Synthesis and Molecular Structures of Dibenzo(perhydrotriazino)aza-14-crown-4 Ethers

Transcription

1 ISSN , Russian Journal of rganic Chemistry, 2011, Vol. 47, No. 5, pp Pleiades Publishing, Ltd., riginal Russian Text Chyong Khong Khieu, A.T. Soldatenkov, Le Tuan An, A. N. Levov, A.F Smol yakov, V.N. Khrustalev, M.Yu. Antipin, 2011, published in Zhurnal rganicheskoi Khimii, 2011, Vol. 47, No. 5, pp Synthesis and Molecular Structures of Dibenzo(perhydrotriazino)aza-14-crown-4 Ethers Chyong Khong Khieu a,a. T. Soldatenkov a, Le Tuan An b, A. N. Levov a, A. F Smol yakov c, V. N. Khrustalev c, and M. Yu. Antipin c arussian University of Peoples Friendship, Moscow, Russia soldatenkovat@yandex.ru bvietnam State University, Hanoi University of Sciences, Vietnam cnesmeyanov Institute of rganoelemental Compounds, Russian Academy of Sciences, Moscow Received July 13, 2010 Abstract By triple condensation of thiourea or guanidine with 1,ω-bis(2-formylphenoxy)-3-oxapentane and ammonium acetate first representatives of the new class of ethers bis(benzo)aza-14-crown-4 were obtained in 28 73% yield that included as a subunit a symm-perhydrotriazine ring. This reaction also proceeds readily with N-monomethyl- and N-monopropenyl-substituted thioureas affording the corresponding derivatives of triazinoazacrown ether. At the same time urea in the similar condensation does not form the expected perhydrotriazinoazacrown ether. The molecular structure of one perhydroazacrown ether as a complex with a chloroform molecule was established by XRD analysis. DI: /S Activated methyl and methylene groups of dialkyl ketones are involved into the condensation with the formyl groups of 1,ω-bis(2-formylphenoxy)-3-oxapentane, podand I, and in the presence of ammonium acetate bis(benzo)aza-14-crown-4 ethers form in 24 41% yield which include as a subunit a γ-piperidone moiety [1]. The goal of this study was the investigation of the direction + CH HC NH 4 Ac I H 2 N NHR 1 HN R 2 25 N H R 2 IIа _ IId 22 N R IIIа _ IIId of the condensation of polyether I with urea, thioureas IIa IIc, or guanidine IId in the presence of ammonium acetate in order to establish the possibility (or impossibility) of the preparation by this procedure the first representatives of dibenzo-(perhydrotriazino)aza-14- crown-4 ethers of type III, a new heterocyclic system. This condensation with urea (20 C, 13 h) furnished a complex mixture that did not contain according to the HPLC-MS data the expected azacrown ether of type III. However at the use of thiourea IIa the macroring IIIa containing a symm-perhydrotriazine subunit was obtained and isolated in an yield of 73%, very high for the synthesis of a crown ether [2]. In the 1 H NMR spectrum of this azacrown, highly symmetric with respect to similar protons, two protons H 1 and H 21 appear at 5.28 ppm as a two-proton doublet of doublets with coupling constants equal 11.6 and 1.2 Hz. Two protons of the thiourea moiety H 22 and H 24 are observed in a weak field at 7.94 ppm as a single narrow doublet (J 1.2 Hz, 2H). Eight aromatic protons give rise to four signals (2H each) as one ABCD system, and they are easily identified by their multiplicity and chemical shifts. Yet for the unambiguous proof of the 766

2 SYNTHESIS AND MLECULAR STRUCTURES F DIBENZ(PERHYDRTRIAZIN)AZA Parameters of hydrogen bonds in complex (IIIa) CHCl 3 a Parameters D H, Å H A, Å D A, Å Angle D H A, deg N 22 H 22N S 1# (2) 166 N 24 H 24N Cl (2) 169 N 24 H 24N Cl 3' (2) 172 N 25 H 25N (2) 124 N 25 H 25N (2) 118 C 24 H 24A S (2) 165 C 24 H 24B S (2) 170 a D is proton-donor, A is proton-acceptor. Symmetric transformation for the equivalent atom: 1#1 x + 1/2, y + 1/2, z + 1. Fig. 1. Molecular structure of complex (IIIa) CHCl 3. The nonhydrogen atoms are represented by 50%-probability ellipsoids of the anisotropic shifts. The alternative positions of the atoms of the disordered chloroform molecule are not shown. In molecule IIIa hydrogen atoms are shown belonging only to the amino groups and also the hydrogen atoms at the asymmetric centers. The hydrogen bonds are shown by dashed lines. structure and for the establishment of the stereochemical characteristics of compound IIIa we grew its single crystal from the CHCl 3 solution and it was subjected to investigation by XRD method. The molecule IIIa formed in the crystal a complex with a chloroform molecule (Fig. 1). Compound IIIa is a 14-membered azacrown ether with four heteroatoms in the macrocycle. The size of the internal cavity of the crown ether, estimated as the doubled average distance between the endocyclic n-electron-donor heteroatoms and their centroid, the center of the quadrangle N , equals 4.04 Ǻ. The conformation of the polyether fragment (C 7 8 C 9 C C 12 C C 15 ) is t -g ( ) -t-t-g (+) -t (t is trans, ±180 ; g is gauche, ±60 ). The molecule of compound IIIa possesses an idealized symmetry C s (m) that however in the crystal is slightly distorted due to the formation of two unsymmetrical intramolecular hydrogen bonds N 25 H 25 8 (see the table and Fig. 1) [N 2.938(2), H 2.33 Ǻ, angle NH 124 ] and N 25 H [N 3.046(2), H 2.52 Ǻ, angle NH 118 ]. wing to the intramolecular hydrogen bonds the donor atoms of the azacrown ring N 25, 8, 11, 14 do not lie in the same plane (mean-square deviation Ǻ). Atoms N 22 and N 24 have the planar-trigonal configuration (the sum of bond angles is and respectively) which slightly tends to pyramidal because of the intermolecular hydrogen bonds (see below). The atom N 25 assumes the pyramidal configuration. The sum of bond angles at these atoms equals The triazine ring in the molecule IIIa has the conformation of a flattened boat (deviations of atoms C 23 and N 25 from the mean-square plane of the other atoms of the ring are and Ǻ respectively). Compound IIIa is a diastereomer with two asymmetric centers (C 1 and C 21 ) and in the crystalit is present as a racemate with the relative configuration of these centers rac-(1r*,21s*). The angle between the planes of the benzene rings of the molecule is Compound IIIa and the chloroform molecule are bound into a complex through an intermolecular hydrogen bonds (see the table and Fig. 1) N 24 H 24 N Cl 3 and C 24 H 24 A S 1 (N 24 H 24 N Cl 3 and C 24 H 24 B S 1 in the case of the alternative position of the disordered chloroform molecule). In the crystal of the molecule of compound IIIa strong centrosymmetrical dimers are formed (see the table and Fig. 2) owing to the intermolecular hydrogen bonds N 22 H 22 N S 1 ( x + 1/2, y + 1/2, z + 1) [N S 3.348(2), H S 2.45 Ǻ, angle NH S 166 ]. The arising dimeric associates are located at the van der Waals distances and are stacked along the b axis (Fig. 3). In order to reveal the generality of this reaction with respect to introducing triazine fragment into azacrown ethers and to study the possibility to extend the range of substituents we carried out under analogous conditions the condensation of dialdehyde I with monomethyl- and monopropenyl-substituted thioureas IIb and IIc. It turned out that N-methylthiourea entered into the three-component reaction with dialdehyde I and ammonia as readily RUSSIAN JURNAL F RGANIC CHEMISTRY Vol. 47 No

3 768 CHYNG KHNG KHIEU et al. yield (63%). Its 1 H NMR spectrum contained the signals of all eight aromatic protons in the form of two ABCD systems. In the same region (6.80 ppm) the broadened signal of proton H 24 was observed. The signals of the other three protons of the triazine ring H 25 (t, J 12.0 Hz), H 1 (d.d, J 12.0 and 1.3 Hz), and H 21 (d, J 12.0 Hz) appeared at 4.65, 5.29, and 5.44 ppm. The protons of the N-allyl moiety give rise to five signals of the appropriate multiplicity: 3.47 (d.d, J 12.3 and 5.0 Hz), 4.76 (d.d, 3 J trans 14.1 and 2 J 1.2 Hz), 5.00 (d.d, 3 J cis 9.0 and 2J 1.2 Hz), 5.24 (d.d, J 12.3 and 5.0 Hz) and 5.83 (m) ppm. Fig. 2. Centrosymmetric dimeric associates of complex (IIIa) CHCl 3. The hydrogen bonds are shown by dashed lines. The alternative positions of the atoms of the disordered chloroform molecule are not shown. Fig. 3. Crystal packing of dimeric associates of complex (IIIa) CHCl 3 along Y axis. The hydrogen bonds are shown by dashed lines. The alternative positions of the atoms of the disordered chloroform molecule are not shown. as thiourea giving 22-methyl-substituted azacrown ether IIIb in a high yield (86%). In its 1 H NMR spectrum the protons of the methyl group were observed as a singlet at 3.03 ppm. Also the signals are pronounced of protons H 25, H 1, and H 21 : a triplet at 4.53 ppm (J 12.6 and 12.4 Hz), a doublet of doublets at 5.27 ppm (J 12.4 and 2.2 Hz), and a doublet at 5.41 ppm (J 12.6 Hz) respectively indicating the presence in the structure IIIb of a linker C 1 H N 25 H C 21 H. The introducing of a methyl group into the thiourea fragment resulted in a considerable shift of the proton signal NH 24 (Δδ 1.16 ppm). At the use in a similar condensation of N-allylthiourea IIc macrocycle IIIc containing an N-allyl moiety was obtained in a good Bringing guanidine IId into analogous condensation with podand I and ammonia resulted in the successful isolation from the reaction mixture in 28% yield of azacrown ether IIId containing a 4-iminoperhydrotriazine subunit. Its IR spectrum contains a very strong absorption band of C=N bond at 1616 cm 1. According to the HPLC-MS data the isolated sample was of 97% purity, and the ion peak [M + 1] +, m/z 355, confirmed the empirical formula of compound IIId. The 1 H NMR spectrum contained signals of all groups of protons corresponding to the formula IIId with the appropriate integral intensities. Thus by the triple condensation of podand I containing two benzaldehyde fragments with ammonia, thioureas, or guanidine was a method developed of preparative synthesis of dibenzoaza-14-crown-4 ethers containing a subunit of symm-perhydrotriazine heterocycle. In keeping with prediction of the internet-program PASS the substances IIIa IIIb in high probability may exhibit the inhibiting properties with respect to proteinkinase CK1 (97, 87, and 82% respectively) and cytochrome CYP2A6 (77, 85, and 80%). Besides the first two compounds may be inhibitors of the permeability of cell membranes (probability 70 and 71%). At the same time azacrown ether IIId is interesting object for checking its properties as agonist of imidazoline receptor (72%) and as inhibitor of polyporopepsin (77%). EXPERIMENTAL 1H NMR spectra were registered on a spectrometer Bruker WP-400 at operating frequency 400 MHz in DMS-d 6 (compounds IIIa, IIIc, IIId) and CDCl 3 (ether IIIb). IR spectra were taken in KBr on a spectrophotometer Specord 75IR. Analysis of reaction mixtures was performed, the purity of the isolated compounds was checked, and mass spectra were obtained on instruments RUSSIAN JURNAL F RGANIC CHEMISTRY Vol. 47 No

4 SYNTHESIS AND MLECULAR STRUCTURES F DIBENZ(PERHYDRTRIAZIN)AZA Finnigan MAT 95 XL (EI, ionizing energy 70 ev) for ethers IIIa, IIId PE SCIEX API 165 (150) Shimadzu HPLC SCL 10Avp, autosampler Gilson 215, EASD Sedex 75 (ionization with ions H + for ethers IIIb, IIIc). XRD study of complex between compound IIIa and chloroform molecule. C 20 H 22 Cl 3 N 3 S, M , monoclinic crystal system, space group C2/c, at 100 K a (12), b (3), c (3) Å, β (1), V (3) Å 3, Z 8, d calc g/cm 3, F(000) 2032, μ mm 1, 2θ max 56. Number of measured reflections 23770, number of independent reflections 5942, number of reflections with I > 2σ(I) Number of refined parameters 289, R 1 [I > 2σ(I)] 0.044, wr 2 (for all data) GF The parameters of the unit cell and the intensities of reflections were measured on an automatic three-circle diffractometer Bruker APEX-II CCD (MK α -radiation, graphite monochromator, φ- and ω-scanning). The structure of complex of compound IIIa with a chloroform molecule was solved by the direct method and refined by the least-squares method in the anisotropic approximation from the nonhydrogen atoms. The chloroform molecule is disordered by two positions with equal population. The hydrogen atoms of NH groups were localized objectively in the difference Fourier-syntheses and were included into the refinement in the isotropic approximation with the fixed position and thermal parameters [U iso (H) = 1.2U eq (N)]. The location of the other hydrogen atoms was calculated geometrically and refined in the isotropic approximation using fixed position (rider model) and themal parameters [U iso (H) = 1.2U equiv (C)]. All calculations were carried out using software SHELXTL [3]. The tables of atomic coordinates, bond lengths and angles, and of the anisotropic thermal parameters of complex (IIIa) CHCl 3 are deposited into the Cambridge Structural Database. Azacrown ethers IIIa IIId. A solution of 3.14 g (10 mmol) of oligoether I, 10 mmol of thiourea IIa IIc or of guanidine IId, and 1.0 г (13 mmol) of ammonium acetate in a mixture of 30 ml of ethanol and 2 ml of acetic acid was stirred for 13 h at 20 C. The separated precipitate was filtered off, washed with ethanol, and purified by recrystallization from chloroform to obtained the product as colorless crystals. 8,11,14-Trioxa-22,24,25-triazatetracyclo[ hexaene-23-thioh (IIIa). Yield 2.70 g (73%), mp C. IR spectrum, ν, cm 1 : 3397, 3322 and 3195 (NH), 1059 (SH). 1 H NMR spectrum, δ, ppm: 3.93 m, 4.00 m, 4.16 m (3H, 4H, 2H resp., CH 2 CH 2 and H 25 ), 5.28 d.d (2H, H 1,21, J 11.6, 1.2 Hz), 6.90 t (2H, H 4,18, J 7.6 Hz), 6.94 d (2H, H 6,16, J 8.0 Hz), 7.25 d (2H, H 3,19, J 7.6 Hz) 7.31 t (2H, H 5,17, J 8.0 Hz), 7.94 d (2H, H 22,24, J 1.2 Hz). Mass spectrum, m/z (I rel, %): 371 [M] + (26), 338 (38), 326 (7), 311 (98), 297 (34), 296 (63), 251 (46), 192 (28), 148 (52), 146 (91), 122 (68), 122 (100), 121 (52), 119 (50), 107 (26), 91 (53), 78 (29), 77 (76), 76 (89); proton ionization mode: 372 [M + 1] +. Found, %: C 61.71; H 5.85; N C 19 H 21 N 3 3 S. Calculated, %: C 61.44; H 5.70; N M Methyl-8,11,14-trioxa-22,24,25-triazatetracyclo[ hexaene-23-thione (IIIb). Yield 2.70 g (73%), mp C. IR spectrum, ν, cm 1 : 3312, 3184 (N H); 1261, 1076, 1055 (C=S). 1 H NMR spectrum, δ, ppm: 3.03 s (3H, NMe), m (8H, CH 2 CH 2 ), 4.53 t (1H, H 25, J 12.6, J 12.4 Hz), 5.27 d.d (1H, H 1, J 12.4, J 2.2 Hz), 5.41 d (1H, H 21, J 12.6 Hz), 6.78 br.s (1H, H 24 ), 6.84 d (2H, H 6,16, J 8.2 Hz), 6.90 t.t, 6.93 t.t (1H each, H 4,18, J 8.2, J 1.5 Hz), 7.20 and 7.24 d.d (1H each, H 3,19, J 7.5, J 1.5 Hz), 7.29 and 7.31 t.t (1H each, H 5,17, J 8.2, J 1.5 Hz). Mass spectrum, m/z (I rel, %): 385 [M] + (8), 356 (2) [M NCH 3 ] +, 352 (5), 311 (14), 297 (6) [M CH 3 NCSNH 2 ] +, 224 (7), 146 (15), 131 (11), 121 (11), 91 (10), 90 (78), 77 (14), 73 (100), 72 (51). Found, %: C 62.28; H 6.15; N C 20 H 23 N 3 3 S. Calculated, %: C 62.34; H 5.97; N M Allyl-8,11,14-trioxa-22,24,25-triazatetracyclo[ hexaene-23-thione (IIIc). Yield 2.60 g (63%), mp C. IR spectrum, ν, cm 1 : 3445, 3311, 3216 (NH), 1630 (CH=CH 2 ), 1058 (C=S). 1 H NMR spectrum, δ, ppm: 3.47 d.d (1H, NCH 2, J 12.3, J 5.0 Hz), m, 4.22 m (4H, 2H and 2H resp., CH 2 CH 2 ), 4.65 t (1H, H 25, J 12.0 Hz), 4.76 d.d (1H, HC=CHH trans, J 14.1, J 1.2 Hz), 5.00 d.d (1H, CH=CH cis H, J 9.0, J 1.2 Hz), 5.24 d.d (1H, NCH 2, J 12.3, J 5.0 Hz), 5.29 d.d (1H, H 1, J 12.0, J 1.3 Hz), 5.44 d (1H, H 21, J 12.0 Hz), 5.83 m (1H, CH=CH 2 ), 6.80 br.s (1H, H 24 ), 6.81 d, 6.83 d (1H each, H 6,16, J 7.8 Hz), 6.89 m (2H, H 4,18 ), 7.18 m, 7.29 m (2H each, H 3,19, H 5,17 ). Mass spectrum, m/z (I rel, %): 411 [M] + (2), 396 (2), 370 (2), 355 (5), 298 (18), 297 (100), 296 (75), 295 (8), 166 (9), 148 (27), 146 (26), 134 (42), 131 (33), 121 (28), 116 (34), 101 (80), 99 (84), 91 (27), 77 (35), 72 (34). Found, %: C 64.03; RUSSIAN JURNAL F RGANIC CHEMISTRY Vol. 47 No

5 770 CHYNG KHNG KHIEU et al. H 6.27; N C 22 H 25 N 3 3 S. Calculated, %: C 64.21; H 6.12; N M Imino-8,11,14-trioxa-22,24,25-triazatetracyclo[ ,7.0 15,20 ]pentacosa-2,4,6,16,18-hexaene (IIId). Yield 1.0 g (28%), mp C. IR spectrum, ν, cm 1 : 3307, 3252 (NH), 3653, 1616 (C=N). 1 H NMR spectrum, δ, ppm: 3.22 m (2H, H 21,25 ), m (6H, CH 2 CH 2 ), 5.42 br.s (1H, H 1 ), m (10H arom, H 22,24 ), 8.58 br.s (1H, C 23 =NH). Mass spectrum, m/z: 355 [M + 1] + (ionization mode). Found, %: C 64.30; H 6.08; N C 19 H 22 N 4 3. Calculated, %: C 64.39; H 6.26; N M REFERENCES 1. Levov, A.N., Strokina, V.M., Komarova, A.I., Le Tuan, An, and Soldatenkov, A.T., Khim. Geterotsikl. Soedin., 2006, p. 139; Levov, A.N., Le Tuan An, Komarova, A.I., Strokina, V.M., Soldatenkov, A.T., and Khrustalev, V.N., Zh. rg. Khim., 2008, vol. 44, p. 457; Le Tuan An, Levov, A.N., Soldatenkov, A.T., and Gruzdev, R.D., Chyong Khong Khieu, Zh. rg. Khim., 2008, vol. 44, p Chyong Khong Khieu, Le Tuan An, Levov, A.N., Nikitina, E.V., and Soldatenkov, A.T., Khim. Geterotsikl. Soedin., 2009, Sheldrick, G.M., Acta Cryst., 2008, A64, vol RUSSIAN JURNAL F RGANIC CHEMISTRY Vol. 47 No