4b). Prepared in a similar manner from the mixture of diketone 1 (5.00 mmol), 2-pyrrolylaldehyde (2b) (5.00 mmol) and ammonium acetate (0.13 mol). White crystals (0.42 g, 44 %). M.p. = 223-224 oC. Found: C 75.30; H 5.61; N 7.05. C25H22N2O3 requires: C 75.36; H 5.57; N 7.03. Mass spectrum (LCMS), m/z (IM, %): 399 [M+1]+ (100). IR (KBr) vmax cm-1: 1600 m, 1249.26 s. 1HNMR (CDCl3, 300 K) SH ppm: 3.80 and 4.04 (4H each, m each, (0CH2CH2)20); 6.21 (1H, br.m, H-4' pyrrol); 6.57 (1H, br.s, H-3' pyrrol); 6.81 (2H, d, J = 8.0 Hz, H-6 and H-16); 6.88 (1H, br.s), signals of H-5', H-4 and H-18 protons are overlapped; 6.89 (2H, d.d, J = 8.0 and 7.8 Hz, H-4, and H-18); 7.07 (2H, d, J = 7.8 Hz, H-3 and H-19); 7.12 (2H, s, H-22 and H-24); 7.26 (2H, t.d, J = 8.0 and 1.6 Hz, H-5 and H-17).
Acknowledgements. This research is funded by Vietnam National Foundation for Science and Technology Development (NAFOSTED) under grant number 104.012012.44. The authors would like also to thank Chembridge Corp. for the opportunity to use LC/MS analysis.
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Received 30.04.2014 Accepted 20.05.2014
